FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Thomas, M Jankovic, J AF Thomas, M Jankovic, J TI Neurodegenerative disease and iron storage in the brain SO CURRENT OPINION IN NEUROLOGY LA English DT Article DE Hallervorden-Spatz; iron in the brain; neurodegeneration; neuroferritinopathy; parkinsonism ID HALLERVORDEN-SPATZ-SYNDROME; RESTLESS LEGS SYNDROME; PARKINSONS-DISEASE; FRIEDREICHS-ATAXIA; SUBSTANTIA-NIGRA; HEREDITARY HEMOCHROMATOSIS; FERRITIN LIGHT; ACERULOPLASMINEMIA; DEFICIENCY; METABOLISM AB Purpose of review Iron is very important for normal regulation of various metabolic pathways. Neurons store iron in the form of ferrous ion or neuromelanin. In specific disorders the axonal transport of iron is impaired, leading to iron deposition which in the presence of reactive oxygen species results in neurodegeneration. Recent findings Recent developments in genetics, including the finding of mutations in the pantothenate kinase gene and ferritin light chain gene, have demonstrated a direct relationship between the presence of a mutation in the iron-regulatory pathways and iron deposition in the brain resulting in neurodegeneration. These two disorders now add to our understanding of the mechanism of disease due to dysfunction of iron-regulatory pathways. In addition to these disorders there may be several other mutations of iron-regulatory genes or related genes that are yet to be found. The animal models of disease have also added value to this area. Summary In this review we provide a summary of recent developments in the field of movement disorders with abnormalities in iron transport, and the current evidence in neurodegenerative disorders such as Parkinson's disease. C1 Baylor Coll Med, Dept Neurol, Parkinsons Dis Ctr & Movement Disorders Clin, Houston, TX 77030 USA. NINDS, Expt Therapeut Branch, Clin Pharmacol Sect, NIH, Bethesda, MD USA. RP Jankovic, J (reprint author), Baylor Coll Med, Dept Neurol, Parkinsons Dis Ctr & Movement Disorders Clin, 6550 Fannin St 1801, Houston, TX 77030 USA. EM josephj@bcm.tmc.edu NR 49 TC 73 Z9 76 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1350-7540 J9 CURR OPIN NEUROL JI Curr. Opin. Neurol. PD AUG PY 2004 VL 17 IS 4 BP 437 EP 442 DI 10.1097/01.wco.0000137534.61244.d1 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 849FW UT WOS:000223525100007 PM 15247539 ER PT J AU Chalela, JA Merino, JG Warach, S AF Chalela, JA Merino, JG Warach, S TI Update on stroke SO CURRENT OPINION IN NEUROLOGY LA English DT Article DE stroke; imaging; epidemiology; risk factors; thrombolysis ID ACUTE ISCHEMIC-STROKE; RISK-FACTORS; INTRACEREBRAL HEMORRHAGES; BLOOD-PRESSURE; TRIAL; HYPERGLYCEMIA; PROUROKINASE; MICROBLEEDS; GUIDELINES; MANAGEMENT AB Purpose of review This review highlights some advances in the areas of epidemiology, therapy, and imaging of acute stroke. Recent findings Studies published in 2003 provided new insights into the epidemiology of stroke. The African American Antiplatelet Stroke Prevention Study found that traditional stroke risk factors are still undiagnosed and undertreated, particularly in minorities. Cohort studies have identified incident silent infarcts as risk factors for stroke and history of type I diabetes as a risk factor for death in patients with acute stroke. Cervical artery dissection, on the other hand, seems to have a benign course. Imaging has become an important tool for understanding the pathophysiology of stroke, as demonstrated in recent publications. New studies have shown the prognostic value of magnetic resonance imaging: it can predict the volume of ischemic tissue that will progress to infarction and detects cerebral microbleeds - a risk factor for intracranial hemorrhage. Computed tomographic scanning may have a role in selecting patients for thrombolysis, particularly when validated scales are used. Despite the barriers to the use of tissue plasminogen activator in the treatment of patients with stroke, data published this year show that it is a safe medication when used routinely in community and university hospitals. In addition to thrombolysis, other general medical measures, such as glucose control and adequate attention to nutritional status, can help improve the outcome of patients with stroke. Summary In acute stroke, recognition and modification of risk factors continue to be challenging tasks. Treatment of acute stroke should involve thrombolysis and attention to medical conditions that may influence outcome. New applications of magnetic resonance imaging and computed tomography may help guide stroke therapy. C1 NINDS, Sect Stroke Diag & Therapeut, NIH, Bethesda, MD 20892 USA. RP Chalela, JA (reprint author), NINDS, Sect Stroke Diag & Therapeut, NIH, 10 Ctr Dr,Room B1D733,MSC 1063, Bethesda, MD 20892 USA. OI Merino, Jose/0000-0002-6676-0008 NR 20 TC 23 Z9 26 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1350-7540 J9 CURR OPIN NEUROL JI Curr. Opin. Neurol. PD AUG PY 2004 VL 17 IS 4 BP 447 EP 451 DI 10.1097/01.wco.0000137536.06986.f9 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 849FW UT WOS:000223525100009 PM 15247541 ER PT J AU Taniuchi, H Schechter, AN Shiloach, J AF Taniuchi, H Schechter, AN Shiloach, J TI Linderstrom-Lang-Schellman's model for protein stabilization revisited SO CURRENT PROTEIN & PEPTIDE SCIENCE LA English DT Review DE Linderstrom-Lang-Schellman's domain; mechanism of cooperative folding of proteins; structural domain of cooperative interactions; fragment complexation; 3D domain swapping; circular permutation; interactions between hydrophobic core residues and surface charges; polarizable hydrophobic core model ID 2 OVERLAPPING FRAGMENTS; AMINO-ACID SEQUENCE; HEART CYTOCHROME-C; TRUNCATED STAPHYLOCOCCAL NUCLEASE; RANDOM CIRCULAR PERMUTATION; PANCREATIC RIBONUCLEASE-A; REFINED CRYSTAL-STRUCTURE; NATIVE DISULFIDE BONDS; HYDROGEN-EXCHANGE; S-PEPTIDE AB The fact that cleavage of single peptide linkages in proteins often leads to extensive conformational alteration, including regions far removed from the cleavage site is not fully understood. We propose, based on the work of Linderstrom-Lang and Schellman, that disruption primarily occurs within protein structural domains that are stabilized by cooperative interactions and that cleavage of single peptide linkages of the domain perturbs the entire cooperative interaction. For this model we review experimental observations: on fragment complexation (ribonuclease A, staphylococcal nuclease and cytochrome c), destabilized N-terminal large fragments (ribonuclease A and nuclease), cooperative folding and stabilization of proteins (ribonuclease A, nuclease and cytochrome c), the close relationship of the three-dimensional structure between fragment complexes and the original protein (ribonuclease A and nuclease), ligand induced stabilization (nuclease), 3D domain swapping, circular permutation (dihydrofolate reductase), evolutionary conservation (cytochrome c fold). Based on analysis of these observations, we conclude that the cooperative interactions of domains are important for the mechanism of 3D domain swapping as well as for stabilization and thereby, determination of the round state of native proteins. Furthermore, analysis of the observations reveals that domains generally contain a hydrophobic core. Further, based on studies of cytochrome c and the Tsao, Evans and Wennerstrom model of electrostatic interactions between two hydrophobic monolayers, we propose the model that the hydrophobic core of a domain is polarizable and responds to the surface charges through its polarizability to stabilize the domain, explaining in part the nature of the cooperative interactions. C1 NIDDK, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Taniuchi, H (reprint author), NIDDK, Biol Chem Lab, NIH, Bldg 10,Room 9N307,MSc 1822, Bethesda, MD 20892 USA. EM htaniuch@helix.nih.gov OI Schechter, Alan N/0000-0002-5235-9408 NR 132 TC 1 Z9 1 U1 0 U2 1 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 1389-2037 J9 CURR PROTEIN PEPT SC JI Curr. Protein Pept. Sci. PD AUG PY 2004 VL 5 IS 4 BP 275 EP 286 DI 10.2174/1389203043379666 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 836GF UT WOS:000222543100006 PM 15320734 ER PT J AU Bonner, JC AF Bonner, JC TI Regulation of PDGF and its receptors in fibrotic diseases SO CYTOKINE & GROWTH FACTOR REVIEWS LA English DT Review DE PDGF; fibrosis; lung; liver; kidney ID GROWTH-FACTOR-BETA; HEPATIC STELLATE CELLS; FACTOR-ALPHA-RECEPTOR; RAT PULMONARY MYOFIBROBLASTS; ACTIVATED PROTEIN-KINASE; SMOOTH-MUSCLE-CELLS; FIBROBLASTS IN-VITRO; INTESTINAL SUBEPITHELIAL MYOFIBROBLASTS; MESANGIAL PROLIFERATIVE NEPHRITIS; PROGRESSIVE SYSTEMIC-SCLEROSIS AB Plate] et-derived growth factor (PDGF) isoforms play a major role in stimulating the replication, survival, and migration of myofibroblasts during the pathogenesis of fibrotic diseases. During fibrogenesis, PDGF is secreted by a variety of cell types as a response to injury, and many pro-inflammatory cytokines mediate their mitogenic effects via the autocrine release of PDGF. PDGF action is determined by the relative expression of PDGF alpha-receptors (PDGFRalpha) and beta-receptors (PDGFRbeta) on the surface of myofibroblasts. These receptors are induced during fibrogenesis, thereby amplifying biological responses to PDGF isoforms. PDGF action is also modulated by extracellular binding proteins and matrix molecules. This review summarizes the literature on the role of PDGF and its receptors in the development of fibrosis in a variety of organ systems, including lung, liver, kidney, and skin. (C) 2004 Published by Elsevier Ltd. C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Bonner, JC (reprint author), CIIT Ctr Hlth Res, POB 12137, Res Triangle Pk, NC 27709 USA. EM jbonner@ciit.org NR 185 TC 343 Z9 368 U1 6 U2 31 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6101 J9 CYTOKINE GROWTH F R JI Cytokine Growth Factor Rev. PD AUG PY 2004 VL 15 IS 4 BP 255 EP 273 DI 10.1016/j.cytogfr.2004.03.006 PG 19 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 838XT UT WOS:000222747400007 PM 15207816 ER PT J AU Kudoh, T Concha, ML Houart, C Dawid, IB Wilson, SW AF Kudoh, T Concha, ML Houart, C Dawid, IB Wilson, SW TI Combinatorial Fgf and Bmp signalling patterns the gastrula ectoderm into prospective neural and epidermal domains SO DEVELOPMENT LA English DT Article DE zebrafish; default model; neural induction ID CENTRAL-NERVOUS-SYSTEM; FIBROBLAST-GROWTH-FACTOR; EMBRYONIC STEM-CELLS; ZEBRAFISH EMBRYO; CHICK-EMBRYO; FATE MAP; NO-TAIL; INDUCTION; EXPRESSION; XENOPUS AB Studies in fish and amphibia have shown that graded Bmp signalling activity regulates dorsal-to-ventral (DV) patterning of the gastrula embryo. In the ectoderm, it is thought that high levels of Bmp activity promote epidermal development ventrally, whereas secreted Bmp antagonists emanating from the organiser induce neural tissue dorsally. However, in zebrafish embryos, the domain of cells destined to contribute to the spinal cord extends all the way to the ventral side of the gastrula, a long way from the organiser. We show that in vegetal (trunk and tail) regions of the zebrafish gastrula, neural specification is initiated at all DV positions of the ectoderm in a manner that is unaffected by levels of Bmp activity and independent of organiser-derived signals. Instead, we find that Fgf activity is required to induce vegetal prospective neural markers and can do so without suppressing Bmp activity. We further show that Bmp signalling does occur within the vegetal prospective neural domain and that Bmp activity promotes the adoption of caudal fate by this tissue. C1 UCL, Dept Anat & Dev Biol, London WC1E 6BT, England. NICHHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. Kings Coll London, MRC, Ctr Dev Neurobiol, London SE1 9RT, England. RP Kudoh, T (reprint author), UCL, Dept Anat & Dev Biol, Gower St, London WC1E 6BT, England. EM t.kudoh@ucl.ac.uk; s.wilson@ucl.ac.uk RI Wilson, Stephen/B-9404-2008; Zebrafish, UCL/A-3125-2009; Houart, Corinne/B-5128-2009; Concha, Miguel/I-2551-2013; OI Wilson, Stephen/0000-0002-8557-5940; Concha, Miguel/0000-0003-3353-9398; Houart, Corinne/0000-0002-2062-3964 FU Wellcome Trust [074376] NR 68 TC 66 Z9 69 U1 1 U2 5 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD AUG PY 2004 VL 131 IS 15 BP 3581 EP 3592 DI 10.1242/dev.01227 PG 12 WC Developmental Biology SC Developmental Biology GA 849CX UT WOS:000223517400008 PM 15262889 ER PT J AU Burton, Q Cole, LK Mulheisen, M Chang, W Wu, DK AF Burton, Q Cole, LK Mulheisen, M Chang, W Wu, DK TI The role of Pax2 in mouse inner ear development SO DEVELOPMENTAL BIOLOGY LA English DT Article DE inner ear; otic vesicle; otx; Pax; cochlea; hair cells; endolymphatic duct; stria vascularis ID BRANCHIOOTORENAL BOR SYNDROME; ACID-SYNTHESIZING ENZYME; RENAL-COLOBOMA SYNDROME; EYES-ABSENT; HAIR-CELLS; MAMMALIAN COCHLEA; PENDRED-SYNDROME; EXPRESSION; GENE; MICE AB The paired box transcription factor, Pax2, is important for cochlear development in the mouse inner ear. Two mutant alleles of Pax2, a knockout and a frameshift Mutation (Pax2(1Neu)), show either agenesis or severe malformation of the cochlea, respectively. In humans, mutations in the PVC2 gene cause renal coloboma syndrome that is characterized by kidney abnormalities, optic nerve colobomas and mild sensorineural deafness. To better understand the role of Pax2 in inner ear development, we examined the inner ear phenotype in the Pax2 knockout mice using paint-fill and gene expression analyses. We show that Pax2 -/- ears often lack a distinct saccule, and the endolymphatic duct and common crus are invariably fused. However, a rudimentary cochlea is always present in all Pax2 knockout inner ears. Cochlear outgrowth in the mutants is arrested at an early stage due to apoptosis of cells that normally express Pax2 in the cochlear anlage. Lack of Pax2 affects tissue specification within the cochlear duct, particularly regions between the sensory tissue and the stria vascularis. Because the cochlear phenotypes observed in Pax2 mutants are more severe than those observed in mice lacking Otx1 and Otx2, we postulate that Pax2 plays a key role in regulating the differential growth within the cochlear duct and thus, its proper outgrowth and coiling. Published by Elsevier Inc. C1 NIDCD, Bethesda, MD 20892 USA. RP Wu, DK (reprint author), NIDCD, 5,Res Ct,Room 2B34, Rockville, MD 20850 USA. EM wud@nidcd.nih.gov NR 42 TC 96 Z9 101 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD AUG 1 PY 2004 VL 272 IS 1 BP 161 EP 175 DI 10.1016/j.ydbio.2004.04.024 PG 15 WC Developmental Biology SC Developmental Biology GA 838EI UT WOS:000222695900013 PM 15242798 ER PT J AU Cheng, AW Tang, HY Cai, JL Zhu, M Zhang, XY Rao, M Mattson, MP AF Cheng, AW Tang, HY Cai, JL Zhu, M Zhang, XY Rao, M Mattson, MP TI Gap junctional communication is required to maintain mouse cortical neural progenitor cells in a proliferative state SO DEVELOPMENTAL BIOLOGY LA English DT Article DE gap junctional communication; neural progenitor cells; basic fibroblast growth factor ID FIBROBLAST-GROWTH-FACTOR; ACTIVATED PROTEIN-KINASE; MEDIATED INTERCELLULAR COMMUNICATION; DEVELOPMENTAL REGULATION; NEURONAL DIFFERENTIATION; DEVELOPING NEOCORTEX; ENDOTHELIAL-CELLS; VENTRICULAR ZONE; CEREBRAL-CORTEX; STEM-CELLS AB The mechanisms that determine whether neural stem cells remain in a proliferative state or differentiate into neurons or glia are largely unknown. Here we establish a pivotal role for gap junction-mediated intercellular communication in determining the proliferation and survival of mouse neural progenitor cells (NPCs). When cultured in the presence of basic fibroblast growth factor (bFGF), NPCs express the gap junction protein connexin 43 and are dye-coupled. Upon withdrawal of bFGF, levels of connexin 43 and dye coupling decrease, and the cells cease proliferating and differentiate into neurons; the induction of gap junctions by bFGF is mediated by p42/p44 mitogen-activated protein kinases. Inhibition of gap junctions abolishes the ability of bFGF to maintain NPCs in a proliferative state resulting in cell differentiation or cell death, while overexpression of connexin 43 promotes NPC self-renewal in the absence of bFGF. In addition to promoting their proliferation, gap junctions are required for the survival of NPCs. Gap junctional communication is therefore both necessary and sufficient to maintain NPCs in a self-renewing state. Published by Elsevier Inc. C1 NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. NIA, Lab Expt Gerontol, Intramural Res Program, Baltimore, MD 21224 USA. RP Cheng, AW (reprint author), NIA, Neurosci Lab, Intramural Res Program, GRC 4F16,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM chengai@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 NR 65 TC 82 Z9 84 U1 1 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 AUG 1 PY 2004 VL 272 IS 1 BP 203 EP 216 DI 10.1016/j.ydbio.2004.04.031 PG 14 WC Developmental Biology SC Developmental Biology GA 838EI UT WOS:000222695900016 PM 15242801 ER PT J AU Blake, DR Meigs, JB Muller, DC Najjar, SS Andres, R Nathan, DM AF Blake, DR Meigs, JB Muller, DC Najjar, SS Andres, R Nathan, DM TI Impaired glucose tolerance, but not impaired fasting glucose, is associated with increased levels of coronary heart disease risk factors - Results from the Baltimore Longitudinal Study on Aging SO DIABETES LA English DT Article ID DENSITY-LIPOPROTEIN CHOLESTEROL; INCIDENT CARDIOVASCULAR EVENTS; DEPENDENT DIABETES-MELLITUS; C-REACTIVE PROTEIN; MORTALITY; PROGRAM; ADULTS; ATHEROSCLEROSIS; DIAGNOSIS; PLASMA AB Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) identify individuals at high risk for progression to diabetes. Whether IFG and IGT have comparable coronary heart disease (CHD) risk factor profiles, independent of their progression to diabetes, is unclear. We determined CHD risk factor levels in 937 nondiabetic individuals at baseline and biannually over a mean follow-up period of 9.6 years. Subjects had no known CHD at baseline and had greater than or equal to 2 (mean 4.2) oral glucose tolerance tests during follow-up. We classified glucose tolerance categories using American Diabetes Association diagnostic criteria or modified criteria that redefined IFG as 100-126 mg/dl, creating a similar baseline prevalence of IFG and IGT. Subjects who developed diabetes during follow-up were excluded from our analysis. Baseline CHD risk factors were similar in subjects with normal glucose tolerance (NGT) and IFG, but significantly more atherogenic in those with IGT or IFG + IGT. These findings were unchanged when the modified criteria were used, suggesting that IGT is phenotypically different from IFG and is associated with increased levels of CHD risk factors. Subjects with isolated IFG had similar levels of CHD risk factors as NGT subjects, even when IFG was redefined with a lower threshold. Although CHD risk factors were increased in the IGT group, the incidence of CHD events was not significantly different among groups, perhaps owing to the limited number of events. The differences in CHD risk factors among prediabetic groups may have clinical implications for screening strategies and CHD risk stratification of individuals with IFG and IGT. C1 Massachusetts Gen Hosp, Diabet Unit, Ctr Diabet, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. NIA, Baltimore, MD 21224 USA. RP Nathan, DM (reprint author), Massachusetts Gen Hosp, Diabet Unit, Ctr Diabet, Bulfinch 408, Boston, MA 02114 USA. EM dnathan@partners.org NR 25 TC 92 Z9 102 U1 0 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD AUG PY 2004 VL 53 IS 8 BP 2095 EP 2100 DI 10.2337/diabetes.53.8.2095 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 842TL UT WOS:000223027000023 PM 15277391 ER PT J AU Resnick, HE Carter, EA Sosenko, JM Henly, SJ Fabsitz, RR Ness, FK Welty, TK Lee, ET Howard, BV AF Resnick, HE Carter, EA Sosenko, JM Henly, SJ Fabsitz, RR Ness, FK Welty, TK Lee, ET Howard, BV TI Incidence of lower-extremity amputation in American Indians SO DIABETES CARE LA English DT Article ID CARDIOVASCULAR-DISEASE MORTALITY; CORONARY HEART-DISEASE; RISK-FACTORS; DIABETES-MELLITUS; VASCULAR-DISEASE; PIMA-INDIANS; ALL-CAUSE; PREVALENCE; COMPLICATIONS; HEALTH AB OBJECTIVE - To define incidence and predictors of nontraumatic lower-extremity amputation (LEA) in a diverse cohort of American Indians with diabetes. RESEARCH DESIGN AND METHODS - The Strong Heart Study is a study of cardiovascular disease and its risk factors in 13 American-Indian communities. Data on the presence/ absence of amputations were collected at each of three serial examinations (1989-1992, 19931995, and 1997-1999) by direct examination of the lower extremity. The logistic regression model was used to quantify the relationship between risk of LEA and potential risk factors, including diabetes duration, HbA(1c), peripheral arterial disease, and renal function. RESULTS - Of the 1,974 individuals With diabetes and without prevalent LEA at baseline, 87 (4.4%) experienced an LEA during 8 years of follow-up, and a total of 157 anatomical sites were amputated among these individuals. Amputation Of toes was most common, followed by below the-knee and above-the-knee amputations. Age-adjusted odds of LEA were higher among individuals with unfavorable combinations of risk factors, such as albuminuria and elevated HbA(1c). Multivariable modeling indicated that male sex, renal dysfunction, high ankle-brachial index, longer duration of diabetes, less than a high school education, increasing systolic blood pressure, and HbA(1c) predicted LEA risk. CONCLUSIONS - The 8-year cumulative incidence of LEA in American Indians with diabetes is 4.4%, with marked differences in risk by sex, educational attainment, renal function, and glycemic control. C1 MedStar Res Inst, Dept Epidemiol & Stat, Hyattsville, MD 20783 USA. Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. Missouri Breaks Res, Timber Lake, SD USA. Mille Lacs Band Ojibwe Indians, Diabet Program, Mille Lacs, MN USA. NHLBI, Bethesda, MD 20892 USA. Univ Minnesota, Sch Nursing, Minneapolis, MN 55455 USA. Univ Miami, Sch Med, Miami, FL USA. RP Resnick, HE (reprint author), MedStar Res Inst, Dept Epidemiol & Stat, 6495 New Hampshire Ave,Suite 201, Hyattsville, MD 20783 USA. EM helaine.c.resnick@medstar.net FU NHLBI NIH HHS [U01-HL-41654, U01-HL-41642, U01-HL-41652] NR 28 TC 38 Z9 39 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 AUG PY 2004 VL 27 IS 8 BP 1885 EP 1891 DI 10.2337/diacare.27.8.1885 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 842TD UT WOS:000223026200005 PM 15277412 ER PT J AU Pavkov, ME Knowler, WC Bennett, PH Nelson, RG AF Pavkov, ME Knowler, WC Bennett, PH Nelson, RG TI Increasing incidence of proteinuria in Pima Indians with Type 2 diabetes SO DIABETOLOGIA LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Association-for-the-Study-of-Diabetes CY SEP 05-09, 2004 CL Munich, GERMANY SP European Assoc Study Diabetes C1 NIDDK, NIH, Phoenix, AZ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2004 VL 47 SU 1 MA 165 BP A63 EP A63 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 855CW UT WOS:000223951600166 ER PT J AU Roglic, G Unwin, NC Bennett, PH AF Roglic, G Unwin, NC Bennett, PH TI Realistic estimates of excess deaths attributable to diabetes SO DIABETOLOGIA LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Association-for-the-Study-of-Diabetes CY SEP 05-09, 2004 CL Munich, GERMANY SP European Assoc Study Diabetes C1 WHO, Hlth Promot Surveillance Prevent & Management Non, CH-1211 Geneva, Switzerland. NIDDKD, NIH, Phoenix, AZ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2004 VL 47 SU 1 MA 323 BP A123 EP A123 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 855CW UT WOS:000223951600324 ER PT J AU Yang, X Jansson, PA Nagaev, I Jack, MM Carvalho, E Sunnerhagen, KS Cam, MC Cushman, SW Smith, U AF Yang, X Jansson, PA Nagaev, I Jack, MM Carvalho, E Sunnerhagen, KS Cam, MC Cushman, SW Smith, U TI Gene expression profiling implicates an impaired adipogenesis in insulin resistance SO DIABETOLOGIA LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Association-for-the-Study-of-Diabetes CY SEP 05-09, 2004 CL Munich, GERMANY SP European Assoc Study Diabetes C1 Lundberg Lab Diabet Res, Dept Internal Med, Gothenburg, Sweden. NIDDK, Expt Diabet Metab & Nutr Sect, NIH, Bethesda, MD USA. Sahlgrens Univ Hosp, Dept Neurosci Rehabil Med, S-41345 Gothenburg, Sweden. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2004 VL 47 SU 1 MA 1291 BP A459 EP A459 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 855CW UT WOS:000223951601289 ER PT J AU Yorek, MA Szabo, C Pacher, P Hirooka, H Stevens, MJ Obrosova, IG AF Yorek, MA Szabo, C Pacher, P Hirooka, H Stevens, MJ Obrosova, IG TI Aldose reductase inhibitor fidarestat counteracts nitrosative stress and poly(ADP-ribose)polymerase activation in experimental diabetic neuropathy SO DIABETOLOGIA LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Association-for-the-Study-of-Diabetes CY SEP 05-09, 2004 CL Munich, GERMANY SP European Assoc Study Diabetes C1 Univ Iowa, Vet Affairs Med Ctr, Iowa City, IA 52242 USA. Inotek Pharmaceut Corp, Biol, Beverly, MA USA. NIAAA, NIH, Rockville, MD 20852 USA. Sanwa Kagaku Kenkyusho Co Ltd, Chem, Kumamoto, Mie, Japan. Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2004 VL 47 SU 1 MA 1026 BP A367 EP A368 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 855CW UT WOS:000223951601024 ER PT J AU Fernandez-Capetillo, O Lee, A Nussenzweig, M Nussenzweig, A AF Fernandez-Capetillo, O Lee, A Nussenzweig, M Nussenzweig, A TI H2AX: the histone guardian of the genome SO DNA REPAIR LA English DT Review DE H2AX; DNA double strand breaks; genomic instability; DNA repair ID DOUBLE-STRAND BREAKS; DNA-DAMAGE CHECKPOINT; CLASS SWITCH RECOMBINATION; CYTIDINE DEAMINASE AID; V(D)J RECOMBINATION; FOCUS FORMATION; REPAIR FACTORS; CELL-CYCLE; SERINE 139; ATM AB At close hand to one's genomic material are the histories that make up the nucleosome. Standing guard, one variant stays hidden doubling as one of the core histories. But, thanks to its prime positioning, a variation in the tail of H2AX enables rapid modification of the historic code in response to DNA damage. A role for H2AX phosphorylation has been demonstrated in DNA repair, cell cycle checkpoints, regulated gene recombination events, and tumor suppression. In this review, we summarize what we have learned about this marker of DNA breaks, and highlight some of the questions that remain to be elucidated about the physiological role of H2AX. We also suggest a model in which chromatin restructuring mediated by H2AX phosphorylation serves to concentrate DNA repair/signaling factors and/or tether DNA ends together, which could explain the pleotropic phenotypes observed in its absence. (C) 2004 Elsevier B.V. All rights reserved. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Rockefeller Univ, Lab Mol Immunol, New York, NY 10021 USA. RP Nussenzweig, A (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM andre_nussenzweig@nih.gov RI Fernandez-Capetillo, Oscar/H-3508-2015 OI Fernandez-Capetillo, Oscar/0000-0002-2690-6885 NR 77 TC 580 Z9 604 U1 8 U2 40 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD AUG-SEP PY 2004 VL 3 IS 8-9 BP 959 EP 967 DI 10.1016/j.dnarep.2004.03.024 PG 9 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 850YQ UT WOS:000223650700020 PM 15279782 ER PT J AU Williams, ML Mager, DE Parenteau, H Gudi, G Tracy, TS Mulheran, M Wainer, IW AF Williams, ML Mager, DE Parenteau, H Gudi, G Tracy, TS Mulheran, M Wainer, IW TI Effects of protein calorie malnutrition on the pharmacokinetics of ketamine in rats SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID HUMAN LIVER-MICROSOMES; COMPARATIVE PHARMACOLOGY; ENERGY MALNUTRITION; N-DEMETHYLATION; KWASHIORKOR; METABOLITES; NUTRITION; DRUG; DIET; ANTIPYRINE AB The effect of protein calorie malnutrition (PCM) on the pharmacokinetics of ketamine (KET) enantiomers has been investigated. Six control and six PCM rats were administered 85 mg/kg racemic KET by intramuscular injection, and plasma concentrations of (S)- and ( R)- KET, norketamine (NKET), and 5,6-dehydronorketamine (DNK) were measured using enantioselective gas chromatography. Pharmacokinetic profiles were analyzed using standard noncompartmental and compartmental modeling methods. The volumes of distribution were similar between control and PCM rats for ( S)- and ( R)- KET. However, total clearance of both KET enantiomers was decreased, resulting in an increase in systemic exposure ( p < 0.05). The KET absorption rate was also increased in PCM rats. A decrease in the clearance of both NKET enantiomers led to a significant increase in exposure in PCM rats ( p < 0.005), and modeling results could not exclude the possibility that PCM induced an increase in the fraction of KET following the NKET pathway, which may further contribute to this increase in exposure. An increase in exposure to DNK enantiomers was also evident in PCM animals compared with controls [ p < 0.005 (DNK1); N. S. (DNK2)], which was in concordance with the decrease in apparent clearance values. These results show that PCM significantly alters the pharmacokinetics of KET and several of its metabolites. C1 NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. Univ Leicester, MRC, Toxicol Unit, Leicester, Leics, England. AstraZeneca Res & Dev, Montreal, PQ, Canada. W Virginia Univ, Sch Pharm, Morgantown, WV 26506 USA. RP Williams, ML (reprint author), NIA, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM Williamsma@grc.nia.nih.gov NR 37 TC 19 Z9 19 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD AUG PY 2004 VL 32 IS 8 BP 786 EP 793 DI 10.1124/dmd.32.8.786 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 838QP UT WOS:000222728400004 PM 15258102 ER PT J AU Gonzalez, FJ Ma, XC Yu, AM Krausz, KW Idle, JR AF Gonzalez, FJ Ma, XC Yu, AM Krausz, KW Idle, JR TI Are there endogenous substrates for xenobiotic metabolizing P450s? Studies using gene knockout and transgenic mice SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 NCI, Lab Metab, Bethesda, MD 20892 USA. Inst Clin Pharmacol, CH-3010 Bern, Switzerland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 24 BP 12 EP 12 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200025 ER PT J AU Pohl, LR AF Pohl, LR TI Mechanisms of idiosyncratic drug toxicity SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 NHLBI, Sect Mol & Cellular Toxicol, NIH, DHHS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 60 BP 30 EP 30 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200061 ER PT J AU Merrick, BA Pieper, R Makusky, AJ Gatlin, C Taylor, J McGrath, AM Zhou, J Zhao, M Bruno, M Madenspacher, J Wetmore, BA Tomer, KB AF Merrick, BA Pieper, R Makusky, AJ Gatlin, C Taylor, J McGrath, AM Zhou, J Zhao, M Bruno, M Madenspacher, J Wetmore, BA Tomer, KB TI Toxicoproteomics and biomarkers of hepatotoxicity using two dimensional gels and mass spectrometry SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 NIEHS, Res Triangle Pk, NC 27709 USA. Large Scale Biol Corp, Germantown, MD 20876 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 61 BP 31 EP 31 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200062 ER PT J AU Negishi, M Yamamoto, Y Tatsuya, S AF Negishi, M Yamamoto, Y Tatsuya, S TI Ligand-independent mechansm of car activation SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 68 BP 34 EP 34 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200069 ER PT J AU Gehring, E Aust, S Miksits, M Thalhammer, T Senderowicz, A Laczka-Ozvegy, C Jager, W AF Gehring, E Aust, S Miksits, M Thalhammer, T Senderowicz, A Laczka-Ozvegy, C Jager, W TI Transport of flavopiridol by ABCG2 in human breast cancer cell lines SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 Univ Vienna, Dept Pathophysiol, A-1010 Vienna, Austria. Univ Vienna, Inst Pharmaceut Chem, A-1010 Vienna, Austria. Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. Hungarian Acad Sci, Budapest, Hungary. NR 0 TC 0 Z9 0 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 108 BP 54 EP 54 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200109 ER PT J AU Paine, MF Hart, HL Zeldin, DC Watkins, PB AF Paine, MF Hart, HL Zeldin, DC Watkins, PB TI The human intestinal cytochrome P450 "pie" SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 NIEHS, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. Univ N Carolina, Div Pharmacotherapy, Chapel Hill, NC 27599 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 180 BP 90 EP 90 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200180 ER PT J AU Forkert, PG Simmonds, AC Ghanayem, BI Sharma, A Reilly, CA Millen, B Yost, GS AF Forkert, PG Simmonds, AC Ghanayem, BI Sharma, A Reilly, CA Millen, B Yost, GS TI Bioactivation of 1,1-dichloroethylene by CYP2E1 and CYP2F in murine lung SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 Queens Univ, Dept Anat & Cell Biol, Kingston, ON K7L 3N6, Canada. NIEHS, Res Triangle Pk, NC 27709 USA. Univ Utah, Dept Pharmacol & Toxicol, Salt Lake City, UT 84112 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 185 BP 93 EP 93 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200185 ER PT J AU Lee, SJ Coulter, SJ Ghanayem, B Goldstein, JA AF Lee, SJ Coulter, SJ Ghanayem, B Goldstein, JA TI Characterization of the CYP3A4*17 allele which is defective in metabolizing nifedipine and is part of a CYP3A haplotype containing the CYP3A5*3 splice variant SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 NIEHS, Human Metab Sect, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 234 BP 117 EP 117 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200232 ER PT J AU Nicol, CJ Yoon, M Ward, JM Yamashida, M Fukamachi, K Peters, JM Gonzalez, FJ AF Nicol, CJ Yoon, M Ward, JM Yamashida, M Fukamachi, K Peters, JM Gonzalez, FJ TI PPAR gamma influences susceptibility to DMBA-induced mammary, ovarian and skin carcinogenesis SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Vet & Tumor Pathol Sect, CCR, Frederick, MD 21702 USA. Penn State Univ, Dept Vet Sci, University Pk, PA 16802 USA. Penn State Univ, Ctr Mol Toxicol, University Pk, PA 16802 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 253 BP 126 EP 126 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200251 ER PT J AU Barbier, O Girard, H Inoue, Y Duez, H Villeneuve, L Kamiya, A Fruchart, JC Guillemette, C Gonzalez, FJ Staels, B AF Barbier, O Girard, H Inoue, Y Duez, H Villeneuve, L Kamiya, A Fruchart, JC Guillemette, C Gonzalez, FJ Staels, B TI Hepatic expression of the UGT1A9 gene is governed by HNF4 alpha SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 Inst Pasteur, F-59019 Lille, France. CHUL, Res Ctr, Oncol & Mol Endocrinol Res Ctr, Quebec City, PQ G14 G2, Canada. NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20814 USA. RI Guillemette, Chantal/J-6463-2012; Staels, Bart/N-9497-2016 OI Staels, Bart/0000-0002-3784-1503 NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 264 BP 132 EP 132 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200262 ER PT J AU Long, L Cwik, MJ Kapetanovic, I McCormick, DL AF Long, L Cwik, MJ Kapetanovic, I McCormick, DL TI In vitro metabolism studies of polyphenon E, a mixture of tea polyphenols being developed for cancer chemoprevention SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 IIT, Res Inst, Life Sci Grp, Chicago, IL 60616 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 300 BP 150 EP 150 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200298 ER PT J AU Nath, SS Ho, MN Furniss, MJ Sharp, LE Green, AG Bradford, WW Green, CE Swezey, R Kapetanovic, IM Iyer, LV AF Nath, SS Ho, MN Furniss, MJ Sharp, LE Green, AG Bradford, WW Green, CE Swezey, R Kapetanovic, IM Iyer, LV TI In vitro metabolism and interaction studies with resveratrol SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 SRI Int, Biosci Div, Menlo Pk, CA 94025 USA. NCI, Chemoprevent Agent Dev Res Grp, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 3 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 306 BP 153 EP 153 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200304 ER PT J AU Miyata, M Tozawa, A Nagata, K Gonzalez, FJ Yamazoe, Y AF Miyata, M Tozawa, A Nagata, K Gonzalez, FJ Yamazoe, Y TI Enhancement of canalicular bile acid output and excretion of non-conjugated bile acids are critical determinants for protection against cholic acid-induced liver toxicity SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 Tohoku Univ, Grad Sch Pharmaceut Sci, Aoba Ku, Sendai, Miyagi 9808578, Japan. NCI, Lab Metab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 348 BP 174 EP 174 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200346 ER PT J AU Leslie, EM Cole, SPC Waalkes, MP AF Leslie, EM Cole, SPC Waalkes, MP TI Arsenic transport by the human multidrug resistance protein 1 (MRP1/ABCC1): Requirement for a tri-glutathione conjugate SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 Queens Univ, Canc Res Labs, Kingston, ON K7L 3N6, Canada. NIEHS, Inorgan Carcinogenesis Sect, LCC, NCI, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 353 BP 176 EP 176 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200351 ER PT J AU Yee, SB Bourdi, M Pohl, LR AF Yee, SB Bourdi, M Pohl, LR TI The hepatoprotective role of interleukin-13 in drug-induced liver disease SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, NIH,DHHS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 455 BP 227 EP 227 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200452 ER PT J AU Welch, KD Reilly, TP Wen, B Goodlett, DR Yi, EC Lee, H Nelson, SD Pohl, LR AF Welch, KD Reilly, TP Wen, B Goodlett, DR Yi, EC Lee, H Nelson, SD Pohl, LR TI Proteomic identification of susceptibility factors in drug-induced liver disease (DILD) SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 NHLBI, NIH, HHS, Bethesda, MD 20892 USA. Bristol Myers Squibb Co, Syracuse, NY 13057 USA. Univ Washington, Seattle, WA 98195 USA. Inst Syst Biol, Seattle, WA 98103 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 456 BP 228 EP 228 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200453 ER PT J AU Adams, ML Radonovich, MF Brady, JN Pohl, LR AF Adams, ML Radonovich, MF Brady, JN Pohl, LR TI Genomic analysis of N-acetyl-L-cysteine hepatoprotection in mice treated with an overdose of acetaminophen SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 NHLBI, Mol & Cellular Toxicol Sect, LMI, NIH,DHHS, Bethesda, MD 20892 USA. NCI, Virus Tumor Biol Sect, NIH, DHHS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 474 BP 237 EP 237 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200471 ER PT J AU Bourdet, DL Pritchard, JB Thakker, DR AF Bourdet, DL Pritchard, JB Thakker, DR TI Interaction of H-2-antagonists with human organic cation transporters hOCT1 (SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3) SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 Univ N Carolina, Sch Pharm, Div Drug Delivery & Disposit, Chapel Hill, NC 27599 USA. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 524 BP 262 EP 262 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200520 ER PT J AU Bauer, B Hartz, AMS Fricker, G Miller, DS AF Bauer, B Hartz, AMS Fricker, G Miller, DS TI Pregnane X receptor (PXR) upregulates P-glycoprotein and MRP2 in blood-brain barrier, liver and kidney in vivo SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 NIEHS, Res Triangle Pk, NC 27709 USA. Univ Heidelberg, Inst Pharm & Mol Biotechnol, D-69120 Heidelberg, Germany. NR 0 TC 1 Z9 1 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 606 BP 303 EP 303 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200602 ER PT J AU Faucette, SR Wang, HB Sueyoshi, T Hempel, N Negishi, M LeCluyse, EL AF Faucette, SR Wang, HB Sueyoshi, T Hempel, N Negishi, M LeCluyse, EL TI Differential roles of human PXR and CAR in the regulation of hepatic CYP2B6 and CYP3A4 gene expression SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 Univ N Carolina, Sch Pharm, Div Drug Delivery & Disposit, Chapel Hill, NC 27599 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RI Hempel, Nadine/F-1700-2014 OI Hempel, Nadine/0000-0002-5574-8783 NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 611 BP 305 EP 305 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200607 ER PT J AU Chen, YP Ferguson, SS Goldstein, JA AF Chen, YP Ferguson, SS Goldstein, JA TI Cooperativity of proximal HPF1 sites in regulation of human CYP2C9 by PXR/CAR SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 612 BP 306 EP 306 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200608 ER PT J AU Smith, CM Faucette, SR Wang, HB Negishi, M LeCluyse, EL AF Smith, CM Faucette, SR Wang, HB Negishi, M LeCluyse, EL TI Regulation of human UGT1A1 by PXR and CAR SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 Univ N Carolina, Sch Pharm, Chapel Hill, NC 27599 USA. NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 615 BP 307 EP 307 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200611 ER PT J AU Squires, EJ Sueyoshi, T Negishi, M AF Squires, EJ Sueyoshi, T Negishi, M TI Cytoplasmic localization of mouse PXR and translocation to the nucleus after treatment with PCN SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 614 BP 307 EP 307 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200610 ER PT J AU Ferguson, SS Chen, YP LeCluyse, E Negishi, M Goldstein, JA AF Ferguson, SS Chen, YP LeCluyse, E Negishi, M Goldstein, JA TI Identification and characterization of regulatory sites in the CYP2C8 promoter SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Sch Pharm, Chapel Hill, NC 27514 USA. NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 618 BP 309 EP 309 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200614 ER PT J AU Kodama, S Koike, C Yamamoto, Y Negishi, M AF Kodama, S Koike, C Yamamoto, Y Negishi, M TI Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate drug-metabolizing and gluconeogenic enzymes SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 623 BP 311 EP 311 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200619 ER PT J AU Jackson, JP Ferguson, SS Moore, R Negishi, M Goldstein, JA AF Jackson, JP Ferguson, SS Moore, R Negishi, M Goldstein, JA TI The nuclear receptor CAR regulates phenytoin induction of CYP2C29 SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 625 BP 312 EP 312 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200621 ER PT J AU Wang, HB Faucette, S Hamilton, GA Coon, DJ Negishi, M LeCluyse, EL AF Wang, HB Faucette, S Hamilton, GA Coon, DJ Negishi, M LeCluyse, EL TI Utilization of primary human hepatocyte-based reporter assay for the identification of hCAR activators in vitro SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 Univ N Carolina, Sch Pharm, Chapel Hill, NC 27599 USA. CellzDirect Inc, Tucson, AZ 85712 USA. NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 624 BP 312 EP 312 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200620 ER PT J AU Swales, KE Kakizaki, S Yamamoto, Y Negishi, M AF Swales, KE Kakizaki, S Yamamoto, Y Negishi, M TI Novel mechanism of CAR-mediated CYP2B6 induction SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 NIEHS, Pharmacogenet Sect, LRDT, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 626 BP 313 EP 313 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200622 ER PT J AU Cheung, C Akiyama, TE Ward, J Nicol, CJ Feigenbaum, L Gonzalez, FJ AF Cheung, C Akiyama, TE Ward, J Nicol, CJ Feigenbaum, L Gonzalez, FJ TI PPAR alpha humanized mice: Mechanism of the differential response to peroxisome proliferators SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 7th European ISSX Meeting CY AUG 29-SEP 02, 2004 CL Vancouver, CANADA C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD AUG PY 2004 VL 36 SU 1 MA 631 BP 315 EP 315 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856DF UT WOS:000224023200627 ER PT J AU Wernyj, RP Morin, PJ AF Wernyj, RP Morin, PJ TI Molecular mechanisms of platinum resistance: still searching for the Achilles' heel SO DRUG RESISTANCE UPDATES LA English DT Review DE drug resistance; platinum compounds; cisplatin; resistance mechanisms; MUC1 ID PHASE-I TRIAL; EPITHELIAL OVARIAN-CANCER; GYNECOLOGIC-ONCOLOGY-GROUP; CISPLATIN RESISTANCE; DRUG-RESISTANCE; CONFERS RESISTANCE; CARCINOMA CELLS; MISMATCH REPAIR; DNA-REPAIR; E-CADHERIN AB The platinum compounds cisplatin and carboplatin are commonly used in cancer chemotherapy. However, tumors frequently develop resistance to these compounds, significantly decreasing their usefulness in the clinic. In the past few years, basic research has unraveled novel and unexpected mechanisms for the development of platinum resistance. For example, it has been reported that MUC1 expression and particularly the localization of its C-terminal subunit to the mitochondria may affect cisplatin resistance. Another recent finding suggests that cisplatin damage may activate DNA-dependent protein kinase (DNA-PK) to initiate a death signal that can be transmitted to neighboring cells through gap junctions, adding to a growing belief that the interactions of cancer cells with their surroundings may be important to the outcome of chemotherapy. While most clinical efforts have focused on identifying alternative regimens for drug-resistant cancer, it might be possible to exploit our knowledge of the mechanism of platinum resistance to specifically reverse resistance and increase platinum efficacy. The strategy of drug resistance reversal therapy (DRRT) may have significant impact on our approaches to the treatment and management of drug-resistant tumors. Published by Elsevier Ltd. C1 NIA, Cellular & Mol Biol Lab, Baltimore, MD 21224 USA. RP Morin, PJ (reprint author), NIA, Cellular & Mol Biol Lab, Baltimore, MD 21224 USA. EM morinp@grc.nia.nih.gov NR 68 TC 68 Z9 73 U1 2 U2 19 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1368-7646 J9 DRUG RESIST UPDATE JI Drug Resist. Update PD AUG-OCT PY 2004 VL 7 IS 4-5 BP 227 EP 232 DI 10.1016/j.drup.2004.08.002 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 876LA UT WOS:000225497100001 PM 15533760 ER PT J AU Tambs, K Hoffman, HJ Engdahl, B Borchgrevink, HM AF Tambs, K Hoffman, HJ Engdahl, B Borchgrevink, HM TI Hearing loss associated with ear infections in Nord-Trondelag, Norway SO EAR AND HEARING LA English DT Article ID ACUTE OTITIS-MEDIA; CHILDREN; IMPAIRMENT; EFFUSION; NOISE AB Objective: We have assessed the effect of recurrent childhood ear infections on adult hearing. We also examined whether adult hearing is poorer with an early age of onset of ear infections compared with later onset. Design: A population-based cohort of 50,398 subjects, 20 yr of age or older, were examined with air-conduction, pure-tone audiometry and reported if they had had recurrent ear infections (ED in childhood (or subsequently) with the age of onset. Results: There were poorer hearing thresholds associated with recurrent El for all frequency ranges from 0.25 kHz to 8 kHz, regardless of age or gender. The effect increased with age from approximately 2 dB among younger subjects (20 to 44 yr old) to approximately 5 to 6 dB among older subjects (65 yr or older). Among younger subjects, the effect of El was somewhat stronger for men, whereas among older subjects the effect was somewhat stronger for women. Early age of onset for EI was associated with poorer hearing thresholds than late onset. The mean loss was close to 9 to 10 dB for all frequency ranges among older subjects reporting onset of El before 2 yr of age. The mean loss was only about 4 dB among older subjects reporting onset of El after 7 yr of age. Conclusions: Reported Els are associated with similar consequences in terms of reduced hearing across frequencies 0.25 to 8 kHz for male and female subjects. The observed effects are stronger among older than among younger subjects, perhaps because effects increase with age or possibly because El affected the hearing more before 1940 than during subsequent decades. Reported early age of onset of El increases the risk of a substantially reduced hearing level later in life. C1 Norwegian Inst Publ Hlth, Div Epidemiol, Epidemiol Sect, N-0403 Oslo, Norway. NIDCD, NIH, Bethesda, MD USA. Norwegian Inst Publ Hlth, Dept Environm Med, N-0403 Oslo, Norway. Norwegian Res Council, Oslo, Norway. RP Tambs, K (reprint author), Norwegian Inst Publ Hlth, Div Epidemiol, Epidemiol Sect, PB 4404, N-0403 Oslo, Norway. EM kristian.tambs@fhi.no FU NIDCD NIH HHS [N01-DC-6-2104] NR 19 TC 9 Z9 9 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-0202 J9 EAR HEARING JI Ear Hear. PD AUG PY 2004 VL 25 IS 4 BP 388 EP 396 DI 10.1097/01.AUD.0000134554.71093.5E PG 9 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 844SR UT WOS:000223180600005 PM 15292778 ER PT J AU Saczynski, JS Margrett, JA Willis, SL AF Saczynski, JS Margrett, JA Willis, SL TI Older adults strategic behavior: Effects of individual versus collaborative cognitive training SO EDUCATIONAL GERONTOLOGY LA English DT Article ID PROSE RECALL; AGE; YOUNG; TASK; INTERVENTIONS; PERFORMANCE; RECOVERY; ABILITY; MEMORY; TRIAL AB Changes in strategic behavior were examined in older married couples participating in a cognitive intervention study. Participants were randomly assigned to: Questionnaire Control, Individual Training, or Collaborative Training. Trained participants completed inductive reasoning training sessions at home individually or as a couple. Participants were assessed at baseline, immediately following training, and a 3-month posttest. Overall, greater strategy use was related to higher ability performance across all groups. Collaborative and individual training groups showed a similar magnitude of strategy use at both posttests in terms of individual performance. Maintenance of strategy use on a collaborative task favored the collaborative group. C1 Johns Hopkins Univ, Baltimore, MD USA. W Virginia Univ, Morgantown, WV 26506 USA. Penn State Univ, University Pk, PA 16802 USA. RP Saczynski, JS (reprint author), NIH, 7201 Wisconsin Ave,Suite 3C-309, Bethesda, MD 20892 USA. EM saczynsj@mail.nih.gov OI Su, Yan/0000-0001-9602-7969; Margrett, Jennifer/0000-0003-0628-5660 NR 53 TC 14 Z9 14 U1 2 U2 6 PU BRUNNER/MAZEL INC PI BRISTOL PA 1900 FROST RD, STE 101, BRISTOL, PA 19007-1598 USA SN 0360-1277 J9 EDUC GERONTOL JI Educ. Gerontol. PD AUG PY 2004 VL 30 IS 7 BP 587 EP 610 DI 10.1080/03601270490466985 PG 24 WC Education & Educational Research; Gerontology SC Education & Educational Research; Geriatrics & Gerontology GA 842GF UT WOS:000222991000003 ER PT J AU Pacak, K Eisenhofer, G Goldstein, DS AF Pacak, K Eisenhofer, G Goldstein, DS TI Functional Imaging of endocrine tumors: Role of positron emission tomography SO ENDOCRINE REVIEWS LA English DT Review ID DIFFERENTIATED THYROID-CANCER; RECOMBINANT HUMAN THYROTROPIN; SOMATOSTATIN RECEPTOR SCINTIGRAPHY; VIRUS THYMIDINE KINASE; FDG-PET; ADRENAL MASSES; IN-VIVO; PREOPERATIVE LOCALIZATION; NEUROENDOCRINE TUMORS; F-18-FDG PET AB This article provides an update on functional imaging approaches for diagnostic localization of endocrine tumors, with emphasis on positron emission tomography (PET). [F-18]Fluorodeoxyglucose PET scanning is now a widely accepted imaging approach in clinical oncology. Benefits include improved patient outcome facilitated by staging and monitoring of disease and better treatment planning. [F-18]Fluorodeoxyglucose PET is also useful in some endocrine tumors, particularly in recurrent or metastatic thyroid cancer where the degree of accumulation of the radionuclide has prognostic value. However, this imaging approach does not take full advantage of the unique characteristics of endocrine tumors. Endocrine tumor cells take up hormone precursors, express receptors and transporters, and synthesize, store, and release hormones. These characteristics offer highly specific targets for PET. Radiopharmaceuticals developed for such approaches include 6-[F-18]fluorodopamine, and [C-11]hydroxyephedrine for localization of pheochromocytomas, [C-11]5-hydroxytryptophan and [C-11]L-dihydroxyphenylalanine for carcinoid tumors, and [C-11]metomidate for adrenocortical tumors. These functional imaging approaches are not meant to supplant conventional imaging modalities but should be used conjointly to better identify specific characteristics of endocrine tumors. This represents a relatively new and evolving approach to imaging that promises to answer specific questions about the behavior and growth of endocrine tumors, their malignant potential, and responsiveness to different treatment modalities. C1 NICHHD, Unit Clin Neuroendocrinol, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), NICHHD, Unit Clin Neuroendocrinol, Pediat & Reprod Endocrinol Branch, NIH, Bldg 10,Room 9D42,10 Ctr Dr MSC-1583, Bethesda, MD 20892 USA. EM karel@mail.nih.gov NR 127 TC 104 Z9 105 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0163-769X J9 ENDOCR REV JI Endocr. Rev. PD AUG PY 2004 VL 25 IS 4 BP 568 EP 580 DI 10.1210/er.2003-0032 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 843RA UT WOS:000223101000003 PM 15294882 ER PT J AU Tiong, JDR Pakiam, JG Wray, S AF Tiong, JDR Pakiam, JG Wray, S TI Gonadotropin releasing hormone-1 expression in incisors of mice SO ENDOCRINOLOGY LA English DT Article ID GENE-EXPRESSION; MESSENGER-RNA; MOUSE; NEURONS; ORIGIN; GNRH; DIFFERENTIATION; HYPOGONADISM; MIGRATION AB GnRH-1 is a decapeptide hormone that regulates gonadal maturation and fertility. In brain, GnRH-1 is secreted by neurons residing mainly in the preoptic/hypothalamic area. These neurons arise from cells in the nasal placode during embryonic development. GnRH-1 mRNA and peptide in the nonhypothalamic region have been described, suggesting other functions of GnRH-1. This paper describes for the first time the expression of GnRH-1 in developing incisors in mice. At embryonic day (E) 12.5, GnRH-1 mRNA and peptide were localized in cells in oral and dental epithelia. At postnatal day (P) 6, before incisor eruption, GnRH-1 was expressed in cells in dental epithelial-derived structures that include the papillary layer, outer dental epithelium, stellate reticulum, stratum intermedium, and enamel-secreting ameloblast cell layer. GnRH-1 expression correlated with cell maturity, becoming stronger in cells farther away from the proliferative zone. From E12.5 through P6, GnRH-1 expression was not detected in neural crest-derived dental mesenchyme or in mesenchyme-derived structures that include dental papilla, dental follicle, and dentin-secreting odontoblast. In addition, GnRH-1 expression was not detected in molars, indicating that expression of GnRH-1 is differentially regulated in incisor vs. molars, with only the former exhibiting continuous growth in this species. In homozygous hypogonadal mice at P1, GnRH-1 peptide expression was not detected, yet incisors were present. However, morphological changes in cells between dental follicle and ameloblast cell layer were noted. Taken together, our results indicate that GnRH-1 expression, although not essential for initiation and formation of incisors, may be important in maturation and/or maintenance of these placodally derived structures. C1 NINDS, NIH, Cellular & Dev Neurobiol Sect, Bethesda, MD 20892 USA. RP Wray, S (reprint author), NINDS, NIH, Cellular & Dev Neurobiol Sect, 36 Convent Dr, Bethesda, MD 20892 USA. EM wrays@ninds.nih.gov OI wray, susan/0000-0001-7670-3915 NR 30 TC 8 Z9 8 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD AUG PY 2004 VL 145 IS 8 BP 3608 EP 3612 DI 10.1210/en.2004-0387 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 837XB UT WOS:000222673500011 PM 15155575 ER PT J AU Martinez, A Julian, M Bregonzio, C Notari, L Moody, TW Cuttitta, F AF Martinez, A Julian, M Bregonzio, C Notari, L Moody, TW Cuttitta, F TI Identification of vasoactive nonpeptidic positive and negative modulators of adrenomedullin using a neutralizing antibody-based screening strategy SO ENDOCRINOLOGY LA English DT Article ID GASTRIN-RELEASING-PEPTIDE; BOMBESIN-LIKE PEPTIDES; GENE-RELATED-PEPTIDE; COMPLEMENT FACTOR-H; MONOCLONAL-ANTIBODY; INSULIN-SECRETION; BINDING-PROTEIN; LUNG-CANCER; CELL-LINES; RECEPTORS AB Adrenomedullin (AM) is a peptide hormone implicated in blood pressure regulation and in the pathophysiology of important diseases, such as hypertension, cancer, and diabetes. However, nonpeptidic modulators of this peptide that could be used to clinically regulate its actions are not available. We present here an efficient new method to screen a large library of small molecules. This technology was applied to the identification of positive and negative modulators of AM function. A two-tier screening strategy was developed in which the first screening entails disruption of the interaction between the peptide and a neutralizing monoclonal antibody. Selected compounds were further characterized by their ability to modulate second messengers in cells containing specific AM receptors. A parallel screen against gastrin-releasing peptide selected a different subset of molecules, confirming the specificity of the screening method. Identified AM-positive regulators reduced blood pressure in vivo, whereas AM-negative regulators mediated vasoconstriction, as predicted by the vasodilatory activity of AM. Binding of the small molecules to immobilized AM was demonstrated by surface plasmon resonance assays, with K-d values ranging from 7.76 x 10(-9) to 4.14 x 10(-6) M. Preclinical development of AM modulators may result in useful drugs for the prevention and treatment of hypertension, cancer, and diabetes. C1 NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. NCI, Vasc Biol Fac, NIH, Bethesda, MD 20892 USA. NIMH, Pharmacol Sect, NIH, Bethesda, MD 20892 USA. NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. San Pablo Ctr Estudios Universitarios Univ, Dept Chem Sci, Madrid 28668, Spain. RP Martinez, A (reprint author), NCI, Cell & Canc Biol Branch, NIH, Bldg 10,Room 13N262, Bethesda, MD 20892 USA. EM martinea@mail.nih.gov RI Martinez, Alfredo/A-3077-2013 OI Martinez, Alfredo/0000-0003-4882-4044 NR 33 TC 33 Z9 36 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 AUG PY 2004 VL 145 IS 8 BP 3858 EP 3865 DI 10.1210/en.2003-1251 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 837XB UT WOS:000222673500042 PM 15107357 ER PT J AU Ray, K Ghosh, SP Northup, JK AF Ray, K Ghosh, SP Northup, JK TI The role of cysteines and charged amino acids in extracellular loops of the human Ca2+ receptor in cell surface expression and receptor activation processes SO ENDOCRINOLOGY LA English DT Article ID CALCIUM-SENSING RECEPTOR; FAMILIAL HYPOCALCIURIC HYPERCALCEMIA; AUTOSOMAL-DOMINANT HYPOCALCEMIA; PROTEIN-COUPLED RECEPTORS; SIGNAL-TRANSDUCTION; CONSTITUTIVE ACTIVITY; BETA-2-ADRENERGIC RECEPTOR; CALCIMIMETIC COMPOUND; TRANSMEMBRANE DOMAIN; HORMONE-RECEPTOR AB The Ca2+ receptor is a plasma-membrane bound G protein-coupled receptor stimulated by extracellular calcium [Ca2+](o) and other di- and poly-cations. We investigated the role in receptor activation of all the charged amino acid residues and cysteines in the three extracellular loops (EL1, 2, and 3) of the human Ca2+ receptor by alanine-scanning mutagenesis. The mutant receptors were transiently expressed in HEK-293 cells, and cell surface expression patterns were analyzed by endoglycosidase-H digestion, immunoblotting, intact cell ELISA, and hydrolysis of phosphoinositides ( PI) induced by [Ca2+](o). The mutation of Cys677 and Cys765 located in EL1 and EL2, respectively, ablated PI hydrolysis completely, showed less than 5% cell surface expression of the wild-type receptor, and were not properly glycosylated. Replacement of the charged residues by using a single mutation or multiple alanine mutations in EL1, 2, and 3 produced only minor changes in receptor activation, except for Glu767 and Lys831. The E767A and K831A mutations in EL2 and EL3, respectively, showed gain-of-function by significantly enhancing apparent [Ca2+](o) affinity. E767A and K831A exhibited EC50 values of 2.1 and 2.8 mM, respectively, for [Ca2+](o)-stimulated PI hydrolysis as opposed to EC50 value of 4.2 mM for the wild-type receptor. Like E767A, substitutions of Glu767 with Gln and Lys was similarly activating, whereas Asp substitution displayed wildtype [Ca2+](o) sensitivity. Substitution of Lys831 with Glu but not with Gln showed similar activating effect as Ala replacement. A double-mutant E767K/K831E in which charged residues were switched positions showed impaired cell surface expression and failed to respond to [Ca2+](o). Taken together, these results suggest that in ELs, two cysteines form critical disulfide links, and the side chains of Glu767 and Lys831 are probably involved in ionic interactions with other prospective oppositely charged residues. Some of these interactions could be important for receptor folding and also may contribute to keep the Ca2+ receptor transmembrane helix bundle in an inactive conformation. C1 Natl Inst Deafness & Other Commun Disorders, Lab Cellular Biol, NIH, Bethesda, MD 20892 USA. RP Ray, K (reprint author), Natl Inst Deafness & Other Commun Disorders, Lab Cellular Biol, 5 Res Court,Room 2A11, Rockville, MD 20850 USA. EM rayk@nidcd.nih.gov NR 28 TC 7 Z9 8 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 AUG PY 2004 VL 145 IS 8 BP 3892 EP 3903 DI 10.1210/en.2003-1653 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 837XB UT WOS:000222673500046 PM 15117879 ER PT J AU Toyoshiba, H Yamanaka, T Sone, H Parham, FM Walker, NJ Martinez, J Portier, CJ AF Toyoshiba, H Yamanaka, T Sone, H Parham, FM Walker, NJ Martinez, J Portier, CJ TI Gene interaction network suggests dioxin induces a significant linkage between aryl hydrocarbon receptor and retinoic acid receptor beta SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID BAYESIAN NETWORKS; EPITHELIAL-CELLS; EXPRESSION DATA; 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN; DIFFERENTIATION; METABOLISM; BINDING; CANCER; TCDD; OVEREXPRESSION AB Gene expression arrays (gene chips) have enabled researchers to roughly quantify the level of mRNA expression for a large number of genes in a single sample. Several methods have been developed for the analysis of gene array data including clustering, outlier detection, and correlation studies. Most of these analyses are aimed at a qualitative identification of what is different between two samples and/or the relationship between two genes. We propose a quantitative, statistically sound methodology for the analysis of gene regulatory networks using gene expression data sets. The method is based on Bayesian networks for direct quantification of gene expression networks. Using the gene expression changes in HPL1A lung airway epithelial cells after exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin at levels of 0.1, 1.0, and 10.0 nM for 24 hr, a gene expression network was hypothesized and analyzed. The method clearly demonstrates support for the assumed network and the hypothesis linking the usual dioxin expression changes to the retinoic acid receptor system. Simulation studies demonstrated the method works well, even for small samples. C1 NIEHS, Lab Computat Biol & Risk Anal, Res Triangle Pk, NC 27709 USA. RP Portier, CJ (reprint author), NIEHS, Lab Computat Biol & Risk Anal, POB 12233, Res Triangle Pk, NC 27709 USA. EM portier@niehs.nih.gov RI Portier, Christopher/A-3160-2010; Walker, Nigel/D-6583-2012 OI Portier, Christopher/0000-0002-0954-0279; Walker, Nigel/0000-0002-9111-6855 NR 47 TC 27 Z9 30 U1 0 U2 6 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 AUG PY 2004 VL 112 IS 12 BP 1217 EP 1224 DI 10.1289/txg.7020 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 849GM UT WOS:000223526700015 PM 15345368 ER PT J AU Xie, YX Trouba, KJ Liu, J Waalkes, MP Germolec, DR AF Xie, YX Trouba, KJ Liu, J Waalkes, MP Germolec, DR TI Biokinetics and subchronic toxic effects of ora arsenite, arsenate, monomethylarsonic acid, and dimethylarsinic acid in v-Ha-ras transgenic (Tg.AC) mice SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID GLUTATHIONE-S-TRANSFERASE; INDUCED MALIGNANT-TRANSFORMATION; ABERRANT GENE-EXPRESSION; FORM POSITIVE FOCI; CELL-PROLIFERATION; REACTIVE OXYGEN; DNA METHYLATION; TRIMETHYLARSINE OXIDE; CHRONIC STIMULATION; URINARY-EXCRETION AB Previous research demonstrated that 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment increased the number of skin papillomas in v-Ha-ras transgenic (Tg.AC) mice that had received sodium arsenite [(As(Ill)] in drinking water, indicating that this model is useful for studying the toxic effects of arsenic in vivo. Because the liver is a known target of arsenic, we examined the pathophysiologic and molecular effects of inorganic and organic arsenical exposure on Tg.AC mouse liver in this study. Tg.AC mice were provided drinking water containing As(III), sodium arsenate [As(V)], monomethylarsonic acid [(MMA(V)], and 1,000 ppm dimethylarsinic acid [DMA(V)] at dosages of 150, 200, 1,500, or 1,000 ppm as arsenic, respectively, for 17 weeks. Control mice received unaltered water. Four weeks after initiation of arsenic treatment, TPA at a dose of 1.25 mug/200 muL acetone was applied twice a week for 2 weeks to the shaved dorsal skin of all mice, including the controls not receiving arsenic. In some cases arsenic exposure reduced body weight gain and caused mortality (including moribundity). Arsenical exposure resulted in a dose-dependent accumulation of arsenic in the liver that was unexpectedly independent of chemical species and produced hepatic global DNA hypomethylation. cDNA microarray and reverse transcriptase-polymerase chain reaction analysis revealed that all arsenicals altered the expression of numerous genes associated with toxicity and cancer. However, organic arsenicals [MMA(V) and DMA(V)] induced a pattern of gene expression dissimilar to that of inorganic arsenicals. In summary, subchronic exposure of Tg.AC mice to inorganic or organic arsenicals resulted in toxic manife-stations, hepatic arsenic accumulation, global DNA hypomethylation, and numerous gene expression changes. These effects may play a role in arsenic-induced hepatotoxicity and carcinogenesis and may be of particular toxicologic relevance. C1 Natl Inst Environm Hlth Sci, Lab Comparat Carcinogenesis, Inorgan Carcinogenesis Sect, NCI, Res Triangle Pk, NC 27709 USA. RP Germolec, DR (reprint author), Natl Inst Environm Hlth Sci, Lab Comparat Carcinogenesis, Inorgan Carcinogenesis Sect, NCI, POB 12233,Mail Drop C1-03, Res Triangle Pk, NC 27709 USA. EM germolec@niehs.nih.gov NR 61 TC 48 Z9 54 U1 0 U2 3 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 AUG PY 2004 VL 112 IS 12 BP 1255 EP 1263 DI 10.1289/txg.7152 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 849GM UT WOS:000223526700019 PM 15345372 ER PT J AU Brown, D Tart, KGT Goehl, TJ AF Brown, D Tart, KGT Goehl, TJ TI Olden times: Looking back on a career at the NIEHS SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27711 USA. RP Brown, D (reprint author), NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27711 USA. EM brown4@niehs.nih.gov; thigpenk@niehs.nih.gov; goehl@niehs.nih.gov NR 0 TC 2 Z9 2 U1 0 U2 0 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 AUG PY 2004 VL 112 IS 11 BP A598 EP A599 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 852GN UT WOS:000223743700001 PM 15289171 ER PT J AU Dearry, A AF Dearry, A TI Impacts of our built environment on public health SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material ID PSYCHOLOGICAL SENSE; PHYSICAL-ACTIVITY; URBAN SPRAWL; NEIGHBORHOOD; COMMUNITIES; LOCATION C1 NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27711 USA. RP Dearry, A (reprint author), NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27711 USA. EM dearry@niehs.nih.gov NR 22 TC 12 Z9 12 U1 0 U2 2 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 AUG PY 2004 VL 112 IS 11 BP A600 EP A601 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 852GN UT WOS:000223743700002 PM 15289172 ER PT J AU Goehl, TJ AF Goehl, TJ TI Addressing applications of genomics data SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. RP Goehl, TJ (reprint author), NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. EM goehl@niehs.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 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 AUG PY 2004 VL 112 IS 12 BP A664 EP A664 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 849GM UT WOS:000223526700003 ER PT J AU Stanford, JB Dunson, DB Tingen, C AF Stanford, JB Dunson, DB Tingen, C TI Studying human fertility: Response to Slama et al. and Joffe et al. SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Letter C1 Univ Utah, Hlth Res Ctr, Dept Family & Prevent Med, Salt Lake City, UT 84112 USA. NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Stanford, JB (reprint author), Univ Utah, Hlth Res Ctr, Dept Family & Prevent Med, Salt Lake City, UT 84112 USA. EM dunson1@niehs.nih.gov NR 8 TC 0 Z9 0 U1 2 U2 3 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 AUG PY 2004 VL 112 IS 11 BP A605 EP A606 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 852GN UT WOS:000223743700005 ER PT J AU Galperin, MY AF Galperin, MY TI Looking at big brothers for clues SO ENVIRONMENTAL MICROBIOLOGY LA English DT Editorial Material ID GENOME SEQUENCE; BACILLUS-ANTHRACIS C1 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 NR 10 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 1462-2912 J9 ENVIRON MICROBIOL JI Environ. Microbiol. PD AUG PY 2004 VL 6 IS 8 BP 767 EP 768 DI 10.1111/j.1462-2920.2004.00682.x PG 2 WC Microbiology SC Microbiology GA 836TL UT WOS:000222578600001 PM 15250878 ER PT J AU Camera, M Frigerio, M Cattaneo, M Abbracchio, MP Jacobson, KA Biglioli, P Tremoli, E AF Camera, M Frigerio, M Cattaneo, M Abbracchio, MP Jacobson, KA Biglioli, P Tremoli, E TI Role of P2Y receptors in agonist-induced tissue factor expression by platelets SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT ESC Congress 2004 CY AUG 28-SEP 01, 2004 CL Munich, GERMANY SP ESC C1 IRCCS, Ctr Cardiol Monzino, Milan, Italy. Univ Milan, San Paolo Hosp, DMCO, Milan, Italy. NIH, Washington, DC USA. RI Jacobson, Kenneth/A-1530-2009; tremoli, elena/C-1035-2011; Abbracchio, Maria Pia/B-9342-2014 OI Jacobson, Kenneth/0000-0001-8104-1493; Abbracchio, Maria Pia/0000-0002-7833-3388 NR 0 TC 0 Z9 0 U1 0 U2 2 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG-SEP PY 2004 VL 25 SU S BP 92 EP 92 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 856PG UT WOS:000224056500361 ER PT J AU Kostis, JB Eirnhorn, P AF Kostis, JB Eirnhorn, P CA ALLHAT Collaborative Research Grp TI Heart failure with preserved and impaired systolic left ventricular dysfunction in ALLHAT SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT ESC Congress 2004 CY AUG 28-SEP 01, 2004 CL Munich, GERMANY SP ESC C1 UMDNJ, Robert Wood Johnson Med Sch, New Brunswick, NJ USA. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG-SEP PY 2004 VL 25 SU S BP 660 EP 660 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 856PG UT WOS:000224056502638 ER PT J AU Kathiresan, S Newton-Cheh, C Gerszten, RE AF Kathiresan, S Newton-Cheh, C Gerszten, RE TI On the interpretation of genetic association studies SO EUROPEAN HEART JOURNAL LA English DT Editorial Material ID POPULATION STRATIFICATION; ASP299GLY POLYMORPHISM; MICE C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA USA. Harvard Univ, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02138 USA. MIT, Cambridge, MA 02139 USA. NHLBI, Frmingham Heart Study, Framingham, MA USA. RP Gerszten, RE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, 149 13th St, Charlestown, MA 02129 USA. EM rgerszten@partners.org NR 18 TC 19 Z9 19 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2004 VL 25 IS 16 BP 1378 EP 1381 DI 10.1016/j.ehj.2004.06.035 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 851IZ UT WOS:000223680100004 PM 15321696 ER PT J AU Smith, MA Anderson, BD AF Smith, MA Anderson, BD TI Commentary on "European collaboration in trials of new agents for children with cancer" by Ablett et al. SO EUROPEAN JOURNAL OF CANCER LA English DT Editorial Material ID HISTONE DEACETYLASE INHIBITOR; HUMAN NEUROBLASTOMA; CELL LINES; TRKB; CYTOTOXICITY; COMBINATION; APOPTOSIS; DRUGS AB Recent progress in establishing a European network to conduct paediatric oncology phase FIT clinical trials calls attention to the challenges facing researchers developing new agents for children with cancer. These challenges include: ensuring that effective infrastructures are in place to safely and efficiently conduct early phase clinical trials in children while meeting all ethical and regulatory requirements associated with such trials; obtaining timely access to new agents from pharmaceutical sponsors for both preclinical testing and for phase I and phase 11 testing; and effectively prioritizing new agents for evaluation in children so that those agents most likely to benefit children with specific cancers are brought forward for clinical testing. The use of public funds to develop and maintain clinical trials infrastructures devoted to paediatric oncology drug development can help in addressing these challenges and can facilitate the timely paediatric evaluation of new agents, thereby contributing to the goal of identifying more effective treatments for children with cancer. (C) 2004 Elsevier Ltd. All rights reserved. C1 NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Smith, MA (reprint author), NCI, Canc Therapy Evaluat Program, 6130,Execut Blvd Room 7025, Bethesda, MD 20892 USA. EM smithm@ctep.nci.nih.gov NR 12 TC 2 Z9 2 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD AUG PY 2004 VL 40 IS 12 BP 1893 EP 1895 DI 10.1016/j.ejca.2004.04.034 PG 3 WC Oncology SC Oncology GA 848GW UT WOS:000223456600020 PM 15288292 ER PT J AU Valent, P Ghannadan, M Akin, C Krauth, MT Selzer, E Mayerhofer, M Sperr, WR Arock, M Samorapoompichit, P Horny, HP Metcalfe, DD AF Valent, P Ghannadan, M Akin, C Krauth, MT Selzer, E Mayerhofer, M Sperr, WR Arock, M Samorapoompichit, P Horny, HP Metcalfe, DD TI On the way to targeted therapy of mast cell neoplasms: identification of molecular targets in neoplastic mast cells and evaluation of arising treatment concepts SO EUROPEAN JOURNAL OF CLINICAL INVESTIGATION LA English DT Review DE CD33; c-kit mutations; KIT; mylotarg; targeted therapy ID ACUTE MYELOID-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; KINASE INHIBITOR STI571; RECEPTOR-ALPHA CHAIN; TOXIN-INTERLEUKIN-3 FUSION PROTEIN; AGGRESSIVE SYSTEMIC MASTOCYTOSIS; BONE-MARROW-TRANSPLANTATION; ENDOTHELIAL GROWTH-FACTOR; SMALL INTERFERING RNA; PROTOONCOGENE C-KIT AB Several emerging treatment concepts for myeloid neoplasms are based on novel drugs targeting cell surface antigens, signalling pathways, or critical effector molecules. Systemic mastocytosis is a haematopoietic neoplasm that behaves as an indolent myeloproliferative disease in most patients, but can also present as aggressive disease or even as an acute leukaemia. In patients with aggressive disease or mast cell leukaemia, the response to conventional therapy is poor in most cases, and the prognosis is grave. Therefore, a number of attempts have been made to define novel treatment strategies for these patients. One promising approach may be to identify novel targets and to develop targeted drug therapies. In this article, we support the notion that neoplastic mast cells indeed express a number of potential molecular targets including immunoreactive CD antigens, the microphthalmia transcription factor (MITF), and members of the Bcl-2 family. In addition, the tyrosine kinase receptor KIT and downstream signalling pathways have been proposed as targets of a specific pharmacological intervention. A particular challenge is the disease-related D816V-mutated variant of KIT, which is resistant against diverse tyrosine kinase inhibitors including STI571, but may be sensitive to more recently developed targeted compounds. The therapeutic potential of target-specific approaches in malignant mast cell disorders should be evaluated in forthcoming clinical trials in the near future. C1 Med Univ Vienna, Dept Internal Med 1, Div Hematol & Hemostaseol, A-1090 Vienna, Austria. NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. Med Univ Vienna, Dept Radiat Therapy, Vienna, Austria. Fac Pharm, Lab Hematol Cellulaire & Mol, Paris, France. Med Univ Vienna, Inst Histol & Embryol, Vienna, Austria. Univ Lubeck, Inst Pathol, Lubeck, Germany. RP Valent, P (reprint author), Med Univ Vienna, Dept Internal Med 1, Div Hematol & Hemostaseol, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. EM peter.valent@meduniwien.ac.at RI Selzer, Edgar/K-7547-2015 NR 125 TC 42 Z9 42 U1 1 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0014-2972 J9 EUR J CLIN INVEST JI Eur. J. Clin. Invest. PD AUG PY 2004 VL 34 SU 2 BP 41 EP 52 DI 10.1111/j.0960-135X.2004.01369.x PG 12 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 861YZ UT WOS:000224455900006 PM 15291805 ER PT J AU Fleming, RV Marques, AR Klempner, MS Schmid, CH Dally, LG Martin, DS Philipp, MT AF Fleming, RV Marques, AR Klempner, MS Schmid, CH Dally, LG Martin, DS Philipp, MT TI Pre-treatment and post-treatment assessment of the C-6 test in patients with persistent symptoms and a history of Lyme borreliosis SO EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY & INFECTIOUS DISEASES LA English DT Article ID LINKED-IMMUNOSORBENT-ASSAY; ANTIBIOTIC-TREATMENT; INVARIABLE REGION; ANTIBODY-RESPONSE; VLSE LIPOPROTEIN; BURGDORFERI VLSE; PEPTIDE ANTIGENS; DISEASE; SERODIAGNOSIS; RECOMBINANT AB It was recently reported that antibody to C-6, a peptide that reproduces an invariable region of the VlsE lipoprotein of Borrelia burgdorferi, declined in titer by a factor of four or more in a significant proportion of patients after successful antibiotic treatment of acute localized or disseminated Lyme borreliosis. The present study evaluated the C-6 test as a predictor of therapy outcome in a population of patients with post-treatment Lyme disease syndrome. The serum specimens tested were from patients with well-documented, previously treated Lyme borreliosis who had persistent musculoskeletal or neurocognitive symptoms. All of the patients had participated in a recent double-blind, placebo-controlled antibiotic trial in which serum samples were collected at baseline and 6 months thereafter, i.show $132#e. 3 months following treatment termination. In this patient population no correlation was found between a decline of C-6 antibody titer of any magnitude and treatment or clinical outcome. Antibodies to C-6 persisted in these patients with post-treatment Lyme disease syndrome following treatment, albeit at a markedly lower prevalence and titer than in untreated patients with acute disseminated Lyme disease. The results indicate that C-6 antibody cannot be used to assess treatment outcome or the presence of active infection in this population. C1 Tulane Univ, Hlth Sci Ctr, Tulane Natl Primate Res Ctr, Div Bacteriol & Parasitol, Covington, LA 70433 USA. Boston Univ, Med Ctr, Dept Med, Boston, MA 02118 USA. NIAID, Clin Invest Lab, Bethesda, MD 20892 USA. Tufts Univ New England Med Ctr, Dept Med, Div Clin Care Res, Boston, MA 02111 USA. EMMES Corp, Rockville, MD 20850 USA. RP Philipp, MT (reprint author), Tulane Univ, Hlth Sci Ctr, Tulane Natl Primate Res Ctr, Div Bacteriol & Parasitol, 18703 3 Rivers Rd, Covington, LA 70433 USA. EM philipp@tpc.tulane.edu OI Schmid, Christopher/0000-0002-0855-5313 FU NCRR NIH HHS [RR00164]; NIAID NIH HHS [N01-AI65308, R01-AI37241, R01-AI49976] NR 12 TC 17 Z9 18 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0934-9723 J9 EUR J CLIN MICROBIOL JI Eur. J. Clin. Microbiol. Infect. Dis. PD AUG PY 2004 VL 23 IS 8 BP 615 EP 618 DI 10.1007/s10096-004-1163-z PG 4 WC Infectious Diseases; Microbiology SC Infectious Diseases; Microbiology GA 847EF UT WOS:000223374800006 PM 15243815 ER PT J AU Rusiecki, JA Holford, TR Zahm, SH Zheng, TZ AF Rusiecki, JA Holford, TR Zahm, SH Zheng, TZ TI Polychlorinated biphenyls and breast cancer risk by combined estrogen and progesterone receptor status SO EUROPEAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE breast cancer; estrogen receptor; polychlorinated biphenyls; progesterone receptor ID ENVIRONMENTAL ORGANOCHLORINE EXPOSURE; NESTED CASE-CONTROL; ADIPOSE-TISSUE; HORMONE RECEPTORS; LONG-ISLAND; WOMEN; SERUM; RESIDUES; PESTICIDES; BLOOD AB Studies have suggested that breast cancer risk factor profiles may vary according to joint estrogen receptor ( ER) and progesterone receptor ( PR) tumor status. Most of the published literature to date which has investigated the association between exposure to organochlorine compounds and breast cancer has reported null or weak associations. If, indeed, the classification by hormonal receptor status identifies different forms of breast cancer, then assessing the risk of exposure to polychlorinated biphenyls ( PCBs) on breast cancer as one disease or stratifying based on ER or PR status alone may obscure the association between PCBs and breast cancer. A hospital-based case-control study of 266 cases and 347 benign breast disease controls was conducted to examine the association of blood serum and adipose tissue concentrations of PCBs with breast cancer by joint ER/PR status. Total PCBs were measured in blood serum, and the following PCB congeners were measured in breast adipose tissue: 74, 118, 138, 153, 156, 170, 180, 183, 187. We did not detect any clear relationship or change in breast cancer risk based on joint ER/PR tumor status for body burden of PCBs, whether measured in blood serum or breast adipose tissue, by total PCBs or for specific congeners. These results confirm previous findings in the literature of no positive association between environmental exposure to PCBs and risk of breast cancer. C1 NCI, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. Yale Univ, Dept Epidemiol & Publ Hlth, Sch Med, New Haven, CT 06520 USA. RP Rusiecki, JA (reprint author), NCI, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Execut Blvd,EPS 8111,MSC 7240, Bethesda, MD 20892 USA. EM rusieckj@mail.nih.gov RI Zahm, Shelia/B-5025-2015 NR 49 TC 14 Z9 14 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0393-2990 J9 EUR J EPIDEMIOL JI Eur. J. Epidemiol. PD AUG PY 2004 VL 19 IS 8 BP 793 EP 801 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 842ZY UT WOS:000223044400016 PM 15469037 ER PT J AU Struewing, JP Hartge, P Wacholder, S Tucker, MA Greene, MH AF Struewing, JP Hartge, P Wacholder, S Tucker, MA Greene, MH TI BRCA1 and sex ratio SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE BRCA1; BRCA2; sex ratio; transmission ratio; mutation ID OVARIAN-CANCER FAMILIES; BREAST-CANCER; MUTATIONS AB Two recent papers suggest distorted sex and transmission ratios associated with BRCA1 mutations. If real, these would provide novel insights into the normal biological function of this gene and have implications for genetic epidemiologic methods used to estimate penetrance. We addressed these observations in two settings: offspring of 283 mutation carriers and 471 mutation negative subjects from BRCA1/2 mutation-positive families with multiple cases of breast and ovarian cancer (NCI families); and relatives of 115 BRCA1/2 mutation carriers from the Washington Ashkenazi Study ( WAS). The male: female ratio was below one in both BRCA1 (0.85, 95% CI 0.7-1.1 in NCI families; 0.90, 95% CI 0.6-1.4 in WAS) and BRCA2 families (0.77, 95% CI 0.5-1.3 and 0.80, 95% CI 0.5-1.2, in the NCI and WAS study groups, respectively). None of the sex ratios deviated significantly from one, and there was no significant difference between BRCA1 and BRCA2 families. The reduced sex ratio was due largely to the offspring of males, a distortion that is probably an artifact of ascertainment biases. Among adult daughters without breast or ovarian cancer born to mutation carriers, as expected, fewer than 50% were mutation carriers (39% in BRCA1 families and 44% in BRCA2 families). It is difficult, due to ascertainment biases, to draw firm conclusions regarding sex ratios in studies of a sex-limited phenotype. Nonetheless, these observations do not support the idea that BRCA1 mutation carriers have a lower ratio of male offspring than BRCA2 mutation carriers. European Journal of Human Genetics ( 2004). C1 NCI, NIH, Canc Res Ctr, Lab Populat Genet, Bethesda, MD 20892 USA. NCI, NIH, Div Canc Epidemiol & Genet, Epidemiol & Genet Program, Bethesda, MD USA. NCI, NIH, Div Canc Epidemiol & Genet, Biostat Branch, Bethesda, MD USA. NCI, NIH, Div Canc Epidemiol & Genet, Genet Epidemiol Branch, Bethesda, MD USA. NCI, NIH, Div Canc Epidemiol & Genet, Clin Genet Branch, Bethesda, MD USA. RP Struewing, JP (reprint author), NCI, NIH, Canc Res Ctr, Lab Populat Genet, 41 Library Dr,Room D702, Bethesda, MD 20892 USA. EM js140a@nih.gov RI Struewing, Jeffery/C-3221-2008; Tucker, Margaret/B-4297-2015; Struewing, Jeffery/I-7502-2013 OI Struewing, Jeffery/0000-0002-4848-3334 NR 7 TC 6 Z9 6 U1 0 U2 0 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 AUG PY 2004 VL 12 IS 8 BP 663 EP 667 DI 10.1038/sj.ejhg.5201210 PG 5 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 839WG UT WOS:000222815000011 PM 15114373 ER PT J AU Yogeeswari, P Thirumurugan, R Kavya, R Samuel, JS Stables, J Sriram, D AF Yogeeswari, P Thirumurugan, R Kavya, R Samuel, JS Stables, J Sriram, D TI 3-Chloro-2-methylphenyl-substituted semicarbazones: synthesis and anticonvulsant activity SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE aryl semicarbazones; 3-Chloro-2-methyl substituted phenyl semicarbazones; anti convulsants; CNS depressants ID ANTIEPILEPTIC DRUG DEVELOPMENT; MAXIMAL ELECTROSHOCK SCREEN; ARYL SEMICARBAZONES; NEUROTOXICITY EVALUATION; DEVELOPMENT PROGRAM; ANALOGS; AGENTS; ARYLSEMICARBAZONES; THIOSEMICARBAZONES; ARYLIDENE AB A series of 3-chloro-2-methylphenyl substituted semicarbazones (3-33) was synthesized and evaluated for anticonvulsant and CNS activities. After intraperitoneal injection to mice or rats, the semicarbazone derivatives were examined in the maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ), and subcutaneous strychnine (scSTY)-induced seizure and neurotoxicity screens. The aryl urea (1) and the semicarbazide (2) showed anticonvulsant activity in the MES and scPTZ screens with acute neurotoxicity, whereas the semicarbazone derivatives showed good anticonvulsant potency in the scSTY screen with moderate activity against MES and scPTZ screens. Compound 21 exhibited anticonvulsant potency against all the three screens with lesser neurotoxicity. Some titled compounds exhibited lesser CNS depression and neurotoxicity compared to phenytoin or carbamazepine as was evident from the CNS studies. (C) 2004 Elsevier SAS. All rights reserved. C1 Birla Inst Technol & Sci, Pharm Grp, Med Chem Res Lab, Pilani 333031, Rajasthan, India. NIH, Epilepsy Branch, Preclin Pharmacol Sect, Bethesda, MD 20892 USA. RP Yogeeswari, P (reprint author), Birla Inst Technol & Sci, Pharm Grp, Med Chem Res Lab, Pilani 333031, Rajasthan, India. EM pyogee@bits-pilani.ac.in OI Rathinasabapathy, Thirumurugan/0000-0002-7330-0552; Jayakar, Selwyn/0000-0002-5792-6408 NR 30 TC 30 Z9 34 U1 0 U2 2 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD AUG PY 2004 VL 39 IS 8 BP 729 EP 734 DI 10.1016/j.ejmech.2004.03.008 PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 850AP UT WOS:000223583500009 PM 15276306 ER PT J AU Gioio, AE Lavina, ZS Jurkovicova, D Zhang, H Eyman, M Giuditta, A Kaplan, BB AF Gioio, AE Lavina, ZS Jurkovicova, D Zhang, H Eyman, M Giuditta, A Kaplan, BB TI Nerve terminals of squid photoreceptor neurons contain a heterogeneous population of mRNAs and translate a transfected reporter mRNA SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE axons; differential mRNA display; green fluorescent protein; protein synthesis; synaptosomes ID LOCAL PROTEIN-SYNTHESIS; LONG-TERM FACILITATION; GIANT-AXON; SYNAPSE FORMATION; GROWTH CONES; PRESYNAPTIC ENDINGS; SYMPATHETIC NEURONS; LYMNAEA-STAGNALIS; ACTIVE POLYSOMES; BETA-TUBULIN AB It is now well established that the distal structural/functional domains of the neuron contain 2a diverse population of mRNAs that program the local synthesis of protein. However, there is still a paucity of information on the composition and function of these mRNA populations in the adult nervous system. To generate empirically, hypotheses regarding the function of the local protein synthetic system, we have compared the mRNAs present in the squid giant axon and its parental cell bodies using differential mRNA display as an unbiased screen. The results of this screen facilitated the identification of 31 mRNAs that encoded cytoskeletal proteins, translation factors, ribosomal proteins, molecular motors, metabolic enzymes, nuclear-encoded mitochondrial mRNAs, and a molecular chaperone. Results of cell fractionation and RT-PCR analyses established that several of these mRNAs were present in polysomes present in the presynaptic nerve terminal of photoreceptor neurons, indicating that these mRNAs were being actively translated. Findings derived from in vitro transfection studies established that these isolated nerve terminals had the ability to translate a heterologous reporter mRNA. Based upon these data, it is hypothesized that the local protein synthetic system plays an important role in the maintenance/remodelling of the cytoarchitecture of the axon and nerve terminal, maintenance of the axon transport and mRNA translation systems, as well as contributing to the viability and function of the local mitochondria. C1 NIMH, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Naples Federico II, Dipartimento Fis Gen & Ambientale, Naples, Italy. RP Kaplan, BB (reprint author), NIMH, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM barry.kaplan@nih.gov OI Zhang, Hengshan/0000-0002-2226-4774 NR 43 TC 33 Z9 34 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD AUG PY 2004 VL 20 IS 4 BP 865 EP 872 DI 10.1111/j.1460-9568.2004.03538.x PG 8 WC Neurosciences SC Neurosciences & Neurology GA 845DR UT WOS:000223216600001 PM 15305855 ER PT J AU Chin, FT Pike, VW Ichise, M Zoghbi, SS Vines, D Vermeulen, E Wikstrom, HV Halldin, C Innis, RB AF Chin, FT Pike, VW Ichise, M Zoghbi, SS Vines, D Vermeulen, E Wikstrom, HV Halldin, C Innis, RB TI A new 18F-labeled ligand for brain 5-HT1A receptors SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Meeting Abstract CT Annual Congress of the European-Association-of-Nuclear-Medicine CY SEP 04-08, 2004 CL Helsinki, FINLAND SP European Assoc Nucl Med C1 NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. Univ Groningen, Dept Med Chem, NL-9700 AB Groningen, Netherlands. Karolinska Inst, Dept Clin Neurosci, S-10401 Stockholm, Sweden. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1619-7070 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD AUG PY 2004 VL 31 SU 2 BP S249 EP S249 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 847UG UT WOS:000223419900222 ER PT J AU Lu, SY Hong, J Musachio, JL Pike, VW AF Lu, SY Hong, J Musachio, JL Pike, VW TI Synthesis of two NCA [carbonyl-11C]-labeled 5-HT1A receptor agonists based on reactions of in situ generated [11C]organocarboxymagnesium halides with amine precursors under microwave-enhanced conditions SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Meeting Abstract CT Annual Congress of the European-Association-of-Nuclear-Medicine CY SEP 04-08, 2004 CL Helsinki, FINLAND SP European Assoc Nucl Med C1 NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1619-7070 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD AUG PY 2004 VL 31 SU 2 BP S249 EP S249 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 847UG UT WOS:000223419900223 ER PT J AU Lu, SY Watts, P Chin, FT Hong, J Musachio, JL Haswell, SJ Pike, VW AF Lu, SY Watts, P Chin, FT Hong, J Musachio, JL Haswell, SJ Pike, VW TI Exploration of a micro-reactor for the synthesis of NCA 11C-and 18F-labeled carboxylic esters SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Meeting Abstract CT Annual Congress of the European-Association-of-Nuclear-Medicine CY SEP 04-08, 2004 CL Helsinki, FINLAND SP European Assoc Nucl Med C1 NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. Univ Hull, Dept Chem, Kingston Upon Hull HU6 7RX, N Humberside, England. NR 0 TC 2 Z9 2 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1619-7070 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD AUG PY 2004 VL 31 SU 2 BP S248 EP S248 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 847UG UT WOS:000223419900218 ER PT J AU Seneca, N Finnema, S Sovago, J Shchukin, E Gulyas, B Farde, L Innis, R Wikstrom, H Halldin, C AF Seneca, N Finnema, S Sovago, J Shchukin, E Gulyas, B Farde, L Innis, R Wikstrom, H Halldin, C TI Effect of amphetamine on dopamine D2 receptors binding in the primate brain with the new agonist ligand [C-11]MNPA SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Meeting Abstract CT Annual Congress of the European-Association-of-Nuclear-Medicine CY SEP 04-08, 2004 CL Helsinki, FINLAND SP European Assoc Nucl Med C1 Karolinska Inst, Psychiat Sect, S-10401 Stockholm, Sweden. NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. Univ Groningen, Dept Med Chem, NL-9700 AB Groningen, Netherlands. RI Sovago, Judit/G-7961-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1619-7070 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD AUG PY 2004 VL 31 SU 2 BP S208 EP S208 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 847UG UT WOS:000223419900028 ER PT J AU Zoueva, OP Rodgers, GP AF Zoueva, OP Rodgers, GP TI Inhibition of beta protein 1 expression enhances beta-globin promoter activity and beta-globin mRNA levels in the human erythroleukemia (K562) cell line SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID TRANSCRIPTION FACTOR GATA-1; OPEN CHROMATIN-STRUCTURE; ZINC-FINGER PROTEIN; KRUPPEL-LIKE FACTOR; HUMAN GAMMA-GLOBIN; REGULATORY ELEMENTS; ERYTHROID-CELLS; BINDING PROTEIN; GENE-EXPRESSION; HOMEOBOX GENES AB Objective. In this paper, we report new observations related to the mechanism of the negative regulation of the important adult beta-globin gene in the erythroid cells at the embryonic-fetal stage of their development. We focused on the role of the silencer II region located upstream of the beta-globin gene, which along with its cognate binding protein BP1, negatively regulates beta-globin transcription. Materials and Methods. We prepared plasmid constructs containing the wild-type silencer II sequence, a mutated silencer II sequence, or a mutated control sequence in the beta-globin promoter 690-bp insert, which in turn was linked to an enhanced green fluorescent protein (EGFP) reporter gene. A human erythroleukemia cell line (K562) with ernbryonic-fetal phenotype was transfected with these EGFP constructs. Results. Flow cytometry and fluorescence digital imaging showed about threefold increase in the beta-globin promoter activity of the mutated silencer II construct. Introduction of a small interfering RNA (siRNA) complementary to BP1 into the cells caused a 75% decrease in BP1 expression and a simultaneous similar to40% elevation of beta-globin promoter activity as well as an increase in beta-globin mRNA levels, as compared with controls. We detected no changes in the mRNA levels of positive regulators of hemoglobin transcription such as EKLF and GATA-1. Conclusion. Our results support the involvement of BP1 in the mechanism of the negative regulation of beta-globin transcription. A better understanding of this mechanism may lay the groundwork for novel gene therapy approaches to inhibit the expression of abnormal structural variants of adult beta globin, such as sickle hemoglobin. (C) 2004 International Society for Experimental Hematology. Published by Elsevier Inc. C1 NIDDKD, Mol & Clin Hematol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Zoueva, OP (reprint author), NIDDKD, Mol & Clin Hematol Branch, Natl Inst Hlth, Bldg 31,Room 9A52,9000 Rockville Pike, Bethesda, MD 20892 USA. EM gprod@helix.nih.gov NR 51 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD AUG PY 2004 VL 32 IS 8 BP 700 EP 708 DI 10.1016/j.exphem.2004.05.024 PG 9 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 850AV UT WOS:000223584200007 PM 15308321 ER PT J AU Choi, U DeRavin, SS Yamashita, K Whiting-Theobald, N Linton, GF Loktionova, NA Pegg, AE Malech, HL AF Choi, U DeRavin, SS Yamashita, K Whiting-Theobald, N Linton, GF Loktionova, NA Pegg, AE Malech, HL TI Nuclear-localizing O-6-benzylguanine-resistant GFP-MGMT fusion protein as a novel in vivo selection marker SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; SEVERE COMBINED IMMUNODEFICIENCY; HEMATOPOIETIC STEM-CELLS; GENE-THERAPY; CD34(+) CELLS; O-6-METHYLGUANINE-DNA METHYLTRANSFERASE; TRANSDUCED CELLS; RESISTANCE GENE; OXIDASE DEFECT; ALKYLTRANSFERASE AB Objective. We characterized a novel in vivo selectable fusion protein, green fluorescence protein-O-6-benzylguanine (BG)-resistant O-6-methylguanine-methyltransferase (GFP-MGMT* [*refers to mutant MGMT]) used to delineate optimum selection regimens for transduced hematopoietic stem cells (HSC) ex vivo and in vivo. Materials and Methods. We transduced human or mouse HSC with retrovirus vector encoding GFP-MGMT* where BG-resistant forms of human P140K-hMGMT* and mouse P144K-mMGMT* were studied. We evaluated selection of transduced HSC ex vivo and in vivo using either BG/1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or BG/temozolomide (TMZ) combinations, evaluating transduction marking by flow cytometry and real-time TaqMan PCR. Results. GFP-MGMT* transduction confers nuclear-localized GFP fluorescence and BG resistance. Optimum selection ex vivo of GFP-MGMT*-transduced HSC occurred with BG (2.5-10 muM)/BCNU (5-10 muM) or TMZ (100-200 muM), which increases marking while preserving maximum viable transduced cells. Starting at low levels (0.1%) or high levels (>30%) of in vivo bone marrow gene making in mice, in vivo selection with BG/BCNU (20/6 mg/kg) (weeks 4 and 5) or BG/TMZ (20/60 mg/kg) (daily x 5 at week 4) increased bone marrow marking to 8.58% +/- 3.52% or 82.0% +/- 3.4% GFP(+) cells, respectively, in the low- or high-level initial marking mice. Conclusions. GFP-MGMT* is an informative tool to explore optimization of in vivo selection regimens using BG/BCNU or BG/TMZ to increase gene marking of HSC. Both timing and dosing of selection regimens and the starting level of marking may all be important to the level of selective increase of in vivo marking achieved. (C) 2004 International Society for Experimental Hematology. Published by Elsevier Inc. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. RP Malech, HL (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Room 11N113,10 Ctr Dr,MSC 1886, Bethesda, MD 20892 USA. EM hmalech@nih.gov OI Malech, Harry/0000-0001-5874-5775 NR 35 TC 9 Z9 9 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD AUG PY 2004 VL 32 IS 8 BP 709 EP 719 DI 10.1016/j.exphem.2004.05.022 PG 11 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 850AV UT WOS:000223584200008 PM 15308322 ER PT J AU Xu, Q Wink, DA Colton, CA AF Xu, Q Wink, DA Colton, CA TI Nitric oxide production and regulation of neuronal NOS in tyrosine hydroxylase containing neurons SO EXPERIMENTAL NEUROLOGY LA English DT Article DE tyrosine hydroxylase; nitric oxide production; nNOS; CAD cells; biopterin; catecholaminergic neuronal cell line ID CENTRAL-NERVOUS-SYSTEM; CNS CELL-LINE; PARKINSONS-DISEASE; IN-VIVO; MITOCHONDRIAL RESPIRATION; NITROSATIVE STRESS; DOPAMINE NEURONS; SYNTHASE; TETRAHYDROBIOPTERIN; CALCIUM AB CAD cells are a murine CNS catecholaminergic (tyrosine hydroxylase-positive; TH+) neuronal cell line that undergoes morphological differentiation to resemble CNS catecholaminergic neurons upon serum deprivation, We show here that CAD cells also express neuronal nitric oxide synthase (nNOS) mRNA and protein and produce readily measurable levels of NO. Since both NO and catecholamines (L-DOPA; dopamine; norepinephrine) are redox active molecules, their production within the same cell may affect the cell's vulnerability to insult, Thus, we examined the regulation of NO production by CAD cells and the effect of NO on cell survival. NO is generated in a dose-dependent fashion by treatment with agents (ionomycin; A23817; KCl) known to increase calcium entry across the cell membrane. The NO level can be increased further by pretreatment with sepiapterin, a membrane permeable precursor for BH4 synthesis, suggesting that the BH4 levels or access required for nNOS activation is limited in CAD cells. Reducing mitochondrial Ca2+ uptake using ruthenium red (RuR) increased ionomycin-mediated NO production over ionomycin alone and indicates a critical role for mitochondria in nNOS regulation. Cell death was significantly increased by ionomycin treatment alone or in conjunction with reduced mitochondrial Ca2+ uptake. However, NO was not the primary mediator of cell death since NOS inhibitors rescued only less than 10% of the cells. These data suggest that endogenous NO production by nNOS is not a major factor in CAD cell death under these conditions. (C) 2004 Elsevier Inc. All rights reserved. C1 Duke Univ, Med Ctr, Div Neurol, Durham, NC 27710 USA. NCI, NIH, Radiat Biol Branch, Bethesda, MD 20892 USA. RP Colton, CA (reprint author), Duke Univ, Med Ctr, Div Neurol, Box 2900, Durham, NC 27710 USA. EM glia01@aol.com FU NIA NIH HHS [AG 19740] NR 66 TC 9 Z9 9 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD AUG PY 2004 VL 188 IS 2 BP 341 EP 350 DI 10.1016/j.expneurol.2004.04.016 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 838PX UT WOS:000222726500017 PM 15246834 ER PT J AU DiPaolo, JA Alvarez-Salas, LM AF DiPaolo, JA Alvarez-Salas, LM TI Advances in the development of therapeutic nucleic acids against cervical cancer SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE antigene; antisense; aptamers; cervical cancer; human papillomavirus; papillomavirus; ribozymes; RNA interference; therapy ID HUMAN-PAPILLOMAVIRUS TYPE-16; CARCINOMA CELL-LINES; DOUBLE-STRANDED-RNA; IN-VITRO SELECTION; C-RAF KINASE; ANTISENSE OLIGONUCLEOTIDES; MESSENGER-RNA; E6 ONCOPROTEIN; HAIRPIN RIBOZYMES; GENE-EXPRESSION AB Cervical cancer is the second most common neoplastic disease affecting women worldwide. Basic, clinical and epidemiological analyses indicate that expression of high-risk human papillomaviruses (HPVs) E6/E7 genes is the primary cause of cervical cancer and represent ideal targets for the application of therapeutic nucleic acids (TNAs). Antisense oligodeoxyribonucleotides (AS-ODNs) and ribozymes (RZs) are the most effective TNAs able to inhibit in vivo tumour growth by eliminating HPV-16 and HPV-18 E6/E7 transcripts. Expression of multiple RZs directed against alternative target sites by triplex expression systems may result in the abrogation of highly variable HPVs. More recently, RNA interference (RNAi) gene knockdown phenomenon, induced by small interfering RNA (siRNA), has demonstrated its potential value as an effective TNA for cervical cancer. siRNA and aptamers; as TNAs will have a place in the armament for cervical cancer. TNAs against cervical cancer is in a dynamic state, and clinical trials will define the TNAs in preventive and therapeutic roles to control tumour growth, debulk tumour mass, prevent metastasis and facilitate immune interaction. C1 NCI, Ctr Canc Res, NIH, Bethesda, MD 20894 USA. CINVESTAV, Dept Genet & Mol Biol, Lab Gene Therapy, Mexico City 07360, DF, Mexico. RP DiPaolo, JA (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20894 USA. NR 140 TC 27 Z9 34 U1 0 U2 1 PU ASHLEY PUBLICATIONS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1471-2598 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD AUG PY 2004 VL 4 IS 8 BP 1251 EP 1264 DI 10.1517/14712598.4.8.1251 PG 14 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 842CU UT WOS:000222981300006 PM 15268660 ER PT J AU Blonder, J Conrads, TP Veenstra, TD AF Blonder, J Conrads, TP Veenstra, TD TI Characterization and quantitation of membrane proteomes using multidimensional MS-based proteomic technologies SO EXPERT REVIEW OF PROTEOMICS LA English DT Review DE isotopic labeling; mass spectrometry; membrane proteomics; multidimensional fractionation; quantitation ID CODED AFFINITY TAGS; PROTEIN-KINASE-C; MASS-SPECTROMETRY; O-18; GENOME; CELLS; ELECTROPHORESIS; DIFFERENTIATION; COMBINATION; MIXTURES AB A major goal of proteomics is to develop methods that enable the systematic characterization of every protein within the cell or particular subcellular proteome using a single analytical platform. Although the equivalent has already been achieved in genomics, reaching this goal in proteomics represents a much greater challenge due to the wide dynamic range of protein expression, numerous post-translational modifications and remarkable physicochemical heterogeneity of proteins. A major analytical challenge has Involved developing more effective means for proteome-scale investigations of membrane proteins, whose solubility differs drastically from that of cytoplasmic proteins. Fortunately, rapid progress has Increased the ability to characterize this critically important class of proteins on a scale analogous to that of aqueous soluble proteins. C1 NCI, SAIC Frederick Inc, Lab Proteom & Analyt Technol, Frederick, MD 21702 USA. RP Blonder, J (reprint author), NCI, SAIC Frederick Inc, Lab Proteom & Analyt Technol, POB B, Frederick, MD 21702 USA. EM blonder@ncifcrf.gov; conrads@ncifcrf.gov; veenstra@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 34 TC 27 Z9 29 U1 1 U2 2 PU FUTURE DRUGS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEYY CENTRAL, LONDON N3 1QB, ENGLAND SN 1478-9450 J9 EXPERT REV PROTEOMIC JI Expert Rev. Proteomics PD AUG PY 2004 VL 1 IS 2 BP 153 EP 163 DI 10.1586/14789450.1.2.153 PG 11 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 939ZV UT WOS:000230114300003 PM 15966810 ER PT J AU Tangrea, MA Wallis, BS Gillespie, JW Gannot, G Emmert-Buck, MR Chuaqui, RF AF Tangrea, MA Wallis, BS Gillespie, JW Gannot, G Emmert-Buck, MR Chuaqui, RF TI Novel proteomic approaches for tissue analysis SO EXPERT REVIEW OF PROTEOMICS LA English DT Review DE LES; protein assays; SELDI; tissue micodissection; tissue proteomics ID POLYMERASE CHAIN-REACTION; PARAFFIN-EMBEDDED TISSUE; CONVERTASE-1 PRO-DOMAIN; PROTEIN MICROARRAYS; MASS-SPECTROMETRY; FUNCTIONAL ANNOTATION; CLINICAL-APPLICATIONS; SELDI-TOF; CANCER; ARRAYS AB Proteomics, the global study of protein expression and characteristics, has recently emerged as a key component In the field of molecular analysis. The dynamic nature of proteins, from Ion channels to chaperones, presents a challenge, yet the understanding of these molecules provides a rich source of Information. When applying proteomic analysis directly to human tissue samples, additional difficulties arise. The following article presents an overview of the current proteomic tools used in the analysis of tissues, beginning with conventional methods such as western blot analysis and 2D polyacrylamide gel electrophoresis. The most current high-throughput techniques being used today are also reviewed. These Include protein arrays, reverse-phase protein lysate arrays, matrix-assisted laser desorption/Ionization, surface-enhanced laser desorption/ionization and layered expression scanning. In addition, bloinformatics as well as Issues regarding tissue preservation and microdissection to obtain pure cell populations are included. Finally, future directions of the tissue proteomics field are discussed. C1 NCI, Pathol Lab, Pathogenet Unit, Gaithersburg, MD 20877 USA. NCI, Sci Applicat Int Corp, Gaithersburg, MD 20877 USA. RP Tangrea, MA (reprint author), NCI, Pathol Lab, Pathogenet Unit, 8717 Grovement Circle, Gaithersburg, MD 20877 USA. EM tangream@mail.nih.gov; wallisb@mial.nih.gov; jgill@mail.nih.gov; gannotg@pop.nci.nih.gov; buckm@mail.nih.gov; chuaquir@mail.nih.gov NR 58 TC 14 Z9 14 U1 0 U2 0 PU FUTURE DRUGS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEYY CENTRAL, LONDON N3 1QB, ENGLAND SN 1478-9450 J9 EXPERT REV PROTEOMIC JI Expert Rev. Proteomics PD AUG PY 2004 VL 1 IS 2 BP 185 EP 192 DI 10.1586/14789450.1.2.185 PG 8 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 939ZV UT WOS:000230114300006 PM 15966813 ER PT J AU Izzotti, A Cartiglia, C Longobardi, M Balansky, RM D'Agostini, F Lubet, RA De Flora, S AF Izzotti, A Cartiglia, C Longobardi, M Balansky, RM D'Agostini, F Lubet, RA De Flora, S TI Alterations of gene expression in skin and lung of mice exposed to light and cigarette smoke SO FASEB JOURNAL LA English DT Article DE environmental cigarette smoke; UV-containing light; multigene expression; cDNA array; hairless mice ID S-TRANSFERASE-P; HAIRLESS MICE; SULINDAC; CARCINOGENESIS; APOPTOSIS; MECHANISM; CELLS; KERATINOCYTES; MODULATION; ACTIVATION AB We previously showed that sunlight-mimicking light induces genotoxic damage not only in skin but also even in lung, bone marrow, and peripheral blood of hairless mice. Moreover, light and smoke acted synergically in the respiratory tract. To clarify the mechanisms involved, we investigated by cDNA-arrays the expression of 746 toxicologically relevant genes in skin and lungs of mice exposed for 28 days to light and/or environmental cigarette smoke. Glutathione-S- transferase-Pi and catalase were overexpressed in the lungs of mice exposed to light only. Moreover, the light induced in skin the expression of genes involved in carcinogenesis, photoaging, and production of genotoxic and oxidizing derivatives traveling at a distance. Smoke induced the expression of multiple genes in both skin and lung, which reflect adaptive responses and mechanisms related to cancer and, possibly, to emphysema and stroke. As shown in mice exposed to both light and smoke, the light tended to increase smoke-induced gene expression in lungs, while smoke tended to attenuate light-induced gene expression in skin. The oral administration of the nonsteroidal anti-inflammatory drug sulindac inhibited the light-induced overexpression of cyclooxygenase-2 and oxidative stress-related genes in skin, and down-regulated smoke-induced genes involved in oxidative stress, removal of damaged proteins, inflammation, and immune response in lung. These results provide a mechanistic insight explaining the systemic alterations induced by both light and smoke in mouse skin and lungs. C1 Univ Genoa, Dept Hlth Sci, I-16132 Genoa, Italy. NCI, Rockville, MD USA. Natl Oncol Ctr, Sofia 1756, Bulgaria. RP Univ Genoa, Dept Hlth Sci, Via A Pastore 1, I-16132 Genoa, Italy. EM sdf@unige.it OI izzotti, alberto/0000-0002-8588-0347 FU NCI NIH HHS [N01-CN-752008] NR 39 TC 43 Z9 46 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD AUG PY 2004 VL 18 IS 11 BP 1559 EP + DI 10.1096/fj.04-1877fje PG 26 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 849QN UT WOS:000223554900028 PM 15289447 ER PT J AU Block, ML Wu, X Pei, Z Li, G Wang, T Qin, L Wilson, B Yang, J Hong, JS Veronesi, B AF Block, ML Wu, X Pei, Z Li, G Wang, T Qin, L Wilson, B Yang, J Hong, JS Veronesi, B TI Nanometer size diesel exhaust particles are selectively toxic to dopaminergic neurons: the role of microglia, phagocytosis, and NADPH oxidase SO FASEB JOURNAL LA English DT Article DE dopaminergic neurotoxicity; oxidative stress; Parkinson's disease ID LIPOPOLYSACCHARIDE-INDUCED NEUROTOXICITY; ROTENONE-INDUCED DEGENERATION; BRONCHIAL EPITHELIAL-CELLS; PARKINSONS-DISEASE; IN-VITRO; PULMONARY INFLAMMATION; ACTIVATED MICROGLIA; TETRAZOLIUM SALT; RAT; DAMAGE AB The contributing role of environmental factors to the development of Parkinson's disease has become increasingly evident. We report that mesencephalic neuron-glia cultures treated with diesel exhaust particles (DEP; 0.22 muM) ( 5 - 50 mug/ml) resulted in a dose-dependent decrease in dopaminergic (DA) neurons, as determined by DA-uptake assay and tyrosine-hydroxylase immunocytochemistry (ICC). The selective toxicity of DEP for DA neurons was demonstrated by the lack of DEP effect on both GABA uptake and Neu-N immunoreactive cell number. The critical role of microglia was demonstrated by the failure of neuron-enriched cultures to exhibit DEP-induced DA neurotoxicity, where DEP-induced DA neuron death was reinstated with the addition of microglia to neuron-enriched cultures. OX-42 ICC staining of DEP treated neuronglia cultures revealed changes in microglia morphology indicative of activation. Intracellular reactive oxygen species and superoxide were produced from enriched-microglia cultures in response to DEP. Neuron-glia cultures from NADPH oxidase deficient (PHOX-/-) mice were insensitive to DEP neurotoxicity when compared with control mice (PHOX+/+). Cytochalasin D inhibited DEP-induced superoxide production in enriched-microglia cultures, implying that DEP must be phagocytized by microglia to produce superoxide. Together, these in vitro data indicate that DEP selectively damages DA neurons through the phagocytic activation of microglial NADPH oxidase and consequent oxidative insult. C1 NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. NIEHS, Div Neurotoxicol, Off Res & Dev, US EPA, Res Triangle Pk, NC 27709 USA. Dalian Med Univ, Dept Physiol, Dalian, Peoples R China. RP NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, MD F1-01,POB 12233, Res Triangle Pk, NC 27709 USA. EM Block@niehs.nih.gov NR 46 TC 158 Z9 166 U1 0 U2 14 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD AUG PY 2004 VL 18 IS 11 BP 1618 EP + DI 10.1096/fj.04-1945fje PG 22 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 849QN UT WOS:000223554900004 PM 15319363 ER PT J AU Brinton, LA Lamb, EJ Moghissi, KS Scoccia, B Althuis, MD Mabie, JE Westhoff, CL AF Brinton, LA Lamb, EJ Moghissi, KS Scoccia, B Althuis, MD Mabie, JE Westhoff, CL TI Ovarian cancer risk associated with varying causes of infertility SO FERTILITY AND STERILITY LA English DT Article; Proceedings Paper CT 59th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 11-15, 2003 CL SAN ANTONIO, TX SP Amer Soc Reproduct Med DE ovarian cancer; risk; epidemiology; infertility; endometriosis; anovulation ID TUBAL-LIGATION; ATYPICAL ENDOMETRIOSIS; FEMALE INFERTILITY; FERTILITY DRUGS; WOMEN; HYSTERECTOMY; COHORT; CARCINOMA; TUMORS; INFLAMMATION AB Objective: To evaluate the risk of ovarian cancer as related to underlying causes of infertility. Design: Retrospective observational cohort study. Setting: Five large reproductive endocrinology practices. Patient(s): A total of 12,193 women evaluated for infertility between 1965 and 1988. Intervention(s): None. Main Outcome Measure(s): Ovarian cancer ascertained through 1999. Result(s): With 45 identified ovarian cancers, this cohort of infertility patients demonstrated a significantly higher rate of ovarian cancer than the general female population (standardized incidence ratio [SIR] = 1.98; 95% confidence interval [CI], 1.4-2.6). The risk was higher for patients with primary infertility (SIR = 2.73) than for those with secondary infertility (SIR = 1.44), and it was particularly high for patients who never subsequently conceived (SIR = 3.33). Women with endometriosis had the highest risk (SIR = 2.48; 95% Cl, 1.3-4.2), with a further elevated risk among those with primary infertility (4.19, 2.0-7.7). Comparisons among the infertile women, which allowed calculation of rate ratios (RRs) after adjustment for multiple factors, also showed links with endometriosis. Compared with women with secondary infertility without endometriosis, patients with primary infertility and endometriosis had a RR of 2.72 (95% Cl, 1.1-6.7). Conclusion(s): Determination of ovarian cancer risk should take into account the type of infertility (primary vs. secondary) and underlying causes. Further study of endometriosis may provide insights into ovarian carcinogenesis. C1 NCI, Hormonal & Reprod Epidemiol Branch, Rockville, MD 20852 USA. Stanford Univ, Dept Obstet & Gynecol, Stanford, CA 94305 USA. Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48202 USA. Univ Illinois, Dept Obstet & Gynecol, Chicago, IL 60680 USA. Informat Management Serv Inc, Rockville, MD USA. Columbia Univ, Dept Obstet & Gynecol, New York, NY 10027 USA. RP Brinton, LA (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, 6120 Execut Blvd,Room 7068, Rockville, MD 20852 USA. EM Brinton@nih.gov RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 41 TC 109 Z9 113 U1 0 U2 3 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 AUG PY 2004 VL 82 IS 2 BP 405 EP 414 DI 10.1016/j.fertnstert.2004.02.109 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 845RW UT WOS:000223263000024 PM 15302291 ER PT J AU Voutetakis, A Sertedaki, A Livadas, S Maniati-Christidi, M Mademtzis, I Bossis, I Dacou-Voutetakis, C Messinis, IE AF Voutetakis, A Sertedaki, A Livadas, S Maniati-Christidi, M Mademtzis, I Bossis, I Dacou-Voutetakis, C Messinis, IE TI Ovulation induction and successful pregnancy outcome in two patients with Prop1 gene mutations SO FERTILITY AND STERILITY LA English DT Article DE combined pituitary hormone deficiency; growth hormone; ovulation; prolactin; Prop1 ID IN-VITRO FERTILIZATION; PITUITARY-HORMONE DEFICIENCY; BIOSYNTHETIC GROWTH-HORMONE; OVARIAN STIMULATION; POOR RESPONDER; WOMEN; GONADOTROPIN; PROLACTIN; SUBSTITUTION; COTREATMENT AB Objective: To describe ovulation induction and pregnancy outcome in a unique model of genetically determined combined pituitary hormone deficiency (CPHD), with respect to the necessity for GH substitution therapy. Design: Case report. Setting: Academic units. Patient(s): Two patients with childhood onset of CPHD (GH, PRL, TSH, LH, FSH) caused by a genetic defect (GA296del mutation) of the Prop1 gene. Main Outcome Measure(s): Ovulation, pregnancy outcome, and fetal growth. Result(s): Successful pregnancy outcome and delivery of normal, full-term newborns were achieved in both patients with the use of gonadotropins and L-T, Growth hormone supplementation was not necessary. No lactation was observed. Conclusion(s): Patients with Prop1 gene mutations constitute a unique model for studying the role of GH and PRL in ovulation, pregnancy, and fetal growth. Our data indicate that for women with CPHD, ovulation and pregnancy are possible with a classic regimen for hypogonadotropic hypogonadism, without the need for GH substitution therapy. (Fertil Steril((R)) 2004;82:454-7. (C) 2004 by American Society for Reproductive Medicine.). C1 Univ Athens, Sch Med, Dept Pediat 1, Aghia Sophia Childrens Hosp,Endocrine Unit, Goudi 11527, Athens, Greece. NIDR, NIH, Bethesda, MD 20892 USA. Univ Thessalia, Sch Med, Dept Obstet & Gynecol, Larisa, Greece. RP Dacou-Voutetakis, C (reprint author), Univ Athens, Sch Med, Dept Pediat 1, Aghia Sophia Childrens Hosp,Endocrine Unit, Goudi 11527, Athens, Greece. EM adacou@med.uoa.gr RI Bossis, Ioannis/J-6883-2012; OI Livadas, Sarantis/0000-0001-9594-1521 NR 32 TC 6 Z9 6 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 AUG PY 2004 VL 82 IS 2 BP 454 EP 457 DI 10.1016/j.fertnstert.2004.03.026 PG 4 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 845RW UT WOS:000223263000033 PM 15302300 ER PT J AU Armstrong, A Neithardt, AB Alvero, R Sharara, FI Bush, M Segars, J AF Armstrong, A Neithardt, AB Alvero, R Sharara, FI Bush, M Segars, J TI The role of fallopian tube anastomosis in training fellows: a survey of current reproductive endocrinology fellows and practitioners SO FERTILITY AND STERILITY LA English DT Editorial Material ID STERILIZATION AB This survey of fellows and reproductive endocrinologists in practice suggests that decreasing numbers of tubal reanastomosis procedures are being performed. This change has occurred both in fellow training and in the clinical practice of reproductive endocrinologists. C1 NICHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Univ Colorado, Hlth Sci Ctr, Aurora, CO USA. Virginia Ctr Reprod Med, Reston, VA USA. George Washington Univ, Washington, DC USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. RP Armstrong, A (reprint author), NICHD, Pediat & Reprod Endocrinol Branch, NIH, 10 Ctr Dr,Bldg 10,9D42, Bethesda, MD 20892 USA. EM armstroa@mail.nih.gov NR 8 TC 4 Z9 4 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 AUG PY 2004 VL 82 IS 2 BP 495 EP 497 DI 10.1016/j.fertnstert.2004.02.107 PG 3 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 845RW UT WOS:000223263000046 PM 15302313 ER PT J AU Schisterman, EF Whitcomb, BW AF Schisterman, EF Whitcomb, BW TI Measurement error! Communication between content experts and statisticians SO FERTILITY AND STERILITY LA English DT Letter ID CHOLESTEROL C1 NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. RP Schisterman, EF (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. OI Schisterman, Enrique/0000-0003-3757-641X NR 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 AUG PY 2004 VL 82 IS 2 BP 514 EP 515 DI 10.1016/j.fertnstert.2004.05.017 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 845RW UT WOS:000223263000053 PM 15302320 ER PT J AU Sokhansanj, BA Wilson, DM AF Sokhansanj, BA Wilson, DM TI Oxidative DNA damage background estimated by a system model of base excision repair SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE oxidative DNA damage; base excision repair; pathway modeling; simulation; free radicals ID PURIFIED HUMAN PROTEINS; MAMMALIAN-CELLS; COMET ASSAY; MITOCHONDRIAL; LESIONS; RECONSTITUTION; GLYCOSYLASES; ENDONUCLEASE; URACIL; SITES AB Human DNA can be damaged by natural metabolism through free radical production. It has been suggested that the equilibrium between innate damage and cellular DNA repair results in an oxidative DNA damage background that potentially contributes to disease and aging. Efforts to quantitatively characterize the human oxidative DNA damage background level, based on measuring 8-oxoguanine lesions as a biomarker, have led to estimates that vary over three to four orders of magnitude, depending on the method of measurement. We applied a previously developed and validated quantitative pathway model of human DNA base excision repair, integrating experimentally determined endogenous damage rates and model parameters from multiple sources. Our estimates of at most 100 8-oxoguanine lesions per cell are consistent with the low end of data from biochemical and cell biology experiments, a result robust to model limitations and parameter variation. Our findings show the power of quantitative system modeling to interpret composite experimental data and make biologically and physiologically relevant predictions for complex human DNA repair pathway mechanisms and capacity. (C) 2004 Elsevier Inc. All rights reserved. C1 Lawrence Livermore Natl Lab, Chem & Mat Sci Directorate, Livermore, CA 94500 USA. NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. RP Sokhansanj, BA (reprint author), Lawrence Livermore Natl Lab, Chem & Mat Sci Directorate, 7000 E Ave, Livermore, CA 94500 USA. EM sokhansanj@llnl.gov NR 33 TC 15 Z9 15 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD AUG 1 PY 2004 VL 37 IS 3 BP 422 EP 427 DI 10.1016/j.freeradbiomed.2004.05.003 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 838VG UT WOS:000222740800014 PM 15223076 ER PT J AU Caplen, NJ AF Caplen, NJ TI Gene therapy progress and prospects. Downregulating gene expression: the impact of RNA interference SO GENE THERAPY LA English DT Review DE RNA interference (RNAi); gene silencing; short (small) interfering RNAs (siRNAs) ID TRANSMEMBRANE PROTEIN SID-1; CULTURED-MAMMALIAN-CELLS; C-ELEGANS; ANTISENSE OLIGONUCLEOTIDES; STABLE SUPPRESSION; TRANSGENIC MICE; ENZYME COMPLEX; FISSION YEAST; HAIRPIN RNAS; GERM-LINE AB The control and maintenance of gene expression is critical for cell development and differentiation. Over the last 2 years, our understanding of the role of RNA as a regulator of gene expression has significantly increased. Small RNA molecules are key elements of a machinery that trigger chromosomal modifications, post-transcriptional gene silencing and protein translational blockade depending on the source, the RNA and the nature of the interaction with the target nucleic acid. Currently, the best characterized of this group of RNA-mediated gene regulation pathways is the post-transcriptional gene silencing mechanism known as RNA interference. RNAi is triggered by double-stranded RNA (dsRNA), which induces the formation of a ribonucleoprotein complex that mediates sequence-specific cleavage of the transcript cognate with the input dsRNA. RNAi has been adapted as a functional genomics tool and it has potential as a therapeutic approach. This review will summarize our current understanding of the RNAi mechanism and the various applications of RNAi-based technologies. C1 NCI, Gene Silencing Sect, Off Sci & Technol Partnerships, Off Director,Ctr Canc Res, Bethesda, MD 20892 USA. RP Caplen, NJ (reprint author), NCI, Gene Silencing Sect, Off Sci & Technol Partnerships, Off Director,Ctr Canc Res, Bldg 37,Room 3128B, Bethesda, MD 20892 USA. RI Caplen, Natasha/H-2768-2016 OI Caplen, Natasha/0000-0002-0001-9460 NR 82 TC 87 Z9 113 U1 2 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD AUG PY 2004 VL 11 IS 16 BP 1241 EP 1248 DI 10.1038/sj.gt.3302324 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 843GR UT WOS:000223067100001 PM 15292914 ER PT J AU Kavaliers, M Agmo, A Choleris, E Gustafsson, JA Korach, KS Muglia, LJ Pfaff, DW Ogawa, S AF Kavaliers, M Agmo, A Choleris, E Gustafsson, JA Korach, KS Muglia, LJ Pfaff, DW Ogawa, S TI Oxytocin and estrogen receptor alpha and beta knockout mice provide SO GENES BRAIN AND BEHAVIOR LA English DT Article DE analgesia; avoidance; mate choice; odor choice; social behavior; social recognition ID MAJOR HISTOCOMPATIBILITY COMPLEX; PARAVENTRICULAR NUCLEUS; SOCIAL RECOGNITION; FEMALE MICE; URINARY PROTEINS; SEXUAL-BEHAVIOR; GENE DISRUPTION; STRESS; MOUSE; DISCRIMINATION AB Social behavior involves both the recognition and production of social cues. Mice with selective deletion (knockout) of either the gene for oxytocin (OT) or genes for the estrogen receptor (ER) -alpha or -beta display impaired social recognition. In this study we demonstrate that these gene knockout mice also provide discriminably different social stimuli in behavioral assays. In an odor choice test, which is a measure of social interest and discrimination, outbred female Swiss-Webster mice discriminated the urine odors of male knockouts (KO: OTKO, alphaERKO, betaERKO) from the odors of their wildtype littermates (WT: OTWT, alphaERWT, betaERWT). Females showed marked initial choices of the urine odors of OTWT and betaERWT males over those of OTKO and betaERKO males, and alphaERKO males over aERWT males. The odors of OTKO and betaERKO males also induced aversive, analgesic responses, with the odors of WTs having no significant effects. Odors of both the alphaERWT and alphaERKO males induced aversive, analgesic responses, with the odors of the WT inducing significantly greater analgesia. The odors of restraint stressed WT and KO males also elicited analgesia with, again, females displaying significantly greater responses to the odors of stressed OTKO and betaERKO males than their WTs, and significantly lower analgesia to the odors of stressed alphaERKO than alphaERWT males. These findings show that the KO mice are discriminated from their WTs on the basis of odor and that the various KOs differ in the relative attractiveness/aversiveness of their odors. Therefore, in behavioral assays one causal route by which gene inactivation alters the social behavior of knockout mice may be mediated through the partners' modified responses to their odors. C1 Univ Western Ontario, Dept Psychol, London, ON N6A 5C2, Canada. Rockefeller Univ, Neurobiol & Behav Lab, New York, NY 10021 USA. Univ Tromso, Dept Psychol, Tromso, Norway. Univ Guelph, Dept Psychol, Guelph, ON N1G 2W1, Canada. Karolinska Inst, Dept Med Nutr, Huddinge, Sweden. Natl Inst Environm Hlth Sci, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC USA. Washington Univ, Dept Pediat, St Louis, MO USA. RP Kavaliers, M (reprint author), Univ Western Ontario, Dept Psychol, London, ON N6A 5C2, Canada. EM kavalier@uwo.ca FU NIMH NIH HHS [MH36273, MH62147] NR 56 TC 24 Z9 24 U1 0 U2 4 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1601-1848 J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD AUG PY 2004 VL 3 IS 4 BP 189 EP 195 DI 10.1111/j.1601-183x.2004.00068.x PG 7 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 843OI UT WOS:000223092800001 PM 15307217 ER PT J AU Huang, ZX Desper, R Schaffer, AA Yin, ZH Li, X Yao, KT AF Huang, ZX Desper, R Schaffer, AA Yin, ZH Li, X Yao, KT TI Construction of tree models for pathogenesis of nasopharyngeal carcinoma SO GENES CHROMOSOMES & CANCER LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; COPY NUMBER CHANGES; SOLID TUMORS; PROMOTER HYPERMETHYLATION; ABNORMAL EXPRESSION; GENETIC ALTERATIONS; PHYLOGENETIC TREES; CELL CARCINOMA; SHORT ARM; CANCER AB Pathogenesis of nasopharyngeal carcinoma (NPC) is a multistep and multipathway process that cannot be fully explained by a fixed linear progression model. We used distance-based and branching-tree methods to construct more general tree-like models for NPC carcinogenesis from 170 comparative genomic hybridization (CGH) samples previously published in five smaller studies. Imbalances were classified into "overlap regions," each containing the most commonly gained or lost band on each chromosome arm as well as adjacent bands that were gained or lost almost as often. The chromosome abnormalities associated With NPC were -3p26-13 (48.9%), - 11q22-25 (38.1%), - 16q12-24 (38.1%), - 14q24-32 (32.4%), - 13q21-32 (22.3%), -9p23-21(21.6%), +12p12 (46%), +12q13-15 (43.9%), +1q22-32 (33.1%), +3q13.1-26.2 (30.2%), and +8q22.1-24.2 (27.3%). NPC can be classified into two groups, one marked by +12p12 and +8q22.1-24.2 and the other by -3p26-13, -11q22-25, -14q24-32, And +1q22-32. The tree models predicted -3p26-13 and +12p12 as early events and +8q22.1-24.2 as a late event. The predictions for -3p26-13 and +8q22.1-24.2 were consistent with previous studies. The prediction for +12p12 is being reported for the first time. Many known NPC-related genes on chromosomal regions of these tree models are discussed, some of which may merit additional study. The potential applications of tree models are also discussed. Published 2004 Wiley-Liss, Inc.(dagger) C1 First Mil Med Univ, Inst Canc, Dept Pathol, Guangzhou 510515, Peoples R China. Natl Inst Hlth, Natl Ctr Biotechnol Informat, Dept Hlth & Human Serv, Computat Biol Branch, Bethesda, MD USA. Cent S Univ, Inst Canc, Changsha, Peoples R China. RP Yao, KT (reprint author), First Mil Med Univ, Inst Canc, Dept Pathol, Guangzhou 510515, Peoples R China. EM schaffer@helix.nih.gov; ktyao@fimmu.com RI Schaffer, Alejandro/F-2902-2012 NR 62 TC 24 Z9 32 U1 1 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD AUG PY 2004 VL 40 IS 4 BP 307 EP 315 DI 10.1002/gcc.20036 PG 9 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 835EA UT WOS:000222461900004 PM 15188453 ER PT J AU Kearns, WG Yamaguchi, H Young, NS Liu, JM AF Kearns, WG Yamaguchi, H Young, NS Liu, JM TI Centrosome amplification and aneuploidy in bone marrow failure patients SO GENES CHROMOSOMES & CANCER LA English DT Article ID CHROMOSOME INSTABILITY; CHECKPOINT GENES; APLASTIC-ANEMIA; CELL-CYCLE; CANCER; ABERRATIONS AB Patients with bone marrow failure are at risk for development of hematopoietic progenitor clones with abnormal numbers of chromosomes (aneuploidy) and leukemia. Numerical centrosome abnormalities or mutations in genes associated with the mitotic spindle checkpoint (BUB1 and MAD2) are two important mechanisms that can induce abnormal mitosis resulting in aneuploid daughter cells. To assess the role of these mechanisms, we used fluorescence in situ hybridization techniques to determine aneuploidy and centrosome copy number and PCR-SSCP to identify gene mutations of BUB1 and MAD2 in marrow cells of 25 patients. No mutations were found in BUB1 or MAD2 genes. However, we found that cells with more than two centrosomes exhibited aneuploidy for three or more chromosomes. We conclude that centrosome amplification may be associated with the development of a clonal population of potentially preleukemic aneuploid cells. (C) 2004 Wiley-Liss, Inc. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Liu, JM (reprint author), Mt Sinai Sch Med, Div Hematol Oncol, 1 Gustave L Levy Pl,Box 1079, New York, NY 10029 USA. EM Johnson.Liu@mssm.edu NR 23 TC 12 Z9 13 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD AUG PY 2004 VL 40 IS 4 BP 329 EP 333 DI 10.1002/gcc.20043 PG 5 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 835EA UT WOS:000222461900007 PM 15188456 ER PT J AU Semsey, S Tolstorukov, MY Virnik, K Zhurkin, VB Adhya, S AF Semsey, S Tolstorukov, MY Virnik, K Zhurkin, VB Adhya, S TI DNA trajectory in the Ga1 repressosome SO GENES & DEVELOPMENT LA English DT Article DE Gal repressor; transcription regulation; DNA loop; oriented heterodimers; operators; HU ID TRANSCRIPTION ACTIVATOR PROTEIN; INTEGRATION HOST FACTOR; MUTANT LAC REPRESSORS; FUNCTIONAL SUBUNIT; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; RNA-POLYMERASE; PROMOTER; GALR; HU AB The Gal repressosome is a higher-order nucleoprotein complex that represses transcription of the gal operon in Escherichia coli. During the repressosome assembly, a DNA loop is formed by the interaction of two GaIR dimers, bound to two spatially separated operators, 0, and 0, flanking the gal promoters. Structure-based genetic analysis indicated that GaIR homodimers interact directly and form a V-shaped stacked tetramer in repressosome, further stabilized by HU binding to an architecturally critical position on the DNA. In this scheme of GaIR tetramerization, the alignment of the operators in the DNA loop could be in either parallel (PL) or antiparallel (AL) mode. As each mode can have two alternative geometries differing in the mutual stacking of the O-E- and O-I- bound GAR dimers, it is possible to have four different DNA trajectories in the repressosome. Feasibilities of these trajectories were tested by in vitro transcription repression assays, first by isolating GAR mutants with altered operator specificity and then by constructing four different potential loops with mutant GaIR heterodimers bound to specifically designed hybrid operators in such a way as to give rise to only one of the four putative trajectories. Results show that 0, and 0, adopt a mutual antiparallel orientation in an under-twisted DNA loop, consistent with the energetically optimal structural model. in this structure the center of the HU-binding site is located at the apex of the DNA loop. The approach reported here can be used to distinguish between otherwise indistinguishable DNA trajectories in complex nucleoprotein machines. C1 NCI, Mol Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. NCI, Lab Expt & Computat Biol, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Adhya, S (reprint author), NCI, Mol Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. EM adhyas@mai.nih.gov RI Semsey, Szabolcs/L-6329-2013 NR 41 TC 31 Z9 31 U1 0 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD AUG 1 PY 2004 VL 18 IS 15 BP 1898 EP 1907 DI 10.1101/gad.1209404 PG 10 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 843IZ UT WOS:000223073500011 PM 15289461 ER PT J AU Klar, AJS AF Klar, AJS TI A genetic mechanism implicates chromosome 11 in schizophrenia and bipolar diseases SO GENETICS LA English DT Article ID GENOME SCAN METAANALYSIS; AFFECTIVE-DISORDER; TRANSLOCATION PROVIDES; IDENTIFICATION; REPLICATION; ASSOCIATION; ABERRATIONS; HANDEDNESS; ASYMMETRY; PSYCHOSIS AB The causes of schizophrenia and bipolar human psychiatric disorders are unknown. A novel somatic cell genetic model Postulated nonrandom segregation of "Watson" vs. "Crick" DNA chains of both copies of a chromosome to specific daughter cells. Such an oriented asymmetric cell division causes development of healthy, functionally nonequivalent brain hemispheres. Genetic translocations of the chromosome may cause disease by disrupting the biased strand-segregation process. Only one-half of chromosome 1 and 11 translocation carriers developing disease were recently explained as a result consistent with the model (KLAR 2002). Is chromosome 1 or 11 involved? Does the translocation breakpoint cause disease? Remarkably, two other unrelated chromosome 11 translocations discovered from the literature likewise caused disease in similar to50% of carriers. Together, their breakpoints lie at three distinct regions spanning similar to40% of chromosome 11. Thus, chromosome 11 is implicated but the breakpoints themselves are unlikely to cause the disease. The results suggest that the genetically caused disease develops without a Mendelian gene mutation. C1 Natl Canc Inst, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. RP Klar, AJS (reprint author), Natl Canc Inst, Lab Eukaryot Gene Express, POB B, Frederick, MD 21702 USA. EM klar@ncifcrf.gov NR 33 TC 26 Z9 26 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 AUG PY 2004 VL 167 IS 4 BP 1833 EP 1840 DI 10.1554/genetics.104.028217 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 851XR UT WOS:000223720300027 PM 15342521 ER PT J AU Klar, AJS AF Klar, AJS TI Cornmentaxy on Klar - Reponse SO GENETICS LA English DT Letter C1 NCI, Gene Regulat & Chromosome Biol Lab, Canc Res Facil, Frederick, MD 21701 USA. RP Klar, AJS (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, Canc Res Facil, 7th St,Bldg 539, Frederick, MD 21701 USA. EM klari@ncifcrf.gov NR 3 TC 3 Z9 3 U1 0 U2 0 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD AUG PY 2004 VL 167 IS 4 BP 2141 EP 2142 DI 10.1534/genetics.104.031708 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 851XR UT WOS:000223720300055 ER PT J AU FitzGerald, PC Shlyakhtenko, A Mir, AA Vinson, C AF FitzGerald, PC Shlyakhtenko, A Mir, AA Vinson, C TI Clustering of DNA sequences in human promoters SO GENOME RESEARCH LA English DT Article ID FACTOR NF-Y; TRANSCRIPTION FACTOR; TATA-BOX; MOLECULAR-BIOLOGY; CRYSTAL-STRUCTURE; FACTOR CREB; BINDING; COMPLEX; PROTEINS; SPECIFICITY AB We have determined the distribution of each of the 65,536 DNA sequences that are eight bases long (8-mer) in a set of 13,010 human genomic promoter sequences aligned relative to the putative transcription start site (TSS). A limited number of 8-mers have peaks in their distribution (cluster), and most cluster within 100 by of the TSS. The 156 DNA sequences exhibiting the greatest statistically significant clustering near the TSS can be placed into nine groups of related sequences. Each group is defined by a consensus sequence, and seven of these consensus sequences are known binding sites for the transcription factors (TFs) SPI, NF-Y, ETS, CREB, TBP, USF, and NRF-1. One sequence, which we named Clusl, is not a known TF binding site. The ninth sequence group is composed of the strand-specific Kozak sequence that clusters downstream of the TSS. An examination of the co-occurrence of these TF consensus sequences indicates a positive correlation for most of them except for sequences bound by TBP (the TATA box). Human mRNA expression data from 29 tissues indicate that the ETS, NRF-1, and Clusl sequences that cluster are predominantly found in the promoters of housekeeping genes (e.g., ribosomal genes). In contrast, TATA is more abundant in the promoters of tissue-specific genes. This analysis identified eight DNA sequences in 5082 promoters that we suggest are important for regulating gene expression. C1 NCI, Genome Anal Unit, NIH, Bethesda, MD 20892 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Vinson, C (reprint author), NCI, Genome Anal Unit, NIH, Bethesda, MD 20892 USA. EM Vinsonc@dc37a.nci.nih.gov NR 40 TC 128 Z9 135 U1 1 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD AUG PY 2004 VL 14 IS 8 BP 1562 EP 1574 DI 10.1101/gr.1953904 PG 13 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 843OG UT WOS:000223092600012 PM 15256515 ER PT J AU Mazzanti, CM Tandle, A Lorang, D Costouros, N Roberts, D Bevilacqua, G Libutti, SK AF Mazzanti, CM Tandle, A Lorang, D Costouros, N Roberts, D Bevilacqua, G Libutti, SK TI Early genetic mechanisms underlying the inhibitory effects of endostatin and fumagillin on human endothelial cells SO GENOME RESEARCH LA English DT Article ID TUMOR-GROWTH; ANGIOGENESIS INHIBITORS; METHIONINE AMINOPEPTIDASE; CANCER; EXPRESSION; ANALOGS; TARGET; AMPLIFICATION; METASTASES; THERAPY AB A tumor needs to initiate angiogenesis in order to develop its own blood supply, to grow, to invade, and to spread. Angiogenesis, under normal conditions, is a tightly regulated balance between endogenous pro- and antiangiogenic factors. In this study, we investigated, by microarray analysis, the effects of two known antiangiogenic agents (endostatin and fumagillin) Oil the gene expression profiles Of human umbilical vein endothelial cells (HUVEC) ill order to elucidate pathways common to the effects of these agents. We observed a majority of gene expression changes within I and 2 h of treatment. The genes demonstrating these early expression changes are involved in cell proliferation, gene transcription, and a number have unknown functions. We selected four genes (DOC1, KLF4, TC-1, ID1) from the microarray profile that showed a similar pattern of expression for both of the antiangiogenic agents we tested. We then used small interfering RNAs (siRNA) in an attempt to better understand the role of these selected genes in the inhibitory activity of these agents. Because the gene expression changes Occurred within I and 2 h of treatment, these genes might be involved in the initial pathways of angiogenesis inhibition. C1 NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Univ Pisa, Dept Oncol, Div Surg Mol & Ultrastruct Pathol, I-56127 Pisa, Italy. Univ Hosp, I-56127 Pisa, Italy. RP Libutti, SK (reprint author), NCI, Surg Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM Steven_Libutti@nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 NR 39 TC 36 Z9 36 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD AUG PY 2004 VL 14 IS 8 BP 1585 EP 1593 DI 10.1101/gr.2552804 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 843OG UT WOS:000223092600014 PM 15289477 ER PT J AU Mukhopadhyay, R Yu, WQ Whitehead, J Xu, JW Lezcano, M Pack, S Kanduri, C Kanduri, M Ginjala, V Vostrov, A Quitschke, W Chernukhin, I Klenova, E Lobanenkov, V Ohlsson, R AF Mukhopadhyay, R Yu, WQ Whitehead, J Xu, JW Lezcano, M Pack, S Kanduri, C Kanduri, M Ginjala, V Vostrov, A Quitschke, W Chernukhin, I Klenova, E Lobanenkov, V Ohlsson, R TI The binding sites for the chromatin insulator protein CTCF map to DNA methylation-free domains genome-wide SO GENOME RESEARCH LA English DT Article ID IMPRINTING CONTROL REGION; GENE; PROMOTER; LOCUS; H19; EPIGENETICS; EXPRESSION; PARENT AB All known vertebrate chromatin insulators interact with the highly conserved, multivalent II-zinc finger nuclear factor CTCF to demarcate expression domains by blocking enhancer or silencer signals in a position-dependent manner. Recent observations document that the properties of CTCF include reading and propagating the epigenetic state of the differentially methylated H19 imprinting control region. To assess whether these findings may reflect a universal role for CTCF targets, we identified more than 200 new CTCF target sites by generating DNA microarrays of clones derived from chromatin-immunopurified (ChIP) DNA followed by ChIP-on-chip hybridization analysis. Target sites include not only known loci involved in multiple cellular functions, Such as metabolism, neurogenesis, growth, apoptosis, and signalling, but potentially also heterochromatic sequences. Using a novel insulator trapping assay, we also show that the majority of these targets manifest insulator functions with a continuous distribution of stringency. As these targets are generally DNA methylation-free as determined by antibodies against 5-methylcytidine and a methyl-binding protein (MBD2), a CTCF-based network correlates with genome-wide epigenetic states. C1 Uppsala Univ, Evolut Biol Ctr, Dept Genet & Dev, S-75236 Uppsala, Sweden. NIAID, Mol Pathol Sect, Immunopathol Lab, NIH, Bethesda, MD 20892 USA. SUNY Stony Brook, Dept Psychiat & Behav Sci, Stony Brook, NY 11794 USA. Univ Essex, Dept Biol Sci, Colchester CO4 3SQ, Essex, England. RP Ohlsson, R (reprint author), Uppsala Univ, Evolut Biol Ctr, Dept Genet & Dev, Norbyvagen 18A, S-75236 Uppsala, Sweden. EM rolf.ohlsson@ebc.uu.se RI Whitehead, Joanne/A-8597-2008; Pack, Svetlana/C-2020-2014 OI Whitehead, Joanne/0000-0002-9602-2081; NR 24 TC 100 Z9 105 U1 0 U2 6 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD AUG PY 2004 VL 14 IS 8 BP 1594 EP 1602 DI 10.1101/gr.2408304 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 843OG UT WOS:000223092600015 PM 15256511 ER PT J AU Ogurtsov, AY Sunyaev, S Kondrashov, AS AF Ogurtsov, AY Sunyaev, S Kondrashov, AS TI Indel-based evolutionary distance and mouse-human divergence SO GENOME RESEARCH LA English DT Article ID PHYLOGENETIC ANALYSIS; MAMMALIAN GENOMES; SEQUENCE; GENES; CHIMPANZEE; PATTERNS; SAMPLES; REGIONS; RATES AB We propose a method for estimating the evolutionary distance between DNA sequences in terms of insertions and deletions (indels), defined as the per site number of indels accumulated in the course of divergence of the two sequences. We derive a maximal likelihood estimate of this distance from differences between lengths of orthologous introns or other segments Of Sequences delimited by conservative markers. When indels accumulate, lengths of orthologous introns diverge only slightly slower than linearly, because long indels occur with substantial frequencies. Thus, saturation is not a major obstacle for estimating indel-based evolutionary distance. For introns of medium lengths, our method recovers the known evolutionary distance between rat and mouse, 0.014 indels per site, with good precision. We estimate that mouse-human divergence exceeds rat-mouse divergence by a factor of 4, so that mouse-human evolutionary distance in terms of selectively neutral indels is 0.056. Because in mammals, indels are similar to14 times less frequent than nucleotide substitutions, mouse-human evolutionary distance in terms of selectively neutral Substitutions is similar to0.8. C1 NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Kondrashov, AS (reprint author), NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. EM kondrashov@ncbi.nlm.nih.gov NR 22 TC 38 Z9 38 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD AUG PY 2004 VL 14 IS 8 BP 1610 EP 1616 DI 10.1101/gr.2450504 PG 7 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 843OG UT WOS:000223092600017 PM 15289479 ER PT J AU Goh, SH Jackson, KA Lee, YT Miller, JL AF Goh, SH Jackson, KA Lee, YT Miller, JL TI Identification of an alternate delta-globin mRNA in adult human erythroid cells SO GENOMICS LA English DT Article ID INTERGENIC TRANSCRIPTION; GENE-EXPRESSION; UPSTREAM; LOCUS; SITE AB Here we describe the identification and characterization of an alternate delta-globin mRNA (Alt-d) discovered during high-throughput sequencing of mRNA from adult human erythroid cells. Alt-d mRNA shares the same coding region, splicing pattern, downstream untranslated region, and site of polyadenylation with the previously defined delta-globin (Delta) mRNA. Alt-d mRNA encodes an additional 145 nt in the upstream untranslated region, suggesting an alternative site of transcriptional initiation and transcription through the previously defined promoter, which contains several protein-binding motifs and a TATA box. Northern blot and PCR analyses demonstrated a restricted expression of Alt-d in fetal liver, bone marrow, and adult reticulocytes. Quantitative PCR demonstrated an Alt-d expression pattern similar to that of the Delta transcripts. In addition to intergenic RNA species and the dominant delta-globin transcripts, these data suggest that a third form of RNA is produced from low-level transcription through the delta-globin gene promoter. (C) 2004 Elsevier Inc. All rights reserved. C1 NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. RP Miller, JL (reprint author), NIDDKD, Biol Chem Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jm7f@nih.gov NR 16 TC 2 Z9 2 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD AUG PY 2004 VL 84 IS 2 BP 431 EP 434 DI 10.1016/j.ygeno.2004.04.009 PG 4 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 837UA UT WOS:000222665200018 PM 15234005 ER PT J AU Lebowitz, BD AF Lebowitz, BD TI Clinical trials in late life: New science in old paradigms SO GERONTOLOGIST LA English DT Editorial Material DE clinical trials; Alzheimer's disease; depression; methodology ID RANDOMIZED CONTROLLED-TRIAL; ALZHEIMER-DISEASE; DIAGNOSTIC-CRITERIA; PRIMARY-CARE; DOUBLE-BLIND; HUMAN-GENOME; BEHAVIORAL SYMPTOMS; ELDERLY OUTPATIENTS; MAJOR DEPRESSION; PLACEBO AB This article, based on a Lawton Award Lecture, addresses the subject of the need to enhance the evidence base in our field in order to influence processes of policy development. Four issues are identified as critical to this: theory-driven targets of public health significance, use of appropriate and sophisticated approaches to research design and statistical modeling, development of instruments and measures, and conclusions that make a difference. Incentives are discussed with particular attention to regulatory approaches. A broad view of research is taken, with examples from studies of Alzheimer's disease and depression in late life. I conclude that new approaches to methodology will enhance our capacity to translate exciting new findings from the basic sciences into the development of therapeutics and that this will, in turn, enhance our capacity to inform the development of public policy. C1 NIMH, Bethesda, MD 20892 USA. RP Lebowitz, BD (reprint author), NIMH, 6001 Execut Blvd,Rm 7160,MSC 9635, Bethesda, MD 20892 USA. EM blebowit@mail.nih.gov NR 58 TC 11 Z9 11 U1 4 U2 4 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD AUG PY 2004 VL 44 IS 4 BP 452 EP 458 PG 7 WC Gerontology SC Geriatrics & Gerontology GA 850EZ UT WOS:000223595300001 PM 15331802 ER PT J AU Marafioti, T Mancini, C Ascani, S Sabattini, E Zinzani, PL Pozzobon, M Pulford, K Falini, B Jaffe, ES Muller-Hermelink, HK Mason, DY Pileri, SA AF Marafioti, T Mancini, C Ascani, S Sabattini, E Zinzani, PL Pozzobon, M Pulford, K Falini, B Jaffe, ES Muller-Hermelink, HK Mason, DY Pileri, SA TI Leukocyte-specific phosphoprotein-1 and PU.1: two useful markers for distinguishing T-cell-rich B-cell lymphoma from lymphocyte-predominant Hodgkin's disease SO HAEMATOLOGICA LA English DT Article DE T-cell-rich B-cell lymphoma; lymphocyte-predominant Hodgkin's disease; lymphocyte-rich classical Hodgkin's disease; LSP1; PU.1; phenotype; diagnosis ID DISTINCT CLINICOPATHOLOGICAL ENTITY; DIFFERENTIAL-DIAGNOSIS; HISTIOCYTE-RICH; LSP1; IMMUNOGLOBULIN; EXPRESSION; TRANSCRIPTION; POPULATIONS; DERIVATION; PROTEIN-1 AB Background and Objectives. T-cell-rich B-cell lymphoma is a rare variant of diffuse large B-cell lymphoma. It shows morphologic, phenotypic and molecular similarities to lymphocyte predominant Hodgkin's disease, and in consequence the two diseases may sometimes be difficult to distinguish. In this paper, we have evaluated the usefulness of the pan-leukocyte marker LSP1 and the transcription factor PU.1 for resolving such diagnostic problems. Design and Methods. Immunohistochemical techniques were used to investigate the expression of LSP1 and PU.1 in 34 tumors, comprising typical examples of T-cell-rich B-cell lymphoma (15 cases), lymphocyte-predominant Hodgkin's disease (13 cases), and lymphocyte-rich classical Hodgkin's disease (6 cases). Results. The neoplastic cells of T-cell-rich B-cell lymphoma were LSP1-positive and PU.1-negative, whereas the lymphocytic and/or histiocytic (LEtH) cells of lymphocyte-predominant Hodgkin's disease were mostly LSP1-negative, with variable PU.1 expression. The two markers did not discriminate between T-cell-rich B-cell lymphoma and lymphocyte-rich classical Hodgkin's disease, whilst they concurred to the distinction between lymphocyte-predominant and lymphocyte-rich classical Hodgkin's disease by integrating the already available tools. Interpretation and Conclusions. Antibodies to LSP1 and PU.1 may represent useful reagents for the differential diagnosis between T-cell-rich B-cell lymphoma and lymphocyte-predominant Hodgkin's disease. C1 Univ Bologna, Inst Haematol & Clin Oncol L&A Seragnoli, Chair Pathol, I-40138 Bologna, Italy. Univ Bologna, Inst Haematol & Clin Oncol L&A Seragnoli, Unit Haematopathol, I-40138 Bologna, Italy. Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Lab Sci, Oxford OX3 9DU, England. John Radcliffe Hosp, Nuffield Dept Clin Lab Sci, Leukaemia Res Fund Immunodiagnost Unit, Oxford OX3 9DU, England. Univ Perugia, Monteluce Hosp, Dept Haematol, I-06100 Perugia, Italy. NCI, Pathol Lab, Bethesda, MD 20892 USA. Univ Wurzburg, Inst Pathol, D-8700 Wurzburg, Germany. RP Pileri, SA (reprint author), Univ Bologna, Inst Haematol L&A Seragnoli, Chair Pathol, Via Massarenti 9, I-40138 Bologna, Italy. EM pileri@med.unibo.it RI Marafioti, Teresa/B-4493-2009; Pulford, Karen/B-3609-2009; Zinzani, Pier Luigi/J-9182-2016 OI Pulford, Karen/0000-0002-2989-789X; Zinzani, Pier Luigi/0000-0002-2112-2651 NR 41 TC 20 Z9 20 U1 0 U2 1 PU FERRATA STORTI FOUNDATION PI PAVIA PA STRADA NUOVA 134, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD AUG PY 2004 VL 89 IS 8 BP 957 EP 964 PG 8 WC Hematology SC Hematology GA 843CP UT WOS:000223053500011 PM 15339679 ER PT J AU Srinivasan, S Dearry, A AF Srinivasan, S Dearry, A TI Environmental health promotion: Progress and future opportunities SO HEALTH EDUCATION & BEHAVIOR LA English DT Article ID PUBLIC-HEALTH C1 NIEHS, Div Extraumal Res & Training, Res Triangle Pk, NC 27709 USA. NIEHS, NIH, Bethesda, MD USA. RP Srinivasan, S (reprint author), NIEHS, Div Extraumal Res & Training, POB 12233,MD EC-21,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM ss688k@nih.gov NR 12 TC 3 Z9 3 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1090-1981 J9 HEALTH EDUC BEHAV JI Health Educ. Behav. PD AUG PY 2004 VL 31 IS 4 BP 526 EP 530 DI 10.1177/1090198104265603 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 839WR UT WOS:000222816100007 PM 15296633 ER PT J AU Gao, B Hong, F Radaeva, S AF Gao, B Hong, F Radaeva, S TI Cholestasis and failure of interferon-alpha treatment - Reply SO HEPATOLOGY LA English DT Letter ID HEPATITIS-C; BILE-ACIDS; THERAPY C1 NIAAA, Sect Liver Biol, NIH, Bethesda, MD USA. RP Gao, B (reprint author), NIAAA, Sect Liver Biol, NIH, Bethesda, MD USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD AUG PY 2004 VL 40 IS 2 BP 499 EP 499 DI 10.1002/hep.20355 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 848AN UT WOS:000223439400029 ER PT J AU Xu, JF Langefeld, CD Zheng, SL Gillanders, EM Chang, BL Isaacs, SD Williams, AH Wiley, KE Dimitrov, L Meyers, DA Walsh, PC Trent, JM Isaacs, WB AF Xu, JF Langefeld, CD Zheng, SL Gillanders, EM Chang, BL Isaacs, SD Williams, AH Wiley, KE Dimitrov, L Meyers, DA Walsh, PC Trent, JM Isaacs, WB TI Interaction effect of PTEN and CDKN1B chromosomal regions on prostate cancer linkage SO HUMAN GENETICS LA English DT Article ID TUMOR-SUPPRESSOR; P27(KIP1); GENE; PTEN/MMAC1; TESTS; IDENTIFICATION; SUSCEPTIBILITY; PROGRESSION; MUTATION; MICE AB The tumor suppressor functions of PTEN and CDKN1B have been extensively characterized. Recent data from mouse models suggest that, for some organs, the combined action of both PTEN and CDKN1B has a stronger tumor suppressor function than each alone; for the prostate, heterozygous knockout of both genes leads to 100% penetrance for prostate cancer. To assess whether such an interaction contributes to an increased risk of prostate cancer in humans, we performed a series of epistatic PTEN and CDKN1B interaction analyses in a collection of 188 high-risk hereditary prostate cancer families. Two different analytical approaches were performed; a nonparametric linkage (NPL) regression analysis that simultaneously models allele sharing at these two regions in all families, and an ordered subset analysis (OSA) that assesses linkage evidence at a target region in a subset of families based on the magnitude of allele sharing at the reference region. The strongest evidence of interaction effect was observed at 10q23-24 and 12p11-13 from both the NPL regression analysis (P=0.0002) in all families and the OSA analyses in subsets of families. A LOD-delta of 3.15 (P=0.01) was observed at 10q23-24 among 54 families with the highest NPL scores at 12p11-13, and a LOD-delta of 2.63 (P=0.02) was observed at 12p11-13 among 34 families with the highest NPL scores at 10q23-24. The evidence for the interaction was stronger when using additional fine-mapping markers in the PTEN (10q23) and CDKN1B (12p13) regions. Our data are consistent with epistatic interactions between the PTEN and CDKN1B genes affecting risk for prostate cancer and demonstrate the utility of modeling epistatic effects in linkage analysis to detect susceptibility genes of complex diseases. C1 Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth, Winston Salem, NC 27103 USA. Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Genom, Winston Salem, NC 27157 USA. NHGRI, NIH, Bethesda, MD USA. Johns Hopkins Med Inst, Dept Urol, Baltimore, MD USA. Translat Genom Res Inst, Phoenix, AZ USA. RP Xu, JF (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth, Winston Salem, NC 27103 USA. EM jxu@wfubmc.edu FU NCI NIH HHS [CA095052, CA58236] NR 29 TC 17 Z9 17 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD AUG PY 2004 VL 115 IS 3 BP 255 EP 262 DI 10.1007/s00439-004-1144-4 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 840MX UT WOS:000222864100011 PM 15185141 ER PT J AU Schilling, G Savonenko, AV Klevytska, A Morton, JL Tucker, SM Poirier, M Gale, A Chan, N Gonzales, V Slunt, HH Coonfield, ML Jenkins, NA Copeland, NG Ross, CA Borchelt, DR AF Schilling, G Savonenko, AV Klevytska, A Morton, JL Tucker, SM Poirier, M Gale, A Chan, N Gonzales, V Slunt, HH Coonfield, ML Jenkins, NA Copeland, NG Ross, CA Borchelt, DR TI Nuclear-targeting of mutant huntingtin fragments produces Huntington's disease-like phenotypes in transgenic mice SO HUMAN MOLECULAR GENETICS LA English DT Article ID NEURONAL INTRANUCLEAR INCLUSIONS; CRE-MEDIATED TRANSCRIPTION; KNOCK-IN MICE; MOUSE MODEL; BINDING-PROTEIN; EXPANDED POLYGLUTAMINE; REPRESSES TRANSCRIPTION; PALLIDOLUYSIAN ATROPHY; CELLULAR TOXICITY; AXONAL-TRANSPORT AB Huntington's disease (HD) results from the expansion of a glutamine repeat near the N-terminus of huntingtin (htt). At post-mortem, neurons in the central nervous system of patients have been found to accumulate N-terminal fragments of mutant htt in nuclear and cytoplasmic inclusions. This pathology has been reproduced in transgenic mice expressing the first 171 amino acids of htt with 82 glutamines along with losses of motoric function, hypoactivity and abbreviated life-span. The relative contributions of nuclear versus cytoplasmic mutant htt to the pathogenesis of disease have not been clarified. To examine whether pathogenic processes in the nucleus disproportionately contribute to disease features in vivo, we fused a nuclear localization signal (NLS) derived from atrophin-1 to the N-terminus of an N171-82Q construct. Two lines of mice (lines 8A and 61) that were identified expressed NLS-N171-82Q at comparable levels and developed phenotypes identical to our previously described HD-N171-82Q mice. Western blot and immunohistochemical analyses revealed that NLS-N171-82Q fragments accumulate in nuclear, but not cytoplasmic, compartments. These data suggest that disruption of nuclear processes may account for many of the disease phenotypes displayed in the mouse models generated by expressing mutant N-terminal fragments of htt. C1 Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. NCI, Mouse Canc Genet Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Schilling, G (reprint author), Ross Bldg 558,720 Rutland Ave, Baltimore, MD 21205 USA. EM gschill1@jhmi.edu RI Ross, Christopher/H-8395-2013 FU NINDS NIH HHS [1 PO1 NS16375, NS 34177, NS 38144] NR 70 TC 60 Z9 61 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 1 PY 2004 VL 13 IS 15 BP 1599 EP 1610 DI 10.1093/hmg/ddh175 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 836MB UT WOS:000222558800006 PM 15190011 ER PT J AU Berman, JJ AF Berman, JJ TI Borderline Ovarian Tumor Workshop, Bethesda, Maryland, August 27-28, 2003 SO HUMAN PATHOLOGY LA English DT Editorial Material C1 NCI, Canc Diag Program, NIH, Rockville, MD USA. RP Berman, JJ (reprint author), NCI, Canc Diag Program, NIH, Rockville, MD USA. NR 1 TC 3 Z9 7 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD AUG PY 2004 VL 35 IS 8 BP 907 EP 909 DI 10.1016/j.humpath.2004.03.002 PG 3 WC Pathology SC Pathology GA 848AT UT WOS:000223440100001 PM 15297958 ER PT J AU Seidman, JD Soslow, RA Vang, R Berman, JJ Stoler, MH Sherman, ME Oliva, E Kajdacsy-Balla, A Berman, DM Copeland, LJ AF Seidman, JD Soslow, RA Vang, R Berman, JJ Stoler, MH Sherman, ME Oliva, E Kajdacsy-Balla, A Berman, DM Copeland, LJ TI Borderline ovarian tumors: Diverse contemporary viewpoints on terminology and diagnostic criteria with illustrative images SO HUMAN PATHOLOGY LA English DT Article DE ovary; ovarian neoplasms; serous borderline tumor; atypical proliferative serous tumor; mucinous borderline tumor; atypical proliferative mucinous tumor; pseudomyxoma peritonei ID TERM-FOLLOW-UP; DISSEMINATED PERITONEAL ADENOMUCINOSIS; MICROPAPILLARY SEROUS CARCINOMA; CLINICOPATHOLOGICAL ANALYSIS; PSEUDOMYXOMA-PERITONEI; MUCINOUS TUMORS; PAPILLARY CYSTADENOMAS; CRIBRIFORM PATTERNS; INTESTINAL-TYPE; MULLERIAN TYPE AB The National Cancer Institute sponsored a Borderline Ovarian Tumor Workshop held in August 2003 in Bethesda, MD. This report was developed from discussions at the Workshop. The participants acknowledged several areas of disagreement on basic terminology issues and agreed that a glossary with example images would help clarify many commonly misunderstood issues. This report defines terminology used in the pathological description of borderline tumors and their variants, and illustrates examples of each of the most common entities. It also addresses controversial aspects of the definitions and issues involving specimen handling and reporting. For those issues where there is disagreement, the terminology and diagnostic approaches reflecting the differing views are presented. (C) 2004 Elsevier Inc. All rights reserved. C1 Washington Hosp Ctr, Dept Pathol, Washington, DC 20010 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD USA. NCI, Div Canc Treatment & Diagnost, Bethesda, MD USA. Univ Virginia Hlth Syst, Dept Pathol, Charlottesville, VA USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Univ Illinois, Dept Pathol, Chicago, IL USA. NCI, Lab Pathol, Bethesda, MD USA. Ohio State Univ, Coll Med & Publ Hlth, James Canc Hosp, Cleveland, OH USA. Ohio State Univ, Coll Med & Publ Hlth, Solove Res Inst, Cleveland, OH USA. RP Seidman, JD (reprint author), Washington Hosp Ctr, Dept Pathol, 110 Irving St NW, Washington, DC 20010 USA. OI Soslow, Robert/0000-0002-7269-5898 NR 57 TC 65 Z9 77 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD AUG PY 2004 VL 35 IS 8 BP 918 EP 933 DI 10.1016/j.humpath.2004.03.004 PG 16 WC Pathology SC Pathology GA 848AT UT WOS:000223440100003 PM 15297960 ER PT J AU Bell, DA Longacre, TA Prat, J Kohn, EC Soslow, RA Ellenson, LH Malpica, A Stoler, MH Kurman, RJ AF Bell, DA Longacre, TA Prat, J Kohn, EC Soslow, RA Ellenson, LH Malpica, A Stoler, MH Kurman, RJ TI Serous borderline (low malignant potential, atypical proliferative) ovarian tumors: Workshop perspectives SO HUMAN PATHOLOGY LA English DT Article DE serous; ovary; borderline; low malignant potential; atypical proliferative ID K-RAS MUTATIONS; TERM FOLLOW-UP; MULLERIAN INCLUSION CYSTS; STAGE-I CARCINOMAS; EPITHELIAL TUMORS; PERITONEAL IMPLANTS; LOW-GRADE; CRIBRIFORM PATTERNS; HISTOLOGIC FEATURES; MICROPAPILLARY AB Although the category of serous borderline ovarian tumor (S-BOT) was established more than 30 years ago, the nomenclature and prognostic significance of various histological features of these neoplasms continues to engender controversy. The Borderline Ovarian Tumor Workshop was held in Bethesda, MD, in August 2003 in an attempt to examine the existing data, establish areas of agreement, and identify areas needing further investigation. This report addresses 6 areas of controversy regarding S-BOT: (1) tumors with and without a micropapillary architecture (typical vs micropapillary type), (2) peritoneal implants, (3) stromal microinvasion, (4) ovarian surface involvement, (5) lymph node involvement, and (6) recurrent tumors. Each of these issues is addressed by summarizing the data in the literature on which the discussions were based, areas of agreement that emerged, divergent opinions and the reasoning behind them, and the conclusions of the participants with recommended nomenclature. (C) 2004 Elsevier Inc. All rights reserved. C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Stanford Univ, Ctr Med, Dept Pathol, Div Surg Pathol, Stanford, CA USA. Univ Autonoma Barcelona, Hosp Santa Creu & Sant Pau, Dept Pathol, Barcelona, Spain. Ctr Canc Res, Lab Pathol, NCI, Bethesda, MD USA. Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. Cornell Univ, Weill Med Coll, Dept Pathol, New York, NY USA. Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Houston, TX USA. Univ Virginia Hlth Syst, Robert E Fechner Lab Surg Pathol, Charlottesville, VA USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Dept Gynecol & Obstet, Baltimore, MD USA. RP Bell, DA (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 105, Boston, MA 02114 USA. RI Prat, Jaime/G-4679-2011; OI Soslow, Robert/0000-0002-7269-5898 NR 76 TC 72 Z9 82 U1 1 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD AUG PY 2004 VL 35 IS 8 BP 934 EP 948 DI 10.1016/j.humpath.2004.03.005 PG 15 WC Pathology SC Pathology GA 848AT UT WOS:000223440100004 PM 15297961 ER PT J AU Ronnett, BM Kajdacsy-Balla, A Gilks, CB Merino, MJ Silva, E Werness, BA Young, RH AF Ronnett, BM Kajdacsy-Balla, A Gilks, CB Merino, MJ Silva, E Werness, BA Young, RH TI Mucinous borderline ovarian tumors: Points of general agreement and persistent controversies regarding nomenclature, diagnostic criteria, and behavior SO HUMAN PATHOLOGY LA English DT Article DE mucinous borderline ovarian tumor; atypical proliferative mucinous tumor; mucinous tumor of low malignant potential; ovary ID DISSEMINATED PERITONEAL ADENOMUCINOSIS; MALIGNANT POTENTIAL TUMORS; TERM-FOLLOW-UP; PSEUDOMYXOMA-PERITONEI; CLINICOPATHOLOGICAL ANALYSIS; EPITHELIAL TUMORS; INTESTINAL-TYPE; PATHOLOGICAL FEATURES; TREATMENT MODALITIES; APPENDICEAL ORIGIN AB This report focuses on the borderline category of ovarian mucinous tumors and summarizes the points of general agreement and persistent controversies identified by experts in the field who participated in the Borderline Ovarian Tumor Workshop held in Bethesda, MD, in August 2003. Points of agreement and persistent controversies regarding nomenclature, diagnostic criteria, and behavior are addressed for the following ovarian mucinous tumor categories: mucinous borderline ovarian tumor (M-BOT; synonymously referred to as atypical proliferative mucinous tumor of ovary or mucinous ovarian tumor of low malignant potential), M-BOT with intraepithelial carcinoma, and M-BOT with microinvasion. The morphologic spectrum of M-BOTs with regard to distinction from mucinous cystadenoma and the confluent glandular/expansile type of invasive mucinous carcinoma is also addressed. Non-ovarian mucinous tumors, including the secondary ovarian mucinous tumors associated with pseudomyxoma peritonei and metastatic mucinous carcinomas with a deceptive pattern of invasion, are recognized as tumors that can simulate primary M-BOTs. Improved classification of these mucinous tumors has clarified the behavior of true M-BOTs by excluding these simulators from the XI-BOT category. (C) 2004 Elsevier Inc. All rights reserved. C1 Johns Hopkins Univ, Sch Med & Hosp, Dept Pathol, Baltimore, MD 21231 USA. Johns Hopkins Univ, Sch Med & Hosp, Dept Gynecol & Obstet, Baltimore, MD 21231 USA. Univ Illinois, Coll Med, Dept Pathol, Chicago, IL 60612 USA. Vancouver Gen Hosp, Dept Pathol, Vancouver, BC V5Z 1M9, Canada. NCI, Dept Pathol, Bethesda, MD USA. Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. Inova Fair Oaks Hosp, Dept Pathol, Fairfax, VA USA. Harvard Univ, Sch Med, Homer Wright Pathol Labs, Boston, MA USA. RP Ronnett, BM (reprint author), Johns Hopkins Univ, Sch Med & Hosp, Dept Pathol, Weinberg Bldg,Room 2242,401 N Broadway, Baltimore, MD 21231 USA. NR 64 TC 69 Z9 79 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD AUG PY 2004 VL 35 IS 8 BP 949 EP 960 DI 10.1016/j.humpath.2004.03.006 PG 12 WC Pathology SC Pathology GA 848AT UT WOS:000223440100005 PM 15297962 ER PT J AU Sherman, ME Berman, J Birrer, MJ Cho, KR Ellenson, LH Gorstein, F Seidman, JD AF Sherman, ME Berman, J Birrer, MJ Cho, KR Ellenson, LH Gorstein, F Seidman, JD TI Current challenges and opportunities for research on borderline ovarian tumors SO HUMAN PATHOLOGY LA English DT Article DE borderline; low malignant potential; ovary; neoplasm; epidemiology; pathology ID INTERPHASE CYTOGENETIC ANALYSIS; K-RAS MUTATIONS; SEROUS TUMORS; CLINICOPATHOLOGICAL FEATURES; PSEUDOMYXOMA-PERITONEI; UNITED-STATES; LOW-GRADE; CARCINOMA; CANCER; ORIGIN AB This article summarizes key issues for future research on borderline ovarian tumors that emerged at a National Cancer Institute-sponsored Borderline Ovarian Tumor Workshop held in August 2003 in Bethesda, MD. Limitations in existing research and opportunities for future advances have been highlighted. The application of new molecular techniques in combination with improved study designs holds promise for elucidating the pathogenesis of these tumors and revealing the source of the extra-ovarian lesions ("implants") with which they are frequently associated. Clarification of the etiology of borderline tumors and the pathogenesis of their associated implants is critical for improving pathological diagnosis, revising the classification system of ovarian neoplasms, and developing optimal, evidence-based clinical management algorithms. (C) 2004 Elsevier Inc. All rights reserved. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diagnost, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Dept Cell & Canc Biol, Bethesda, MD 20892 USA. Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. Cornell Univ, Weill Med Coll, New York, NY USA. Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. Washington Hosp Ctr, Dept Pathol, Washington, DC 20010 USA. RP Sherman, ME (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 7080, Bethesda, MD 20892 USA. NR 58 TC 22 Z9 23 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD AUG PY 2004 VL 35 IS 8 BP 961 EP 970 DI 10.1016/j.humpath.2004.03.007 PG 10 WC Pathology SC Pathology GA 848AT UT WOS:000223440100006 PM 15297963 ER PT J AU Mitchell, GF Parise, H Vita, JA Larson, MG Warner, E Keaney, JF Keyes, MJ Levy, D Vasan, RS Benjamin, EJ AF Mitchell, GF Parise, H Vita, JA Larson, MG Warner, E Keaney, JF Keyes, MJ Levy, D Vasan, RS Benjamin, EJ TI Local shear stress and brachial artery flow-mediated dilation - The Framingham Heart Study SO HYPERTENSION LA English DT Article DE endothelium; microcirculation; risk factors ID ENDOTHELIAL DYSFUNCTION; PULSE PRESSURE; HYPERCHOLESTEROLEMIC PATIENTS; CORONARY-ARTERIES; NITRIC-OXIDE; ATHEROSCLEROSIS; HUMANS; HYPEREMIA; VASODILATION; REACTIVITY AB Endothelium-dependent flow-mediated dilation is a homeostatic response to short-term increases in local shear stress. Flow-mediated dilation of the brachial artery in response to postischemic reactive hyperemia is impaired in patients with cardiovascular disease risk factors and may reflect local endothelial dysfunction in the brachial artery. However, previous studies have largely neglected the effect of risk factors on evoked shear stress, which is the stimulus for dilation. We evaluated brachial artery percent dilation and evoked diastolic shear stress during reactive hyperemia using high-resolution ultrasound and Doppler in 2045 participants ( 1107 women, mean age 61 years) in the Framingham Offspring Study. In age- and sex-adjusted models, baseline and hyperemic shear stress were related to brachial artery percent dilation. In stepwise multivariable analyses examining clinical correlates of percent dilation ( without shear stress in the model), age, sex, mean arterial pressure, pulse pressure, heart rate, body mass index, lipid medication use, and hormone replacement therapy were related to percent dilation (R-2 = 0.189; P < 0.001). When hyperemic shear stress was incorporated, the overall R-2 improved (R-2 = 0.335; P < 0.001), but relationships between risk factors and percent dilation were attenuated ( age and mean arterial pressure) or no longer significant ( all others). In contrast, risk factors were related to baseline and hyperemic shear stress in multivariable analyses. Evoked hyperemic shear stress is a major correlate of brachial artery flow-mediated dilation. The associations between many risk factors and brachial artery flow-mediated dilation may be attributable to reduced stimulus for dilation rather than impaired local conduit artery response during hyperemia. C1 Cardiovasc Engn Inc, Holliston, MA 01746 USA. Boston Univ, Sch Med, Dept Math & Stat, Boston, MA 02215 USA. Boston Univ, Sch Med, Evans Dept Med, Boston, MA 02215 USA. Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02215 USA. Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02215 USA. Natl Heart Lung & Blood Inst Framingham Study, Framingham, MA USA. RP Mitchell, GF (reprint author), Cardiovasc Engn Inc, 327 Fiske St, Holliston, MA 01746 USA. EM GaryFMitchell@mindspring.com OI Vita, Joseph/0000-0001-5607-1797; Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [N01-HC-38038, R01-HL60040, R01-HL70100] NR 28 TC 233 Z9 236 U1 6 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD AUG PY 2004 VL 44 IS 2 BP 134 EP 139 DI 10.1161/01.HYP.0000137305.77635.68 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 842AS UT WOS:000222975300010 PM 15249547 ER PT J AU DeStefano, AL Larson, MG Mitchell, GF Benjamin, EJ Vasan, RS Li, J Corey, D Levy, D AF DeStefano, AL Larson, MG Mitchell, GF Benjamin, EJ Vasan, RS Li, J Corey, D Levy, D TI Genome-wide scan for pulse pressure in the National Heart, Lung and Blood Institute's Framingham Heart Study SO HYPERTENSION LA English DT Article DE genetics; blood pressure; human ID QUANTITATIVE TRAIT LOCUS; LINKAGE ANALYSIS; PEDIGREES; HYPERTENSION; COMPONENTS; FAMILIES; STENOSIS; DISEASE; RISK AB The objective of this study was to assess heritability and identify chromosomal regions showing evidence of linkage to pulse pressure ( PP), a simple indicator of proximal conduit vessel stiffness. Blood pressure data were analyzed for 8478 members of the National Heart, Lung and Blood Institute's (NHLBI) Framingham Heart Study. Long-term PP was defined using 2-stage analysis. First, the difference between systolic and diastolic blood pressure was averaged over all qualifying clinic examinations. In the second stage, mean PP was adjusted for mean age, time period of examination, and body mass index by regression analysis. PP values were available for 6421 individuals in 1593 families for heritability estimation and for 2492 individuals in 330 families for linkage analysis. Microsatellite markers covering the genome at 10 cM intervals were typed by the NHLBI Mammalian Genotyping Service; genome scan data were available on 1585 individuals with PP data. Heritability estimates of long-term PP accounting for hypertension treatment and for ignoring treatment were 0.52 and 0.51, respectively. Variance component linkage analysis identified several locations with suggestive evidence of linkage: chromosome 15 at 122 cM ( logarithm of odds [LOD] = 2.94), chromosome 7 at 71 cM (LOD = 2.42), chromosome 5 at 53 cM (LOD = 2.03), and chromosome 10 at 81 cM (LOD = 1.83) for PP accounting for treatment. LOD scores were slightly lower when ignoring treatment, with the exception of a peak on chromosome 10 at 81 cM (LOD = 2.58). In conclusion, we have demonstrated a substantial genetic component to PP and have identified 4 chromosomal regions that may harbor genes influencing vascular stiffness. C1 Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Neurol, Cardiol Sect, Boston, MA 02215 USA. Boston Univ, Sch Med, Dept Epidemiol & Prevent Med, Cardiol Sect, Boston, MA 02215 USA. Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. Cardiovasc Engn Inc, Holliston, MA USA. RP DeStefano, AL (reprint author), Boston Univ, Sch Publ Hlth, Dept Biostat, 715 Albany St,T418E, Boston, MA 02118 USA. EM adestef@bu.edu OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [N01-HC-25195] NR 22 TC 36 Z9 36 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD AUG PY 2004 VL 44 IS 2 BP 152 EP 155 DI 10.1161/01.HYP.0000135248.62303.81 PG 4 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 842AS UT WOS:000222975300013 PM 15210652 ER PT J AU Cebral, JR Summers, RM AF Cebral, JR Summers, RM TI Tracheal and central bronchial aerodynamics using virtual bronchoscopy and computational fluid dynamics SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE bronchus; computational fluid dynamics; trachea; virtual bronchoscopy; visualization; Wegener's granulomatosis ID HELICAL CT; AIR-FLOW; TRIANGULATIONS; BIFURCATIONS; SIMULATIONS; STENOSES; MODEL AB Virtual bronchoscopy reconstructions of the airway noninvasively provide useful morphologic information of structural abnormalities such as stenoses and masses. In this paper, we show how virtual bronchoscopy can be used to perform aerodynamic calculations in anatomically realistic models. Pressure and flow patterns in a human airway were computed noninvasively. These showed decreased pressure and increased shear stress in the region of a stenosis. C1 NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. George Mason Univ, Sch Comp Sci, Fairfax, VA 22030 USA. RP Summers, RM (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. EM rms@nih.gov NR 35 TC 31 Z9 32 U1 0 U2 2 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 AUG PY 2004 VL 23 IS 8 BP 1021 EP 1033 DI 10.1109/TMI.2004.828680 PG 13 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 842UJ UT WOS:000223029500010 PM 15338735 ER PT J AU Shechter, G Ozturk, C Resar, JR McVeigh, ER AF Shechter, G Ozturk, C Resar, JR McVeigh, ER TI Respiratory motion of the heart from free breathing coronary angiograms SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE chest imaging; magnetic resonance imaging; modeling; motion analysis; motion compensation; X-ray angiography ID LEFT-VENTRICULAR MOTION; CARDIAC MOTION; MR-IMAGES; RECONSTRUCTION; ARTERIES; INSPIRATION; TRACKING AB Respiratory motion compensation for cardiac imaging requires knowledge of the heart's motion and deformation during breathing. This paper presents a method for measuring the natural tidal respiratory motion of the heart from free breathing coronary angiograms. A three-dimensional (3-D) deformation field describing the cardiac and respiratory motion of the coronary arteries is recovered from a biplane acquisition. A cardiac respiratory parametric model is formulated and used to decompose the deformation field into cardiac and respiratory components. Angiograms from ten patients were analyzed. A 3-D translation motion model was sufficient for describing the motion of the heart in only two patients. For all patients, the heart translated caudally (mean, 4.9 +/- 1.9 mm; range, 2.4 to 8.0 mm) and underwent a cranio-dorsal rotation (mean, 1.5degrees +/- 0.9degrees; range, 0.2degrees to 3.5degrees) during inspiration. In eight patients, the heart also translated anteriorly (mean, 1.3 +/- 1.8 mm; range, -0.4 to 5.1 mm) and rotated in a caudo-dextral direction (mean, 1.2degrees +/- 1.3degrees; range, -1.9degrees to 3.2degrees). C1 NHLBI, Cardiac Energet Lab, NIH, DHHS, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Biomed Engn, Sch Med, Baltimore, MD 21205 USA. NHLBI, Vasc Biol Branch, NIH, DHHS, Bethesda, MD 20892 USA. RP Shechter, G (reprint author), NHLBI, Cardiac Energet Lab, NIH, DHHS, Bethesda, MD 20892 USA. EM guy@jhu.edu RI Ozturk, Cengizhan/A-6177-2016 OI Ozturk, Cengizhan/0000-0002-6966-0774 FU Intramural NIH HHS [Z01 HL004608-08] NR 28 TC 71 Z9 72 U1 1 U2 2 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 AUG PY 2004 VL 23 IS 8 BP 1046 EP 1056 DI 10.1109/TMI.2004.828676 PG 11 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 842UJ UT WOS:000223029500012 PM 15338737 ER PT J AU Su, H Bidere, N Lenardo, M AF Su, H Bidere, N Lenardo, M TI Another fork in the road: Foxo3a regulates NF-kappa B activation SO IMMUNITY LA English DT Editorial Material ID TRANSCRIPTION FACTORS; CELL-PROLIFERATION; DIFFERENTIATION C1 NIAID, Mol Dev Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Su, H (reprint author), NIAID, Mol Dev Sect, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RI Su, Helen/H-9541-2015; bidere, nicolas/K-8887-2015 OI Su, Helen/0000-0002-5582-9110; bidere, nicolas/0000-0001-9177-0008 NR 11 TC 3 Z9 3 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD AUG PY 2004 VL 21 IS 2 BP 133 EP 134 DI 10.1016/j.immuni.2004.07.015 PG 2 WC Immunology SC Immunology GA 848BK UT WOS:000223441900001 PM 15308093 ER PT J AU Park, JH Yu, Q Erman, B Appelbaum, JS Montoya-Durango, D Grimes, JL Singer, A AF Park, JH Yu, Q Erman, B Appelbaum, JS Montoya-Durango, D Grimes, JL Singer, A TI Suppression of IL7R alpha transcription by IL-7 and other prosurvival cytokines: A novel mechanism for maximizing IL-7-dependent T cell survival SO IMMUNITY LA English DT Article ID ZINC-FINGER PROTEIN; IN-VIVO; HOMEOSTATIC PROLIFERATION; RECEPTOR SIGNALS; REPRESSOR GFI1; NAIVE; INTERLEUKIN-7; EXPRESSION; ACTIVATION; CHAIN AB Survival of naive T cells is dependent upon IL-7, which is present in vivo in limiting amounts with the result that naive T cells must compete for IL-7-mediated survival signals. It would seem imperative during T cell homeostasis that limiting IL-7 be shared by the greatest possible number of T cells. We now describe a novel regulatory mechanism that specifically suppresses IL7Ralpha transcription in response to IL-7 and other prosurvival cytokines (IL-2, IL-4, IL-6, and IL-15). Consequently, IL7R expression is reduced on T cells that have received cytokine-mediated survival signals so they do not compete with unsignaled T cells for remaining IL-7. Interestingly, cytokine-mediated suppression of IL7Ralpha transcription involves different molecular mechanisms in CD4(+) and CD8(+) T cells, as CD8(+) T cells utilize the transcriptional repressor GFI1 while CD4(+) T cells do not. We suggest that this homeostatic regulatory mechanism promotes survival of the maximum possible number of T cells for the amount of IL-7 available. C1 NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. Univ Louisville, Dept Surg, Sch Med, Louisville, KY 40202 USA. Univ Louisville, Inst Cellular Therapeut, Sch Med, Louisville, KY 40202 USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, Bldg 10,Room 4B36, Bethesda, MD 20892 USA. EM singera@nih.gov RI Park, Jung Hyun /B-5712-2015 OI Park, Jung Hyun /0000-0002-9547-9055 NR 38 TC 290 Z9 294 U1 1 U2 8 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD AUG PY 2004 VL 21 IS 2 BP 289 EP 302 DI 10.1016/j.immuni.2004.07.016 PG 14 WC Immunology SC Immunology GA 848BK UT WOS:000223441900016 PM 15308108 ER PT J AU Nejad, S Bryceson, Y Dissen, E Sundvold-Gjerstad, V Naper, C Rolstad, B Spurkland, A Vaage, JT AF Nejad, S Bryceson, Y Dissen, E Sundvold-Gjerstad, V Naper, C Rolstad, B Spurkland, A Vaage, JT TI cDNA cloning of a rat orthologue of SH2D2A encoding T-cell-specific adaptor protein (TSAd): expression in T and NK cells SO IMMUNOGENETICS LA English DT Article DE signal transduction; adapter molecules; lymphocytes ID NATURAL-KILLER-CELLS; ACTIVATION; RECEPTOR; DOMAIN AB The T-cell-specific adapter protein (TSAd), encoded by the SH2D2A gene, has been implicated in modulation of proximal signaling events as well as in transcriptional regulation in human T cells. We have isolated its rat homologue (rSH2D2A) from an NK cell cDNA library and mapped the corresponding gene to chromosome 2 with a hamster-rat radiation hybrid cell panel. rSH2D2A encodes a 376 amino acid protein (rTSAd) which shows greater homology to mouse than human TSAd. In rats, rTSAd was specifically expressed by NK cells and T cells but not by other leukocytes tested. Similarly, in humans we observed abundant transcripts for TSAd in NK cells and T cells. The data suggest that TSAd may have a regulatory role in cellular activation of T and NK cells. C1 Univ Oslo, Inst Basic Med Sci, Dept Anat, N-0317 Oslo, Norway. NIAID, NIH Karolinska Inst Grad Partnership Program, Immunogenet Lab, NIH, Rockville, MD 20852 USA. Rikshosp Univ Hosp, Inst Immunol, N-0027 Oslo, Norway. RP Spurkland, A (reprint author), Univ Oslo, Inst Basic Med Sci, Dept Anat, POB 1105, N-0317 Oslo, Norway. EM anne.spurkland@medisin.uio.no OI Spurkland, Anne/0000-0003-4421-0766; Bryceson, Yenan/0000-0002-7783-9934 NR 14 TC 9 Z9 9 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0093-7711 J9 IMMUNOGENETICS JI Immunogenetics PD AUG PY 2004 VL 56 IS 5 BP 338 EP 342 DI 10.1007/s00251-004-0695-9 PG 5 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 847DY UT WOS:000223374100004 PM 15300336 ER PT J AU Chowdhury, D Sen, R AF Chowdhury, D Sen, R TI Regulation of immunoglobulin heavy-chain gene rearrangements SO IMMUNOLOGICAL REVIEWS LA English DT Review ID B-CELL-DEVELOPMENT; COMMON LYMPHOID PROGENITORS; RECOMBINATION SIGNAL SEQUENCES; MOUSE BONE-MARROW; HOMOLOGY-DIRECTED RECOMBINATION; TCR-BETA LOCUS; V(D)J RECOMBINATION; ALLELIC EXCLUSION; TRANSGENIC MICE; PRO-B AB Regulated assembly of antigen receptor gene segments to produce functional genes is a hallmark of B- and T-lymphocyte development. The immunoglobulin heavy-chain (IgH) and T-cell receptor beta-chain genes rearrange first in B and T lineages, respectively. Both loci require two recombination events to assemble functional genes; D-to-J recombination occurs first followed by V-to-DJ recombination. Despite similarities in overall rearrangement patterns, each locus has unique regulatory features. Here, we review the characteristics of IgH gene rearrangements such as developmental timing, deletion versus inversion, D-H gene segment utilization, ordered recombination of V-H gene segments, and feedback inhibition of rearrangement in pre-B cells. We summarize chromatin structural features of the locus before and during recombination and, wherever possible, incorporate these into working hypotheses for understanding regulation of IgH gene recombination. The picture emerges that the IgH locus is activated in discrete, independently regulated domains. A domain encompassing D-H and J(H) gene segments is activated first, within which recombination is initiated. V-H genes are activated subsequently and, in part, by interleukin-7. These observations lead to a model for feedback inhibition of IgH rearrangements. C1 NIA, Cellular & Mol Biol Lab, Baltimore, MD 21224 USA. RP Sen, R (reprint author), NIA, Cellular & Mol Biol Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM rs465z@nih.gov NR 99 TC 33 Z9 35 U1 0 U2 6 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD AUG PY 2004 VL 200 BP 182 EP 196 DI 10.1111/j.0105-2896.2004.00177.x PG 15 WC Immunology SC Immunology GA 843RZ UT WOS:000223105500015 PM 15242405 ER PT J AU Jones, JM Gellert, M AF Jones, JM Gellert, M TI The taming of a transposon: V(D)J recombination and the immune system SO IMMUNOLOGICAL REVIEWS LA English DT Review ID STRAND BREAK REPAIR; CRITICAL CONTROL POINT; SINGLE ACTIVE-SITE; C-TERMINAL REGION; SYNAPTIC COMPLEX; RAG2 PROTEINS; SIGNAL SEQUENCE; RETROVIRAL INTEGRASES; ESCHERICHIA-COLI; MU-TRANSPOSASE AB The genes that encode immunoglobulins and T-cell receptors must be assembled from the multiple variable (V), joining (J), and sometimes diversity (D) gene segments present in the germline loci. This process of V(D)J recombination is the major source of the immense diversity of the immune repertoire of jawed vertebrates. The recombinase that initiates the process, recombination-activating genes 1 (RAG1) and RAG2, belongs to a large family that includes transposases and retroviral integrases. RAG1/2 cleaves the DNA adjacent to the gene segments to be recombined, and the segments are then joined together by DNA repair factors. A decade of biochemical research on RAG1/2 has revealed many similarities to transposition, culminating with the observation that RAG1/2 can carry out transpositional strand transfer. Here, we discuss the parallels between V(D)J recombination and transposition, focusing specifically on the assembly of the recombination nucleoprotein complex, the mechanism of cleavage, the disassembly of post-cleavage complexes, and aberrant reactions carried out by the recombinase that do not result in successful locus rearrangement and may be deleterious to the organism. This work highlights the considerable diversity of transposition systems and their relation to V(D)J recombination. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20007 USA. RP Gellert, M (reprint author), NIDDKD, Mol Biol Lab, NIH, Bldg 5,Room 241, Bethesda, MD 20892 USA. EM gellert@helix.nih.gov NR 125 TC 60 Z9 62 U1 2 U2 9 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD AUG PY 2004 VL 200 BP 233 EP 248 DI 10.1111/j.0105-2896.2004.00168.x PG 16 WC Immunology SC Immunology GA 843RZ UT WOS:000223105500019 PM 15242409 ER PT J AU Drecktrah, D Knodler, LA Steele-Mortimer, O AF Drecktrah, D Knodler, LA Steele-Mortimer, O TI Modulation and utilization of host cell phosphoinositides by Salmonella spp. SO INFECTION AND IMMUNITY LA English DT Review ID ENTERICA SEROVAR TYPHIMURIUM; CYTOSOLIC PHOSPHOLIPASE A(2); III SECRETION SYSTEM; EPITHELIAL-CELLS; PHOSPHATIDYLINOSITOL 3-PHOSPHATE; ACTIN CYTOSKELETON; CONTAINING VACUOLE; NADPH OXIDASE; BACTERIAL INTERNALIZATION; SIGNAL-TRANSDUCTION C1 NIAID, Rocky Mt Lab, Lab Intracellular Parasites, Hamilton, MT 59840 USA. RP Steele-Mortimer, O (reprint author), NIAID, Rocky Mt Lab, Lab Intracellular Parasites, 903 S 4th St, Hamilton, MT 59840 USA. EM omortimer@niaid.nih.gov NR 59 TC 15 Z9 16 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 AUG PY 2004 VL 72 IS 8 BP 4331 EP 4335 DI 10.1128/IAI.72.8.4331-4335.2004 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 841LW UT WOS:000222932600001 PM 15271887 ER PT J AU Moayeri, M Martinez, NW Wiggins, J Young, HA Leppla, SH AF Moayeri, M Martinez, NW Wiggins, J Young, HA Leppla, SH TI Mouse susceptibility to anthrax lethal toxin is influenced by genetic factors in addition to those controlling macrophage sensitivity SO INFECTION AND IMMUNITY LA English DT Article ID BACILLUS-ANTHRACIS; RESISTANCE; MICE; DEFICIENT; PROTEIN; RAT AB Bacillus anthracis lethal toxin (LT) produces symptoms of anthrax in mice and induces rapid lysis of macrophages (Mphi) derived from certain inbred strains. We used nine inbred strains and two inducible nitric oxide synthase (iNOS) knockout C57BL/6J strains polymorphic for the LT Mphi sensitivity Kif1C locus to analyze the role of Mphi sensitivity (to lysis) in LT-mediated cytokine responses and lethality. LT-mediated induction of cytokines KC, MCP-1/JE, MIP-2, eotaxin, and interleukin-1beta occurred only in mice having LT-sensitive Mphi. However, while iNOS knockout C57BL/6J mice having LT-sensitive Mphi were much more susceptible to LT than the knockout mice with LT-resistant Mphi, a comparison of susceptibilities to LT in the larger set of inbred mouse strains showed a lack of correlation between Mphi sensitivity and animal susceptibility to toxin. For example, C3H/HeJ mice, harboring LT-sensitive Mphi and having the associated LT-mediated cytokine response, were more resistant than mice with LT-resistant Mphi and no cytokine burst. Toll-like receptor 4 (Tlr4)-deficient, lipopolysaccharide-nonresponsive mice were not more resistant to LT. We also found that CAST/Ei mice are uniquely sensitive to LT and may provide an economical bioassay for toxin-directed therapeutics. The data indicate that while the cytokine response to LT in mice requires Mphi lysis and while Mphi sensitivity in the C57BL/6J background is sufficient for BALB/cJ-like mortality of that strain, the contribution of Mphi sensitivity and cytokine response to animal susceptibility to LT differs among other inbred strains. Thus, LT-mediated lethality in mice is influenced by genetic factors in addition to those controlling Mphi lysis and cytokine response and is independent of Tlr4 function. C1 NIAID, Microbial Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Lab Expt Immunol, Frederick, MD 21702 USA. RP Leppla, SH (reprint author), NIAID, Microbial Pathogenesis Sect, NIH, Bldg 30,Room 303, Bethesda, MD 20892 USA. EM sleppla@niaid.nih.gov NR 19 TC 68 Z9 70 U1 0 U2 3 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 AUG PY 2004 VL 72 IS 8 BP 4439 EP 4447 DI 10.1128/IAI.72.8.4439-4447.2004 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 841LW UT WOS:000222932600015 PM 15271901 ER PT J AU Rhodin, NR Cutalo, JM Tomer, KB McArthur, WP Brady, LJ AF Rhodin, NR Cutalo, JM Tomer, KB McArthur, WP Brady, LJ TI Characterization of the Streptococcus mutans P1 epitope recognized by immunomodulatory monoclonal antibody 6-11A SO INFECTION AND IMMUNITY LA English DT Article ID IONIZATION MASS-SPECTROMETRY; ANTIGEN-ANTIBODY COMPLEXES; SURFACE PROTEIN ANTIGEN; TETANUS TOXIN ANTIGEN; MONOCLONAL-ANTIBODY; LIMITED PROTEOLYSIS; DENTAL-CARIES; T-CELLS; IMMUNE-COMPLEX; CONFORMATIONAL EPITOPE AB Monoclonal antibody (MAb) 6-11A directed against Streptococcus mutans surface adhesin P1 was shown previously to influence the mucosal immunogenicity of this organism in BALB/c mice. The specificity of anti-P1 serum inummoglobulin G (IgG) and secretory IgA antibodies and the subclass distribution of anti-P1 serum IgG antibodies were altered, and the ability of elicited serum antibodies to inhibit S. mutans adherence in vitro was in certain cases increased. MAb 6-11A is known to recognize an epitope dependent on the presence of the proline-rich region of the protein, although it does not bind directly to the isolated P-region domain. In this report, we show that MAb 6-11A recognizes a complex discontinuous epitope that requires the simultaneous presence of the alanine-rich repeat domain (A-region) and the P-region. Formation of the core epitope requires the interaction of these segments of P1. Residues amino terminal to the A-region also contributed to recognition by MAb 6-11A but were not essential for binding. Characterization of the MAb 6-11A epitope will enable insight into potential mechanisms of immuno-modulation and broaden our understanding of the tertiary structure of P1. C1 Univ Florida, Dept Oral Biol, Coll Dent, Gainesville, FL 32610 USA. Natl Inst Environm Hlth Sci, Lab Struct Biol, Natl Inst Hlth, Dept Hlth & Human Serv Res, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dent Res Ctr, Chapel Hill, NC 27599 USA. RP Brady, LJ (reprint author), Univ Florida, Dept Oral Biol, Coll Dent, POB 100424, Gainesville, FL 32610 USA. EM jbrady@dental.ufl.edu RI Tomer, Kenneth/E-8018-2013 FU NIDCR NIH HHS [T32-DE07200, DE13882, R01 DE013882, T32 DE007200] NR 70 TC 12 Z9 13 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD AUG PY 2004 VL 72 IS 8 BP 4680 EP 4688 DI 10.1128/IAI.72.8.4680-4688.2004 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 841LW UT WOS:000222932600043 PM 15271929 ER PT J AU Gnanasekar, M Rao, KVN He, YX Mishra, PK Nutman, TB Kaliraj, P Ramaswamy, K AF Gnanasekar, M Rao, KVN He, YX Mishra, PK Nutman, TB Kaliraj, P Ramaswamy, K TI Novel phage display-based subtractive screening to identify vaccine candidates of Brugia malayi SO INFECTION AND IMMUNITY LA English DT Article ID PROTECTIVE IMMUNITY; BANCROFTIAN FILARIASIS; LYMPHATIC FILARIASIS; ONCHOCERCA-VOLVULUS; MOLECULAR-CLONING; FILAMENTOUS PHAGE; BALB/C MICE; THIOREDOXIN PEROXIDASES; ANCYLOSTOMA-CANINUM; DIROFILARIA-IMMITIS AB This study describes a novel phage display method based on an iterative subtraction strategy to identify candidate vaccine antigens of Brugia malayi. A cDNA library of the infective larval stage of B. malayi expressed on the surface of T7 phage was sequentially screened with sera samples from human subjects showing different manifestations of the disease. Antigens that selectively and specifically bind to immune sera were then enriched using a multi-step panning procedure. This strategy identified five antigens, four of which were previously reported (ALT-2, TPX-2, VAH and COX-2) and the other one was a novel cuticular collagen (Col-4). Sera from immune individuals specifically recognized all the five antigens. However, ALT-2 appeared to be the most predominantly recognized antigen by the immune sera. Therefore, it was decided to evaluate the vaccine potential of recombinant ALT-2 (rALT-2) in a mouse and jird model. The results presented show that immunization with rALT-2 conferred over 73% protection against a challenge infection in the jird model and over 64% protection in the mouse model. The present study suggests that phage display-based cDNA screening may be a powerful tool to identify candidate vaccine antigens of infectious agents. C1 Univ Illinois, Coll Med, Dept Biomed Sci, Rockford, IL 61107 USA. Anna Univ, Ctr Biotechnol, Madras 600025, Tamil Nadu, India. NIAID, Parasit Dis Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Ramaswamy, K (reprint author), Univ Illinois, Coll Med, Dept Biomed Sci, Rockford, IL 61107 USA. EM ramswamy@uic.edu RI Mishra, Pankaj/H-4191-2011 FU NIAID NIH HHS [AI-39006, R56 AI064745-01A1, R01 AI039066, R01 AI064745, R01 AI064745-01A2, R29 AI039066, R56 AI064745, AI 02642] NR 52 TC 64 Z9 76 U1 1 U2 6 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 AUG PY 2004 VL 72 IS 8 BP 4707 EP 4715 DI 10.1128/IAI.72.8.4707-4715.2004 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 841LW UT WOS:000222932600046 PM 15271932 ER PT J AU Eggers, V Fugener, K Hein, OV Rommelspacher, H Heyes, MP Kox, WJ Spies, CD AF Eggers, V Fugener, K Hein, OV Rommelspacher, H Heyes, MP Kox, WJ Spies, CD TI Antibiotic-mediated release of tumour necrosis factor alpha and norharman in patients with hospital-acquired pneumonia and septic encephalopathy SO INTENSIVE CARE MEDICINE LA English DT Article DE tumour necrosis factor (TNF-alpha); norharman; quinolinic acid; septic encephalopathy; cephalosporins; hospital-acquired pneumonia (HAP) ID QUINOLINIC ACID FORMATION; INDUCED ENDOTOXIN RELEASE; BRONCHOALVEOLAR LAVAGE; NOSOCOMIAL INFECTIONS; ESCHERICHIA-COLI; THP-1 CELLS; SEPSIS; CEFTAZIDIME; DEFINITIONS; TRYPTOPHAN AB Objective. To investigate antibiotic-mediated release of tumour necrosis factor (TNF)-alpha and norharman in patients with hospital-acquired pneumonia with and without additional septic encephalopathy. Design. Prospective observational study with a retrospective post hoc analysis. Setting. Surgical intensive care unit (ICU) at a university hospital. Patients. Thirty-seven patients were consecutively included (9 patients with hospital-acquired pneumonia, 11 patients with hospital-acquired pneumonia and septic encephalopathy, 17 control patients) in the study. Pneumonia was defined according to the criteria of the American Thoracic Society. Interventions. Patients received cephalosporins for antibiotic treatment of hospital-acquired pneumonia. Blood samples were taken before, immediately after and 4 h after application of cephalosporins. Measurements and results. Of the pneumonia patients, 55% developed septic encephalopathy. ICU stay, complications and mortality were significantly increased. An increased release of TNF-alpha was immediately seen in all pneumonia patients after antibiotics compared to controls, whereas the level did not differ between patients with and without septic encephalopathy. Norharman was significantly increased in pneumonia patients 4 h after antibiotic treatment, in tendency more enhanced in the pneumonia patients without encephalopathy. Conclusions. Patients with hospital-acquired pneumonia and septic encephalopathy had a significantly longer ICU stay with higher mortality rate compared to patients with hospital-acquired pneumonia alone. Antibiotic-mediated TNF-alpha release may induce the kynurenine pathway. TNF-alpha activates indolamine-2,3-dioxygenase with neurotoxic quinolinic acid as the end product. Norharman seems to counteract this mechanism and seems to play a role in neuroprotection. The worse outcome of patients with encephalopathy expresses the need to investigate protective factors and mechanisms. C1 Humboldt Univ, Univ Hosp Charite, Dept Anaesthesiol & Intens Care Med, D-10117 Berlin, Germany. Free Univ Berlin, Med Ctr, Univ Hosp Charite, Dept Clin Neurobiol, D-12200 Berlin, Germany. NIMH, Lab Neurotoxicol, Bethesda, MD 20892 USA. RP Spies, CD (reprint author), Humboldt Univ, Univ Hosp Charite, Dept Anaesthesiol & Intens Care Med, Campus Mitte,Schumannstr 20-21, D-10117 Berlin, Germany. EM claudia.spies@charite.de NR 36 TC 16 Z9 16 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0342-4642 J9 INTENS CARE MED JI Intensive Care Med. PD AUG PY 2004 VL 30 IS 8 BP 1544 EP 1551 DI 10.1007/s00134-004-2285-6 PG 8 WC Critical Care Medicine SC General & Internal Medicine GA 842OT UT WOS:000223014400007 PM 15112034 ER PT J AU Rastogi, T Vaz, M Spiegelman, D Reddy, KS Bharathi, AV Stampfer, MJ Willett, WC Ascherio, A AF Rastogi, T Vaz, M Spiegelman, D Reddy, KS Bharathi, AV Stampfer, MJ Willett, WC Ascherio, A TI Physical activity and risk of coronary heart disease in India SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE physical activity; leisure-time exercise; sedentary lifestyles; coronary heart disease; India; developing countries ID VIGOROUS EXERCISE; PREVENTION; HEALTH; WOMEN; HYPERTENSION; WALKING; MEN AB Background Physical exercise has been inversely associated with coronary heart disease (CHD) risk in Western populations; however, the association has not been examined in India where physical inactivity levels in urban areas are now comparable with the West. Methods We conducted a hospital-based case-control study and collected data from 350 cases of acute myocardial infarction and 700 controls matched on age, gender, and hospital in New Delhi and Bangalore. We used conditional logistic regression to control for the matching and other risk factors. Results Of the controls, 48% participated in some form of leisure-time exercise compared with 38% of cases. In age- and sex-adjusted analyses, people in the highest level of leisure-time exercise (>145 metabolic equivalents [MET]-minutes per day, equivalent to 36 minutes of brisk walking per day) had a relative risk of 0.45 (95% CI: 0.31, 0.66) compared with non-exercisers. Multivariate adjustment for other risk factors did not substantially alter the association. We observed a positive association between non-work sedentary activity and CHD risk; people with >3.6 hours per day of sedentary activity (for example, television viewing) had an elevated risk of 1.88 (95% CI: 1.09, 3.20) compared with <70 minutes per day in multivariate analysis. Conclusion Leisure-time exercise, including as much as 35-40 minutes per day of brisk walking, was protective for CHD risk and sedentary lifestyles were positively associated with risk of CHD. Given limited resources for care of CHD in India and the important role of physical exercise in disease risk in urban India, improvements in physical activity should be promoted. C1 Harvard Univ, Sch Publ Hlth, Dept Nutr, Cambridge, MA 02138 USA. St Johns Med Coll & Hosp, Div Nutr, Bangalore, Karnataka, India. Harvard Univ, Sch Publ Hlth, Dept Biostat, Cambridge, MA 02138 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Cambridge, MA 02138 USA. All India Inst Med Sci, Dept Cardiol, New Delhi 110029, India. RP Rastogi, T (reprint author), NCI, NEB, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Execut Blvd,EPS 320, Rockville, MD 20852 USA. EM trastogi@post.harvard.edu NR 34 TC 40 Z9 40 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD AUG PY 2004 VL 33 IS 4 BP 759 EP 767 DI 10.1093/ije/dyh042 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 855AB UT WOS:000223944100024 PM 15044412 ER PT J AU Basso, O Wilcox, AJ Weinberg, CR Baird, DD Olsen, J AF Basso, O Wilcox, AJ Weinberg, CR Baird, DD Olsen, J TI Height and risk of severe pre-eclampsia. A study within the Danish National Birth Cohort SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE height; pregnancy complications; pre-eclampsia (severe); cohort study ID SELF-REPORTED WEIGHT; CARDIOVASCULAR-DISEASE; SHORT STATURE; WOMEN; MORTALITY; PROGNOSIS; PREGNANCY; FATHERS AB Background Pre-eclampsia shares a number of risk factors with cardiovascular disease (CVD). Women with recurrent pre-eclampsia or pre-eclampsia early in pregnancy reportedly have an increased long-term risk of CVD. Short stature is a risk factor for CVD but has rarely been examined in relation to pre-eclampsia. Methods We used data from 59 968 singleton live births in the Danish National Birth Cohort born between 1998 and 2001 to assess risk of severe pre-eclampsia/eclampsia (296 cases) in relation to self-reported height. We examined the association in multiple logistic regressions stratified by parity. Results Among primiparas there was a weak association (compared with women <165 cm, women >172 cm had on OR of 0.79, 95% CI: 0.55, 1.14). Among multiparas, the tallest women had an adjusted OR of 0.42 (95% CI: 0.20, 0.87) of developing severe pre-eclampsia compared with women <165 cm. The OR per centimetre was 0.94 (95% CI: 0.91, 0.97). Self-reported pre-existing hypertension did not explain this association, which also persisted when the analysis was restricted to non-overweight women. Conclusions Short stature was associated with a higher risk of severe pre-eclampsia in multiparas participating in the Danish National Birth Cohort. C1 Danish Epidemiol Sci Ctr, Dept Epidemiol & Social Med, DK-8000 Aarhus C, Denmark. NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Basso, O (reprint author), Danish Epidemiol Sci Ctr, Dept Epidemiol & Social Med, Vennelyst Blvd 6,Bldg 260, DK-8000 Aarhus C, Denmark. EM ob@soci.au.dk RI Basso, Olga/E-5384-2010; Olsen, Jorn/F-8801-2015; OI Basso, Olga/0000-0001-9298-4921; Olsen, Jorn/0000-0001-7462-5140; Wilcox, Allen/0000-0002-3376-1311; Baird, Donna/0000-0002-5544-2653 NR 29 TC 12 Z9 12 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD AUG PY 2004 VL 33 IS 4 BP 858 EP 863 DI 10.1093/ije/dyh116 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 855AB UT WOS:000223944100042 PM 15155701 ER PT J AU Amano, T Fu, LZ Sahu, S Markey, M Shi, YB AF Amano, T Fu, LZ Sahu, S Markey, M Shi, YB TI Substrate specificity of Xenopus matrix metalloproteinase stromelysin-3 SO INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE LA English DT Article DE matrix metalloproteinase; stromelysin-3; proteinase unhibitor; Xenopus laevis; extracellular matrix ID HORMONE RESPONSE GENES; EXTRACELLULAR-MATRIX; IN-VIVO; MOUSE STROMELYSIN-3; EXPRESSION PATTERN; FROG METAMORPHOSIS; CELL-MIGRATION; MESSENGER-RNA; APOPTOSIS; ACTIVATION AB The matrix metalloproteinase stromelysin-3 (ST3 or MMP11) was initially identified as a breast carcinoma associated protease and has since been shown to be highly expressed in diverse carcinomas and in developmental processes that involve extensive cell death (apoptosis) and tissue remodeling. Unlike other MMPs, purified ST3 has little activity toward known extracellular matrix (ECM) proteins in vitro but cleaves strongly a few non-ECM, extracellular proteins, including human alpha1-proteinase inhibitor (alpha1-PI). To investigate the possibility of alpha1-PI as a conserved physiological substrate for ST3 during vertebrate development, we analyzed the ability of Xenopus laevis ST3 catalytic domain to cleave frog alpha1-PI. Surprisingly, we found the ST3 failed to recognize the site in alpha1-PI equivalent to the major cleavage site in human a I-PI by mammalian ST3. Sequence and mutagenic analysis revealed that multiple substitutions at P2-P3' positions between human and Xenopus alpha1-PI contributed to the inability of Xenopus alpha1-PI to be cleaved by ST3. Our studies showed that (A)(G/A)(A)(M)(F/A)(L) (P3-P3') as a preferred cleavage site for ST3. We further demonstrated that mutations in the cleavage sites affected cleavage by ST3 differently from several other MMPs. These findings, together with earlier reports on ST3, showed that ST3 has distinct substrate specificities compared to other MMPs. Our results further suggest that alpha1-PI is unlikely to be a physiological substrate for ST3, at least with regard to evolutionarily conserved developmental processes. C1 NICHHD, Lab Gene Regulat & Dev, NIH, Sect Mol Morphogenesis, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), NICHHD, Lab Gene Regulat & Dev, NIH, Sect Mol Morphogenesis, Bldg 18T,Room 106, Bethesda, MD 20892 USA. EM shi@helix.nih.gov NR 59 TC 10 Z9 10 U1 0 U2 0 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1107-3756 J9 INT J MOL MED JI Int. J. Mol. Med. PD AUG PY 2004 VL 14 IS 2 BP 233 EP 239 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 838PW UT WOS:000222726400017 PM 15254771 ER PT J AU Jia, G Sone, H Nishimura, N Satoh, M Tohyama, C AF Jia, G Sone, H Nishimura, N Satoh, M Tohyama, C TI Metallothionein (I/II) suppresses genotoxicity caused by dimethylarsinic acid SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE dimethylarsinic acid; metallothionein; oxidative DNA damage; apoptosis; oxidative stress ID OXIDATIVE STRESS; DNA-DAMAGE; NULL MICE; GENE-EXPRESSION; INORGANIC ARSENICS; PROTECTIVE ROLE; INDUCED CYTOTOXICITY; HEME OXYGENASE; FREE-RADICALS; CARCINOGENESIS AB Arsenic is an environmental chemical of considerable concern due to its association with an increased risk of human cancer. Dimethylarsinic acid (DMAA) is one of the major methylated metabolites of ingested arsenicals in most mammals. To better clarify the role of metallothionein (MT) in modifying DMAA genotoxicity, MT-I/II null mice, and the corresponding wild-type mice, were exposed to DMAA (0, 188, 375 or 750 mg/kg body weight) via a single oral dose. Twenty-four hours after the DMAA injection, there was increased formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in serum and urine and a higher number of DNA strand breaks in peripheral blood cells. These increased levels were concomitant with increasing dose concentrations of DMAA in both strains of mice and they were significantly higher in MT-I/II null mice than in wild-type mice. Furthermore, the induction of apoptotic cells in the urinary bladder epithelium of MT-I/II null mice was significantly higher than in dose-matched wild-type mice exposed to DMAA. On the other hand, in both liver and in the alveolar and bronchial areas of the lung, the extent of DMAA-induced apoptosis was not different between wild-type and MT-I/II null mice and was increased in both strains. In addition, the concentration of hepatic MT in wild-type mice increased in a DMAA dose-dependent manner but was undetectable in MT-I/II null mice and could not subsequently be induced by DMAA. In conclusion, DMAA exposure causes oxidative stress, DNA damage and specific induction of apoptosis in target organs of arsenic carcinogenesis, which may be attributable to the mechanism(s) of arsenic-induced carcinogenesis in rodents. MT exhibited some protective roles during DNA damage presumably by acting as an antioxidant. C1 Natl Inst Environm Studies, Hlth Effects Res Team, Tsukuba, Ibaraki 3058506, Japan. Natl Inst Environm Studies, Environm Hlth Sci Div, Tsukuba, Ibaraki 3058506, Japan. Peking Univ, Sch Publ Hlth, Dept Occupat & Environm Hlth Sci, Beijing 100083, Peoples R China. Gifu Pharmaceut Univ, Dept Hyg, Gifu 5028585, Japan. RP Sone, H (reprint author), NIEHS, Lab Computat Biol & Risk Anal, 111 TW Alexander Dr,Mail Drop A3-06, Res Triangle Pk, NC 27709 USA. EM sone@niehs.nih.gov NR 66 TC 13 Z9 17 U1 0 U2 0 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 AUG PY 2004 VL 25 IS 2 BP 325 EP 333 PG 9 WC Oncology SC Oncology GA 838RG UT WOS:000222730200010 PM 15254729 ER PT J AU Neumann, SA Sollers, JJ Thayer, JF Waldstein, SR AF Neumann, SA Sollers, JJ Thayer, JF Waldstein, SR TI Alexithymia predicts attenuated autonomic reactivity, but prolonged recovery to anger recall in young women SO INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY LA English DT Article DE Alexithymia; autonomic reactivity; recovery; impedance cardiography; heart rate variability ID CORONARY-ARTERY-DISEASE; HEART-RATE-VARIABILITY; CARDIOVASCULAR REACTIVITY; BLOOD-PRESSURE; COPING STYLES; TEST BATTERY; STRESS; RESPONSES; SCALE; RISK AB Alexithymia has been prospectively associated with all-cause mortality and with cardiovascular morbidity. Here, stress-induced autonomic reactivity and recovery were examined as potential pathways linking alexithymia to cardiovascular disease. The relation of alexithymia to blood pressure, heart rate, and other cardiovascular parameters derived from impedance cardiography (N = 80) and heart rate variability (N = 40) was evaluated during rest, an anger recall task and recovery in women (ages 18-30). During anger recall, alexithymia was associated with significantly attenuated heart rate and stroke index reactivity, greater low frequency power, and with marginally dampened blood pressure and high frequency power reactivity. Overall, this response pattern suggests blunted sympathetic activation and diminished vagal withdrawal. Alexithymia was also related to slower diastolic blood pressure and quicker preejection period recovery implying abbreviated sympathetic arousal and possibly greater vagal modulation. These results impart some evidence for the hypoarousal model of alexithymia during reactivity, but the hyperarousal model during recovery. Autonomic dysregulation during and following acute emotional stress is suggested as a possible physiological pathway connecting alexithymia to cardiovascular disease. (C) 2004 Elsevier B.V. All rights reserved. C1 Univ Pittsburgh, Dept Psychiat, Cardivasc Behav Med Res Training Program, Pittsburgh, PA 15260 USA. NIA, Lab Personal & Cognit, Gerontol Res Ctr, Baltimore, MD 21224 USA. Univ Maryland Baltimore Cty, Dept Psychol, Baltimore, MD 21250 USA. Univ Maryland, Sch Med, Ctr Geriatr Res Educ & Clin, Baltimore, MD 21250 USA. NIA, Baltimore Vet Affairs Med Ctr, Baltimore, MD 21250 USA. RP Neumann, SA (reprint author), Univ Pittsburgh, Dept Psychiat, Cardivasc Behav Med Res Training Program, 3811 Ohara St,506 OEH, Pittsburgh, PA 15260 USA. EM neumannsa@msx.upmc.edu; sollersj@grc.nia.nih.gov; thayer@lpc.grc.nia.nih.gov; waldstei@umbc.edu FU NHLBI NIH HHS [HL07560-19]; NIA NIH HHS [AG15112] NR 57 TC 41 Z9 42 U1 2 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8760 J9 INT J PSYCHOPHYSIOL JI Int. J. Psychophysiol. PD AUG PY 2004 VL 53 IS 3 BP 183 EP 195 DI 10.1016/j.ijpsycho.2004.03.008 PG 13 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 841LX UT WOS:000222932700003 PM 15246672 ER PT J AU Menard, C Susil, RC Choyke, P Gustafson, GS Kammerer, W Ning, H Miller, RW Ullman, KL Crouse, NS Smith, S Lessard, E Pouliot, J Wright, V McVeigh, E Coleman, CN Camphausen, K AF Menard, C Susil, RC Choyke, P Gustafson, GS Kammerer, W Ning, H Miller, RW Ullman, KL Crouse, NS Smith, S Lessard, E Pouliot, J Wright, V McVeigh, E Coleman, CN Camphausen, K TI MRI-guided HDR prostate brachytherapy in standard 1.5T scanner SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE prostate cancer; brachytherapy; MRI; image guidance ID DOSE-RATE BRACHYTHERAPY; CONTRAST-ENHANCED MRI; CANCER; BIOPSY; OPTIMIZATION; RADIOTHERAPY; FEASIBILITY; ESCALATION; STAGE; PSA AB Purpose: Magnetic resonance imaging (MRI) provides superior visualization of the prostate and surrounding anatomy, making it the modality of choice for imaging the prostate gland. This pilot study was performed to determine the feasibility and dosimetric quality achieved when placing high-dose-rate prostate brachytherapy catheters under MRI guidance in a standard "closed-bore" 1.5T scanner. Methods and Materials: Patients with intermediate-risk and high-risk localized prostate cancer received MRI-guided high-dose-rate brachytherapy boosts before and after a course of external beam radiotherapy. Using a custom visualization and targeting program, the brachytherapy catheters were placed and adjusted under MRI guidance until satisfactory implant geometry was achieved. Inverse treatment planning was performed using high-resolution T-2-weighted MRI. Results: Ten brachytherapy procedures were performed on 5 patients. The median percentage of volume receiving 100% of prescribed minimal peripheral dose (V-100) achieved was 94% (mean, 92%; 95% confidence interval, 89-95%). The urethral V-125 ranged from 0% to 18% (median, 5%), and the rectal V-75. ranged from 0% to 3.1% (median, 0.3%). In all cases, lesions highly suspicious for malignancy could be visualized on the procedural MRI, and extracapsular disease was identified in 2 patients. Conclusion: High-dose-rate prostate brachytherapy in a standard 1.5T MRI scanner is feasible and achieves favorable dosimetry within a reasonable period with high-quality image guidance. Although the procedure was well tolerated in the acute setting, additional follow-up is required to determine the long-term safety and efficacy of this approach. (C) 2004 Elsevier Inc. C1 NCI, Radiat Oncol Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NHLBI, Dept Radiol, Ctr Clin, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NHLBI, Dept Anesthesia, Ctr Clin, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NHLBI, Cardiac Energet Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA. William Beaumont Hosp, Dept Radiat Oncol, Royal Oak, MI USA. Univ Calif San Francisco, Sch Med, Dept Radiat Oncol, San Francisco, CA 94143 USA. RP Menard, C (reprint author), NCI, Radiat Oncol Branch, NIH, Dept Hlth & Human Serv, Bldg 10,Rm B3B69,900 Rockville Pike, Bethesda, MD 20892 USA. EM menardc@mail.nih.gov FU Intramural NIH HHS [Z01 HL004608-08] NR 36 TC 73 Z9 75 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD AUG 1 PY 2004 VL 59 IS 5 BP 1414 EP 1423 DI 10.1016/j.ijrobp.2004.01.016 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 841LY UT WOS:000222932800020 PM 15275727 ER PT J AU Sparreboom, A Marsh, S Mathijssen, RHJ Verweij, J McLeod, HL AF Sparreboom, A Marsh, S Mathijssen, RHJ Verweij, J McLeod, HL TI Pharmacogenetics of tipifarnib (R115777) transport and metabolism in cancer patients SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE tipifarnib; R115777; pharmacogenetics; polymorphisms ID TRANSFERASE INHIBITOR R115777; EXPRESSION LEVEL; MDR1 GENE; PHASE-I; CYP3A4; C3435T AB The purpose of this study was to perform exploratory relationships between the pharmacokinetics of the farnesyl transferase inhibitor, tipifarnib (R115777, Zarnestra) and allelic variants of genes coding for ATP binding-cassette transporters and drug-metabolizing enzymes. Twenty-eight patients with advanced solid tumors were treated with tipifarnib administered orally at a dose of 200 or 300 mg. Blood samples were collected for pharmacokinetics and genotyping of 10 variants in genes encoding P-glycoprotein (ABCB1), cytochrome P450 isozymes CYP3A4 and CYP3A5, and UDP glucuronosyltransferase isozyme UGT1A1. The homozygous T-allele of ABCB1*8 (1236C > T) was associated with a trend for a higher area under the curve of tipifarnib as compared to patients with only one or no variant alleles [mean (+/-SD), 5,303 +/- 1,620 ng.h/mL vs. 3,619 +/- 1,275 ng.h/mL; P = 0.047). No statistically significant differences were observed with any other genetic variant (P > 0.15). Overall, this study indicates that ABCB1 genotype might be correlated with tipifarnib pharmacokinetics, although considerable overlap in exposure measures between genotype groups was observed. C1 NCI, Med Oncol Clin Res Unit, Clin Pharmacol Res Core, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. Erasmus MC Daniel Den Hoed Canc Ctr, Dept Med Oncol, Rotterdam, Netherlands. RP Sparreboom, A (reprint author), NCI, Med Oncol Clin Res Unit, Clin Pharmacol Res Core, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM SparrebA@mail.nih.gov RI Sparreboom, Alex/B-3247-2008 FU NIGMS NIH HHS [U01 GM63340] NR 22 TC 13 Z9 15 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 J9 INVEST NEW DRUG JI Invest. New Drugs PD AUG PY 2004 VL 22 IS 3 BP 285 EP 289 DI 10.1023/B:DRUG.0000026254.97350.fe PG 5 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 816TO UT WOS:000221132400008 PM 15122075 ER PT J AU Burdette-Radoux, S Tozer, RG Lohmann, RC Quirt, I Ernst, DS Walsh, W Wainman, N Colevas, AD Eisenhauer, EA AF Burdette-Radoux, S Tozer, RG Lohmann, RC Quirt, I Ernst, DS Walsh, W Wainman, N Colevas, AD Eisenhauer, EA TI Phase II trial of flavopiridol, a cyclin dependent kinase inhibitor, in untreated metastatic malignant melanoma SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE melanoma; flavopiridol; cyclin; cyclin-dependent kinase ID CARCINOMA-CELLS; GROWTH-INHIBITION; CANCER CELLS; APOPTOSIS; NEOPLASMS; INFUSION; SURVIVAL; BENEFIT; ARREST AB Purpose: To test the activity of the cyclin dependent kinase (cdk) inhibitor flavopiridol in malignant melanoma, a disease with frequent abnormalities of the cyclin dependent kinase system. Patients and methods: Patients had histologically proven, unidimensionally measurable malignant melanoma, incurable by standard therapy. Prior adjuvant immunotherapy was allowed, but patients were otherwise untreated for advanced disease. Flavopiridol was administered at a dose of 50 mg/m(2) IV over 1 hour daily x 3 days every 3 weeks. Patients were assessed for response every 2 cycles. Results: 17 patients were accrued over 5 months. No objective responses were documented in the 16 patients evaluable for response. Seven patients (44%) had stable disease after 2 cycles, with a median of 2.8 months (range 1.8-9.2). The most common treatment-related non-hematologic toxicities were diarrhea (82%), nausea (47%), fatigue (41%), anorexia (35%) and vomiting (29%). Most treatment-related toxicities were mild, except for diarrhea (grade 3 in 3 patients, grade 4 in 1 patient), nausea (grade 3 in 1 patient) and tumor pain (grade 3 in 1 patient). Hematologic toxicities were minimal, none worse than grade 2. Eighty-eight percent of patients received greater than or equal to90% planned dose intensity; 2 patients had dose reductions for gastrointestinal (GI) toxicity. Conclusions: Flavopiridol is well tolerated at the dose regimen used in this study, with an acceptable (primarily GI) toxicity profile. Although 7 of the 16 patients had stable disease ranging from 1.8 to 9.2 months in duration, there was no evidence of significant clinical activity in malignant melanoma by objective response criteria. C1 McGill Univ, Montreal, PQ, Canada. Hamilton Reg Canc Ctr, Hamilton, ON L8V 1C3, Canada. London Reg Canc Ctr, London, ON N6A 4L6, Canada. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. Tom Baker Canc Clin, Calgary, AB, Canada. NCIC Clin Trials Grp, Kingston, ON, Canada. NCI, CTEP, Rockville, MD USA. RP Burdette-Radoux, S (reprint author), Univ Vermont, Fletcher Allen Hlth Care, Hematol Oncol Unit, UHC Campus,St Joseph 3,1 S Prospect St, Burlington, VT 05401 USA. EM Susan.Burdette-Radoux@vtmednet.org NR 28 TC 59 Z9 65 U1 0 U2 3 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 J9 INVEST NEW DRUG JI Invest. New Drugs PD AUG PY 2004 VL 22 IS 3 BP 315 EP 322 DI 10.1023/B:DRUG.0000026258.02846.1c PG 8 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 816TO UT WOS:000221132400012 PM 15122079 ER PT J AU Smaoui, N Beltaief, O BenHamed, S M'Rad, R Maazoul, F Ouertani, A Chaabouni, H Hejtmancik, JF AF Smaoui, N Beltaief, O BenHamed, S M'Rad, R Maazoul, F Ouertani, A Chaabouni, H Hejtmancik, JF TI A homozygous splice mutation in the HSF4 gene is associated with an autosomal recessive congenital cataract SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID SHOCK TRANSCRIPTION FACTORS; MARNER CATARACT; FAMILY; ACTIVATOR; LINKAGE; EXPRESSION; COLOBOMA; DOMAIN; MAPS; MAF AB PURPOSE. To map the locus and identify the gene causing autosomal recessive congenital cataracts in a large consanguineous Tunisian family. METHODS. DNA was extracted from blood samples from a large Tunisian family with an autosomal recessive, congenital, total white cataract. A genome-wide scan was performed with microsatellite markers. All exons and the splice sites of the HSF4 gene were sequenced in all members of the Tunisian family and in control individuals. RT-PCR was used to detect different transcripts of the HSF4 gene in the human lens. The transcripts were cloned in a TA cloning vector and sequenced. RESULTS. Two-point linkage analyses showed linkage to markers on 16q22 with a maximum lod score of 17.78 at theta = 0.01 with D16S3043. Haplotype analysis refined the critical region to a 1.8-cM (4.8-Mb) interval, flanked by D16S3031 and D16S3095. This region contains HSF4, some mutations of which cause the autosomal dominant Marner cataract. Sequencing of HSF4 showed a homozygous mutation in the 5' splice site of intron 12 ( c. 1327 + 4A-->G), which causes the skipping of exon 12. A more detailed study of the transcripts resulting from alternative splicing of the HSF4 gene in the lens is also reported, showing the major transcript HSF4b. CONCLUSIONS. This is the first report describing association of an autosomal recessive cataract with the HSF4 locus on 16q21q22.1 and the first description of HSF4 splice variants in the lens showing that HSF4b is the major transcript. C1 NEI, OGVFB, NIH, Bethesda, MD 20892 USA. EPS Charles Nicolle, Serv Malad Congenitales & Hereditaires, Tunis, Tunisia. EPS Charles Nicolle, Serv Ophtalmol, Tunis, Tunisia. RP Hejtmancik, JF (reprint author), NEI, OGVFB, NIH, Bldg 10,Room 10B10,10 Ctr Dr MSC 1860, Bethesda, MD 20892 USA. EM f3h@helix.nih.gov NR 24 TC 68 Z9 71 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 AUG PY 2004 VL 45 IS 8 BP 2716 EP 2721 DI 10.1167/iovs.031370 PG 6 WC Ophthalmology SC Ophthalmology GA 841DC UT WOS:000222908500035 PM 15277496 ER PT J AU Kim, H Robinson, MR Lizak, MJ Tansey, G Lutz, RJ Yuan, P Wang, NS Csaky, KG AF Kim, H Robinson, MR Lizak, MJ Tansey, G Lutz, RJ Yuan, P Wang, NS Csaky, KG TI Controlled drug release from an ocular implant: An evaluation using dynamic three-dimensional magnetic resonance imaging SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID RADIOACTIVELY LABELED MICROSPHERES; BLOOD-FLOW; CYTOMEGALOVIRUS RETINITIS; GANCICLOVIR IMPLANT; VITREOUS-HUMOR; MACACA-IRUS; RABBIT EYE; DELIVERY; FLUORESCEIN; DIFFUSION AB PURPOSE. The ability of an episcleral implant at the equator of the eye to deliver drugs to the posterior segment was evaluated, using a sustained-release implant containing gadolinium-DTPA (Gd-DTPA). The movement of this drug surrogate was assessed with magnetic resonance imaging (MRI) in the rabbit eye. The results were compared with a similar implant placed in the vitreous cavity through a scleral incision at the equator. METHODS. Polymer-based implants releasing Gd-DTPA were manufactured and placed in the subconjunctival space on the episclera or in the vitreous cavity in live rabbit eyes ( in vivo) and in freshly enucleated eyes ( ex vivo). Release rates of implants in vitro were also determined. Dynamic three-dimensional MRI was performed using a 4.7-Tesla MRI system for 8 hours. MR images were developed and analyzed on computer. RESULTS. Episcleral implants in vivo delivered a mean total of 2.7 mug Gd-DTPA into the vitreous, representing only 0.12% of the total amount of compound released from the implant in vitro. No Gd-DTPA was detected in the posterior segment of the eye. Ex vivo, the Gd-DTPA concentration in the vitreous was 30 times higher. In vivo eyes with intravitreal implants placed at the equator delivered Gd-DTPA throughout the vitreous cavity and posterior segment. Compartmental analysis of the ocular drug distribution from an episcleral implant showed that the elimination rate constant of Gd-DTPA from the subconjunctival space into the episcleral veins and conjunctival lymphatics was 3-log units higher than the transport rate constant for Gd-DTPA movement into the vitreous. CONCLUSIONS. In vivo, episcleral implants at the equator of the eye did not deliver a significant amount of Gd-DTPA into the vitreous, and no compound was identified in the posterior segment. A 30-fold increase in vitreous Gd-DTPA concentration occurred in the enucleated eyes, suggesting that there are significant barriers to the movement of drugs from the episcleral space into the vitreous in vivo. Dynamic three-dimensional MRI using Gd-DTPA, and possibly other contrast agents, may be useful in understanding the spatial relationships of ocular drug distribution and clearance mechanisms in the eye. C1 NEI, NIH, Bethesda, MD 20892 USA. Off Res Serv, Div Bioengn & Phys Sci, Bethesda, MD USA. NINDS, MRI Res Facil, NIH, Bethesda, MD 20892 USA. NIH, Dept Pharm, Ctr Clin, Bethesda, MD 20892 USA. Univ Maryland, Dept Chem Engn, College Pk, MD 20742 USA. RP Robinson, MR (reprint author), NEI, NIH, 10-10S229,10 Ctr Dr,MSC 1863, Bethesda, MD 20892 USA. EM robinsonm@nci.nih.gov RI Wang, Nam Sun/E-4253-2016 NR 50 TC 79 Z9 83 U1 2 U2 8 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 AUG PY 2004 VL 45 IS 8 BP 2722 EP 2731 DI 10.1167/iovs.04-0091 PG 10 WC Ophthalmology SC Ophthalmology GA 841DC UT WOS:000222908500036 PM 15277497 ER PT J AU Gordiyenko, N Campos, M Lee, JW Fariss, RN Sztein, J Rodriguez, IR AF Gordiyenko, N Campos, M Lee, JW Fariss, RN Sztein, J Rodriguez, IR TI RPE cells internalize low-density lipoprotein (LDL) and oxidized LDL (oxLDL) in large quantities in vitro and in vivo SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID RETINAL-PIGMENT EPITHELIUM; SCAVENGER RECEPTORS; MACULAR DEGENERATION; APOLIPOPROTEIN-B; BRUCHS MEMBRANE; AGE; CHOLESTEROL; ATHEROSCLEROSIS; ACCUMULATION; PHOSPHOLIPIDS AB Purpose. To determine whether plasma low-density lipoprotein (LDL) could be internalized by the RPE and which receptors may be involved. A secondary objective was to determine whether ARPE19 cells could be used as a model to investigate cholesterol processing in the RPE. Methods. Commercially available human LDL was labeled with rhodamine or AlexaFluor 568. Immunofluorescence was performed using commercially available antibodies to LDL-R, CD36, and LOX-1. Cells and tissues were imaged using epifluorescence and confocal fluorescence microscopy. Immunoblot analysis and RT-PCR were performed using published techniques. Results. Intravenously injected rhodamine-labeled LDL (rhoLDL) was detected in the rat RPE by fluorescence confocal microscopy 24 hours after injection. The rhoLDL was present in some areas and absent in others. Cultured ARPE19 cells were also found to internalize LDL and oxidized LDL (oxLDL) readily. Using AlexaFluor 568-labeled LDL we determined that the average cultured RPE cell could internalize approximately 12 to 16 pg of LDL and oxLDL in 24 hours. Immunoblots readily detected the presence of CD36 and LDL-R in the cultured RPE cells but not LOX-1, whereas RT-PCR detected mRNA for all three receptors. Dual-labeling experiments using AlexaFluor 568-labeled LDL and AlexaFluor 488 for the immunolocalization of the receptors showed colocalization of LDL-R with the internalized LDL and CD36 with oxLDL particles. Conclusions. Plasma LDL readily enters the RPE through the choriocapillaris but is not found homogenously throughout the retina. This may suggest some form of regulation to the permeability of the fenestrated choroidal endothelial cell junctions. ARPE19 cells are a good model for studying the internalization mechanisms of LDL and oxLDL in vitro. LDL may be used as a vector to carry hydrophobic molecules into the RPE. C1 NEI, Retinal Cell & Mol Biol Lab, Sect Mech Retinal Dis, NIH, Bethesda, MD 20892 USA. NEI, Vet Res & Resources Sect, NIH, Bethesda, MD 20892 USA. RP Rodriguez, IR (reprint author), NEI, Retinal Cell & Mol Biol Lab, Sect Mech Retinal Dis, NIH, 7 Mem Dr MSC 0706, Bethesda, MD 20892 USA. EM rodriguezi@nei.nih.gov RI Sztein, Jorge/B-7165-2012; OI Sztein, Jorge Mario/0000-0001-7047-2634 NR 26 TC 55 Z9 55 U1 1 U2 4 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 AUG PY 2004 VL 45 IS 8 BP 2822 EP 2829 DI 10.1167/iovs.04-0074 PG 8 WC Ophthalmology SC Ophthalmology GA 841DC UT WOS:000222908500048 PM 15277509 ER PT J AU Rodriguez, IR Alam, S Lee, JW AF Rodriguez, IR Alam, S Lee, JW TI Cytotoxicity of oxidized low-density lipoprotein in cultured RPE cells is dependent on the formation of 7-ketocholesterol SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID OX-LDL RECEPTOR-1; ENDOTHELIAL-CELLS; MACULAR DEGENERATION; SCAVENGER RECEPTORS; OUTER SEGMENTS; CHOLESTEROL; AGE; ATHEROSCLEROSIS; OXYSTEROLS; OXIDATION AB Purpose. To determine which components present in oxidized LDL are responsible for the cytotoxicity associated with its internalization by culture ARPE19 cells. Methods. ARPE19 cells were grown in 24-well and 96-well plates. Cell viability was measured by MTT and/or adenosine triphosphate (ATP) content. LDL was oxidized with Cu+2 and oxysterol content analyzed by a novel HPLC method. Results. OxLDL showed increased cytotoxicity with prolonged oxidation. Analysis of the oxLDL showed a predominance of the 7-oxygenated products, 7alpha-hydroxycholesterol (7alphaHCh), 7beta-hydroxycholesterol (7betaHCh), and 7-ketocholesterol (7kCh). Addition of these oxysterols to the ARPE19 cell in free form indicated that 7kCh is the most cytotoxic of the oxysterols but at physiologically unrealistic concentrations. Partitioning of individual oxysterols into nonoxidized LDL at concentrations similar to those found in the oxLDL also indicated that 7kCh is the most cytotoxic of the oxysterols. Transition metals are tightly bound by LDL and play an important role in the oxidation of LDL, but do not seem to enhance its cytotoxicity directly. Conclusions. Prolonged oxidation of LDL increases the levels of 7kCh due to further oxidation of 7alphaHCh and 7betaHCh. The formation of 7KCh seems to be responsible for most of the cytotoxicity associated with oxLDL internalization in ARPE19 cells. C1 NEI, Retinal Cell & Mol Biol Lab, Sect Mech Retinal Dis, NIH, Bethesda, MD 20892 USA. RP Rodriguez, IR (reprint author), NEI, Retinal Cell & Mol Biol Lab, Sect Mech Retinal Dis, NIH, 7 Mem Dr MSC 0706, Bethesda, MD 20892 USA. EM rodriguezi@nei.nih.gov NR 27 TC 43 Z9 43 U1 1 U2 3 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 AUG PY 2004 VL 45 IS 8 BP 2830 EP 2837 DI 10.1167/iovs.04-0075 PG 8 WC Ophthalmology SC Ophthalmology GA 841DC UT WOS:000222908500049 PM 15277510 ER PT J AU Zivotofsky, AZ AF Zivotofsky, AZ TI The Duncker illusion: Intersubject variability, brief exposure, and the role of eye movements in its generation SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID CHEVREUL PENDULUM ILLUSION; MULLER-LYER-ILLUSION; INDUCED MOTION; STIMULUS MOTION; SMOOTH-PURSUIT; SELF-MOTION; CAPTURE; RESPONSES; TARGET; PATH AB Purpose. The Duncker illusion, also known as induced motion, is the illusory component of an object's motion that results from background movement. The origins of this robust phenomenon are still subject to debate. The goal of this study was to examine the role eye movements play in its generation. Methods. The Duncker illusion was generated by rear-projecting an LED target and a random-dot background onto a semi-translucent screen. Each moved under independent control of mirror galvanometers. The background was either stationary or moved vertically, whereas the target moved horizontally with various degrees of a vertical component. Using a two-alternative, forced-choice cancellation paradigm involving multiple interleaved staircases, seven human subjects quantified the illusion under a variety of conditions. These conditions included varying the exposure time from 50 to 200 ms. Results. The strength of the illusion did not decrease, even when exposures too brief to generate eye movement were used. Four of the subjects showed no difference between long and short exposures (P>0.12). In two the illusion was stronger for short exposures (P<0.05), and in one the illusion was not quantifiable. There was little intrasubject variability across trial types, yet there was a large intersubject variability in the strength of the illusion. Conclusions. The illusion is robust in that it is perceived under a wide variety of conditions by all observers. By varying the parameters, it was possible to demonstrate that eye movements do not play a role in generating the illusion and that this robust illusion is most likely caused by the visual system attributing relative motion between target and background to target motion and ignoring any true background movement. The mechanism by which this occurs varies in degree between individuals. C1 Bar Ilan Univ, Brain Sci Program, Ramat Gan, Israel. NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Zivotofsky, AZ (reprint author), Bar Ilan Univ, Brain Sci Program, Ramat Gan, Israel. EM zivotoa@mail.biu.ac.il NR 24 TC 8 Z9 8 U1 1 U2 3 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 AUG PY 2004 VL 45 IS 8 BP 2867 EP 2872 DI 10.1167/iovs.04-0031 PG 6 WC Ophthalmology SC Ophthalmology GA 841DC UT WOS:000222908500054 PM 15277515 ER PT J AU Self, WT Pierce, R Stadtman, TC AF Self, WT Pierce, R Stadtman, TC TI Cloning and heterologous expression of a Methanococcus vannielii gene encoding a selenium-binding protein SO IUBMB LIFE LA English DT Article DE bound selenium; immunoaffinity chromatography; hydrophobic protein; selenite; selenium mobilization; sequence homology ID FORMATE DEHYDROGENASE; SELENOCYSTEINE; IDENTIFICATION; BIOSYNTHESIS AB The activation and incorporation of selenium into selenocysteine containing selenoproteins has been well established in an Escherichia coli model system but there is little specific information concerning the transport and intracellular trafficking of selenium in biological systems in general. A selenium transport role is a possible function of a novel 42 kDa selenium-binding protein that recently was purified from Methanococcus vannielii. The gene encoding a monomer of this protein ( Sbp) has been cloned, sequenced and heterologously expressed in E. coli. The 8.8 kDa gene product contains 81 amino acids. The recombinant Sbp ( rSbp) protein was shown to bind selenium from added selenite. The bound selenium appeared predominantly in dimeric and tetrameric forms of the protein. The gene encoding Sbp occurs in an operon that contains a carbonic anhydrase gene and selenocysteine-containing formate dehydrogenase genes, suggesting possible roles in selenium-dependent formate metabolism. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Stadtman, TC (reprint author), NHLBI, Biochem Lab, NIH, Bldg 50,Room 2120, Bethesda, MD 20892 USA. EM stadtmat@nhlbi.nih.gov RI Self, William/A-6704-2008 NR 16 TC 7 Z9 10 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1521-6543 J9 IUBMB LIFE JI IUBMB Life PD AUG PY 2004 VL 56 IS 8 BP 501 EP 507 DI 10.1080/15216540400010818 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 869IG UT WOS:000224976000007 PM 15545230 ER PT J AU Hessol, NA Seaberg, EC Preston-Martin, S Massad, LS Sacks, HS Silver, S Melnick, S Abulafia, O Levine, AM AF Hessol, NA Seaberg, EC Preston-Martin, S Massad, LS Sacks, HS Silver, S Melnick, S Abulafia, O Levine, AM CA WIHS Collaborative Study Grp TI Cancer risk among participants in the women's interagency HIV study SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE AIDS; cancer; HIV infection; malignancy; standardized incidence ratio ID COMBINATION ANTIRETROVIRAL THERAPY; INVASIVE CERVICAL-CANCER; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; KAPOSIS-SARCOMA; AIDS; INFECTION; ERA; MALIGNANCIES; LYMPHOMA AB Background: The HIV epidemic has been associated with an increased incidence of specific cancers. However, less is known about cancers occurring in HIV-infected women than men. Methods: To determine the risk of cancer among HIV-infected and at-risk HIV-uninfected women, cancer incidence data from the Women's Interagency HIV Study (WIHS) were compared with data from the population-based United States Surveillance, Epidemiology, and End Results (SEER) registry. Age- and race-adjusted standardized incidence ratios (SIRs) were computed and exact statistical tests were used to measure significance. Results: Among the 1950 women participants (1554 HIV infected, 391 HIV uninfected, and 5 HIV seroconverters), 48 cancers were diagnosed during study follow-up. Among HIV-infected women, significantly (P < 0.05) increased incidence rates were observed for all cancer types (SIR = 1.9), Kaposi sarcoma (SIR = 213.5), non-Hodgkin lymphoma (NHL) (SIR = 19.0), and lung cancer (SIR = 6.3) when compared with SEER rates. Lung cancer incidence was also elevated (P = 0.07) among the HIV-uninfected women (SIR = 6.9), when compared with SEER rates, and was similar to the SIR for HIV-infected women. While the incidence rate of NHL among HIV- infected women was significantly lower during the era of highly active antiretroviral therapy (HAART) compared with the pre-HAART era (relative risk 0.15, P = 0.005), the incidence of NHL among HIV-infected WIHS participants remained significantly higher than in the US population (SIR = 6.4, 95% CI = 1.3-15.5). Conclusion: In the HAART era, the higher rates of cancer among HIV-infected women, coupled with increased life expectancy, should lead to more intensive cancer screening and prevention efforts in this population. C1 Univ Calif San Francisco, Dept Med, San Francisco, CA 94122 USA. Johns Hopkins Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Univ So Calif, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90089 USA. So Illinois Sch Med, Springfield, IL USA. Mt Sinai Sch Med, New York, NY USA. George Washington Univ, Med Ctr, Washington, DC 20052 USA. NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. SUNY Hlth Sci Ctr, Brooklyn, NY 11203 USA. RP Hessol, NA (reprint author), Univ Calif San Francisco, Dept Med, 405 Irving St,2nd Floor, San Francisco, CA 94122 USA. EM nancyh@itsa.ucsf.edu FU NCRR NIH HHS [M01-RR00083, M01-RR00079, M01-RRR00071]; NIAID NIH HHS [U01-AI-31834, U01-AI-34993, U01-AI-34989, U01-AI-35004, U10-AI-42590, U01-AI-34994]; NICHD NIH HHS [U01-HD-32632] NR 29 TC 54 Z9 54 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 1 PY 2004 VL 36 IS 4 BP 978 EP 985 DI 10.1097/00126334-200408010-00013 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 838LU UT WOS:000222715600013 PM 15220706 ER PT J AU Fleisher, TA Oliveira, JB AF Fleisher, TA Oliveira, JB TI Functional and molecular evaluation of lymphocytes SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Review DE lymphocytes; immune deficiency; diagnostic immunology ID SEVERE COMBINED IMMUNODEFICIENCY; HYPER-IGM SYNDROME; B-CELL DEVELOPMENT; FLOW-CYTOMETRY; CYTOKINE PRODUCTION; T-CELLS; LINKED AGAMMAGLOBULINEMIA; BACTERIAL-INFECTIONS; IMMUNE-RESPONSE; MUTATIONS AB The laboratory plays a central role in the evaluation of immune function and is critical in the diagnosis and treatment of immune deficiencies. The range of options available to evaluate lymphocyte function has expanded dramatically as our understanding of the immune system has expanded. As the choices of laboratory tests increase, so also does the need to choose testing in such a way as to appropriately direct the evaluation. Typically, this approach involves starting with screening tests and, on the basis of the results of these tests, deciding whether more sophisticated and expensive testing is warranted. The remarkable developments over the past decade leading to the identification of numerous gene defects underlying a variety of immune deficiencies has moved mutation analysis into the realm of the clinical laboratory. This information could be indispensable for immune deficiency diagnosis, prenatal screening, carrier detection, and family counseling. In this review a sequential approach to evaluating lymphocyte function is presented, starting with readily available screening tests and followed by more complex in vitro testing, including the application of newer assays. The various approaches are presented from the perspective of appropriate use and information garnered, whereas actual details of test procedures are not discussed but are referenced. The evolution of immune function testing suggests that it will continue to develop, and future assays are likely to provide even more insight into specific aspects of the immune response and be linked to immune deficiencies not yet defined. C1 NIH, Serv Immunol, Dept Lab Med, Ctr Clin,Dept Hlth & Human Serv, Bethesda, MD USA. RP Fleisher, TA (reprint author), 10 Cr Dr,MSC 1508, Bethesda, MD 20892 USA. EM tfleisher@nih.gov NR 71 TC 19 Z9 19 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD AUG PY 2004 VL 114 IS 2 BP 227 EP 234 DI 10.1016/j.jaci.2004.06.001 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 847OU UT WOS:000223405600002 PM 15316494 ER PT J AU Chinen, J Shearer, WT AF Chinen, J Shearer, WT TI Advances in asthma, allergy and immunology series 2004: Basic and clinical immunology SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE immunology; regulatory T cells; immunodeficiency; HIV; gene therapy; lymphocyte subsets ID SEVERE COMBINED IMMUNODEFICIENCY; REGULATORY T-CELLS; GENE-THERAPY; HIV-1 REPLICATION; DEFICIENCY; RESPONSES; INFECTION; DISEASE; EXPRESSION; CHILDREN AB This review highlights some of the most significant advances in basic and clinical immunology that were published from August 2002 to December 2003, focusing on manuscripts that appeared in the Journal. Articles selected were those considered most relevant to Journal readers. With regard to basic immunology, this report includes articles describing FcepsilonRI expression in mucosal Langerhans cells and type II dendritic cells, mechanisms of T(H)1 and T(H)2 regulation, the role of Foxp3 in the development of CD4(+)CD25(+) regulatory T cells, and the increasing importance of Toll receptors in immunity. Articles related to clinical immunology that were selected include the first report of lymphocyte subsets values from a large cohort of normal children; the description of new genetic defects in primary immunodeficiencies; a description of the complications of gene therapy for X-linked severe combined immunodeficiency; a report of 79 patients with hyper-IgM syndrome; a report of the mechanism of action and complications of intravenous immunoglobulin; a report of new approaches for immunotherapy; and an article on advances in HIV infection and management, including a report of defensins, small molecules with anti-HIV properties. Also summarized is an article that studied the immune system during a prolonged stay in the Antarctic, a model for human studies on the effect of environmental conditions similar to space expeditions. C1 NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Dept Pediat Allergy & Immunol Sect, Houston, TX 77030 USA. RP Chinen, J (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, 49 Covent Dr,Bldg 49,Room 4A18, Bethesda, MD 20892 USA. EM jchinen@nhgri.nih.gov NR 54 TC 18 Z9 20 U1 2 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD AUG PY 2004 VL 114 IS 2 BP 398 EP 405 DI 10.1016/j.jaci.2004.05.036 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 847OU UT WOS:000223405600030 PM 15316523 ER PT J AU Budge, PJ Graham, BS AF Budge, PJ Graham, BS TI Inhibition of respiratory syncytial virus by RhoA-derived peptides: implications for the development of improved antiviral agents targeting heparin-binding viruses SO JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY LA English DT Article DE RSV; polyanions; fusion inhibition; dextran sulphate; sulphated polysaccharides; antiviral agents; post-attachment neutralization; human immunodeficiency virus; HIV; heparin; heparan sulphate ID HIV-INFECTION; SULFATED POLYSACCHARIDES; ENVELOPE GLYCOPROTEIN; PARAMYXOVIRUS FUSION; SYNTHETIC PEPTIDES; MEMBRANE-FUSION; IN-VITRO; GP120; ATTACHMENT; REGION AB The respiratory syncytial virus (RSV) fusion glycoprotein (F) can interact with the small intracellular GTPase RhoA, and peptides derived from RhoA inhibit RSV replication. These observations initially suggested that RhoA-derived peptides might inhibit RSV replication by disrupting an in vivo interaction between RSV F and RhoA. However, recent data indicate that the antiviral activity of RhoA-derived peptides is not due to competitive inhibition of an hypothesized F-RhoA interaction, but is rather a function of the peptides' intrinsic biophysical properties. We summarize here what is known about the mechanism of RSV inhibition by these peptides and give our opinion regarding the potential implications of this work with regards to RSV biology, and to the development of antiviral agents targeting RSV and other enveloped viruses. C1 NIAID, Viral Pathogenesis Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Med Ctr, Dept Microbiol & Immunol, Nashville, TN 37232 USA. RP Graham, BS (reprint author), NIAID, Viral Pathogenesis Lab, Vaccine Res Ctr, NIH, MSC 3017,Bldg 40,Room 2502,40 Convent Dr, Bethesda, MD 20892 USA. EM bgraham@nih.gov NR 37 TC 13 Z9 15 U1 0 U2 7 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 AUG PY 2004 VL 54 IS 2 BP 299 EP 302 DI 10.1093/jac/dkh355 PG 4 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA 847DE UT WOS:000223372100002 PM 15254023 ER PT J AU Lefman, J Zhang, PJ Hirai, T Weis, RM Juliani, J Bliss, D Kessel, M Bos, E Peters, PJ Subramaniam, S AF Lefman, J Zhang, PJ Hirai, T Weis, RM Juliani, J Bliss, D Kessel, M Bos, E Peters, PJ Subramaniam, S TI Three-dimensional electron microscopic Imaging of membrane invaginations in Escherichia coli overproducing the chemotaxis receptor Tsr SO JOURNAL OF BACTERIOLOGY LA English DT Article ID BACTERIAL CHEMOTAXIS; CHEMORECEPTOR COMPLEX; LIGAND-BINDING; CURVATURE; CLATHRIN; CELLS; LOCALIZATION; ENDOCYTOSIS; SENSITIVITY; SUBUNIT AB Electron tomography is a powerful method for determining the three-dimensional structures of large macromolecular assemblies, such as cells, organelles, and multiprotein complexes, when crystallographic averaging methods are not applicable. Here we used electron tomographic imaging to determine the molecular architecture of Escherichia coli cells engineered to overproduce the bacterial chemotaxis receptor Tsr. Tomograms constructed from fixed, cryosectioned cells revealed that overproduction of Tsr led to formation of an extended internal membrane network composed of stacks and extended tubular structures. We present an interpretation of the tomogram in terms of the packing arrangement of Tsr using constraints derived from previous X-ray and electron-crystallographic studies of receptor clusters. Our results imply that the interaction between the cytoplasmic ends of Tsr is likely to stabilize the presence of the membrane networks in cells overproducing Tsr. We propose that membrane invaginations that are potentially capable of supporting axial interactions between receptor clusters in apposing membranes could also be present in wild-type E. coli and that such receptor aggregates could play an important role in signal transduction during bacterial chemotaxis. C1 Natl Canc Inst, Cell Biol Lab, Natl Inst Hlth, Bethesda, MD 20817 USA. Univ Massachusetts, Dept Chem, Amherst, MA 01003 USA. Netherlands Canc Inst, Div Tumor Biol, Amsterdam, Netherlands. RP Subramaniam, S (reprint author), Natl Canc Inst, Cell Biol Lab, Natl Inst Hlth, Bethesda, MD 20817 USA. EM ss1@nih.gov RI Hirai, Teruhisa/G-2105-2015 OI Hirai, Teruhisa/0000-0002-2114-8149 NR 33 TC 41 Z9 41 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD AUG PY 2004 VL 186 IS 15 BP 5052 EP 5061 DI 10.1128/jb.186.15.5052-5061.2004 PG 10 WC Microbiology SC Microbiology GA 840RJ UT WOS:000222876700030 PM 15262942 ER PT J AU Klein, DC AF Klein, DC TI The 2004 Aschoff/Pittendrigh Lecture: Theory of the origin of the pineal gland - A tale of conflict and resolution SO JOURNAL OF BIOLOGICAL RHYTHMS LA English DT Review DE pinealocyte; retinal photoreceptor; melatonin synthesis; retinoid recycling; serotonin -> melatonin pathway ID ARYLALKYLAMINE N-ACETYLTRANSFERASE; HYDROXYINDOLE-O-METHYLTRANSFERASE; RETINAL-PIGMENT EPITHELIUM; S-ANTIGEN; MACULAR DEGENERATION; MELATONIN SYNTHESIS; RAT PINEAL; PROTEASOMAL PROTEOLYSIS; LIPOFUSCIN FLUOROPHORE; CHICK PINEAL AB A theory is presented that explains the evolution of the pinealocyte from the common ancestral photoreceptor of both the pinealocyte and retinal photoreceptor. Central to the hypothesis is the previously unrecognized conflict between the two chemistries that define these cells-melatonin synthesis and retinoid recycling. At the core of the conflict is the formation of adducts. composed of two molecules of retinaldehyde and one molecule of serotonin, analogous to formation in the retina of the toxic bis-retinyl ethanolamine (A2E). The hypothesis argues that early in chordate evolution, at a point before the genes required for melatonin synthesis were acquired, retinaldehyde-which is essential for photon capture-was depleted by reacting with naturally occurring arylalkylamines (tyramine, serotonin, tryptamine, phenylethylamine) and xenobiotic arylalkylamines. This generated toxic bis-retinyl arylalkylamines (A2AAs). The acquisition of arylalkylamine N-acetyltransferase (AANAT) prevented this by N-acetylating the arylalkylamines. Hydroxyindole-O-methyltransferase enhanced detoxification in the primitive photoreceptor by increasing the lipid solubility of serotonin and bis-retinyl serotonin. After the serotonin --> melatonin pathway was established, the next step leading toward the pinealocyte was the evolution of a daily rhythm in melatonin and the capacity to recognize it as a signal of darkness. The shift in melatonin from metabolic garbage to information developed a pressure to improve the reliability of the melatonin signal, which in turn led to higher levels of serotonin in the photodetector. This generated the conflict between serotonin and retinaldehyde, which was resolved by the cellular segregation of the two chemistries. The result, in primates, is a pineal gland that does not detect light and a retinal photodetector that does not make melatonin. High levels of AANAT in the latter tissue might serve the same function AANAT had when first acquired-prevention of A2AA formation. C1 NICHHD, Sect Neuroendocrinol, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Klein, DC (reprint author), NICHHD, Sect Neuroendocrinol, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. EM kleind@mail.nih.gov RI Jelinek, Milan/C-8515-2011 NR 102 TC 63 Z9 63 U1 0 U2 4 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0748-7304 J9 J BIOL RHYTHM JI J. Biol. Rhythms PD AUG PY 2004 VL 19 IS 4 BP 264 EP 279 DI 10.1177/0748730404267340 PG 16 WC Biology; Physiology SC Life Sciences & Biomedicine - Other Topics; Physiology GA 838DK UT WOS:000222693400002 PM 15245646 ER PT J AU Ahmet, I Wan, RQ Iyun, T Krawczyk, M Mattson, MP Lakatta, EG Talan, MI AF Ahmet, I Wan, RQ Iyun, T Krawczyk, M Mattson, MP Lakatta, EG Talan, MI TI Cardioprotective potential of intermittent fasting in rats SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 8th Annual Scientific Meeting of the Heart-Failure-Society-of-American CY SEP 12-15, 2004 CL Toronto, CANADA SP Heart Failure Soc Amer C1 NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 0 TC 0 Z9 0 U1 0 U2 3 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2004 VL 10 IS 4 SU S MA 261 BP S89 EP S89 DI 10.1016/j.cardfail.2004.06.260 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 853VV UT WOS:000223857900260 ER PT J AU Romanova, LY Hashimoto, S Chay, KO Blagosklonny, MV Sabe, H Mushinski, JF AF Romanova, LY Hashimoto, S Chay, KO Blagosklonny, MV Sabe, H Mushinski, JF TI Phosphorylation of paxillin tyrosines 31 and 118 controls polarization and motility of lymphoid cells and is PMA-sensitive SO JOURNAL OF CELL SCIENCE LA English DT Article DE paxillin; B-lymphocytes; phorbol esters; polarization; motility ID PROTEIN-KINASE-C; FOCAL ADHESION KINASE; PHORBOL ESTER; GROWTH-FACTOR; SH3 DOMAIN; ACTIN CYTOSKELETON; SIGNALING PATHWAYS; PHOSPHATASE-PEST; BINDING PROTEIN; LIM DOMAINS AB Tyrosine phosphorylation of paxillin regulates actin cytoskeleton-dependent changes in cell morphology and motility in adherent cells. In this report we investigated the involvement of paxillin tyrosine phosphorylation in the regulation of actin cytoskeleton-dependent polarization and motility of a non-adherent IL-3-dependent murine pre-B lymphocytic cell line Baf3. We also assessed the effect of phorbol myristate acetate (PMA), a phorbol ester analogous to those currently in clinical trials for the treatment of leukemia, on paxillin phosphorylation. Using tyrosine-to-phenylalanine phosphorylation mutants of paxillin and phosphospecific antibody we demonstrated that IL-3 stimulated phosphorylation of paxillin tyrosine residues 31 and 118, whereas the tyrosines 40 and 181 were constitutively phosphorylated. Phosphorylation of paxillin residues 31 and 118 was required for cell polarization and motility. In the presence of IL-3, PMA dramatically reduced the phosphorylation of residues 31 and 118, which was accompanied by inhibition of cell polarization and motility. This PMA effect was partially recapitulated by expression of exogenous tyrosine 31 and 118 mutants of paxillin. We also demonstrated that PMA inhibited the IL-3-induced and activation-dependent tyrosine phosphorylation of focal adhesion kinase. Thus, our results indicate that phosphorylation of paxillin tyrosine residues 31 and 118 regulates actin-dependent polarization and motility of pre-B Baf3 cells, both of which could be inhibited by PMA. They also suggest that inhibition of upstream signaling by PMA contributes to the decrease of paxillin phosphorylation and subsequent changes in cell morphology. C1 NCI, Mol Genet Sect, Genet Lab, NCI, Bethesda, MD 20892 USA. NCI, Med Branch, NCI, Bethesda, MD 20892 USA. Osaka Biosci Inst, Dept Biol Mol, Suita, Osaka 5650874, Japan. RP Romanova, LY (reprint author), NCI, Mol Genet Sect, Genet Lab, NCI, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM iromanova@partners.org RI Hashimoto, Shigeru/D-7138-2012; Sabe, Hisataka/A-4066-2012 NR 48 TC 20 Z9 21 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD AUG 1 PY 2004 VL 117 IS 17 BP 3759 EP 3768 DI 10.1242/jcs.01206 PG 10 WC Cell Biology SC Cell Biology GA 852CP UT WOS:000223733100007 PM 15252114 ER PT J AU Le Stunff, H Milstien, S Spiegel, S AF Le Stunff, H Milstien, S Spiegel, S TI Generation and metabolism of bioactive sphingosine-1-phosphate SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Review DE sphingosine-1-phosphate; signaling; metabolism; sphingolipid; sphingosine; sphingosine kinase; S1P phosphohydrolase; S1P lyase ID SPHINGOSINE KINASE TYPE-2; PROTEIN-COUPLED RECEPTORS; LIPID PHOSPHATE PHOSPHATASES; FACTOR-INDUCED ACTIVATION; MOLECULAR-CLONING; LYSOPHOSPHATIDIC ACID; FUNCTIONAL-CHARACTERIZATION; CELL-GROWTH; SPHINGOLIPID METABOLISM; SIGNAL-TRANSDUCTION AB Sphingosine-1-phosphate (S1P) is a bioactive lysosphingophospholipid that has been implicated in the regulation of vital biological processes. Abundant evidence indicates that S1P acts as both an intracellular messenger and an extracellular ligand for a family of five specific G protein-coupled S1P receptors (S1PRs). Cellular levels of S1P are tightly regulated in a spatio-temporal manner through its synthesis catalyzed by sphingosine kinases (SphKs) and degradation by S1P lyase (SPL) and specific S1P phosphohydrolases. Over the past decade, the identification and cloning of genes encoding SIP metabolizing enzymes has increased rapidly. Overexpression and deletion of these enzymes has provided important insights into the intracellular and the "inside-out" functions of S1P. The purpose of this review is to summarize the current knowledge of SI P metabolizing enzymes, their enzymatic properties, and their roles in the control of cellular functions by S1P. Published 2004 Wiley-Liss, Inc. C1 Virginia Commonwealth Univ, Sch Med, Dept Biochem, Richmond, VA 23298 USA. Univ Paris 11, CNRS, Lab Activat Cellulaire & Transduct Signaux, Inst Biochim & Biophys Mol & Cellulaire,UMR 8619, F-91405 Orsay, France. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Virginia Commonwealth Univ, Sch Med, Dept Biochem, Richmond, VA 23298 USA. EM sspiegel@vcu.edu FU NCI NIH HHS [CA61774]; NIAID NIH HHS [AI50094]; NIGMS NIH HHS [GM43880] NR 103 TC 87 Z9 89 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 AUG 1 PY 2004 VL 92 IS 5 BP 882 EP 899 DI 10.1002/h=jcb.20097 PG 18 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 842CV UT WOS:000222981500003 PM 15258913 ER PT J AU Jones, TH Clark, DA Edwards, AA Davidson, DW Spande, TF Snelling, RR AF Jones, TH Clark, DA Edwards, AA Davidson, DW Spande, TF Snelling, RR TI The chemistry of exploding ants, Camponotus spp. (cylindricus complex) SO JOURNAL OF CHEMICAL ECOLOGY LA English DT Article DE Camponotus spp.; Hymenoptera; Formicidae; polyacetate-derived aromatics; acyclic terpenes; chemotaxonomy; territoriality; autothysis ID MANDIBULAR GLAND SECRETION; TRAIL PHEROMONE; DICARBOXYLIC-ACIDS; METHYL-OXIDATION; CARPENTER ANTS; ZARAGOZIC ACID; HYMENOPTERA; FORMICIDAE; DERIVATIVES; ALDEHYDES AB A detailed comparative analysis of the exocrine chemistry of nine Bruneian Camponotus species in the cylindricus complex is reported. Workers of these species are known to have hypertrophied mandibular glands and release their glandular contents suicidally from the head by rupturing the intersegmental membrane of the gaster. All of the species produce mixtures of polyacetate-derived aromatics, including hydroxyacetophenones, which display pH-dependent color changes, and aliphatic hydrocarbons and alcohols. In addition, three species contained (6R)-2,6-dimethyl-(2E)-octen-1,8-dioic acid (9) or (3S)-8-hydroxycitro-nellic acid (10a), previously unreported from insects. These compounds were characterized from their spectral data, and confirmed by comparison with synthetic samples. The allomonal role of these compounds is based on numerous field observations, and their chemotaxonomic value is presented. C1 Virginia Mil Inst, Dept Chem, Lexington, VA 24450 USA. Univ Brunei Darussalam, Dept Chem, Gadong 1410, Brunei. Univ Utah, Dept Biol, Salt Lake City, UT 84112 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Nat Hist Museum Los Angeles Cty, Div Entomol, Los Angeles, CA 90007 USA. RP Jones, TH (reprint author), Virginia Mil Inst, Dept Chem, Lexington, VA 24450 USA. EM jonesth@mail.vmi.edu NR 38 TC 14 Z9 15 U1 4 U2 27 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0098-0331 EI 1573-1561 J9 J CHEM ECOL JI J. Chem. Ecol. PD AUG PY 2004 VL 30 IS 8 BP 1479 EP 1492 DI 10.1023/B:JOEC.0000042063.01424.28 PG 14 WC Biochemistry & Molecular Biology; Ecology SC Biochemistry & Molecular Biology; Environmental Sciences & Ecology GA 855NB UT WOS:000223979100001 PM 15537154 ER PT J AU Weise, M Drinkard, B Mehlinger, SL Holzer, SM Eisenhofer, G Charmandari, E Chrousos, GP Merke, DP AF Weise, M Drinkard, B Mehlinger, SL Holzer, SM Eisenhofer, G Charmandari, E Chrousos, GP Merke, DP TI Stress dose of hydrocortisone is not beneficial in patients with classic congenital adrenal hyperplasia undergoing short-term, high-intensity exercise SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID 21-HYDROXYLASE DEFICIENCY; HYPOGLYCEMIA; CHILDREN; EPINEPHRINE; RESPONSES; 2-DEOXY-D-GLUCOSE; BIOAVAILABILITY; CHILDHOOD; CORTISOL; ILLNESS AB Classic congenital adrenal hyperplasia (CAH) is associated with impaired function of the adrenal cortex and medulla leading to decreased production of cortisol and epinephrine. As a result, the normal exercise-induced rise in blood glucose is markedly blunted in such individuals. We examined whether an extra dose of hydrocortisone, similar to that given during other forms of physical stress such as intercurrent illness, would normalize blood glucose levels during exercise in patients with CAH. We studied hormonal, metabolic, and cardiorespiratory parameters in response to a standardized high-intensity exercise protocol in nine adolescent patients with classic CAH. Patients were assigned to receive either an additional morning dose of hydrocortisone or placebo, in addition to their usual glucocorticoid and mineralocorticoid replacement in a randomized, double-blind, crossover design 1 h before exercising. Although plasma cortisol levels approximately doubled after administration of the additional hydrocortisone dose compared with the usual single dose, fasting and exercise-induced blood glucose levels did not differ. In addition, no differences were observed in the serum concentrations of the glucose-modulating hormones epinephrine, insulin, glucagon, and GH and of the metabolic parameters lactate and free fatty acids. Although maximal heart rate was slightly higher after stress dosing (193 +/- 3 vs. 191 +/- 3 beats/min, mean +/- SEM, P < 0.05), this did not affect exercise performance or perceived exertion. We conclude that patients with classic CAH do not benefit from additional hydrocortisone during short-term, high-intensity exercise. Although this has not been tested with long-term exercise, a high degree of caution should be used when considering the frequent use of additional hydrocortisone administration with exercise, given the adverse side effects of glucocorticoid excess. C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Warren Grant Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. RP Merke, DP (reprint author), NIH, Ctr Clin, Bldg 10,Room 13S260,10 Ctr Dr MSC 1932, Bethesda, MD 20892 USA. EM dmerke@nih.gov RI Charmandari, Evangelia/B-6701-2011 NR 25 TC 28 Z9 29 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 AUG PY 2004 VL 89 IS 8 BP 3679 EP 3684 DI 10.1210/jc.2003-032051 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 843IQ UT WOS:000223072400009 PM 15292287 ER PT J AU Courcoutsakis, NA Patronas, NJ Cassarino, D Griffin, K Keil, M Ross, JL Carney, JA Stratakis, CA AF Courcoutsakis, NA Patronas, NJ Cassarino, D Griffin, K Keil, M Ross, JL Carney, JA Stratakis, CA TI Hypodense nodularity on computed tomography: Novel imaging and pathology of micronodular adrenocortical hyperplasia associated with myelolipomatous changes SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CARNEY COMPLEX; CUSHINGS-SYNDROME; DISEASE; GENETICS C1 NICHHD, Sect Endocrinol & Genet, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIH, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Philadelphia, PA 19107 USA. Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. RP Stratakis, CA (reprint author), NICHHD, Sect Endocrinol & Genet, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N262,10 Ctr Dr,MSC 1862, Bethesda, MD 20892 USA. EM stratakc@cc1.nichd.nih.gov NR 7 TC 8 Z9 8 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 AUG PY 2004 VL 89 IS 8 BP 3737 EP 3738 DI 10.1210/jc.2004-0055 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 843IQ UT WOS:000223072400020 PM 15292298 ER PT J AU Hao, W Skarulis, MC Simonds, WF Weinstein, LS Agarwal, SK Mateo, C James-Newton, L Hobbs, GR Gibril, F Jensen, RT Marx, SJ AF Hao, W Skarulis, MC Simonds, WF Weinstein, LS Agarwal, SK Mateo, C James-Newton, L Hobbs, GR Gibril, F Jensen, RT Marx, SJ TI Multiple endocrine neoplasia type 1 variant with frequent prolactinoma and rare gastrinoma SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID FAMILIAL ISOLATED HYPERPARATHYROIDISM; ZOLLINGER-ELLISON-SYNDROME; SYNDROME TYPE-I; MEN1 GENE; GERMLINE MUTATIONS; THYMIC CARCINOIDS; CUSHINGS-DISEASE; 4 KINDREDS; IDENTIFICATION; NEWFOUNDLAND AB No variant of multiple endocrine neoplasia type 1 (MEN1) has been reproducible among families. We examined two large kindreds with MEN1 variants, and we compared these to past reports. The two kindreds were followed up for 20-30 yr with MEN1 tumors in 30 members. Results in cases from two kindreds were that 93% showed parathyroid adenoma, 40% pituitary tumor (always prolactinoma), and 27% enteropancreatic endocrine tumor. The latter included 10% insulinoma, 7% nonfunctioning islet tumor, but only 10% gastrinoma. Compared with prior large series, this lower prevalence of gastrinoma (10% vs. 42%, P < 0.01) and higher prevalence of prolactinoma (40% vs. 22%, P < 0.01) define this variant. Many possible biases of retrospective analyses were excluded as possible explanations. Previously sequenced DNA showed no characteristic MEN1 mutation in these two kindreds and in a third, reported previously; the lack of any shared MEN1 mutation also excluded common ancestry for MEN1 among the three kindreds. The causes for differences between this variant and typical MEN1 are unknown. In conclusion, this variant shows more frequent prolactinoma and less frequent gastrinoma than typical MEN1; the variant is reproducible among kindreds. MEN1 carriers in such families should have periodic monitoring adjusted for the expected penetrance of tumors. C1 NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. W Virginia Univ, Sch Med, Dept Community Med & Stat, Morgantown, WV 26506 USA. RP Marx, SJ (reprint author), NIDDKD, Metab Dis Branch, NIH, Bldg 10,Room 9C-101,9000 Rockville Pike, Bethesda, MD 20892 USA. EM stephenm@intra.niddk.nih.gov RI Agarwal, Sunita/D-1428-2016; OI Agarwal, Sunita/0000-0002-7557-3191; Weinstein, Lee/0000-0002-1899-5152 NR 49 TC 38 Z9 38 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 AUG PY 2004 VL 89 IS 8 BP 3776 EP 3784 DI 10.1210/jc.2003-031511 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 843IQ UT WOS:000223072400026 PM 15292304 ER PT J AU Ilias, I Chang, R Pacak, K Oldfield, EH Wesley, R Doppman, J Nieman, LK AF Ilias, I Chang, R Pacak, K Oldfield, EH Wesley, R Doppman, J Nieman, LK TI Jugular venous sampling: An alternative to petrosal sinus sampling for the diagnostic evaluation of adrenocorticotropic hormone-dependent Cushing's syndrome SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CORTICOTROPIN-RELEASING-HORMONE; DEXAMETHASONE SUPPRESSION TEST; ECTOPIC ACTH-SECRETION; DIFFERENTIAL-DIAGNOSIS; ITALIAN MULTICENTER; STIMULATION TEST; DISEASE; VEIN; PITUITARY; COMPLICATIONS AB Bilateral sampling of the inferior petrosal sinuses (IPSS) to distinguish Cushing's disease from the ectopic ACTH syndrome is accurate but risky and technically difficult. Bilateral sampling of the internal jugular vein (JVS) is simpler and presumably safer. To compare jugular and petrosal sinus venous sampling for distinguishing Cushing's disease from ectopic ACTH syndrome, we studied 74 patients with surgically proven Cushing's disease, 11 with surgically confirmed, and three with occult ectopic ACTH secretion. Patients underwent JVS and IPSS with administration of CRH on separate days. Ratios of central-to-peripheral ACTH in venous samples were calculated. At 100% specificity, IPSS correctly identified 61 of 65 patients with Cushing's disease [sensitivity, 94%; confidence interval (CI), 84-98%]. When patients with abnormal venous drainage were excluded, sensitivity was 98% (CI, 90-100%). JVS had a sensitivity of 83% (CI, 71-91%) at 100% specificity. Receiver operated characteristics plot areas under the curve were similar (0.968 +/- 0.020 and 0.974 +/- 0.016, area under the curve +/- SE, JVS vs. IPSS). Although petrosal sampling had better diagnostic accuracy, CIs overlapped (95% CI, 90-100% vs. 86% CI, 78-94%). Centers with limited sampling experience may choose to use the simpler JVS and refer patients for IPSS when the results are negative. C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Radiol, NIH, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Biostat & Clin Epidemiol Serv, Bethesda, MD 20892 USA. NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Nieman, LK (reprint author), Bldg 10,Room 9D42 MSC 1583,10 Ctr Dr, Bethesda, MD 20892 USA. EM NiemanL@nih.gov NR 39 TC 30 Z9 35 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 AUG PY 2004 VL 89 IS 8 BP 3795 EP 3800 DI 10.1210/jc.2003-032014 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 843IQ UT WOS:000223072400029 PM 15292307 ER PT J AU Kalantaridou, SN Naka, KK Papanikolaou, E Kazakos, N Kravariti, M Calis, KA Paraskevaidis, EA Sideris, DA Tsatsoulis, A Chrousos, GP Michalis, LK AF Kalantaridou, SN Naka, KK Papanikolaou, E Kazakos, N Kravariti, M Calis, KA Paraskevaidis, EA Sideris, DA Tsatsoulis, A Chrousos, GP Michalis, LK TI Impaired endothelial function in young women with premature ovarian failure: Normalization with hormone therapy SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CORONARY-HEART-DISEASE; HEALTHY POSTMENOPAUSAL WOMEN; ESTROGEN PLUS PROGESTIN; RANDOMIZED CONTROLLED TRIAL; FLOW-MEDIATED VASODILATION; NATURAL MENOPAUSE; REPLACEMENT THERAPY; CARDIOVASCULAR MORTALITY; ENDOGENOUS ESTROGEN; BRACHIAL-ARTERY AB Normal menopause is associated with vascular endothelial dysfunction, an early stage of atherosclerosis. The effect of premature ovarian failure ( or premature menopause) on endothelial function in young women is unknown. Endothelial function was assessed in 18 women with premature ovarian failure before and after 6 months of hormone therapy and was compared with the endothelial function of 20 age- and body mass index-matched premenopausal women. Brachial artery diameter was measured both during hyperemia ( an index of endothelium-dependent vasodilation) and in response to glyceryl trinitrate ( an index of endothelium-independent vasodilation). Flow-mediated dilation was significantly lower in women with premature ovarian failure at baseline ( increase in brachial artery diameter during hyperemia by 3.06 +/- 4.33%) than in control women ( increase by 8.84 +/- 2.15%; P < 0.0005). Glyceryl trinitrate-induced vasodilation did not differ between the groups. After hormone therapy for 6 months, flow-mediated dilation was improved in women with premature ovarian failure, increasing by more than 2-fold (7.41 +/- 3.86%; P < 0.005 compared with pretreatment) and reaching normal values ( P not significant compared with control women). Glyceryl trinitrate-induced vasodilation did not change after treatment in women with premature ovarian failure. Young women with premature ovarian failure have significant vascular endothelial dysfunction. Early onset of endothelial dysfunction associated with sex steroid deficiency may contribute to the increased risk of cardiovascular disease and mortality in young women with premature ovarian failure. Hormone therapy restores endothelial function within 6 months of treatment. C1 Univ Ioannina, Sch Med, Univ Hosp,Div Reprod Endocrinol, Dept Obstet & Gynecol, Ioannina 45500, Greece. Univ Ioannina, Sch Med, Michaeleid Cardiac Res Ctr, Ioannina 45500, Greece. Univ Ioannina, Sch Med, Univ Hosp, Dept Endocrinol, Ioannina 45500, Greece. NICHHD, Ctr Clin, Dept Pharm, NIH, Bethesda, MD 20892 USA. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Kalantaridou, SN (reprint author), 3 Kosti Palama St, Ioannina 45221, Greece. EM sophia_kalantaridou@hotmail.com NR 42 TC 100 Z9 107 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 AUG PY 2004 VL 89 IS 8 BP 3907 EP 3913 DI 10.1210/jc.2004-0015 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 843IQ UT WOS:000223072400048 PM 15292326 ER PT J AU Looker, HC Krakoff, J Funahashi, T Matsuzawa, Y Tanaka, S Nelson, RG Knowler, WC Lindsay, RS Hanson, RL AF Looker, HC Krakoff, J Funahashi, T Matsuzawa, Y Tanaka, S Nelson, RG Knowler, WC Lindsay, RS Hanson, RL TI Adiponectin concentrations are influenced by renal function and diabetes duration in Pima Indians with type 2 diabetes SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ADIPOSE-SPECIFIC PROTEIN; INSULIN-RESISTANCE; ESSENTIAL-HYPERTENSION; RISK-FACTORS; MELLITUS; PROGRESSION; POPULATION; DISEASE; HYPOADIPONECTINEMIA; HYPERINSULINEMIA AB Adiponectin is produced exclusively by adipocytes, and its serum concentration is inversely associated with adiposity. This study examines the relationship among diabetes, renal function, and serum adiponectin in Pima Indians. Serum adiponectin was measured in 1069 people in whom glycemia and renal function had been measured. Serum adiponectin, adjusted for age, sex, and body mass index, was lowest in those with impaired glucose regulation or diabetes of less than 10 yr duration and highest in those with normal glucose tolerance or diabetes of duration of at least 10 yr. Both urinary albumin to creatinine ratio (ACR) and serum creatinine were positively correlated with adiponectin ( Spearman's r = 0.43; P < 0.0001, and r = 0.37; P < 0.0001, respectively) in diabetic subjects. After stratification by albuminuria (normoalbuminuria ACR < 30 mg/g, microalbuminuria ACR = 30 - 299 mg/g, and macroalbuminuria ACR >= 300 mg/g), the highest adiponectin concentration was in the macroalbuminuria group ( geometric mean = 9.6 mu g/ml) and the lowest was in the normoalbuminuric group ( geometric mean = 5.6 mu g/ml). After adjustment for age, sex, body mass index, and diabetes duration, the serum adiponectin concentration in the macroalbuminuria group was significantly higher than in both other groups ( P < 0.0001). Serum adiponectin is lowest in the presence of impaired glucose regulation and early diabetes. In the presence of diabetes, serum adiponectin is positively associated with abnormal renal function and diabetes duration. C1 NIDDK, Phoenix, AZ 85014 USA. Osaka Univ, Grad Sch Med, Dept Internal Med & Mol Sci, Suita, Osaka 5650871, Japan. Univ Glasgow, Glasgow G11 6NT, Lanark, Scotland. RP Looker, HC (reprint author), NIDDK, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. EM hlooker@mail.nih.gov RI Nelson, Robert/B-1470-2012; Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 NR 30 TC 81 Z9 94 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 AUG PY 2004 VL 89 IS 8 BP 4010 EP 4017 DI 10.1210/jc.2003-031916 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 843IQ UT WOS:000223072400064 PM 15292342 ER PT J AU Jain, A Fedarko, NS Collins, MT Gelman, R Ankrom, MA Tayback, M Fisher, LW AF Jain, A Fedarko, NS Collins, MT Gelman, R Ankrom, MA Tayback, M Fisher, LW TI Serum levels of matrix extracellular phosphoglycoprotein (MEPE) in normal humans correlate with serum phosphorus, parathyroid hormone and bone mineral density. SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID COMPLEMENT-MEDIATED ATTACK; SIALOPROTEIN; OSTEOMALACIA; OSTEOPONTIN; PHOSPHATE; PROTEINS; EVASION; BINDING; FGF23; OF45 AB Matrix extracellular phosphoglyco-protein (MEPE), a member of the Small Integrin Binding Ligand N-linked Glycoprotein (SIBLING) family, is primarily expressed in normal bone and has been proposed as a phosphaturic factor because of high expression and secretion in oncogenic hypophosphatemic osteomalacia tumors. In order to begin to address the role of MEPE in normal human physiology, we developed a competitive ELISA to measure serum levels of MEPE. The ELISA was used to characterize the distribution pattern in a population consisting of 114 normal adult subjects. The mean value of MEPE was 476 +/- 247 ng/ml and levels decreased significantly with increasing age. MEPE levels were also significantly correlated with serum phosphorus and parathyroid hormone (PTH). In addition, MEPE levels correlated significantly with measures of bone mineral density in the femoral neck and total hip in a subset of 60 elderly subjects. The results are consistent with MEPE being involved in phosphate and bone metabolism in a normal population. C1 Johns Hopkins Univ, Dept Med, Div Geriatr Med, Baltimore, MD 21224 USA. Johns Hopkins Bayview Med Ctr, Gen Clin Res Ctr, Baltimore, MD 21224 USA. Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, DHHS, Bethesda, MD 20892 USA. RP Jain, A (reprint author), Johns Hopkins Univ, Dept Med, Div Geriatr Med, Baltimore, MD 21224 USA. FU NCI NIH HHS [CA87311]; NCRR NIH HHS [M01 RR02719] NR 19 TC 42 Z9 43 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 AUG PY 2004 VL 89 IS 8 BP 4158 EP 4161 DI 10.1210/jc.2003.032031 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 843IQ UT WOS:000223072400086 PM 15292364 ER PT J AU Reveiz, LH Ospina, E Zorrilla, AFC AF Reveiz, LH Ospina, E Zorrilla, AFC TI Should we consider Embase in Latin America? SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Letter ID PUBLICATION BIAS; METAANALYSES C1 Edificio Consultorios Clin Reina Sofia, Bogota, Colombia. NCI, Bethesda, MD 20892 USA. RP Reveiz, LH (reprint author), Edificio Consultorios Clin Reina Sofia, Diagonal 127A,31-48 Cons 221, Bogota, Colombia. EM lureveiz@colsanitas.com NR 9 TC 1 Z9 1 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD AUG PY 2004 VL 57 IS 8 BP 866 EP 866 DI 10.1016/j.jclinepi.2004.02.005 PG 1 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 865RD UT WOS:000224719400018 PM 15485742 ER PT J AU Boehm, M Olive, M True, AL Crook, MF San, H Qu, X Nabel, EG AF Boehm, M Olive, M True, AL Crook, MF San, H Qu, X Nabel, EG TI Bone marrow-derived immune cells regulate vascular disease through a p27(Kip1)-dependent mechanism SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID DEPENDENT KINASE INHIBITOR; SMOOTH-MUSCLE-CELLS; PROGENITOR CELLS; DOWN-REGULATION; MICE LACKING; ATHEROSCLEROSIS; P27(KIP1); PROLIFERATION; LYMPHOCYTES; PATHOGENESIS AB The cyclin-dependent kinase inhibitors are key regulators of cell cycle progression. Although implicated in carcinogenesis, they inhibit the proliferation of a variety of normal cell types, and their role in diverse human diseases is not fully understood. Here, we report that p27(Kip1) plays a major role in cardiovascular disease through its effects on the proliferation of bone marrow-derived (BM-derived) immune cells that migrate into vascular lesions. Lesion formation after mechanical arterial injury was markedly increased in mice with homozygous deletion of p27(Kip1), characterized by prominent vascular infiltration by immune and inflammatory cells. Vascular occlusion was substantially increased when BM-derived cells from p27(-/-) mice repopulated vascular lesions induced by mechanical injury in p27(+/+) recipients, in contrast to p27(+/+) BM donors. To determine the contribution of immune cells to vascular injury, transplantation was performed with BM derived from RAG(-/-) and RAG(+/+) mice. PAG(+/+) BM markedly exacerbated vascular proliferative lesions compared with what was found in RAG(-/-) donors. Taken together, these findings suggest that vascular repair and regeneration is regulated by the proliferation of BM-derived hematopoietic and nonhematopoietic cells through a p27(Kip1)-dependent mechanism and that immune cells largely mediate these effects. C1 NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. RP Nabel, EG (reprint author), NHLBI, Cardiovasc Branch, NIH, Bldg 50,Room 4523,50 Ctr Dr, Bethesda, MD 20892 USA. EM nabele@nhlbi.nih.gov NR 37 TC 48 Z9 48 U1 0 U2 3 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 AUG PY 2004 VL 114 IS 3 BP 419 EP 426 DI 10.1172/jci200420176 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 843HP UT WOS:000223069600016 PM 15286808 ER PT J AU Berzofsky, JA Ahlers, JD Janik, J Morris, J Oh, S Terabe, M Belyakov, IM AF Berzofsky, JA Ahlers, JD Janik, J Morris, J Oh, S Terabe, M Belyakov, IM TI Progress on new vaccine strategies against chronic viral infections SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Review ID HEPATITIS-C VIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; CYTOTOXIC T-LYMPHOCYTES; HUMAN-PAPILLOMAVIRUS TYPE-16; CELLULAR IMMUNE-RESPONSES; NEUTRALIZING ANTIBODY-RESPONSE; COLONY-STIMULATING FACTOR; CHRONIC HIV-1 INFECTION; HIGH-AVIDITY CTL; CERVICAL-CANCER AB Among the most cost-effective strategies for preventing viral infections, vaccines have proven effective primarily against viruses causing acute, self-limited infections. For these it has been sufficient for the vaccine to mimic the natural virus. However, viruses causing chronic infection do not elicit an immune response sufficient to clear the infection and, as a result, vaccines for these viruses must elicit more effective responses - quantitative and qualitative - than does the natural virus. Here we examine the immunologic and virologic basis for vaccines against three such viruses, HIV, hepatitis C virus, and human papillomavirus, and review progress in clinical trials to date. We also explore novel strategies for increasing the immunogenicity and efficacy of vaccines. C1 NCI, Mol Immunogenet & Vaccine Res Sect, Vaccine Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. NCI, Clin Trials Team, Metab Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Berzofsky, JA (reprint author), NCI, Mol Immunogenet & Vaccine Res Sect, Vaccine Branch, Ctr Canc Res,NIH, Bldg 10,Room 6B-12,10 Ctr Dr, Bethesda, MD 20892 USA. EM berzofsk@helix.nih.gov NR 149 TC 87 Z9 95 U1 0 U2 4 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 AUG PY 2004 VL 114 IS 4 BP 450 EP 462 DI 10.1172/JCI200422674 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 846AR UT WOS:000223287500002 PM 15314679 ER PT J AU Yu, ZY Theoret, MR Touloukian, CE Surman, DR Garman, SC Feigenbaum, L Baxter, TK Baker, BM Restifo, NP AF Yu, ZY Theoret, MR Touloukian, CE Surman, DR Garman, SC Feigenbaum, L Baxter, TK Baker, BM Restifo, NP TI Poor immunogenicity of a self/tumor antigen derives from peptide-MHC-I instability and is independent of tolerance SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID T-CELL-ACTIVATION; MELANOMA-REACTIVE CTL; METASTATIC MELANOMA; IMMUNOLOGICAL SYNAPSE; TUMOR-REGRESSION; GP100 MELANOMA; AVIDITY; AUTOIMMUNITY; IMMUNIZATION; LYMPHOCYTES AB Understanding the mechanisms underlying the poor immunogenicity of human self/tumor antigens is challenging because of experimental limitations in humans. Here, we developed a human-mouse chimeric model that allows us to investigate the roles of the frequency and self-reactivity of antigen-specific T cells in determination of the immunogenicity of an epitope (amino acids 209-217) derived from a human melanoma antigen, gp100. In these transgenic mice, CD8(+) T cells express the variable regions of a human T cell receptor (hTCR) specific for an HLA-A*0201-restricted gp100(209-217). Immunization of hTCR-transgenic mice with gp100(209-217) peptide elicited minimal T cell responses, even in mice in which the epitope was knocked out. Conversely, a modified epitope, gp100(209-217(2M)), was significantly more immunogenic. Both biological and physical assays revealed a fast rate of dissociation of the native peptide from the HLA-A*0201 molecule and a considerably slower rate of dissociation of the modified peptide. In vivo, the time allowed for dissociation of peptide-MHC complexes on APCs prior to their exposure to T cells significantly affected the induction of immune responses. These findings indicate that the poor immunogenicity of some self/tumor antigens is due to the instability of the peptide-MHC complex rather than to the continual deletion or tolerization of self-reactive T cells. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. NIAID, Struct Biol Sect, NIH, Rockville, MD 20852 USA. NCI, Sci Applicat Int Corp, Frederick, MD 21701 USA. Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA. Univ Notre Dame, Walther Canc Res Ctr, Notre Dame, IN 46556 USA. RP Restifo, NP (reprint author), NCI, Surg Branch, NIH, Bldg 10,Room 2B46, Bethesda, MD 20892 USA. EM Nicholas_Restifo@nih.gov RI Restifo, Nicholas/A-5713-2008; Baker, Brian/B-4584-2009; OI Baker, Brian/0000-0002-0864-0964; Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 BC010763-01, Z99 CA999999]; NIGMS NIH HHS [GM 067079, R01 GM067079] NR 42 TC 71 Z9 76 U1 0 U2 4 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 AUG PY 2004 VL 114 IS 4 BP 551 EP 559 DI 10.1172/JCI200421695 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 846AR UT WOS:000223287500015 PM 15314692 ER PT J AU Dancey, JE AF Dancey, JE TI Epidermal growth factor receptor and epidermal growth factor receptor therapies in renal cell carcinoma: Do we need a better mouse trap? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID PHASE-II TRIAL; TUMOR-SUPPRESSOR GENE; ANTIBODY C225; FACTOR-ALPHA; INTERFERON GAMMA-1B; ACQUIRED-RESISTANCE; EXPRESSION; CANCER; ANGIOGENESIS; MODULATION C1 NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Rockville, MD USA. RP Dancey, JE (reprint author), NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Rockville, MD USA. NR 24 TC 18 Z9 18 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 AUG 1 PY 2004 VL 22 IS 15 BP 2975 EP 2977 DI 10.1200/JCO.2004.04.934 PG 3 WC Oncology SC Oncology GA 843VN UT WOS:000223115000001 PM 15210735 ER PT J AU Schneider, EC Epstein, AM Malin, JL Kahn, KL Emanuel, EJ AF Schneider, EC Epstein, AM Malin, JL Kahn, KL Emanuel, EJ TI Developing a system to assess the quality of cancer care: ASCO's national initiative on cancer care quality SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID COLONY-STIMULATING FACTORS; CLINICAL-ONCOLOGY SURVEY; BREAST-CANCER; AMERICAN-SOCIETY; HEALTH-CARE; INSURANCE-COVERAGE; RACIAL DISPARITIES; PROSTATE-CANCER; DATA-BASE; OUTCOMES C1 Harvard Univ, Sch Publ Hlth, Dept Hlth Policy Management, Cambridge, MA 02138 USA. Brigham & Womens Hosp, Div Gen Med, Sect Hlth Policy, Boston, MA 02115 USA. Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. NIH, Dept Clin Bioeth, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Schneider, EC (reprint author), Harvard Univ, Sch Publ Hlth, Dept Hlth Policy Management, Cambridge, MA 02138 USA. OI Schneider, Eric/0000-0002-1132-5084 NR 43 TC 84 Z9 84 U1 1 U2 3 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 AUG 1 PY 2004 VL 22 IS 15 BP 2985 EP 2991 DI 10.1200/JCO.2004.09.087 PG 7 WC Oncology SC Oncology GA 843VN UT WOS:000223115000004 PM 15284249 ER PT J AU Ayanian, JZ Chrischilles, EA Wallace, RB Fletcher, RH Fouad, MN Kiefe, CI Harrington, DP Weeks, JC Kahn, KL Malin, JL Lipscomb, J Potosky, AL Provenzale, DT Sandler, RS van Ryn, M West, DW AF Ayanian, JZ Chrischilles, EA Wallace, RB Fletcher, RH Fouad, MN Kiefe, CI Harrington, DP Weeks, JC Kahn, KL Malin, JL Lipscomb, J Potosky, AL Provenzale, DT Sandler, RS van Ryn, M West, DW CA Canc Care Outcomes Res Surveillanc TI Understanding cancer treatment and outcomes: The Cancer Care Outcomes Research and Surveillance Consortium SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID QUALITY-OF-LIFE; COLORECTAL-CANCER; RECTAL-CANCER; LUNG-CANCER; ADJUVANT CHEMOTHERAPY; RACIAL-DIFFERENCES; RADIATION-THERAPY; PROCEDURE VOLUME; HOSPITAL VOLUME; COLON-CANCER C1 No Calif Canc Ctr, Union City, CA USA. Dept Vet Affairs Med Ctr, Minneapolis, MN USA. Univ N Carolina, Dept Med, Div Gastroenterol & Hepatol, Chapel Hill, NC USA. Dept Vet Affairs Med Ctr, Durham, NC USA. NCI, Div Canc Control & Populat Sci, Rockville, MD USA. Univ Calif Los Angeles, Dept Med, Div Gen Internal Med Hlth Serv Res & Hematol Onco, Los Angeles, CA 90024 USA. RAND Corp, Santa Monica, CA USA. Dana Farber Canc Inst, Dept Biostat Sci, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Univ Alabama, Dept Med, Div Prevent Med, Birmingham, AL 35294 USA. Harvard Univ, Sch Med, Harvard Pilgrim Hlth Care, Dept Ambulatory Care & Prevent, Cambridge, MA 02138 USA. Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Div Gen Med, Boston, MA 02115 USA. RP Ayanian, JZ (reprint author), Brigham & Womens Hosp, Dept Med, Div Gen Med, 75 Francis St, Boston, MA 02115 USA. RI VAN RYN, MICHELLE/B-1664-2010 FU NCI NIH HHS [U01 CA93324, U01 CA93326, U01 CA93329, U01 CA93332, U01 CA93339, U01 CA93344, U01 CA93348] NR 39 TC 169 Z9 170 U1 1 U2 9 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 AUG 1 PY 2004 VL 22 IS 15 BP 2992 EP 2996 DI 10.1200/JCO.2004.06.020 PG 5 WC Oncology SC Oncology GA 843VN UT WOS:000223115000005 PM 15284250 ER PT J AU Tan, AR Yang, XW Hewitt, SM Berman, A Lepper, ER Sparreboom, A Parr, AL Figg, WD Chow, C Steinberg, SM Bacharach, SL Whatley, M Carrasquillo, JA Brahim, JS Ettenberg, SA Lipkowitz, S Swain, SM AF Tan, AR Yang, XW Hewitt, SM Berman, A Lepper, ER Sparreboom, A Parr, AL Figg, WD Chow, C Steinberg, SM Bacharach, SL Whatley, M Carrasquillo, JA Brahim, JS Ettenberg, SA Lipkowitz, S Swain, SM TI Evaluation of biologic end points and pharmacokinetics in patients with metastatic breast cancer after treatment with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CELL LUNG-CANCER; ZD1839 IRESSA; PHASE-I; ALPHA-1-ACID GLYCOPROTEIN; DRUG-INTERACTIONS; SOLID TUMORS; C-KIT; EXPRESSION; THERAPY; OSI-774 AB Purpose To evaluate changes in epidermal growth factor receptor (EGFR) phosphorylation and its downstream signaling in tumor and surrogate tissue biopsies in patients with metastatic breast cancer treated with erlotinib, an EGFR tyrosine kinase inhibitor, and to assess relationships between biomarkers in tumor and normal tissues and between biomarkers and pharmacokinetics. Patients and Methods Eighteen patients were treated orally with 150 mg/d of erlotinib. Ki67, EGFR, phosphorylated EGFR (pEGFR), phosphorylated mitogen-activated protein kinase (pMAPK) and phosphorylated AKT (pAKT) in 15 paired tumor, skin, and buccal mucosa biopsies (at baseline and after 1 month of therapy) were examined by immunohistochemistry and analyzed quantitatively. Pharmacokinetic sampling was also obtained. Results The stratum corneum layer and Ki67 in keratinocytes of the epidermis in 15 paired skin biopsies significantly decreased after treatment (P = .0005 and P = .0003, respectively). No significant change in Ki67 was detected in 15 tumors, and no responses were observed. One was EGFR-positive and displayed heterogeneous expression of the receptor, and 14 were EGFR-negative. In the EGFR-positive tumor, pEGFR, pMAPK, and pAKT were reduced after treatment. Paradoxically, pEGFR was increased in EGFR-negative tumors post-treatment (P = .001). Although markers were reduced in surrogate and tumor tissues in the patient with EGFR-positive tumor, no apparent associations were observed in patients with EGFR-negative tumor. Conclusion Erlotinib has inhibitory biologic effects on normal surrogate tissues and on an EGFR-positive tumor. The lack of reduced tumor proliferation may be attributed to the heterogeneous expression of receptor in the EGFR-positive patient and absence of target in this cohort of heavily pretreated patients. C1 NIH, Dept Diagnost Radiol, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NIH, Dept Nucl Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. NCI, Canc Therapeut Branch, Pathol Lab, Bethesda, MD 20892 USA. NCI, Med Oncol Clin Res Unit, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. RP Swain, SM (reprint author), NCI, Canc Therapeut Branch, Ctr Canc Res, 8901 Wisconsin Ave,Bldg 8,Room 5101, Bethesda, MD 20889 USA. EM swains@mail.nih.gov RI Sparreboom, Alex/B-3247-2008; Carrasquillo, Jorge/E-7120-2010; Figg Sr, William/M-2411-2016; OI Hewitt, Stephen/0000-0001-8283-1788; Carrasquillo, Jorge/0000-0002-8513-5734; Swain, Sandra/0000-0002-1320-3830 NR 38 TC 135 Z9 140 U1 0 U2 3 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 AUG 1 PY 2004 VL 22 IS 15 BP 3080 EP 3090 DI 10.1200/JCO.2004.08.189 PG 11 WC Oncology SC Oncology GA 843VN UT WOS:000223115000016 PM 15284258 ER PT J AU Paoluzzi, L Singh, AS Price, DK Danesi, R Mathijssen, RHJ Verweij, J Figg, WD Sparreboom, A AF Paoluzzi, L Singh, AS Price, DK Danesi, R Mathijssen, RHJ Verweij, J Figg, WD Sparreboom, A TI Influence of genetic variants in UGT1A1 and UGT1A9 on the in vivo glucuronidation of SN-38 SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE UGT1A1; UGT1A9; irinotecan; pharmacokinetics; genetic variants; SN-38 ID HUMAN UDP-GLUCURONOSYLTRANSFERASES; JAPANESE CANCER-PATIENTS; IRINOTECAN TOXICITY; 7-ETHYL-10-HYDROXYCAMPTOTHECIN SN-38; CLINICAL PHARMACOKINETICS; ACTIVE METABOLITE; COLORECTAL-CANCER; POLYMORPHISMS; CPT-11; PHARMACOGENOMICS AB The uridine diphosphate glucuronosyltransferose (UGT) 1A1 and 1A9 isoforms are involved in the phase 11 biotransformation of the irinotecan metabolite, SN-38. Recently, several variants in the UGT1A1 and UGT1A9 genes have been described with altered functionality in vitro. The aim of this study was to evaluate the functional consequence of the UGT1A1(TA)(7)TAA (UMA1*28), UGT1A9 766G>A (D256N; UGT1A9*5), and UGT1A9 98T>C (M33T; UGT1A9*3) variants in Caucasian patients treated with irinotecan, Pharmacokinetic studies were performed after the first course of irinotecan in 47 males and 47 females. The mean (+/- SD) area under the curves (AUCs) of irinotecan and SN-38 were 20,348 +/- 6466 ng(.)h/mL and 629 +/- 370 ng(.)h/mL, respectively, which is in line with earlier findings. For UGT1A9*5, no variant alleles were observed, whereas for UGT1A9*3, 1 patient with the variant allele was found (allele frequency, 0.633%). The distribution of the UGT1A1*28 variant showed 44 wildtype patients (Wt), 37 heterozygotes (Het), and 5 homozygotes (Var). The median AUC ratio of SN-38G to SN-38 was significantly reduced in carriers of the variant UGT1A1*28 allele (7.00 [Wt] vs. 6.26 [Het] vs. 2.51 Mar]; p =.022). It is concluded that UGT1A9 functional variants are rare in Caucasians and likely to be clinically insignificant in irinotecan regimens. Screening for the UGT1A1*28 polymorphism may identify patients with altered SN-38 pharmacokinetics. C1 NCI, Clin Pharmacol Res Core, Bethesda, MD 20892 USA. Regina Elena Inst Canc Res, Div Med Oncol, I-00161 Rome, Italy. Howard Hughes Med Inst, Bethesda, MD 20817 USA. NCI, Mol Pharmacol Sect, Bethesda, MD 20892 USA. Univ Pisa, Dept Oncol, Pisa, Italy. Erasmus MC, Dr Daniel Den Hoed Canc Ctr, Rotterdam, Netherlands. RP Figg, WD (reprint author), NCI, Clin Pharmacol Res Core, Bldg 10,Room SA01,MSC 1910,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016; OI Paoluzzi, Luca/0000-0002-2656-5224 NR 34 TC 77 Z9 81 U1 0 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0091-2700 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD AUG PY 2004 VL 44 IS 8 BP 854 EP 860 DI 10.1177/0091270004267159 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 840TU UT WOS:000222883600003 PM 15286088 ER PT J AU Dimmock, JR Gunda, SGR Vashishtha, SC Zello, GA Das, U Nienaber, KH Stables, JP Allen, TM Santos, CL AF Dimmock, JR Gunda, SGR Vashishtha, SC Zello, GA Das, U Nienaber, KH Stables, JP Allen, TM Santos, CL TI Anticonvulsants containing the N-(3-aryl-2-propenoyl) amido pharmacophore SO JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY LA English DT Article DE anticonvulsants; N-acyl-4-piperidones; molecular modeling; semicarbazones; thiosemicarbazones ID ANTIEPILEPTIC DRUG DEVELOPMENT; SYSTEM AB A series of 1-(3-aryl-2-propenoyl)-4-oxopiperidines (1) as well as some related semicarbazones (2) and thiosemicarbazones (3) were prepared in order to determine whether the relative locations of aryl rings and amidic groups would lead to novel anticonvulsant agents. Initially the compounds were administered intraperitoneally to mice and examined in the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and neurotoxicity (NT) screens. The biodata revealed that anticonvulsant properties were displayed by most of the compounds in series (1), in half of the semicarbazones (2) while protection was absent by members of series (3). Molecular modeling was utilized in order to compare the positions of a phenyl ring in relation to amidic groups in representative compounds in series (1-3) with previously reported anticonvulsant agents. Molecular simplification of 4-oxo-1-(3-phenyl-2-propenoyl)piperidine (1a) led to 1-(3-phenyl-2-propenoyl)piperidine (7) and N,N-diethylcinnamamide (8) with retention of anticonvulsant properties. Both (1a) and (8) afforded protection in the hippocampal kindling screen in rats. When administered orally to rats, (1a) and (8) demonstrated activity in the MES screen and in the case of (8), a huge protection index was observed revealing it to be an important lead compound. The IC(50) values of all of the compounds towards murine P388 cells were in excess of 50 muM while several compounds displayed cytotoxicity towards Mycobacterium tuberculosis. C1 Univ Saskatchewan, Coll Pharm & Nutr, Saskatoon, SK S7N 5C9, Canada. Univ Saskatchewan, Dept Biochem, Saskatoon, SK S7N 5E5, Canada. Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. Univ Alberta, Dept Pharmacol, Edmonton, AB T6G 2H7, Canada. RP Dimmock, JR (reprint author), Univ Saskatchewan, Coll Pharm & Nutr, Saskatoon, SK S7N 5C9, Canada. EM dinunock@skyway.usask.ca NR 28 TC 5 Z9 5 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1475-6366 J9 J ENZYM INHIB MED CH JI J. Enzym. Inhib. Med. Chem. PD AUG PY 2004 VL 19 IS 4 BP 303 EP 312 DI 10.1080/1475636042000210063 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 847DC UT WOS:000223371900002 PM 15558945 ER PT J AU Liu, YQ Saxena, A Zheng, CG Carlsen, S Xiang, J AF Liu, YQ Saxena, A Zheng, CG Carlsen, S Xiang, J TI Combined alpha tumor necrosis factor gene therapy and engineered dendritic cell vaccine in combating well-established tumors SO JOURNAL OF GENE MEDICINE LA English DT Article DE TNF-alpha; gene therapy; engineered dendritic cell vaccine; cytotoxic T lymphocyte; antitumor immunity ID IN-VIVO TUMOR; TNF-ALPHA; ANTITUMOR IMMUNITY; ADENOVIRUS VECTORS; PHASE-I; IONIZING-RADIATION; INTERFERON-GAMMA; KAPPA-B; GM-CSF; MURINE AB Background Although current immunotherapeutic strategies including adenovirus (AdV)-mediated gene therapy and dendritic cell (DC) vaccine can all stimulate antitumor cytotoxic T lymphocyte (CLT) responses, their therapeutic efficiency has still been limited to generation of prophylactic antitumor immunity against re-challenge with the parental tumor cells or growth inhibition of small tumors in vivo. However, it is the well-established tumors in animal models that mimic clinical patients with existing tumor burdens. Alpha tumor necrosis factor (TNF-alpha) is a multifunctional and immunoregulatory cytokine that induces antitumor activity and activates immune cells such as DCs and T cells. We hypothesized that a combined immunotherapy including gene therapy and DC vaccine would have some advantages over each modality administered as a monotherapy. Methods We investigated the antitumor immunotherapeutic efficiency of gene therapy by intratumoral injection of AdVTNF-alpha and DC vaccine using subcutaneous injection of TNF-alpha-gene-engineerect DCTNF-alpha cells, and further developed a combined AdV-mediated TNF-alpha-gene therapy and TNF-alpha-gene-engineered DCTNF-alpha vaccine in combating welt-established MO4 tumors expressing the ovalbumin (OVA) gene in an animal model. Results Our data show that vaccination of DCTNF-alpha cells pulsed with the OVA I peptide can (i) stimulate type 1 immune response with enhanced antitumor CTL activities, (ii) induce protective immunity against challenge of 5 x 105 MO4 tumor cells, and (iii) reduce growth of the small (3 - 4 mm in diameter), but not large, established MO4 tumors (6-8 mm in diameter). Our data also show that AdVTNF-alpha-mediated gene therapy can completely eradicate small tumors in 6 out of 8 (75%) mice due to the extensive tumor necrosis formation, but not the large tumors (0%). Interestingly, a combined AdVTNF-alpha-mediated gene therapy and TNF-alpha-gene-engineered DCTNF-alpha vaccine is able to cure 3 out of 8 (38%) mice bearing large MO4 tumors, indicating that the combined immunotherapy strategy is much more efficient in combating well-established tumors than monotherapy of either gene therapy or DC vaccine alone. Conclusions This novel combined immunotherapy may become a tool of considerable conceptual interest in the implementation of future clinical objectives. Copyright (C) 2004 John Wiley Sons, Ltd. C1 Univ Saskatchewan, Res Unit, Saskatchewan Canc Agcy, Dept Microbiol, Saskatoon, SK S7N 4H4, Canada. Univ Saskatchewan, Res Unit, Saskatchewan Canc Agcy, Dept Immunol & Oncol, Saskatoon, SK S7N 4H4, Canada. Univ Saskatchewan, Dept Pathol, Saskatoon, SK S7N 0W0, Canada. NIDR, Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. RP Xiang, J (reprint author), Saskatoon Canc Ctr, 20 Campus Dr, Saskatoon, SK S7N 4H4, Canada. EM JXiang@scf.sk.ca NR 54 TC 13 Z9 16 U1 1 U2 2 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1099-498X J9 J GENE MED JI J. Gene. Med. PD AUG PY 2004 VL 6 IS 8 BP 857 EP 868 DI 10.1002/jgm.579 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 847YL UT WOS:000223433900003 PM 15293344 ER PT J AU Goold, SD Green, SA Biddle, AK Benavides, E Danis, M AF Goold, SD Green, SA Biddle, AK Benavides, E Danis, M TI Will insured citizens give up benefit coverage to include the uninsured? SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE public opinion; consumer participation; medically uninsured; health priorities; resource allocation ID DEMOCRATIC DECISION-MAKING; HEALTH-CARE; PROCEDURAL JUSTICE; INSURANCE; PREFERENCES; ANTECEDENTS; JUDGMENTS; MEDICARE AB OBJECTIVE: To describe the willingness of insured citizens to trade off their own health benefits to cover the uninsured. DESIGN: Descriptive study of individual and group decisions and decision making using quantitative and qualitative methods. SETTING AND PARTICIPANTS: Twenty-nine groups of citizens (N= 282) residing throughout Minnesota. INTERVENTIONS: Groups participated in Choosing Healthplans All Together (CHAT), a simulation exercise in which participants choose whether and how extensively to cover health services in a hypothetical health plan constrained by limited resources. We describe individual and group decisions, and group dialogue concerning whether to allocate 2% of their premium to cover uninsured children in Minnesota, or 4% of their premium to cover uninsured children and adults. MEASUREMENTS AND MAIN RESULTS: While discussing coverage for the uninsured, groups presented arguments about personal responsibility, community benefit, caring for the vulnerable, social impact, and perceptions of personal risk. All groups chose to insure children; 22 of 29 groups also insured adults. More individuals chose to cover the uninsured at the end of the exercise, after group deliberation, than before (66% vs 54%; P < .001). Individual selections differed from group selections more often for the uninsured category than any other. Nevertheless, 89% of participants were willing to abide by the health plan developed by their group. CONCLUSION: In the context of tradeoffs with their own health insurance benefits, groups of Minnesotans presented value-based arguments about covering the uninsured. All 29 groups and two thirds of individuals chose to contribute a portion of their premium to insure all children and most groups chose also to insure uninsured adults. C1 Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA. NIH, Sect Eth & Hlth Policy, Dept Clin Bioeth, Bethesda, MD 20892 USA. Univ N Carolina, Dept Hlth Policy & Adm, Chapel Hill, NC USA. RP Goold, SD (reprint author), Univ Michigan, Sch Med, Dept Internal Med, 300 NIB,Room 7C27, Ann Arbor, MI 48109 USA. EM sgoold@umich.edu OI Biddle, Andrea/0000-0003-0273-7439; Goold, Susan Dorr/0000-0002-0258-9774 NR 34 TC 13 Z9 13 U1 0 U2 2 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD AUG PY 2004 VL 19 IS 8 BP 868 EP 874 DI 10.1111/j.1525-1497.2004.32102.x PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 834OW UT WOS:000222421400009 PM 15242473 ER PT J AU Kocisko, DA Morrey, JD Race, RE Chen, JC Caughey, B AF Kocisko, DA Morrey, JD Race, RE Chen, JC Caughey, B TI Evaluation of new cell culture inhibitors of protease-resistant prion protein against scrapie infection in mice SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; INCUBATION PERIOD; PRP ACCUMULATION; DEXTRAN SULFATE; CONGO RED; QUINACRINE; THERAPY; SPLEEN; MOUSE; DRUGS AB In vitro inhibitors of the accumulation of abnormal (protease-resistant) prion protein (PrP-res) can sometimes prolong the lives of scrapie-infected rodents. Here, transgenic mice were used to test the in vivo anti-scrapie activities of new PrP-res inhibitors, which, because they are approved drugs or edible natural products, might be considered for clinical trials in humans or livestock with transmissible spongiform encephalopathies (TSEs). These inhibitors were amodiaquine, thioridazine, thiothixene, trifluoperazine, tetrandrine, tannic acid and polyphenolic extracts of tea, grape seed and pine bark. Test compounds were administered for several weeks beginning 1-2 weeks prior to, or 2 weeks after, intracerebral or intraperitoneal 263K scrapie challenge. Tannic acid was also tested by direct preincubation with inoculum. None of the compounds significantly prolonged the scrapie incubation periods. These results highlight the need to assess TSE inhibitors active in cell culture against TSE infections in vivo prior to testing these compounds in humans and livestock. C1 NIAID, Rocky Mt Lab, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. Utah State Univ, Inst Antiviral Res, Anim Dairy & Vet Sci Dept, Logan, UT 84322 USA. Utah State Univ, Inst Antiviral Res, Ctr Biotechnol, Logan, UT 84322 USA. RP Kocisko, DA (reprint author), NIAID, Rocky Mt Lab, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. EM DKocisko@niaid.nih.gov FU NIAID NIH HHS [N01-AI-15435] NR 27 TC 28 Z9 31 U1 0 U2 1 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD AUG PY 2004 VL 85 BP 2479 EP 2483 DI 10.1099/vir.0.80082-0 PN 8 PG 5 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 845XU UT WOS:000223279500041 PM 15269390 ER PT J AU Bennink, JR AF Bennink, JR TI Making the connection: Antibody responsiveness and MHC genes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IMMUNE-RESPONSE; INBRED MICE; HYPERSENSITIVITY; LOCUS C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Bennink, JR (reprint author), NIAID, Viral Dis Lab, NIH, 4 Ctr Dr,MSC 0440,Bldg 4,Room 201, Bethesda, MD 20892 USA. EM jbennink@nih.gov NR 9 TC 0 Z9 0 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 AUG 1 PY 2004 VL 173 IS 3 BP 1499 EP 1499 PG 1 WC Immunology SC Immunology GA 839TF UT WOS:000222807100001 PM 15265874 ER PT J AU Teleshova, N Kenney, J Jones, J Marshall, J Van Nest, G Dufour, J Bohm, R Lifson, JA Gettie, A Pope, M AF Teleshova, N Kenney, J Jones, J Marshall, J Van Nest, G Dufour, J Bohm, R Lifson, JA Gettie, A Pope, M TI CpG-C immunostimulatory oligodeoxyribonucleotide activation of plasmacytoid dendritic cells in rhesus macaques to augment the activation of IFN-gamma-secreting Simian immunodeficiency virus-specific T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTERFERON-PRODUCING CELLS; HIV-INFECTED INDIVIDUALS; HERPES-SIMPLEX-VIRUS; DOUBLE-STRANDED-RNA; MHC CLASS-II; HUMAN BLOOD; IN-VITRO; B-CELL; ANTIGEN PRESENTATION; ALPHA-INTERFERON AB There are two principle subsets of dendritic cells (Ms); CD11c(+)CD123(-) myeloid DCs (MDCs) and CD11c(-)CD123(+) plasmacytoid DCs (PDCs). DC activation via TNF-TNFRs (e.g., CD40L) and TLRs (e.g., immunostimulatory oligodeoxyribonucleotides (ISS-ODNs)) is crucial for maximal stimulation of innate and adaptive immunity. Macaque DC biology is being studied to improve HIV vaccines using the SIV macaque model. Using lineage (Lin) markers to exclude non-DCs, Lin(-)HLA-DR(+)CD11c(+)CD123(-) MDCs and Lin(-)HLA-DR(+)CD11c(-)CD123(+) PDCs were identified in the blood of uninfected macaques and healthy macaques infected with SIV or simian-human immunodeficiency virus. Overnight culture of DC-enriched Lin-depleted cells increased CD80 and CD86 expression. IL-12 production and CD80/CD86 expression by MDC/PDC mixtures was further enhanced by CD40L and ISS-ODN treatment. A CpG-B ISS-ODN increased CD80/CD86 expression by PDCs, but resulted in little IFN-alpha secretion unless IL-3 was added. In contrast, a CpG-C ISS-ODN and aldrithiol-2-inactivated (AT-2) SIV induced considerable PDC activation and IFN-a release without needing exogenous IL-3. The CpG-C ISS-ODN also stimulated IL-12 release (unlike AT-2 SIV) and augmented DC immunostimulatory activity, increasing SIV-specific T cell IFN-gamma production induced by AT-2 SIV-presenting MDC/PDC-enriched mixtures. These data highlight the functional capacities of MDCs and PDCs in naive as well as healthy, infected macaques, revealing a promising CpG-C ISS-ODN-driven DC activation strategy that boosts immune function to augment preventative and therapeutic vaccine efficacy. C1 Populat Council, Ctr Biomed Res, New York, NY 10021 USA. Dynvax Technol Berkeley, Albany, CA 94710 USA. Tulane Univ, Tulane Natl Primate Res Ctr, Covington, LA 70433 USA. NCI, Retroviral Pathogenesis Lab, AIDS Vaccine Program, Sci Applicat Int Corp, Frederick, MD 21702 USA. Aaron Diamond AIDS Res Ctr, New York, NY 10016 USA. RP Pope, M (reprint author), Populat Council, Ctr Biomed Res, 1230 York Ave, New York, NY 10021 USA. EM mpope@popcouncil.org FU NCRR NIH HHS [RR00164]; NIAID NIH HHS [R01 AI40877, R21 AI52060] NR 85 TC 56 Z9 58 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2004 VL 173 IS 3 BP 1647 EP 1657 PG 11 WC Immunology SC Immunology GA 839TF UT WOS:000222807100020 PM 15265893 ER PT J AU Zhang, J Chiang, YPJ Hodes, RJ Siraganian, RP AF Zhang, J Chiang, YPJ Hodes, RJ Siraganian, RP TI Inactivation of c-Cbl or Cbl-b differentially affects signaling from the high affinity IgE receptor SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CELL ANTIGEN RECEPTOR; PROTEIN-TYROSINE KINASE; FC-EPSILON-RI; T-CELLS; PHOSPHATIDYLINOSITOL 3-KINASE; PROTOONCOGENE PRODUCT; MEDIATED UBIQUITINATION; NEGATIVE REGULATION; RBL-2H3 CELLS; SH3 DOMAIN AB The Cbl family of proteins negatively regulate signaling from tyrosine kinase-coupled receptors. Among the three members of this family, only c-Cbl and Cbl-b are expressed in hemopoietic cells. To examine the role of c-Cbl and Cbl-b in FcepsilonRI signaling, mast cell cultures from wild-type, c-Cbl(-/-), and Cbl-b(-/-) mice were generated. Cell growth rates and cell surface expression of FcepsilonRI were similar in the different cell populations. Compared with control cells, Cbl-b inactivation resulted in increases in FcepsilonRI-induced Ca2+ response and histamine release. FcepsilonRI-induced tyrosine phosphorylation of total cellular proteins, Syk, and phospholipase C-gamma was also enhanced by Cbl-b deficiency, whereas receptor-initiated phosphorylation of Vav, JNK, and p38 kinases was not changed in these cells. In contrast to Cbl-b, c-Cbl deficiency had no detectable effect on FcepsilonRI-induced histamine release or on the phosphorylation of total cellular proteins or Syk. The absence of c-Cbl increased the phosphorylation of ERK after receptor stimulation, but resulted in slightly reduced p38 phosphorylation and Ca2+ response. These results suggest that Cbl-b and c-Cbl have divergent effects on FcepsilonRI signal transduction and that Cbl-b, but not c-Cbl, functions as a negative regulator of FcepsilonRI-induced degranulation. C1 Natl Inst Dental & Craniofacial Res, RAST Sect, NIH, Oral Infect & Immun Branch, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Siraganian, RP (reprint author), Natl Inst Dental & Craniofacial Res, RAST Sect, NIH, Oral Infect & Immun Branch, Bldg 10-Room 1N106, Bethesda, MD 20892 USA. EM rs53x@nih.gov NR 43 TC 26 Z9 27 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2004 VL 173 IS 3 BP 1811 EP 1818 PG 8 WC Immunology SC Immunology GA 839TF UT WOS:000222807100039 PM 15265912 ER PT J AU Bonniaud, P Kolb, M Galt, T Robertson, J Robbins, C Stampfli, M Lavery, C Margetts, PJ Roberts, AB Gauldie, J AF Bonniaud, P Kolb, M Galt, T Robertson, J Robbins, C Stampfli, M Lavery, C Margetts, PJ Roberts, AB Gauldie, J TI Smad3 null mice develop airspace enlargement and are resistant to TGF-beta-mediated pulmonary fibrosis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TISSUE GROWTH-FACTOR; MATRIX-METALLOPROTEINASE EXPRESSION; ALVEOLAR MACROPHAGES; SIGNAL-TRANSDUCTION; TARGETED DISRUPTION; LUNG FIBROSIS; MESSENGER-RNA; LACKING SMAD3; GENE-TRANSFER; INHIBITOR AB Transforming growth factor-beta1 plays a key role in the pathogenesis of pulmonary fibrosis, mediating extracellular matrix (ECM) gene expression through a series of intracellular signaling molecules, including Smad2 and Smad3. We show that Smad3 null mice (knockout (KO)) develop progressive age-related increases in the size of alveolar spaces, associated with high spontaneous presence of matrix metalloproteinases (MMP-9 and MMP-12) in the lung. Moreover, transient overexpression of active TGF-beta1 in lungs, using adenoviral vector-mediated gene transfer, resulted in progressive pulmonary fibrosis in wild-type mice, whereas no fibrosis was seen in the lungs of Smad3 KO mice up to 28 days. Significantly higher levels of matrix components (procollagen 3A1, connective tissue growth factor) and antiproteinases (plasminogen activator inhibitor-1, tissue inhibitor of metalloproteinase-1) were detected in wild-type lungs 4 days after TGF-beta1 administration, while no such changes were seen in KO lungs. These data suggest a pivotal role of the Smad3 pathway in ECM metabolism. Basal activity of the pathway is required to maintain alveolar integrity and ECM homeostasis, but excessive signaling through the pathway results in fibrosis characterized by inhibited degradation and enhanced ECM deposition. The Smad3 pathway is involved in pathogenic mechanisms mediating tissue destruction (lack of repair) and fibrogenesis (excessive repair). C1 McMaster Univ, Dept Pathol & Mol Med, Ctr Gene Therapeut, Hamilton, ON L8N 3Z5, Canada. CHU Bocage, Serv Pneumol & Reanimat Resp, Dijon, France. Univ Bourgogne, Dijon, France. Univ Wurzburg, Med Klin, D-8700 Wurzburg, Germany. NCI, NIH, Bethesda, MD 20892 USA. RP Gauldie, J (reprint author), McMaster Univ, Dept Pathol & Mol Med, Ctr Gene Therapeut, 1200 Main St W,Room 2N16, Hamilton, ON L8N 3Z5, Canada. EM gauldie@mcmaster.ca NR 62 TC 212 Z9 222 U1 1 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 AUG 1 PY 2004 VL 173 IS 3 BP 2099 EP 2108 PG 10 WC Immunology SC Immunology GA 839TF UT WOS:000222807100073 PM 15265946 ER PT J AU Ferrari, G Neal, W Ottinger, J Jones, AM Edwards, BH Goepfert, P Betts, MR Koup, RA Buchbinder, S McElrath, MJ Tartaglia, J Weinhold, KJ AF Ferrari, G Neal, W Ottinger, J Jones, AM Edwards, BH Goepfert, P Betts, MR Koup, RA Buchbinder, S McElrath, MJ Tartaglia, J Weinhold, KJ TI Absence of immunodominant anti-gag p17 (SL9) responses among gag CTL-Positive, HIV-uninfected vaccine recipients expressing the HLA-A*0201 allele SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; IMMUNODEFICIENCY-VIRUS TYPE-1; HEPATITIS-C VIRUS; PRIMARY IMMUNE-RESPONSE; LOW VIRAL LOAD; CELL RESPONSES; PRIMARY INFECTION; PERIPHERAL-BLOOD; RHESUS-MONKEYS; PLASMA VIREMIA AB According to a number of previous reports, control of HIV replication in humans appears to be linked to the presence of anti-HIV-1 Gag-specific CD8 responses. During the chronic phase of HIV-1 infection, up to 75% of the HIV-infected individuals who express the histocompatibility leukocyte Ag (HLA)-A*0201 recognize the Gag p17 SLYNTVATL (aa residues 77-85) epitope (SL9). However, the role of the anti-SL9 CD8 CTL in controlling HIV-1 infection remains controversial. In this study we determined whether the pattern of SL9 immunodominance in uninfected, HLA-A*0201 HIV vaccine recipients is similar to that seen in chronically HIV-infected subjects. The presence of anti-SL9 responses was determined using a panel of highly sensitive cellular immunoassays, including peptide:MHC tetramer binding, IFN-gamma ELISPOT, and cytokine flow cytometry. Thirteen HLA-A*0201 vaccinees with documented anti-Gag CD8 CTL reactivities were tested, and none had a detectable anti-SL9 response. These findings strongly suggest that the pattern of SL9 epitope immunodominance previously reported among chronically infected, HLA-A*0201-positive patients is not recapitulated in noninfected recipients of Gag-containing canarypox-based candidate vaccines and may be influenced by the relative immunogenicity of these constructs. C1 Duke Univ, Med Ctr, Dept Surg, Durham, NC 27707 USA. Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27707 USA. Univ Alabama, Dept Med, Div Infect Dis, Birmingham, AL 35294 USA. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. San Francisco Dept Publ Hlth, San Francisco, CA 94102 USA. Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Aventis Pasteur, Toronto, ON, Canada. RP Ferrari, G (reprint author), Duke Univ, Med Ctr, Dept Surg, POB 2926, Durham, NC 27707 USA. EM gflmp@duke.edu RI Ferrari, Guido/A-6088-2015 FU NIAID NIH HHS [5U01AI46725, 5R01AI50483, 3P30AI28662] NR 66 TC 22 Z9 25 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2004 VL 173 IS 3 BP 2126 EP 2133 PG 8 WC Immunology SC Immunology GA 839TF UT WOS:000222807100076 PM 15265949 ER PT J AU Castle, PE Schiffman, M Bratti, MC Hildesheim, A Herrero, R Hutchinson, ML Rodriguez, AC Wacholder, S Sherman, ME Kendall, H Viscidi, RP Jeronimo, J Schussler, JE Burk, RD AF Castle, PE Schiffman, M Bratti, MC Hildesheim, A Herrero, R Hutchinson, ML Rodriguez, AC Wacholder, S Sherman, ME Kendall, H Viscidi, RP Jeronimo, J Schussler, JE Burk, RD TI A population-based study of vaginal human papillomavirus infection in hysterectomized women SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CERVICAL INTRAEPITHELIAL NEOPLASIA; POLYMERASE-CHAIN-REACTION; POST-CONE BIOPSY; RURAL COSTA-RICA; FOLLOW-UP; PREVALENCE; CANCER; DNA; SEROPREVALENCE; WORLDWIDE AB We compared point prevalences and determinants of human papillomavirus (HPV) DNA detection by testing enrollment vaginal specimens from hysterectomized women (n=569) and enrollment cervical specimens from nonhysterectomized women (n=6098) greater than or equal to30 years old, using MY09/MY11 L1 consensus-primer polymerase chain reaction. The subjects were participating in a population-based cohort study (n=10,049) in Guanacaste, Costa Rica, that was initiated in 1993. Non-cancer-associated HPV types, especially types 61, 71, and 72, were detected more frequently in the vaginal specimens from hysterectomized women (23.7% [95% confidence interval {CI}, 20.3%-27.4%]) than in the cervical specimens from nonhysterectomized women (16.7% [95% CI, 15.7%-17.6%]) (P=.0001). There was no difference between the prevalences of cancer-associated HPV types in hysterectomized women and those in nonhysterectomized women; in both groups, the prevalence of HPV DNA was greater in women with multiple lifetime sex partners. We infer from our data that the cervical transformation zone may not be needed for cancer-associated HPV infection but may be uniquely susceptible to HPV-induced carcinogenesis; we also infer that specific phylogenetic groups of HPV (i.e., A3/A4/A15) may have a predilection for vaginal epithelium. C1 NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. Informat Management Serv Inc, Silver Spring, MD USA. Brown Univ, Women & Infants Hosp, Providence, RI USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. Costa Rican Fdn Training Hlth Sci, Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, 6120 Execut Blvd,Rm 7074,EPS MSC 7234, Bethesda, MD 20892 USA. EM castlep@mail.nih.gov FU NCI NIH HHS [N01CP31061, CA78527, N01CP21081] NR 24 TC 48 Z9 48 U1 0 U2 0 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 AUG 1 PY 2004 VL 190 IS 3 BP 458 EP 467 DI 10.1086/421916 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 836IQ UT WOS:000222549500005 PM 15243917 ER PT J AU Le, T Cherry, JD Chang, SJ Knoll, MD Lee, ML Barenkamp, S Bernstein, D Edelman, R Edwards, KM Greenberg, D Keitel, W Treanor, J Ward, JI AF Le, T Cherry, JD Chang, SJ Knoll, MD Lee, ML Barenkamp, S Bernstein, D Edelman, R Edwards, KM Greenberg, D Keitel, W Treanor, J Ward, JI TI Immune responses and antibody decay after immunization of adolescents and adults with an acellular pertussis vaccine: The APERT study SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID BORDETELLA-PERTUSSIS; CHANGING EPIDEMIOLOGY; HOUSEHOLD EXPOSURE; COUGH ILLNESSES; HEALTHY-ADULTS; YOUNG INFANTS; UNITED-STATES; TRIAL; INFECTIONS; ANTIGENS AB As part of a prospective acellular pertussis (ACP) vaccine efficacy trial, 5 serum samples were obtained, over an 18-month period, from 101 ACP-vaccine recipients and 99 control subjects, to assess ACP antibody response and decay. Immunoglobulin (Ig) G and IgA antibodies to pertussis toxin ( PT), filamentous hemagglutinin (FHA), pertactin (PRN), and fimbriae 2/3 (FIM) were measured by enzyme-linked immunosorbant assay, and titers of agglutinin were determined. Of the subjects, 16% - 19% had preimmunization values of antibodies to PT that were above the assay's limit of quantitation (LOQ); in contrast, 36% - 63% of the subjects had preimmunization values of antibodies to FHA, PRN, or FIM that were above the LOQ. Substantial increases in titers of IgG and IgA antibodies to the 3 ACP antigens ( PT, FHA, and PRN) were observed. Over the 18-months, the percent decay in IgG and IgA antibodies ranged from 56% to 73% and from 57% to 70%, respectively; the IgG antibody response and decay suggests that geometric mean titers likely remain above the LOQ for 2 - 9 years and above the threshold of detection for 4 - 13 years. These findings support the use of ACP booster immunizations for adolescents and adults, to provide sustained levels of antibody. C1 Univ Calif Los Angeles, Los Angeles Cty Harbor Med Ctr, Ctr Vaccine Res, Sch Med,Res & Educ Inst, Torrance, CA 90502 USA. NIAID, NIH, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. Univ Pittsburgh, Childrens Hosp Pittsburgh, Sch Med, Pittsburgh, PA USA. Cincinnati Chidrens Hosp Med Ctr, Div Infect Dis, Cincinnati, OH USA. Vanderbilt Univ, Med Ctr, Pediat Clin Res Off, Nashville, TN USA. St Louis Univ, St Louis, MO 63103 USA. Baylor Coll Med, Houston, TX 77030 USA. Univ Rochester, Rochester, NY USA. RP Ward, JI (reprint author), Univ Calif Los Angeles, Los Angeles Cty Harbor Med Ctr, Ctr Vaccine Res, Sch Med,Res & Educ Inst, 1124 W Carson St,Blddg E-6, Torrance, CA 90502 USA. EM joelward@ucla.edu FU NIAID NIH HHS [N01-AI-45249] NR 47 TC 85 Z9 87 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 AUG 1 PY 2004 VL 190 IS 3 BP 535 EP 544 DI 10.1086/422035 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 836IQ UT WOS:000222549500017 PM 15243929 ER PT J AU Lurain, NS Robert, ES Xu, JH Camarca, M Landay, A Kovacs, AA Reichelderfer, PS AF Lurain, NS Robert, ES Xu, JH Camarca, M Landay, A Kovacs, AA Reichelderfer, PS TI HIV type 1 and cytomegalovirus coinfection in the female genital tract SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 9th International Cytomegalovirus Workshop CY MAY 20-25, 2003 CL Maastricht, NETHERLANDS ID MENSTRUAL-CYCLE; HOMOSEXUAL MEN; VIRUS; WOMEN; INFECTION; SEMEN; RISK AB The relationship between human immunodeficiency virus(HIV) type 1 and human cytomegalovirus (CMV) was studied in blood, saliva, and cervicovaginal lavage (CVL) specimens from 33 HIV-1-infected women. An association between HIV-1 RNA and CMV DNA was found in the CVL specimens, which also were tested for cytokine levels. Women with detectable CMV DNA in CVL specimens were more likely to have higher interleukin (IL) -1beta and IL-8 levels than were women with undetectable CMV DNA in CVL specimens. More than 1 strain of CMV was detected in specimens from 2 patients. These results suggest mechanisms by which CMV coinfection could affect HIV-1 disease progression. C1 Rush Univ, Med Ctr, Dept Immunol Microbiol, Chicago, IL 60612 USA. WESTAT Corp, Rockville, MD 20850 USA. NICHHD, NIH, Rockville, MD USA. Los Angeles Cty & Univ So Calif Med Ctr, Los Angeles, CA USA. RP Lurain, NS (reprint author), Rush Univ, Med Ctr, Dept Immunol Microbiol, 1653 W Congress Pkwy, Chicago, IL 60612 USA. EM nlurain@rush.edu FU NIAID NIH HHS [R01 AI052065, N01-AI-15123, R01 AI052065-01]; NICHD NIH HHS [P01-HD-40539, P01 HD040539]; PHS HHS [282-98-0015] NR 15 TC 20 Z9 21 U1 0 U2 0 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 AUG 1 PY 2004 VL 190 IS 3 BP 619 EP 623 DI 10.1086/422533 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 836IQ UT WOS:000222549500028 PM 15243940 ER PT J AU Marr, KA Balajee, SA McLaughlin, L Tabouret, M Bentsen, C Walsh, TJ AF Marr, KA Balajee, SA McLaughlin, L Tabouret, M Bentsen, C Walsh, TJ TI Detection of galactomannan antigenemia by enzyme immunoassay for the diagnosis of invasive aspergillosis: Variables that affect performance SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 42nd Annual Meeting of the American-Society-of-Hematology CY DEC 01-05, 2000 CL SAN FRANCISCO, CA SP Amer Soc Hematol ID LINKED-IMMUNOSORBENT-ASSAY; LATEX AGGLUTINATION-TEST; PULMONARY ASPERGILLOSIS; MARROW-TRANSPLANTATION; SERUM GALACTOMANNAN; FUNGAL-INFECTIONS; IMMUNOCOMPROMISED PATIENTS; MARKERS; GRANULOCYTOPENIA; REPRODUCIBILITY AB Invasive aspergillosis (IA) is a frequent complication of blood or marrow transplantation. Previous studies have reported that the Aspergillus galactomannan enzyme immunoassay ( GM EIA) may be a useful diagnostic tool for IA, but its sensitivity is variable. We examined the performance of the GM EIA in 986 serum samples from 67 patients. Results demonstrated that decreasing the index cutoff for positivity to 0.5 increased its sensitivity, with minimal loss of specificity. The low cutoff increased the duration of test positivity before diagnosis by clinical means. Sensitivity was highest in patients who did not receive preventative mold-active antifungals (87.5%). A rabbit model demonstrated that the level of circulating antigen correlated with the tissue fungus burden. A quantifiable response to antifungal therapy in clinical samples and the rabbit model supports the development of this assay for early diagnosis and therapeutic monitoring. The 0.5 cutoff may allow for better performance as an early diagnostic test. C1 Fred Hutchinson Canc Res Ctr, Program Infect Dis, Seattle, WA 98109 USA. Univ Washington, Seattle, WA 98195 USA. Biorad Labs, Redmond, WA USA. NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Marr, KA (reprint author), Fred Hutchinson Canc Res Ctr, Program Infect Dis, 1100 Fairview Ave N,D3-100, Seattle, WA 98109 USA. EM kmarr@fhcrc.org FU NCI NIH HHS [CA-18029]; NIAID NIH HHS [U01 AI05592] NR 30 TC 281 Z9 303 U1 0 U2 7 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 AUG 1 PY 2004 VL 190 IS 3 BP 641 EP 649 DI 10.1086/422009 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 836IQ UT WOS:000222549500031 PM 15243943 ER PT J AU Jaubert, J Patel, S Cheng, J Segre, JA AF Jaubert, J Patel, S Cheng, J Segre, JA TI Tetracycline-regulated transactivators driven by the involucrin promoter to achieve epidermal conditional gene expression SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article DE conditional gene expression; differentiation; epidermis; involucrin promoter; tetracycline-regulated ID TRANSGENIC MICE; DIFFERENTIATION; SKIN; KERATINOCYTES; HYPERPLASIA; EPITHELIA; MOUSE AB To achieve conditional gene expression in the differentiated layers of the epidermis, we generated transgenic micewith the tetracycline-regulated transactivator proteins, tTA (tetracycline transactivator) and rtTA (reverse tetracycline transactivator), expressed from the human involucrin promoter. Interaction with tetracycline turns off or turns on the tTA and rtTA molecules, respectively, allowing for regulation of downstream target genes during development and postnatally. These transactivator lines were crossed with reporter mice driving LacZ expression from a tetracycline response element to analyze the specificity and levels of target gene expression. Quantitative beta-galactosidase experiments demonstrate a 30-fold induction, specific to epithelial tissues. Immunohistochemistry results illustrate that the beta-galactosidase staining follows that of endogenous involucrin expression. Induction initiates at embryonic day 14.5 with expression over the entire epidermal surface by E16.5. Together with other driver lines, expressing tetracycline transactivators in the mitotically active layers of the epidermis, these mice willallow investigators to specifically modulate expression of target genes to specific stages of epidermal differentiation. C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Segre, JA (reprint author), NHGRI, NIH, 49 Convent Dr, Bethesda, MD 20892 USA. EM jsegre@nhgri.nih.gov NR 24 TC 18 Z9 18 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2004 VL 123 IS 2 BP 313 EP 318 DI 10.1111/j.0022-202X.2004.23203.x PG 6 WC Dermatology SC Dermatology GA 835LA UT WOS:000222483400012 PM 15245431 ER PT J AU Blankenburg, S Konig, IR Moessner, R Laspe, P Thoms, KM Krueger, U Khan, G Westphal, G Volkenandt, M Reich, K Ziegler, A Kraemer, KH Neumann, C Emmert, S AF Blankenburg, S Konig, IR Moessner, R Laspe, P Thoms, KM Krueger, U Khan, G Westphal, G Volkenandt, M Reich, K Ziegler, A Kraemer, KH Neumann, C Emmert, S TI Assessment of 4 xeroderma pigmentosum group C and G gene polymorphisms and risk of cutaneous malignant melanoma: A case-control study SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 34th Annual Meeting of the European-Society-for-Dermatological-Research CY SEP 09-11, 2004 CL Vienna, AUSTRIA SP European Soc Dermatol Res, Serono, Galderma, Novartis, Chanel, LVMH C1 Univ Gottingen, Dept Dermatol, D-3400 Gottingen, Germany. Univ Hosp Schleswig Holstein, Inst Med Biometry & Stat, Schleswig Holstein, Germany. Univ Gottingen, Dept Occupat & Social Med, D-3400 Gottingen, Germany. Univ Munich, Dept Dermatol, D-80539 Munich, Germany. NCI, Basic Res Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2004 VL 123 IS 2 MA 297 PG 1 WC Dermatology SC Dermatology GA 835LA UT WOS:000222483400325 ER PT J AU Finkelstein, SE Heimann, DM Klebanoff, CA Antony, PA Gattinoni, L Hinrichs, CS Hwang, LN Palmer, DC Spiess, PJ Surman, DR Wrzesiniski, C Yu, ZY Rosenberg, SA Restifo, NP AF Finkelstein, SE Heimann, DM Klebanoff, CA Antony, PA Gattinoni, L Hinrichs, CS Hwang, LN Palmer, DC Spiess, PJ Surman, DR Wrzesiniski, C Yu, ZY Rosenberg, SA Restifo, NP TI Bedside to bench and back again: how animal models are guiding the development of new immunotherapies for cancer SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Review DE IFN-gamma; MHC; interleukin; melanoma; adoptive cell transfer; vaccination; active immunization; cytokine; tumor ID CD8(+) T-CELLS; METASTATIC MELANOMA; PROGNOSTIC FACTORS; TUMOR REJECTION; THERAPY; ANTIGENS; AUTOIMMUNITY; LYMPHOCYTES; REGRESSION; VITILIGO AB Immunotherapy. using adoptive cell transfer is a promising approach that can result in the regression of bulky, invasive cancer in some patients. However, currently available therapies remain less successful than desired. To study the mechanisms of action and possible improvements in cell-transfer therapies, we use a murine model system with analogous components to the treatment of patients. T cell receptor transgenic CD8(+) T cells (pmel-1) specifically recognizing the melanocyte differentiation antigen gp100 are adoptively transferred into lympho-depleted mice bearing large, established, 14-day subcutaneous B16 melanoma (0.5-1 cm in diameter) on the day of treatment. Adoptive cell transfer in combination with interleukin interleukin-2 or interleukin-15 cytokine administration and vaccination using an altered form of the target antigen, gp100, can result in the complete and durable regression of large tumor burdens. Complete responders frequently develop autoimmunity with vitiligo at the former tumor site that often spreads to involve the whole coat. These findings have important implications for the design of immunotherapy trials in humans. C1 NCI, NIH, Surg Branch, Bethesda, MD 20892 USA. RP Restifo, NP (reprint author), NCI, NIH, Surg Branch, Bldg 10,Room 2B-46,10 Ctr Dr, Bethesda, MD 20892 USA. EM Nicholas_Restifo@nih.gov RI Gattinoni, Luca/A-2281-2008; Wrzesinski, Claudia/A-3077-2008; Restifo, Nicholas/A-5713-2008; Klebanoff, Christopher/B-8088-2008; Palmer, Douglas/B-9454-2008; Klebanoff, Christopher/D-9581-2011; OI Gattinoni, Luca/0000-0003-2239-3282; Palmer, Douglas/0000-0001-5018-5734; Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 SC003811-32, Z99 CA999999, Z01 BC010763-01] NR 21 TC 36 Z9 38 U1 0 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 AUG PY 2004 VL 76 IS 2 BP 333 EP 337 DI 10.1189/jlb.03041.20 PG 5 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 842CQ UT WOS:000222980900006 PM 15155774 ER PT J AU Shibusawa, Y Isozaki, M Yanagida, A Shindo, H Ito, Y AF Shibusawa, Y Isozaki, M Yanagida, A Shindo, H Ito, Y TI Purification of glucosyltransferase from Streptococcus sobrinus cell culture medium by combined use of batch extraction and countercurrent chromatography with a polymer phase system SO JOURNAL OF LIQUID CHROMATOGRAPHY & RELATED TECHNOLOGIES LA English DT Article DE countercurrent chromatography (CCC); hydroxyapatite chromatography; glucosyltransferase; aqueous polymer two-phase systems; Streptococcus sobrinus ID COIL PLANET CENTRIFUGE; ONE-STEP PURIFICATION; STATIONARY-PHASE; MUTANS STREPTOCOCCI; ROTARY SEALS; PROTEINS; SEPARATION; PARTITION; APPARATUS; ADHERENCE AB Glucosyltransferase (GTF), a cariogenic factor of Streptococcus sobrinus (SS), was extracted from a large quantity of cell culture medium by batch extraction with aqueous polymer two-phase systems (APTPs). The small quantity of the extract was further purified by countercurrent chromatography (CCC) using polyethylene glycol (PEG) 8000-dextran T500 system at pH 9.2, by eluting the impurities with the upper mobile phase at 1.0 mL/min. After the elution, the GTF still remaining in the dextran-rich lower stationary phase was collected. The GTF fractions were subjected to hydroxyapatite chromatography to eliminate polymers, such as PEG 8000 and dextran T500. Purified fractions were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and GTF enzyme activity, which rose over 270 fold from that in the original culture medium. C1 Tokyo Univ Pharm & Life Sci, Div Struct Biol & Analyt Sci, Tokyo 1920392, Japan. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Shibusawa, Y (reprint author), Tokyo Univ Pharm & Life Sci, Div Struct Biol & Analyt Sci, 1432-1 Horinouchi, Tokyo 1920392, Japan. EM sibusawa@ps.toyaku.ac.jp NR 34 TC 2 Z9 3 U1 0 U2 1 PU MARCEL DEKKER INC PI NEW YORK PA 270 MADISON AVE, NEW YORK, NY 10016 USA SN 1082-6076 J9 J LIQ CHROMATOGR R T JI J. Liq. Chromatogr. Relat. Technol. PD AUG PY 2004 VL 27 IS 14 BP 2217 EP 2234 DI 10.1081/JLC-200025713 PG 18 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 853KH UT WOS:000223826000007 ER PT J AU Aletras, AH Aral, AE AF Aletras, AH Aral, AE TI Meta-DENSE complex acquisition for reduced intravoxel dephasing SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE myocardial; contraction; cardiac; function; SPAMM; DENSE; HARP; tagging; heart; MRI ID STIMULATED ECHOES; NMR-SPECTROSCOPY; HUMAN HEART; MRI AB Displacement encoding with stimulated echoes (DENSE) with a meta-DENSE readout and RF phase cycling to suppress the STEAM anti-echo is described for reducing intravoxel dephasing signal loss. This RF phase cycling scheme, when combined with existing meta-DENSE suppression of the T-1 recovering signal, yields higher quality DENSE myocardial strain maps. Phantom and human images are provided to demonstrate the technique, which is capable of acquiring phase contrast displacement encoded images at low encoding gradient strengths providing better spatial resolution and less signal loss due to intravoxel dephasing than prior methods. Published by Elsevier Inc. C1 NHLBI, Cardiac Energet Lab, US Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Aletras, AH (reprint author), NHLBI, Cardiac Energet Lab, US Dept Hlth & Human Serv, NIH, Bldg 10, Bethesda, MD 20892 USA. EM AletrasA@nhlbi.nih.gov OI Aletras, Anthony/0000-0002-3786-3817 NR 12 TC 18 Z9 18 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD AUG PY 2004 VL 169 IS 2 BP 246 EP 249 DI 10.1016/j.jmr.2004.05.008 PG 4 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 842BR UT WOS:000222978100007 PM 15261619 ER PT J AU Shibanuma, N Sheehan, FT Lipsky, PE Stanhope, SJ AF Shibanuma, N Sheehan, FT Lipsky, PE Stanhope, SJ TI Sensitivity of femoral orientation estimates to condylar surface and MR image plane location SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article; Proceedings Paper CT 9th Annual Meeting of the ISMRM CY APR 21-27, 2001 CL GLASGOW, SCOTLAND SP ISMRM DE knee; coordinate system; geometry; bone shape; orientation; osteo-alignment ID PATELLOFEMORAL JOINT; QUADRICEPS CONTRACTION; COMPUTED-TOMOGRAPHY; PATELLAR TRACKING; KNEE; MALALIGNMENT; KINEMATICS; SUBLUXATION; PATTERNS; MOTION AB Purpose: To define the femoral anatomic region that provides the most reliable reference for measuring femoral orientation, from which patellofemoral and tibiofemoral orientation can be measured. Materials and Methods: After a three-dimensional image-based osteo-alignment procedure, two independent estimates of distal femoral orientation, the anterior (AFA) and posterior femoral angles (PFA), were acquired. These sets were comprised of 31 axial femoral orientation estimates each (obtained across a region 10 mm above to 20 mm below the patellar center) from 42 normal axial magnetic resonance (MR) image sets. An analysis of variance was conducted to determine the influence of image plane location, sex, and side on femoral orientation measures. Results: The AFA presented greater variability across subjects (average SD = 3.13degrees) as compared to the PFA (average SD = 1.78degrees). There were significant differences in the AFA based on image plane location and sex. In contrast, no differences were found between sides, sexes, or image plane locations for the PFA. Conclusion: In total, the posterior femoral condylar surface is more reliable than the anterior condylar surface for measuring femoral orientation and is best measured at least 8 mm below the patellar center. C1 NIH, Phys Disabil Branch, Bethesda, MD 20892 USA. Kobe Univ, Sch Med, Dept Orthopaed Surg, Kobe, Hyogo, Japan. NIAMSD, NIH, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Dept Phys Therapy & Rehabil Sci, Baltimore, MD 21201 USA. RP Sheehan, FT (reprint author), NIH, Phys Disabil Branch, Bldg 10,Room 6S235,MSC 1604, Bethesda, MD 20892 USA. EM fsheehan@cc.nih.gov RI sheehan, frances/B-6962-2009 NR 20 TC 10 Z9 10 U1 0 U2 0 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 AUG PY 2004 VL 20 IS 2 BP 300 EP 305 DI 10.1002/jmri.20106 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 841KB UT WOS:000222927600023 PM 15269957 ER PT J AU Naz, S Griffith, AJ Riazuddin, S Hampton, LL Battey, JF Khan, SN Riazuddin, S Wilcox, ER Friedman, TB AF Naz, S Griffith, AJ Riazuddin, S Hampton, LL Battey, JF Khan, SN Riazuddin, S Wilcox, ER Friedman, TB TI Mutations of ESPN cause autosomal recessive deafness and vestibular dysfunction SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID ACTIN-BUNDLING PROTEINS; AUDITORY HAIR-CELLS; STEREOCILIA AB We mapped a human deafness locus DFNB36 to chromosome 1p36.3 in two consanguineous families segregating recessively inherited deafness and vestibular areflexia. This phenotype co-segregates with either of two frameshift mutations, 1988delAGAG and 2469delGTCA, in ESPN, which encodes a calcium-insensitive actin-bundling protein called espin. A recessive mutation of ESPN is known to cause hearing loss and vestibular dysfunction in the jerker mouse. Our results establish espin as an essential protein for hearing and vestibular function in humans. The abnormal vestibular phenotype associated with ESPN mutations will be a useful clinical marker for refining the differential diagnosis of nonsyndromic deafness. C1 NIDCD, Sect Human Genet, Mol Genet Lab, NIH, Rockville, MD 20850 USA. NIDCD, Sect Gene Struct & Funct, LMG, NIH, Rockville, MD USA. NIDCD, Hearing Sect, NIH, Rockville, MD USA. NINDS, Sect G Prot Coupled Receptors, NIH, Bethesda, MD 20892 USA. Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. RP Friedman, TB (reprint author), NIDCD, Sect Human Genet, Mol Genet Lab, NIH, Rockville, MD 20850 USA. EM friedman@nidcd.nih.gov; friedman@nidcd.nih.gov RI Nasim Khan, Shaheen/F-2135-2015; naz, sadaf/F-4406-2015; SHEIKH, RIAZUDDIN/L-2406-2015; OI Naz, Sadaf/0000-0002-1912-0235 FU NIDCD NIH HHS [Z01 DC000035-07, Z01 DC000039-07, Z01 DC000064-03] NR 18 TC 62 Z9 66 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 AUG PY 2004 VL 41 IS 8 BP 591 EP 595 DI 10.1136/jmg.2004.018523 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 842YE UT WOS:000223039800003 PM 15286153 ER PT J AU Bossis, I Voutetakis, A Matyakhina, L Pack, S Abu-Asab, M Bourdeau, I Griffin, KJ Courcoutsakis, N Stergiopoulos, S Batista, D Tsokos, M Stratakis, CA AF Bossis, I Voutetakis, A Matyakhina, L Pack, S Abu-Asab, M Bourdeau, I Griffin, KJ Courcoutsakis, N Stergiopoulos, S Batista, D Tsokos, M Stratakis, CA TI A pleiomorphic GH pituitary adenoma from a Carney complex patient displays universal allelic loss at the protein kinase A regulatory subunit 1A (PRKARIA) locus SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID SPOTTY SKIN PIGMENTATION; ENDOCRINE OVERACTIVITY; CHROMOGRANIN-A; TUMORS; MYXOMAS; GENETICS; SCHWANNOMAS; NEOPLASIA; MUTATIONS; CANCER AB Carney complex (CNC) is a familial multiple endocrine neoplasia syndrome associated with GH-producing pituitary tumours and transmitted as an autosomal dominant trait. Mutations of the PRKAR1A gene are responsible for approximately half the known CNC cases but have never found in sporadic pituitary tumours. Pituitary tissue was obtained from an acromegalic CNC patient heterozygote for a common (PRKARIA)(i)-inactivating mutation. Both immunohistochemistry and electron microscopy showed a highly pleiomorphic pituitary adenoma. The cell culture population appeared morphologically heterogeneous and remained so after more than 30 passages. The mixture was comprised of cells strongly immunostained for GH, spindle-shaped myofibroblast-like cells, and cuboid cells with large axonal projections ( negative for GH). The population appeared to have both epithelial and mesenchymal cells. Both at baseline and at passage 30, cytogenetic analysis indicated the presence of normal 46, XY diploid karyotype, whereas losses of the PRKARIA(i) locus were demonstrated in more than 98% of the cells by fluorescent in situ hybridisation, supporting this gene's involvement in pituitary tumorigenesis. Allelic loss may have occurred in a single precursor cell type that differentiated and clonally expanded into several phenotypes. Epithelial-to-mesenchymal transition may also occur in CNC-associated pleiomorphic pituitary adenomas. C1 NICHD, Sect Endocrinol & Genet, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NCI, Sect Ultrafast Pathol, Pathol Lab, NIH, Bethesda, MD 20892 USA. NIDCR, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20872 USA. RP Stratakis, CA (reprint author), NICHD, Sect Endocrinol & Genet, Dev Endocrinol Branch, NIH, Nldg 10,Room 10N262,10 Ctr Dr 1862, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov RI Levesque, Isabelle/A-1899-2012; Pack, Svetlana/C-2020-2014; OI Abu-Asab, Mones/0000-0002-4047-1232 NR 27 TC 24 Z9 24 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 AUG PY 2004 VL 41 IS 8 BP 596 EP 600 DI 10.1136/jmg.2004.020214 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 842YE UT WOS:000223039800004 PM 15286154 ER PT J AU Eller, N Golding, H Inoue, S Beining, P Inman, J Matthews, N Scott, DE Golding, B AF Eller, N Golding, H Inoue, S Beining, P Inman, J Matthews, N Scott, DE Golding, B TI Systemic and mucosal immunity in rhesus macaques immunized with HIV-1 peptide and gp120 conjugated to Brucella abortus SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Article DE antibodies; CD8(+) T cells; interferon-gamma; tumor necrosis factor; V3-peptide ID T-CELLS; IL-12 EXPRESSION; IFN-GAMMA; V3 LOOP; RESPONSES; STIMULATION; INDUCTION; INFECTION; CD4(+); MICE AB HIV vaccine testing in primates is an important method for determining the possibility of vaccine benefit in humans. Goals of HIV-1 vaccination include establishing neutralizing antibodies and a strong CD8(+) T-cell response. We tested a novel vaccine conjugate for its ability to elicit relevant immune responses to HIV proteins and peptides in rhesus macaques. A neutralizing epitope, V3 loop peptide from HIV-1 envelope, was coupled to heat-inactivated Brucella abortus (V3-HKBA). Rhesus macaques were immunized with this conjugate in the anterior thigh. After two immunizations V3-specific antibodies were found in the sera and at mucosal sites. Neutralizing activity of these antibodies was demonstrated by syncytia inhibition assays. Cellular immune recall responses were demonstrated by antigen-specific induction of interferon-gamma and Regulation on Activation Noraml T Cell Expressed and Secreted (RANTES) secretion in vitro. These results confirm and extend preliminary studies in mice that suggest HKBA is an effective carrier that promotes neutralizing antibody secretion at relevant mucosal sites, as well as cellular immune responses that are correlated with viral protection. C1 Off Blood Res & Review, Div Hematol, Lab Plasma Derivat, Bethesda, MD USA. US FDA, Lab Retrovirus Res, Div Viral Prod, Off Vaccines Res & Review,Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Golding, B (reprint author), DH, HFM-345,1401 Woodmont,Rockville Pike, Rockville, MD 20852 USA. EM golding@cber.fda.gov NR 22 TC 2 Z9 3 U1 0 U2 0 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD AUG PY 2004 VL 33 IS 4 BP 167 EP 174 DI 10.1111/j.1600-0684.2004.00068.x PG 8 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 834OZ UT WOS:000222421700001 PM 15271066 ER PT J AU Jakupciak, JP Wang, W Barker, PE Srivastava, S Atha, DH AF Jakupciak, JP Wang, W Barker, PE Srivastava, S Atha, DH TI Analytical validation of telomerase activity for cancer early detection - TRAP/PCR-CE and hTERT mRNA quantification assay for high-throughput screening of tumor cells SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID CAPILLARY-ELECTROPHORESIS; PROGNOSTIC INDICATORS; CATALYTIC SUBUNIT; COLORECTAL-CANCER; EPITHELIAL-CELLS; EXPRESSION; BIOMARKER; PROLIFERATION; INHIBITION; COMPONENTS AB Activation of telomerase plays a critical role in unlimited proliferation and immortalization of cells. Telomerase activity has been shown to correlate with tumor progression, indicating that tumors expressing this enzyme possess aggressive clinical behavior and that telomerase activity may be a useful biomarker for early detection of cancer. However, measurements of telomerase activity by current methods such as telomeric repeat amplification protocol (TRAP)/polymerase chain reaction (PCR) or antibody-based radioimmunoassay (RIA) are low-throughput and not robust enough to easily accommodate the required statistical analysis to determine whether telomerase activity is a practical biomarker. As part of the National Cancer Institute Early Detection Research Network of analytical validation, we have developed a robot assisted TRAP assay (RApidTRAP) of telomerase, a potential biomarker for cancer early detection. Measurements of human telomerase reverse transcriptase catalytic subunit (hTERT) mRNA were performed in concert with measurement of telomerase activity. For this purpose we determined hTERT mRNA concentration and telomerase activity in human normal (RPE-28) and cancer (A549) cell fines as well as in human serum (SRM 1951A). Telomerase activity measurements were made using the TRAP/PCR capillary electrophoresis (CE) method on (50 to 1000) cells/reaction isolated from cell extracts. Measurement of hTERT mRNA was made using specific primers and probes on a LightCycler in the range of (10 to 7000) cells/reaction. Comparison of high-throughput telomerase activity measurements using the robot and those performed manually were consistent in sensitivity and reproducibility. Using this combination of telomerase activity and hTERT mRNA measurements, the automated system improved efficiency over traditional TRAP/PCR methods. C1 NIST, Div Biotechnol, Gaithersburg, MD 20899 USA. NCI, Canc Biomarkers Res Grp, Rockville, MD USA. RP Atha, DH (reprint author), NIST, Div Biotechnol, 100 Bur Dr,MS 8311, Gaithersburg, MD 20899 USA. EM donald.atha@nist.gov NR 34 TC 15 Z9 17 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 J9 J MOL DIAGN JI J. Mol. Diagn. PD AUG PY 2004 VL 6 IS 3 BP 157 EP 165 DI 10.1016/S1525-1578(10)60506-5 PG 9 WC Pathology SC Pathology GA 840SV UT WOS:000222880800001 PM 15269291 ER PT J AU Martins, C Cavaco, B Tonon, G Kaye, FJ Soares, J Fonseca, I AF Martins, C Cavaco, B Tonon, G Kaye, FJ Soares, J Fonseca, I TI A study of MECT1-MAML2 in mucoepidermoid carcinoma and Warthin's tumor of salivary glands SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID IN-SITU HYBRIDIZATION; PAROTID-GLAND; CHROMOSOME-ABNORMALITIES; REARRANGEMENTS; TRANSLOCATION; NEOPLASMS; T(11-19)(Q21-P13.1); ABERRATIONS; FUSION; CHILD AB The t(11;19)(q21;p13) chromosomal translocation has been described in two distinct types of salivary gland neoplasms: mucoepidermoid carcinoma (MEC) and Warthin's tumor (WT). Since this translocation. has been recently shown to generate a MECT1-MAML2 fusion gene, we evaluated 10 primary MEC and seven primary WT to further define the molecular association of these two entities using cytogenetic, as well as in situ hybridization (ISH) and reverse transcriptase-polymerase chain reaction (RT-PCR) analyses directed against the fusion gene. A karyotype was established in all neoplasms except for two MEC cases. Of the eight karyotyped MECs, five showed the t(11; 19)(q21;p13), two had a normal karyotype, and one case presented a -Y and +X. Three of the WT revealed a normal karyotype and four had several abnormalities which did not involve chromosomes 11 and 19. ISH analysis performed in cytogenetic suspension and/or in tumor paraffin sections demonstrated MAML2 rearrangement in 7 of 10 cases of MEC: all five cases with t(11;19), one case with normal karyotype, and one unkaryotyped case. RT-PCR analysis confirmed the expression of the MECT1-MAML2 gene in all MEC cases that were positive by ISH analysis. Neither the t(11;19) nor MECTI-MAML2 was detected in any case of WT, nor in control samples from polymorphous low-grade adenocarcinoma, acinic cell carcinoma, or normal parotid gland tissue. We have demonstrated that ISH and RT-PCR are sensitive methods for detecting MECT1-MAML2 in MEC. In contrast, we did not detect the t(11;19) nor MECT1-MAML2 expression in seven cases of WT. C1 Inst Portugues Oncol Francis Gentil, Dept Patol Morfol, P-1099023 Lisbon, Portugal. Inst Portugues Oncol Francis Gentil, CIPM, P-1099023 Lisbon, Portugal. NCI, Bethesda, MD USA. USN Hosp, Bethesda, MD 20814 USA. RP Fonseca, I (reprint author), Inst Portugues Oncol Francis Gentil, Dept Patol Morfol, Rua Prof Lima Basto, P-1099023 Lisbon, Portugal. EM ifonseca@ipolisboa.min-saude.pt RI kaye, frederic/E-2437-2011; Soares, Jorge/C-7429-2015; Fonseca, Isabel/A-7396-2008; OI Soares, Jorge/0000-0002-1359-6494; Fonseca, Isabel/0000-0002-1359-6494; Martins, Carmo/0000-0002-7901-7600; Cavaco, Branca/0000-0001-8946-8635 NR 36 TC 70 Z9 71 U1 0 U2 2 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 1525-1578 J9 J MOL DIAGN JI J. Mol. Diagn. PD AUG PY 2004 VL 6 IS 3 BP 205 EP 210 DI 10.1016/S1525-1578(10)60511-9 PG 6 WC Pathology SC Pathology GA 840SV UT WOS:000222880800006 PM 15269296 ER PT J AU Bobzin, SC Cardellina, JH Gerwick, WH Okuda, RK AF Bobzin, SC Cardellina, JH Gerwick, WH Okuda, RK TI Special issue in honor of D. John Faulkner and Paul J. Scheuer SO JOURNAL OF NATURAL PRODUCTS LA English DT Editorial Material C1 Ceres Inc, Malibu, CA USA. NCI, Frederick, MD 21701 USA. Oregon State Univ, Corvallis, OR 97331 USA. San Jose State Univ, San Jose, CA 95192 USA. RP Bobzin, SC (reprint author), Ceres Inc, Malibu, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD AUG PY 2004 VL 67 IS 8 BP 1201 EP 1201 DI 10.1021/np049784a PG 1 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 850GW UT WOS:000223600200001 ER PT J AU Daly, JW AF Daly, JW TI Marine toxins and nonmarine toxins: Convergence or symbiotic organisms SO JOURNAL OF NATURAL PRODUCTS LA English DT Review ID FROG BRACHYCEPHALUS-EPHIPPIUM; TETRODOTOXIN-LIKE SUBSTANCE; COSTA RICAN FROG; RED-SPOTTED NEWT; NATURAL-PRODUCTS; TARICHA-GRANULOSA; ATELOPUS-ZETEKI; NOTOPHTHALMUS-VIRIDESCENS; EVOLUTIONARY RESPONSE; PIPERIDINE ALKALOIDS AB Bioactive marine natural products occur only rarely in nonmarine sources. The converse also is true. Divergent evolutionary pathways for the biosynthesis of bioactive secondary metabolites seem to be the rule. Marine biosynthetic pathways lead to a wide variety of different structural classes, among which polyethers, macrolides, terpenes, unusual amino acids/peptides, and alkaloids are notable. Nonmarine biosynthetic pathways also lead to a similar wide variety of structural classes. However, the structures are usually quite different from the marine analogues. The alkaloids of plants are notable, but again there appears little convergence between the marine and nonmarine alkaloids. However, tetrodotoxin, a remarkable, highly polar, marine alkaloid, does occur in various amphibians. The occurrence and possible origin of tetrodotoxin and congeners, including chiriquitoxin, and of the saxitoxin analogue zetekitoxin in amphibians are reviewed. C1 NIDDKD, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. RP Daly, JW (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. EM jdaly@nih.gov NR 84 TC 46 Z9 51 U1 1 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD AUG PY 2004 VL 67 IS 8 BP 1211 EP 1215 DI 10.1021/np040016t PG 5 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 850GW UT WOS:000223600200005 PM 15332834 ER PT J AU Newman, DJ Cragg, GM AF Newman, DJ Cragg, GM TI Marine natural products and related compounds in clinical and advanced preclinical trials SO JOURNAL OF NATURAL PRODUCTS LA English DT Review ID WHIP PSEUDOPTEROGORGIA-ELISABETHAE; ANTIPROLIFERATIVE AGENT DIDEMNIN; ALPHA-GALACTOSYLCERAMIDE KRN7000; SPONGE KIRKPATRICKIA-VARIALOSA; CANDIDATUS ENDOBUGULA SERTULA; POTENT CYTOTOXIC DEPSIPEPTIDE; BEE VENOM PHOSPHOLIPASE-A2; PRACTICAL TOTAL-SYNTHESIS; MOLLUSK ELYSIA-RUFESCENS; VIVO ANTITUMOR-ACTIVITY AB The marine environment has proven to be a very rich source of extremely potent compounds that have demonstrated significant activities in antitumor, antiinflammatory, analgesia, immunomodulation, allergy, and anti-viral assays. Although the case can and has been made that the nucleosides such as Ara-A and Ara-C are derived from knowledge gained from investigations of bioactive marine nucleosides, no drug directly from marine sources (whether isolated or by total synthesis) has yet made it to the commercial sector in any disease. However, as shown in this review, there are now significant numbers of very interesting molecules that have come from marine sources, or have been synthesized as a result of knowledge gained from a prototypical compound, that are either in or approaching Phase II/III clinical trials in cancer, analgesia, allergy, and cognitive diseases. A substantial number of other potential agents are following in their wake in preclinical trials in these and in other diseases. C1 NCI Frederick, Natl Prod Branch, Dev Therapeut Program, Frederick, MD 21702 USA. RP Newman, DJ (reprint author), NCI Frederick, Natl Prod Branch, Dev Therapeut Program, POB B, Frederick, MD 21702 USA. EM dn22a@nih.gov NR 328 TC 433 Z9 462 U1 16 U2 117 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD AUG PY 2004 VL 67 IS 8 BP 1216 EP 1238 DI 10.1021/np040031y PG 23 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 850GW UT WOS:000223600200006 PM 15332835 ER PT J AU Andersen, RJ Ireland, CM Molinski, TF Bewley, CA AF Andersen, RJ Ireland, CM Molinski, TF Bewley, CA TI Research achievement award-D. John Faulkner SO JOURNAL OF NATURAL PRODUCTS LA English DT Review ID MARINE NATURAL-PRODUCTS; SPONGE DYSIDEA-HERBACEA; ANTIFUNGAL CYCLIC-PEPTIDES; NUDIBRANCH HEXABRANCHUS-SANGUINEUS; PULMONATE SIPHONARIA-DENTICULATA; TRISUBSTITUTED OLEFINIC BONDS; APLYSINA-FISTULARIS VERONGIA; THEONELLA-SWINHOEI; JUVENILE-HORMONE; POLYPROPIONATE METABOLITES AB David John Faulkner, one of the pioneers of marine natural products chemistry and the 2003 recipient of the ASP Research Achievement Award, passed away on November 23, 2002. John was very pleased to learn that he'd been named as the award recipient and was intending to present the ASP Research Achievement Award Address at the annual meeting in July 2003, Chapel Hill, North Carolina. John's untimely death left an unprecedented event in the history of the ASP-a posthumous Research Achievement Award to a deserving individual and an untimely loss for us all. We are bereft of a colleague, a friend, and a mentor, and the opportunity to hear John's words on the occasion of his own award. In tribute to John, we have assembled a retrospective of John's work that is not meant to be a comprehensive review (this would take considerably more space) but a selection of highlights and personal vignettes from some of those that trained in marine natural products under his mentorship. This paper is a written account of the symposium presented by the authors at the ASP Annual Meeting in Chapel Hill, North Carolina, on July 16, 2003. C1 Univ Calif Davis, Dept Chem, Davis, CA 95616 USA. Univ British Columbia, Dept Chem, Vancouver, BC V6T 1Z1, Canada. Univ British Columbia, Dept Biochem & Mol Biol, Vancouver, BC V6T 1Z1, Canada. Univ Utah, Dept Med Chem, Salt Lake City, UT 84112 USA. NIH, Bioorgan Chem Lab, NIDDK, Bethesda, MD 20892 USA. RP Molinski, TF (reprint author), Univ Calif Davis, Dept Chem, Davis, CA 95616 USA. EM tfmolinski@ucdavis.edu NR 130 TC 3 Z9 3 U1 1 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD AUG PY 2004 VL 67 IS 8 BP 1239 EP 1251 DI 10.1021/np049912v PG 13 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 850GW UT WOS:000223600200007 PM 15332836 ER PT J AU Bewley, CA Ray, S Cohen, F Collins, SK Overman, LE AF Bewley, CA Ray, S Cohen, F Collins, SK Overman, LE TI Inhibition of HIV-1 envelope-mediated fusion by synthetic batzelladine analogues SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID SPONGE CRAMBE-CRAMBE; ENANTIOSELECTIVE TOTAL-SYNTHESIS; POLYCYCLIC GUANIDINE ALKALOIDS; PTILOMYCALIN-A; CELL-FUSION; GP120; STEREOCHEMISTRY; GLYCOPROTEINS; CRAMBESCIDINS; MINIMIZATION AB Marine natural products that feature polycyclic guanidine motifs, such as crambescidins and batzelladines, are known to have antiviral activities toward some viruses including HSV and HIV. In this study we evaluated a synthetic library containing 28 batzelladine analogues, the structures of which encompass and surpass variations seen in natural batzelladines, for their ability to inhibit HIV-1 envelope-mediated cell-cell fusion. Clear structure-activity relationships were revealed and indicated that the best inhibitors of fusion were most similar in structure to natural batzelladine F, with IC50 values ranging from 0.8 to 3.0muM. Proceeding from the earlier finding that some batzelladines block gp120-CD4 binding, modeling studies of inhibitors binding to the CD4 binding site on gp120 were carried out. The lowest energy models suggest a preferred orientation for inhibitor binding that is consistent with the observed structure-activity relationships. C1 NIDDKD, Bioorgan Chem Lab, DHHS, NIH, Bethesda, MD 20892 USA. Univ Calif Irvine, Dept Chem, Irvine, CA 92697 USA. RP Bewley, CA (reprint author), NIDDKD, Bioorgan Chem Lab, DHHS, NIH, Bethesda, MD 20892 USA. EM caroleb@mail.nih.gov; leoverma@uci.edu OI Overman, Larry/0000-0001-9462-0195 FU NHLBI NIH HHS [HL-25854] NR 28 TC 31 Z9 33 U1 1 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD AUG PY 2004 VL 67 IS 8 BP 1319 EP 1324 DI 10.1021/np049958o PG 6 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 850GW UT WOS:000223600200020 PM 15332849 ER PT J AU Oku, N Gustafson, KR Cartner, LK Wilson, JA Shigematsu, N Hess, S Pannell, LK Boyd, MR McMahon, JB AF Oku, N Gustafson, KR Cartner, LK Wilson, JA Shigematsu, N Hess, S Pannell, LK Boyd, MR McMahon, JB TI Neamphamide A, a new HIV-Inhibitory depsipeptide from the Papua New Guinea marine sponge Neamphius huxleyi SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID LIQUID-CHROMATOGRAPHIC RESOLUTION; CALLIPELTIN-A; ASYMMETRIC-SYNTHESIS; NATURAL PRODUCT; 2,3,4,6-TETRA-O-ACETYL-BETA-D-GLUCOPYRANOSYL ISOTHIOCYANATE; STEREOSELECTIVE SYNTHESIS; ABSOLUTE STEREOCHEMISTRY; CYCLIC DEPSIPEPTIDE; AMINO-ACIDS; DERIVATIZATION AB A new HIV-inhibitory cyclic depsipeptide, neamphamide A (2), was isolated from a Papua New Guinea collection of the marine sponge Neamphius huxleyi. Its structure was established through interpretation of spectroscopic data and by acid hydrolysis, derivatization of the free amino acids, and LC-MS analysis of the derivatives. Neamphamide A (2) contains 11 amino acid residues and an amide-linked 3-hydroxy-2,4,6-trimethylheptanoic acid moiety. The amino acid constituents were identified as L-Leu, L-NMeGln, D-Arg, D- and L-Asn, two residues of D-allo-Thr, L-homoproline, (3S,4R)-3,4-dimethyl-L-glutamine, beta-methoxytyrosine, and 4-amino-7-guanidino-2,3-dihydroxyheptanoic acid. In a cell-based XTT assay, 2 exhibited potent cytoprotective activity against HIV-1 infection with an EC50 of approximately 28 nM. C1 NCI, Mol Targets Dev Program, Ctr Canc Res, Frederick, MD 21702 USA. SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. NIDDKD, Bioorgan Chem Lab, Bethesda, MD 20892 USA. Univ S Alabama, Coll Med, USA Canc Res Inst, Mobile, AL 36688 USA. RP Gustafson, KR (reprint author), NCI, Mol Targets Dev Program, Ctr Canc Res, Bldg 1052,Room 121, Frederick, MD 21702 USA. RI Shigematsu, Naoyuki/B-9374-2014 FU NCI NIH HHS [N01-CO-12400] NR 25 TC 77 Z9 84 U1 1 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD AUG PY 2004 VL 67 IS 8 BP 1407 EP 1411 DI 10.1021/np040003f PG 5 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 850GW UT WOS:000223600200036 PM 15332865 ER PT J AU Lopanik, N Gustafson, KR Lindquist, N AF Lopanik, N Gustafson, KR Lindquist, N TI Structure of bryostatin 20: A symbiont-produced chemical Defense for larvae of the host bryozoan, Bugula neritina SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID ANTINEOPLASTIC AGENTS; MARINE; METABOLITES; BACTERIA; EMBRYOS AB Larvae of the marine bryozoan Bugula neritina are defended against potential predators by high concentrations of bryostatins, which are produced by a bacterial symbiont of the bryozoan. From the larvae of B. neritina, three bryostatins, bryostatin 10 (1), the novel bryostatin 20 (2), and an as yet uncharacterized bryostatin, were isolated that were unpalatable to fish. These deterrent bryostatins represent the first example from the marine environment of a microbial symbiont producing an antipredator defense for its host. The structure of bryostatin 20 (2) was determined by spectral comparison with previously described bryostatins. C1 Univ N Carolina, Inst Marine Sci, Morehead City, NC 28557 USA. Univ Delaware, Coll Marine Studies, Lewes, DE 19958 USA. NCI, Mol Targets Dev Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Lindquist, N (reprint author), Univ N Carolina, Inst Marine Sci, Morehead City, NC 28557 USA. EM nlindquist@unc.edu NR 22 TC 56 Z9 60 U1 0 U2 18 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD AUG PY 2004 VL 67 IS 8 BP 1412 EP 1414 DI 10.1021/np040007k PG 3 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 850GW UT WOS:000223600200037 PM 15332866 ER PT J AU Mattson, MP Cutler, RG Lu, C AF Mattson, MP Cutler, RG Lu, C TI Raft lipid abnormalities, oxidative stress and neurodegenerative disorders SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 NIA, Neurosci Lab, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 1 EP 1 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900004 ER PT J AU Nielsen, JA Szuchet, S Hudson, LD AF Nielsen, JA Szuchet, S Hudson, LD TI A potential cell survival function for the LAG gene SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 NINDS, Lab Dev Neurogenet, NIH, Bethesda, MD 20892 USA. Univ Chicago, Brain Res Inst, Dept Neurol, Chicago, IL 60637 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 9 EP 9 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900031 ER PT J AU Hewett, SJ Espey, MG Wink, DA Uliasz, TF AF Hewett, SJ Espey, MG Wink, DA Uliasz, TF TI The neurotoxicity of nitroxyl anion SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 Univ Connecticut, Sch Med, Farmington, CT USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 21 EP 21 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900077 ER PT J AU Mattson, MP AF Mattson, MP TI Neurohormesis: mechanisms and implications for cognitive impairment in aging SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 NIA, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 0 TC 0 Z9 0 U1 1 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 24 EP 24 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900085 ER PT J AU McPherson, CA Wine, RN d'Hellencourt, CL Harry, GJ AF McPherson, CA Wine, RN d'Hellencourt, CL Harry, GJ TI Microglia activation and fate following neurodegeneration in the mouse hippocampus SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 NIEHS, Res Triangle Pk, NC 27709 USA. Univ Reunion, Lab Biochim & Genet Mol, St Denis Messageries, Reunion. NR 0 TC 0 Z9 0 U1 0 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 40 EP 40 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900137 ER PT J AU Tifft, CJ AF Tifft, CJ TI Inflammation in the pathogenesis of ganglioside storage disorders SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 Childrens Natl Med Ctr, Div Genet & Metab, Washington, DC 20010 USA. NIDDK, NIH, Genet Dev & Dis Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 54 EP 54 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900193 ER PT J AU Zhu, JP Xu, W Cadet, JL Ali, SF Angulo, JA AF Zhu, JP Xu, W Cadet, JL Ali, SF Angulo, JA TI Influence from the neurokinin-1 receptor in methamphetamine-induced damage of striatal neurons SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 CUNY Hunter Coll, Dept Biol Sci, New York, NY 10021 USA. NIDA, Mol Neuropsychiat Sect, NIH, Baltimore, MD USA. US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, Neurochem Lab, Jefferson, AR 72079 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 60 EP 60 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900213 ER PT J AU Harry, GJ Wine, RN McPherson, CA d'Hellencourt, CL AF Harry, GJ Wine, RN McPherson, CA d'Hellencourt, CL TI Neuronal expression of tumor necrosis factor receptors and glia in acute hippocampal injury: neuronal death and survival SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 NIEHS, NIH, DHHS, Res Triangle Pk, NC 27709 USA. Univ La Reunion, St Denis Messageries, Reunion. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 76 EP 76 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900268 ER PT J AU Dobolyi, A Palkovits, M Usdin, TB AF Dobolyi, A Palkovits, M Usdin, TB TI Distribution of mRNAs encoding latent transforming growth factor binding proteins in the rat brain SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 NIMH, Genet Lab, NIH, Bethesda, MD 20892 USA. RI Dobolyi, Arpad/B-9089-2008; Palkovits, Miklos/F-2707-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 77 EP 77 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900272 ER PT J AU Kim, HY Calderon, F Akbar, M Wen, Z AF Kim, HY Calderon, F Akbar, M Wen, Z TI Role of docosahexaenoic acid in neuronal differentiation and survival SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 NIAAA, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 82 EP 82 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900289 ER PT J AU Salem, N Moriguchi, T Lim, S Ahmad, A Mervis, R Catalan, J AF Salem, N Moriguchi, T Lim, S Ahmad, A Mervis, R Catalan, J TI Cognitive deficits and reduced neuronal size in DHA-deficient rats SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. NeuroStruct Res Labs Inc, Tampa, FL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 82 EP 82 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900288 ER PT J AU Castagnet, PI Cole, NB Nussbaum, RL Murphy, EJ AF Castagnet, PI Cole, NB Nussbaum, RL Murphy, EJ TI Alteration of fatty acid uptake in HEK cells by wild type, A30P or A53T alpha-synuclein expression involves a protein component SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 Univ N Dakota, Dept Physiol, Grand Forks, ND 58201 USA. NHGRI, Genet Dis Res Branch, 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 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 93 EP 93 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900325 ER PT J AU Castagnet, PI Cole, NB Nussbaum, RL Murphy, EJ AF Castagnet, PI Cole, NB Nussbaum, RL Murphy, EJ TI Expression of A30P or A53T alpha-synuclein mutants alters cellular fatty acid uptake and trafficking SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 Univ N Dakota, Dept Physiol Pharmacol & Therapeut, Grand Forks, ND 58201 USA. NHGRI, Genet Dis Res Branch, 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 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 93 EP 93 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900324 ER PT J AU Kim, Y Block, M Yang, L Beal, F Hong, J Joh, T AF Kim, Y Block, M Yang, L Beal, F Hong, J Joh, T TI Matrix metal loproteinase-3 inhibition prevents dopamine neuronal degeneration SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 Cornell Univ, Coll Med, Burke Med Res Inst, Dept Mol Neurobiol, White Plains, NY 10605 USA. Weill Med Coll, New York, NY USA. Cornell Univ, Grad Sch Med Sci, Dept Neurol & Neurosci, New York, NY 10021 USA. NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 96 EP 96 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900334 ER PT J AU Lundquist, JJ Dudek, SM AF Lundquist, JJ Dudek, SM TI A covalently-bound extracellular signal regulated kinase complex revealed through LTP-inducing stimuli SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 NIEHS, Res Triangle Pk, NC 27709 USA. RI yu, yan/C-2322-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 102 EP 102 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900356 ER PT J AU Duan, W Mattson, MP AF Duan, W Mattson, MP TI Intervention in Huntington's disease: targeting serotonin and BDNF signaling SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 35th Annual Meeting of the Transactions-of-the-American-Society-for-Neurochemistry CY AUG 14-18, 2004 CL New York, NY SP Transact Amer Soc Neurochem C1 NIA, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 SU 1 BP 110 EP 110 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 852NB UT WOS:000223760900386 ER PT J AU Chalimoniuk, M King-Pospisil, K Pedersen, WA Malecki, A Wylegala, E Mattson, MP Hennig, B Toborek, M AF Chalimoniuk, M King-Pospisil, K Pedersen, WA Malecki, A Wylegala, E Mattson, MP Hennig, B Toborek, M TI Arachidonic acid increases choline acetyltransferase activity in spinal cord neurons through a protein kinase C-mediated mechanism SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE arachidonic acid; choline acetyltransferase; protein kinase C; spinal cord neurons ID NMDA RECEPTOR CURRENTS; CENTRAL-NERVOUS-SYSTEM; FATTY-ACIDS; PC12 CELLS; RAT-BRAIN; INJURY; PHOSPHORYLATION; EXPRESSION; ACTIVATION; GROWTH AB Arachidonic acid (AA) plays an important role as a signaling factor in the CNS. Therefore, exposure to AA may affect cholinergic neurons in the spinal cord. To test this hypothesis, mRNA expression and activity of choline acetyltransferase (ChAT) was measured in cultured spinal cord neurons treated with increasing concentrations (0.1-10 mum) of AA. Exposure to AA increased mRNA levels and activity of ChAT in dose- and time-dependent manners. The most marked effect of AA on ChAT expression was observed in spinal cord neurons treated with 10 mum AA for 1 h. To study the mechanisms associated with these effects, ChAT mRNA levels and activity were measured in cultured spinal cord neurons exposed to AA and inhibitors of protein kinase C (PKC), such as 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dichloride (H-7) and chelerythrine. Inhibition of PKC completely prevented an AA-induced increase in ChAT expression. In addition, exposure of spinal cord neurons to phorbol-12-myristate-13-acetate (PMA), an activator of PKC, mimicked AA-induced stimulation of ChAT activity. The AA-mediated increase in ChAT mRNA levels and activity was also prevented by treatments with EGTA, indicating the role of calcium metabolism in induction of this enzyme. In contrast, treatments with 7-nitroindazole (7-NI, a specific inhibitor of neuronal nitric oxide synthase), sodium vanadate (NaV, a non-specific inhibitor of phosphatases), and N-acetyl-cysteine (NAC, an antioxidant) had no effect on AA-induced changes in ChAT activity. The protein synthesis inhibitor cycloheximide completely blocked AA-mediated increase in ChAT activity. These results indicate that the AA-evoked increase in ChAT activity in spinal cord neurons is mediated by PKC, presumably at the transcriptional level. C1 Univ Kentucky, Med Ctr, Dept Surg, Div Neurosurg,Mol Neurosci & Vasc Biol Lab, Lexington, KY 40536 USA. Polish Acad Sci, Med Res Ctr, Dept Cellular Signaling, Warsaw, Poland. Creighton Univ, Med Ctr, Ctr Aging Alzheimers Dis & Neurodgenerat Disorder, Omaha, NE USA. Silesian Med Univ, Dept Pharmacol, Katowice, Poland. Railway Hosp, Dept Ophthalmol, Katowice, Poland. NIA, Neurosci Lab, Baltimore, MD 21224 USA. Univ Kentucky, Coll Agr, Lexington, KY USA. RP Toborek, M (reprint author), Univ Kentucky, Med Ctr, Dept Surg, Div Neurosurg,Mol Neurosci & Vasc Biol Lab, 800 Rose St, Lexington, KY 40536 USA. EM mjtobo00@uky.edu RI Mattson, Mark/F-6038-2012 FU NIEHS NIH HHS [P42 ES007380] NR 49 TC 13 Z9 15 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 IS 3 BP 629 EP 636 DI 10.1111/j.1471-4159.2004.02535.x PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 838NQ UT WOS:000222720500012 PM 15255940 ER PT J AU Wu, X Zhu, DM Jiang, XY Okagaki, P Mearow, K Zhu, GS McCall, S Banaudha, K Lipsky, RH Marini, AM AF Wu, X Zhu, DM Jiang, XY Okagaki, P Mearow, K Zhu, GS McCall, S Banaudha, K Lipsky, RH Marini, AM TI AMPA protects cultured neurons against glutamate excitotoxicity through a phosphatidylinositol 3-kinase-dependent activation in extracellular signal-regulated kinase to upregulate BDNF gene expression SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE Akt; AMPA; aniracetam; BDNF; ERK1/2; neuroprotection ID METHYL-D-ASPARTATE; CEREBELLAR GRANULE CELLS; CENTRAL-NERVOUS-SYSTEM; RECEPTOR-MEDIATED NEUROPROTECTION; FAMILY TRANSCRIPTION FACTOR; NEUROTROPHIC FACTOR; RAT CEREBELLAR; CORTICAL-NEURONS; TYROSINE KINASES; GROWTH-FACTOR AB The signal transduction and molecular mechanisms underlying alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)-mediated neuroprotection are unknown. In the present study, we determined a major AMPA receptor-mediated neuroprotective pathway. Exposure of cerebellar granule cells to AMPA (500 mum) + aniracetam (1 mum), a known blocker of AMPA receptor desensitization, evoked an accumulation of brain-derived neurotropic factor (BDNF) in the culture medium and enhanced TrkB-tyrosine phosphorylation following the release of BDNF. AMPA also activated the src-family tyrosine kinase, Lyn, and the downstream target of the phosphatidylinositol 3-kinase (PI3-K) pathway, Akt. Extracellular signal regulated kinase (ERK), a component of the mitogen-activated protein kinase (MAPK) pathway, was also activated. K252a, a selective inhibitor of neurotrophin signaling, blocked the AMPA-mediated neuroprotection. The involvement of BDNF release in protecting neurons by AMPA was confirmed using a BDNF-blocking antibody. AMPA-mediated neuroprotection is blocked by PP1, an inhibitor of src family kinases, LY294002, a PI3-K inhibitor, or U0126, a MAPK kinase (MEK) inhibitor. Neuroprotective concentrations of AMPA increased BDNF mRNA levels that was blocked by the AMPA receptor antagonist, 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX). The increase in BDNF gene expression appeared to be the downstream target of the PI3-K-dependent activation of the MAPK cascade since MEK or the PI3-K inhibitor blocked the AMPA receptor-mediated increase in BDNF mRNA. Thus, AMPA receptors protect neurons through a mechanism involving BDNF release, TrkB receptor activation, and a signaling pathway involving a PI3-K dependent activation of MAPK that increases BDNF expression. C1 Uniformed Serv Univ Hlth Sci, Dept Neurol & Neurosci, Bethesda, MD 20814 USA. Armed Forces Inst Pathol, Dept Cellular Pathol & Genet, Div Mol Pathol, Washington, DC 20306 USA. Mem Univ Newfoundland, St Johns, NF, Canada. NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. RP Marini, AM (reprint author), Uniformed Serv Univ Hlth Sci, Dept Neurol & Neurosci, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM amarini@usuhs.mil OI Lipsky, Robert/0000-0001-7753-1473 NR 57 TC 67 Z9 69 U1 0 U2 4 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 IS 4 BP 807 EP 818 DI 10.1111/j.1471-4159.2004.02526.x PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 842WC UT WOS:000223034200006 PM 15287886 ER PT J AU Calderon, F Kim, HY AF Calderon, F Kim, HY TI Docosahexaenoic acid promotes neurite growth in hippocampal neurons SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE differentiation; docosahexaenoic acid; hippocampus; n-3 fatty acid deficiency; neurite growth; primary culture ID POLYUNSATURATED FATTY-ACIDS; RETINOID-X-RECEPTOR; RAT PC12 CELLS; SIGNAL-TRANSDUCTION; RAPID METHOD; MOUSE-BRAIN; DEFICIENCY; DIFFERENTIATION; RELEASE; CULTURE AB Docosahexanoic acid (22:6n-3; DHA) deficiency during development is associated with impairment in learning and memory, suggesting an important role of DHA in neuronal development. Here we provide evidence that DHA promotes neuronal differentiation in rat embryonic hippocampal primary cultures. DHA deficiency in vitro was spontaneously induced by culturing hippocampal cells in chemically defined medium. DHA supplementation improved DHA levels to values observed in freshly isolated hippocampus. We found that DHA supplementation in culture increased the population of neurons with longer neurite length per neuron and with higher number of branches. However, supplementation with arachidonic, oleic or docosapentaenoic acid did not have any effect, indicating specificity of the DHA action on neurite growth. Furthermore, hippocampal cultures obtained from n-3 fatty acid deficient animals contained a lower DHA level and a neuronal population with shorter neurite length per neuron in comparison to those obtained from animals with adequate n-3 fatty acids. DHA supplementation to the deficient group recovered the neurite length to the level similar to n-3 fatty acid adequate cultures. Our data demonstrates that DHA uniquely promotes neurite growth in hippocampal neurons. Inadequate neurite development due to DHA deficiency may contribute to the cognitive impairment associated with n-3 fatty acid deficiency. C1 NIAAA, Sect Mass Spectrometry, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. RP Kim, HY (reprint author), NIAAA, Sect Mass Spectrometry, Lab Membrane Biochem & Biophys, NIH, 12420 Parklawn Dr, Rockville, MD 20852 USA. EM hykim@nih.gov NR 47 TC 204 Z9 214 U1 2 U2 14 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2004 VL 90 IS 4 BP 979 EP 988 DI 10.1111/j.1471-4159.2004.02520.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 842WC UT WOS:000223034200024 PM 15287904 ER PT J AU McFarland, HF Martin, R AF McFarland, HF Martin, R TI Re: GAMES issue SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Letter C1 NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20814 USA. RP McFarland, HF (reprint author), NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20814 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD AUG PY 2004 VL 153 IS 1-2 BP 3 EP 3 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 847BC UT WOS:000223362700003 PM 15334745 ER PT J AU Kumar, MV Nagineni, CN Chin, MS Hooks, JJ Detrick, B AF Kumar, MV Nagineni, CN Chin, MS Hooks, JJ Detrick, B TI Innate immunity in the retina: Toll-like receptor (TLR) signaling in human retinal pigment epithelial cells SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE Toll-like receptors; dsRNA; interferon-beta; retinal pigment epithelial cells; innate immunity; cytokines; poly I : C ID NF-KAPPA-B; PATTERN-RECOGNITION RECEPTORS; DOUBLE-STRANDED-RNA; GENE-EXPRESSION; DIFFERENTIAL EXPRESSION; HUMAN CYTOMEGALOVIRUS; TOXOPLASMA-GONDII; ENDOTHELIAL-CELLS; DENDRITIC CELLS; CUTTING EDGE AB Toll-like receptors (TLRs) are crucial components of innate immunity that participate in host defense against microbial pathogens. We evaluated the expression and function of TLRs in human retinal pigment epithelial (RPE) cells. Real time PCR analysis revealed gene expression for TLRs 1-7, 9, and 10 in RPE cells. TLRs 1 and 3 were the most highly expressed TLRs. Protein expression for TLRs 2, 3, and 4 was observed on RPE cells and this expression was augmented by treatment with poly I:C or interferon-gamma (IFN-gamma). TLR 3 is the receptor for dsRNA, an intermediate of virus replication. Because RPE cells express TLR 3 and are frequently the site of virus replication within the retina, we evaluated TLR 3 signaling. RPE cells treated with poly I:C produced IFN-beta but not IFN-alpha, and this was inhibited by the treatment of RPE cells with anti-TLR 3 antibody. Human recombinant IFN-beta was shown to be biologically active on RPE cells by inhibiting viral replication. Poly I:C treatment of RPE resulted in an increase in the production of IL-6, IL-8, MCP-1, and sICAM-1. The presence of TLRs on RPE cells and the resultant TLR signaling in RPE cells suggest that these molecules may play an important role in innate and adaptive immune responses within the retina. (C) 2004 Elsevier B.V. All rights reserved. C1 Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA. NEI, Immunol Lab, Virol & Immunol Sect, NIH, Bethesda, MD 20892 USA. RP Detrick, B (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, 600 N Wolfe St,Meyer B-125A, Baltimore, MD 21287 USA. EM bdetrick@jhmi.edu NR 51 TC 114 Z9 126 U1 0 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD AUG PY 2004 VL 153 IS 1-2 BP 7 EP 15 DI 10.1016/j.jneuroim.2004.04.018 PG 9 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 847BC UT WOS:000223362700007 PM 15265658 ER PT J AU Yuhas, Y Weizman, A Chrousos, GP Ovadia, H Ashkenazi, S AF Yuhas, Y Weizman, A Chrousos, GP Ovadia, H Ashkenazi, S TI Involvement of the neuropeptide corticotropin-releasing hormone in an animal model of Shigella-related seizures SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE Shigella; seizures; cortricotropin-releasing hormone (CRH); children ID CHILDHOOD SHIGELLOSIS; MANIFESTATIONS; ENHANCEMENT; DYSENTERIAE AB Convulsions are common complications of shigellosis in children. Corticotropin-releasing hormone (CRH), a stress neurohormone, has been implicated in the susceptibility of young children to seizures. We investigated the role of CRH in Shigella-related seizures. Pretreatment with Shigella dysenteriae sonicate enhanced mice response to pentylenetetrazole (PTZ)-induced seizures. Preinjection of antalarmin, a CRH-receptor 1 antagonist, decreased both the mean convulsion score (MCS: 1.6 vs. 1.1, p<0.05) and the percent of mice having seizures (48% vs. 28%, p=0.03). This indicates that CRH plays a role in the increased susceptibility to seizures following exposure to S. dysenteriae. (C) 2004 Elsevier B.V. All rights reserved. C1 Felsenstein Med Res Ctr, Infect Dis Lab, IL-49100 Petah Tiqwa, Israel. Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Schneider Childrens Med Ctr Israel, IL-49100 Petah Tiqwa, Israel. RP Yuhas, Y (reprint author), Felsenstein Med Res Ctr, Infect Dis Lab, Beilinson Campus, IL-49100 Petah Tiqwa, Israel. EM yuhas@post.tau.ac.il NR 13 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD AUG PY 2004 VL 153 IS 1-2 BP 36 EP 39 DI 10.1016/j.jneuroim.2004.04.009 PG 4 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 847BC UT WOS:000223362700010 PM 15265661 ER PT J AU Tonelli, LH Gunsolly, CA Belyavskaya, E Atwood, AR Sternberg, EM AF Tonelli, LH Gunsolly, CA Belyavskaya, E Atwood, AR Sternberg, EM TI Increased pro-thyrotropin-releasing hormone transcription in hypophysiotropic neurons of Lewis rats SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE thyroid hormone receptors; neuroendocrine; neuroimmune; inbred rats; in situ hybridization; quantitative RT-PCR ID PITUITARY-THYROID AXIS; GENE-EXPRESSION; IMMUNE-SYSTEM; FISCHER RATS; PARAVENTRICULAR NUCLEUS; MESSENGER-RNA; RECEPTOR; LIPOPOLYSACCHARIDE; PROLACTIN; GLUCOCORTICOIDS AB The expression of pro-thyrotropin-releasing hormone (pro-TRH) mRNA was analyzed in the hypothalamus of inflammatory susceptible LEW/N and resistant F344/N rats at baseline and in adrenalectomized and lipopolysaccharide-treated animals. In saline-treated control animals, increased pro-TRH transcription was detected in LEW/N with respect to F344/N rats. This increased LEW/N pro-TRH expression was stable regardless of condition in contrast to F344/N increased pro-TRH transcription post-adrenalectomy and decreased pro-TRH after lipopolysaccharide administration. The LEW/N increase in pro-TRH mRNA was independent of changes in hormonal status suggesting alteration of the thyroid axis at the central level in this strain. (C) 2004 Elsevier B.V. All rights reserved. C1 NIMH, Sect Neuroendocrine Immunol & Behav, DHHS, Bethesda, MD 20892 USA. RP Sternberg, EM (reprint author), NIMH, Sect Neuroendocrine Immunol & Behav, DHHS, 36 Convent Dr MSC 4020,Bldg 36,Room 1A23, Bethesda, MD 20892 USA. EM ems@codon.nih.gov NR 26 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD AUG PY 2004 VL 153 IS 1-2 BP 143 EP 149 DI 10.1016/j.jneuroim.2004.05.002 PG 7 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 847BC UT WOS:000223362700021 PM 15265672 ER PT J AU van der Veen, RC Dietlin, TA Karapetian, AN Holland, SM Hofman, FM AF van der Veen, RC Dietlin, TA Karapetian, AN Holland, SM Hofman, FM TI Extra-cellular superoxide promotes T cell expansion through inactivation of nitric oxide SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE nitric oxide; superoxide; T lymphocytes; spleen; EAE ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; CHRONIC GRANULOMATOUS-DISEASE; CENTRAL-NERVOUS-SYSTEM; INTERFERON-GAMMA; DEFICIENT MICE; IFN-GAMMA; SYNTHASE; INHIBITION; ANTIGEN; IMMUNOSUPPRESSION AB The mechanism and regulation of immunosuppression by nitric oxide (NO) is unclear. Extra-cellular superoxide (EC-O-2(-)) production by NADPH-oxidase (phox) may prevent NO-mediated suppression of T cell proliferation. p47(phox-/-) mice are resistant to experimental allergic encephalomyelitis (EAE), coinciding with enhanced splenic NO activity, but no causal link was established. Here, we demonstrate such link, since p47(phox-/-) mice developed severe EAE by adoptive transfer, but only if NO production during ex vivo donor cell reactivation was inhibited. EC-O-2(-) production increased during cognate T cell reactivation, while inhibition of EC-O-2(-) by exogenous superoxide dismutase enhanced NO activity. By inhibiting NO, EC-O-2(-) production promotes T cell expansion during peripheral immune-response activation, not during tissue inflammation. (C) 2004 Elsevier B.V. All rights reserved. C1 Univ So Calif, Kech Sch Med, Dept Neurol, MCH 142, Los Angeles, CA 90033 USA. NIAID, Host Def Lab, Bethesda, MD 20892 USA. Univ So Calif, Kech Sch Med, Dept Pathol, MCH 142, Los Angeles, CA 90033 USA. RP van der Veen, RC (reprint author), Univ So Calif, Kech Sch Med, Dept Neurol, MCH 142, 1333 San Pablo St, Los Angeles, CA 90033 USA. EM vanderve@usc.edu NR 28 TC 17 Z9 18 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD AUG PY 2004 VL 153 IS 1-2 BP 183 EP 189 DI 10.1016/j.jneuroim.2004.05.008 PG 7 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 847BC UT WOS:000223362700025 PM 15265676 ER PT J AU Periz, G Fortini, ME AF Periz, G Fortini, ME TI Functional reconstitution of gamma-secretase through coordinated expression of presenilin, nicastrin, Aph-1, and Pen-2 SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Review DE gamma-secretase; APP; Alzheimer's disease; notch; signal transduction ID AMYLOID PRECURSOR PROTEIN; REGULATED INTRAMEMBRANE PROTEOLYSIS; BETA-PEPTIDE PRODUCTION; INTRACELLULAR DOMAIN; ALZHEIMERS-DISEASE; TRANSMEMBRANE DOMAIN; TERMINAL FRAGMENT; IN-VIVO; A-BETA; CAENORHABDITIS-ELEGANS AB The gamma-secretase complex has emerged as an unusual membrane-bound aspartyl protease with the ability to cleave certain substrate proteins at peptide bonds believed to be buried within the hydrophobic environment of the lipid bilayer. This cleavage is responsible for a key biochemical step in signaling from several different cell-surface receptors, and it is also crucial in generating the neurotoxic amyloid peptides that are central to the pathogenesis of Alzheimer's disease. Active gamma-secretase is a multimeric protein complex consisting of at least four different proteins, presenilin, nicastrin, Aph-1, and Pen-2, with presenilin serving as the catalytically active core of the aspartyl protease. Presenilin itself undergoes endoproteolytic maturation, a process that is tightly regulated during the assembly and maturation of gamma-secretase, and that depends on the three cofactors nicastrin, Aph-1, and Pen-2. Recent studies have demonstrated that presenilin and its three cofactors are likely to be the major proteins needed for functional reconstitution of active gamma-secretase and have begun to elucidate the specific functions of the cofactors in the ordered assembly of gamma-secretase. Published 2004 Wiley-Liss, lnc.(dagger) C1 NCI, Lab Prot Dynam & Signaling, Frederick, MD 21701 USA. RP Fortini, ME (reprint author), NCI, Lab Prot Dynam & Signaling, 1050 Boyles St, Frederick, MD 21701 USA. EM fortini@ncifcrf.gov FU NIA NIH HHS [R01AG14583] NR 113 TC 47 Z9 49 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD AUG 1 PY 2004 VL 77 IS 3 BP 309 EP 322 DI 10.1002/jnr.20203 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 840SZ UT WOS:000222881300001 PM 15248287 ER PT J AU Getchell, TV Peng, XJ Green, CP Stromberg, AJ Chen, KC Mattson, MP Getchell, ML AF Getchell, TV Peng, XJ Green, CP Stromberg, AJ Chen, KC Mattson, MP Getchell, ML TI In silico analysis of gene expression profiles in the olfactory mucosae of aging senescence-accelerated mice SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Review DE microarrays; bioinformatics analysis; gene profiling; molecular senescence; Gompertz equation ID LEUKEMIA INHIBITORY FACTOR; TISSUE-PLASMINOGEN ACTIVATOR; AGE-RELATED TRENDS; PEROXISOMAL MEMBRANE-PROTEIN; PUTATIVE PHEROMONE RECEPTORS; EPIDERMAL GROWTH-FACTOR; FALSE DISCOVERY RATE; BLOOD-BRAIN-BARRIER; OXIDATIVE STRESS; P-GLYCOPROTEIN AB We utilized high-density Affymetrix oligonucleotide arrays to investigate gene expression in the olfactory mucosae of near age-matched aging senescence-accelerated mice (SAM). The senescence-prone (SAMP) strain has a significantly shorter lifespan than does the senescence-resistant (SAMR) strain. To analyze our data, we applied biostatistical methods that included a correlation analysis to evaluate sources of methodologic and biological variability; a two-sided t-test to identify a sub-population of Present genes with a biologically relevant P-value <0.05; and a false discovery rate (FDR) analysis adjusted to a stringent 5% level that yielded 127 genes with a P-value of <0.001 that were differentially regulated in near age-matched SAMPs (SAMP-Os; 13.75 months) compared to SAMRs (SAMR-Os, 12.5 months). Volcano plots related the variability in the mean hybridization signals as determined by the two-sided t-test to fold changes in gene expression. The genes were categorized into the six functional groups used previously in gene profiling experiments to identify candidate genes that may be relevant for senescence at the genomic and cellular levels in the aging mouse brain (Lee et al. [2000] Nat Genet 25:294-297) and in the olfactory mucosa (Getchell et al. [2003] Ageing Res Rev 2:211-243), which serves several functions that include chemosensory detection, immune barrier function, xenobiotic metabolism, and neurogenesis. Because SAMR-Os and SAMP-Os have substantially different median lifespans, we related the rate constant a in the Gompertz equation on aging to intrinsic as opposed to environmental mechanisms of senescence based on our analysis of genes modulated during aging in the olfactory mucosa. (C) 2004 Wiley-Liss, Inc. C1 Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA. Univ Kentucky, Dept Physiol, Lexington, KY 40536 USA. Univ Kentucky, Dept Stat, Lexington, KY 40536 USA. Univ Kentucky, Dept Mol & Biomed Pharmacol, Lexington, KY 40536 USA. Univ Kentucky, Dept Anat & Neurobiol, Lexington, KY 40536 USA. NIA, Neurosci Lab, Baltimore, MD 21224 USA. RP Getchell, TV (reprint author), Univ Kentucky, Sanders Brown Ctr Aging, 800 S Limestone St, Lexington, KY 40536 USA. EM tgetche@uky.edu RI Mattson, Mark/F-6038-2012 FU NCRR NIH HHS [1P-20RR16481-01]; NIA NIH HHS [AG-016824-23] NR 178 TC 8 Z9 8 U1 4 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD AUG 1 PY 2004 VL 77 IS 3 BP 430 EP 452 DI 10.1002/jnr.20157 PG 23 WC Neurosciences SC Neurosciences & Neurology GA 840SZ UT WOS:000222881300013 PM 15248299 ER PT J AU Sundaram, SK Freedman, NMT Carrasquillo, JA Carson, JM Whatley, M Libutti, SK Sellers, D Bacharach, SL AF Sundaram, SK Freedman, NMT Carrasquillo, JA Carson, JM Whatley, M Libutti, SK Sellers, D Bacharach, SL TI Simplified kinetic analysis of tumor F-18-FDG uptake: A dynamic approach SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE F-18-FDG; Patlak; standardized uptake value ID POSITRON-EMISSION-TOMOGRAPHY; PARAMETRIC IMAGES; METABOLIC-RATE; PET; DEOXYGLUCOSE; THERAPY; SUV AB Standardized uptake value (SUV) is often used to quantify F-18-FDG tumor use. Although useful, SUV suffers from known quantitative inaccuracies. Simplified kinetic analysis (SKA) methods have been proposed to overcome the shortcomings of SUV. Most SKA methods rely on a single time point (SKA-S), not on tumor uptake rate. We describe a hybrid between Patlak analysis and existing SKA-S methods, using multiple time points (SKA-M) but reduced imaging time and without measurement of an input function. We compared SKA-M with a published SKA-S method and with Patlak analysis. Methods: Twenty-seven dynamic F-18-FDG scans were performed on 11 cancer patients. A population-based F-18-FDG input function was generated from an independent patient population. SKA-M was calculated using this population input function and either a short, late, dynamic acquisition over the tumor (starting 25-35 min after injection and ending similar to55 min after injection) or dynamic imaging 10 or 25 min to similar to55 min after injection but using only every second or third time point, to permit a 2- or 3-field-of-view study. SKA-S was also calculated. Both SKA-M and SKA-S were compared with the gold standard, Patlak analysis. Results: Both SKA-M (1 field of view) and SKA-S correlated well with Patlak slope (r > 0.99, P < 0.001, and r = 0.96, P < 0.001, respectively), as did multilevel SKA-M (r > 0.99 and P < 0.001 for both). Mean values of SKA-M (25-min start time) and SKA-S were statistically different from Patlak analysis (P < 0.001 and P < 0.04, respectively). One-level SKA-M differed from the Patlak influx constant by only -1.0% +/- 1.4%, whereas SKA-S differed by 15.1% +/- 3.9%. With 1-level SKA-M, only 2 of 27 studies differed from K-i by more than 20%, whereas with SKA-S, 10 of 27 studies differed by more than 20% from K-i. Conclusion: Both SKA-M and SKA-S compared well with Patlak analysis. SKA-M (1 or multiple levels) had lower variability and bias than did SKA-S, compared with Patlak analysis. SKA-M may be preferred over SUV or SKA-S when a large unmetabolized F-18-FDG fraction is expected and 1-3 fields of view are sufficient. C1 NIH, Bethesda, MD 20892 USA. Hadassah Univ Hosp, IL-91120 Jerusalem, Israel. RP Bacharach, SL (reprint author), NIH, Bldg 10,Room 1C401, Bethesda, MD 20892 USA. EM steve-bacharach@nih.gov RI Carrasquillo, Jorge/E-7120-2010; Sundaram, Senthil/B-3905-2013; OI Sundaram, Senthil/0000-0002-0382-0536; Carrasquillo, Jorge/0000-0002-8513-5734 NR 14 TC 23 Z9 24 U1 0 U2 4 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD AUG PY 2004 VL 45 IS 8 BP 1328 EP 1333 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 844VG UT WOS:000223188300023 PM 15299057 ER PT J AU Toyama, H Ichise, M Liow, JS Modell, KJ Vines, DC Esaki, T Cook, M Seidel, J Sokoloff, L Green, MV Innis, RB AF Toyama, H Ichise, M Liow, JS Modell, KJ Vines, DC Esaki, T Cook, M Seidel, J Sokoloff, L Green, MV Innis, RB TI Absolute quantification of regional cerebral glucose utilization in mice by F-18-FDG small animal PET scanning and 2-C-14-DG autoradiography SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE small animal PET; mouse; F-18-FDG; anesthesia; cerebral glucose metabolism ID BLOOD-FLOW; RAT; ISOFLURANE; ANESTHESIA; KETAMINE; XYLAZINE; BRAIN; SENSITIVITY; METABOLISM; DIAZEPAM AB The purpose of this study was to evaluate the feasibility of absolute quantification of regional cerebral glucose utilization (rCMR(glc)) in mice by use of F-18-FDG and a small animal PET scanner. rCMR(glc), determined with F-18-FDG PET was compared with values determined simultaneously by the autoradiographic 2-C-14-DG method. In addition, we compared the rCMR(glc), values under isoflurane, ketamine and xylazine anesthesia, and awake states. Methods: Immediately after injection of F-18-FDG and 2-C-14-DG into mice, timed arterial samples were drawn over 45 min to determine the time courses of F-18-FDG and 2-C-14-DG. Animals were euthanized at 45 min and their brain was imaged with the PET scanner. The brains were then processed for 2-C-14-DG autoradiography. Regions of interest were manually placed over cortical regions on corresponding coronal F-18-FDG PET and 2-C-14-DG autoradiographic images. rCMR(glc), values were calculated for both tracers by the autoradiographic 2-C-14-DG method with modifications for the different rate and lumped constants for the 2 tracers. Results: Average rCMR(glc), values in cerebral cortex with F-18-FDG PET under normoglycemic conditions (isoflurane and awake) were generally lower (by 8.3%) but strongly correlated with those of 2-C-14-DG (r(2) = 0.95). On the other hand, under hyperglycemic conditions (ketamine/xylazine) average cortical rCMRglc values with F-18-FDG PET were higher (by 17.3%) than those with 2-C-14-DG. Values for rCMR(glc) and uptake (percentage injected dose per gram [%ID/gl) with F-18-FDG PET were significantly lower under both isoflurane and ketamine/xylazine anesthesia than in the awake mice. However, the reductions of rCMR(glc), were markedly greater under isoflurane (by 57%) than under ketamine and xylazine (by 19%), whereas more marked reductions of %ID/g were observed with ketamine/xylazine (by 54%) than with isoflurane (by 37%). These reverse differences between isoflurane and ketamine/xylazine may be due to competitive effect of F-18-FDG and glucose uptake to the brain under hyperglycemia. Conclusion: We were able to obtain accurate absolute quantification of rCMR(glc), with mouse F-18-FDG PET imaging as confirmed by concurrent use of the autoradiographic 2-C-14-DG method. Underestimation of rCMR(glc) by F-18-FDG in normoglycemic conditions may be due to partial-volume effects. Computation of rCMR(glc) from F-18-FDG data in hyperglycemic animals may require, however, alternative rate and lumped constants for F-18-FDG. C1 NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. NIMH, Cerebral Metab Lab, NIH, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Nucl Med, Bethesda, MD 20892 USA. RP Toyama, H (reprint author), Fujita Hlth Univ, Dept Radiol, 1-98,Dengakugakubo, Toyoake, Aichi 4701192, Japan. EM htoyama@fujita-hu.ac.jp NR 27 TC 64 Z9 64 U1 2 U2 10 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD AUG PY 2004 VL 45 IS 8 BP 1398 EP 1405 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 844VG UT WOS:000223188300033 PM 15299067 ER PT J AU Kirrane, EF Hoppin, JA Umbach, DM Samanic, C Sandler, DP AF Kirrane, EF Hoppin, JA Umbach, DM Samanic, C Sandler, DP TI Patterns of pesticide use and their determinants among wives of farmer pesticide applicators in the agricultural health study SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID RED-RIVER VALLEY; WOMENS HEALTH; RISK-FACTORS; EXPOSURE; CANCER; CHILDREN; MINNESOTA; MORTALITY; FAMILIES; STATES AB Pesticide exposure among farmers' wives is poorly characterized. Using questionnaire data from a cohort study of licensed pesticide applicators and their spouses, we investigated patterns of pesticide use among farmers' wives (n = 31,173). Wives reported a wide range of pesticide use: 36% never used pesticides during their lifetimes, whereas heaviest pesticide users (10%) reported lifetime use of 3 or more agncultural pesticides plus commonly used residential pesticides. We identified 5 ordinal pesticide-use categories and studied factors associated with each category through polytomous logistic regression. Engaging in field work and household hygiene practices that could increase exposure were associated with pesticide use, and associations appeared to strengthen with increasing pesticide use category. Farm women reporting the heaviest pesticide use could exacerbate their exposure by engaging in practices that could increase pesticide contact. C1 NIEHS, Epidemiol Branch, US Dept HHS, NIH, Res Triangle Pk, NC 27709 USA. Coda Inc, Durham, NC USA. NCI, US Dept HHS, NIH, Rockville, MD USA. RP Hoppin, JA (reprint author), NIEHS, Epidemiol Branch, US Dept HHS, NIH, MD A3 05,Box 12233, Res Triangle Pk, NC 27709 USA. EM hoppin1@niehs.nih.gov OI Sandler, Dale/0000-0002-6776-0018 NR 37 TC 17 Z9 18 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-2752 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD AUG PY 2004 VL 46 IS 8 BP 856 EP 865 DI 10.1097/01.jom.0000135521.15169.3e PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 845WU UT WOS:000223276800014 PM 15300138 ER PT J AU Redlich, M Maly, A Aframian, D Shabat, S Ezov, N Levin-Harrus, T Nyska, M Nyska, A AF Redlich, M Maly, A Aframian, D Shabat, S Ezov, N Levin-Harrus, T Nyska, M Nyska, A TI Histopathologic changes in dental and oral soft tissues in 2-butoxyethanol-induced hemolysis and thrombosis in rats SO JOURNAL OF ORAL PATHOLOGY & MEDICINE LA English DT Article DE 2-butoxyethanol; dentition; hemolysis; rat; thrombosis; tongue ID SICKLE-CELL-ANEMIA; FEMALE F344 RATS; BUTOXYACETIC ACID; INHALATION EXPOSURE; TEMPORAL ARTERITIS; NECROSIS; ERYTHROCYTES; INFARCTION; PULP; INGESTION AB BACKGROUND: 2-Butoxyethanol (2-BE; ethylene glycol monobutyl ether) is extensively used as a solvent in surface coatings, such as lacquers, enamels, and varnishes in industrial and household cleaning products. Its major toxicity is manifested in the circulation, as it induces hemolytic anemia and thrombosis in various organs. While 2-BE has been implicated in the induction of anemia in different species, the rat has proven most sensitive, especially the female of this species. The purpose of this study was to document the effects of 2-BE on dentition, the periodontal ligament, the tongue, the salivary glands, and the oral mucosa in male and female Fischer 344 rats. METHODS: The experiment included 40 rats divided into five groups. Four groups were exposed to 2, 3, or 4 daily doses of 2-BE, and a fifth group served as control. The rats were killed on days 2, 3, 4, and 29. The teeth and soft oral tissues were prepared for histopathologic observation. RESULTS: The histopathologic analysis showed that the major effect of 2-BE was exerted on the odontoblasts of the incisors and on molars, with greater effect on the incisors. Foci of damaged muscle cells in the tongue were also observed. The blood vessels were dilated and congested, and a primary thrombosis was seen in the dental pulp. CONCLUSIONS: The results of this study revealed a resemblance between the dental injuries in this rat model and those seen in sickle cell anemia in humans. This 2-BE animal model holds potential to assist in the discovery of preventive measures and/or treatment for dental injuries that occur in human diseases with hemolytic anemia. C1 Hebrew Univ Jerusalem, Hadassah Med Sch, Fac Med Dent, Dept Orthodont, IL-91120 Jerusalem, Israel. Hebrew Univ Jerusalem, Hadassah Med Sch, Fac Med Dent, Dept Pathol, IL-91120 Jerusalem, Israel. Hebrew Univ Jerusalem, Hadassah Med Sch, Fac Med Dent, Dept Oral Biol & Oral Med, IL-91120 Jerusalem, Israel. Sapir Med Ctr, Dept Orthopaed Surg, Kefar Sava, Israel. Harlan Biotech Israel Ltd, Kiryat Weizmann, Rehovot, Israel. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. RP Redlich, M (reprint author), Hebrew Univ Jerusalem, Hadassah Med Sch, Fac Med Dent, Dept Orthodont, POB 12271, IL-91120 Jerusalem, Israel. EM mredlich@zahav.net.il NR 35 TC 4 Z9 5 U1 0 U2 0 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0904-2512 J9 J ORAL PATHOL MED JI J. Oral Pathol. Med. PD AUG PY 2004 VL 33 IS 7 BP 424 EP 429 DI 10.1111/j.1600-0714.2004.00224.x PG 6 WC Dentistry, Oral Surgery & Medicine; Pathology SC Dentistry, Oral Surgery & Medicine; Pathology GA 837ET UT WOS:000222611900008 PM 15250835 ER PT J AU Brindle, TJ Nitz, AJ Uhl, TL Kifer, E Shapiro, R AF Brindle, TJ Nitz, AJ Uhl, TL Kifer, E Shapiro, R TI Measures of accuracy for active shoulder movements at 3 different speeds with kinesthetic and visual feedback SO JOURNAL OF ORTHOPAEDIC & SPORTS PHYSICAL THERAPY LA English DT Article DE kinesthesia; proprioception; target accuracy; upper extremity ID SINGLE-JOINT MOVEMENTS; ORGANIZING PRINCIPLES; POSITION SENSE; INSENSITIVE STRATEGY; SENSORIMOTOR SYSTEM; REACHING MOVEMENTS; MUSCLE FATIGUE; PROPRIOCEPTION; IMPAIRMENTS; INSTABILITY AB Study Design: Repeated-measures experiment. Objective: To compare measures of end point accuracy (EPA) for 2 feedback conditions: (1) visual and kinesthetic feedback and (2) kinesthetic feedback alone, during shoulder movements, at 3 different speeds. Background: Shoulder joint kinesthesia is typically reported with EPA measures, such as constant error. Reporting multiple measures of EPA, such as variable error and absolute error, could provide a more detailed description of performance. Methods and Measures: Subjects were seated with the shoulder abducted 90degrees in the scapular plane and externally rotated 75degrees, with the forearm placed in a custom shoulder wheel. Subjects internally rotated the shoulder 270 to a target position at 480 of shoulder external rotation for both conditions. Motion analysis was used to determine peak angular velocity and 3 EPA measures for shoulder movements. Each EPA measure was compared between the 2 feedback conditions and among the 3 speeds with a separate 2-way analysis of variance. Results: Movements performed with kinesthetic feedback alone, measured by constant error (P<.01), variable error (P<.01), and absolute error (P<.01), were less accurate than movements performed with visual and kinesthetic feedback. Faster movements were less accurate when measured by constant error (P = .01) and absolute error (P<.01) than slower movements. Subjects tended to overshoot the target in the absence of visual feedback; however, movement speed played minimal role in the overshooting. Conclusions: Multiple measures of EPA, such as constant, variable, and absolute error during simple restricted shoulder movements may provide additional information regarding the evaluation of a motor performance or identify different central nervous system control mechanisms for joint kinesthesia. C1 NIH, Phys Disabil Branch, Bethesda, MD 20892 USA. Univ Kentucky, Dept Rehabil Sci, Div Phys Therapy, Lexington, KY USA. Univ Kentucky, Dept Rehabil Sci, Div Athlet Training, Lexington, KY USA. Univ Kentucky, Coll Educ, Lexington, KY USA. Univ Kentucky, Dept Kinesiol & Hlth Promot, Lexington, KY USA. Univ Kentucky, Biodynam Lab, Lexington, KY USA. RP Brindle, TJ (reprint author), NIH, Phys Disabil Branch, Bldg 10 Room 65235,10 Ctr Dr MCS 1604, Bethesda, MD 20892 USA. EM Tbrindle@nih.gov NR 37 TC 5 Z9 5 U1 0 U2 7 PU J O S P T, PI ALEXANDRIA PA 1111 NORTH FAIRFAX ST, STE 100, ALEXANDRIA, VA 22314-1436 USA SN 0190-6011 J9 J ORTHOP SPORT PHYS JI J. Orthop. Sports Phys. Ther. PD AUG PY 2004 VL 34 IS 8 BP 468 EP 478 PG 11 WC Orthopedics; Rehabilitation; Sport Sciences SC Orthopedics; Rehabilitation; Sport Sciences GA 845PG UT WOS:000223256200006 PM 15373010 ER PT J AU Teruya, K Murphy, AC Burlin, T Appella, E Mazur, SJ AF Teruya, K Murphy, AC Burlin, T Appella, E Mazur, SJ TI Fmoc-based chemical synthesis and selective binding to supercoiled DNA of the p53 C-terminal segment and its phosphorylated and acetylated derivatives SO JOURNAL OF PEPTIDE SCIENCE LA English DT Article DE p53 C-terminal domain; peptide thiolester condensation; photolabile protecting group; safety-catch resin approach; selective binding to supercoiled DNA ID SOLID-PHASE SYNTHESIS; TUMOR-SUPPRESSOR P53; AMINO-ACID FLUORIDES; POLYPEPTIDE-SYNTHESIS; PEPTIDE THIOESTERS; PROTEIN-SYNTHESIS; LIGATION; DOMAIN; AUXILIARY; STRATEGY AB The C-terminal domain of p53 comprises a linker, the tetramerization domain and the regulatory domain, and contains at least seven sites of potential post-translational modification. An improved strategy was developed for the synthesis of large peptides that contain phosphorylated amino acids and p53(303-393), a 91-amino acid peptide, and three post-translationally modified derivatives were synthesized through the sequential condensation of three partially protected segments. Peptide thiolesters were prepared using the sulfonamide-based 'safety-catch' resin approach and employing Fmoc-based solid-phase peptide synthesis. At the N-terminus of the middle building block, a photolabile protecting group, 3,4-dimethoxy-6-nitrobenzyloxycarbonyl, was incorporated to differentiate the N-terminal amino group from the side-chain amino groups. Two sequential couplings were accomplished following this protection strategy. The synthetic products, p53(303-393) and its phosphorylated or acetylated derivatives, exhibited the ability to bind specifically to supercoiled DNA, which is one of the characteristics of this domain. Published in 2004 by the European Peptide Society and John Wiley Sons, Ltd. C1 NCI, NIH, Bethesda, MD 20892 USA. NIMH, NIH, Bethesda, MD 20892 USA. RP Mazur, SJ (reprint author), NCI, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM mazurs@mail.nih.gov NR 48 TC 6 Z9 10 U1 0 U2 4 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1075-2617 J9 J PEPT SCI JI J. Pept. Sci. PD AUG PY 2004 VL 10 IS 8 BP 479 EP 493 DI 10.1002/psc.552 PG 15 WC Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 846DX UT WOS:000223296400001 PM 15347136 ER PT J AU Allik, J McCrae, RR AF Allik, J McCrae, RR TI Escapable conclusions: Toomela (2003) and the universality of trait structure SO JOURNAL OF PERSONALITY AND SOCIAL PSYCHOLOGY LA English DT Article ID NEO-PI-R; 5-FACTOR MODEL; PROCRUSTES ROTATION; PERSONALITY-FACTORS; ABILITY; RATINGS AB A. Toomela (2003) concluded that personality structure may be shaped by a cultural mechanism, word meaning structure, and that the apparent universality of the Five-Factor Model (FFM) was the result of inadequate sampling of concrete thinkers. A reanalysis using targeted rotation showed that the intended structure was generally replicated; small deviations in the most concrete thinkers were probably due to measurement error. The reanalysis authors found no evidence of structural differences in a second sample of adults classified as concrete or abstract thinkers. The FFM structure has been replicated in many samples containing individuals with cognitive or educational limitations; observer ratings may be preferred if these limitations are severe. To date, there is no compelling evidence that culture affects personality structure. C1 Univ Tartu, Dept Psychol, EE-50090 Tartu, Estonia. Estinian Ctr Behav & Hlth Sci, Tartu, Estonia. NIA, Lab Personal & Cognit, Dept Hlth & Human Serv, NIH, Baltimore, MD 21224 USA. RP McCrae, RR (reprint author), Gerontol Res Ctr, Box 3,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM jeffin@lpc.gre.nia.nih.gov RI Allik, Juri/D-5609-2009 OI Allik, Juri/0000-0002-8358-4747 NR 30 TC 12 Z9 13 U1 2 U2 5 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-3514 J9 J PERS SOC PSYCHOL JI J. Pers. Soc. Psychol. PD AUG PY 2004 VL 87 IS 2 BP 261 EP 265 DI 10.1037/022-3514.87.2.261 PG 5 WC Psychology, Social SC Psychology GA 840KD UT WOS:000222856500008 PM 15301631 ER PT J AU Bishop, C Tessmer, JL Ullrich, T Rice, KC Walker, PD AF Bishop, C Tessmer, JL Ullrich, T Rice, KC Walker, PD TI Serotonin 5-HT2A receptors underlie increased motor behaviors induced in dopamine-depleted rats by intrastriatal 5-HT2A/2C agonism SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID NEONATAL 6-HYDROXYDOPAMINE LESION; MESSENGER-RNA; ADULT-RAT; PARKINSONS-DISEASE; GENE-EXPRESSION; BINDING-SITES; BRAIN-LESIONS; BASAL GANGLIA; NEURONS; HYPERINNERVATION AB Gene expression studies have suggested that dopamine (DA) depletion increases the sensitivity of striatal direct pathway neurons to the effects of serotonin (5-HT) via the 5-HT2 receptor. The present study examined the possible influence(s) of 5-HT2A or 5-HT2C receptor-mediated signaling locally within the striatum on motor behavior triggered by 5-HT2 receptor agonism in the neonatal DA-depleted rat. Male Sprague-Dawley rats were treated with 6-hydroxydopamine (6-OHDA; 60 mug in 5 mul per lateral ventricle) on postnatal day 3 to achieve near-total DA depletion bilaterally. Sixty days later, sham-operated (saline-injected) or 6-OHDA- treated rats were challenged with the 5-HT2A/2C agonist DOI [(+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane] or saline either by systemic treatment or bilateral intrastriatal infusion. Motor behavior was quantified for 60 min after agonist injection using computerized activity monitors. Systemic DOI treatment (0.2 or 2.0 mg/kg i.p.) was more effective in inducing motor activity in the DA-depleted group compared with intact controls. Intrastriatal DOI infusion (1.0 or 10.0 mug/side) also produced a significant rise in motor activity in the DA-depleted group during the 30- to 60-min period of behavioral analysis but did not influence behavior in intact animals. The effects of intrastriatal DOI infusion were blocked by intrastriatal coinfusion of the 5-HT2 antagonist ketanserin (1.0 mug) and the 5-HT2A-preferring antagonist M100907 [(R)-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol; 1.0 mug] but not the 5-HT2C-preferring antagonist RS102221 [8-[5-(2,4-dimethoxy-5-(4-trifluoromethylsulfo-amido)phenyl-5-oxopentyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione; 1.0 mug]. Such results support the hypothesis that 5-HT2A receptor-mediated signaling events are strengthened within the striatum under conditions of DA depletion to provide a more potent regulation of motor activity. C1 Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI 48201 USA. Wayne State Univ, Sch Med, Dept Psychiat & Behav Neurosci, Detroit, MI 48201 USA. NIDDKD, Med Chem Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Walker, PD (reprint author), Wayne State Univ, Sch Med, Dept Anat & Cell Biol, 540 E Canfield, Detroit, MI 48201 USA. EM pdwalker@med.wayne.edu FU NINDS NIH HHS [NS 39013] NR 40 TC 29 Z9 29 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD AUG PY 2004 VL 310 IS 2 BP 687 EP 694 DI 10.1124/jpet.104.066365 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 838QQ UT WOS:000222728500032 PM 15044557 ER PT J AU Bates, SE Medina-Perez, WY Kohlhagen, G Antony, S Nadjem, T Robey, RW Pommier, Y AF Bates, SE Medina-Perez, WY Kohlhagen, G Antony, S Nadjem, T Robey, RW Pommier, Y TI ABCG2 mediates differential resistance to SN-38 (7-ethyl-10-hydroxycamptothecin) and homocamptothecins SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID RING-MODIFIED CAMPTOTHECIN; DNA TOPOISOMERASE-I; COLON-CARCINOMA CELLS; BREAST-CANCER CELLS; MULTIDRUG-RESISTANCE; HALF-TRANSPORTER; SUBSTRATE-SPECIFICITY; ANTITUMOR-ACTIVITY; DRUG-RESISTANCE; MXR ABCG2 AB One activity potentially limiting the efficacy of camptothecin anticancer agents is their cellular efflux by the ATP-binding cassette half-transporter, ABCG2. Homocamptothecins are novel anticancer drugs that inhibit topoisomerase 1 with a greater potency than camptothecins. Homocamptothecins differ from camptothecins by their E-ring, which is seven-membered instead of the six-membered ring of camptothecins. We report herein that, like camptothecins, homocamptothecin and its difluoro derivative BN80915 are substrates for ABCG2. However, the resistance of three selected cell lines overexpressing wild-type or mutant ABCG2 to homocamptothecin or BN80915 was less than resistance to SN-38 (7-ethyl-10-hydroxycamptothecin), indicating that both the seven-membered E-ring present in homocamptothecin and the A- and B-ring modifications present in SN-38 are involved in substrate recognition by ABCG2. HEK-293 cells transfected with vectors encoding wild-type or mutant ABCG2 were found to be less resistant to both homocamptothecins than to SN-38. However, transfectants overexpressing mutant ABCG2 had relative resistance values for homocamptothecin and BN80915 4- to 14-fold higher than cells expressing wild-type ABCG2, suggesting that the gain of function resulting from mutation at amino acid 482, although not affecting SN-38, extends to the homocamptothecins. Resistance was reversed by the ABCG2 inhibitor fumitremorgin C. BN80915 was 17-fold more potent than SN-38 in wild-type ABCG2- transfected cells, suggesting that BN80915 has the potential to overcome ABCG2- related resistance to SN-38, the active metabolite of CPT-11 (irinotecan). C1 NCI, Canc Therapeut Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), 9000 Rockville Pike,Bldg 10 Rm 12C103, Bethesda, MD 20892 USA. EM sebates@helix.nih.gov NR 39 TC 50 Z9 54 U1 0 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 AUG PY 2004 VL 310 IS 2 BP 836 EP 842 DI 10.1124/jpet.103.063149 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 838QQ UT WOS:000222728500050 PM 15075385 ER PT J AU O'Sullivan, GJ Clifford, JJ Tomiyama, K Koshikawa, N Drago, J Sibley, DR Croke, DT Waddington, JL AF O'Sullivan, GJ Clifford, JJ Tomiyama, K Koshikawa, N Drago, J Sibley, DR Croke, DT Waddington, JL TI D-1-like dopamine receptor-mediated function in congenic mutants with D-1 vs. D5 receptor "knockout" SO JOURNAL OF RECEPTORS AND SIGNAL TRANSDUCTION LA English DT Article; Proceedings Paper CT 6th World Congress of the International-Brain-Research-Organization CY JUL, 2003 CL Prague, CZECH REPUBLIC SP Int Brain Res Org DE D-1-like dopamine receptors; D-1 receptor "knockout"; D-5 receptor "knockout"; behavior; ethological assessment; genetic background; compensation processes ID TARGETED GENE DELETION; OROFACIAL MOVEMENTS; MICE; PHENOTYPE; BRAIN; EXPRESSION; ANTAGONIST; RESOLUTION; DEFICIENT; LOCOMOTOR AB Current understanding of the functional roles of individual dopamine D-1-like [D-1 D-5] and D-2-like [D-2L/S, D-3, D-4] receptor subtypes remains incomplete. In particular, the lack of pharmacological agonists and antagonists able to distinguish between D-1 and D-5 receptors means that any differential roles in the regulation of behavior are poorly understood. Mutant mice with targeted gene deletion ("knockout") of individual dopamine receptor subtypes offer an important alternative approach to resolving these functional roles. In congenic D-1 mutants examined ethologically, progressive increases in specific topographies of behavior over wildtypes were considerably greater than those in D-1 mutants on a mixed genetic background; D-1 knockout appears to influence the neuronal substrate(s) of habituation to disrupt sculpture of the changing topography of behavior from initial exploration through to quiescence. Similarly, the D-1 receptor appears to regulate specific topographies of orofacial movement in the mouse as these are "sculpted" in a time-dependent manner. Although the well-recognized role of the D-1-like family in regulating several aspects of behavioral topography has been assumed to involve primarily D-1 receptors, this presumption may require modification to accommodate a subtle but not negligible role for their D-5 counterparts as evidenced in the phenotype of congenic D-5 mutants. C1 Royal Coll Surgeons Ireland, Dept Clin Pharmacol, Inst Biopharmaceut Sci, Dublin 2, Ireland. Nihon Univ, Sch Dent, Dept Pharmacol, Tokyo, Japan. Univ Melbourne, Howard Florey Inst Expt Physiol & Med, Melbourne, Vic, Australia. NINDS, Mol Neuropharmacol Sect, Bethesda, MD USA. Royal Coll Surgeons Ireland, Dept Biochem, Inst Biopharmaceut Sci, Dublin, Ireland. RP Waddington, JL (reprint author), Royal Coll Surgeons Ireland, Dept Clin Pharmacol, Inst Biopharmaceut Sci, St Stephens Green, Dublin 2, Ireland. EM jwadding@rcsi.ie NR 37 TC 8 Z9 8 U1 0 U2 0 PU MARCEL DEKKER INC PI NEW YORK PA 270 MADISON AVE, NEW YORK, NY 10016 USA SN 1079-9893 J9 J RECEPT SIG TRANSD JI J. Recept. Signal Transduct. PD AUG PY 2004 VL 24 IS 3 BP 107 EP 116 DI 10.1081/LRST-200032078 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 860AC UT WOS:000224308500002 PM 15521357 ER PT J AU Yang, ZW Sibley, DR Jose, PA AF Yang, ZW Sibley, DR Jose, PA TI D-5 dopamine receptor knockout mice and hypertension SO JOURNAL OF RECEPTORS AND SIGNAL TRANSDUCTION LA English DT Article; Proceedings Paper CT 6th World Congress of the International-Brain-Research-Organization CY JUL, 2003 CL Prague, CZECH REPUBLIC SP Int Brain Res Org DE dopamine receptor genes; sodium transport; G protein/effector complex; hypertension ID ROSTRAL VENTROLATERAL MEDULLA; SYMPATHETIC-NERVOUS-SYSTEM; SALT-SENSITIVE RATS; BLOOD-PRESSURE REGULATION; NA+-H+ EXCHANGER; ANGIOTENSIN-II; COUPLING DEFECT; AREA POSTREMA; G-PROTEINS; GENETIC-HYPERTENSION AB Abnormalities in dopamine production and receptor function have been described in human essential hypertension and rodent models of genetic hypertension. All of the five dopamine receptor genes (D-1, D-2, D-3, D-4, and D-5) expressed in mammals and some of their regulators are in loci linked to hypertension in humans and in rodents. Under normal conditions, D-1-like receptors (D-1 and D-5) inhibit sodium transport in the kidney and the intestine. However, in the Dahl salt-sensitive and spontaneously hypertensive rats, and humans with essential hypertension, the D-1-like receptor-mediated inhibition of sodium transport is impaired because of an uncoupling of the D-1-like receptor from its G protein/effector complex. The uncoupling is genetic, and receptor-, organ-, and nephron segment-specific. In human essential hypertension, the uncoupling of the D-1 receptor from its G protein/effector complex is caused by an agonist-independent serine phosphorylation/desensitization by constitutively active variants of the G protein-coupled receptor kinase type 4. The D-5 receptor is also important in blood pressure regulation. Disruption of the D-5 or the D-1 receptor gene in mice increases blood pressure. However, unlike the D-1 receptor, the hypertension in D-5 receptor null mice is caused by increased activity of the sympathetic nervous system, apparently due to activation of oxytocin, V, vasopressin, and non-N-methyl D-aspartate receptors in the central nervous system. The cause of the activation of these receptors remains to be determined. C1 Georgetown Univ, Med Ctr, Washington, DC 20007 USA. NINDS, Bethesda, MD 20892 USA. RP Yang, ZW (reprint author), Georgetown Med Ctr, Washington, DC USA. EM zy4@georgetown.edu NR 125 TC 14 Z9 22 U1 0 U2 0 PU MARCEL DEKKER INC PI NEW YORK PA 270 MADISON AVE, NEW YORK, NY 10016 USA SN 1079-9893 J9 J RECEPT SIG TRANSD JI J. Recept. Signal Transduct. PD AUG PY 2004 VL 24 IS 3 BP 149 EP 164 DI 10.1081/LRST-200029971 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 860AC UT WOS:000224308500005 PM 15521360 ER PT J AU Wang, Q Anzick, S Richter, WF Meltzer, P Simons, SS AF Wang, Q Anzick, S Richter, WF Meltzer, P Simons, SS TI Modulation of transcriptional sensitivity of mineralocorticoid and estrogen receptors SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE mineralocorticoid receptors; estrogen receptors; dose-response curve; partial agonist activity; co-activators; co-repressors ID NUCLEAR HORMONE RECEPTORS; PARTIAL AGONIST ACTIVITY; GLUCOCORTICOID-RECEPTOR; STEROID-RECEPTOR; INDUCTION PROPERTIES; ANDROGEN RECEPTOR; RESPONSE ELEMENT; TRANSACTIVATION DOMAIN; ANTAGONIST COMPLEXES; GENE-TRANSCRIPTION AB Recent reports describe the ability of factors to modulate the position of the dose-response curve of receptor-agonist complexes, and the amount of partial agonist activity of receptor-antagonist complexes, of androgen, glucocorticoid (GRs), and progesterone receptors (PRs). We now ask whether this modulation extends to the two remaining steroid receptors: mineralocorticoid (MRs) and estrogen receptors (ERs). These studies of MR were facilitated by our discovery that the antiglucocorticoid dexamethasone 21-mesylate (Dex-Mes) is a new anti mineralocorticoid with significant amounts of partial agonist activity. Elevated levels of MR, the co-activators TIF2 and SRC-1, and the co-repressor SMRT do modulate the dose-response curve and partial agonist activity of MR complexes. Interestingly, the precise responses are indistinguishable from those seen with GRs in the same cells. Thus, the unequal transactivation of common genes by MRs versus GRs probably cannot be explained by differential responses to changing cellular concentrations of homologous receptor, co-activators, or co-repressors. We also find that the dose-response curve of ER-estradiol complexes is left-shifted to lower steroid concentrations by higher amounts of exogenous ER. Therefore, the modulation of either the dose-response curve of agonists or the partial agonist activity of antisteroid, and in many cases the modulation of both properties, is a common phenomenon for all of the classical steroid receptors. Published by Elsevier Ltd. C1 NIDDK, LMCB, NIH, Steroid Hormones Sect, Bethesda, MD 20892 USA. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Simons, SS (reprint author), NIDDK, LMCB, NIH, Steroid Hormones Sect, Room B2A-07,Bldg 8, Bethesda, MD 20892 USA. NR 66 TC 24 Z9 24 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD AUG PY 2004 VL 91 IS 4-5 BP 197 EP 210 DI 10.1016/j.jsbmb.2004.04.007 PG 14 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 856KG UT WOS:000224043500002 PM 15336697 ER PT J AU Borgnia, MJ Shi, D Zhang, PJ Milne, JLS AF Borgnia, MJ Shi, D Zhang, PJ Milne, JLS TI Visualization of alpha-helical features in a density map constructed using 9 molecular images of the 1.8 MDa icosahedral core of pyruvate dehydrogenase SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE electron cryo-microscopy; macromolecular protein complex; single particle analysis; three-dimensional reconstruction ID PARTICLE ELECTRON CRYOMICROSCOPY; CRYOELECTRON MICROSCOPY; 3-DIMENSIONAL STRUCTURE; ESCHERICHIA-COLI; RESOLUTION; PROTEIN; ANGSTROM; COMPLEX; ARCHITECTURE; FOLD AB Strategies to achieve the highest resolutions in structures of protein complexes determined by cryo-electron microscopy generally involve averaging information from large numbers of individual molecular images. However, significant limitations are posed by heterogeneity in image quality and in protein conformation that are inherent to large data sets of images. Here, we demonstrate that the combination of iterative refinement and stringent molecular sorting is an effective method to obtain substantial improvements in map quality of the 1.8 MDa icosahedral catalytic core of the pyruvate dehydrogenase complex from Bacillus stearotherinophilus. From a starting set of 42 945 images of the core complex, we show that using only the best 139 particles in the data set produces a map that is superior to those constructed with greater numbers of images, and that the location of many of the alpha-helices in the structure can be unambiguously visualized in a map constructed from as few as 9 particles. Published by Elsevier Inc. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Milne, JLS (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM jmilne@nih.gov NR 26 TC 14 Z9 16 U1 1 U2 5 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 AUG PY 2004 VL 147 IS 2 BP 136 EP 145 DI 10.1016/j.jsb.2004.02.007 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 842AL UT WOS:000222974500005 PM 15193642 ER PT J AU Zimmerman, SB AF Zimmerman, SB TI Studies on the compaction of isolated nucleoids from Escherichia coli SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE chloramphenicol; DNA; Escherichia coli; nucleoid; polylysine; spermidine ID SPERMIDINE NUCLEOIDS; DIVISION CYCLE; DNA PROTECTION; CONDENSATION; CHROMOSOME; PROTEINS; RELEASE; STABILIZATION; REPLICATION; CYTOPLASM AB The genomic DNA of Escherichia coli is contained in one or two compact bodies known as nucleoids. Isolation of typically shaped nucleoids requires control of DNA expansion, accomplished here by a modification of the polylysine-spermidine procedure. The ability to control expansion of in vitro nucleoids has application in nucleoid purification and in preparation of samples for high-resolution imaging, and may allow an increased resolution in gene localization studies. Polylysine of relatively low average molecular weight (similar to3 kDa) is used to produce lysates containing nucleoids that are several-fold expanded relative to the sizes of in vivo nucleoids. These expanded forms can be converted to compact forms similar in dimensions to the cellular nucleoids by either a further addition of polylysine or by incubation of diluted lysates at 37 degreesC. The incubation at 37 degreesC is accompanied by autolytic degradation of most ribosomal RNA. Hyperchromism and circular dichroism spectra indicate that polylysine-DNA complexes are modified during the incubation. Compact forms of the nucleoid can be progressively reexpanded by exposure to salt solutions. Nucleoid compaction was similar in lysates made from rapidly or slowly growing cells or from cells that had been briefly treated with chloramphenicol to reduce linkages between DNA and cell envelope. Published by Elsevier Inc. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Zimmerman, SB (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM stevenz@bdg5.niddk.nih.gov NR 56 TC 8 Z9 8 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD AUG PY 2004 VL 147 IS 2 BP 146 EP 158 DI 10.1016/j.jsb.2004.02.003 PG 13 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 842AL UT WOS:000222974500006 PM 15193643 ER PT J AU Ahvazi, B Boeshans, KM Rastinejad, F AF Ahvazi, B Boeshans, KM Rastinejad, F TI The emerging structural understanding of transglutaminase 3 SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Review DE transglutaminase 3; X-ray crystallography; calcium ion; GTP binding ID CORNIFIED CELL-ENVELOPE; COAGULATION FACTOR-XIII; CROSS-LINKING ENZYMES; ULTRASTRUCTURAL-LOCALIZATION; 3-DIMENSIONAL STRUCTURE; PROTRANSGLUTAMINASE-E; BINDING PROTEIN; CALCIUM-IONS; GTP-BINDING; EXPRESSION AB Transglutaminases (TGase; protein-glutamine: amine gamma-glutamyl-transferase) are a family of calcium-dependent acyl-transfer enzymes ubiquitously expressed in mammalian cells and responsible for catalyzing covalent cross-links between proteins or peptides. A series of recent crystal structures have revealed the overall architecture of TGase enzymes, and provided a deep look at their active site, calcium and magnesium ions, and the manner by which guanine nucleotides interact with this enzyme. These structures, backed with extensive biochemical studies, are providing new insights as to how access to the enzyme's active site may be gated through the coordinated changes in cellular calcium and magnesium concentrations and GTP/GDP. Calcium-activated TGase 3 can bind, hydrolyze, and is inhibited by GTP, despite lacking structural homology with other GTP binding proteins. A structure based sequence homology among the TGase enzyme family shows that these essential structural features are shared among other members of the TGase family. Published by Elsevier Inc. C1 NIAMSD, Xray Crystallog Facil, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. Univ Virginia, Dept Pharmacol & Biochem & Mol Genet, Hlth Syst, Charlottesville, VA 22908 USA. RP Ahvazi, B (reprint author), NIAMSD, Xray Crystallog Facil, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. EM Ahvazib@mail.nih.gov NR 48 TC 20 Z9 21 U1 2 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD AUG PY 2004 VL 147 IS 2 BP 200 EP 207 DI 10.1016/j.jsb.2004.03.009 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 842AL UT WOS:000222974500011 PM 15193648 ER PT J AU Stayer, C Sporn, A Gogtay, N Tossell, J Lenane, M Gochman, P Rapoport, JL AF Stayer, C Sporn, A Gogtay, N Tossell, J Lenane, M Gochman, P Rapoport, JL TI Looking for childhood schizophrenia: Case series of false positives SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE childhood-onset schizophrenia; transient psychosis; brief reactive psychosis; anxiety psychosis; factitious disorder by proxy ID ONSET SCHIZOPHRENIA; PSYCHOSIS AB Extensive experience with the diagnosis of childhood-onset schizophrenia indicates a high rate of false positives. Most mislabeled patients have chronic disabling, affective, or behavioral disorders. The authors report the cases of three children who passed stringent initial childhood-onset schizophrenia "screens" but had no chronic psychotic disorder. For two, the European literature yielded more fitting diagnoses: psychosis not otherwise specified (e.g., reactive or psychogenic psychosis, paranoid schizophrenia), single episode in full remission (e.g., anxiety psychosis), and factitious disorder (DSM-IV 300.16). These cases illustrate that transient psychotic illnesses can be misdiagnosed as childhood-onset schizophrenia. Proper identification can prevent years of inappropriate therapies. C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Rapoport, JL (reprint author), NIMH, Child Psychiat Branch, Bldg 10,Room 3N 202, Bethesda, MD 20892 USA. EM rapoport@helix.nih.gov RI Gogtay, Nitin/A-3035-2008 NR 10 TC 9 Z9 10 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD AUG PY 2004 VL 43 IS 8 BP 1026 EP 1029 DI 10.1097/01.chi.0000127573.34038.e4 PG 4 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 840LX UT WOS:000222861200014 PM 15266198 ER PT J AU Hinshaw, SP Hoagwood, K Jensen, PS Kratochvil, C Bickman, L Clarke, G Abikoff, HB Atkins, M Vitiello, B AF Hinshaw, SP Hoagwood, K Jensen, PS Kratochvil, C Bickman, L Clarke, G Abikoff, HB Atkins, M Vitiello, B TI AACAP 2001 Research Forum: Challenges and recommendations regarding recruitment and retention of participants in research investigations SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE research; subjects; recruitment; retention; clinical trials; regulatory agencies ID RANDOMIZED CLINICAL-TRIALS; TREATMENT STRATEGIES; CHILDREN; PSYCHOTHERAPY; PREVENTION; SERVICES AB Objective: Clinical research depends on the participation of representative samples. At the 2001 Annual Meeting of the American Academy of Child and Adolescent Psychiatry, the Workgroup on Research conducted a research forum with the purpose of improving recruitment and retention of children and adolescents in research protocols. Method: An interdisciplinary group of participants focused on (1) consumers and families, (2) communities, (3) professionals and health care delivery systems, (4) regulatory bodies, and (5) alternative research designs. Obstacles and challenges were identified and solutions were discussed. Results: Key recommendations include the following: Investigators must become involved with community stakeholders and more explicitly communicate with families about research procedures, risks, and benefits; budgets should include explicit items for case management and referrals to families who do not meet entry criteria; the culture of clinical settings must incorporate research conducted by clinicians; regulatory bodies must streamline and coordinate protocols and procedures; designs emphasizing flexible treatment strategies and adaptive treatments should be encouraged; and health care systems should consider changing incentives for research participation, including the radical notion that reimbursement be made in terms of improvement rather than service units. Conclusions: An integrated approach is recommended, requiring direct involvement of investigators in communities where research is to be conducted. C1 Univ Calif Berkeley, Dept Psychol, Berkeley, CA 94720 USA. Columbia Univ, Dept Psychiat, New York, NY USA. Univ Nebraska, Ctr Med, Omaha, NE 68198 USA. Vanderbilt Univ, Ctr Mental Hlth Policy, Nashville, TN USA. Ctr Hlth Res, Portland, OR USA. NYU, Sch Med, Ctr Child Study, New York, NY 10016 USA. Univ Illinois, Inst Juvenile Res, Chicago, IL USA. NIMH, Bethesda, MD 20892 USA. RP Hinshaw, SP (reprint author), Univ Calif Berkeley, Dept Psychol, Telman Hall 1650, Berkeley, CA 94720 USA. EM hinshaw@socrates.berkeley.edu OI Jensen, Peter/0000-0003-2387-0650; Bickman, Leonard/0000-0002-0746-3791 NR 26 TC 19 Z9 19 U1 1 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD AUG PY 2004 VL 43 IS 8 BP 1037 EP 1045 DI 10.1097/01.chi.0000129222.89433.3d PG 9 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 840LX UT WOS:000222861200016 PM 15266200 ER PT J AU March, J Kratochvil, C Clarke, G Beardslee, W Derivan, A Emslie, G Green, EP Heiligenstein, J Hinshaw, S Hoagwood, K Jensen, P Lavori, P Leonard, H McNulty, J Michaels, MA Mossholder, A Osher, T Petti, T Prentice, E Vitiello, B Wells, K AF March, J Kratochvil, C Clarke, G Beardslee, W Derivan, A Emslie, G Green, EP Heiligenstein, J Hinshaw, S Hoagwood, K Jensen, P Lavori, P Leonard, H McNulty, J Michaels, MA Mossholder, A Osher, T Petti, T Prentice, E Vitiello, B Wells, K TI AACAP 2002 Research Forum: Placebo and alternatives to placebo in randomized controlled trials in pediatric psychopharmacology SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE placebo; treatment; randomized controlled trial; psychopharmacology; adolescence ID CLINICAL-TRIALS; MENTAL-HEALTH; CHILDREN; FLUOXETINE; DESIGNS; MTA; ADOLESCENTS; STRATEGIES; GUIDELINES; DEPRESSION AB Objective: The use of placebo in the pediatric age group has come under increasing scrutiny. At the 2002 Annual Meeting of the American Academy of Child and Adolescent Psychiatry, the Academy's Workgroup on Research conducted a research forum. The purpose was to identify challenges and their solutions regarding the use of placebo in randomized controlled trials in pediatric psychopharmacology. Method: Workgroups focused on problems and solutions in five areas: ethics and human subjects, research design and statistics, partnering with consumers, U.S. Food and Drug Administration and pharmaceutical industry perspectives, and psychosocial treatments. Results: In many but not all circumstances, inclusion of a placebo control is essential to meet the scientific goals of treatment outcome research. Innovative research designs; involvement of consumers in planning and implementing research; flexibility by industry, academia, the National Institutes of Health, and regulatory agencies acting in partnership; and concomitant use of evidence-based psychosocial services can and should assist in making placebo-controlled trials acceptable. Conclusions: Properly designed placebo-controlled trials remain necessary, ethical, and feasible. C1 Duke Univ, Med Ctr, Durham, NC 27706 USA. Univ Nebraska, Med Ctr, Omaha, NE 68182 USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Children & Adults Attent Deficit Disorders, Landover, MD USA. Columbia Univ, New York, NY 10027 USA. Stanford Univ, Stanford, CA 94305 USA. Brown Univ, Providence, RI 02912 USA. Natl Alliance Mentally Ill, Arlington, VA USA. US FDA, Rockville, MD 20857 USA. Federat Families Childrens Mental Hlth, Alexandria, VA USA. Indiana Univ, Med Ctr, Indianapolis, IN 46204 USA. NIMH, Bethesda, MD 20892 USA. RP March, J (reprint author), Duke Univ, Med Ctr, Durham, NC 27706 USA. EM jsmarch@acpub.duke.edu OI Jensen, Peter/0000-0003-2387-0650 NR 36 TC 27 Z9 27 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD AUG PY 2004 VL 43 IS 8 BP 1046 EP 1056 DI 10.1097/01.chi.0000129606.83206.77 PG 11 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 840LX UT WOS:000222861200017 PM 15266201 ER PT J AU Gilligan, JJ Vieira, NE Yergey, AL AF Gilligan, JJ Vieira, NE Yergey, AL TI Solvation of propanediol ions by water molecules in the gas phase SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Article ID PROTON AFFINITIES; EQUILIBRIA; HYDRATION; CLUSTERS; ELECTROSPRAY; ASSOCIATION; CHEMISTRY; DIAMINES AB The thermochemical properties of protonated hydrates of 1,2- and 1,3-propanediols have been investigated using electrospray ionization-high pressure mass spectrometry. The binding enthalpies, entropies, and free energies of the stepwise hydration of protonated propanediols with one to three waters are reported. The observed negative entropy change [DeltaDeltaS(1,3)(o) for the addition of the third water to 1,3-propanediol(.)H(+)(H2O)(2) suggests a stable structure due to an increased number of hydrogen bonds and the loss of the intramolecular hydrogen bond in the water cluster ion. The thermochemical properties of two isomers of butanediol were also investigated in order to further elucidate the structures of the protonated propanediols. (C) 2004 American Society for Mass Spectrometry. C1 NICHHD, Sect Mass Spectrometry & Metab, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Yergey, AL (reprint author), NICHHD, Sect Mass Spectrometry & Metab, Lab Cellular & Mol Biophys, NIH, 10 Ctr Dr,Room 10-9D52, Bethesda, MD 20892 USA. EM aly@helix.nih.gov NR 19 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1044-0305 J9 J AM SOC MASS SPECTR JI J. Am. Soc. Mass Spectrom. PD AUG PY 2004 VL 15 IS 8 BP 1123 EP 1127 DI 10.1016/j.jasmus.2004.03.007 PG 5 WC Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Chemistry; Spectroscopy GA 843AZ UT WOS:000223048500001 ER PT J AU Huang, BX Kim, HY Dass, C AF Huang, BX Kim, HY Dass, C TI Probing three-dimensional structure of bovine serum albumin by chemical cross-linking and mass spectrometry SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Article ID SATURATED FATTY-ACIDS; BINDING-SITES; PROTEIN-INTERACTION; CRYSTAL-STRUCTURE; IDENTIFICATION; O-18; REAGENTS; REVEALS AB Serum albumin is the principal transporter of fatty acids that are otherwise insoluble in circulating plasma. While the crystal structure of human serum albumin (HSA) as well as its binding with fatty acids has been characterized, the three dimensional structure of bovine serum albumin (BSA) has not been determined although both albumins share 76% sequence homology. In this study we used mass spectrometry coupled with chemical cross-linking, to probe the tertiary structure of BSA. BSA was modified with lysine specific cross-linkers, bis(sulfosuccinimidyl) suberate (BS3), disuccinimidyl suberate (DSS) or disuccinimidyl glutarate (DSG), digested with trypsin and analyzed by tandem mass spectrometry. With O-18 labeling during the digestion, through-space cross-linked peptides were readily identified in mass spectra by a characteristic 8 Da shift. From the cross-linked peptides identified in this study, we found that 12 pairs of lysine residues were separated within 20 A, while 5 pairs were spaced between 20 and 24 A. The spatial distance constraints generated from five K-K pairs in BSA were consistent with the corresponding distance obtained from the crystal structure of HSA, although only six equivalent K-K pairs could be compared. According to our data, the distance between K235 of IIA and K374 of IIB domain in BSA was farther by 7-11 Angstrom than that expected from the crystal structure of HSA, suggesting structural differences between BSA and HSA in this region. The distance constraints obtained for lysine residues using various cross-linkers should be valuable in assisting the determination of the 3-D structure of BSA. (C) 2004 American Society for Mass Spectrometry. C1 NIAAA, Sect Mass Spectrometry, Lab Membrane Biophys & Biochem, NIH, Bethesda, MD 20892 USA. Univ Memphis, Dept Chem, Memphis, TN 38152 USA. RP Kim, HY (reprint author), NIAAA, Sect Mass Spectrometry, Lab Membrane Biophys & Biochem, NIH, 12420 Parklawn Dr, Bethesda, MD 20892 USA. EM hykim@nih.gov NR 23 TC 224 Z9 235 U1 6 U2 70 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1044-0305 J9 J AM SOC MASS SPECTR JI J. Am. Soc. Mass Spectrom. PD AUG PY 2004 VL 15 IS 8 BP 1237 EP 1247 DI 10.1016/j.jasms.2004.05.004 PG 11 WC Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Chemistry; Spectroscopy GA 843AZ UT WOS:000223048500014 PM 15276171 ER PT J AU Li, XK Jones, M Irvine, T Rusk, RA Mori, Y Hashimoto, I von Ramm, OT Li, J Zetts, A Pemberton, J Sahn, DJ AF Li, XK Jones, M Irvine, T Rusk, RA Mori, Y Hashimoto, I von Ramm, OT Li, J Zetts, A Pemberton, J Sahn, DJ TI Real-time 3-dimensional echocardiography for quantification of the difference in left ventricular versus right ventricular stroke volume in a chronic animal model study: Improved results using C-scans for quantifying aortic regurgitation SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article ID IN-VITRO; QUANTITATIVE ASSESSMENT; MAGNETIC-RESONANCE; ORIFICE AREA; RECONSTRUCTION; VALIDATION; MASS; VIVO; FLOW; COMPUTATION AB Objective: The purpose of our study was to test the applicability of calculating the difference between left ventricular (LV) and right ventricular (RV) stroke volume (SV) for assessing the severity of aortic (Ao) regurgitation (AR) using a real-time 3-dimensional (3D) echocardiographic (RT3DE) imaging system. Methods: The Ao valve was incised in 5 juvenile sheep, 6 to 10 weeks before the study, to produce AR (mean regurgitant fraction = 0.50). Simultaneous hemodynamic and RT3DE images were obtained on open-chest animals with Ao and pulmonary flows derived by Ao and pulmonary electromagnetic flow-meters balanced against each other. Four stages (baseline, volume loading, sodium nitroprusside, and angiotensin infusion) were used to produce a total of 16 different hemodynamic states. Epicardial scanning was done with a 2.5-MHz probe to sequentially record first the RV and then the LV cavities. Cavity volumes from the 3D echocardiography data were determined from angled sector planes (B-scans) and parallel cutting planes (C-scans, which are planes perpendicular to the direction of the volume interrogation). AR volumes were determined from 3D images by computing and then subtracting RV SVs from LV SVs and then these were compared with electromagnetic flowmeter-derived SV and regurgitant volumes. Results: There was close correlation between RV and LV SVs of the RT3DE and electromagnetic methods (C-scans: LV, r = 0.98, standard error of the estimate [SEE] = 2.62 mL, P = .0001; RV, r = 0.89, SEE = 2.67 mL, P < .0001; and B-scans: LV, r = 0.95, SEE = 3.55 M., P = .0001; RV, r = 0.77, SEE = 2.78 mL, P = .0003). Because of the small size of the RV in this model, the correlation was closer for C-scans than B-scans for RV SV. AR volume estimation also showed that C-scan (r = 0.93, SEE = 4.23 mL, P < .0001) had closer correlation than B-scan (r = 0.89, SEE = 4.87 mL, P < .0001). However, B-scan-derived AR fraction showed closer correlation than did C-scan (r = 0.82 vs r = 0.85, respectively). Conclusion. In this animal model, RT3DE imaging had the ability to reliably quantify both LV (B- and C-scans) and RV SVs and to assess the severity of AR. C1 Oregon Hlth Sci Univ, Clin Care Ctr Congenital Heart Dis, Portland, OR 97239 USA. NHLBI, Bethesda, MD 20892 USA. Duke Univ, Durham, NC USA. RP Sahn, DJ (reprint author), Oregon Hlth Sci Univ, Clin Care Ctr Congenital Heart Dis, 3181 SW Sam Jackson Pk Rd,L608, Portland, OR 97239 USA. EM sahnd@ohsu.edu NR 24 TC 6 Z9 7 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD AUG PY 2004 VL 17 IS 8 BP 870 EP 875 DI 10.1016/j.echo.2004.04.018 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 843UT UT WOS:000223112800012 PM 15282492 ER PT J AU Spurney, CF Leatherbury, L Lo, CW AF Spurney, CF Leatherbury, L Lo, CW TI High-frequency ultrasound database profiling growth, development, and cardiovascular function in C57BL/6J mouse fetuses SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article ID VENTRICULAR-FUNCTION; TEI-INDEX; ECHOCARDIOGRAPHY; DOPPLER; HEART; MICE AB Background: High-frequency ultrasound is effective for noninvasive phenotypic analysis of cardiovascular development and function in mutagenized fetal mice. However, lacking is a normative database of echocardiographic variables for monitoring growth and cardiovascular function. Methods: C57BL/6J fetal mice were scanned in utero using an ultrasound system with a 15-MHz linear phased-array transducer. Pregnant mothers were anesthetized with 1% isoflurane mixed with 100% oxygen. Quantitative variables for monitoring fetal growth and cardiac function were obtained in several imaging planes and modalities. Results: Fetal growth measurements increased linearly. Inflow velocities showed significant A-wave dominance. The E wave progressively increased during development. Cardiac function was best assessed through M-mode analysis, but short-axis images were difficult to obtain. Spectral Doppler was readily obtained and the myocardial performance index was calculated. Conclusions: These results provide an essential foundation for the evaluation of cardiovascular defects in mutagenized and transgenic mice. C1 Childrens Natl Med Ctr, Dept Cardiol, Washington, DC 20010 USA. NHLBI, Dev Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Spurney, CF (reprint author), Childrens Natl Med Ctr, Dept Cardiol, 111 Michigan Ave NW, Washington, DC 20010 USA. FU NHLBI NIH HHS [Z01-HL005701] NR 12 TC 26 Z9 26 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD AUG PY 2004 VL 17 IS 8 BP 893 EP 900 DI 10.1016/j.echo.2004.04.028 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 843UT UT WOS:000223112800015 PM 15282495 ER PT J AU Hoyt, DB Holcomb, J Abraham, E Atkins, J Sopko, G AF Hoyt, DB Holcomb, J Abraham, E Atkins, J Sopko, G TI Working Group on Trauma Research Program summary report SO JOURNAL OF TRAUMA-INJURY INFECTION AND CRITICAL CARE LA English DT Editorial Material ID RESUSCITATION RESEARCH; SCIENTIFIC PRIORITIES C1 Univ Calif San Diego, Med Ctr, San Diego, CA 92103 USA. USA, Inst Surg Res, San Antonio, TX USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. Walter Reed Army Inst Res, Silver Spring, MD USA. NHLBI, Bethesda, MD 20892 USA. RP Hoyt, DB (reprint author), Univ Calif San Diego, Med Ctr, 200 W Arbor Dr, San Diego, CA 92103 USA. NR 6 TC 9 Z9 10 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5282 J9 J TRAUMA JI J. Trauma-Injury Infect. Crit. Care PD AUG PY 2004 VL 57 IS 2 BP 410 EP 415 DI 10.1097/00005373-200408000-00038 PG 6 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA 859YG UT WOS:000224303700042 PM 15345998 ER PT J AU Bonville, CA Lau, VK DeLeon, JM Gao, JL Easton, AJ Rosenberg, HF Domachowske, JB AF Bonville, CA Lau, VK DeLeon, JM Gao, JL Easton, AJ Rosenberg, HF Domachowske, JB TI Functional antagonism of chemokine receptor CCR1 reduces mortality in acute pneumovirus infection in vivo SO JOURNAL OF VIROLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; MACROPHAGE-INFLAMMATORY PROTEIN-1-ALPHA; PNEUMONIA VIRUS; HOST-DEFENSE; RANTES; MICE; PATHOGENESIS; RECRUITMENT; MIP-1-ALPHA; EXPRESSION AB We present an antiviral-immunomodulatory therapeutic strategy involving the chemokine receptor antagonist Met-RANTES, which yields significant survival in the setting of an otherwise fatal respiratory virus infection. In previous work, we demonstrated that infection with the natural rodent pathogen pneumonia virus of mice involves robust virus replication accompanied by cellular inflammation modulated by the CC chemokine macrophage inflammatory protein 1alpha (MIP-1alpha). We found that the antiviral agent ribavirin limited virus replication in vivo but had no impact on morbidity and mortality associated with this disease in the absence of immunomodulatory control. We show here that ribavirin reduces mortality, from 100% to 10 and 30%, respectively, in gene-deleted CCR1(-/-) mice and in wild-type mice treated with the small-molecule chemokine receptor antagonist, Met-RANTES. As MIP-1alpha-mediated inflammation is a common response to several distantly related respiratory virus pathogens, specific antiviral therapy in conjunction with blockade of the MIP-1alpha/CCR1 inflammatory cascade may ultimately prove to be a useful, generalized approach to severe respiratory virus infection and its pathological sequelae in human subjects. C1 SUNY Upstate Med Univ, Dept Pediat, Syracuse, NY 13210 USA. NIAID, Labs Host Def & Allerg Dis, NIH, Bethesda, MD 20892 USA. Univ Warwick, Dept Biol Sci, Coventry CV4 7AL, W Midlands, England. RP Domachowske, JB (reprint author), SUNY Upstate Med Univ, Dept Pediat, 750 E Adams St, Syracuse, NY 13210 USA. EM domachoj@upstate.edu NR 26 TC 51 Z9 51 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 AUG PY 2004 VL 78 IS 15 BP 7984 EP 7989 DI 10.1128/JVI.78.15.7984-78989.2004 PG 6 WC Virology SC Virology GA 839AL UT WOS:000222755600013 PM 15254170 ER PT J AU Kuyumcu-Martinez, M Belliot, G Sosnovtsev, SV Chang, KO Green, KY Lloyd, RE AF Kuyumcu-Martinez, M Belliot, G Sosnovtsev, SV Chang, KO Green, KY Lloyd, RE TI Calicivirus 3C-like proteinase inhibits cellular translation by cleavage of poly(A)-binding protein SO JOURNAL OF VIROLOGY LA English DT Article ID RABBIT HEMORRHAGIC-DISEASE; POLY(A) BINDING-PROTEIN; NORWALK-LIKE VIRUSES; INITIATION-FACTOR 4G; 3C GENE-PRODUCT; FELINE CALICIVIRUS; IN-VITRO; NONSTRUCTURAL POLYPROTEIN; MESSENGER-RNA; EPIDEMIC GASTROENTERITIS AB Caliciviruses are single-stranded RNA viruses that cause a wide range of diseases in both humans and animals, but little is known about the regulation of cellular translation during infection. We used two distinct calicivirus strains, MD145-12 (genus Norovirus) and feline calicivirus (FCV) (genus Vesivirus), to investigate potential strategies used by the caliciviruses to inhibit cellular translation. Recombinant 3C-like proteinases (r3CL(pro)) from norovirus and FCV were found to cleave poly(A)-binding protein (PABP) in the absence of other viral proteins. The norovirus r3CL(pro) PABP cleavage products were indistinguishable from those generated by poliovirus (PV) 3C(pro) cleavage, while the FCV r3CL(pro) products differed due to cleavage at an alternate cleavage site 24 amino acids downstream of one of the PV 3C(pro) cleavage sites. All cleavages by calicivirus or PV proteases separated the C-terminal domain of PABP that binds translation factors eIF4B and eRF3 from the N-terminal RNA-binding domain of PABP. The effect of PABP cleavage by the norovirus r3CL(pro) was analyzed in HeLa cell translation extracts, and the presence of r3CL(pro) inhibited translation of both endogenous and exogenous mRNAs. Translation inhibition was poly(A) dependent, and replenishment-of the extracts with PABP restored translation. Analysis of FCV-infected feline kidney cells showed that the levels of de novo cellular protein synthesis decreased over time as virus-specific proteins accumulated, and cleavage of PABP occurred in virus-infected cells. Our data indicate that the calicivirus 3CL(pro), like PV 3C(pro), mediates the cleavage of PABP as part of its strategy to inhibit cellular translation. PABP cleavage may be a common mechanism among certain virus families to manipulate cellular translation. C1 Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. NIAID, Infect Dis Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Lloyd, RE (reprint author), Baylor Coll Med, Dept Mol Virol & Microbiol, 739E, Houston, TX 77030 USA. EM rlloyd@bcm.tmc.edu FU NIAID NIH HHS [AI50237, R01 AI050237, R56 AI050237]; NIGMS NIH HHS [GM59803, R01 GM059803] NR 64 TC 58 Z9 62 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 AUG PY 2004 VL 78 IS 15 BP 8172 EP 8182 DI 10.1128/JVI.78.15.8172-8182.2004 PG 11 WC Virology SC Virology GA 839AL UT WOS:000222755600031 PM 15254188 ER PT J AU Maeda, K Nakata, H Koh, Y Miyakawa, T Ogata, H Takaoka, Y Shibayama, S Sagawa, K Fukushima, D Moravek, J Koyanagi, Y Mitsuya, H AF Maeda, K Nakata, H Koh, Y Miyakawa, T Ogata, H Takaoka, Y Shibayama, S Sagawa, K Fukushima, D Moravek, J Koyanagi, Y Mitsuya, H TI Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-Chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro SO JOURNAL OF VIROLOGY LA English DT Article ID SMALL-MOLECULE; HIV-1 INFECTION; MONONUCLEAR PHAGOCYTES; HEPATITIS-C; CHEMOKINE; REPLICATION; RESISTANCE; THERAPY; BINDING; ENTRY AB We identified a novel spirodiketopiperazine (SDP) derivative, AK602/ON04128/GW873140, which specifically blocked the binding of macrophage inflammatory protein 1alpha (MIP-1alpha) to CCR5 with a high affinity (K-d of approximate to3 nM), potently blocked human immunodeficiency virus type 1 (HIV-1) gp120/CCR5 binding and exerted potent activity against a wide spectrum of laboratory and primary R5 HIV-1 isolates, including multidrug-resistant HIV-1 (HIV-1(MDR)) (50% inhibitory concentration values of 0.1 to 0.6 nM) in vitro. AK602 competitively blocked the binding to CCR5 expressed on Chinese hamster ovary cells of two monoclonal antibodies, 45523, directed against multidomain epitopes of CCR5, and 45531, specific against the C-terminal half of the second extracellular loop (ECL2B) of CCR5. AK602, despite its much greater anti-HIV-1 activity than other previously published CCR5 inhibitors, including TAK-779 and SCH-C, preserved RANTES (regulated on activation normal T-cell expressed and secreted) and MIP-1beta binding to CCR5(+) cells and their functions, including CC-chemokine-induced chemotaxis and CCR5 internalization, while TAK-779 and SCH-C fully blocked the CC-chemokine/CCR5 interactions. Pharmacokinetic studies revealed favorable oral bioavailability in rodents. These data warrant further development of AK602 as a potential therapeutic for HIV-1 infection. C1 Kumamoto Univ, Sch Med, Dept Hematol, Kumamoto 8608556, Japan. Kumamoto Univ, Sch Med, Dept Infect Dis, Kumamoto 8608556, Japan. Ono Pharmaceut Co Ltd, Minase Res Inst, Osaka 6188585, Japan. Tohoku Univ, Grad Sch Med, Dept Virol, Sendai, Miyagi 9808575, Japan. Moravek Biochem Inc, Brea, CA 92821 USA. NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. RP Mitsuya, H (reprint author), Kumamoto Univ, Sch Med, Dept Hematol, 1-1-1 Honjo, Kumamoto 8608556, Japan. EM hmitsuya@helix.nih.gov NR 36 TC 181 Z9 194 U1 1 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2004 VL 78 IS 16 BP 8654 EP 8662 DI 10.1128/JVI.78.16.8654-8662.2004 PG 9 WC Virology SC Virology GA 843AH UT WOS:000223046000025 PM 15280474 ER PT J AU Johnson, TR Varga, SM Braciale, TJ Graham, BS AF Johnson, TR Varga, SM Braciale, TJ Graham, BS TI V beta 14(+) T cells mediate the vaccine-enhanced disease induced by immunization with respiratory syncytial virus (RSV) G glycoprotein but not with formalin-inactivated RSV SO JOURNAL OF VIROLOGY LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; ATTACHMENT G GLYCOPROTEIN; BALB/C MICE; PULMONARY EOSINOPHILIA; COTTON RATS; G-PROTEIN; EXPRESSION PATTERNS; CYTOKINE EXPRESSION; F-GLYCOPROTEIN; LUNG-DISEASE AB Mice immunized with respiratory syncytial virus (RSV) G glycoprotein or with formalin-inactivated RSV (FI-RSV) exhibit severe disease following RSV challenge. This results in type 2 cytokine production and pulmonary eosinophilia, both hallmarks of vaccine-enhanced disease. RSV G-induced T-cell responses were shown to be restricted to CD4(+) T cells expressing Vbeta14 in the T-cell receptor (TCR), and the deletion of these T cells resulted in less severe disease. We therefore examined the role of Vbeta14(+) T cells in FI-RSV-induced disease. BALB/c mice were immunized with vaccinia virus expressing secreted RSV G (vvGs) or with FI-RSV. At the time of challenge with live RSV, mice were injected with antibody to the Vbeta14 component of the TCR. vvGs-immunized mice treated with anti-Vbeta14 had reduced cytokine levels in the lung. Eosinophil recruitment to the lung was also significantly reduced. In contrast, depletion of Vbeta14(+) T cells in FI-RSV-immunized mice had little impact on cytokine production or pulmonary eosinophilia. An analysis of TCR Vbeta chain usage confirmed a bias toward Vbeta14 expression on CD4(+) T cells from wGs-immunized mice, whereas the CD4(+) T cells in FI-RSV-immunized mice expressed a diverse array of Vbeta chains. These data show that although FI-RSV and vvGs induce responses resulting in similar immunopathology, the T-cell repertoire mediating the response is different for each immunogen and suggest that the immune responses elicited by RSV G are not the basis for FI-RSV vaccine-enhanced disease. C1 NIAID, Viral Pathogenesis Lab, VRC, NIH, Bethesda, MD 20892 USA. Univ Virginia, Hlth Sci Ctr, Bernie B Carter Ctr Immunol Res, Charlottesville, VA 22908 USA. RP Johnson, TR (reprint author), NIAID, Viral Pathogenesis Lab, VRC, NIH, Bldg 40,Room 2614,40 Convent Dr,MSC 3017, Bethesda, MD 20892 USA. EM teresaj@nih.gov RI Varga, Steven/C-2009-2009 FU NHLBI NIH HHS [HL-33391, R01 HL033391, R01 HL071875]; NIAID NIH HHS [AI-37293, R01 AI037293] NR 55 TC 42 Z9 46 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 AUG PY 2004 VL 78 IS 16 BP 8753 EP 8760 DI 10.1128/JVI.78.16.8753-8760.2004 PG 8 WC Virology SC Virology GA 843AH UT WOS:000223046000034 PM 15280483 ER PT J AU Nikolenko, GN Svarovskaia, ES Delviks, KA Pathak, VK AF Nikolenko, GN Svarovskaia, ES Delviks, KA Pathak, VK TI Antiretroviral drug resistance mutations in human immunodeficiency virus type 1 reverse transcriptase increase template-switching frequency SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; HIGH NEGATIVE INTERFERENCE; DIRECT-REPEAT DELETION; HIGH-LEVEL RESISTANCE; RETROVIRAL RECOMBINATION; STRAND TRANSFER; IN-VIVO; NUCLEOCAPSID PROTEIN; COMBINATION THERAPY; LENTIVIRAL VECTOR AB Template-switching events during reverse transcription are necessary for completion of retroviral replication and recombination. Structural determinants of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) that influence its template-switching frequency are not known. To identify determinants of HIV-1 RT that affect the frequency of template switching, we developed an in vivo assay in which RT template-switching events during viral replication resulted in functional reconstitution of the green fluorescent protein gene. A survey of single amino acid substitutions near the polymerase active site or deoxynucleoside triphosphate-binding site of HIV-1 RT indicated that several substitutions increased the rate of RT template switching. Several mutations associated with resistance to antiviral nucleoside analogs (K65R, L74V, E89G, Q151N, and M184I) dramatically increased RT template-switching frequencies by two- to sixfold in a single replication cycle. In contrast, substitutions in the RNase H domain (H539N, D549N) decreased the frequency of RT template switching by twofold. Depletion of intracellular nucleotide pools by hydroxyurea treatment of cells used as targets for infection resulted in a 1.8-fold increase in the frequency of RT template switching. These results indicate that the dynamic steady state between polymerase and RNase H activities is an important determinant of HIV-1 RT template switching and establish that HIV-1 recombination occurs by the previously described dynamic copy choice mechanism. These results also indicate that mutations conferring resistance to antiviral drugs can increase the frequency of RT template switching and may influence the rate of retroviral recombination and viral evolution. C1 NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Pathak, VK (reprint author), NCI, HIV Drug Resistance Program, Bldg 535,Rm 334, Frederick, MD 21702 USA. EM VPATHAK@ncifcrf.gov RI Delviks-Frankenberry, Krista/M-4822-2013 NR 84 TC 62 Z9 62 U1 0 U2 3 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 AUG PY 2004 VL 78 IS 16 BP 8761 EP 8770 DI 10.1128/JVI-78.16.8761-8770.2004 PG 10 WC Virology SC Virology GA 843AH UT WOS:000223046000035 PM 15280484 ER PT J AU Hu, PF Reuben, DB Crimmins, EM Harris, TB Huang, MH Seeman, TE AF Hu, PF Reuben, DB Crimmins, EM Harris, TB Huang, MH Seeman, TE TI The effects of serum beta-carotene concentration and burden of inflammation on all-cause mortality risk in high-functioning older persons: MacArthur studies of successful aging SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID DIETARY ANTIOXIDANT VITAMINS; BASE-LINE CHARACTERISTICS; REACTIVE PROTEIN-LEVELS; CORONARY-HEART-DISEASE; CARDIOVASCULAR-DISEASE; LUNG-CANCER; ALPHA-TOCOPHEROL; PREVENTION; MARKERS; PLASMA AB Background. It remains unclear to what extent the associations between low serum beta-carotene concentration and increased risk for cardiovascular disease and cancers are attributable to inflammation. The objective of this study was to evaluate simultaneously the effects of serum beta-carotene concentration and inflammation on the subsequent all-cause mortality risk in high-functioning older persons. Methods. The authors conducted a prospective cohort study using information from 672 participants from the MacArthur Studies of Successful Aging. Baseline information was obtained for serum concentrations of beta-carotene, C-reactive protein, interleukin-6, cholesterols, and albumin; body mass index; waist:hip ratio; prevalent medical conditions; health behaviors; and medications. Sex-specific univariate and multivariate logistic regression analyses were used to study the effects of low beta-carotene, high inflammation burden, or both on 7-year all-cause mortality rates while adjusting for other confounders. Results. The serum beta-carotene concentration was inversely associated with C-reactive protein and interleukin-6 levels. After adjustment for inflammation markers and other covariates, the relative risks for low beta-carotene for the 7-year all-cause mortality risk were 2.30 (95% confidence interval [CI], 1.23 to 4.31) in men and 0.85 (95% CL 0.42 to 1.75) in women. Compared with men with high beta-carotene levels and low inflammation, the multiply adjusted relative risk for low beta-carotene and high inflammation burden was 3.78 (95% CL 1.69 to 8.47) in men. Conclusions. Low levels of serum beta-carotene are independently associated with an increased all-cause mortality risk in older men, even after adjustment for the effects of inflammation and other risk factors. In men, but not women, a synergistic effect occurs between low beta-carotene concentration and high inflammation burden in predicting higher mortality rates. C1 Univ Calif Los Angeles, Sch Med, Multicampus Program Geriatr Med & Gerontol, Los Angeles, CA 90095 USA. Univ So Calif, Andrus Gerontol Ctr, Los Angeles, CA USA. NIA, Lab Epidemiol, NIH, Bethesda, MD USA. RP Hu, PF (reprint author), Univ Calif Los Angeles, Sch Med, Multicampus Program Geriatr Med & Gerontol, 10945 Le Conte Ave,Suite 2339, Los Angeles, CA 90095 USA. EM phu@mednet.ucla.edu FU NIA NIH HHS [AG-17056, P06 AG10415-11, AG-17265] NR 25 TC 24 Z9 24 U1 1 U2 4 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD AUG PY 2004 VL 59 IS 8 BP 849 EP 854 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 851PS UT WOS:000223697800013 PM 15345737 ER PT J AU Blanco, D Vicent, S Elizegi, E Pino, I Fraga, MF Esteller, M Saffiotti, U Lecanda, F Montuenga, LM AF Blanco, D Vicent, S Elizegi, E Pino, I Fraga, MF Esteller, M Saffiotti, U Lecanda, F Montuenga, LM TI Altered expression of adhesion molecules and epithelial-mesenchymal transition in silica-induced rat lung carcinogenesis SO LABORATORY INVESTIGATION LA English DT Article DE adhesion molecules; cadherin; catenin; tight junction; lung cancer; EMT; DNA methylation ID BETA-CATENIN EXPRESSION; E-CADHERIN EXPRESSION; ADENOMATOUS-POLYPOSIS-COLI; CELL-CELL ADHESION; GROWTH-FACTOR-BETA; N-CADHERIN; TRANSFORMING GROWTH-FACTOR-BETA-1; BREAST-CANCER; PROLIFERATIVE ACTIVITY; CLINICAL-SIGNIFICANCE AB Loss of the epithelial phenotype and disruption of adhesion molecules is a hallmark in the epithelial-mesenchymal transition (EMT) reported in several types of cancer. Most of the studies about the relevance of adhesion and junction molecules in lung cancer have been performed using established tumors or in vitro models. The sequential molecular events leading to EMT during lung cancer progression are still not well understood. We have used a rat model for multistep lung carcinogenesis to study the status of adherens and tight junction proteins and mesenchymal markers during EMT. After silica-induced chronic inflammation, rats sequentially develop epithelial hyperplasia, preneoplastic lesions, and tumors such as adenocarcinomas and squamous cell carcinomas. In comparison with normal and hyperplastic bronchiolar epithelium and with hyperplastic alveolar type II cells, the expression levels of E-cadherin, alpha-catenin and beta-catenin were significantly reduced in adenomatoid preneoplastic lesions and in late tumors. The loss of E-cadherin in tumors was associated with its promoter hypermethylation. alpha- and beta-catenin dysregulation lead to cytoplasmic accumulation in some carcinomas. No nuclear P-catenin localization was found at any stage of any preneoplastic or neoplastic lesion. Zonula occludens protein-1 was markedly decreased in 66% of adenocarcinomas and in 100% squamous cell carcinomas. The mesenchymal-associated proteins N-cadherin and vimentin were analyzed as markers for EMT. N-cadherin was de novo expressed in 32% of adenocarcinomas and 33% of squamous cell carcinomas. Vimentin-positive tumor cells were found in 35% of adenocarcinomas and 88% of squamous cell carcinomas. Mesenchymal markers were absent in precursor lesions, both hyperplastic and adenomatoid. The present results show that silica-induced rat lung carcinogenesis is a good model to study EMT in vivo, and also provide in vivo evidence suggesting that the changes in cell-cell adhesion molecules are an early event in lung carcinogenesis, while EMT occurs at a later stage. C1 Univ Navarra, Sch Med, Dept Histol & Pathol, CIMA,Carcinogenesis Unit, E-31080 Pamplona, Spain. Univ Navarra, CIMA, Ctr Appl Biomed Res, Div Oncol, E-31080 Pamplona, Spain. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. Spanish Natl Canc Ctr CNIO, Mol Pathol Program, Canc Epigenet Lab, Madrid, Spain. RP Montuenga, LM (reprint author), Univ Navarra, Sch Med, Dept Histol & Pathol, CIMA,Carcinogenesis Unit, E-31080 Pamplona, Spain. EM lmontuenga@unav.es RI Esteller, Manel/L-5956-2014; OI Esteller, Manel/0000-0003-4490-6093; Vicent, Silvestre/0000-0002-9457-6881 NR 77 TC 60 Z9 61 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD AUG PY 2004 VL 84 IS 8 BP 999 EP 1012 DI 10.1038/labinvest.3700129 PG 14 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 841PQ UT WOS:000222943500007 PM 15195114 ER PT J AU Mahanty, S Bray, M AF Mahanty, S Bray, M TI Pathogenesis of filoviral haemorrhagic fevers SO LANCET INFECTIOUS DISEASES LA English DT Review ID EBOLA-VIRUS INFECTION; ANTIINFLAMMATORY CYTOKINE PROFILE; LIPID RAFT MICRODOMAINS; NF-KAPPA-B; DENDRITIC CELLS; DC-SIGN; ENDOTHELIAL-CELLS; MARBURG VIRUSES; RHESUS-MONKEYS; IN-VITRO AB The filoviruses, marburgvirus and ebolavirus, cause epidemics of haemorrhagic fever with high case-fatality rates. The severe illness results from a complex of pathogenetic mechanisms that enable the virus to suppress innate and adaptive immune responses, infect and kill a broad variety of cell types, and elicit strong inflammatory responses and disseminated intravascular coagulation, producing a syndrome resembling septic shock. Most experimental data have been obtained on Zaire ebolavirus, which causes uniformly lethal disease in experimentally infected non-human primates but produces a broader range of outcomes in naturally infected human beings. 10-30% of patients can survive the illness by mobilising adaptive immune responses, and there is limited evidence that mild or symptomless infections also occur. The other filoviruses that have caused human disease, Sudan ebolavirus, Ivory Coast ebolavirus, and marburgvirus, produce a similar illness but with somewhat lower case-fatality rates. Variations in outcome during an epidemic might be due partly to genetically determined differences in innate immune responses to the viruses. Recent studies in non-human primates have shown that blocking of certain host responses, such as the coagulation cascade, can result in reduced viral replication and improved host survival. C1 NIAID, Malaria Vaccine Dev Unit, NIH, Rockville, MD 20852 USA. NIAID, Biodef Clin Res Branch, Off Clin Res, Off Director,NIH, Rockville, MD 20852 USA. RP Bray, M (reprint author), 6700A Rockledge Dr,Room 5128, Bethesda, MD 20892 USA. EM mbray@niaid.nih.gov OI Mahanty, Siddhartha/0000-0003-1068-0524 NR 126 TC 143 Z9 160 U1 2 U2 53 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1473-3099 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD AUG PY 2004 VL 4 IS 8 BP 487 EP 498 DI 10.1016/S1473-3099(04)01103-X PG 12 WC Infectious Diseases SC Infectious Diseases GA 842IB UT WOS:000222995900018 PM 15288821 ER PT J AU Kennedy, TC Hirsch, FR AF Kennedy, TC Hirsch, FR TI Using molecular markers in sputum for the early detection of lung cancer: A review SO LUNG CANCER LA English DT Article; Proceedings Paper CT Conference on Trends Diagnosis and Therapy of Lung Cancer CY FEB 13-14, 2004 CL Munster, GERMANY DE non-small-cell lung carcinoma; sputum; biological markers ID SQUAMOUS-CELL CARCINOMA; AIR-FLOW OBSTRUCTION; ABERRANT METHYLATION; IMAGE CYTOMETRY; HEAVY SMOKERS; CYTOLOGY; FLUORESCENCE; BRONCHOSCOPY; EXPERIENCE; P16(INK4A) AB Recent exciting advances have been made in identifying potential molecular markers in sputum which may soon be ready for validation trials to indicate high risk for lung cancer, especially central airway squamous cell lung cancer. Hopefully, a set of biomarkers will. be identified with higher sensitivity, specificity, and enough lead-time compared to traditional cytopathology to justify endobronchial evaluation and local therapy to help reduce lung-cancer mortality in high-risk patients. (C) 2004 Elsevier Science Ltd. C1 Univ Colorado, Ctr Canc, Specialized Program Res Excellence, NCI, Denver, CO 80262 USA. RP Kennedy, TC (reprint author), 1721 E,19th Ave 366, Denver, CO 80218 USA. EM tchesk@AOL.com NR 46 TC 13 Z9 13 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0169-5002 J9 LUNG CANCER-J IASLC JI Lung Cancer PD AUG PY 2004 VL 45 SU 2 BP S21 EP S27 DI 10.1016/j.lungcan.2004.07.000 PG 7 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 850KO UT WOS:000223610300004 PM 15552778 ER PT J AU Guttman, MA Dick, AJ Raman, VK Arai, AE Lederman, RJ McVeigh, ER AF Guttman, MA Dick, AJ Raman, VK Arai, AE Lederman, RJ McVeigh, ER TI Imaging of myocardial infarction for diagnosis and intervention using real-time interactive MRI without ECG-gating or breath-holding SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE real-time; interventional; MRI; infarct; delayed hyperenhancement; SSFP; FISP; myocardial ischemia; perfusion ID PERFUSION; TSENSE AB Current methods for MRI of infarcted myocardium require ECG-gating and breath-holding during contrast-enhanced segmented k-space inversion-recovery (IR) imaging. However, ECG-gating can be problematic in MRI, and breath-holding can be difficult for some patients. This work demonstrates that infarcted tissue can be visualized without ECG-gating or breath-holding with the use of intermittent inversion pulses during real-time (RT) interactive imaging with steady-state free precession (SSFP). The sequence generates a RT image stream containing a myocardium-nulled image every few frames, which allows nearly simultaneous observation of both infarcted regions and wall motion. First-pass perfusion and wall motion can be simultaneously observed with minor parameter modifications. This method may reduce diagnostic scan time, expand the target population, improve patient comfort, and facilitate targeted, interventional treatment of infarcted myocardium. C1 NHLBI, NIH, Lab Cardiac Energet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NHLBI, Cardiovasc Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Guttman, MA (reprint author), NHLBI, NIH, Lab Cardiac Energet, Dept Hlth & Human Serv, 10 Ctr Dr,Bldg 10,Room B1D416, Bethesda, MD 20892 USA. EM mguttman@nih.gov OI lederman, robert/0000-0003-1202-6673 FU Intramural NIH HHS [Z01 HL004608-08, Z01 HL005062-05] NR 16 TC 20 Z9 21 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD AUG PY 2004 VL 52 IS 2 BP 354 EP 361 DI 10.1002//mm.20174 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 843XU UT WOS:000223121400016 PM 15282818 ER PT J AU Rao, RS Graubard, BI Breen, N Gastwirth, JL AF Rao, RS Graubard, BI Breen, N Gastwirth, JL TI Understanding the factors underlying disparities in cancer screening rates using the Peters-Belson approach - Results from the 1998 National Health Interview Survey SO MEDICAL CARE LA English DT Article DE ethnic/racial disparity; Peters-Belson; cancer screening; survey methods ID BREAST-CANCER; COLORECTAL-CANCER; REDUCING MORTALITY; COST-EFFECTIVENESS; PREVENTIVE CARE; UNITED-STATES; ETHNIC-GROUPS; WOMEN; MAMMOGRAPHY; GUIDELINES AB Background: Cancer screening rates vary substantially by race and ethnicity. We applied the Peters-Belson approach, often used in wage discrimination studies, to analyze disparities in cancer screening rates between different groups using the 1998 National Health Interview Survey. Methods: A regression model predicting the probability of getting screened is fit to the majority group and then used to estimate the expected values for minority group members had they been members of the majority group. The average difference between the observed and expected values for a minority group is the part of the disparity that is not explained by the covariates. Results: The observed disparities in colorectal cancer screening (5.88%) and digital rectal screening (8.54%) between white and black men were explained fully by the difference in their covariate distributions. Only half of the disparity in the observed screening rates (13.54% for colorectal and 17.47% for digital rectal) between white and Hispanic men was explained by the difference in covariates between the groups. The entire disparity observed in mammography screening rates for black and Hispanic women (2.71% and 6.53%, respectively) compared with white women was explained by the difference in covariate distributions. Conclusions: We found that the covariates that explain the disparity in screening rates between the white and the black population do not explain the disparity between the white and the Hispanic population. Knowing how much of a health disparity is explained by measured covariates can be used to develop more effective interventions and policies to eliminate disparity. C1 NCI, Div Canc Epidemiol & Genet, Biostat Branch, DHHS, Bethesda, MD 20892 USA. NCI, Hlth Serv & Econ Branch, Appl Res Program, DHHS, Bethesda, MD 20892 USA. George Washington Univ, Dept Stat, Washington, DC 20052 USA. RP Graubard, BI (reprint author), NCI, Div Canc Epidemiol & Genet, Biostat Branch, DHHS, 6120 Execut Blvd,EPS 8024,MSC 7244, Bethesda, MD 20892 USA. EM graubarb@mail.nih.gov NR 48 TC 48 Z9 48 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD AUG PY 2004 VL 42 IS 8 BP 789 EP 800 DI 10.1097/01.mlr.0000132838.29236.7e PG 12 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 841WH UT WOS:000222962100010 PM 15258481 ER PT J AU Warren, MB Torres-Cabala, CA Turner, ML Merino, MJ Matrosova, VY Nickerson, ML Ma, WB Linehan, WM Zbar, B Schmidt, LS AF Warren, MB Torres-Cabala, CA Turner, ML Merino, MJ Matrosova, VY Nickerson, ML Ma, WB Linehan, WM Zbar, B Schmidt, LS TI Expression of Birt-Hogg-Dube gene mRNA in normal and neoplastic human tissues SO MODERN PATHOLOGY LA English DT Article DE Birt-Hogg-Dube syndrome; BHD gene; renal carcinoma; tumor suppressor gene; fluorescent in situ hybridization; mRNA expression ID RENAL-CELL CARCINOMA; GERMAN-SHEPHERD DOG; SPONTANEOUS PNEUMOTHORAX; NODULAR DERMATOFIBROSIS; KIDNEY NEOPLASIA; HAIR FOLLICLE; TUMORS; BHD; CANCER; MAPS AB Birt-Hogg-Dube(BHD) syndrome is an inherited autosomal genodermatosis characterized by hamartomas of the hair follicle called fibrofolliculomas and an increased risk for developing spontaneous pneumothorax, lung cysts and renal neoplasia. BHD was localized to chromosome 17p11.2 by linkage analysis in BHD families, and germline insertion/deletion and nonsense mutations in a novel gene were identified which were predicted to prematurely truncate the BHD protein, folliculin. No homology to other human proteins was found although folliculin was conserved across species. As a first step toward understanding the function of BHD in the cell and how BHD mutations can lead to the BHD phenotype, we measured the expression of BHD mRNA in normal and neoplastic human tissues by fluorescent in situ hybridization. BHD mRNA was expressed in a variety of tissues, including the skin and its appendages, the distal nephron of the kidney, stromal cells and type 1 pneumocytes of the lung, acinar cells of the pancreas and parotid gland, and epithelial ducts of the breast and prostate. In the brain, BHD mRNA was expressed in neurons of the cerebrum, and Purkinje cells in the cerebellum. BHD mRNA was also expressed in macrophage and lymphocytes in the tonsils and spleen. Tissues with reduced expression of BHD mRNA included heart, muscle and liver. BHD mRNA was expressed strongly in the proliferating epithelial strands of fibrofolliculomas, the cutaneous lesions characteristic of BHD, but not in renal tumors from BHD patients. These results indicate a wide expression pattern for BHD mRNA in many tissues, including skin, lung and kidney, which are involved in the BHD phenotype, and support a tumor suppressor role for BHD in renal cancer. C1 NCI, Immunobiol Lab, Ctr Canc Res, Frederick, MD 21702 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Pathol, Bethesda, MD 20814 USA. NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Schmidt, LS (reprint author), NCI, Immunobiol Lab, Ctr Canc Res, Bldg 560,Rm 12-69, Frederick, MD 21702 USA. EM schmidtl@mail.ncifcrf.gov FU PHS HHS [N01-C012400] NR 21 TC 76 Z9 79 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD AUG PY 2004 VL 17 IS 8 BP 998 EP 1011 DI 10.1038/modpathol.3800152 PG 14 WC Pathology SC Pathology GA 843WS UT WOS:000223118300014 PM 15143337 ER PT J AU Chiang, YJ Kim, SH Tessarollo, L Campisi, J Hodes, RJ AF Chiang, YJ Kim, SH Tessarollo, L Campisi, J Hodes, RJ TI Telomere-associated protein TIN2 is essential for early embryonic development through a telomerase-independent pathway SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID POLY(ADP-RIBOSE) POLYMERASE; STEM-CELLS; TRF1; LENGTH; DNA; MAINTENANCE; REGULATOR AB TIN2 is a negative regulator of telomere elongation that interacts with telomeric DNA repeat binding factor 1 (TRF1) and affects telomere length by a telomerase-dependent mechanism. Here we show that inactivation of the mouse TRF1-interacting protein 2 (TIN2) gene results in early embryonic lethality. We further observed that the embryonic lethality of TIN2 mutant mice was not affected by inactivation of the telomerase reverse transcriptase gene, indicating that embryonic lethality is not the result of telomerase-dependent changes in telomere length or function. Our findings suggest that TIN2 has a role independent of telomere length regulation that is essential for embryonic development and cell viability. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NIA, NIH, Bethesda, MD 20892 USA. Univ Calif Berkeley, Lawrence Berkeley Lab, Div Life Sci, Berkeley, CA 94720 USA. NCI, Canc Res Ctr, Mouse Canc Genet Program, Frederick, MD 21702 USA. RP Chiang, YJ (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,4B36,9000 Rockville Pike, Bethesda, MD 20892 USA. EM chiangj@mail.nih.gov NR 22 TC 43 Z9 47 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2004 VL 24 IS 15 BP 6631 EP 6634 DI 10.1128/mcb.24.15.6631-6634.2004 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 839DZ UT WOS:000222764800009 PM 15254230 ER PT J AU Liu, XF Ishida, H Raziuddin, R Miki, T AF Liu, XF Ishida, H Raziuddin, R Miki, T TI Nucleotide exchange factor ECT2 interacts with the polarity protein complex Par6/Par3/protein kinase C zeta (PKC zeta) and regulates PKC xi activity SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CELL-CELL CONTACT; RHO-GTPASES; ASYMMETRIC LOCALIZATION; EPITHELIAL-CELLS; TIGHT JUNCTIONS; CDC42; PAR-6; APKC; CYTOKINESIS; ACTIVATION AB Regulation of cell polarity is an important biological event that governs diverse cell functions such as localization of embryonic determinants and establishment of tissue and organ architecture. The Rho family GTPases and the polarity complex Par6/Par3/atypical protein kinase C (PKC) play a key role in the signaling pathway, but the molecules that regulate upstream signaling are still not known. Here we identified the guanine nucleotide exchange factor ECT2 as an activator of the polarity complex. ECT2 interacted with Par6 as well as Par3 and PKCzeta. Coexpression of Par6 and ECT2 efficiently activated Cdc42 in vivo. Overexpression of ECT2 also stimulated the PKC activity, whereas dominant-negative ECT2 inhibited the increase in PKCzeta activity stimulated by Par6. ECT2 localization was detected at sites of cell-cell contact as well as in the nucleus of MDCK cells. The expression and localization of ECT2 were regulated by calcium, which is a critical regulator of cell-cell adhesion. Together, these results suggest that ECT2 regulates the polarity complex Par6/Par3/PKCzeta and possibly plays a role in epithelial cell polarity. C1 NCI, Basic Res Lab, Mol Tumor Biol Sect, Bethesda, MD 20892 USA. RP Miki, T (reprint author), NCI, Cell Biol Lab, Mol Tumor Biol Sect, Bldg 37,Room 2144,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM toru@helix.nih.gov NR 43 TC 56 Z9 63 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 AUG PY 2004 VL 24 IS 15 BP 6665 EP 6675 DI 10.1128/mcb.24.15.6665-6675.2004 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 839DZ UT WOS:000222764800013 PM 15254234 ER PT J AU Kawai, T Fan, JS Mazan-Mamczarz, K Gorospe, M AF Kawai, T Fan, JS Mazan-Mamczarz, K Gorospe, M TI Global mRNA stabilization preferentially linked to translational repression during the endoplasmic reticulum stress response SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID AU-RICH ELEMENT; BINDING PROTEIN HUR; SACCHAROMYCES-CEREVISIAE; TRANSCRIPTION FACTORS; CELLS; STABILITY; EXPRESSION; MECHANISMS; ALPHA; IDENTIFICATION AB The stability of mRNAs undergoing translation has long been a controversial question. Here, we systematically investigate links between mRNA turnover and translation during the endoplasmic reticulum (ER) stress response, a process during which protein synthesis is potently regulated. cDNA array-based approaches to assess the stability and translational status of each mRNA were devised. First, ER stress-triggered changes in mRNA stability were studied by comparing differences in steady-state mRNA levels with differences in gene transcription. Second, changes in translational status were monitored by studying ER stress-induced shifts in the relative distribution of each mRNA along sucrose gradients. Together, the array-derived data reveal complex links between mRNA stability and translation, with all regulatory groups represented: both stabilized and destabilized mRNAs were found among translationally induced as well as translationally suppressed mRNA collections. Remarkably, however, the subset of stabilized mRNAs was prominently enriched in translationally suppressed transcripts, suggesting that ER stress was capable of causing the stabilization of mRNAs associated with a global reduction in protein synthesis. The cDNA array-based approach described here can be applied to global analyses of mRNA turnover and translation and can serve to investigate subsets of mRNAs subject to joint posttranscriptional control. C1 NIA, LCMB, IRP, NIH, Baltimore, MD 21224 USA. RP Gorospe, M (reprint author), NIA, LCMB, IRP, NIH, Box 12,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM myriam-gorospe@nih.gov NR 47 TC 55 Z9 57 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2004 VL 24 IS 15 BP 6773 EP 6787 DI 10.1128/MCB.24.15.6773-6787.2004 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 839DZ UT WOS:000222764800023 PM 15254244 ER PT J AU Zhang, F Sumibcay, L Hinnebusch, AG Swanson, MJ AF Zhang, F Sumibcay, L Hinnebusch, AG Swanson, MJ TI A triad of subunits from the Gal11/tail domain of Srb mediator is an in vivo target of transcriptional activator Gcn4p SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RNA-POLYMERASE-II; TATA-BINDING PROTEIN; SACCHAROMYCES-CEREVISIAE; PREINITIATION COMPLEX; MULTISUBUNIT COMPLEX; COACTIVATOR COMPLEX; YEAST; HOLOENZYME; RECRUITMENT; REQUIREMENT AB The Srb mediator is an important transcriptional coactivator for Gcn4p in the yeast Saccharomyces cerevisiae. We show that three subunits of the Gal11/tail domain of mediator, Gal11p, Pgd1p, and Med2p, and the head domain subunit Srb2p make overlapping contributions to the interaction of mediator with recombinant Gcn4p in vitro. Each of these proteins, along with the tail subunit Sin4p, also contributes to the recruitment of mediator by Gcn4p to target promoters in vivo. We found that Gal11p, Med2p, and Pgd1p reside in a stable subcomplex in sin4Delta cells that interacts with Gcn4p in vitro and that is recruited independently of the rest of mediator by Gcn4p in vivo. Thus, the Gal11p/Med2p/Pgd1p triad is both necessary for recruitment of intact mediator and appears to be sufficient for recruitment by Gcn4p as a free subcomplex. The med2Delta mutation impairs the recruitment of TATA binding protein (TBP) and RNA polymerase 11 to the promoter and the induction of transcription at ARG1, demonstrating the importance of the tail domain for activation by Gcn4p in vivo. Even though the Gal11p/Med2p/Pgd1p triad is the only portion of Srb mediator recruited efficiently to the promoter in the sin4Delta strain, this mutant shows high-level TBP recruitment and wild-type transcriptional induction at ARG1. Hence, the Gal11p/Med2p/Pgd1p triad may contribute to TBP recruitment independently of the rest of mediator. C1 NICHHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), NIH, Bldg 6A,Room B1A13, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov NR 43 TC 78 Z9 80 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 AUG PY 2004 VL 24 IS 15 BP 6871 EP 6886 DI 10.1128/mcb.24.15.6871-6886.2004 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 839DZ UT WOS:000222764800031 PM 15254252 ER PT J AU Yu, P Di Prospero, NA Sapko, MT Cai, T Chen, A Melendez-Ferro, M Du, F Whetsell, WO Guidetti, P Schwarcz, R Tagle, DA AF Yu, P Di Prospero, NA Sapko, MT Cai, T Chen, A Melendez-Ferro, M Du, F Whetsell, WO Guidetti, P Schwarcz, R Tagle, DA TI Biochemical and phenotypic abnormalities in kynurenine aminotransferase II-deficient mice SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RAT-BRAIN SLICES; GLUTAMINE TRANSAMINASE-K; DENDRITIC SPINE DENSITY; AMINO-ACID RECEPTORS; QUINOLINIC ACID; HUNTINGTONS-DISEASE; ENDOGENOUS EXCITANT; UNANESTHETIZED RATS; NEURONAL DEATH; 3-HYDROXYKYNURENINE AB Kynurenic acid (KYNA) can act as an endogenous modulator of excitatory neurotransmission and has been implicated in the pathogenesis of several neurological and psychiatric diseases. To evaluate its role in the brain, we disrupted the murine gene for kynurenine aminotransferase II (KAT II), the principal enzyme responsible for the synthesis of KYNA in the rat brain. mKat-2(-/-) mice showed no detectable KAT II mRNA or protein. Total brain KAT activity and KYNA levels were reduced during the first month but returned to normal levels thereafter. In contrast, liver KAT activity and KYNA levels in mKat-2(-/-) mice were decreased by >90% throughout life, though no hepatic abnormalities were observed histologically. KYNA-associated metabolites kynurenine, 3-hydroxykynurenine, and quinolinic acid were unchanged in the brain and liver of knockout mice. mKat-2(-/-) mice began to manifest hyperactivity and abnormal motor coordination at 2 weeks of age but were indistinguishable from wild type after I month of age. Golgi staining of cortical and striatal neurons revealed enlarged dendritic spines and a significant increase in spine density in 3-week-old mKat-2(-/-) mice but not in 2-month-old animals. Our results show that gene targeting of mKat-2 in mice leads to early and transitory decreases in brain KAT activity and KYNA levels with commensurate behavioral and neuropathological changes and suggest that compensatory changes or ontogenic expression of another isoform may account for the normalization of KYNA levels in the adult mKat-2(-/-) brain. C1 NHGRI, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, Expt Med Sect, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21228 USA. Vanderbilt Univ, Med Ctr, Dept Pathol, Nashville, TN 37235 USA. RP Tagle, DA (reprint author), NINDS, Ctr Neurosci, NIH, Rm 2133,6001 Execut Blvd, Bethesda, MD 20892 USA. EM tagled@ninds.nih.gov FU NICHD NIH HHS [HD 16596, P01 HD016596]; NINDS NIH HHS [NS 25296, R01 NS025296] NR 70 TC 42 Z9 46 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2004 VL 24 IS 16 BP 6919 EP 6930 DI 10.1128/MCB.24.16.6919-6930.2004 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 843AF UT WOS:000223045600004 PM 15282294 ER PT J AU Choi, WS Hiragun, T Lee, JH Kim, YM Kim, HP Chahdi, A Her, E Han, JW Beaven, MA AF Choi, WS Hiragun, T Lee, JH Kim, YM Kim, HP Chahdi, A Her, E Han, JW Beaven, MA TI Activation of RBL-2H3 mast cells is dependent on tyrosine phosphorylation of phospholipase D2 by Fyn and Fgr SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PROTEIN-KINASE-C; FC-EPSILON-RI; ADP-RIBOSYLATION FACTOR; MUSCARINIC ACETYLCHOLINE-RECEPTOR; SRC FAMILY KINASES; PHOSPHATIDIC-ACID; IGE RECEPTOR; RAT-BRAIN; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; ALLERGIC RESPONSE AB Both phospholipase D1 (PLD1) and PLD2 regulate degranulation when RBL-2H3 cells are stimulated via the immunoglobulin E receptor, FcepsilonRI. However, the activation mechanism for PLD2 is unclear. As reported here, PLD2 but not PLD1 is phosphorylated through the Src kinases, Fyn and Fgr, and this phosphorylation appears to regulate PLD2 activation and degranulation. For example, only hemagglutinin-tagged PLD2 was tyrosine phosphorylated in antigen-stimulated cells that had been made to express HA-PLD1 and HA-PLD2. This phosphorylation was blocked by a Src kinase inhibitor or by small interfering RNAs directed against Fyn and Fgr and was enhanced by overexpression of Fyn and Fgr but not by other Src kinases. The phosphorylation and activity of PLD2 were further enhanced by the tyrosine phosphatase inhibitor, Na3VO4. Mutation of PLD2 at tyrosines 11, 14, 165, or 470 partially impaired, and mutation of all tyrosines blocked, PLD2 phosphorylation and activation, although two of these mutations were detrimental to PLD2 function. PLD2 phosphorylation preceded degranulation, both events were equally sensitive to inhibition of Src kinase activity, and both were enhanced by coexpression of PLD2 and the Src kinases. The findings provide the first description of a mechanism for activation of PLD2 in a physiological setting and of a role for Fgr in FcepsilonRI-mediated signaling. C1 NHLBI, Lab Mol Immunol, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Konkuk Univ, Coll Med, Dept Immunol, Chungcheongbuk Do 380701, South Korea. Sungkyunkwan Univ, Coll Pharm, Suwon 440746, South Korea. RP Beaven, MA (reprint author), NHLBI, Lab Mol Immunol, NIH, Dept Hlth & Human Serv, Bldg 10,Rm 8N109, Bethesda, MD 20892 USA. EM wahnchoi@kku.edu; beavenm@nhlbi.nih.gov NR 63 TC 31 Z9 35 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2004 VL 24 IS 16 BP 6980 EP 6992 DI 10.1128/MCB.24.16.6980-6992.2004 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 843AF UT WOS:000223045600009 PM 15282299 ER PT J AU Chiang, YJ Hemann, MT Hathcock, KS Tessarollo, L Feigenbaum, L Hahn, WC Hodes, RJ AF Chiang, YJ Hemann, MT Hathcock, KS Tessarollo, L Feigenbaum, L Hahn, WC Hodes, RJ TI Expression of telomerase RNA template, but not telomerase reverse transcriptase, is limiting for telomere length maintenance in vivo SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CATALYTIC SUBUNIT; DYSKERATOSIS-CONGENITA; MOUSE TELOMERASE; MICE; CELLS; CANCER; MTERT; ELONGATION; SENESCENCE; COMPONENT AB Telomerase consists of two essential components, the telomerase RNA template (TR) and telomerase reverse transcriptase (TERT). The haplo-insufficiency of TR was recently shown to cause one form of human dyskeratosis congenita, an inherited disease marked by abnormal telomere shortening. Consistent with this finding, we recently reported that mice heterozygous for inactivation of mouse TR exhibit a similar haplo-insufficiency and are deficient in the ability to elongate telomeres in vivo. To further assess the genetic regulation of telomerase activity, we have compared the abilities of TR-deficient and TERT-deficient mice to maintain or elongate telomeres in interspecies crosses. Homozygous TERT knockout mice had no telomerase activity and failed to maintain telomere length. In contrast, TERT+/- heterozygotes had no detectable defect in telomere elongation compared to wild-type controls, whereas TR+/- heterozygotes were deficient in telomere elongation. Levels of TERT mRNA in heterozygous mice were one-third to one-half the levels expressed in wild-type mice, similar to the reductions in telomerase RNA observed in TR heterozygotes. These findings indicate that both TR and TERT are essential for telomere maintenance and elongation but that gene copy number and transcriptional regulation of TR, but not TERT, are limiting for telomerase activity under the in vivo conditions analyzed. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NIA, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. SAIC Frederick Inc, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. SAIC Frederick Inc, Transgen Med Model Lab, Frederick, MD 21702 USA. NCI, Frederick, MD 21702 USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Chiang, YJ (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,4B36,9000 Rockville Pike, Bethesda, MD 20892 USA. EM chiangj@mail.nih.gov FU NCI NIH HHS [CA16519, K01 CA094223, K01 CA94223, P01 CA016519] NR 37 TC 72 Z9 77 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 AUG PY 2004 VL 24 IS 16 BP 7024 EP 7031 DI 10.1128/MCB.24.16.7024-7031.2004 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 843AF UT WOS:000223045600013 PM 15282303 ER PT J AU Ross, ED Baxa, U Wickner, RB AF Ross, ED Baxa, U Wickner, RB TI Scrambled prion domains form prions and amyloid SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID YEAST SACCHAROMYCES-CEREVISIAE; GUANIDINE-HYDROCHLORIDE; IN-VITRO; PROTEIN AGGREGATION; HSP104 INACTIVATION; URE2 PROTEIN; PROPAGATION; DETERMINANT; GENERATION; MUTATION AB The [URE3] prion of Saccharomyces cerevisiae is a self-propagating amyloid form of Ure2p. The aminoterminal prion domain of Ure2p is necessary and sufficient for prion formation and has a high glutamine (Q) and asparagine (N) content. Such Q/N-rich domains are found in two other yeast prion proteins, Sup35p and Rnq1p, although none of the many other yeast Q/N-rich domain proteins have yet been found to be prions. To examine the role of amino acid sequence composition in prion formation, we used Ure2p as a model system and generated five Ure2p variants in which the order of the amino acids in the prion domain was randomly shuffled while keeping the amino acid composition and C-terminal domain unchanged. Surprisingly, all five formed prions in vivo, with a range of frequencies and stabilities, and the prion domains of all five readily formed amyloid fibers in vitro. Although it is unclear whether other amyloid-forming proteins would be equally resistant to scrambling, this result demonstrates that [URE3] formation is driven primarily by amino acid composition, largely independent of primary sequence. C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. RP NIDDKD, Lab Biochem & Genet, NIH, Bldg 8,Room 225,8 Ctr Dr,MSC 0830, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov OI Ross, Eric/0000-0002-6473-9977 NR 50 TC 105 Z9 105 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2004 VL 24 IS 16 BP 7206 EP 7213 DI 10.1128/MCB.24.16.7206-7213.2004 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 843AF UT WOS:000223045600029 PM 15282319 ER PT J AU Ullian, EM Barkis, WB Chen, S Diamond, JS Barres, BA AF Ullian, EM Barkis, WB Chen, S Diamond, JS Barres, BA TI Invulnerability of retinal ganglion cells to NMDA excitotoxicity SO MOLECULAR AND CELLULAR NEUROSCIENCE LA English DT Article ID NITRIC-OXIDE SYNTHASE; EXCITATORY SYNAPTIC-TRANSMISSION; METABOTROPIC GLUTAMATE RECEPTORS; D-ASPARTATE EXCITOTOXICITY; SUBUNIT MESSENGER-RNAS; ADULT-RAT RETINA; IN-VITRO; INNER RETINA; DEVELOPMENTAL REGULATION; AMACRINE CELLS AB NMDA excitotoxicity has been proposed to mediate the death of retinal ganglion cells (RGCs) in glaucoma and ischemia. Here, we reexamine the effects of glutamate and NMDA on rat RGCs in vitro and in situ. We show that highly purified RGCs express NR1 and NR2 receptor subunits by Western blotting and immunostaining, and functional NMDA receptor channels by whole-cell patch-clamp recording. Nevertheless, high concentrations of glutamate or NMDA failed to induce the death of purified RGCs, even after prolonged exposure for 24 h. RGCs co-cultured together with ephrins, astrocytes, or mixed retinal cells were similarly invulnerable to glutamate and NMDA, though their NMDA currents were 4-fold larger. In contrast, even a short exposure to glutamate or NMDA induced the rapid and profound excitotoxic death of most hippocampal neurons in culture. To determine whether RGCs in an intact retina are vulnerable to excitotoxicity, we retrogradely labeled RGCs in vivo using fluorogold and exposed acutely isolated intact retinas to high concentrations of glutamate or NMDA. This produced a substantial and rapid loss of amacrine cells; however, RGCs were not affected. Nonetheless, RGCs expressed NMDA currents in situ that were larger than those reported for amacrine cells. Interestingly, the NMDA receptors expressed by RGCs were extrasynaptically localized both in vitro and in situ. These results indicate that RGCs in vitro and in situ are relatively invulnerable to glutamate and NMDA excitotoxicity compared to amacrine cells, and indicate that important, as yet unidentified, determinants downstream of NMDA receptors control vulnerability to excitotoxicity. (C) 2004 Elsevier Inc. All rights reserved. C1 Stanford Univ, Sch Med, Dept Neurobiol, Stanford, CA 94305 USA. NINDS, SPU, NIH, Bethesda, MD 20892 USA. RP Ullian, EM (reprint author), Stanford Univ, Sch Med, Dept Neurobiol, Fairchild Sci Bldg D235,299 Campus Dr, Stanford, CA 94305 USA. EM emu@Stanford.EDU RI Diamond, Jeffrey/C-1835-2015 OI Diamond, Jeffrey/0000-0002-1770-2629 FU PHS HHS [R01 11030] NR 97 TC 84 Z9 87 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 1044-7431 J9 MOL CELL NEUROSCI JI Mol. Cell. Neurosci. PD AUG PY 2004 VL 26 IS 4 BP 544 EP 557 DI 10.1016/j.mcn.2004.05.002 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 844WV UT WOS:000223192700006 PM 15276156 ER PT J AU Naslavsky, N Weigert, R Donaldson, JG AF Naslavsky, N Weigert, R Donaldson, JG TI Characterization of a nonclathrin endocytic pathway: Membrane cargo and lipid requirements SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID GPI-ANCHORED PROTEINS; METHYL-BETA-CYCLODEXTRIN; PLASMA-MEMBRANE; ENDOPLASMIC-RETICULUM; CLATHRIN; CHOLESTEROL; TRANSPORT; CELL; RAFTS; ARF6 AB Clathrin-independent endocytosis internalizes plasma membrane proteins that lack cytoplasmic sequences recognized by clathrin adaptor proteins. There is evidence for different clathrin-independent pathways but whether they share common features has not been systematically tested. Here, we examined whether CD59, an endogenous glycosylphosphatidyl inositol-anchored protein (GPI-AP), and major histocompatibility protein class I (MHCI), an endogenous, integral membrane protein, entered cells through a common mechanism and followed a similar itinerary. At early times of internalization, CD59 and MHCI were found in the same Arf6-associated endosomes before joining clathrin cargo proteins such as transferrin in common sorting endosomes. CD59 and MHCI, but not transferrin, also were observed in the Arf6-associated tubular recycling membranes. Endocytosis of CD59 and MHCI required free membrane cholesterol because it was inhibited by filipin binding to the cell surface. Expression of active Arf6 stimulated endocytosis of GPI-APs and MHCI to the same extent and led to their accumulation in Arf6 endosomes that labeled intensely with filipin. This blocked delivery of GPI-APs and MHCI to early sorting endosomes and to lysosomes for degradation. Endocytosis of transferrin was not affected by any of these treatments. These observations suggest common mechanisms for endocytosis without clathrin. C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Naslavsky, N (reprint author), NHLBI, Cell Biol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM jdonalds@helix.nih.gov NR 43 TC 207 Z9 208 U1 4 U2 9 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 AUG PY 2004 VL 15 IS 8 BP 3542 EP 3552 DI 10.1091/mbc.E04-02-0151 PG 11 WC Cell Biology SC Cell Biology GA 841SK UT WOS:000222951500005 PM 15146059 ER PT J AU Smith, CA Dho, SE Donaldson, J Tepass, U McGlade, CJ AF Smith, CA Dho, SE Donaldson, J Tepass, U McGlade, CJ TI The cell fate determinant numb interacts with EHD/Rme-1 family proteins and has a role in endocytic recycling SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID MAMMALIAN NUMB; EH-DOMAIN; PLASMA-MEMBRANE; ASYMMETRIC SEGREGATION; CORTICAL NEUROGENESIS; SIGNAL-TRANSDUCTION; MULTIPLE ROLES; SMAD PATHWAY; MOUSE NUMB; RECEPTOR AB The adaptor protein Numb is necessary for the cell fate specification of progenitor cells in the Drosophila nervous system. Numb is evolutionarily conserved and previous studies have provided evidence for a similar functional role during mammalian development. The Numb protein has multiple protein-protein interaction regions including a phosphotyrosine binding (PTB) domain and a carboxy-terminal domain that contains conserved interaction motifs including an EH (Eps15 Homology) domain binding motif and a-adaptin binding site. In this study we identify the EHD/Rme-1/Pincher family of endocytic proteins as Numb interacting partners in mammals and Drosophila. The EHD/Rme-1 proteins function in recycling of plasma membrane receptors internalized by both clathrin-mediated endocytosis and a clathrin-independent pathway regulated by ADP ribosylation factor 6 (Arf6). Here we report that Numb colocalizes with endogenous EHD4/Pincher and Arf6 and that Arf6 mutants alter Numb subcellular localization. In addition, we present evidence that Numb has a novel function in endosomal recycling and intracellular trafficking of receptors. C1 Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON M5G 1X8, Canada. Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2M9, Canada. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Toronto, Dept Zool, Toronto, ON M5S 3G5, Canada. RP McGlade, CJ (reprint author), Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM jmcglade@sickkids.ca NR 50 TC 73 Z9 73 U1 0 U2 3 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 AUG PY 2004 VL 15 IS 8 BP 3698 EP 3708 DI 10.1091/mbc.E04-01-0026 PG 11 WC Cell Biology SC Cell Biology GA 841SK UT WOS:000222951500017 PM 15155807 ER PT J AU Weigert, R Yeung, AC Li, J Donaldson, JG AF Weigert, R Yeung, AC Li, J Donaldson, JG TI Rab22a regulates the recycling of membrane proteins internalized independently of clathrin SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID ENDOCYTIC PATHWAY; PLASMA-MEMBRANE; TRANS-GOLGI; MYOSIN VB; ENDOSOMES; CELL; COMPARTMENT; RECEPTOR; GTPASES; RAB11 AB Plasma membrane proteins that are internalized independently of clathrin, such as major histocompatibility complex class I (MHCI), are internalized in vesicles that fuse with the early endosomes containing clathrin-derived cargo. From there, MHCI is either transported to the late endosome for degradation or is recycled back to the plasma membrane via tubular structures that lack clathrin-dependent recycling cargo, e.g., transferrin. Here, we show that the small GTPase Rab22a is associated with these tubular recycling intermediates containing MHCI. Expression of a dominant negative mutant of Rab22a or small interfering RNA-mediated depletion of Rab22a inhibited both formation of the recycling tubules and MHCI recycling. By contrast, cells expressing the constitutively active mutant of Rab22a exhibited prominent recycling tubules and accumulated vesicles at the periphery, but MHCI recycling was still blocked. These results suggest that Rab22a activation is required for tubule formation and Rab22a inactivation for final fusion of recycling membranes with the surface. The trafficking of transferrin was only modestly affected by these treatments. Dominant negative mutant of Rab11a also inhibited recycling of MHCI but not the formation of recycling tubules, suggesting that Rab22a and Rab11a might coordinate different steps of MHCI recycling. C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Donaldson, JG (reprint author), NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM jdonalds@helix.nih.gov NR 46 TC 102 Z9 103 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD AUG PY 2004 VL 15 IS 8 BP 3758 EP 3770 DI 10.1091/mbc.E04-04-0342 PG 13 WC Cell Biology SC Cell Biology GA 841SK UT WOS:000222951500023 PM 15181155 ER PT J AU Kang, Y Hebron, H Ozbun, L Mariano, J Minoo, P Jakowlew, SB AF Kang, Y Hebron, H Ozbun, L Mariano, J Minoo, P Jakowlew, SB TI Nkx2.1 transcription factor in lung cells and a transforming growth factor-beta 1 heterozygous mouse model of lung carcinogenesis SO MOLECULAR CARCINOGENESIS LA English DT Article DE Nkx2.1; lung carcinogenesis; TGF-beta 1; mouse model; transcription factor ID GROWTH-FACTOR-BETA; PROTEIN-B GENE; ENHANCER-BINDING PROTEIN; II RECEPTOR GENE; N-MYC EXPRESSION; TGF-BETA; BRANCHING MORPHOGENESIS; PROMOTER REGION; ORGAN-CULTURES; DNA-BINDING AB The Nkx2.1 homeobox gene and transforming growth factor-beta1 (TGF-beta1) are essential for organogenesis and differentiation of the mouse lung. NKX2.1 is a marker of human lung carcinomas, but it is not known whether this gene participates in early tumorigenesis. Addition of TGF-beta1 to TGF-beta1 -responsive nontumorigenic mouse lung cells cotransfected with a NKX2.1Luc luciferase reporter and either a Sp1 or Sp3 plasmid showed a significant increase or decrease, respectively, in NKX2.1Luc transcription. Cotransfection of Sp3 and dominant-negative TGF-beta type II receptor plasmids negated the effect of Sp1. Cotransfected Sp1 plasmid with either dominant-negative Smad2 or Smad3 or Smad4 plasmids significantly decreased NKX2.1Luc transcription. Electrophoretic mobility shift assays revealed binding of Sp1 and Smad4 to the NKX2.1 promoter. With a TGF-beta1 heterozygous mouse model, Nkx2.1 mRNA and protein in lungs of TGF-beta1 heterozygous mice were significantly lower compared to wildtype (WT) littermates. Competitive reverse transcription (RT)-polymerase chain reaction (PCR) and immunostaining showed that Nkx2.1 mRNA and protein decreased significantly in adenomas and adenocarcinomas compared to normal lung tissue. Our in vitro data showed that regulation of Nkx2.1 by TGF-beta1 occurs through TGF-beta type II receptor and Smad signaling, with Sp1 and Sp3 in lung cells. Our in vivo data showed reduced Nkx2.1 in lungs of TGF-beta1 heterozygous mice compared to WT mice, that is detectable in adenomas, and that is further reduced in carcinogenesis, and that correlates with reduction of Sp1, Sp3, and Smads in lung adenocarcinomas. Our findings suggest that reduced Nkx2.1 and TGF-beta1 signaling components may contribute to tumorigenesis in the lungs of TGF-beta1 heterozygous mice. Published 2004 Wiley-Liss, Inc. C1 Natl Canc Inst, Cell & Canc Biol Branch, Rockville, MD 20850 USA. Univ So Calif, Sch Med, Womens & Childrens Hosp, Los Angeles, CA USA. RP Jakowlew, SB (reprint author), Natl Canc Inst, Cell & Canc Biol Branch, 9610 Med Ctr Dr,Suite 300, Rockville, MD 20850 USA. NR 68 TC 14 Z9 19 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD AUG PY 2004 VL 40 IS 4 BP 212 EP 231 DI 10.1002/mc.20034 PG 20 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 845EU UT WOS:000223220500003 PM 15264213 ER PT J AU Gao, ZG Zhang, XY Zuberi, A Hwang, D Quon, MJ Lefevre, M Ye, JP AF Gao, ZG Zhang, XY Zuberi, A Hwang, D Quon, MJ Lefevre, M Ye, JP TI Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID KAPPA-B KINASE; PHOSPHATIDYLINOSITOL 3-KINASE ACTIVITY; N-TERMINAL KINASE; RECEPTOR SUBSTRATE-1; GLUCOSE-TRANSPORT; PHORBOL ESTERS; IN-VIVO; TARGETED DISRUPTION; SIGNALING CASCADE; SKELETAL-MUSCLE AB Insulin receptor substrate (IRS) has been suggested as a molecular target of free fatty acids (FFAs) for insulin resistance. However, the signaling pathways by which FFAs lead to the inhibition of IRS function remain to be established. In this study, we explored the FFA-signaling pathway that contributes to serine phosphorylation and degradation of IRS-1 in adipocytes and in dietary obese mice. Linoleic acid, an FFA used in this study, resulted in a reduction in insulin-induced glucose uptake in 3T3-L1 adipocytes. This mimics insulin resistance induced by high-fat diet in C57BL/6J mice. The reduction in glucose uptake is associated with a decrease in IRS-1, but not IRS-2 or GLUT4 protein abundance. Decrease in IRS-1 protein was proceeded by IRS-1 (serine 307) phosphorylation that was catalyzed by serine kinases inhibitor kappaB kinase (IKK) and c-JUN NH2-terminal kinase (JNK). IKK and JNK were activated by linoleic acid and inhibition of the two kinases led to prevention of IRS-1 reduction. We demonstrate that protein kinase C (PKC)theta is expressed in adipocytes. In 3T3-L1 adipocytes and fat tissue, PKCtheta was activated by fatty acids as indicated by its phosphorylation status, and by its protein level, respectively. Activation of PKCtheta contributes to IKK and JNK activation as inhibition of PKCtheta by calphostin C blocked activation of the latter kinases. Inhibition of either PKCtheta or IKK plus JNK by chemical inhibitors resulted in protection of IRS-1 function and insulin sensitivity in 3T3-L1 adipocytes. These data suggest that: 1) activation of PKCtheta contributes to IKK and JNK activation by FFAs; 2) IKK and JNK mediate PKCtheta signals for IRS-1 serine phosphorylation and degradation; and 3) this molecular mechanism may be responsible for insulin resistance associated with hyperlipidemia. C1 Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. Univ Calif Davis, Western Human Nutr Res Ctr, Davis, CA 95616 USA. Univ Calif Davis, Dept Nutr, Davis, CA 95616 USA. NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Ye, JP (reprint author), Louisiana State Univ, Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM yej@pbrc.edu RI Quon, Michael/B-1970-2008; Lefevre, Michael/B-5030-2014; OI Lefevre, Michael/0000-0002-2046-3593; Quon, Michael/0000-0002-9601-9915; Quon , Michael /0000-0002-5289-3707 NR 55 TC 205 Z9 224 U1 1 U2 14 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 AUG PY 2004 VL 18 IS 8 BP 2024 EP 2034 DI 10.1210/me.2003-0383 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 841CT UT WOS:000222907600013 PM 15143153 ER PT J AU Shah, BH Yesilkaya, A Olivares-Reyes, JA Chen, HD Hunyady, L Catt, KJ AF Shah, BH Yesilkaya, A Olivares-Reyes, JA Chen, HD Hunyady, L Catt, KJ TI Differential pathways of angiotensin II-induced extracellularly regulated kinase 1/2 phosphorylation in specific cell types: Role of heparin-binding epidermal growth factor SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID FACTOR RECEPTOR TRANSACTIVATION; PROTEIN-COUPLED RECEPTORS; SMOOTH-MUSCLE-CELLS; INDUCED CARDIAC-HYPERTROPHY; FACTOR (EGF)-LIKE DOMAIN; HB-EGF; TYROSINE KINASES; MESANGIAL CELLS; ERK ACTIVATION; INTERNALIZATION AB Stimulation of the angiotensin II (Ang II) type 1 receptor (AT(1)-R) causes phosphorylation of extra-cellularly regulated kinases 1 and 2 (ERK1/2) via epidermal growth factor receptor (EGF-R) transactivation-dependent or -independent pathways in Ang II target cells. Here we examined the mechanisms involved in agonist-induced EGF-R transactivation and subsequent ERK1/2 phosphorylation in clone 9 (C9) hepatocytes, which express endogenous AT(1)-R, and COS-7 and human embryonic kidney (HEK) 293 cells transfected with the AT(1)-R. Ang II-induced ERK1/2 activation was attenuated by inhibition of Src kinase and of matrix metalloproteinases (MMPs) in C9 and COS-7 cells, but not in HEK 293 cells. Agonist-mediated MMP activation in C9 cells led to shedding of heparin-binding EGF (HB-EGF) and stimulation of ERK1/2 phosphorylation. Blockade of HB-EGF action by neutralizing antibody or its selective inhibitor, CRM197, attenuated ERK1/2 activation by Ang II. Consistent with its agonist action, HB-EGF stimulation of these cells caused marked phosphorylation of the EGF-R and its adapter molecule, Shc, as well as ERK1/2 and its dependent protein, p90 ribosomal S6 kinase, in a manner similar to that elicited by Ang II or EGF. Although the Tyr319 residue of the AT(1)-R has been proposed to be an essential regulator of EGF-R transactivation, stimulation of wild-type and mutant (Y319F) AT(1)-R expressed in COS-7 cells caused EGF-R transactivation and subsequent ERK1/2 phosphorylation through release of HB-EGF in a Src-dependent manner. In contrast, the noninvolvement of MMPs in HEK 293 cells, which may reflect the absence of Src activation by Ang II, was associated with lack of transactivation of the EGF-R. These data demonstrate that the individual actions of Ang II on EGF-R transactivation in specific cell types are related to differential involvement of MMP-dependent HB-EGF release. C1 NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. Akdeniz Univ, Tip Fak, TR-07070 Antalya, Turkey. Inst Politecn Nacl, Ctr Invest & Estudios Avanzados, Mexico City, DF, Mexico. Semmelweis Univ, Fac Med, Dept Physiol, H-1444 Budapest, Hungary. RP Catt, KJ (reprint author), NICHHD, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Room 6A36, Bethesda, MD 20892 USA. EM catt@helix.nih.gov NR 54 TC 57 Z9 63 U1 0 U2 1 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 AUG PY 2004 VL 18 IS 8 BP 2035 EP 2048 DI 10.1210/me.2003-0476 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 841CT UT WOS:000222907600014 PM 15143154 ER PT J AU Wilson, HR Zhou, JG Yu, DG Court, DL AF Wilson, HR Zhou, JG Yu, DG Court, DL TI Translation repression by an RNA polymerase elongation complex SO MOLECULAR MICROBIOLOGY LA English DT Article ID NUSA GENE PROTEIN; ESCHERICHIA-COLI; BACTERIOPHAGE-LAMBDA; TRANSCRIPTION ANTITERMINATION; PHAGE-LAMBDA; MUTATIONS; RESISTANT; SITE; RECOGNITION; EXPRESSION AB Bacteriophage lambda N and bacterial Nus proteins together with a unique site NUT in the leader of the early viral N gene transcript bind RNA polymerase (RNAP) and form a highly processive antitermination complex; N bound at NUT also represses N translation. In this study, we investigate whether N and NUT cause N translation repression as part of the antitermination complex by testing conditions that inhibit the formation of the N-modified transcription complex for their effect on N-mediated translation repression. We show that nus and nut mutations that in combination destabilize multiple interactions in the antitermination complex prevent N-mediated translation repression. Likewise, transcription of the nut-N region by T7 RNAP, which does not lead to the assembly of an effective antitermination complex when N is supplied, eliminates translation repression. We also demonstrate that a unique mutant beta subunit of RNAP reduces N-mediated translation repression, and that overexpression of transcription factor NusA suppresses this defect. We conclude that the N-modified RNAP transcription complex is necessary to repress N translation. C1 NCI, Mol Control & Genet Sect, Frederick, MD 21702 USA. Inst Biotechnol, Beijing 100850, Peoples R China. RP Court, DL (reprint author), NCI, Mol Control & Genet Sect, Frederick, MD 21702 USA. EM court@ncifcrf.gov NR 29 TC 13 Z9 14 U1 0 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD AUG PY 2004 VL 53 IS 3 BP 821 EP 828 DI 10.1111/j.1365-2958.2004.04170.x PG 8 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 838OF UT WOS:000222722000010 PM 15255895 ER PT J AU Maric, D Barker, JL AF Maric, D Barker, JL TI Neural stem cells redefined - A FACS perspective SO MOLECULAR NEUROBIOLOGY LA English DT Article DE central nervous system; development; cortex; neural stem cells; neural progenitors; fluorescence-activated cell sorting; cell fate ID CENTRAL-NERVOUS-SYSTEM; CORTICAL PROGENITOR CELLS; FIBROBLAST-GROWTH-FACTOR; EMBRYONIC RAT NEOCORTEX; RADIAL GLIAL-CELLS; PRECURSOR CELLS; TETANUS TOXIN; DEVELOPMENTAL-CHANGES; SELF-RENEWAL; IN-VITRO AB Using the generally accepted ontogenetic definition, neural stem cells (NSCs) are characterized as undifferentiated cells originating from the neuroectoderm that have the capacity both to perpetually self-renew without differentiating and to generate multiple types of lineage-restricted progenitors (LRP). LRPs can themselves undergo limited self-renewal, then ultimately differentiate into highly specialized cells that compose the nervous system. However, this physiologically delimited definition of NSCs has been increasingly blurred in the current state of the field, as the great majority of studies have retrospectively inferred the existence of NSCs based on their deferred functional capability rather than prospectively identifying the actual cells that created the outcome. Further complicating the matter is the use of a wide variety of neuroepithelial or neurosphere preparations as a source of putative NSCs, without due consideration that these preparations are themselves composed of heterogeneous populations of both NSCs and LRPs. This article focuses on recent attempts using FACS strategies to prospectively isolate NSCs from different types of LRPs as they appear in vivo and reveals the contrasting differences among these populations at molecular, phenotypic, and functional levels. Thus, the strategies presented here provide a framework for more precise studies of NSC and LRP cell biology in the future. C1 NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Maric, D (reprint author), NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. EM maricd@ninds.nih.gov NR 97 TC 30 Z9 32 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD AUG PY 2004 VL 30 IS 1 BP 49 EP 76 DI 10.1385/MN:30:1:049 PG 28 WC Neurosciences SC Neurosciences & Neurology GA 843HM UT WOS:000223069300004 PM 15247488 ER PT J AU Gautam, D Heard, TS Cui, YH Miller, G Bloodworth, L Wess, J AF Gautam, D Heard, TS Cui, YH Miller, G Bloodworth, L Wess, J TI Cholinergic stimulation of salivary secretion studied with M-1 and M-3 muscarinic receptor single- and double-knockout mice SO MOLECULAR PHARMACOLOGY LA English DT Article ID ANTIMUSCARINIC AGENT SOLIFENACIN; RAT PAROTID-GLAND; ACETYLCHOLINE-RECEPTOR; SUBLINGUAL GLANDS; SUBTYPES; PILOCARPINE; LACKING; BLADDER; PROFILES; MOUSE AB Identification of the specific muscarinic acetylcholine receptor (mAChR) subtypes mediating stimulation of salivary secretion is of considerable clinical interest. Recent pharmacological and molecular genetic studies have yielded somewhat confusing and partially contradictory results regarding the involvement of individual mAChRs in this activity. In the present study, we re-examined the roles of M-1 and M-3 mAChRs in muscarinic agonist-mediated stimulation of salivary secretion by using M-1 and M-3 receptor single-knockout ( KO) mice and newly generated M-1/M-3 receptor double-KO mice. When applied at a low dose (1 mg/kg, s.c.), the muscarinic agonist pilocarpine showed significantly reduced secretory activity in both M-1 and M 3 receptor single-KO mice. However, when applied at higher doses, pilocarpine induced only modestly reduced (5 mg/kg, s.c.) or unchanged (15 mg/kg, s.c.) salivation responses, respectively, in M-1 and M-3 receptor single-KO mice, indicating that the presence of either M-1 or M-3 receptors is sufficient to mediate robust salivary output. Quantitative reverse transcriptase-polymerase chain reaction studies with salivary gland tissue showed that the inactivation of the M-1 or M-3 mAChR genes did not lead to significantly altered mRNA levels of the remaining mAChR subtypes. Strikingly, the sialagogue activity of pilocarpine was abolished in M-1/M-3 receptor double-KO mice. However, salivary glands from M-1/M-3 receptor double-KO mice remained responsive to stimulation by the beta-adrenergic receptor agonist, (S)-isoproterenol. Taken together these studies support the concept that a mixture of M-1 and M-3 receptors mediates cholinergic stimulation of salivary flow. C1 NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NIH, Natl Ctr Res Resources, Vet Resources Program, Bethesda, MD 20892 USA. RP Wess, J (reprint author), NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Room B1A-05,8 Ctr Dr MSC 0810, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov NR 41 TC 77 Z9 79 U1 0 U2 2 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 AUG PY 2004 VL 66 IS 2 BP 260 EP 267 DI 10.1124/mol.66.2.260 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 839NM UT WOS:000222791800008 PM 15266016 ER PT J AU Gray, T Nettesheim, P Loftin, C Koo, JS Bonner, J Peddada, S Langenbach, R AF Gray, T Nettesheim, P Loftin, C Koo, JS Bonner, J Peddada, S Langenbach, R TI Interleukin-1 beta-induced mucin production in human airway epithelium is mediated by cyclooxygenase-2, prostaglandin E-2 receptors, and cyclic AMP-protein kinase A signaling SO MOLECULAR PHARMACOLOGY LA English DT Article ID GOBLET CELL HYPERPLASIA; NECROSIS-FACTOR-ALPHA; GENE-EXPRESSION; OLIGOMERIC MUCINS; MUC5AC; MUCUS; DIFFERENTIATION; IDENTIFICATION; GLYCOFORMS; ANTAGONIST AB We reported recently that interleukin (IL)-1beta exposure resulted in a prolonged increase in MUC5AC mucin production in normal, well differentiated, human tracheobronchial epithelial (NHTBE) cell cultures, without significantly increasing MUC5AC mRNA (Am J Physiol 286: L320-L330, 2004). The goal of the present study was to elucidate the signaling pathways involved in IL-1beta-induced MUC5AC production. We found that IL-1beta increased cyclooxygenase-2 (COX-2) mRNA expression and prostaglandin ( PG) E 2 production and that the COX-2 inhibitor celecoxib suppressed IL-1beta-induced MUC5AC production. Addition of exogenous PGE(2) to NHTBE cultures also increased MUC5AC production and IL-1beta-induced Muc5ac hypersecretion in tracheas from wild-type but not from COX-2(-/-) mice. NHTBE cells expressed all four E-prostanoid (EP) receptor subtypes and misoprostol, an EP2 and EP4 agonist, increased MUC5AC production, whereas sulprostone, an EP1 and EP3 agonist, did not. Furthermore, specific protein kinase A (PKA) inhibitors blocked IL-1beta and PGE(2)-induced MUC5AC production. However, neither inhibition of epidermal growth factor receptor ( EGFR) activation with the tyrosine kinase inhibitor 4-(3-chloroanilino)-6,7-dimethoxyquinazoline HCl (AG-1478) or EGFR blocking antibody nor inhibition of extracellular signal-regulated kinase/P-38 mitogen activated protein kinases with specific inhibitors blocked IL-1beta stimulation of MUC5AC mucin production. We also observed that tumor necrosis factor (TNF)-alpha, platelet activating factor (PAF), and lipopolysaccharide (LPS) induced COX-2 and increased MUC5AC production that was blocked by celecoxib, suggesting a common signaling pathway of inflammatory mediator-induced MUC5AC production in NHTBE cells. We conclude that the induction of MUC5AC by IL-1beta, TNF-alpha, PAF, and LPS involves COX-2-generated PGE(2), activation of EP2 and/or EP4 receptor(s), and cAMP-PKA-mediated signaling. C1 NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Pulm Pathobiol Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Gray, T (reprint author), NIEHS, Mol Carcinogenesis Lab, MD C4-09,POB 12233, Res Triangle Pk, NC 27709 USA. EM grayt@niehs.nih.gov RI Peddada, Shyamal/D-1278-2012 NR 45 TC 70 Z9 74 U1 1 U2 2 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 AUG PY 2004 VL 66 IS 2 BP 337 EP 346 DI 10.1124/mol.66.2.337 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 839NM UT WOS:000222791800017 PM 15266025 ER PT J AU Gould, TD Quiroz, JA Singh, J Zarate, CA Manji, HK AF Gould, TD Quiroz, JA Singh, J Zarate, CA Manji, HK TI Emerging experimental therapeutics for bipolar disorder: insights from the molecular and cellular actions of current mood stabilizers SO MOLECULAR PSYCHIATRY LA English DT Review DE depression; mania; pharmacology; manic-depressive illness; neurotrophic factors; valproic acid; PAP phosphatase; pramipexole; zinc ID PROTEIN-KINASE-C; GLYCOGEN-SYNTHASE KINASE-3; BRAIN ADENOSINE RECEPTORS; MANIC-DEPRESSIVE ILLNESS; HIPPOCAMPAL-KINDLED RAT; DI-N-PROPYLACETATE; INOSITOL-POLYPHOSPHATE 1-PHOSPHATASE; CHRONIC CARBAMAZEPINE TREATMENT; BETA-ADRENERGIC RECEPTORS; INSULIN-MIMETIC ACTION AB Bipolar disorder afflicts approximately 1 - 3% of both men and women, and is coincident with major economic, societal, medical, and interpersonal consequences. Current mediations used for its treatment are associated with variable rates of efficacy and often intolerable side effects. While preclinical and clinical knowledge in the neurosciences has expanded at a tremendous rate, recent years have seen no major breakthroughs in the development of novel types of treatment for bipolar disorder. We review here approaches to develop novel treatments specifically for bipolar disorder. Deliberate (ie not by serendipity) treatments may come from one of two general mechanisms: ( 1) Understanding the mechanism of action of current medications and thereafter designing novel drugs that mimics these mechanism(s); ( 2) Basing medication development upon the hypothetical or proven underlying pathophysiology of bipolar disorder. In this review, we focus upon the first approach. Molecular and cellular targets of current mood stabilizers include lithium inhibitable enzymes where lithium competes for a magnesium binding site ( inositol monophosphatase, inositol polyphosphate 1-phosphatase, glycogen synthase kinase-3 (GSK-3), fructose 1,6-bisphosphatase, bisphosphate nucleotidase, phosphoglucomutase), valproate inhibitable enzymes ( succinate semialdehyde dehydrogenase, succinate semialdehyde reductase, histone deacetylase), targets of carbamazepine ( sodium channels, adenosine receptors, adenylate cyclase), and signaling pathways regulated by multiple drugs of different classes (phosphoinositol/protein kinase C, cyclic AMP, arachidonic acid, neurotrophic pathways). While the task of developing novel medications for bipolar disorder is truly daunting, we are hopeful that understanding the mechanism of action of current mood stabilizers will ultimately lead clinical trials with more specific medications and thus better treatments those who suffer from this devastating illness. C1 NIMH, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Manji, HK (reprint author), NIMH, Mol Pathophysiol Lab, NIH, Bldg 49,Room B1EE16, Bethesda, MD 20892 USA. EM manji@nih.gov NR 262 TC 146 Z9 152 U1 9 U2 22 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 AUG PY 2004 VL 9 IS 8 BP 734 EP 755 DI 10.1038/sj.mp.4001518 PG 22 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 840IP UT WOS:000222851700003 PM 15136794 ER PT J AU Quiroz, JA Singh, J Gould, TD Denicoff, KD Zarate, CD Manji, HK AF Quiroz, JA Singh, J Gould, TD Denicoff, KD Zarate, CD Manji, HK TI Emerging experimental therapeutics for bipolar disorder: clues from the molecular pathophysiology SO MOLECULAR PSYCHIATRY LA English DT Review DE depression; mania; NMDA; glutamate; memantine; riluzole; felbamate; zinc; corticotropin-releasing factor; glucocorticoids; neuroplasticity; mitochondria ID METHYL-D-ASPARTATE; METABOTROPIC GLUTAMATE RECEPTORS; MAJOR DEPRESSIVE DISORDER; PLACEBO-CONTROLLED TRIAL; ANTIDEPRESSANT ADMINISTRATION INCREASES; PHOSPHODIESTERASE INHIBITOR ROLIPRAM; PITUITARY-ADRENOCORTICAL AXIS; HIPPOCAMPAL VOLUME LOSS; LONG-TERM POTENTIATION; HUMAN POSTMORTEM BRAIN AB Bipolar affective disorder (manic-depressive illness) is a common, severe, chronic, and often life-threatening illness, associated with significant comorbidity. The recognition of the significant morbidity and mortality of patients with bipolar disorder, as well as the growing appreciation that a high percentage of patients respond poorly to existing treatments, has made the task of discovering new therapeutic agents, that are both efficacious and have few side effects increasingly more important. Most recent agents introduced into the pharmacopeia for the treatment of bipolar disorder have been anticonvulsants and atypical antipsychotics. We propose that novel treatments developed specifically for bipolar disorder will arise from ( 1) understanding more precisely the molecular mechanisms of treatments that are clearly efficacious or ( 2) developing medications based on the knowledge obtained of the underlying pathophysiology of bipolar disorder. Knowledge with regard to the underlying pathophysiology of bipolar disorder is increasing at a rapid pace, including alterations in intracellular signaling cascades as well as impairments of cellular plasticity and resilience in critical neuronal circuits. We propose that therapeutics designed to enhance cellular plasticity and resilience and that counter maladaptive stress-responsive systems may have considerable utility for the treatment of bipolar disorder. Therapeutic strategies designed to address cellular resilience and plasticity include the regulation of neurotrophic pathways, glucocorticoid signaling, phosphodiesterase activity, and glutamatergic throughput and mitochondrial function. While the task of developing novel medications for bipolar disorder is truly daunting, these and similar approaches will ultimately lead to better medications for the millions who suffer from this devastating illness. C1 NIMH, Mol Pathophysiol Lab, NIH, HHS, Bethesda, MD 20892 USA. RP Manji, HK (reprint author), NIMH, Mol Pathophysiol Lab, NIH, HHS, Bldg 49,Room B1EE16, Bethesda, MD 20892 USA. EM manji@nih.gov NR 248 TC 44 Z9 47 U1 6 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 AUG PY 2004 VL 9 IS 8 BP 756 EP 776 DI 10.1038/sj.mp.4001521 PG 21 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 840IP UT WOS:000222851700004 PM 15136795 ER PT J AU Henderson, GE Davis, AM King, NMP Easter, MM Zimmer, CR Rothschild, BB Wilfond, BS Nelson, DK Churchill, LR AF Henderson, GE Davis, AM King, NMP Easter, MM Zimmer, CR Rothschild, BB Wilfond, BS Nelson, DK Churchill, LR TI Uncertain benefit: Investigators' views and communications in early phase gene transfer trials SO MOLECULAR THERAPY LA English DT Article DE gene therapy; clinical trials phase I/*standards; disclosure; ethics medical; informed consent; interviews; research/*standards; researcher-subject relations; uncertainty ID CLINICAL-TRIALS; INFORMED-CONSENT; THERAPY; ONCOLOGISTS; PHYSICIANS; IMPACT AB We report on a study of potential sources of therapeutic misconception in early phase gene transfer research, examining how investigators and their consent forms represent the prospect for direct benefit. Our analysis demonstrates that even though half of Pis said they expected direct medical benefit for their subjects, they did not necessarily convey this to their subjects. What they reported telling subjects resembled what was written in their consent form, which suggests that, far from being irrelevant, the consent, form is an influential component of the consent process. We also demonstrate that the language used to describe direct benefit in consent forms and Pis' discussions was mostly vague, ambiguous, and indeterminate about benefit, rather than clearly negative. This was especially true for cancer and vascular disease trials. Our respondents found the problem of balancing hopes and expectations, for themselves and for their subjects, extraordinarily challenging. In the current era, investigators face such challenges without consistent normative guidance or agreed-upon standards for how to talk about scientific promise and uncertainty in early phase trials. This dilemma cannot be effectively addressed by individual investigators alone, but must be acknowledged and openly discussed by the scientific community at large. C1 Univ N Carolina, Sch Med, Dept Social Med, Chapel Hill, NC 27599 USA. NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Dept Med, Ctr Clin & Res Eth, Nashville, TN 37212 USA. Univ N Carolina, Odum Inst, Chapel Hill, NC 27599 USA. RP Henderson, GE (reprint author), Univ N Carolina, Sch Med, Dept Social Med, Chapel Hill, NC 27599 USA. EM ghenders@med.unc.edu OI Davis, Arlene/0000-0001-6486-0446 FU NHGRI NIH HHS [R01 HG020287-01] NR 23 TC 33 Z9 34 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD AUG PY 2004 VL 10 IS 2 BP 225 EP 231 DI 10.1016/j.ymthe.2004.05.013 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 855BN UT WOS:000223948000011 PM 15294169 ER PT J AU Foltynie, T Goldberg, TE Lewis, SGJ Blackwell, AD Kolachana, BS Weinberger, DR Robbins, TW Barker, RA AF Foltynie, T Goldberg, TE Lewis, SGJ Blackwell, AD Kolachana, BS Weinberger, DR Robbins, TW Barker, RA TI Planning ability in Parkinson's disease is influenced by the COMT Val(158)Met polymorphism SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; cognitive; phenotype; COMT; polymorphism ID SPATIAL WORKING-MEMORY; POSITRON EMISSION TOMOGRAPHY; D1 DOPAMINE-RECEPTORS; PREFRONTAL CORTEX; FUNCTIONAL POLYMORPHISM; COGNITIVE DEFICITS; FRONTAL-CORTEX; LONDON TASK; HUMAN BRAIN; PERFORMANCE AB Parkinson's disease (PD) patients show a range of executive deficits involving dopaminergic transmission in the prefrontal cortex. In this study, we have investigated the impact of catechol-O-methyl-transferase (COMT) val(158)met polymorphisms on performance of the Tower of London (TOL) test of planning by PD patients. Motor and cognitive assessments were performed on 288 patients as part of a population-based study of PD. These patients were subsequently genotyped for the COMT val(158)met polymorphism. Patients with high activity COMT genotypes performed significantly better at the TOL task than those with low activity genotypes. Subgroup analyses suggest that this effect is greatest in patients exposed to dopaminergic agents. We hypothesise that the inferior performance in patients with the low activity COMT genotype is attributable to a state of relative hyperdoparninergic activity in the dorsolateral prefrontal cortex compared with that in the striatum. We suggest that polymorphisms of common genes, which regulate central nervous system dopaminergic transmission, can influence some of the phenotypic manifestations of PD. (C) 2004 Movement Disorder Society. C1 Univ Cambridge, Cambridge Ctr Brain Repair, Cambridge CB2 2PY, England. Natl Inst Mental Hlth, Clin Brain Disorders Branch, Bethesda, MD USA. Addenbrookes Hosp, Dept Psychiat, Cambridge, England. Univ Cambridge, Dept Expt Psychol, Cambridge CB2 1TN, England. RP Foltynie, T (reprint author), Univ Cambridge, Cambridge Ctr Brain Repair, Forvie Site,Robinson Way, Cambridge CB2 2PY, England. EM tf210@medschl.cam.ac.uk FU Medical Research Council [G0001067] NR 50 TC 75 Z9 77 U1 4 U2 9 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD AUG PY 2004 VL 19 IS 8 BP 885 EP 891 DI 10.1002/mds.20118 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 846KA UT WOS:000223313200002 PM 15300652 ER PT J AU Roh, TY Ngau, WC Cui, KR Landsman, D Zhao, KJ AF Roh, TY Ngau, WC Cui, KR Landsman, D Zhao, KJ TI High-resolution genome-wide mapping of histone modifications SO NATURE BIOTECHNOLOGY LA English DT Article ID YEAST HETEROCHROMATIN; ACETYLATION; H4; TRANSCRIPTOME; DEACETYLATION; NUCLEOSOME; TELOMERES; PROMOTER; GCN5P AB The expression patterns of eukaryotic genomes are controlled by their chromatin structure, consisting of nucleosome subunits in which DNA of approximately 146 bp is wrapped around a core of 8 histone molecules(1). Post-translational histone modifications play an essential role in modifying chromatin structure(.)(2) Here we apply a combination of SAGE 3 and chromatin immunoprecipitation (ChIP) protocols to determine the distribution of hyperacetylated histones H3 and H4 in the Saccharomyces cerevisiae genome. We call this approach genome-wide mapping technique (GMAT). Using GMAT, we find that the highest acetylation levels are detected in the 5 end of a gene's coding region, but not in the promoter. Furthermore, we show that the histone acetyltransferase, GCN5p, regulates H3 acetylation in the promoter and 5 end of the coding regions. These findings indicate that GMAT should find valuable applications in mapping target sites of chromatin-modifying enzymes. C1 NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. Natl Biotechnol Ctr, Computat Biol Branch, Natl Lib Med, NIH, Bethesda, MD 20894 USA. RP Zhao, KJ (reprint author), NHLBI, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM zhaok@nhlbi.nih.gov RI Landsman, David/C-5923-2009; OI Landsman, David/0000-0002-9819-6675 NR 22 TC 146 Z9 162 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD AUG PY 2004 VL 22 IS 8 BP 1013 EP 1016 DI 10.1038/nbt990 PG 4 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 842YB UT WOS:000223039500031 PM 15235610 ER PT J AU Verges, M Luton, F Gruber, C Tiemann, F Reinders, LG Huang, L Burlingame, AL Haft, CR Mostov, KE AF Verges, M Luton, F Gruber, C Tiemann, F Reinders, LG Huang, L Burlingame, AL Haft, CR Mostov, KE TI The mammalian retromer regulates transcytosis of the polymeric immunoglobulin receptor SO NATURE CELL BIOLOGY LA English DT Article ID POLARIZED EPITHELIAL-CELLS; GOLGI RETROGRADE TRANSPORT; SORTING NEXINS; IG RECEPTOR; YEAST; IDENTIFICATION; PROTEIN; RETRIEVAL; DOMAINS; VPS35P AB Epithelial cells have separate apical and basolateral plasma membrane domains with distinct compositions. After delivery to one surface, proteins can be endocytosed and then recycled, degraded or transcytosed to the opposite surface. Proper sorting into the transcytotic pathway is essential for maintaining polarity, as most proteins are endocytosed many times during their lifespan(1). The polymeric immunoglobulin receptor (pIgR) transcytoses polymeric IgA (pIgA) from the basolateral to the apical surface of epithelial cells and hepatocytes(2,3). However, the molecular machinery that controls polarized sorting of pIgR-pIgA and other receptors is only partially understood. The retromer is a multimeric protein complex, originally described in yeast, which mediates intracellular sorting of Vps10p, a receptor that transports vacuolar enzymes(4). The yeast retromer contains two sub-complexes. One includes the Vps5p and Vps17p subunits, which provide mechanical force for vesicle budding(5,6). The other is the Vps35p-Vps29p-Vps26p subcomplex, which provides cargo specificity(7). The mammalian retromer binds to the mannose 6-phosphate receptor, which sorts lysosomal enzymes from the trans-Golgi network to the lysosomal pathway(8,9). Here, we show a function for the mammalian Vps35-Vps29-Vps26 retromer subcomplex in promoting pIgR-pIgA transcytosis. C1 Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA. Atugen AG, D-13125 Berlin, Germany. Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA. NIDDKD, Div Endocrinol Diabet & Metab Dis, NIH, Bethesda, MD 20892 USA. RP Mostov, KE (reprint author), Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. EM mostov@itsa.ucsf.edu RI Huang, Lan/C-3618-2011 FU NIDDK NIH HHS [P30 DK 26743] NR 33 TC 109 Z9 114 U1 2 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD AUG PY 2004 VL 6 IS 8 BP 763 EP 769 DI 10.1038/ncb1153 PG 7 WC Cell Biology SC Cell Biology GA 842YA UT WOS:000223039400015 PM 15247922 ER PT J AU Cichon, S Buervenich, S Kirov, G Akula, N Dimitrova, A Green, E Schumacher, J Klopp, N Becker, T Ohlraun, S Schulze, TG Tullius, M Gross, MM Jones, L Krastev, S Nikolov, I Hamshere, M Jones, I Czerski, PM Leszczynska-Rodziewicz, A Kapelski, P Van Den Bogaert, A Illig, T Hauser, J Maier, W Berrettini, W Byerley, W Coryell, W Gershon, ES Kelsoe, JR McInnis, MG Murphy, DL Nurnberger, JI Reich, T Scheftner, W O'Donovan, MC Propping, P Owen, MJ Rietschel, M Nothen, MM McMahon, FJ Craddock, N AF Cichon, S Buervenich, S Kirov, G Akula, N Dimitrova, A Green, E Schumacher, J Klopp, N Becker, T Ohlraun, S Schulze, TG Tullius, M Gross, MM Jones, L Krastev, S Nikolov, I Hamshere, M Jones, I Czerski, PM Leszczynska-Rodziewicz, A Kapelski, P Van Den Bogaert, A Illig, T Hauser, J Maier, W Berrettini, W Byerley, W Coryell, W Gershon, ES Kelsoe, JR McInnis, MG Murphy, DL Nurnberger, JI Reich, T Scheftner, W O'Donovan, MC Propping, P Owen, MJ Rietschel, M Nothen, MM McMahon, FJ Craddock, N TI Lack of support for a genetic association of the XBP1 promoter polymorphism with bipolar disorder in probands of European origin SO NATURE GENETICS LA English DT Letter ID POPULATION-STRUCTURE; LINKAGE; DISEQUILIBRIUM C1 Univ Bonn, Life & Brain Ctr, D-5300 Bonn, Germany. Univ Antwerp, Dept Med Genet, B-2020 Antwerp, Belgium. NIMH, Genet Basis Mood & Anviety Disorders, Mood & Anxiety Program, NIH,US Dept HHS, Bethesda, MD 20892 USA. Univ Wales Coll Med, Dept Psychol Med, Neuropsychiat Genet Unit, Cardiff CF4 4XN, S Glam, Wales. Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany. GSF Natl Res Ctr Environm & Hlth, Neuherberg, Germany. Univ Bonn, Inst Med Biometry Informat & Epidemiol, D-5300 Bonn, Germany. Cent Inst Mental Hlth, Div Genet Epidemiol Psychiat, D-6800 Mannheim, Germany. Univ Bonn, Dept Psychiat, D-5300 Bonn, Germany. Med Univ Birmingham, Queen Elizabeth Psychiat Hosp, Dept Med Genet, Birmingham, W Midlands, England. Med Univ Sofia, Dept Psychiat, Sofia, Bulgaria. Univ Wales Coll Med, Dept Psychol Med, Biostat Bioinformat Unit, Cardiff CF4 4XN, S Glam, Wales. Univ Med Sci Poznan, Dept Adult Psychiat, Poznan, Poland. Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. Univ Calif Irvine, Irvine, CA USA. Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. Johns Hopkins Univ, Dept Psychiat & Behav Sci, Baltimore, MD USA. NIMH, Clin Sci Lab, Mood & Anxiety Program, NIH,US Dept HHS, Bethesda, MD 20892 USA. Indiana Univ, Sch Med, Dept Psychiat, Indianapolis, IN 46202 USA. Washington Univ, Dept Psychiat, St Louis, MO USA. Rush Univ, Med Ctr, Dept Psychiat, Chicago, IL 60612 USA. RP Cichon, S (reprint author), Univ Bonn, Life & Brain Ctr, D-5300 Bonn, Germany. EM sven.cichon@uni-bonn.de RI McMahon, Francis/A-7290-2009; Jones, Ian/B-4925-2009; Czerski, Piotr/B-8446-2011; turton, miranda/F-4682-2011; McInnis, Melvin/F-6963-2012; Schulze, Thomas/H-2157-2013; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; Schumacher, Johannes/F-4970-2015; OI Czerski, Piotr/0000-0003-0745-5916; McInnis, Melvin/0000-0002-0375-6247; Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; Schumacher, Johannes/0000-0001-9217-6457; Nothen, Markus/0000-0002-8770-2464 NR 7 TC 44 Z9 46 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD AUG PY 2004 VL 36 IS 8 BP 783 EP 784 DI 10.1038/ng0804-783 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 842AG UT WOS:000222974000002 PM 15284840 ER PT J AU Engel, N West, AG Felsenfeld, G Bartolomei, MS AF Engel, N West, AG Felsenfeld, G Bartolomei, MS TI Antagonism between DNA hypermethylation and enhancer-blocking activity at the H19 DMD is uncovered by CpG mutations SO NATURE GENETICS LA English DT Article ID IMPRINTED EXPRESSION; SEQUENCE UPSTREAM; PROTEIN CTCF; METHYLATION; GENE; IGF2; INSULATOR; ELEMENT; REGION; DELETION AB Imprinted expression at the H19-Igf2 locus depends on a differentially methylated domain (DMD) that acts both as a maternal-specific, methylation-sensitive insulator and as a paternal-specific site of hypermethylation. Four repeats in the DMD bind CCCTC-binding factor ( CTCF) on the maternal allele and have been proposed to attract methylation on the paternal allele. We introduced point mutations into the DMD to deplete the repeats of CpGs while retaining CTCF-binding and enhancer-blocking activity. Maternal inheritance of the mutations left H19 expression and Igf2 imprinting intact, consistent with the idea that the DMD acts as an insulator. Conversely, paternal inheritance of these mutations disrupted maintenance of DMD methylation, resulting in biallelic H19 expression. Furthermore, an insulator was established on the paternally inherited mutated allele in vivo, reducing Igf2 expression and resulting in a 40% reduction in size of newborn offspring. Thus, the nine CpG mutations in the DMD showed that the two parental-specific roles of the H19 DMD, methylation maintenance and insulator assembly, are antagonistic. C1 Univ Penn, Sch Med, Howard Hughes Med Inst, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA. NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Bartolomei, MS (reprint author), Univ Penn, Sch Med, Howard Hughes Med Inst, Philadelphia, PA 19104 USA. EM bartolom@mail.med.upenn.edu OI West, Adam/0000-0003-3502-7804 NR 30 TC 76 Z9 81 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD AUG PY 2004 VL 36 IS 8 BP 883 EP 888 DI 10.1038/ng1399 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 842AG UT WOS:000222974000023 PM 15273688 ER PT J AU Quill, H Giovanni, M AF Quill, H Giovanni, M TI Working with dangerous bugs SO NATURE IMMUNOLOGY LA English DT Editorial Material AB As part of the national effort in the US to protect civilians from bioterrorist attacks, the US National Institute of Allergy and Infectious Diseases (NIAID) was charged with the development of diverse research resources. The NIAID Resources for Biodefense Research program is forging new collaborations between immunologists and infectious disease experts and is reinvigorating research in the general area of immune protection against pathogenic infection. C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Quill, H (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hquill@niaid.nih.gov NR 0 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD AUG PY 2004 VL 5 IS 8 BP 765 EP 767 DI 10.1038/ni0804-765 PG 3 WC Immunology SC Immunology GA 841TX UT WOS:000222955600003 PM 15282555 ER PT J AU Watanabe, T Kitani, A Murray, PJ Strober, W AF Watanabe, T Kitani, A Murray, PJ Strober, W TI NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses SO NATURE IMMUNOLOGY LA English DT Article ID NF-KAPPA-B; INFLAMMATORY-BOWEL-DISEASE; INTESTINAL EPITHELIAL-CELLS; CROHNS-DISEASE; C-REL; MURAMYL DIPEPTIDE; BACTERIAL PEPTIDOGLYCAN; HOST RECOGNITION; GENE; ACTIVATION AB The mechanism by which mutations in CARD15, which encodes nucleotide-binding oligomerization domain 2 (NOD2), cause Crohn disease is poorly understood. Because signaling via mutated NOD2 proteins leads to defective activation of the transcription factor NF-kappaB, one proposal is that mutations cause deficient NF-kappaB-dependent T helper type 1 (T(H)1) responses and increased susceptibility to infection. However, this idea is inconsistent with the increased T(H)1 responses characteristic of Crohn disease. Here we used Card15(-/-) mice to show that intact NOD2 signaling inhibited Toll-like receptor 2-driven activation of NFkappaB, particularly of the NF-kappaB subunit c-Rel. Moreover, NOD2 deficiency or the presence of a Crohn disease-like Card15 mutation increased Toll-like receptor 2-mediated activation of NF-kappaB-c-Rel, and T(H)1 responses were enhanced. Thus, CARD15 mutations may lead to disease by causing excessive T(H)1 responses. C1 NIAID, Mucosal Immun Sect, Host Def Lab, NIH, Bethesda, MD 20892 USA. St Jude Childrens Res Hosp, Dept Infect Dis, Memphis, TN 38105 USA. RP Strober, W (reprint author), NIAID, Mucosal Immun Sect, Host Def Lab, NIH, Bldg 10 Room 11N238,10 Ctr Dr, Bethesda, MD 20892 USA. EM wstrober@niaid.nih.gov FU NCI NIH HHS [P30 CA21765] NR 49 TC 575 Z9 594 U1 1 U2 20 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD AUG PY 2004 VL 5 IS 8 BP 800 EP 808 DI 10.1038/ni1092 PG 9 WC Immunology SC Immunology GA 841TX UT WOS:000222955600011 PM 15220916 ER PT J AU Jackson, SH Devadas, S Kwon, J Pinto, LA Williams, MS AF Jackson, SH Devadas, S Kwon, J Pinto, LA Williams, MS TI T cells express a phagocyte-type NADPH oxidase that is activated after T cell receptor stimulation SO NATURE IMMUNOLOGY LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; DINUCLEOTIDE PHOSPHATE-OXIDASE; OXYGEN-SPECIES GENERATION; FAS LIGAND EXPRESSION; SMOOTH-MUSCLE-CELLS; REACTIVE-OXYGEN; ANGIOTENSIN-II; HYDROGEN-PEROXIDE; KINASE ACTIVATION; NAD(P)H OXIDASE AB T cell receptor (TCR) stimulation induces rapid generation of reactive oxygen species, although the mechanisms for this are unclear. Here we found that T cells expressed a functional phagocyte-type nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. TCR crosslinking induced oxidase activation through the recruitment of preformed Fas ligand and Fas. TCR stimulation induced three separable events generating reactive oxygen species: rapid hydrogen peroxide production independent of Fas or NADPH oxidase; sustained hydrogen peroxide production dependent on both Fas and NADPH oxidase; and delayed superoxide production that was dependent on Fas ligand and Fas yet independent of NADPH oxidase. NADPH oxidase-deficient T cells showed enhanced activation of the kinase Erk and a relative increase in T helper type 1 cytokine secretion. Thus, mature T cells express a phagocyte-type NADPH oxidase that regulates elements of TCR signaling. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Amer Red Cross, Dept Immunol, Rockville, MD 20855 USA. Sci Applicat Int Corp, Natl Canc Inst, Frederick, MD 21702 USA. RP Williams, MS (reprint author), Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. EM willmark@usa.redcross.org NR 52 TC 217 Z9 219 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD AUG PY 2004 VL 5 IS 8 BP 818 EP 827 DI 10.1038/ni1096 PG 10 WC Immunology SC Immunology GA 841TX UT WOS:000222955600013 PM 15258578 ER PT J AU Caplen, NJ AF Caplen, NJ TI RNAi quashes polyQ SO NATURE MEDICINE LA English DT Editorial Material ID GENE-EXPRESSION AB RNA interference in the brain inhibits neurodegeneration in a polyglutamine disease, SCA1. Is this now the way forward for the clinical treatment of certain genetic disorders ( pages 816 - 820)? C1 NCI, Gene Silencing Sect, Off SCi & Technol Partnerships, Off Director,Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Caplen, NJ (reprint author), NCI, Gene Silencing Sect, Off SCi & Technol Partnerships, Off Director,Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM ncaplen@mail.nih.gov RI Caplen, Natasha/H-2768-2016 OI Caplen, Natasha/0000-0002-0001-9460 NR 10 TC 4 Z9 4 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD AUG PY 2004 VL 10 IS 8 BP 775 EP 776 DI 10.1038/nm0804-775 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 843DK UT WOS:000223055700012 PM 15286770 ER PT J AU Pantaleo, G Koup, RA AF Pantaleo, G Koup, RA TI Correlates of immune protection in HIV-1 infection: what we know, what we don't know, what we should know SO NATURE MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL RESPONSES; VIRAL LOAD; CD8(+) LYMPHOCYTES; ANTIBODY-RESPONSE; RHESUS MACAQUES; CLINICAL AIDS; VACCINE; DNA; PREVENTION AB The field of vaccinology began in ignorance of how protection was instilled in vaccine recipients. Today, a greater knowledge of immunology allows us to better understand what is being stimulated by various vaccines that leads to their protective effects: that is, their correlates of protection. Here we describe what is known about the correlates of protection for existing vaccines against a range of different viral diseases and discuss the correlates of protection against disease during natural infection with HIV-1. We will also discuss why it is important to design phase 3 clinical trials of HIV vaccines to determine the correlates of protection for each individual vaccine. C1 Univ Lausanne, CHU Vaudois, Dept Med, Div Immunol & Allergy,Lab AIDS Immunopathogenesis, CH-1011 Lausanne, Switzerland. NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Pantaleo, G (reprint author), Univ Lausanne, CHU Vaudois, Dept Med, Div Immunol & Allergy,Lab AIDS Immunopathogenesis, CH-1011 Lausanne, Switzerland. EM giuseppe.pantaleo@chuv.hospvd.ch; rkoup@mil.nih.gov RI Pantaleo, Giuseppe/K-6163-2016 NR 48 TC 329 Z9 336 U1 4 U2 22 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD AUG PY 2004 VL 10 IS 8 BP 806 EP 810 DI 10.1038/nm0804-806 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 843DK UT WOS:000223055700032 PM 15286782 ER PT J AU Xia, HB Mao, QW Eliason, SL Harper, SQ Martins, IH Orr, HT Paulson, HL Yang, L Kotin, RM Davidson, BL AF Xia, HB Mao, QW Eliason, SL Harper, SQ Martins, IH Orr, HT Paulson, HL Yang, L Kotin, RM Davidson, BL TI RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia SO NATURE MEDICINE LA English DT Article ID SCA1 TRANSGENIC MICE; INDUCED DISEASE; CELLS; INTERFERENCE; TYPE-1; GENES; LOCALIZATION; AGGREGATION; EXPRESSION; VECTORS AB The dominant polyglutamine expansion diseases, which include spinocerebellar ataxia type 1 (SCA1) and Huntington disease, are progressive, untreatable, neurodegenerative disorders. In inducible mouse models of SCA1 and Huntington disease, repression of mutant allele expression improves disease phenotypes. Thus, therapies designed to inhibit expression of the mutant gene would be beneficial. Here we evaluate the ability of RNA interference (RNAi) to inhibit polyglutamine-induced neurodegeneration caused by mutant ataxin-1 in a mouse model of SCA1. Upon intracerebellar injection, recombinant adeno-associated virus (AAV) vectors expressing short hairpin RNAs profoundly improved motor coordination, restored cerebellar morphology and resolved characteristic ataxin-1 inclusions in Purkinje cells of SCA1 mice. Our data demonstrate in vivo the potential use of RNAi as therapy for dominant neurodegenerative disease. C1 Univ Iowa, Program Gene Therapy, Iowa City, IA 52242 USA. Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA. Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. Univ Minnesota, Inst Human Genet, Minneapolis, MN 55455 USA. Univ Iowa, Dept Neurol, Iowa City, IA 52242 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Univ Iowa, Dept Physiol & Biophys, Iowa City, IA 52242 USA. RP Davidson, BL (reprint author), Univ Iowa, Program Gene Therapy, Iowa City, IA 52242 USA. EM beverly-davidson@uiowa.edu RI kotin, robert/B-8954-2008 NR 25 TC 441 Z9 478 U1 2 U2 18 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD AUG PY 2004 VL 10 IS 8 BP 816 EP 820 DI 10.1038/nm1076 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 843DK UT WOS:000223055700035 PM 15235598 ER PT J AU Traggiai, E Becker, S Subbarao, K Kolesnikova, L Uematsu, Y Gismondo, MR Murphy, BR Rappuoli, R Lanzavecchia, A AF Traggiai, E Becker, S Subbarao, K Kolesnikova, L Uematsu, Y Gismondo, MR Murphy, BR Rappuoli, R Lanzavecchia, A TI An efficient method to make human monoclonal antibodies from memory B cells: potent neutralization of SARS coronavirus SO NATURE MEDICINE LA English DT Article ID ACUTE RESPIRATORY SYNDROME; SYNCYTIAL VIRUS-INFECTION; HONG-KONG; MOUSE; IDENTIFICATION; GENERATION; DISEASES; MYELOMA; STRAINS; MICE AB Passive serotherapy can confer immediate protection against microbial infection, but methods to rapidly generate human neutralizing monoclonal antibodies are not yet available. We have developed an improved method for Epstein-Barr virus transformation of human B cells. We used this method to analyze the memory repertoire of a patient who recovered from severe acute respiratory syndrome coronavirus (SARS-CoV) infection and to isolate monoclonal antibodies specific for different viral proteins, including 35 antibodies with in vitro neutralizing activity ranging from 10(-8)M to 10(-11)M. One such antibody confers protection in vivo in a mouse model of SARS-CoV infection. These results show that it is possible to interrogate the memory repertoire of immune donors to rapidly and efficiently isolate neutralizing antibodies that have been selected in the course of natural infection. C1 Inst Res Biomed, CH-6500 Belllinzona, Switzerland. Inst Virol, D-35037 Marburg, Germany. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Chiron Vaccines, I-53100 Siena, Italy. Osped L Sacco, Ist Microbiol, I-20175 Milan, Italy. RP Lanzavecchia, A (reprint author), Inst Res Biomed, Via Vela 6, CH-6500 Belllinzona, Switzerland. EM lanzavecchia@irb.unisi.ch RI traggiai, elisabetta/A-2316-2009 NR 30 TC 332 Z9 353 U1 4 U2 19 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD AUG PY 2004 VL 10 IS 8 BP 871 EP 875 DI 10.1038/nm1080 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 843DK UT WOS:000223055700043 PM 15247913 ER PT J AU Singer, JH Lassova, L Vardi, N Diamond, JS AF Singer, JH Lassova, L Vardi, N Diamond, JS TI Coordinated multivesicular release at a mammalian ribbon synapse SO NATURE NEUROSCIENCE LA English DT Article ID ROD BIPOLAR CELLS; AII AMACRINE CELLS; RABBIT RETINA; QUANTAL ANALYSIS; RAT RETINA; ASYNCHRONOUS RELEASE; EXCITATORY SYNAPSES; SIGNAL INTERNEURONS; TIME-COURSE; VESICLES AB Traditional models of synaptic transmission hold that release sites within an active zone operate independently. Although the release of multiple vesicles (multivesicular release; MVR) from single active zones occurs at some central synapses, MVR is not thought to require coordination among release sites. Ribbon synapses seem to be optimized to release many vesicles over an extended period, but the dynamics of MVR at ribbon synapses is unknown. We examined MVR at a ribbon synapse in a retinal slice preparation using paired recordings from presynaptic rod bipolar and postsynaptic AII amacrine cells. When evoked release was highly desynchronized, discrete postsynaptic events were larger than quantal miniature excitatory postsynaptic currents (mEPSCs) but had the same time course. The amplitude of these multiquantal mEPSCs, which seem to arise from the essentially simultaneous release of multiple vesicles, was reduced by lowering release probability. The release synchrony reflected in these multivesicular events suggests that release within an active zone is coordinated during MVR. C1 NINDS, Synapt Physiol Unit, NIH, Bethesda, MD 20892 USA. Univ Penn, Dept Neurosci, Philadelphia, PA 19104 USA. RP Singer, JH (reprint author), NINDS, Synapt Physiol Unit, NIH, MSC-4066,Bldg 26,Room 2C-09, Bethesda, MD 20892 USA. EM singerj@ninds.nih.gov RI Diamond, Jeffrey/C-1835-2015 OI Diamond, Jeffrey/0000-0002-1770-2629 FU NEI NIH HHS [EY00828, EY11105]; NINDS NIH HHS [K22 NS043365] NR 47 TC 128 Z9 128 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD AUG PY 2004 VL 7 IS 8 BP 826 EP 833 DI 10.1038/nn1280 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 841LH UT WOS:000222930800012 PM 15235608 ER PT J AU Poirier, MC AF Poirier, MC TI Chemical-induced DNA damage and human cancer risk SO NATURE REVIEWS CANCER LA English DT Review ID WHITE BLOOD-CELLS; EXFOLIATED UROTHELIAL CELLS; ESOPHAGEAL BALLOON CYTOLOGY; 4-AMINOBIPHENYL-DNA ADDUCTS; CIGARETTE-SMOKING; BLADDER-CANCER; ANIMAL-MODELS; HUMAN TISSUES; LUNG-CANCER; CHINA AB Chemical carcinogenesis involves a complex series of events, the earliest of which typically include DNA damage and the fixation of DNA mutations. Sophisticated new techniques have been developed to quantify DNA damage and to correlate the amount of damage with cancer risk. Approaches such as these are underway in Linxian, China, where food contains high levels of DNA-damaging, carcinogenic polycyclic aromatic hydrocarbons (PAHs), and where there is high mortality from oesophageal cancer. Gaining better insight into the mechanisms by which PAH exposure might increase oesophageal cancer risk could lead to new strategies for cancer prevention. C1 NCI, Carcinogen DNA Interact Sect, LCCTP, NIH, Bethesda, MD 20892 USA. RP Poirier, MC (reprint author), NCI, Carcinogen DNA Interact Sect, LCCTP, NIH, Bldg 37 Room 4032,37 Convent Dr,MSC-4255, Bethesda, MD 20892 USA. EM poirierm@exchange.nih.gov NR 67 TC 129 Z9 131 U1 3 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X J9 NAT REV CANCER JI Nat. Rev. Cancer PD AUG PY 2004 VL 4 IS 8 BP 630 EP 637 DI 10.1038/nrc1410 PG 8 WC Oncology SC Oncology GA 842XZ UT WOS:000223039300015 PM 15286742 ER PT J AU Collins, FS AF Collins, FS TI Francis S. Collins SO NATURE REVIEWS DRUG DISCOVERY LA English DT Editorial Material C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Collins, FS (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 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 AUG PY 2004 VL 3 IS 8 BP 640 EP 640 DI 10.1038/nrd1488 PG 1 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 842LG UT WOS:000223005000008 PM 15317147 ER PT J AU Wynn, TA AF Wynn, TA TI Fibrotic disease and the T(H)1/T(H)2 paradigm SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID INDUCED PULMONARY-FIBROSIS; GROWTH-FACTOR-BETA; INDUCED AIRWAY HYPERREACTIVITY; HUMAN-LUNG FIBROBLASTS; INTERLEUKIN (IL)-13 RESPONSES; HEPATIC STELLATE CELLS; MICE LACKING SMAD3; REGULATORY T-CELLS; IN-VIVO; INTERFERON-GAMMA AB Tissue fibrosis ( scarring) is a leading cause of morbidity and mortality. Current treatments for fibrotic disorders, such as idiopathic pulmonary fibrosis, hepatic fibrosis and systemic sclerosis, target the inflammatory cascade, but they have been widely unsuccessful, largely because the mechanisms that are involved in fibrogenesis are now known to be distinct from those involved in inflammation. Several experimental models have recently been developed to dissect the molecular mechanisms of wound healing and fibrosis. It is hoped that by better understanding the immunological mechanisms that initiate, sustain and suppress the fibrotic process, we will achieve the elusive goal of targeted and effective therapeutics for fibroproliferative diseases. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Wynn, TA (reprint author), NIAID, Parasit Dis Lab, NIH, 50 S Dr,Room 6154,MSC 8003, Bethesda, MD 20892 USA. EM twynn@niaid.nih.gov RI Wynn, Thomas/C-2797-2011 FU Intramural NIH HHS [Z01 AI000829-10, Z01 AI001019-01] NR 129 TC 662 Z9 690 U1 6 U2 47 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD AUG PY 2004 VL 4 IS 8 BP 583 EP 594 DI 10.1038/nri1412 PG 12 WC Immunology SC Immunology GA 843DD UT WOS:000223055000011 PM 15286725 ER PT J AU Perfetto, SP Chattopadhyay, PK Roederer, M AF Perfetto, SP Chattopadhyay, PK Roederer, M TI Innovation - Seventeen-colour flow cytometry: unravelling the immune system SO NATURE REVIEWS IMMUNOLOGY LA English DT Editorial Material ID MEMORY T-CELLS; DISTRIBUTION DIFFERENCES/; HIV-1 INFECTION; FLUORESCENCE; SUBSETS; NAIVE; PROGRESSION; LYMPHOCYTES; 11-COLOR; AIDS AB The increasing need for polychromatic approaches to flow cytometry, coupled with rapid technological advances, has pushed the frontiers of flow cytometry beyond 12-colour systems. Recent breakthroughs have allowed the design and implementation of instruments that measure 19 parameters ( 17 fluorescent colours and 2 physical parameters). This article describes the instrumentation and considers the reagents, analysis and applications for this powerful, new extension of flow-cytometric technology. C1 NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Perfetto, SP (reprint author), NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, 40 Convent Dr,Room 5507, Bethesda, MD 20892 USA. EM sperfetto@nih.gov RI Chattopadhyay, Pratip/B-9227-2008; Roederer, Mario/G-1887-2011; OI Chattopadhyay, Pratip/0000-0002-5457-9666 FU Intramural NIH HHS [Z99 AI999999] NR 27 TC 509 Z9 532 U1 6 U2 49 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD AUG PY 2004 VL 4 IS 8 BP 648 EP U5 DI 10.1038/nri1416 PG 9 WC Immunology SC Immunology GA 843DD UT WOS:000223055000017 PM 15286731 ER PT J AU Graziewicz, MA Longley, MJ Bienstock, RJ Zeviani, M Copeland, WC AF Graziewicz, MA Longley, MJ Bienstock, RJ Zeviani, M Copeland, WC TI Structure-function defects of human mitochondrial DNA polymerase in autosomal dominant progressive external ophthalmoplegia SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID MULTIPLE DELETIONS; ESCHERICHIA-COLI; KLENOW FRAGMENT; GAMMA-A; MUTATIONS; ALIGNMENT; BINDING; MTDNA; IDENTIFICATION; REPLICATION AB Progressive external ophthalmoplegia (PEO) is a mitochondrial disorder associated with mutations in the POLG gene encoding the mitochondrial DNA polymerase (pol gamma). Four autosomal dominant mutations that cause PEO encode the amino acid substitutions G923D, R943H, Y955C and A957S in the polymerase domain of pol gamma. A homology model of the pol gamma catalytic domain in complex with DNA was developed to investigate the effects of these mutations. Two mutations causing the most severe disease phenotype, Y955C and R943H, change residues that directly interact with the incoming dNTP. Polymerase mutants exhibit 0.03 - 30% wild-type polymerase activity and a 2- to 35-fold decrease in nucleotide selectivity in vitro. The reduced selectivity and catalytic efficiency of the autosomal dominant PEO mutants predict in vivo dysfunction, and the extent of biochemical defects correlates with the clinical severity of the disease. C1 NIEHS, Genet Mol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Comp Sci Lab, NIH, Res Triangle Pk, NC 27709 USA. Polish Acad Sci, Inst Biochem & Biophys, PL-02106 Warsaw, Poland. Natl Neurol Inst Carlo Besta, Unit Mol Neurogenet, I-20126 Milan, Italy. RP Copeland, WC (reprint author), NIEHS, Genet Mol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM copelan1@niehs.nih.gov RI Zeviani, Massimo/K-2891-2014; OI Bienstock, Rachelle/0000-0001-5228-3610 NR 36 TC 95 Z9 98 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD AUG PY 2004 VL 11 IS 8 BP 770 EP 776 DI 10.1038/nsmb805 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 841LF UT WOS:000222930600022 PM 15258572 ER PT J AU Jankowsky, JL Slunt, HH Gonzales, V Jenkins, NA Copeland, NG Borchelt, DR AF Jankowsky, JL Slunt, HH Gonzales, V Jenkins, NA Copeland, NG Borchelt, DR TI APP processing and amyloid deposition in mice haplo-insufficient for presenilin 1 SO NEUROBIOLOGY OF AGING LA English DT Article DE presenilin 1; Alzheimer's disease; transgenic mice; amyloid; neuropathology ID FAMILIAL ALZHEIMERS-DISEASE; GAMMA-SECRETASE CLEAVAGE; PRECURSOR PROTEIN; TRANSGENIC MICE; BETA-PROTEIN; IN-VIVO; MUTANT PRESENILIN-1; MISSENSE MUTATIONS; TERMINAL FRAGMENTS; NICASTRIN AB More than 70 different mutations in presenilin 1 (PS1) have been associated with inherited early onset Alzheimer's disease (AD). How all these different mutations cause disease has not been clearly delineated. Our laboratory has previously shown that co-expression of mutant PS1 in mice transgenic for amyloid precursor protein (APPswe) dramatically accelerates the rate of amyloid deposition in the brain. In our original animals mutant PS1 was substantially over-expressed, and the stabilized pool of mouse PS1 fragments was largely replaced by the human protein. In this setting the accelerated amyloid pathology in the double transgenic mice could have been due, in part, to decreased endogenous PS1 activity. To investigate this possibility, we generated APP transgenic mice with reduced levels of endogenous PS1. We find that mice harboring only one functional PS1 allele and co-expressing Mo/HuAPPswe do not develop amyloid deposits at ages comparable to mice expressing mutant PS1. We next tested whether hypo-expression of mutant PS1 could accelerate the rate of amyloid deposition using an unusual line of transgenic mice expressing PSIdE9 at low levels, finding no significant acceleration. Our findings demonstrate that the accelerated amyloid pathology, caused by so many different mutations in PS1, is clearly not a result of haplo-insufficiency that might result from inactivating mutations. Instead, our data are consistent with a gain of property mechanism. (C) 2003 Elsevier Inc. All rights reserved. C1 Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. NCI, Frederick Canc Res & Dev Ctr, Mouse Canc Genet Program, Frederick, MD 21702 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Borchelt, DR (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, 558 Ross Res Bldg,720 Rutland Ave, Baltimore, MD 21205 USA. EM drbor@jhmi.edu FU NIA NIH HHS [5P01AG14248, P50AG05146]; NINDS NIH HHS [T32NS07435] NR 43 TC 69 Z9 71 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD AUG PY 2004 VL 25 IS 7 BP 885 EP 892 DI 10.1016/j.neurobiolaging.2003.09.008 PG 8 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 838JQ UT WOS:000222709900006 PM 15212842 ER PT J AU Torre, P Mattison, JA Fowler, CG Lane, MA Roth, GS Ingram, DK AF Torre, P Mattison, JA Fowler, CG Lane, MA Roth, GS Ingram, DK TI Assessment of auditory function in rhesus monkeys (Macaca mulatta): effects of age and calorie restriction SO NEUROBIOLOGY OF AGING LA English DT Article DE aging; caloric restriction; auditory function; rhesus monkey ID SPONTANEOUS OTOACOUSTIC EMISSIONS; MIDDLE LATENCY RESPONSES; UNIVERSITY-OF-WISCONSIN; BRAIN-STEM RESPONSE; DIETARY RESTRICTION; NONHUMAN PRIMATE; HEARING-LOSS; HUMANS; POTENTIALS; PRESBYACUSIS AB Age-related alterations in auditory function were evaluated in adult male rhesus monkeys (Macaca mulatta) involved in a long-term study evaluating the effects of caloric restriction (CR) on aging. We assessed 26 monkeys in a control group fed a low fat, high fiber diet at approximately ad libitum levels and 24 monkeys in a CR group that were fed the same diet reduced in amount by 30% compared to age- and weight-matched controls. The following measures of auditory function were obtained while monkeys were maintained under anesthesia: (1) distortion product otoacoustic emissions (DPOAEs); (2) auditory brainstem responses (ABRs); and (3) middle latency responses (MLRs). All DPOAE measures and peak 11 amplitude significantly decreased with age, while peak IV latency and ABR threshold significantly increased with age. We found no significant effects of CR on any auditory parameters examined. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Wisconsin, Dept Populat Hlth Sci, Madison, WI USA. Univ Wisconsin, Dept Communicat Disorders, Madison, WI USA. NIA, Lab Expt Gerontol, Gerontol Res Ctr, NIH, Madison, WI USA. RP Torre, P (reprint author), San Diego State Univ, Sch Speech Language & Hearing Sci, 5500 Campanile Dr,CC117, San Diego, CA 92182 USA. EM ptorre@mail.sdsu.edu NR 35 TC 20 Z9 21 U1 0 U2 2 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 AUG PY 2004 VL 25 IS 7 BP 945 EP 954 DI 10.1016/j.neurobiolaging.2003.09.006 PG 10 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 838JQ UT WOS:000222709900012 PM 15212848 ER PT J AU Chatterjie, N Stables, JP Wang, H Alexander, GJ AF Chatterjie, N Stables, JP Wang, H Alexander, GJ TI Anti-narcoleptic agent modafinil and its sulfone: A novel facile synthesis and potential anti-epileptic activity SO NEUROCHEMICAL RESEARCH LA English DT Article DE anti-epileptic; anti-narcoleptic; chemical synthesis; chirality; modafinil; modafinil sulfone; neuroprotectant; toxicity ID D-AMPHETAMINE; DRUGS; NEUROPROTECTION; AMANTADINE; DISORDER; PLACEBO AB We report a facile procedure to synthesize racemic modafinil (diphenylmethylsulfinylacetamide), which is now being used in pharmacotherapy, and its achiral oxidized derivative (diphenylmethylsulfonyl acetamide). Modafinil is of interest more than for its potential anti-narcoleptic activity. It has also been reported to have neuroprotective properties and may potentially be effective in the enhancement of vigilance and cognitive performance. Finally, it may also protect from subclinical seizures that have been implicated as causative factors in autistic spectrum disorders and other neurodegenerative conditions. This agent can now be synthesized simply and in larger amounts than previously, making it more readily available for testing in various research modalities. The described procedure also lends itself to production of several other amides of potential interest. We are currently in the process of synthesizing and testing several new derivatives in this series. The anticonvulsant properties of modafinil and its sulfone derivative have not previously been extensively described in the literature. It may be of interest to note that the oxidized derivative of modafinil is also nontoxic and almost as effective as an anticonvulsant as the parent. C1 New York State Inst Basic Res Dev Disabil, Dept Neurochem, Staten Isl, NY 10314 USA. NINDS, Preclin Screening Program, Bethesda, MD 20892 USA. CUNY Coll Staten Isl, Staten Isl, NY 10314 USA. RP Chatterjie, N (reprint author), New York State Inst Basic Res Dev Disabil, Dept Neurochem, 1050 Forest Hill Rd, Staten Isl, NY 10314 USA. EM chemexp@aol.com NR 22 TC 17 Z9 18 U1 4 U2 10 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 AUG PY 2004 VL 29 IS 8 BP 1481 EP 1486 DI 10.1023/B:NERE.0000029559.20581.1a PG 6 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 825HB UT WOS:000221745700003 PM 15260124 ER PT J AU Horovitz, SG Rossion, B Skudlarski, P Gore, JC AF Horovitz, SG Rossion, B Skudlarski, P Gore, JC TI Parametric design and correlational analyses help integrating fMRI and electrophysiological data during face processing SO NEUROIMAGE LA English DT Article DE face perception; fMRI; ERP ID HUMAN NEURAL SYSTEM; FUNCTIONAL MRI; TEMPORAL CORTEX; OCCIPITOTEMPORAL CORTEX; N170 COMPONENT; BRAIN ACTIVITY; VISUAL-CORTEX; PERCEPTION; FUSIFORM; AREA AB Face perception is typically associated with activation in the inferior occipital, superior temporal (STG), and fusiform gyri (FG) and with an occipitotemporal electrophysiological component peaking around 170 ms on the scalp, the N170. However, the relationship between the N170 and the multiple face-sensitive activations observed in neuroimaging is unclear. It has been recently shown that the amplitude of the N170 component monotonically decreases as gaussian noise is added to a picture of a face [Jemel et al., 2003]. To help clarify the sources of the N170 without a priori assumptions regarding their number and locations, ERPs and fMRI were recorded in five subjects in the same experiment, in separate sessions. We used a parametric paradigm in which the amplitude of the N170 was modulated by varying the level of noise in a picture, and identified regions where the percent signal change in fMRI correlated with the ERP data. N170 signals were observed for pictures of both cars and faces but were stronger for faces. A monotonic decrease with added noise was observed for the N170 at right hemisphere sites but was less clear on the left and occipital central sites. Correlations between fMRI signal and N170 amplitudes for faces were highly significant (P < 0.001) in bilateral fusiform gyrus and superior temporal gyrus. For cars, the strongest correlations were observed in the parahippocampal region and in the STG (P < 0.005). Besides contributing to clarify the spatiotemporal course of face processing, this study illustrates how ERP information may be used synergistically in fMRI analyses. Parametric designs may be developed further to provide some timing information on fMRI activity and help identify the generators of ERP signals. (C) 2004 Elsevier Inc. All rights reserved. C1 Vanderbilt Univ, Inst Imaging Sci, Nashville, TN 37203 USA. Univ Catholique Louvain, Unite Neurosci Cognit, B-1348 Louvain, La Neuve, Belgium. Yale Univ, Sch Med, Dept Diagnost Radiol, New Haven, CT 06510 USA. RP Horovitz, SG (reprint author), NINDS, Adv MRI, LFMI, NIH, 9000 Rockville Pike,Bldg 10-B1D723, Bethesda, MD 20982 USA. EM silvina.horovitz@aya.yale.edu FU NIBIB NIH HHS [EB-0046102] NR 46 TC 85 Z9 87 U1 1 U2 4 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 AUG PY 2004 VL 22 IS 4 BP 1587 EP 1595 DI 10.1016/j.neuroimage.2004.04.018 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 844KC UT WOS:000223156000016 PM 15275915 ER PT J AU Gobbini, MI Leibenluft, E Santiago, N Haxby, JV AF Gobbini, MI Leibenluft, E Santiago, N Haxby, JV TI Social and emotional attachment in the neural representation of faces SO NEUROIMAGE LA English DT Article ID HUMAN AMYGDALA; TEMPORAL CORTEX; EYE GAZE; BRAIN; MIND; RECOGNITION; PERCEPTION; ACTIVATION; FAMILIAR; SYSTEMS AB To dissociate the role of visual familiarity from the role of social and emotional factors in recognizing familiar individuals, we measured neural activity using functional magnetic resonance imaging (fMRI) while subjects viewed (1) faces of personally familiar individuals (i.e. friends and family), (2) faces of famous individuals, and (3) faces of strangers. Personally familiar faces evoked a stronger response than did famous familiar faces and unfamiliar faces in areas that have been associated with 'theory of mind', and a weaker response in the amygdala. These response modulations may reflect the spontaneous activation of social knowledge about the personality and attitudes of close friends and relatives and the less guarded attitude one has around these people. These results suggest that familiarity causes changes in neural response that extend beyond a visual memory for a face. (C) 2004 Elsevier Inc. All rights reserved. C1 Princeton Univ, Dept Psychol, Princeton, NJ 08544 USA. NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20982 USA. Univ Pisa, Dipartimento Sci Uomo & Ambiente, I-56100 Pisa, Italy. RP Gobbini, MI (reprint author), Princeton Univ, Dept Psychol, Princeton, NJ 08544 USA. EM mgobbini@princeton.edu NR 51 TC 150 Z9 153 U1 5 U2 30 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 AUG PY 2004 VL 22 IS 4 BP 1628 EP 1635 DI 10.1016/j.neuroimage.2004.03.049 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 844KC UT WOS:000223156000020 PM 15275919 ER PT J AU Heilig, M AF Heilig, M TI The NPY system in stress, anxiety and depression SO NEUROPEPTIDES LA English DT Review ID NEUROPEPTIDE-Y NPY; CORTICOTROPIN-RELEASING HORMONE; MESSENGER-RNA EXPRESSION; ELECTROCONVULSIVE SHOCKS INCREASE; PERIAQUEDUCTAL GRAY-MATTER; SOCIAL-INTERACTION TEST; GENETIC ANIMAL-MODEL; ANTAGONIST BIBO 3304; SENSITIVE LINE RATS; ELEVATED PLUS-MAZE AB NPY antagonizes behavioral consequences of stress through actions within the brain. Behavioral anti-stress actions of NPY are noteworthy in that (1) their magnitude surpasses that of other endogenous compounds; (2) they are produced across a wide range of animal models, normally thought to reflect different aspects of emotionality. This suggests that NPY acts with a high potency on a common core mechanism of emotionality and behavioral stress responses. Behavioral studies in genetically modified animals support this hypothesis. Increased emotionality is seen upon inactivation of NPY transmission, while the opposite is found when NPY signalling is made overactive. Several brain structures are involved in mediating anti-stress actions of NPY, with the most extensive evidence available for amygdala and hippocampus, and some evidence for regions within the septum, and locus coeruleus. Antistress actions of NPY are mimicked by Y1-receptor agonists, and blocked by Y1 antagonists, although Y5 receptors may substitute for Y1 actions in some cases. Blockade of Y2 receptors produces anti-stress effects indistinguishable from those produced by Y1 agonism, presumably through potentiation of presynaptic release of endogenous NPY. Together, available data point to the potential of the NPY system as a target for novel pharmacological treatments of stress-related disorders, including anxiety and depression. Development of Y2 antagonists presently appears to offer the most promising strategy for developing these clinical treatments. (C) 2004 Elsevier Ltd. All rights reserved. C1 Huddinge Univ Hosp, Karolinska Inst, Neurotec Dept, Div Psychiat, S-14186 Huddinge, Sweden. NIAAA, Clin Sci Lab, NIH, Bethesda, MD USA. RP Heilig, M (reprint author), Huddinge Univ Hosp, Karolinska Inst, Neurotec Dept, Div Psychiat, M57, S-14186 Huddinge, Sweden. EM markus.heilig@neurotec.ki.se OI Heilig, Markus/0000-0003-2706-2482 NR 117 TC 302 Z9 314 U1 1 U2 20 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4179 J9 NEUROPEPTIDES JI Neuropeptides PD AUG PY 2004 VL 38 IS 4 BP 213 EP 224 DI 10.1016/j.npep.2004.05.002 PG 12 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 858EI UT WOS:000224172700008 PM 15337373 ER PT J AU Wessell, RH Ahmed, SM Menniti, FS Dunbar, GL Chase, TN Oh, JD AF Wessell, RH Ahmed, SM Menniti, FS Dunbar, GL Chase, TN Oh, JD TI NR2B selective NMDA receptor antagonist CP-101,606 prevents levodopa-induced motor response alterations in hemi-parkinsonian rats SO NEUROPHARMACOLOGY LA English DT Article DE NMDA; NR2B; GluR1; basal ganglia; 6-hydroxydopamine; Parkinson's disease ID ELEMENT-BINDING PROTEIN; TYROSINE PHOSPHORYLATION; INDUCED DYSKINESIAS; L-DOPA; ANTIPARKINSONIAN ACTIONS; SYNAPTIC PLASTICITY; STRIATAL NEURONS; SPATIAL MEMORY; KINASE-II; DISEASE AB Sensitization of NMDA receptors containing the NR2B subunit has been increasingly associated with various forms of synaptic plasticity, including those implicated in the pathogenesis of extrapyramidal motor dysfunction. To determine whether activation of NR2B containing receptors contributes to the development and maintenance of levodopa-induced response changes in parkinsonian animals, we evaluated the effects of the selective NR2B antagonist CP-101,606 on these response alterations in unilateral 6-hydroxydopamine (6-OHDA) lesioned rats. Three weeks of twice-daily levodopa treatment decreased the duration of the rotational response to acute levodopa challenge. The response alteration was associated with an increase in GluR1 (S831) phosphorylation in medium spiny neurons of the dorsolateral striatum. Both the attenuated rotational response and augmented GluR1 phosphorylation were decreased by CP-101,606 treatment. These CP-101,606 effects were observed when the compound was administered either at the end of chronic levodopa treatment (ameliorative effect) or together with the twice-daily levodopa treatment for 3 weeks (preventive effect). Furthermore, concurrent administration of CP-101,606 with levodopa potentiated the ability of levodopa challenge to reverse the 6-OHDA lesion-induced contralateral forelimb movement deficit as measured in a drag test. These results suggest that activation of NR2B subunit containing NMDA receptors contributes to both the development and maintenance of levodopa-induced motor response alterations, through a mechanism that involves an increase in GluR1 phosphorylation in striatal spiny neurons. (C) 2004 Elsevier Ltd. All rights reserved. C1 Cent Michigan Univ, BRAIN Ctr, Dept Psychol, Mt Pleasant, MI 48858 USA. Pfizer Global Res & Dev, CNS Discovery, Groton, CT 06340 USA. NINDS, ETB, NIH, Bethesda, MD 20892 USA. RP Oh, JD (reprint author), Cent Michigan Univ, BRAIN Ctr, Dept Psychol, Sloan 224,HP 2181, Mt Pleasant, MI 48858 USA. EM oh1jd@cmich.edu OI Menniti, Frank/0000-0003-2612-9534; Ahmed, Syed Mukhtar/0000-0002-9183-9957 NR 49 TC 68 Z9 70 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD AUG PY 2004 VL 47 IS 2 BP 184 EP 194 DI 10.1016/j.neuropharm.2004.03.011 PG 11 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 840EX UT WOS:000222841100004 PM 15223297 ER PT J AU Rasmusson, AM Vasek, J Lipschitz, DS Vojvodal, D Mustone, ME Shi, QH Gudmundsen, G Morgan, CA Wolfe, J Charney, DS AF Rasmusson, AM Vasek, J Lipschitz, DS Vojvodal, D Mustone, ME Shi, QH Gudmundsen, G Morgan, CA Wolfe, J Charney, DS TI An increased capacity for adrenal DHEA release is associated with decreased avoidance and negative mood symptoms in women with PTSD SO NEUROPSYCHOPHARMACOLOGY LA English DT Review DE post-traumatic stress disorder; PTSD; cortisol; DHEA; premenopausal women; HPA axis ID POSTTRAUMATIC-STRESS-DISORDER; URINARY CORTISOL EXCRETION; DEHYDROEPIANDROSTERONE-SULFATE DHEAS; DEXAMETHASONE-SUPPRESSION TEST; SUSTAINED CHILDHOOD ABUSE; MAJOR DEPRESSION; MENSTRUAL-CYCLE; GLUCOCORTICOID-RECEPTOR; 21-HYDROXYLASE DEFICIENCY; ANTIGLUCOCORTICOID ACTION AB We recently found increased adrenal cortisol responses to adrenocorticotropic hormone (ACTH)(1-24) and increased pituitary ACTH and adrenal cortisol responses to corticotropin-releasing factor in premenopausal women with chronic post-traumatic stress disorder (PTSD) compared to healthy nontraumatized subjects. This pattern of hypothalamic-pituitary-adrenal axis (HPA) hyper-reactivity has been previously seen in healthy individuals treated with the antiglucocorticoid mifepristone. We therefore investigated whether endogenous plasma levels of antiglucocorticoids such as dehydroepiandrosteroine (DHEA) and progesterone were increased in premenopausal women with PTSD at baseline or in response to adrenal activation by ACTH(1-24). The study revealed that DHEA responses to 250 mug ACTH(1-24) were increased in 13 PTSD subjects compared to 13 healthy nontraumatized subjects, while DHEA levels were generally increased in the PTSD subjects compared to seven healthy traumatized subjects. Cortisol responses to ACTH(1-24) were also higher in the women with PTSD, while progesterone levels and responses were not different among the three groups. In addition, among the PTSD subjects, the peak change in DHEA in response to ACTH(1-24) was negatively correlated with the total Clinician Administered PTSD Scale score, while the peak DHEA to cortisol ratio was inversely associated with negative mood symptoms measured by the Profile of Mood States scale. This work suggests that an increased capacity for DHEA release in response to extreme adrenal activation may influence the pattern of HPA axis adaptation to extreme stress, as well as mitigate the severity of PTSD and negative mood symptoms in premenopausal women with PTSD. C1 Yale Univ, Dept Psychiat, Sch Med, Boston, MA USA. VA Boston Healthcare Syst, VA Natl Ctr PTSD, Clin Neurosci Div, West Haven, CT USA. Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. VA Boston Healthcare Syst, VA Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA USA. New York Med Coll, Sch Publ Hlth, Learning Ctr, Valhalla, NY 10595 USA. NIMH, Mood & Anxiety Disorders Branch, Bethesda, MD 20892 USA. RP Rasmusson, AM (reprint author), VA Connecticut Healthcare Syst, Psychiat Serv 116A, 950 Campbell Ave, West Haven, CT 06516 USA. EM ann.rasmusson@yale.edu FU NIDA NIH HHS [1K12DA14038-01]; NIMH NIH HHS [MH30929] NR 111 TC 79 Z9 83 U1 2 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD AUG PY 2004 VL 29 IS 8 BP 1546 EP 1557 DI 10.1038/sj.npp.1300432 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 841OW UT WOS:000222941200017 PM 15199367 ER PT J AU Augustson, EM Marcus, SE AF Augustson, EM Marcus, SE TI Use of the Current Population Survey to characterize subpopulations of continued smokers: A national perspective on the "hardcore" smoker phenomenon SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID PREDICTING SMOKING CESSATION; PRECONTEMPLATING SMOKERS; UNITED-STATES; TRANSTHEORETICAL MODEL; CIGARETTE-SMOKING; PREVALENCE; BEHAVIORS; ADDICTION; SUBTYPES; FUTURE AB The existence of "hardcore" smokers, those most likely to have substantial difficulty quitting, may have far reaching impact on how to best allocate cessation resources. It has been suggested that hardcore smokers make up only a small fraction of current smokers and therefore do not represent a significant public health problem. However, little is known about the prevalence and nature of this subgroup of smokers in the United States. Based on a national sample, the 1998-1999 Tobacco Use Supplement to the Current Population Survey, we categorized, based on smoking pattern, groups of current smokers who were over age 25 years (N=33,568). We compared hardcore smokers with other groups of current smokers on demographic, environmental, and smoking variables to assess whether hardcore smokers represent a unique group. Hardcore smokers were defined as established daily smokers, consuming 15 or more cigarettes per day with no reported history of quit attempts. Hardcore smokers represent 13.7% of all current smokers and 17.6% of all established smokers. They are more likely to be male, unmarried, not in the work force, and have lower education. They also are more likely to have started smoking at a younger age, smoke more, and are less likely to report contact with smoking restrictions. This analysis suggests that hardcore smokers are distinct from other groups of smokers. These results also indicate that hardcore smokers account for a substantial proportion of smokers and as such may represent a significant public health challenge that needs to be addressed. C1 NCI, Tobacco Control Res Branch, DCCPS, Bethesda, MD 20892 USA. RP Augustson, EM (reprint author), NCI, Tobacco Control Res Branch, DCCPS, 6130 Execut Blvd,Suite 109,MSC 8318, Bethesda, MD 20892 USA. EM augustse@mail.nih.gov NR 46 TC 57 Z9 57 U1 0 U2 4 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD AUG PY 2004 VL 6 IS 4 BP 621 EP 629 DI 10.1080/14622200410001727876 PG 9 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 855OA UT WOS:000223982400005 PM 15370158 ER PT J AU Harris, CC Hussain, SP Hofseth, LJ Wogan, G Wang, XW AF Harris, CC Hussain, SP Hofseth, LJ Wogan, G Wang, XW TI Radical causes of human cancer SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 3rd International Conference on the Biology, Chemistry and Therapeutic Applications of Nitric Oxide/4th Annual Meeting of the Nitric-Oxide-Society-of-Japan CY MAY 24-28, 2004 CL Nara, JAPAN SP Nitr Oxide Soc Japan C1 NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD AUG PY 2004 VL 11 IS 1 BP 38 EP 38 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 856CX UT WOS:000224022300035 ER PT J AU Crawford, JH Irby, C Parrovi, K Shiva, S Darley-Usmar, VM Ho, C Gladwin, MT Patel, RP AF Crawford, JH Irby, C Parrovi, K Shiva, S Darley-Usmar, VM Ho, C Gladwin, MT Patel, RP TI Vasoactivity of nitrite and erythrocytes supports a novel mechanism of hypoxic vasodilation SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 3rd International Conference on the Biology, Chemistry and Therapeutic Applications of Nitric Oxide/4th Annual Meeting of the Nitric-Oxide-Society-of-Japan CY MAY 24-28, 2004 CL Nara, JAPAN SP Nitr Oxide Soc Japan C1 Univ Alabama, Birmingham, AL USA. NIH, Bethesda, MD USA. Carnegie Mellon Univ, Pittsburgh, PA 15213 USA. RI Ho, Chien/O-6112-2016 OI Ho, Chien/0000-0002-4094-9232 NR 0 TC 0 Z9 0 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 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD AUG PY 2004 VL 11 IS 1 BP 49 EP 50 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 856CX UT WOS:000224022300075 ER PT J AU Thomas, DD Espey, MG Ridnour, L Harris, CC Hosfseth, L Wink, DA AF Thomas, DD Espey, MG Ridnour, L Harris, CC Hosfseth, L Wink, DA TI HIF-1A and p53 are regulated by distinct threshold nitric oxide concentrations in human breast MCF7 cells SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 3rd International Conference on the Biology, Chemistry and Therapeutic Applications of Nitric Oxide/4th Annual Meeting of the Nitric-Oxide-Society-of-Japan CY MAY 24-28, 2004 CL Nara, JAPAN SP Nitr Oxide Soc Japan C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD AUG PY 2004 VL 11 IS 1 BP 62 EP 63 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 856CX UT WOS:000224022300122 ER PT J AU Hussain, SP Trivers, G Hofseth, L He, PJ Shaikh, I Mechanic, L Doja, S Jiang, WD Sublesky, J AF Hussain, SP Trivers, G Hofseth, L He, PJ Shaikh, I Mechanic, L Doja, S Jiang, WD Sublesky, J TI Nitric oxide regulates murine spontaneous tumorigenesis SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 3rd International Conference on the Biology, Chemistry and Therapeutic Applications of Nitric Oxide/4th Annual Meeting of the Nitric-Oxide-Society-of-Japan CY MAY 24-28, 2004 CL Nara, JAPAN SP Nitr Oxide Soc Japan C1 NCI, NIH, Bethesda, MD 20892 USA. Univ Virginia, Hlth Sci Ctr, Charlottesville, VA 22908 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD AUG PY 2004 VL 11 IS 1 BP 63 EP 63 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 856CX UT WOS:000224022300123 ER PT J AU Morris, CR Poljakovic, M Morris, SM Gladwin, MT AF Morris, CR Poljakovic, M Morris, SM Gladwin, MT TI Decreased L-arginine bioavailability and elevated arginase activity in sickle cell disease: a novel pathway towards pulmonary hypertension? SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 3rd International Conference on the Biology, Chemistry and Therapeutic Applications of Nitric Oxide/4th Annual Meeting of the Nitric-Oxide-Society-of-Japan CY MAY 24-28, 2004 CL Nara, JAPAN SP Nitr Oxide Soc Japan C1 Childrens Hosp, Oakland, CA 94609 USA. Res Ctr Oakland, Oakland, CA USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD AUG PY 2004 VL 11 IS 1 BP 72 EP 73 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 856CX UT WOS:000224022300157 ER PT J AU Yamada, K Iyama, T Matsumoto, K Koshiishi, I Utsumi, H AF Yamada, K Iyama, T Matsumoto, K Koshiishi, I Utsumi, H TI Separative ESR imaging of NO and lipid radicals in renal tissue from disease model SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 3rd International Conference on the Biology, Chemistry and Therapeutic Applications of Nitric Oxide/4th Annual Meeting of the Nitric-Oxide-Society-of-Japan CY MAY 24-28, 2004 CL Nara, JAPAN SP Nitr Oxide Soc Japan C1 Kyushu Univ, Grad Sch Pharmaceut Sci, Fukuoka 812, Japan. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD AUG PY 2004 VL 11 IS 1 BP 116 EP 116 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 856CX UT WOS:000224022300309 ER PT J AU Schechter, AN Cannon, RO Gladwin, MT AF Schechter, AN Cannon, RO Gladwin, MT TI Therapeutic implications of nitrite reduction to nitric oxide physiologically by deoxyheme proteins SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract CT 3rd International Conference on the Biology, Chemistry and Therapeutic Applications of Nitric Oxide/4th Annual Meeting of the Nitric-Oxide-Society-of-Japan CY MAY 24-28, 2004 CL Nara, JAPAN SP Nitr Oxide Soc Japan C1 NIDDK, Biol Chem Lab, Bethesda, MD 20892 USA. NHLBI, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD AUG PY 2004 VL 11 IS 1 BP 129 EP 129 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 856CX UT WOS:000224022300356 ER PT J AU Subramanian, S Matsumoto, KI Mitchell, JB Krishna, MC AF Subramanian, S Matsumoto, KI Mitchell, JB Krishna, MC TI Radio frequency continuous-wave and time-domain EPR imaging and Overhauser-enhanced magnetic resonance imaging of small animals: instrumental developments and comparison of relative merits for functional imaging SO NMR IN BIOMEDICINE LA English DT Review DE functional imaging; EPRI; MRI; OMRI; single point imaging; tumor hypoxia; in vivo oxymetry; spectral-spatial imaging; tissue redox status ID ELECTRON-PARAMAGNETIC-RESONANCE; LOOP-GAP RESONATOR; RADIOFREQUENCY FT EPR; IN-VIVO OXYMETRY; LITHIUM PHTHALOCYANINE; FREE-RADICALS; HIGH-RESOLUTION; SPIN LABELS; ELECTROCHEMICAL PREPARATION; PROJECTION RECONSTRUCTION AB Electron paramagnetic resonance (EPR) imaging in the continuous wave (CW) and time-domain modes, as well as Overhauser-enhanced magnetic resonance imaging in vivo is described. The review is based mainly on the CW and time-domain EPR instrumentation at 300 MHz developed in our laboratory, and the relative merits of these methods for functional in vivo imaging of small animals to assess hypoxia and tissue redox status are described. Overhauser imaging of small animals at magnetic fields in the range 10-15 mT that is being carried out in our laboratory for tumor imaging and the evaluation of tumor hypoxia based on quantitative evaluation of Overhauser enhancement is also described. Alternate approaches to spectral-spatial imaging using the transverse decay constants to infer in situ line widths and hence ill vivo pO(2) using CW and time-domain EPR imaging are also discussed. The nature of the spin probes used, the quality of the images obtained in all the three methods, the achievable resolution, limitations and possible future directions in small animal functional imaging with these modalities are summarized. Copyright (C) 2004 John Wiley Sons, Ltd. C1 NCI, CCR, Radiat Biol Branch, Biomed Imaging Sect,NIH, Bethesda, MD 20892 USA. RP Krishna, MC (reprint author), NCI, CCR, Radiat Biol Branch, Biomed Imaging Sect,NIH, Bethesda, MD 20892 USA. EM murali@helix.nih.gov RI Frank, David/E-8213-2012 NR 126 TC 55 Z9 55 U1 0 U2 12 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD AUG PY 2004 VL 17 IS 5 BP 263 EP 294 DI 10.1002/nbm.897 PG 32 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 856VJ UT WOS:000224073100004 PM 15366027 ER PT J AU Jagoda, EM Vaquero, JJ Seidel, J Green, MV Eckelman, WC AF Jagoda, EM Vaquero, JJ Seidel, J Green, MV Eckelman, WC TI Experiment assessment of mass effects in the rat: implications for small animal PET imaging SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE animal imaging; PET; FDG; FMT; FCWAY ID H-3 WAY-100635; IN-VIVO; BRAIN; LOCALIZATION; RECEPTOR; BINDING; CANCER AB In vivo imaging using positron emission tomography (PET) is important in the development of new radiopharmaceuticals in rodent animal models for use as biochemical probes, diagnostic agents, or in drug development. We have shown mathematically that, if small animal imaging studies in rodents are to have the same "quality" as human PET studies, the same number of coincidence events must be detected from a typical rodent imaging "voxel" as from the human imaging voxel. To achieve this using the same specific activity preparation. we show that roughly the same total amount of radiopharmaceutical must be given to a rodent as to a human subject. At high specific activities. the mass associated with human doses, when administered to a rodent, may not decrease the uptake of radioactivity at non saturable sites or sites where an enzyme has a high capacity for a substrate. However, in the case of binding sites of low density such as receptors. the increased mass injected could saturate the receptor and lead to physiologic effects and non-linear kinetics. Because of the importance of the mass injected for small animal PET imaging, we experimentally compared high and low mass preparations using ex vivo biodistribution and phosphorimaging of three compounds: 2-fluoro-2-deoxyglucose (FDG), 6-fluoro-L-metatyrosine (FMT) and one receptor-directed compound, the serotonin 5HT(1A) receptor ligand, trans-4-fluoro-N-{2-[4-(2-methoxylphenyl) piperazino]ethyl}-N-(2-pyridyl) cyclohexane- carboxamide (FCWAY). Changes in the mass injected per rat did not affect the distribution of FDG, FMT, and FCWAY in the range of 0.6-1.9 nmol per rat. Changes in the target to nontarget ratio were observed for injected masses of FCWAY in the range of similar to5-50 nmol per rat. If the specific activity of such compounds and/or the sensitivity of small animal scanners are not increased relative to human studies. small animal PET imaging will not correctly portray the "true" tracer distribution. These difficulties will only be exacerbated in animals smaller than the rat, e.g., mice. Published by Elsevier Inc. C1 Warren Grant Magnuson Clin Ctr, PET Dept, Bethesda, MD 20892 USA. NIH, Dept Nucl Med, Bethesda, MD 20892 USA. RP Eckelman, WC (reprint author), Warren Grant Magnuson Clin Ctr, PET Dept, Bethesda, MD 20892 USA. EM eckelman@nih.gov RI Vaquero, Juan Jose/D-3033-2009 OI Vaquero, Juan Jose/0000-0001-9200-361X NR 24 TC 51 Z9 52 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 AUG PY 2004 VL 31 IS 6 BP 771 EP 779 DI 10.1016/j.nucmedbio.2004.04.003 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 840TK UT WOS:000222882600011 PM 15246368 ER PT J AU Brady, ED Chong, HS Milenic, DE Brechbiel, MW AF Brady, ED Chong, HS Milenic, DE Brechbiel, MW TI Development of a spectroscopic assay for bifunctional ligand-protein conjugates based on copper SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE radioimmunotherapy; monoclonal antibodies; ligand-to-protein ratio; copper-64; arsenazo III; UV/Vis spectroscopy ID MONOCLONAL-ANTIBODIES; SPECTROPHOTOMETRIC METHOD; CANCER-THERAPY; COMPLEXES; RADIOPHARMACEUTICALS; DERIVATIVES; DTPA; ACID; PHARMACOKINETICS; RADIONUCLIDES AB A simple, non-radioactive method for the determination of ligand-to-protein ratio (L/P) for novel ligand-antibody conjugates has been developed based on an exchange equilibrium with the purple Cu(II) complex of arsenazo III. The method requires a UV/Vis spectrometer and has been verified for monoclonal antibody Herceptin conjugates of a variety of ligand modalities, including common macrocyclic compounds NOTA and TETA. and with a new bifunctional tachpyridine (1H-Pyrrole-1-butanamide,N-[4-[[(1alpha,3alpha,5alpha)-3,5-bis[(2-pyridinylmethyl)amino]cyclohexyl](2-pyridinylmethyl)amino]butyl]-2,5-dihydro-2,5-dioxo-(9CI)). The spectroscopically derived values for L/P were verified by titration of the ligand-antibody conjugate with Cu-64. In each case, the value obtained by UV/Vis spectroscopy matches that found by radiolabeling. The method is rapid, taking less than 30 minutes with each ligand in this study. Published by Elsevier Inc. C1 NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Brady, ED (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. EM bradye@mail.nih.gov FU NCI NIH HHS [R24 CA86307] NR 37 TC 22 Z9 22 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 AUG PY 2004 VL 31 IS 6 BP 795 EP 802 DI 10.1016/j.nucmedbio.2004.04.004 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 840TK UT WOS:000222882600014 PM 15246371 ER PT J AU Saleem, RA Banerjee-Basu, S Murphy, TC Baxevanis, A Walter, MA AF Saleem, RA Banerjee-Basu, S Murphy, TC Baxevanis, A Walter, MA TI Essential structural and functional determinants within the forkhead domain of FOXC1 SO NUCLEIC ACIDS RESEARCH LA English DT Article ID MUTATION CONGENITAL-HYDROCEPHALUS; HELIX TRANSCRIPTION FACTORS; AXENFELD-RIEGER-SYNDROME; DNA-BINDING DOMAIN; CARDIOVASCULAR DEVELOPMENT; MISSENSE MUTATIONS; MOLECULAR-GENETICS; MF1; PROTEINS; FKHL7 AB The forkhead domain (FHD)-containing developmental transcription factor FOXC1 is mutated in patients presenting with Axenfeld-Rieger malformations. In this paper, we report the introduction of positive, negative or neutral charged amino acids into critical positions within the forkhead domain of FOXC1 in an effort to better understand the essential structural and functional determinants within the FHD. We found that FOXC1 is intolerant of mutations at l87. Additionally alterations of amino acids within alpha-helix 1 of the FOXC1 FHD affected both nuclear localization and transactivation. Amino acids within a-helix 3 were also found to be necessary for transactivation and can have roles in correct localization. Interestingly, changing amino acids within alpha-helix 3, particularly R127, resulted in altered DNA-binding specificity and granted FOXC1 the ability to bind to a novel DNA sequence. Given the limited topological variation of FHDs, due to the high conservation of residues, we anticipate that models of forkhead domain function derived from these data will be relevant to other members of the FOX family of transcription factors. C1 Univ Alberta, Dept Med Genet, Edmonton, AB T6G 2H7, Canada. Univ Alberta, Dept Ophthalmol, Edmonton, AB T6G 2H7, Canada. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Walter, MA (reprint author), Univ Alberta, Dept Med Genet, 832 Med Sci Bldg, Edmonton, AB T6G 2H7, Canada. EM mwalter@ualberta.ca NR 36 TC 21 Z9 21 U1 1 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 AUG PY 2004 VL 32 IS 14 BP 4182 EP 4193 DI 10.1093/nar/gkh742 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 854MZ UT WOS:000223909300011 PM 15299087 ER PT J AU Nakajima, T Fujino, S Nakanishi, G Kim, YS Jetten, AM AF Nakajima, T Fujino, S Nakanishi, G Kim, YS Jetten, AM TI TIP27: a novel repressor of the nuclear orphan receptor TAK1/TR4 SO NUCLEIC ACIDS RESEARCH LA English DT Article ID TESTIS-ASSOCIATED RECEPTOR; STEROID-RECEPTOR; TRANSCRIPTIONAL ACTIVATION; MOLECULAR-CLONING; GENE-EXPRESSION; TR4; SUPERFAMILY; PROTEIN; BINDING; MOTIF AB The nuclear orphan receptor TAK1/TR4 functions as a positive as well as a negative regulator of transcription; however, little is known about the factors regulating or mediating its activity. Yeast two-hybrid analysis using the ligand-binding domain (LBD) of TAK1 as bait identified a novel TAK1-interacting protein, referred to as TIP27, which functions as a repressor of TAK1-mediated transactivation. TIP27 is a 27 kDa protein containing two zinc finger motifs. Mammalian two-hybrid analysis showed that TIP27 interacts specifically with TAK1 and not with several other nuclear receptors tested. The region between Asp(39) and Lys(79) of TIP27, referred to as TAK1-interaction domain (TID), is critical for its interaction with TAK1 while the TAK1-LBD from helix 3 until the C-terminus is required for the optimal interaction with TIP27. Pull-down assays demonstrated that the TIP27 physically interacts with TAK1 and supported the critical importance of the TID. Confocal microscopy showed that in the nucleus, TIP27 and TAK1 co-localize. TIP27 acts as a strong repressor of DR1-dependent transcriptional activation by TAK1. This repression does not involve the inhibition of TAK1 homodimerization or DR1 binding but may be due to an effect on co-activator recruitment by TAK1. Our results indicate that TIP27 functions as a TAK1-selective repressor. C1 NIEHS, Cell Biol Sect, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Jetten, AM (reprint author), NIEHS, Cell Biol Sect, Div Intramural Res, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM jetten@niehs.nih.gov OI Jetten, Anton/0000-0003-0954-4445 NR 39 TC 35 Z9 38 U1 0 U2 4 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 AUG PY 2004 VL 32 IS 14 BP 4194 EP 4204 DI 10.1093/nar/gkh741 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 854MZ UT WOS:000223909300012 PM 15302918 ER PT J AU Mirza, NM Kadow, K Palmer, M Solano, H Rosche, C Yanovski, JA AF Mirza, NM Kadow, K Palmer, M Solano, H Rosche, C Yanovski, JA TI Prevalence of overweight among inner city Hispanic-American children and adolescents SO OBESITY RESEARCH LA English DT Article DE overweight; Hispanic-American children and adolescents; clinical comorbidities; physical activity; dietary patterns ID OBESITY; CHILDHOOD; MORTALITY; WEIGHT; HEALTH; YOUTH; RISK; ADRENARCHE; PREDICTORS; ADIPOSITY AB Objective: National surveys have pointed to a particularly high risk of pediatric overweight among U.S. Hispanics. However, the data have been primarily from the Mexican-American community. We studied the prevalence of overweight and clinical comorbidities in children and youth of predominantly El Salvadoran ancestry. Research Methods and Procedures: A sample of 309 Hispanic youth, 6-18 years was surveyed from two inner city Washington, DC, clinics. BMI; triceps skinfold (TSF) and subscapular skinfold thickness (SSSF); bioelectrical impedance analysis (BIA); and blood pressure measures were obtained, along with information regarding physical activity, sedentary behavior, dietary history, family, and personal medical history. Results: Thirty-eight percent were overweight (BMI greater than or equal to 95th percentile) and 22% at risk for overweight (BMI 85-94th percentile). Thirty-four percent had TSF greater than or equal to 90th percentile and 29% had SSSF greater than or equal to 90th percentile. Fifty-one percent of males and 70% of females had body fat > 30%. Compared to their nonoverweight counterparts, overweight youth had significantly higher systolic blood pressure (111.4 +/- 1.3 vs. 104.5 +/- 0.9 mm Hg, p < 0.0001). Among children younger than 11 years, overweight was associated with onset of adrenarche (23% vs. 10%, p = 0.01). Participation in one or more sports teams was negatively correlated with overweight) p = 0.04). Discussion: The prevalence of overweight and at risk for overweight in this sample was twice the national average for U.S. children and 1.7 times greater than that of MexicanAmerican children in national surveys. Overweight was associated with advanced pubertal development, high body fat, elevated blood pressure, and decreased sports participation. C1 Childrens Natl Med Ctr, Dept Pediat, Washington, DC 20010 USA. NICHHD, Unit Growth & Obes, Dev Endocrinol Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Mirza, NM (reprint author), Childrens Natl Med Ctr, Dept Pediat, Washington, DC 20010 USA. EM nmirza@cnmc.org FU Intramural NIH HHS [Z01 HD000641-12, Z99 HD999999]; NCRR NIH HHS [M01 RR013297, RR17613]; NICHD NIH HHS [Z01 HD-00641] NR 45 TC 32 Z9 32 U1 0 U2 1 PU NORTH AMER ASSOC STUDY OBESITY PI SILVER SPRING PA 8630 FENTON ST, SUITE 918, SILVER SPRING, MD 20910 USA SN 1071-7323 J9 OBES RES JI Obes. Res. PD AUG PY 2004 VL 12 IS 8 BP 1298 EP 1310 DI 10.1038/oby.2004.164 PG 13 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 851MF UT WOS:000223688500015 PM 15340113 ER PT J AU Tulloch-Reid, MK Hanson, RL Sebring, NG Reynolds, JC Premkumar, A Genovese, DJ Sumner, AE AF Tulloch-Reid, MK Hanson, RL Sebring, NG Reynolds, JC Premkumar, A Genovese, DJ Sumner, AE TI Both subcutaneous and visceral adipose tissue correlate highly with insulin resistance in African Americans SO OBESITY RESEARCH LA English DT Article DE abdominal obesity; colinearity; insulin resistance complications; African American ID NUCLEAR-MAGNETIC-RESONANCE; NON-HISPANIC WHITES; RACIAL-DIFFERENCES; ABDOMINAL ADIPOSITY; GLUCOSE-TOLERANCE; JAPANESE-AMERICANS; METABOLIC SYNDROME; MUSCLE COMPOSITION; LIPOPROTEIN LEVELS; FAT DISTRIBUTION AB Objective: The contribution of visceral adipose tissue (VAT) to insulin resistance is well-established; however, the role of subcutaneous abdominal adipose tissue (SAT) in insulin resistance remains controversial. Sex may determine which of these two components of abdominal obesity is more strongly related to insulin resistance and its consequences. The aim of this study was to determine whether both VAT and SAT contribute to insulin resistance in African Americans and to examine the effects of sex on this relationship. Research Methods and Procedures: This was a cross-sectional study of 78 nondiabetic African-American volunteers (44 men, 35 women; age 33.8 +/- 7.3 years; BMI 30.9 +/- 7.4 kg/m(2)). VAT and SAT volumes were measured using serial computerized tomography slices from the dome of the diaphragm to the iliac crest. The insulin sensitivity index (S,) was determined from the minimal model using data obtained from the frequently sampled intravenous glucose tolerance test. Results: In men, both VAT and SAT were negatively correlated with S-I (r for both correlations = -0.57; p < 0.01). In women, the correlation coefficient between VAT and S, was -0.50 (p < 0.01) and between SAT and S-I was -0.67 (p < 0.01). In women, the correlation coefficient for SI with SAT was significantly greater than the correlation coefficient with VAT (p = 0.02). Discussion: Both SAT and VAT are strongly correlated with insulin resistance in African Americans. For AfricanAmerican women, SAT may have a greater effect than VAT on insulin resistance. C1 NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Diabet & Arthrit Epidemiol Sect, Phoenix, AZ USA. NIH, Dept Nutr, Bethesda, MD 20892 USA. NIH, Dept Nucl Med, Bethesda, MD 20892 USA. NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. RP Sumner, AE (reprint author), NIDDK, Clin Endocrinol Branch, NIH, Bldg 10,Room 8S 235D,MSC 1770, Bethesda, MD 20892 USA. EM AnneS@intra.niddk.nih.gov RI Tulloch-Reid, Marshall/E-4383-2012; Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 NR 38 TC 57 Z9 59 U1 0 U2 1 PU NORTH AMER ASSOC STUDY OBESITY PI SILVER SPRING PA 8630 FENTON ST, SUITE 918, SILVER SPRING, MD 20910 USA SN 1071-7323 J9 OBES RES JI Obes. Res. PD AUG PY 2004 VL 12 IS 8 BP 1352 EP 1359 DI 10.1038/oby.2004.170 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 851MF UT WOS:000223688500021 PM 15340119 ER PT J AU Klebanoff, MA Schwebke, JR Zhang, J Nansel, TR Yu, KF Andrews, WW AF Klebanoff, MA Schwebke, JR Zhang, J Nansel, TR Yu, KF Andrews, WW TI Vulvovaginal symptoms in women with bacterial vaginosis SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID FLORA AB OBJECTIVE: A substantial, but highly variable, percentage of women with bacterial vaginosis are said to be asymptomatic. The purpose of this study was to estimate the prevalence of symptoms among women with bacterial vaginosis compared with women without bacterial vaginosis by direct, explicit, and detailed questioning of these women. METHODS: Women presenting for a routine health care visit at 12 health department clinics in Birmingham, Alabama, were recruited to participate in a longitudinal study of vaginal flora. At the first visit, they underwent a pelvic examination, lower genital tract microbiological evaluation, and an interview that included detailed questions regarding lower genital tract symptoms. The prevalence of symptoms among women with and without bacterial vaginosis (Gram stain score 7 or higher) was compared. RESULTS: Among 2,888 women without gonorrhea, Chlamydia, or trichomonas, 75% of women with and 82% of women without bacterial vaginosis never noted any vaginal odor in the past 6 months (P <.001). Me corresponding values were 63% and 65% for never noting vaginal "wetness" (P =.02); 58% and 57% for vaginal discharge (P =.65); 91% and 86% for irritation (P =.004); 88% and 85% for itching (P =.64); and 96% and 94% for dysuria (P =.002), respectively. Cumulatively, 58% of women with bacterial vaginosis noted odor, discharge, and/or wetness in the past 6 months compared with 57% of women without bacterial vaginosis (P =.70). CONCLUSION: The 2 classic symptoms of bacterial vaginosis discharge and odor are each reported by a minority of women with bacterial vaginosis and are only slightly more prevalent than among women without bacterial vaginosis. (C) 2004 by The American College of Obstetricians and Gynecologists. C1 NICHHD, Div Epidemiol Stat & Prevent Res, Natl Inst Hlth, Bethesda, MD 20892 USA. Univ Alabama, Dept Med, Tuscaloosa, AL 35487 USA. Univ Alabama, Dept Obstet & Gynecol, Tuscaloosa, AL 35487 USA. RP Klebanoff, MA (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, Natl Inst Hlth, Bldg 6100,Room 7B05, Bethesda, MD 20892 USA. EM mk90h@nih.gov OI Nansel, Tonja/0000-0002-8298-7595 FU NICHD NIH HHS [N0-1-HD-8-3293] NR 13 TC 86 Z9 99 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD AUG PY 2004 VL 104 IS 2 BP 267 EP 272 DI 10.1097/01.AOG.0000134783.98382.b0 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 875IX UT WOS:000225414800011 PM 15291998 ER PT J AU Jackson, RA Vittinghoff, E Kanaya, AM Miles, TP Resnick, HE Kritchevsky, SB Simonsick, EM Brown, JS AF Jackson, RA Vittinghoff, E Kanaya, AM Miles, TP Resnick, HE Kritchevsky, SB Simonsick, EM Brown, JS CA Health Aging Body Composi TI Urinary incontinence in elderly women: Findings from the health, aging, and body composition study SO OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 22nd Annual Scientific Meeting of the American-Urogynecologic-Society CY OCT 25-27, 2001 CL Chicago, IL SP Amer Urogynecol Soc ID PELVIC ORGAN PROLAPSE; RISK-FACTORS; ESTROGEN SUPPLEMENTATION; POSTMENOPAUSAL WOMEN; STRESS-INCONTINENCE; AFRICAN-AMERICAN; OLDER ADULTS; WEIGHT-LOSS; LATER LIFE; PREVALENCE AB OBJECTIVE: To estimate the prevalence of and risk factors for stress and urge incontinence in a biracial sample of well-functioning older women. METHODS: We performed a cross-sectional analysis of 1,584 white and black women, aged 70-79 years, enrolled in a longitudinal cohort study. Participants were asked about incontinence, medical problems, and demographic and reproductive characteristics and underwent physical measurements. Using multivariable logistic regression, we compared women reporting at least weekly incontinence with those without incontinence. RESULTS: Overall, 21% reported incontinence at least weekly. Of these, 42% reported predominantly urge incontinence, and 40% reported stress. Nearly twice as many white women as black women reported weekly incontinence (27% versus 14%, P <.001). Factors associated with urge incontinence included white race (odds ratio [OR] 3.1, 95% confidence interval [CI] 2.0-4.8), diabetes treated with insulin (OR 3.5, 95% CI 1.6-7.9), depressive symptoms (OR 2.7, 95% CI 1.4-5.3), current oral estrogen use (OR 1.7,95% CI 1.1-2.6), arthritis (OR 1.7,95% CI 1.1-2.6), and decreased physical performance (OR 1.6 per point on 0-4 scale, 95% CI 1.1-2.3). Factors associated with stress incontinence were chronic obstructive pulmonary disease (OR 5.6, 95% CI 1.3-23.2), white race (OR 4.1, 95% CI 2.5-6.7), current oral estrogen use (OR 2.0, 95% CI 1.3-3.1), arthritis (OR 1.6, 95% CI 1.0-2.4), and high body mass index (OR 1.3 per 5 kg/m(2), 95% CI 1.1-1.6). CONCLUSION: Urinary incontinence is highly prevalent, even in well-functioning older women, whites in particular. Many risk factors differ for stress and urge incontinence, suggesting differing etiologies and prevention strategies. (C) 2004 by The American College of Obstetricians and Gynecologists. C1 Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Biostat & Epidemiol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Med, Div Gen Internal Med, San Francisco, CA 94143 USA. Univ Louisville, Dept Family & Community Med, Louisville, KY 40292 USA. MedStar Res Inst, Washington, DC USA. Wake Forest Univ, Hlth Sci Med Ctr, J Paul Sticht Ctr Aging, Winston Salem, NC 27109 USA. NIA, Intramural Res Program, Baltimore, MD 21224 USA. RP Jackson, RA (reprint author), San Francisco Gen Hosp, Dept Obstet & Gynecol, 6D 1001 Potrero Ave, San Francisco, CA 94110 USA. EM jacksonr@obgyn.ucsf.edu OI Miles, Toni/0000-0003-0823-2319 FU NIA NIH HHS [N01-AG-2101, N01-AG-6-2103, N01-AG-6-2106] NR 43 TC 115 Z9 117 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD AUG PY 2004 VL 104 IS 2 BP 301 EP 307 DI 10.1097/01.AOG.0000133482.20685.d1 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 875IX UT WOS:000225414800016 PM 15292003 ER PT J AU Tsilou, ET Rubin, BI Reed, GF McCain, L Huizing, M White, J Kaiser-Kupfer, MI Gahl, W AF Tsilou, ET Rubin, BI Reed, GF McCain, L Huizing, M White, J Kaiser-Kupfer, MI Gahl, W TI Milder ocular findings in Hermansky-Pudlak syndrome type 3 compared with Hermansky-Pudlak syndrome type 1 SO OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY MAY 05-10, 2002 CL FT LAUDERDALE, FL SP Assoc Res Vis & Ophthalmol ID VESICLE FORMATION; BETA-3A SUBUNIT; GENE; MUTATIONS; ALBINISM; FORM; TRAFFICKING; DEFICIENCY; DISORDERS; ADAPTER AB Purpose: To compare clinically 2 different subtypes of Hermansky-Pudlak syndrome (HPS), type 1 (HPS-1) and type 3 (HPS-3). Design: Cross-sectional study of a series of patients. Participants: Sixteen patients with HPS-1 and 14 patients with HPS-3 were studied. Methods: Complete eye examination, including best-corrected visual acuity and photographs and photographic grading of iris transillumination and macular transparency using a previously established grading system. Results: Snellen visual acuity was 20/160-2 in the HPS-1 group and 20/125+2 in the HPS-3 group (P = 0.017). Iris grading was statistically significant for less translucence in the HPS-3 patients. The HPS-3 patients also tended to have less transparent maculas, but the difference was not statistically significant. Conclusions: Patients with HPS-3 have less severe ophthalmic manifestations than patients with HPS-1. Ophthalmologists treating patients with albinism should consider HPS in their differential diagnosis even in the case of mild iris and macular hypopigmentation. (C) 2004 by the American Academy of Ophthalmology. C1 NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. NEI, Div Biometry & Epidemiol, NIH, Bethesda, MD 20892 USA. NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Dept Lab Med, Minneapolis, MN 55455 USA. RP Tsilou, ET (reprint author), NEI, Ophthalm Genet & Visual Funct Branch, NIH, 10 Ctr Dr,MSC-1860,Bldg 10,Room 10N226, Bethesda, MD 20892 USA. EM tsiloue@nei.nih.gov NR 22 TC 11 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD AUG PY 2004 VL 111 IS 8 BP 1599 EP 1603 DI 10.1016/j.ophtha.203.12.058 PG 5 WC Ophthalmology SC Ophthalmology GA 841RP UT WOS:000222949400028 PM 15288994 ER PT J AU Chou, KL Hurtig, HI Stern, MB Colcher, A Ravina, B Newberg, A Mozley, PD Siderowf, A AF Chou, KL Hurtig, HI Stern, MB Colcher, A Ravina, B Newberg, A Mozley, PD Siderowf, A TI Diagnostic accuracy of [Tc-99m]TRODAT-1 SPECT imaging in early Parkinson's disease SO PARKINSONISM & RELATED DISORDERS LA English DT Article; Proceedings Paper CT 16th Annual Symposium on Etiology, Pathogenesis and Treatment of Parkinsons Disease and Other Movement Disorders CY OCT 13, 2002 CL New York, NY DE Parkinson's disease; dopamine transporter imaging; diagnosis; SPECT; TRODAT ID PROGRESSIVE SUPRANUCLEAR PALSY; MULTIPLE SYSTEM ATROPHY; DOPAMINE TRANSPORTERS; CLINICAL-DIAGNOSIS; BINDING AB We evaluated the diagnostic accuracy of SPECT imaging using [Tc-99m]TRODAT-1 (TRODAT), a relatively inexpensive technetium-labeled dopamine transporter ligand, in distinguishing 29 patients with early PD from 38 healthy volunteers. Mean TRODAT uptake values were significantly decreased in the caudate (p = 0.0097) and anterior and posterior putamen (p < 0.0001) of PD patients compared to controls. Using the posterior putamen as the main region of interest resulted in the greatest accuracy (sensitivity 0.79, specificity 0.92). These findings show that TRODAT imaging can accurately differentiate early PD patients from controls and has the potential to improve the diagnosis of patients with early signs of PD. (C) 2004 Elsevier Ltd. All rights reserved. C1 Univ Penn, Penn Hosp, Sch Med, Parkinsons Dis & Movement Disorders Ctr, Philadelphia, PA 19107 USA. Natl Inst Neurol Disorders & Stroke, Rockville, MD USA. Univ Penn, Dept Radiol, Philadelphia, PA USA. Eli Lilly & Co, Corp Ctr, Indianapolis, IN USA. RP Chou, KL (reprint author), Univ Penn, Penn Hosp, Sch Med, Parkinsons Dis & Movement Disorders Ctr, 330 S 9th St, Philadelphia, PA 19107 USA. EM chouk@uphs.upenn.edu OI Chou, Kelvin/0000-0002-2597-7315 FU AHRQ HHS [K08 HS 00004]; NIA NIH HHS [R01 AG 17524] NR 17 TC 24 Z9 31 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD AUG PY 2004 VL 10 IS 6 BP 375 EP 379 DI 10.1016/j.parkreldis.2004.04.002 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 846AA UT WOS:000223285800007 PM 15261880 ER PT J AU Alvarado, CS Straus, SE Li, SY Dale, JK Mann, K Le, A Lauer, SJ AF Alvarado, CS Straus, SE Li, SY Dale, JK Mann, K Le, A Lauer, SJ TI Autoimmune lymphoproliferative syndrome: A cause of chronic splenomegaly, lymphadenopathy, and cytopenias in children - Report on diagnosis and management of five patients SO PEDIATRIC BLOOD & CANCER LA English DT Article DE ALPS; apoptosis; cytopenias; lymphadenopathy; splenomegaly; triglycerides ID FAS GENE-MUTATIONS; LYMPHOCYTE APOPTOSIS; SYNDROME ALPS; DISORDER; DOMINANT; EXPRESSION; FAMILIES; DEFECTS; DISEASE AB Autoimmune lymphoproliferative syndrome (ALPS) usually manifests in early childhood with splenomegaly, lymphadenopathy, and cytopenias. In most patients, it results from mutations in genes that regulate lymphocyte apoptosis via the Fas pathway. Here, we report five children with ALPS. All five children had splenomegaly, cytopenias, and hypertriglyceridemia at presentation; four had lymphadenopathy. Mutations in the Fas receptor gene were demonstrated in three children. Clinical picture is variable: in only one child manifestations are severe enough to require immunosuppressive therapy. Diagnosis of ALPS can be challenging and increased awareness of the disease can result in more directed diagnostic approaches as well as earlier initiation of treatment. (C) 2004 Wiley-Liss, Inc. C1 Emory Univ, Sch Med, Dept Pediat, Div Hematol Oncol BMT,Childrens Healthcare Atlant, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Dept Med, Vet Adm Hosp,Lipid Res Lab, Atlanta, GA 30322 USA. NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Alvarado, CS (reprint author), Emory Univ, Sch Med, Dept Pediat, Div Hematol Oncol BMT,Childrens Healthcare Atlant, 2040 Ridgewood Dr,Suite 100, Atlanta, GA 30322 USA. EM carlos_alvarado@oz.ped.emory.edu NR 21 TC 8 Z9 11 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD AUG PY 2004 VL 43 IS 2 BP 164 EP 169 DI 10.1002/pbc.20079 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 835JM UT WOS:000222479000015 PM 15236285 ER PT J AU Abzug, MJ Walsh, TJ AF Abzug, MJ Walsh, TJ TI Interferon-gamma and colony-stimulating factors as adjuvant therapy for refractory fungal infections in children SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE fungal infection; cytokines; interferon-gamma; colony-stimulating factor; children ID NEUTROPHIL-MEDIATED ACTIVITY; ADMINISTERED IN-VIVO; ASPERGILLUS-FUMIGATUS; ANTIFUNGAL ACTIVITY; CANDIDA-ALBICANS; CYTOKINES; LEUKEMIA; MACROPHAGES; PATHOGENS; PATIENT AB A human immunodeficiency virus-infected boy with Scedosporium apiospermum otomastoiditis and a girl with diabetes mellitus and Mucor sinusitis and orbital cellulitis had life-threatening disease progression despite antifungal treatment. Interferon-gamma and granulocyte-macrophage or granulocyte colony-stimulating factor were added, with good functional outcome in both children. Adjunctive therapy with interferon-gamma, granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor can be considered for refractory invasive fungal infections. C1 Childrens Hosp, Dept Pediat, Denver, CO 80218 USA. Univ Colorado, Sch Med, Denver, CO 80202 USA. Natl Canc Inst, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD USA. RP Abzug, MJ (reprint author), Childrens Hosp, Dept Pediat, Box B055,1056 E 19th Ave, Denver, CO 80218 USA. EM abzug.mark@tchden.org NR 29 TC 48 Z9 53 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD AUG PY 2004 VL 23 IS 8 BP 769 EP 773 DI 10.1097/01.inf.0000134314.65398.bf PG 5 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 847KO UT WOS:000223391400013 PM 15295229 ER PT J AU Shankaran, S Das, A Bauer, CR Bada, HS Lester, B Wright, LL Smeriglio, V AF Shankaran, S Das, A Bauer, CR Bada, HS Lester, B Wright, LL Smeriglio, V TI Association between patterns of maternal substance use and infant birth weight, length, and head circumference SO PEDIATRICS LA English DT Article DE prenatal; cocaine; alcohol; tobacco; marijuana; infant birth weight; length; head circumference ID FULL-TERM INFANTS; DRUG-USE; PRENATAL ALCOHOL; COCAINE EXPOSURE; FETAL GROWTH; LIFE-STYLE; SMOKING; PREGNANCY; MECONIUM; VALIDITY AB Objective. To determine the effects of patterns of drug use during term pregnancy on infant growth parameters at birth. Methods. Histories of cocaine, opiate, alcohol, tobacco, and marijuana use during the 3-month period before pregnancy and the 3 trimesters of pregnancy were recorded at the infants' 1-month visit. Patterns of use were categorized as consistently high, moderate, or low/none or increasing/decreasing, and effects on growth parameters were analyzed in multivariate linear regression analyses, with adjustment for clinical site, maternal age, prepregnancy weight, multidrug use, and socioeconomic status. Results. A total of 241 cocaine-exposed women and 410 non-cocaine-exposed women participated in the study. In the cocaine-exposed group, 75% used alcohol, 90% used tobacco, and 53% used marijuana; in the non cocaine-exposed group, 57% used alcohol, 34% used tobacco, and 19% used marijuana. Birth weight, birth length, and head circumference were significantly greater among infants born to women who used no drugs, compared with women with any cocaine, opiate, alcohol, tobacco, or marijuana use, and were greater among infants born to cocaine nonusers, compared with cocaine users. With adjustment for confounders, birth weight was significantly affected by cocaine ( deficit of 250 g with consistently low pattern) and tobacco ( deficits of 232 g with consistently high pattern, 173 g with consistently moderate pattern, 153 g with decreasing pattern, and 103 g with consistently low pattern). Head size was affected by cocaine (deficit of 0.98 cm with consistently moderate pattern) and tobacco (deficits of 0.72 cm with consistently high pattern and 0.89 cm with consistently moderate pattern). Birth length was affected by tobacco use only (deficits of 0.82 cm with consistently high pattern and 0.98 cm with decreasing use). Conclusion. Patterns of tobacco use during pregnancy affect birth weight, length, and head circumference, whereas cocaine affects birth weight and head size, when adjustments are made for confounders, including multidrug use. C1 Wayne State Univ, Detroit, MI USA. Res Triangle Inst, Chapel Hill, NC USA. Univ Miami, Miami, FL 33152 USA. Univ Tennessee, Memphis, TN USA. Women & Infants Hosp Rhode Isl, Providence, RI USA. NICHHD, Bethesda, MD 20892 USA. NIDA, Bethesda, MD 20892 USA. RP Shankaran, S (reprint author), Childrens Hosp Michigan, 3901 Beaubien, Detroit, MI 48201 USA. EM sshankar@med.wayne.edu NR 32 TC 26 Z9 28 U1 0 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 AUG PY 2004 VL 114 IS 2 BP 226 EP 234 PG 9 WC Pediatrics SC Pediatrics GA 842YG UT WOS:000223040000056 ER PT J AU Taylor, P Worrell, C Steinberg, SM Hazra, R Jankelevich, S Wood, LV Zwerski, S Yarchoan, R Zeichner, S AF Taylor, P Worrell, C Steinberg, SM Hazra, R Jankelevich, S Wood, LV Zwerski, S Yarchoan, R Zeichner, S TI Natural history of lipid abnormalities and fat redistribution among human immunodeficiency virus-infected children receiving long-term, protease inhibitor-containing, highly active antiretroviral therapy regimens SO PEDIATRICS LA English DT Article DE human immunodeficiency virus; protease inhibitor; lipid; fat ID LIPODYSTROPHY SYNDROME; HIV; HYPERLIPIDEMIA; PREDICTION; COHORT AB Objective. To characterize the type and frequency of biochemical lipid abnormalities and physical changes in body composition associated with the use of protease inhibitor (PI)-containing antiretroviral therapy among human immunodeficiency virus-infected children treated for up to 6 years. Methods. A retrospective study of human immunodeficiency virus-infected pediatric patients enrolled in research protocols between August 1995 and December 2001 was performed. All patients who had received a PI for greater than or equal to2 years as part of their investigational antiretroviral treatment regimens during the study period were eligible. Of the 110 patients identified as having received PI therapy, 94 met the study criteria. Results. Of the 94 patients evaluated, 9 patients (10%) developed fat redistribution as well as dyslipidemia, 49 patients (52%) developed dyslipidemia without associated physical changes, and 36 patients (38%) exhibited no elevation of lipid levels or physical signs of fat redistribution. For all 9 patients with fat redistribution, the onset of the physical changes was closely associated with changes during pubertal development. Fat redistribution was also associated with lower viral loads and higher, more sustained levels of dyslipidemia. The onset of dyslipidemia and fat redistribution peaked between 10 and 15 years of age. Conclusion. Among pediatric patients receiving PI therapy, there seems to be an age range in which children are at greater risk of developing hypercholesterolemia and subsequent fat redistribution, suggesting that unidentified physiologic changes associated with puberty may predispose pediatric patients treated with PI therapy to developing lipodystrophy. C1 NCI, Pediat HIV Working Grp, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. RP Zeichner, S (reprint author), NCI, Pediat HIV Working Grp, HIV & AIDS Malignancy Branch, NIH, 9000 Rockville Pike,Bldg 10,Rm 10S255, Bethesda, MD 20892 USA. EM zeichner@nih.gov NR 25 TC 30 Z9 30 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD AUG PY 2004 VL 114 IS 2 BP 235 EP 242 PG 8 WC Pediatrics SC Pediatrics GA 842YG UT WOS:000223040000057 ER PT J AU Marciano, BE Rosenzweig, SD Kleiner, DE Anderson, VL Darnell, DN Anaya-O'Brien, S Hilligoss, DM Malech, HL Gallin, JI Holland, SM AF Marciano, BE Rosenzweig, SD Kleiner, DE Anderson, VL Darnell, DN Anaya-O'Brien, S Hilligoss, DM Malech, HL Gallin, JI Holland, SM TI Gastrointestinal involvement in chronic granulomatous disease SO PEDIATRICS LA English DT Article DE chronic granulomatous disease; inflammatory bowel disease; interferon-gamma; colitis; obstruction; steroids ID INFLAMMATORY-BOWEL-DISEASE; TRIMETHOPRIM-SULFAMETHOXAZOLE; CLINICAL-ASPECTS; CROHNS-DISEASE; COLITIS; MANIFESTATIONS; COMPLICATIONS; CORTICOSTEROIDS; OBSTRUCTION; INFECTIONS AB Objective. Chronic granulomatous disease (CGD) is a rare disorder of phagocyte oxidative metabolism. In addition to infectious complications, granulomatous lesions often involve hollow viscera, especially the gastrointestinal (GI) tract. The objective of this study was to evaluate the clinical presentation, prevalence, and consequences of GI involvement in patients with CGD. Methods. The medical records of 140 patients with CGD (67% X-linked) followed at the National Institutes of Health were reviewed and abstracted for GI manifestations. All available GI pathology was reviewed. Results. GI involvement was recorded in 46 (32.8%) of 140 patients with CGD, 89% of whom had X-linked inheritance. The median age at the time of initial GI manifestations was 5 years (range: 0.8-30 years); 70% of the affected patients presented with GI involvement in the first decade of life. Abdominal pain was the most frequent symptom (100%), and hypoalbuminemia was the most frequent sign ( 70%). Prednisone controlled symptoms and signs in the majority of affected patients, but relapse of symptoms occurred in 71%. GI involvement had no effect on mortality and was unassociated with interferon-gamma use. Conclusion. GI involvement is a common and recurring problem in CGD, especially in those with X-linked inheritance. Currently, there is no clear evidence for an infectious cause. The frequency of GI involvement is unaffected by the use of interferon-gamma and does not affect mortality. GI involvement should be sought in patients who have CGD with abdominal pain, growth delay, or hypoalbuminemia. C1 NIAID, Host Def Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Holland, SM (reprint author), Bldg 10-11N103,10 Ctr Dr,MSC 1886, Bethesda, MD 20892 USA. EM smh@nih.gov OI Kleiner, David/0000-0003-3442-4453 NR 40 TC 166 Z9 170 U1 0 U2 8 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 AUG PY 2004 VL 114 IS 2 BP 462 EP 468 DI 10.1542/peds.114.2.462 PG 7 WC Pediatrics SC Pediatrics GA 842YG UT WOS:000223040000019 PM 15286231 ER PT J CA Natl High Blood Pressure Educ Prog TI The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents SO PEDIATRICS LA English DT Review ID LEFT-VENTRICULAR MASS; CARDIOVASCULAR RISK-FACTORS; AMERICAN-HEART-ASSOCIATION; INTIMAL-MEDIAL THICKNESS; JOINT NATIONAL COMMITTEE; BODY-FAT DISTRIBUTION; RENOVASCULAR HYPERTENSION; SODIUM-INTAKE; YOUNG-ADULTS; DOUBLE-BLIND C1 NHLBI, Natl High Blood Pressure Educ Program, NIH, Bethesda, MD 20892 USA. RP NHLBI, Natl High Blood Pressure Educ Program, NIH, Bldg 31,Room 4A10,Ctr Dr,MSC 2480, Bethesda, MD 20892 USA. NR 136 TC 180 Z9 334 U1 6 U2 16 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD AUG PY 2004 VL 114 IS 2 SU S BP 555 EP 576 PG 22 WC Pediatrics SC Pediatrics GA 843ES UT WOS:000223059900001 ER PT J AU Atienza, AA Stephens, MAP Townsend, AL AF Atienza, AA Stephens, MAP Townsend, AL TI Role stressors as predictors of changes in womens' optimistic expectations SO PERSONALITY AND INDIVIDUAL DIFFERENCES LA English DT Article DE optimism; stress; social roles; women; caregiving; personality ID LIFE ORIENTATION TEST; GENERALIZED OUTCOME EXPECTANCIES; ARTERY BYPASS-SURGERY; DISPOSITIONAL OPTIMISM; DEPRESSIVE SYMPTOMS; MULTIPLE IDENTITIES; TRAIT ANXIETY; PESSIMISM; PERSONALITY; HEALTH AB Theorists have suggested that optimistic expectations can be modified by stress. The present longitudinal study predicted that stress in women's roles would reduce optimism over one year for 182 women who occupied the roles of caregiver, mother, wife, and employee. Results revealed that while 62% of participants reported little or no change in optimism, 38% reported increases or decreases in optimism over one year. Consistent with predictions, increases in wife and employee stress predicted decreased optimism over one year. Increases in wife stress remained predictive of decreased optimism, even after considering baseline role stressors and changes in stress in the other three roles. The present findings highlight the importance of stress as a contextual factors that can change or influence optimism. (C) 2003 Elsevier Ltd. All rights reserved. C1 Stanford Univ, Sch Med, Ctr Res Dis Prevent, Stanford, CA 94305 USA. Kent State Univ, Dept Psychol, Kent, OH 44240 USA. Case Western Reserve Univ, Mandel Sch Appl Social Sci, Cleveland, OH 44106 USA. RP Atienza, AA (reprint author), NCI, Hlth Promot Res Branch, 6130 Execut Blvd,EPN 4074A, Bethesda, MD 20892 USA. EM atienzaa@mail.nih.gov NR 66 TC 13 Z9 14 U1 6 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0191-8869 J9 PERS INDIV DIFFER JI Pers. Individ. Differ. PD AUG PY 2004 VL 37 IS 3 BP 471 EP 484 DI 10.1016/j.paid.2003.09.016 PG 14 WC Psychology, Social SC Psychology GA 844FR UT WOS:000223143700003 ER PT J AU Blaisdell, J Jorge-Nebert, LF Coulter, S Ferguson, SS Lee, SJ Chanas, B Xi, T Mohrenweiser, H Ghanayem, B Goldstein, JA AF Blaisdell, J Jorge-Nebert, LF Coulter, S Ferguson, SS Lee, SJ Chanas, B Xi, T Mohrenweiser, H Ghanayem, B Goldstein, JA TI Discovery of new potentially defective alleles of human CYP2C9 SO PHARMACOGENETICS LA English DT Article DE alleles; cDNA expression; CYP2C9; CYP2C9 poor metabolizers; polymorphisms; tolbutamide ID CONSTITUTIVE ANDROSTANE RECEPTOR; HUMAN LIVER-MICROSOMES; AMINO-ACID; CYTOCHROME P4502C9; FUNCTIONAL-CHARACTERIZATION; IDENTIFICATION; VARIANTS; POLYMORPHISMS; PHARMACOKINETICS; PHENYTOIN AB CYP2C9 is a clinically important enzyme, responsible for the metabolism of numerous clinically important therapeutic drugs. In the present study, we discovered 38 single nucleotide polymorphisms in CYP2C9 by resequencing of genomic DNA from 92 individuals from three different racial groups. Haplotype analysis predicted that there are at least 21 alleles of CYP2C9 in this group of individuals. Six new alleles were identified that contained coding changes: L19I (CYP2C9*7), R150H (CYP2C9*8), H251R (CYP2C9*9), E272G (CYP2C9*10), R335W(CYP2C9*11) and P489S (CYP2C9*12). When expressed in a bacterial cDNA expression system, several alleles exhibited altered catalytic activity. CYP2C9*11 appeared to be a putative poor metabolizer allele, exhibiting a three-fold increase in the K-m and more than a two-fold decrease in the intrinsic clearance for tolbutamide. Examination of the crystal structure of human CYP2C9 reveals that R335 is located in the turn between the J and J' helices and forms a hydrogen-bonding ion pair with D341 from the J' helix. Abolishing this interaction in CYP2C9*11 individuals could destabilize the secondary structure and alter the substrate affinity. This new putative poor metabolizer (PM) allele was found in Africans. A second potentially PM allele CYP2C9*12 found in a racially unidentified sample also exhibited a modest decrease in the V-max and the intrinsic clearance for tolbutamide in a recombinant system. Further clinical studies are needed to determine the effect of these new polymorphisms on the metabolism of CYP2C9 substrates. (C) 2004 Lippincoft Williams Wilkins. C1 NIEHS, Lab Pharmacol & Chem, Human Metab Sect, Res Triangle Pk, NC 27709 USA. Univ Panama, Coll Pharm, Panama City, Panama. Univ Panama, DNA & Human Genom Inst, Panama City, Panama. Lawrence Livermore Natl Lab, Livermore, CA USA. RP Goldstein, JA (reprint author), NIEHS, Lab Pharmacol & Chem, Human Metab Sect, POB 12233, Res Triangle Pk, NC 27709 USA. EM goldstel@niehs.nih.gov RI Goldstein, Joyce/A-6681-2012; OI Coulter, Sherry/0000-0002-2732-3470 NR 33 TC 112 Z9 117 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0960-314X J9 PHARMACOGENETICS JI Pharmacogenetics PD AUG PY 2004 VL 14 IS 8 BP 527 EP 537 DI 10.1097/01.fpc.0000114759.08559.51 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 847XD UT WOS:000223430400006 PM 15284535 ER PT J AU Bartoshuk, LM Duffy, V Green, BG Hoffman, HJ Ko, CW Lucchina, LA Marks, LE Snyder, DJ Weiffenbach, JM AF Bartoshuk, LM Duffy, V Green, BG Hoffman, HJ Ko, CW Lucchina, LA Marks, LE Snyder, DJ Weiffenbach, JM TI Valid across-group comparisons with labeled scales: the gLMS versus magnitude matching SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE magnitude matching; general labeled magnitude scale; taste ID PAIN; PSYCHOPHYSICS; SWEETNESS; JUDGMENTS; LOUDNESS; TASTE AB Labeled scales are commonly used for across-group comparisons. The labels consist of adjective/adverb intensity descriptors (e.g., a "very strong"). The relative distances among descriptors are essentially constant but the absolute perceived intensities they denote vary with the domain to which they are applied (e.g., a "very strong" rose odor is weaker than a "very strong" headache), as if descriptors were printed on an elastic ruler that compresses or expands to fit the domain of interest. Variation in individual experience also causes the elastic ruler to compress or expand. Taste varies genetically: super-tasters perceive the most intense tastes; nontasters, the weakest; and medium tasters, intermediate tastes. Taste intensity descriptors on conventional-labeled scales denote different absolute perceived intensities to the three groups making comparisons across the groups invalid. Magnitude matching provides valid comparisons by asking subjects to express tastes relative to a standard not related to taste (e.g., super-tasters match tastes to louder sounds than do nontasters). Borrowing the logic of magnitude matching, we constructed a labeled scale using descriptors unrelated to taste. We reasoned that expressing tastes on a scale labeled in terms of all sensory experience might work. We generalized an existing scale, the Labeled Magnitude Scale (LMS), by placing the label "strongest imaginable sensation of any kind" at the top. One hundred subjects rated tastes and tones using the generalized LMS (gLMS) and magnitude matching. The two methods produced similar results suggesting that the gLMS is valid for taste comparisons across nontasters, medium tasters, and supertasters. (C) 2004 Published by Elsevier Inc. C1 Yale Univ, Sch Med, New Haven, CT 06520 USA. Gillette Adv Technol Ctr, Needham, MA 02492 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. NIH, Bethesda, MD 20892 USA. John B Pierce Fdn Lab, New Haven, CT 06519 USA. Univ Connecticut, Storrs, CT 06269 USA. RP Bartoshuk, LM (reprint author), Yale Univ, Sch Med, POB 208041, New Haven, CT 06520 USA. EM Linda.Bartoshuk@Yale.edu FU NIDCD NIH HHS [DC 00283] NR 43 TC 184 Z9 186 U1 7 U2 25 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD AUG PY 2004 VL 82 IS 1 BP 109 EP 114 DI 10.1016/j.physbeh.2004.02.033 PG 6 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 839TI UT WOS:000222807400018 PM 15234598 ER PT J AU Jiao, ZX Mollaaghababa, R Pavan, WJ Antonellis, A Green, ED Hornyak, TJ AF Jiao, ZX Mollaaghababa, R Pavan, WJ Antonellis, A Green, ED Hornyak, TJ TI Direct interaction of sox10 with the promoter of murine Dopachrome tautomerase (Dct) and synergistic activation of Dct expression with mitf SO PIGMENT CELL RESEARCH LA English DT Article DE melanocyte; Mitf; Sox10; transcription; dopachrome tautomerase; tyrosinase-related protein-2; neural crest ID TYROSINASE-RELATED PROTEIN-2; TRANSCRIPTION FACTOR SOX10; CREST-DERIVED MELANOCYTES; WAARDENBURG-SYNDROME; PHYSICALLY INTERACT; DISTINCT ROLES; MICROPHTHALMIA; GENE; SEQUENCE; IDENTIFICATION AB The murine dopachrome tautomerase (Dct) gene is expressed early in melanocyte development during embryogenesis, prior to other members of the tyrosinase gene family important for regulating pigmentation. We have used deletion mutants of the Dct promoter, transfections with developmentally relevant transcription factors, and gel shift assays to define transcriptional determinants of Dct expression. Deletion mutagenesis studies show that sequences within the proximal 459 nucleotides are critical for high level expression in melanocytic cells. This region of the promoter contains candidate binding sites for the transcription factors Sox10 and Mitf. Transfections into 293T and NIH3T3 cells show that Sox10 and Mitf independently activate Dct expression, and, when co-transfected, synergistically activate Dct expression. To support the notion that Sox10 acts directly upon the Dct promoter to activate gene expression, direct interaction of Sox10 was demonstrated using gel shifts of oligonucleotide probes derived from promoter sequences within the region required for Sox10-dependent induction. These results suggest that a combinatorial transcription factor interaction is important for expression of Dct in neural crest-derived melanocytes, and support a model for sequential gene activation in melanocyte development whereby Mitf, a Sox10-dependent transcription factor, is expressed initially before an early melanocyte differentiation gene, Dct, is expressed. C1 Henry Ford Hlth Syst, Dept Dermatol, Detroit, MI USA. NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Hornyak, TJ (reprint author), NCI, Dermatol Branch, Canc Res Ctr, NIH, Bldg 10-12N242, Bethesda, MD 20892 USA. EM hornyakt@mail.nih.gov FU NIAMS NIH HHS [R01 AR47951, K08 AR-01992, R03 AR-45001] NR 45 TC 61 Z9 62 U1 1 U2 5 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0893-5785 J9 PIGM CELL RES JI Pigm. Cell. Res. PD AUG PY 2004 VL 17 IS 4 BP 352 EP 362 DI 10.1111/j.1600-0749.2004.00154.x PG 11 WC Cell Biology; Dermatology SC Cell Biology; Dermatology GA 837EY UT WOS:000222612500005 PM 15250937 ER PT J AU Kinghorn, AD Su, BN Jang, DS Chang, LC Lee, D Gu, JQ Carcache-Blanco, EJ Powlus, AD Lee, SK Park, EJ Cuendet, M Gills, JJ Bhat, K Park, HS Mata-Greenwood, E Song, LL Jong, MH Pezzuto, JM AF Kinghorn, AD Su, BN Jang, DS Chang, LC Lee, D Gu, JQ Carcache-Blanco, EJ Powlus, AD Lee, SK Park, EJ Cuendet, M Gills, JJ Bhat, K Park, HS Mata-Greenwood, E Song, LL Jong, MH Pezzuto, JM TI Natural inhibitors of carcinogenesis SO PLANTA MEDICA LA English DT Review DE edible plants; in vitro bioassays; mouse mammary organ culture; potential cancer chernopreventive agents; plant secondary metabolites; flavonoids; stilbenoids; withanolides; structure-activity; relationships ID CANCER CHEMOPREVENTIVE ACTIVITY; ACTIVITY-GUIDED ISOLATION; INDUCE QUINONE REDUCTASE; VINIFERA CELL-CULTURES; PHASE-II ENZYME; GREEN TEA; EUPHORBIA-QUINQUECOSTATA; CHEMICAL CARCINOGENESIS; BIOACTIVE CONSTITUENTS; PHYSALIS-PHILADELPHICA AB Previous collaborative work by our group has led to the discovery of several plant isolates and derivatives with activities in in vivo models of cancer chemoprevention, including deguelin, resveratrol, bruceantin, brassinin, 4'-bromoflavone, and oxomate. Using a panel of in vitro bioassays to monitor chromatographic fractionation, a diverse group of plant secondary metabolites has been identified as potential cancer chemopreventive agents from mainly edible plants. Nearly 50 new compounds have been isolated as bioactive principles in one or more in vitro bioassays in work performed over the last five years. Included among these new active compounds are alkaloids, flavonoids, stilbenoids, and withanolides, as well as a novel stilbenolignan and the first representatives of the norwithanolides, which have a 27-carbon atom skeleton. In addition, over 100 active compounds of prieviously known structure have been obtained. Based on this large pool of potential cancer chemopreventive compounds, structure-activity relationships are discussed in terms of the quinone reductase induction ability of flavonoids and withanolides and the cyclooxygenase-1 and -2 inhibitory activities of flavanones, flavones and stilbenoids. Several of the bioactive compounds were found to be active when evaluated in a mouse mammary organ culture assay; when used as a secondary discriminator in our work. The compounds (2S)-abyssinone II, (2S)-2',4'-dihydroxy-2"-(1-hydroxy-1-methylethyl)dihydrofuro[2,3-h]-flavanone, 3'-[gamma-hydroxymethyl-(E)-gamma-methylallyl]-2,4,2',4'-tetrahydroxychalcone 11'-O-coumarate, isolicoflavonol, isoliquiritigenin, and ixocarpalactone A are regarded as promising leads as potential cancer chemopreventive agents. C1 Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, Program Collaborat Res Pharmaceut Sci, Chicago, IL USA. Purdue Univ, Sch Pharm, W Lafayette, IN 47907 USA. Ewha Womans Univ, Coll Pharm, Seoul, South Korea. Univ Minnesota, Dept Chem, Duluth, MN 55812 USA. Korea Res Inst Biosci & Biotechnol, Taejon, South Korea. Univ Arizona, Coll Pharm, Tucson, AZ 85721 USA. NCI, DTP Tumor Hypoxia Lab, Frederick, MD 21701 USA. NCI, Canc Therapeut Branch, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA. Northwestern Univ, Chicago, IL 60611 USA. Univ Illinois, Coll Pharm, Dept Biopharmaceut Sci, Chicago, IL USA. Loyola Univ, Dept Pathol, Maywood, IL 60153 USA. RP Kinghorn, AD (reprint author), Ohio State Univ, Coll Pharm, 500 W 12th Ave, Columbus, OH 43210 USA. EM kinghorn.4@osu.edu; jpezzuto@purdue.edu RI Lee, Dongho/G-4626-2013; OI Kinghorn, A. Douglas/0000-0002-6647-8707 FU NCI NIH HHS [P01 CA48112] NR 108 TC 117 Z9 128 U1 2 U2 18 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 J9 PLANTA MED JI Planta Med. PD AUG PY 2004 VL 70 IS 8 BP 691 EP 705 DI 10.1055/s-2004-827198 PG 15 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA 850XB UT WOS:000223646600001 PM 15326546 ER PT J AU Ramirez, AG Suarez, L Chalela, P Talavera, GA Marti, J Trapido, EJ Villarreal, R Perez-Stable, EJ AF Ramirez, AG Suarez, L Chalela, P Talavera, GA Marti, J Trapido, EJ Villarreal, R Perez-Stable, EJ TI Cancer risk factors among men of diverse Hispanic or Latino origins SO PREVENTIVE MEDICINE LA English DT Article DE Latino men; cancer risk factors; minority; health behavior ID SELF-REPORTED SMOKING; BEHAVIOR AB Background. Personal health behaviors play a fundamental role in premature cancer morbidity and mortality. However, routine risk factor data on Latino groups are lacking. Knowledge of cancer risk prevalence by ethnoregional groups is particularly important for development of effective prevention and control strategies. Methods. Using the diverse populations and sites involved in the National Hispanic Leadership Initiative on Cancer (NHLIC): En Accion, this paper examines prevalence of six cancer risk factors among Mexican, Puerto Rican, Cuban, and Central American adult males in eight U.S. cities. Data were collected through two telephone surveys. The 1993-1994 sample consisted of 4170 males (2041 <40 years and 2120 greater than or equal to40 years). The 1997-1998 sample consisted of 4486 males (2286 <40 years and 2200 greater than or equal to40 years). Results. Clear differences exist in risk factor prevalence among Latino subgroups. Overall, riskiest behaviors were found among Mexican American men in Texas, more of whom smoked, engaged in acute alcohol drinking, and had poorer diets and higher obesity levels than other Latino men. Conclusions. Root causes of these ethnoregional differences are likely due to both economic and cultural factors. Cancer prevention and control strategies and programs should be tailored to address specific needs of each population group. (C) 2004 The Institute For Cancer Prevention and Elsevier Inc. All rights reserved. C1 Baylor Coll Med, Dept Med, Chron Dis Prevent & Control Res Ctr, San Antonio, TX 78230 USA. Texas Dept Hlth, Austin, TX 78756 USA. San Diego State Univ, San Diego, CA 92182 USA. Brooklyn Hosp Ctr, Brooklyn, NY 11201 USA. NCI, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX 78229 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Ramirez, AG (reprint author), Baylor Coll Med, Dept Med, Chron Dis Prevent & Control Res Ctr, 8207 Callaghan Rd,Suite 110, San Antonio, TX 78230 USA. EM aramirez@bcm.tmc.edu FU NCI NIH HHS [U01-CA59379] NR 26 TC 14 Z9 14 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 0091-7435 J9 PREV MED JI Prev. Med. PD AUG PY 2004 VL 39 IS 2 BP 263 EP 269 DI 10.1016/j.ypmed.2004.03.034 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 839TO UT WOS:000222808000006 PM 15226034 ER PT J AU Hewitt, M Devesa, SS Breen, N AF Hewitt, M Devesa, SS Breen, N TI Cervical cancer screening among US women: analyses of the 2000 National Health Interview Survey SO PREVENTIVE MEDICINE LA English DT Article DE cervical cancer; cancer prevention and control; Pap tests; mass screening; utilization; health care surveys ID LOW-INCOME; PAP SMEAR; PREVENTIVE SERVICES; HISPANIC WOMEN; UNITED-STATES; PUBLIC-HEALTH; BREAST; CARE; AMERICAN; RATES AB Background. Cervical cancer screening is not fully utilized among all groups of women in the United States, especially women without access to health care and older women. Methods. Papanicolaou (Pap) test use among U.S. women age 18 and older is examined using data from the 2000 National Health Interview Survey (NHIS). Results. Among women who had not had a hysterectomy (n = 13,745), 83% reported having had a Pap test within the past 3 years. Logistic regression analyses showed that women with no contact with a primary care provider in the past year were very unlikely to have reported a recent Pap test. Other characteristics associated with lower rates of Pap test use included lacking a usual source of care, low family income, low educational attainment, and being unmarried. Having no health insurance coverage was associated with lower Pap test use among women under 65. Despite higher insurance coverage, being age 65 and older was associated with low use. Rates of recent Pap test were higher among African-American women. Conclusions. Policies to generalize insurance coverage and a usual source of health care would likely increase use of Pap testing. Also needed are health system changes such as automated reminders to assist health care providers implement appropriate screening. Renewed efforts by physicians and targeted public health messages are needed to improve screening among older women without a prior Pap test. (C) 2004 The Institute For Cancer Prevention and Elsevier Inc. All rights reserved. C1 Natl Acad Sci, Inst Med, Natl Canc Policy Board, Washington, DC 20001 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20852 USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20852 USA. RP Hewitt, M (reprint author), Natl Acad Sci, Inst Med, Natl Canc Policy Board, 500 5th St NW, Washington, DC 20001 USA. EM Mhewitt@nas.edu NR 52 TC 110 Z9 112 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 0091-7435 J9 PREV MED JI Prev. Med. PD AUG PY 2004 VL 39 IS 2 BP 270 EP 278 DI 10.1016/j.ypmed.2004.03.035 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 839TO UT WOS:000222808000007 PM 15226035 ER PT J AU Bewley, C AF Bewley, C TI Blocking HIV-1 envelope-mediated fusion with exogenous and engineered proteins and peptides SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 19 BP 56 EP 56 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100020 ER PT J AU Yang, W AF Yang, W TI Structural views of DNA lesions and their repair SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc ID CRYSTAL-STRUCTURE; REPLICATION; POLYMERASE C1 NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RI Yang, Wei/D-4926-2011 OI Yang, Wei/0000-0002-3591-2195 NR 4 TC 2 Z9 2 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 28 BP 59 EP 59 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100029 ER PT J AU Dowd, CS Kim, P Shenoy, G Nguyen, QA Zhang, L Zhang, Y White, S Duncan, K Rock, CO Barry, CE AF Dowd, CS Kim, P Shenoy, G Nguyen, QA Zhang, L Zhang, Y White, S Duncan, K Rock, CO Barry, CE TI Approaches to tuberculosis drug discovery: Thiolactomycin, a case study SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Labs Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 NIAID, NIH, Rockville, MD USA. St Jude Childrens Res Hosp, Dept Infect Dis, Memphis, TN 38105 USA. St Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USA. GlaxoSmithKline, Stevenage, Herts, England. RI Barry, III, Clifton/H-3839-2012 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 46 BP 65 EP 65 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100047 ER PT J AU Sechi, S Smith, V AF Sechi, S Smith, V TI NIH funding mechanisms and opportunities SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 NIH, Div Diabet Digest & Kidney Dis, Bethesda, MD 20892 USA. NIH, Ctr Sci Review, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 48 BP 65 EP 66 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100049 ER PT J AU Bennion, BJ Kulp, KS Lightstone, FC Knize, MG Montgomery, JL Bennett, LM Felton, JS AF Bennion, BJ Kulp, KS Lightstone, FC Knize, MG Montgomery, JL Bennett, LM Felton, JS TI Dietary constituents affect receptor activation and cell proliferation in human breast cancer cells SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, Livermore, CA USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 73 BP 74 EP 74 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100074 ER PT J AU Umland, TC Wolff, EC Park, MH Davies, DR AF Umland, TC Wolff, EC Park, MH Davies, DR TI A new crystal structure of deoxyhypusine synthase reveals the configuration of the active enzyme and of an enzyme : NAD : inhibitor ternary complex SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 Hauptman Woodward Med Res Inst, Buffalo, NY USA. SUNY Buffalo, Dept Biol Struct, Sch Med, Buffalo, NY 14260 USA. NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 84 BP 77 EP 77 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100085 ER PT J AU Kuhn, JF Tomer, KB AF Kuhn, JF Tomer, KB TI A study of the anthrax toxin proteins using mass spectrometry SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 103 BP 83 EP 84 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100104 ER PT J AU Pazgier, M Prahl, A Lubkowski, J AF Pazgier, M Prahl, A Lubkowski, J TI Structure/function analysis for human beta-defensin 1 SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 NCI, Frederick, MD 21701 USA. RI Pazgier, Marzena/B-7295-2012; Prahl, Adam/H-7654-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 104 BP 84 EP 84 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100105 ER PT J AU Schultz, A Ugarov, MV Tempez, A Novikov, A Carroff, M Negra, SD Le Beyec, Y Pautrat, M Smentkowski, V Wang, H AF Schultz, A Ugarov, MV Tempez, A Novikov, A Carroff, M Negra, SD Le Beyec, Y Pautrat, M Smentkowski, V Wang, H TI Nanocluster MALDI matrices combined with MALDI-ion mobility-oTOFMS for analysis of biological tissue surfaces SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 Ionwerks, Houston, TX USA. Inst Phys Nucl, CNRS, IN2P3, F-91406 Orsay, France. Inst Phys Nucl, CNRS, IN2P, F-91406 Orsay, France. GE Co, Global Res Ctr, Niskayuna, NY USA. NIDA, NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 113 BP 87 EP 87 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100114 ER PT J AU Woods, AS AF Woods, AS TI The biological magnets SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 NIDA, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 117 BP 89 EP 89 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100118 ER PT J AU Hettich, RL Ataman, D Sharp, J AF Hettich, RL Ataman, D Sharp, J TI Protein surface mapping by mass spectrometry to monitor pH-dependent structural changes SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 Oak Ridge Natl Lab, Div Chem Sci, Oak Ridge, TN USA. NIEHS, Res Triangle Pk, NC 27709 USA. RI Hettich, Robert/N-1458-2016 OI Hettich, Robert/0000-0001-7708-786X NR 0 TC 0 Z9 0 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 120 BP 90 EP 90 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100121 ER PT J AU Gomara, DZ Nussinov, R AF Gomara, DZ Nussinov, R TI Exploration of structural models of highly repetitive polyglutamine sequences: beta-helix like organization and possible pathological implications in Huntington disease SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 NCI, Lab Expt & Computat Biol, Frederick, MD 21701 USA. SAIC Frederick Inc, Lab Expt & Computat Biol, Basic Res Program, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 157 BP 102 EP 102 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100158 ER PT J AU Bai, Y Zhou, H Zhou, Y AF Bai, Y Zhou, H Zhou, Y TI Critical nucleation size in the folding of small apparently two-state proteins SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 NCI, Biochem Lab, Bethesda, MD 20892 USA. SUNY Buffalo, Dept Physiol & Biophys, Howard Hughes Med Inst, Ctr Single Mol Biophys, Buffalo, NY 14260 USA. RI Zhou, Hongyi/B-3339-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 168 BP 105 EP 105 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100169 ER PT J AU Byeon, IL Louis, JM Gronenborn, AM AF Byeon, IL Louis, JM Gronenborn, AM TI A captured folding intermidiate in dimerization and domain-swapping of GB1 SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 NIH, Lcp, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 171 BP 106 EP 106 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100172 ER PT J AU Gruschus, JM Eisenberg, E Green, LE Ferretti, JA AF Gruschus, JM Eisenberg, E Green, LE Ferretti, JA TI Model structure of the Hsp70/Hsp40 chaperone complex SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 205 BP 117 EP 117 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100206 ER PT J AU Dey, A D'Souza, V Hibbert, C Mirro, J York, D Rein, A Summers, MF AF Dey, A D'Souza, V Hibbert, C Mirro, J York, D Rein, A Summers, MF TI Characterization of a high-affinity nucleocapsid protein binding site within the Moloney murine leukemia virus RNA packaging signal SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 UMBC, Howard Hughes Med Inst, Baltimore, MD USA. NCI, Frederick Canc Res & Dev Ctr, HIV Drug Resistance Program, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 216 BP 120 EP 121 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100217 ER PT J AU Legler, PM Cai, M Clore, GM AF Legler, PM Cai, M Clore, GM TI Solution structure of the IIBmannitol transporter of the E.coli phosphotransferase system SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 NIH, Chem Phys Lab, Bethesda, MD 20892 USA. RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 NR 0 TC 0 Z9 0 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 251 BP 132 EP 132 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100252 ER PT J AU Kennedy, RG Hong, MK Kovaleski, BJ Datta, SA Rein, A Kleiman, L Musier-Forsyth, K AF Kennedy, RG Hong, MK Kovaleski, BJ Datta, SA Rein, A Kleiman, L Musier-Forsyth, K TI The role of Lysyl-tRNA synthetase in tRNA primer packaging SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 Univ Minnesota, Dept Chem, Minneapolis, MN 55455 USA. NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. Sir Mortimer B Davis Jewish Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada. McGill Univ, Jewish Gen Hosp, McGill AIDS Ctr, Montreal, PQ H3T 1E2, Canada. NR 0 TC 0 Z9 0 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 259 BP 135 EP 135 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100260 ER PT J AU Hwang, K Lee, H Maeng, J Gruschus, J Mack, J Ju, J Saunders, X Bardon, F Nirenberg, M Ferretti, J AF Hwang, K Lee, H Maeng, J Gruschus, J Mack, J Ju, J Saunders, X Bardon, F Nirenberg, M Ferretti, J TI Amide exchange properties and lifetimes of the wild type and Y54M vnd/NK-2 homeodomain bound to two consensus DNA sequences SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 NIH, Bethesda, MD 20892 USA. Howard Univ, Washington, DC 20059 USA. Georgetown Univ, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 347 BP 163 EP 163 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100348 ER PT J AU Schmeisser, H Kontsek, P Schreiber, G Zoon, KC AF Schmeisser, H Kontsek, P Schreiber, G Zoon, KC TI Differences in interactions between interferon alpha 2 a,b,c subvariants and receptor subunit IFNAR2-EC SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 NCI, Metab Branch, CCR, Bethesda, MD 20892 USA. SAS, Inst Neuroimmunol, Bratislava, Slovakia. Weizmann Inst Sci, IL-76100 Rehovot, Israel. RI Schreiber, Gideon/C-7332-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 413 BP 186 EP 186 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100414 ER PT J AU Ghosh, A Shieh, J Pan, C Chou, JY AF Ghosh, A Shieh, J Pan, C Chou, JY TI A potential new role of glucose-6-phosphatase in brain glucose homeostasis SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 NICHHD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 428 BP 191 EP 191 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100429 ER PT J AU Che, Y Brooks, BR Marshall, GR AF Che, Y Brooks, BR Marshall, GR TI Towards novel therapeutics against HIV infection and drug resistances SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 NHLBI, NIH, Bethesda, MD 20892 USA. Washington Univ, Dept Biochem & Mol Biophys, St Louis, MO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 433 BP 192 EP 193 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100434 ER PT J AU Heymann, B Iwasaki, K Chang, N Belnap, DM Yim, YT Greene, LE Eisenberg, E Steven, AC AF Heymann, B Iwasaki, K Chang, N Belnap, DM Yim, YT Greene, LE Eisenberg, E Steven, AC TI Cryo-electron microscopy of clathrin baskets with C58J, a chimera of a J-domain and the C-terminal domain of AP180, and with and without the uncoating ATPase, Hsc70 SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 CALTECH, Pasadena, CA 91125 USA. RIKEN Harima Inst, Membrane Dynam Res Grp, Mikazuki, Hyogo, Japan. NIAMS, Lsbr, NIH, Bethesda, MD USA. NHLBI, Lcb, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 460 BP 202 EP 202 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100461 ER PT J AU Feng, H Takei, J Lipsitz, R Tjandra, N Bai, Y AF Feng, H Takei, J Lipsitz, R Tjandra, N Bai, Y TI The high-resolution structure of a protein intermediate state: Implications for protein folding SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 518 BP 219 EP 220 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100519 ER PT J AU Vu, NT Feng, H Bai, Y AF Vu, NT Feng, H Bai, Y TI The folding pathway of barnase: The rate-limiting transition state and a hidden intermediate under native conditions SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 519 BP 220 EP 220 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100520 ER PT J AU Mohanty, S Zubkov, S Gronenborn, A AF Mohanty, S Zubkov, S Gronenborn, A TI Structural characterization of the Antheraea polyphemus pheromone binding protein in acidic pH SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 SUNY Stony Brook, Stony Brook, NY 11794 USA. NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NR 2 TC 1 Z9 1 U1 0 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 562 BP 234 EP 235 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100563 ER PT J AU Kim, S Jacobson, KA AF Kim, S Jacobson, KA TI The design of a neoceptor and neoligand applied to the human A(2A) adenosine receptor SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 18th Symposium of the Protein-Society CY AUG 14-18, 2004 CL San Diego, CA SP Protein Soc, Abbott Lab Fund, Amer Peptide Soc, Amgen, Biogen Idec, DARPA, Eli Lilly & Co, Eli Lilly Res Labs, Biotechnol Discovery Res, Genencor Int, Genentech Inc, Merck Res Labs, Natl Sci Fdn, NIH, New England BioLabs, Novartis Inst Biomed Res, Pfizer Inc, Protein Soc Educ Comm, Protein Soc Young Protein Sci Comm, Roche Pharmaceut, Sunesis Pharmaceut Inc C1 NIDDK, Mol Recognit Sect, NIH, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 SU 1 MA 572 BP 237 EP 238 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 866TL UT WOS:000224796100573 ER PT J AU Gruschus, JM Greene, LE Eisenberg, E Ferretti, JA AF Gruschus, JM Greene, LE Eisenberg, E Ferretti, JA TI Experimentally biased model structure of the Hsc70/auxilin complex: Substrate transfer and interdomain structural change SO PROTEIN SCIENCE LA English DT Article DE protein-protein docking; molecular modeling; DELPHI; solvation enthalpy and free energy; DnaJ DnaK; cyclin G-associated kinase GAK; distance-dependent dielectric; nucleotide binding; X-ray ID MOLECULAR CHAPERONE DNAK; SHOCK COGNATE PROTEIN; ESCHERICHIA-COLI DNAJ; INDUCED CONFORMATIONAL-CHANGE; CLATHRIN-COATED VESICLES; J-DOMAIN; ATP HYDROLYSIS; CRYSTAL-STRUCTURE; ACTIVE-SITE; HSC70 AB A model structure of the Hsc70/auxilin complex has been constructed to gain insight into interprotein substrate transfer and ATP hydrolysis induced conformational changes in the multidomain Hsc70 structure. The Hsc70/auxilin system, which is a member of the Hsp70/Hsp40 chaperone system family, uncoats clathrin-coated vesicles in an ATP hydrolysis-driven process. Incorporating previous results from NMR and mutant binding studies, the auxilin J-domain was docked into the Hsc70 ATPase domain lower cleft using rigid backbone/flexible side chain molecular dynamics, and the Hsc70 substrate binding domain was docked by a similar procedure. For comparison, J-domain and substrate binding domain docking sites were obtained by the rigid-body docking programs DOT and MOCK, filtered and ranked by the program ClusPro, and relaxed using the same rigid backbone/flexible side chain dynamics. The substrate binding domain sites were assessed in terms of conserved surface complementarity and feasibility in the context of substrate transfer, both for auxilin and another Hsp40 protein, Hsc20. This assessment favors placement of the substrate binding domain near D152 on the ATPase domain surface adjacent to the J-domain invariant HPD segment, with the Hsc70 interdomain linker in the lower cleft. Examining Hsc70 interdomain energetics, we propose that long-range electrostatic interactions, perhaps due to a difference in the pKa values of bound ATP and ADP, could play a major role in the structural change induced by ATP hydrolysis. Interdomain electrostatic interactions also appear to play a role in stimulation of ATPase activity due to J-domain binding and substrate binding by Hsc70. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gruschus, JM (reprint author), NHLBI, Biophys Chem Lab, NIH, 50 S Dr,MSC-8013, Bethesda, MD 20892 USA. EM gruschus@helix.nih.gov NR 54 TC 15 Z9 15 U1 1 U2 5 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2004 VL 13 IS 8 BP 2029 EP 2044 DI 10.1110/ps.03390504 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 841KN UT WOS:000222928800007 PM 15273304 ER PT J AU Petricoin, EF Fishman, DA Conrads, TP Veenstra, TD Liotta, LA AF Petricoin, EF Fishman, DA Conrads, TP Veenstra, TD Liotta, LA TI Lessons from Kitty Hawk: From feasibility to routine clinical use for the field of proteomic pattern diagnostics SO PROTEOMICS LA English DT Article DE cancer; diagnostics; mass spectrometry; patterns ID MASS-SPECTROMETRY; OVARIAN-CANCER; SERUM; IDENTIFICATION; MARKERS AB Proteomic pattern diagnostics is a rapidly evolving field of science. Despite the increasingly large number of laboratories reporting exciting success with this concept, recent speculation concerning reproducibility and the nature and identities of the information content of the pattern constituents have served to defocus and polarize the community. These controversies will be rendered obsolete as the field accelerates into a new realm of clinical diagnostics. This new era will see the currently dry biomarker pipeline flooded with new candidate molecules, and the mass spectrometer will continue its maturation into a dominant clinical platform. We reflect on the important lessons gleaned from the Wright brothers' attempts at controlled heavier-than-air flight as a model for perseverance and a view to the very near future for proteomic pattern diagnostics. C1 NCI, FDA, Clin Proteom Program, Off Cell & Gene Therapies,CBER, Bethesda, MD 20892 USA. Northwestern Univ, Natl Ovarian Canc Early Detect Program, Chicago, IL 60611 USA. SAIC Frederick Inc, Lab Proteom & Analyt Technol, NCI, Biomed Proteom Program, Frederick, MD USA. NCI, FDA, Clin Proteom Program, Lab Pathol,Ctr Canc Res,NIH, Bethesda, MD USA. RP Petricoin, EF (reprint author), NCI, FDA, Clin Proteom Program, Off Cell & Gene Therapies,CBER, Bldg 29A,Room 2D12,8800 Rockville Pike, Bethesda, MD 20892 USA. EM petricoin@cber.fda.gov NR 24 TC 26 Z9 27 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1615-9853 J9 PROTEOMICS JI Proteomics PD AUG PY 2004 VL 4 IS 8 BP 2357 EP 2360 DI 10.1002/pmic.200400865 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 844DK UT WOS:000223137300018 PM 15274129 ER PT J AU Hasler, G Pine, DS Gamma, A Milos, G Ajdacic, V Eich, D Rossler, W Angst, J AF Hasler, G Pine, DS Gamma, A Milos, G Ajdacic, V Eich, D Rossler, W Angst, J TI The associations between psychopathology and being overweight: a 20-year prospective study SO PSYCHOLOGICAL MEDICINE LA English DT Article ID BODY-MASS INDEX; BINGE-EATING DISORDER; UNITED-STATES; WEIGHT CHANGE; OBESE ADOLESCENTS; MENTAL-DISORDERS; YOUNG ADULTHOOD; ZURICH COHORT; DEPRESSION; POPULATION AB Background. Psychiatric disorders and being overweight are major health problems with increasing prevalence. The purpose of this study was to test the hypothesis that being overweight is associated with a range of psychiatric conditions including minor and atypical depressive disorders, binge eating, and aggression. Method. Prospective community-based cohort study of young adults (n = 591) followed between ages 19 and 40. Information derived from six subsequent semi-structured diagnostic interviews conducted by professionals over twenty years. Outcomes were being overweight [body-mass index (BMI) > 25] and average yearly weight change between ages 20 and 40 (BMI slope). Results. 18.9% of the participants were classified as being overweight. Being overweight turned out to be a stable trait: 77.7% of subjects were assigned to the same weight class at each interview. Atypical depression and binge eating were positively associated with both, increased weight gain and being overweight, while psychiatric conditions associated with aggressive behaviors (aggressive personality traits, sociopathy) were positively associated with being overweight, but were not related to the rate of weight change. Generalized anxiety disorder was negatively associated with overweight. These results persisted after controlling for substance use, levels of physical activity, demographic variables and family history of weight problems. Conclusions. This study shows relatively strong associations between eating-related and aggressive psychopathology and being overweight. Given the high prevalence rates of these conditions, this study encourages further research on the causality of psychopathology-overweight associations that might provide insight on novel preventive approaches for major health problems. C1 NIMH, NIH, Mood & Anxiety Disorders Program, Intramural Res Program, Bethesda, MD 20892 USA. Psychiat Univ Hosp, Zurich, Switzerland. Univ Zurich, Dept Psychiat, Eating Disorders Unit, Zurich, Switzerland. RP Hasler, G (reprint author), NIMH, NIH, Mood & Anxiety Disorders Program, Intramural Res Program, 15K North Dr,Room 300C,MSC 2670, Bethesda, MD 20892 USA. EM g.hasler@bluewin.ch RI Hasler, Gregor/E-4845-2012; OI Hasler, Gregor/0000-0002-8311-0138; Ajdacic-Gross, Vladeta/0000-0002-7032-9237 NR 71 TC 110 Z9 111 U1 3 U2 11 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 0033-2917 J9 PSYCHOL MED JI Psychol. Med. PD AUG PY 2004 VL 34 IS 6 BP 1047 EP 1057 DI 10.1017/S0033291703001697 PG 11 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 857GL UT WOS:000224104300009 PM 15554575 ER PT J AU Stout, JC Busemeyer, JR Lin, AL Grant, SJ Bonson, KR AF Stout, JC Busemeyer, JR Lin, AL Grant, SJ Bonson, KR TI Cognitive modeling analysis of decision-making processes in cocaine abusers SO PSYCHONOMIC BULLETIN & REVIEW LA English DT Article ID FUTURE CONSEQUENCES; PREFRONTAL CORTEX; HEROIN-ADDICTS; INSENSITIVITY; PERFORMANCE; DEFICITS; DAMAGE; TIME; TASK AB This article examines the theoretical basis of decision-making deficits exhibited by cocaine abusers in a laboratory decision-making task first described by Bechara, Damasio, Damasio, and Anderson (1994). A total of 12 male cocaine abusers and 14 comparison subjects performed the task, and the cocaine group performed significantly worse than the comparison group. A cognitive modeling analysis (Busemeyer & Stout, 2002) was used to estimate three parameters that measure importance of the cognitive, motivational, and response processes for determining the observed performance deficit. The results of this analysis indicated, for the first time, that motivational and choice consistency factors, but not learning/memory were mainly responsible for the decision-making deficit of the cocaine abusers in this task. C1 Indiana Univ, Dept Psychol, Bloomington, IN 47405 USA. Natl Inst Drug Abuse, Bethesda, MD USA. RP Stout, JC (reprint author), Indiana Univ, Dept Psychol, 1101 E 10th St, Bloomington, IN 47405 USA. EM jcstout@indiana.edu FU NIDA NIH HHS [DA-R01 014119] NR 19 TC 90 Z9 94 U1 3 U2 8 PU PSYCHONOMIC SOC INC PI AUSTIN PA 1710 FORTVIEW RD, AUSTIN, TX 78704 USA SN 1069-9384 J9 PSYCHON B REV JI Psychon. Bull. Rev. PD AUG PY 2004 VL 11 IS 4 BP 742 EP 747 DI 10.3758/BF03196629 PG 6 WC Psychology, Mathematical; Psychology, Experimental SC Psychology GA 870AZ UT WOS:000225027700015 PM 15581127 ER PT J AU Quinlan, MG Sharf, R Lee, DY Wise, RA Ranaldi, R AF Quinlan, MG Sharf, R Lee, DY Wise, RA Ranaldi, R TI Blockade of substantia nigra dopamine D1 receptors reduces intravenous cocaine reward in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE cocaine; reward; substantia nigra; SCH 23390 ID VENTRAL TEGMENTAL AREA; NUCLEUS-ACCUMBENS; GLUTAMATE RECEPTORS; CAUDATE-PUTAMEN; REINFORCEMENT; NEURONS; AMYGDALA; LOCALIZATION; FLUPENTIXOL; ANTAGONIST AB Rationale. We have recently found that blockade of dopamine D1-type receptors in the ventral tegmental area reduces the rewarding effects of intravenous cocaine; here, we explored the possibility that blockade of D1 receptors in the adjacent substantia nigra (SN)-not usually considered part of reward circuitry-might have similar effects. Objective. To test the hypothesis that blockade of dopamine D1 receptors in the SN reduces the rewarding effects of cocaine. Methods. Twenty one rats were prepared with intravenous catheters and with bilateral guide cannulae implanted such that injections could be made directly into the SN or just dorsal to the SN. The rats were trained to self-administer intravenous cocaine (1.0 mg/kg per injection) on a fixed-ratio 1 (FR1) schedule of reinforcement. After stable responding developed, 13 of the animals were tested following pretreatment with bilateral microinjections of SCH 23390 at doses of 0, 1, 2 or 4 mug/0.5 mul into the SN and 8 were tested with injections of 0 mug or 4 mug/0.5 mul into a site 2 mm dorsal to the SN site. Results. Microinjections of SCH 23390 in the SN significantly increased rates of cocaine self-administration, while injections dorsal to SN had no significant effect on responding. Conclusions. These data suggest that blockade of dendritically released DA in the SN reduces the rewarding effects of cocaine. These findings complement accumulating evidence that the rewarding effects of cocaine are not restricted to the drug's ability to elevate dopamine levels in the nucleus accumbens. C1 CUNY Queens Coll, Dept Psychol, Flushing, NY 11367 USA. NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,US Dept HHS, Baltimore, MD USA. RP Ranaldi, R (reprint author), CUNY Queens Coll, Dept Psychol, 65-30 Kissena Blvd, Flushing, NY 11367 USA. EM rranaldi@qc1.qc.edu RI Wise, Roy/A-6465-2012 FU NIDA NIH HHS [DA01720] NR 43 TC 14 Z9 14 U1 3 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD AUG PY 2004 VL 175 IS 1 BP 53 EP 59 DI 10.1007/s00213-003-1771-9 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 846DY UT WOS:000223296500007 PM 14767633 ER PT J AU Stefanski, R Justinova, Z Hayashi, T Takebayashi, M Goldberg, SR Su, TP AF Stefanski, R Justinova, Z Hayashi, T Takebayashi, M Goldberg, SR Su, TP TI Sigma(1) receptor upregulation after chronic methamphetamine self-administration in rats: a study with yoked controls SO PSYCHOPHARMACOLOGY LA English DT Article DE sigma; receptor; methamphetamine; drug self-administration; yoked control; midbrain; D; autoreceptor ID CONDITIONED PLACE PREFERENCE; DOPAMINE NEURONS; BINDING-SITES; COCAINE ADDICTION; INVOLVEMENT; DYNAMICS; BRAIN; NEUROADAPTATIONS; SENSITIZATION; CORTEX AB Rationale. Sigma(1) receptors (Sig-1R) are implicated in behavioral sensitization, conditioned place preference, and cellular restructuring induced by psychostimulants. We previously reported that rats which actively self-administered methamphetamine for 5 weeks and were then withdrawn from methamphetamine for 24 h showed downregulation of dopamine D-2 autoreceptors (approximately 30%) in the midbrain and this was not seen in rats that passively received injections of methamphetamine or saline at the same time (yoked controls). Involvement of Sig-1R in the self-administration of psychostimulants, however, has never been reported. Objectives. This study examined neuroadaptive changes in Sig-1R in the brains of rats self-administering methamphetamine. Methods. Three groups of rats were tested simultaneously 5 days per week, for 5 weeks (25 daily sessions). Two groups served as yoked controls and passively received an injection of either 0.1 mg/kg methamphetamine or saline (not contingent on responding) each time a response-contingent injection of 0.1 mg/kg methamphetamine was actively self-administered by the first group of rats. Protein and mRNA levels of Sig-1R were then measured by Western and Northern blottings, respectively. Results. There was a marked upregulation of Sig-1R proteins (50%) in the midbrain and altered levels of Sig-1R mRNA in the frontal cortex and hippocampus of rats that learned to actively self-administer methamphetamine, but not in yoked methamphetamine- or saline-control rats. Conclusions. Neuroadaptive increases in Sig-1R seen in this study may contribute to the reinforcing effects of methamphetamine. This upregulation of Sig-1R may be mediated by increased protein kinase A activity due to downregulation of dopamine D-2 autoreceptors. C1 NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, IRP,NIH,DHHS, Baltimore, MD 21224 USA. NIDA, Cellular Pathobiol Unit DDPS, Cellular Neurobiol Res Branch, IRP,NIH,DHHS, Baltimore, MD 21224 USA. Inst Psychiat & Neurol, Dept Pharmacol, PL-02957 Warsaw, Poland. Natl Hosp Org Kure Med Ctr, Inst Clin Res, Lab Psychooncol, Kure 7370023, Japan. RP Goldberg, SR (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, IRP,NIH,DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM sgoldber@intra.nida.nih.gov RI Hayashi, Teruo/A-9690-2008; Justinova, Zuzana/A-9109-2011 OI Justinova, Zuzana/0000-0001-5793-7484 NR 30 TC 43 Z9 44 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD AUG PY 2004 VL 175 IS 1 BP 68 EP 75 DI 10.1007/s00213-004-1779-9 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 846DY UT WOS:000223296500009 PM 15029471 ER PT J AU Neumeister, A Young, T Stastny, J AF Neumeister, A Young, T Stastny, J TI Implications of genetic research on the rolle of the serotonin in depression: emphasis on the serotonin type 1(A) receptor and the serotonin transporter SO PSYCHOPHARMACOLOGY LA English DT Review DE depression; 5-HT; pathophysiology; genes; serotonin type 1(A) receptor; serotonin transporter; pharmacogenetics; pharmacogenomics ID POSITRON-EMISSION-TOMOGRAPHY; ACUTE TRYPTOPHAN DEPLETION; TRIDIMENSIONAL PERSONALITY QUESTIONNAIRE; VIOLENT SUICIDAL-BEHAVIOR; ONSET ALZHEIMERS-DISEASE; ANXIETY-RELATED TRAITS; HUMAN 5-HT1A RECEPTOR; MAJOR DEPRESSION; PROMOTER POLYMORPHISM; KNOCKOUT MICE AB Serotonin systems appear to play a key role in the pathophysiology of major depressive disorder. Consequently, ongoing research determines whether serotonin related genes account for the very robust differential behavioral and neural mechanisms that discriminate patients with depression from healthy controls. Serotonin type 1(A) receptors and the serotonin transporters are reduced in depression, and recent genetic research in animals and humans has implicated both in depression. Preclinical studies have utilized a variety of animal models that have been used to explain pathophysiological mechanisms in humans, although it is not clear at all whether these models constitute relevant models for depression in humans. However, data from preclinical studies can generate hypotheses that are tested in humans by combining genetic data with behavioral and physiological challenge paradigms and neuroimaging. These studies will enhance our understanding about combined influences from multiple interacting genes, as well as from environmental factors on brain circuits and their function, and about how these mechanisms may contribute to the pathophysiology of neuropsychiatric disorders. C1 Yale Univ, Sch Med, Dept Psychiat, VA Natl Ctr PTSD 116A,Clin Neurosci Div, West Haven, CT 06516 USA. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Univ Vienna, Dept Gen Psychiat, Vienna, Austria. RP Neumeister, A (reprint author), Yale Univ, Sch Med, Dept Psychiat, VA Natl Ctr PTSD 116A,Clin Neurosci Div, 950 Campbell Ave, West Haven, CT 06516 USA. EM Alexander.Neumeister@yale.edu NR 144 TC 59 Z9 62 U1 3 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD AUG PY 2004 VL 174 IS 4 BP 512 EP 524 DI 10.1007/s00213-004-1950-3 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 848NM UT WOS:000223474400008 PM 15249991 ER PT J AU Heinz, A Goldman, D Gallinat, J Schumann, G Puls, L AF Heinz, A Goldman, D Gallinat, J Schumann, G Puls, L TI Pharmacogenetic insights to monoaminergic dysfunction in alcohol dependence SO PSYCHOPHARMACOLOGY LA English DT Review DE SPECT; beta-CIT; genetic constitution; alcoholism; withdrawal; depression ID DOPAMINE TRANSPORTER GENE; CORTICAL PYRAMIDAL NEURONS; RECEPTOR-BINDING CHARACTERISTICS; METHYLTRANSFERASE COMT GENE; SEROTONIN TRANSPORTER; CEREBROSPINAL-FLUID; RHESUS-MONKEYS; IN-VIVO; 5-HYDROXYINDOLEACETIC ACID; ALLELIC ASSOCIATION AB Rationale: Alcohol dependence is characterized by the development of tolerance, withdrawal symptoms, and craving for alcohol. Chronic alcohol consumption causes neuroadaptive changes in the central dopaminergic and serotonergic system, which are partially reversible after detoxification. The severity and time-course of recovery of these neuroadaptive changes may depend on the genetic constitution of monoamine transporters and receptors and contribute to the relapse risk of alcoholics. Objectives: To assess the interaction between the genetic constitution and the in vivo availability of dopamine and serotonin transporters and receptors, chronic alcohol intake, alcohol craving and withdrawal. Methods: Review of brain imaging studies that assess the genotype and availability of dopamine and serotonin transporters in detoxified alcoholics and healthy control subjects. Results: Chronic alcohol intake induced neuroadaptive reductions in striatal dopamine transporter (DAT) availability, which were reversible during early abstinence. A polymorphism of the DAT gene (SLC6A3) was associated with the in vivo transporter availability and with the severity of alcohol withdrawal. Neurotoxic reductions in 5-HTT protein expression were limited to homozygous carriers of the long allele in the 5-HTT gene (SCL6A4) regulatory region and correlated with negative mood states. Conclusion: Genetic constitution interacts with the in vivo availability of central dopamine and serotonin transporters during alcohol detoxification and may affect the severity of alcohol withdrawal and clinical depression. C1 Charite Univ Med Berlin, Dept Psychiat, D-10117 Berlin, Germany. NIAAA, NIH, Rockville, MD 20852 USA. Cent Inst Mental Hlth Mannheim, Dept Psychiat, Mannheim, Germany. RP Heinz, A (reprint author), Charite Univ Med Berlin, Dept Psychiat, Campus Charite Mitte,Schumannstr 20-21, D-10117 Berlin, Germany. EM andreas.heinz@charite.de RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 117 TC 40 Z9 43 U1 4 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD AUG PY 2004 VL 174 IS 4 BP 561 EP 570 DI 10.1007/s00213-004-1903-x PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 848NM UT WOS:000223474400012 PM 15148564 ER PT J AU Sharov, AA AF Sharov, AA TI Bioeconomics of managing the spread of exotic pest species with barrier zones SO RISK ANALYSIS LA English DT Article DE barrier zone; bioeconomics; biological invasion; gypsy moth; model ID GYPSY-MOTH LEPIDOPTERA; NORTH-AMERICA; LYMANTRIIDAE; MANAGEMENT; INVASIONS; MODEL; SLOW AB Exotic pests are serious threats to North American ecosystems; thus, economic analysis of decisions about eradication, stopping, or slowing their spread may be critical to ecosystem management. The proposed bioeconomic model assumes that the rate of population expansion can be reduced (even to negative values in a case of eradication) if certain management actions are taken along the population front. The area of management can be viewed as a dynamic barrier zone that moves together with the population front. The lower is the target rate of spread, the higher would be both benefits and costs of the project. The problem is to find the optimal target rate of spread at which the present value of net benefits from managing population spread reaches its maximum value. If a population spreads along an infinite habitat strip, the target rate of spread is optimal if the slope of the cost function versus the rate of spread is equal to the ratio of the average pest-related damage per unit time and unit area to the discount rate. In a more complex model where the potential area of expansion is limited, two local maxima of net benefits may exist: one for eradication and another for slowing the spread. If both maxima are present, their heights are compared and the strategy that corresponds to a higher value of net benefits is selected. The optimal strategy changes. from eradication to slowing the spread and finally to doing nothing as the area occupied by,the species increases. The model shows that slowing the spread of pest species generates economic benefits even if a relatively small area remains uninfested. The cost of slowing the spread can be estimated from a model of population expansion via establishment of isolated colonies beyond the moving front. The model is applied to managing the spread of the gypsy moth (Lymantria dispar) populations in the United States. C1 NIA, Baltimore, MD 21224 USA. RP Sharov, AA (reprint author), NIA, Baltimore, MD 21224 USA. EM Sharoval@gre.nia.nih.gov NR 45 TC 30 Z9 32 U1 1 U2 11 PU BLACKWELL PUBLISHERS PI MALDEN PA 350 MAIN STREET, STE 6, MALDEN, MA 02148 USA SN 0272-4332 J9 RISK ANAL JI Risk Anal. PD AUG PY 2004 VL 24 IS 4 BP 879 EP 892 DI 10.1111/j.0272-4332.2004.00486.x PG 14 WC Public, Environmental & Occupational Health; Mathematics, Interdisciplinary Applications; Social Sciences, Mathematical Methods SC Public, Environmental & Occupational Health; Mathematics; Mathematical Methods In Social Sciences GA 856OG UT WOS:000224053900010 PM 15357807 ER PT J AU Leon, F Roy, G AF Leon, F Roy, G TI CD7 and CD103 as markers for the clinical enumeration of small-bowel Intraepithelial lymphocytes SO SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY LA English DT Letter ID CELIAC-DISEASE; GAMMA-DELTA; INTESTINE; QUANTITATION; SUBSETS; SPRUE C1 NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. Hosp Ramon y Cajal, Serv Inmunol, ES-28034 Madrid, Spain. RP Leon, F (reprint author), NIAID, Lab Mol Immunol, NIH, Bldg 10,Room 11N214,10 Ctr Dr, Bethesda, MD 20892 USA. EM fleon@niaid.nih.gov NR 17 TC 1 Z9 1 U1 0 U2 0 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0036-5521 J9 SCAND J GASTROENTERO JI Scand. J. Gastroenterol. PD AUG PY 2004 VL 39 IS 8 BP 802 EP 802 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 846VV UT WOS:000223348200022 PM 15513373 ER PT J AU Ohida, T Osaki, Y Doi, Y Tanihata, T Minowa, M Suzuki, K Wada, K Suzuki, K Kaneita, Y AF Ohida, T Osaki, Y Doi, Y Tanihata, T Minowa, M Suzuki, K Wada, K Suzuki, K Kaneita, Y TI An epidemiologic study of self-reported sleep problems among Japanese adolescents SO SLEEP LA English DT Article DE sleep problems; adolescents; lifestyle; Japan; epidemiology ID HIGH-SCHOOL-STUDENTS; CIGARETTE-SMOKING; PSYCHIATRIC-DISORDERS; CHINESE ADOLESCENTS; GENERAL-POPULATION; LIFE-STYLE; POOR SLEEP; INSOMNIA; JUNIOR; DISTURBANCE AB Study Objective: To examine the prevalence and correlates of sleep problems in Japanese adolescents. Design and Setting: The survey was designed as a cross-sectional sampling. The targets of the survey were junior and senior high schools throughout Japan. Sample schools were selected by stratified cluster sampling. Self-reported anonymous questionnaires were sent to sample schools for all students to fill out. Participants: A total of 107,907 adolescents responded, and 106,297 questionnaires were subjected to analysis. Measurements and Results: The overall prevalences of sleep problems in the month preceding the questionnaire were difficulty initiating sleep (boys: 15.3%, girls: 16.0%); nocturnal sleep duration less than 6 hours (boys: 28.7%, girls: 32.6%); excessive daytime sleepiness (boys: 33.3%, girls: 39.2%), and subjectively insufficient sleep (boys: 38.1%, girls: 39.0%). Multiple logistic regression analysis showed that female sex, being a senior high-school student, and having an unhealthy lifestyle (psychological stress, smoking, and drinking alcohol) were risk factors for sleep problems. Conclusion: Self-reported sleep problems in Japanese adolescents were common and were associated with multiple factors. There is a need for health education directed at solving sleep problems in Japanese adolescents. C1 Nihon Univ, Sch Med, Dept Publ Hlth, Itabashi Ku, Tokyo 1738610, Japan. Tottori Univ, Fac Med, Dept Social Med, Div Environm & Prevent Med, Tottori 680, Japan. NIMH, Natl Ctr Neurol & Psychiat, Bethesda, MD 20892 USA. RP Ohida, T (reprint author), Nihon Univ, Sch Med, Dept Publ Hlth, Itabashi Ku, 30-1 Oyaguchikamimachi, Tokyo 1738610, Japan. EM tohida@niph.go.jp NR 35 TC 73 Z9 76 U1 2 U2 9 PU AMER ACADEMY SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CENTER STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PD AUG 1 PY 2004 VL 27 IS 5 BP 978 EP 985 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 848EX UT WOS:000223451400022 PM 15453558 ER PT J AU Tornwall, ME Virtamo, J Korhonen, PA Virtanen, MJ Albanes, D Huttunen, JK AF Tornwall, ME Virtamo, J Korhonen, PA Virtanen, MJ Albanes, D Huttunen, JK TI Postintervention effect of alpha tocopherol and beta carotene on different strokes - A 6-year follow-up of the Alpha Tocopherol, Beta Carotene Cancer Prevention Study SO STROKE LA English DT Article DE stroke; primary prevention; randomized controlled trials; antioxidants ID VITAMIN-E; CARDIOVASCULAR-DISEASE; HOSPITAL DISCHARGE; CONTROLLED-TRIAL; SUPPLEMENTATION; RISK; AGGREGATION; MECHANISM; HUMANS; HEALTH AB Background and Purpose - In the Alpha Tocopherol, Beta Carotene Cancer Prevention Study, alpha tocopherol supplementation decreased risk of cerebral infarction by 14% (95% CI, - 25% to - 1%), and beta carotene increased risk of intracerebral hemorrhage by 62% ( 95% CI, 10% to 132%). We report here the 6-year postintervention effects of alpha tocopherol and beta carotene supplementation on stroke and its subtypes. Methods - A total of 29 133 male smokers, aged 50 to 69 years, were randomized to receive 50 mg of alpha tocopherol, 20 mg of beta carotene, both, or placebo daily for 5 to 8 years. At the beginning of the post-trial follow-up, 24 382 men were still at risk for first-ever stroke. During the post-trial follow-up, 1327 men experienced a stroke: 1087 cerebral infarctions, 148 intracerebral hemorrhages, 64 subarachnoid hemorrhages, and 28 unspecified strokes. Results - Post-trial risk for cerebral infarction was elevated among those who had received alpha tocopherol compared with those who had not ( relative risk [RR], 1.13; 95% CI, 1.00 to 1.27), whereas beta carotene had no effect ( RR, 0.97; 95% CI, 0.86 to 1.09). Alpha tocopherol supplementation was associated with a postintervention RR of 1.01 ( 95% CI, 0.73 to 1.39) for intracerebral hemorrhage and 1.38 ( 95% CI, 0.84 to 2.26) for subarachnoid hemorrhage. The corresponding RRs associated with beta carotene supplementation were 1.38 ( 95% CI, 0.99 to 1.91) and 1.09 ( 95% CI, 0.67 to 1.77), respectively. Conclusions - Neither alpha tocopherol nor beta carotene supplementation had any postintervention preventive effects on stroke. The post-trial increase in cerebral infarction risk among recipients of alpha tocopherol may present a rebound of the reduced risk of cerebral infarction during the intervention. C1 Natl Inst Publ Hlth, Dept Epidemiol & Hlth Promot, Helsinki 00300, Finland. NCI, Bethesda, MD 20892 USA. RP Tornwall, ME (reprint author), Natl Inst Publ Hlth, Dept Epidemiol & Hlth Promot, Mannerheimintie 166, Helsinki 00300, Finland. EM markareetta.tornwall@ktl.fi RI Albanes, Demetrius/B-9749-2015 FU CCR NIH HHS [N01-RC-45035]; NCI NIH HHS [N01-CN-45165] NR 21 TC 13 Z9 14 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD AUG PY 2004 VL 35 IS 8 BP 1908 EP 1913 DI 10.1161/01.STR.0000131750.60270.42 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 840CZ UT WOS:000222835900030 PM 15205487 ER PT J AU Goldstein, LB Samsa, GP Matchar, DB Horner, RD AF Goldstein, LB Samsa, GP Matchar, DB Horner, RD TI Charlson Index comorbidity adjustment for ischemic stroke outcome studies SO STROKE LA English DT Article DE stroke; outcome; morbidity; mortality; outcome assessment ID CANADIAN NEUROLOGICAL SCALE; RETROSPECTIVE ASSESSMENT; SEVERITY; ACCURACY; CLASSIFICATION; PREDICTORS; VALIDATION; ICD-9-CM; RECOVERY; MODEL AB Background and Purpose-The Charlson Index is commonly used in outcome studies to adjust for patient comorbid conditions, but has not been specifically validated for use in studies of ischemic stroke. The purpose of the present study was to determine whether outcomes of ischemic stroke patients varied on the basis of the Charlson Index. Methods-The Department of Veterans Affairs (VA) Stroke Study prospectively identified stroke patients admitted to 9 VA hospitals between April 1995 and March 1997. The Charlson Index was scored on the basis of discharge International Classification of Diseases, 9th Revision, Clinical Modification coding and dichotomized (low comorbidity 0 or 1 versus high greater than or equal to2) for analysis. Validity was assessed on the basis of modified Rankin score at hospital discharge ( good outcome 0 or 1 versus poor greater than or equal to2 or dead) and 1-year mortality, adjusting for initial stroke severity. Results-Of the 960 enrolled ischemic stroke patients, 23% had a Charlson Index of 0, 34% 1, 22% 2, 12% 3, and 8% greater than or equal to4. Forty-eight percent of those with a low Charlson Index had a good outcome at discharge versus 37% of those with a high Charlson Index (P < 0.001). For 1-year mortality, the proportions were 16% versus 26%, respectively (P < 0.001). Logistic regression adjusting for initial stroke severity showed that those with a high Charlson Index had 36% increased odds of having a poor outcome at discharge (P = 0.038) and 72% greater odds of death at 1 year (P = 0.001). Every 1-point increase in Charlson Index was independently associated with a 15% increase in the odds of a poor outcome at discharge (P < 0.005) and a 29% increase in the odds of death by 1 year (P < 0.001). Conclusions-These data support the validity of the Charlson Index as a measure of comorbidity for use in ischemic stroke outcome studies. C1 Duke Univ, Med Ctr, Ctr Clin Hlth Policy Res, Stroke Policy Program, Durham, NC 27710 USA. Duke Univ, Dept Gen Internal Med, Durham, NC 27710 USA. Duke Univ, Dept Med Neurol, Durham, NC 27710 USA. Duke Univ, Ctr Cerebrovasc Dis, Durham, NC 27710 USA. Durham VA Med Ctr, Durham, NC USA. NINDS, Off Minor Hlth & Res, Bethesda, MD USA. RP Goldstein, LB (reprint author), Duke Univ, Med Ctr, Ctr Clin Hlth Policy Res, Stroke Policy Program, Box 3651, Durham, NC 27710 USA. EM golds004@mc.duke.edu OI Matchar, David/0000-0003-3020-2108 FU NINDS NIH HHS [K24 NS02165] NR 17 TC 208 Z9 213 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD AUG PY 2004 VL 35 IS 8 BP 1941 EP 1945 DI 10.1161/01.STR.0000135225.80898.1c PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 840CZ UT WOS:000222835900036 PM 15232123 ER PT J AU Schou, M Halldin, C Sovago, J Pike, VW Hall, H Gulyas, B Mozley, PD Dobson, D Shchukin, E Innis, RB Farde, L AF Schou, M Halldin, C Sovago, J Pike, VW Hall, H Gulyas, B Mozley, PD Dobson, D Shchukin, E Innis, RB Farde, L TI PET evaluation of novel radiofluorinated reboxetine analogs as norepinephrine transporter probes in the monkey brain SO SYNAPSE LA English DT Article DE norepinephrine transporter; PET; monkey; reboxetine; FMeNER; FMeNER-D-2 ID H-3 NISOXETINE; UPTAKE SITES; AUTORADIOGRAPHY; RADIOLIGAND; BINDING; DEPRESSION; RECEPTORS AB (SS)-2-(alpha-(2-Fluoromethoxyphenoxy)benzyl)morpholine ((SS)-FMeNER) was found to be a selective high-affinity ligand for the norepinephrine transporter (NET). ((S,S)-FMeNER) was labeled with fluorine-18 (t(1/2) = 109.8 min) by O-fluoromethylation of desfluoromethoxy-(S,S)-FMeNER with [F-18]bromofluoromethane. An analog, di-deuterated in the fluoromethoxy group ((SS)-FMeNER-D-2), was similarly labeled with di-deutero-[F-18]bromofluoromethane. These two new radioligands were obtained in radiochemical purities greater than 98% and with specific radioactivities ranging from 111-185 GBq/mumol at the end of synthesis (75 min). After intravenous injection of (SS)-[F-18]FMeNER into cynomolgus monkey, PET examination with the head in the field of view revealed skull-bound radioactivity, contaminating images of the brain, and indicated fast defluorination of the radioligand. Defluorination was much reduced in similar PET experiments with (SS)[F-18] FMeNER-D-2. Ratios of radioactivity in the lower brainstem, mesencephalon, thalamus, and temporal cortex to striatum obtained with (SS)-[F-18]FMeNER-D-2 at 160 min after i.v. injection were 1.5, 1.6, 1.3, and 1.5, respectively. In another PET experiment, pretreatment of the monkey with the selective NET inhibitor, desipramine, decreased the radioactivity ratios in all examined regions to near unity (e.g., to a ratio of 1.03 in mesencephalon). Labeled metabolites of (S,S)-[F-18]FMeNER-D-2 or (S,S)-[F-18]FMeNER found in plasma were all more polar than the parent radioligand. In vitro autoradiography of(SS)-[F-18]FMeNER-D-2 on post-mortem human brain cryosections furthermore showed specific binding to NET in the locus coeruleus and thalamus. (SS)-[F-18]FMeNER-D-2 is the first useful radiofluorinated ligand for imaging brain NET in monkey in vivo and is superior to (SS)-[C-11]MeNER because a specific binding peak equilibrium is obtained during the PET experiment at a lower noise level. (C) 2004 Wiley-Liss, Inc. C1 Karolinska Hosp, Karolinska Inst, Dept Clin Neurosci, Psychiat Sect, S-17176 Stockholm, Sweden. NIMH, Mol Imaging Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. Eli Lilly & Co, Indianapolis, IN 46285 USA. RP Halldin, C (reprint author), Karolinska Hosp, Karolinska Inst, Dept Clin Neurosci, Psychiat Sect, S-17176 Stockholm, Sweden. EM christer.halidin@ks.se RI Sovago, Judit/G-7961-2011; Gulyas, Balazs/F-9508-2015 NR 20 TC 79 Z9 80 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 AUG PY 2004 VL 53 IS 2 BP 57 EP 67 DI 10.1002/syn.20031 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 834SF UT WOS:000222430300001 PM 15170818 ER PT J AU Takebayashi, M Hayashi, T Su, TP AF Takebayashi, M Hayashi, T Su, TP TI sigma-1 receptors potentiate epidermal growth factor signaling towards neuritogenesis in PC12 cells: Potential relation to lipid raft reconstitution SO SYNAPSE LA English DT Article DE EGF; NGF; neurite; ERK; raft; lipid raft; microdomain; cholesterol; sphingolipid; ganglioside; sigma receptor; sigma-1 ID LONG-TERM POTENTIATION; BINDING-SITES; NEURONAL DIFFERENTIATION; TYROSINE KINASE; EGF RECEPTOR; CHOLESTEROL; ACTIVATION; OVEREXPRESSION; MICRODOMAINS; GANGLIOSIDE AB We previously demonstrated that overexpression of sigma-1 receptors (sigma-1R) potentiated neurite sprouting caused by nerve growth factor in PC 12 cells (Takebayashi et al. [2002] J Pharmacol Exp Ther 202:1227-1237). In this study we examined if sigma-1R may be involved in the action of epidermal growth factor (EGF). EGF is conventionally recognized as a mitogenic factor that stimulates only the proliferation of various types of cells, including PC12 cells. We found here that in sigma-1 receptor-overexpressing PC12 cells (sigma-1R OE cells), EGF markedly stimulates neuritogenesis without affecting cellular proliferation. EGF receptors (EGFR) are largely reduced in lipid rafts and are enriched in non-raft regions in sigma-1R OE cells. The enrichment of EGFR in the non-raft region is correlated with enhanced downstream signaling of EGFR including the phosphorylation of both EGFR and extracellular signal-regulated kinases (ERKs). Destruction of cholesterol-containing rafts by treating cells with methyl-beta-cyclodextrin also causes a reduction of EGFR in lipid rafts, a concomitant increase in the phosphorylation of both EGFR and ERK, and an increase in the EGF-induced neurite sprouting in wildtype cells. Furthermore, while overexpression of sigma-1R increases the level of lipid raft-associated cholesterol, the overexpression alters the levels of gangliosides in lipid rafts: GM1 and GM2 are decreased, whereas GD1a is increased. We conclude that sigma-1R cause the remodeling of lipid rafts, at least by increasing the level of lipid raft-associated cholesterol and by altering the levels of certain critical lipid raft-forming gangliosides. sigma-1R may thus play an important role in directing EGF signaling towards neuritogenesis, perhaps by shifting EGFR from the lipid raft into non-raft regions. Published 2004 Wiley-Liss, Inc. C1 NIDA, IRP, NIH, Cellular Pathobiol Unit,Dev & Plast Sect,Cellular, Baltimore, MD 21224 USA. RP Su, TP (reprint author), NIDA, IRP, NIH, Cellular Pathobiol Unit,Dev & Plast Sect,Cellular, Triad Bldg,5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM TSU@intra.mda.mh.gov RI Hayashi, Teruo/A-9690-2008 NR 46 TC 57 Z9 60 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 AUG PY 2004 VL 53 IS 2 BP 90 EP 103 DI 10.1002/syn.20041 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 834SF UT WOS:000222430300004 PM 15170821 ER PT J AU Di Marco, MP Chen, J Wainer, IW Ducharme, MP AF Di Marco, MP Chen, J Wainer, IW Ducharme, MP TI A population pharmacokinetic-metabolism model for individualizing ciprofloxacin therapy in ophthalmology SO THERAPEUTIC DRUG MONITORING LA English DT Article DE ciprofloxacin; eye infections; pharmacokinetic-metabolism; population modeling (PK-MB); CYP 1A2 ID IMPAIRED RENAL-FUNCTION; PSEUDOMONAS KERATITIS; TOPICAL CIPROFLOXACIN; URINARY METABOLITES; AQUEOUS-HUMOR; CAFFEINE; FLUOROQUINOLONES; PENETRATION; RABBITS; CYP1A2 AB The purpose of this study was to construct a population pharmacokinetic (PK) metabolism (MB) model to describe ciprofloxacin (C) concentrations in plasma and vitreous and aqueous humors in 26 patients. Ciprofloxacin was given as a 3-day oral prophylactic treatment to 26 patients before vitrectomy. Plasma, vitreous and aqueous humor samples were collected from patients at different times on the day of surgery. Patients were phenotyped for CYP 1A2 activity using caffeine. Ciprofloxacin and caffeine concentrations were determined using validated HPLC assays. All concentrations of ciprofloxacin were simultaneously modeled using a four-compartment PK-MB model. Creatinine clearance and CYP1A2 activity were modeled as surrogate markers of renal and hepatic clearances, respectively. Population PK was performed with IT2S(R), and simulations were performed with ADAPT-II(R). No eye infections were observed in any of the patients enrolled in the study, and there were only minimal effects on vitreous and aqueous concentrations after ocular drops were added to the oral treatments. The model that best described the concentrations of ciprofloxacin in serum and in aqueous and vitreous humor was a four-compartment PK linear model. Simulated AUCs of ciprofloxacin mean concentrations in the aqueous and vitreous humors were 17 +/- 9 and 10 +/- 8% of the systemic AUC, respectively. The terminal elimination half-life of the compound was (mean +/- SD) 5.0 +/- 2.8 hours. The apparent volume of distribution (V-ss/F) was calculated to be 122.1 +/- 39.7 L. This PK-MB model may be very useful in optimizing treatments of various eye infections with ciprofloxacin. The results of this study suggest that giving ciprofloxacin orally for 2 days preceding surgery may prevent endophthalmitis from occurring, consequently abrogating the need for administering antibiotics via intraocular injections. C1 Univ Montreal, Fac Pharm, Montreal, PQ H3C 3J7, Canada. McGill Univ, Dept Ophthalmol, Montreal, PQ H3A 2T5, Canada. NIA, Gerontol Res Ctr, NIH, Baltimore, MD USA. MDS Pharma Serv, Montreal, PQ H4R 2N6, Canada. RP Ducharme, MP (reprint author), MDS Pharma Serv, Montreal, PQ H4R 2N6, Canada. EM Murray.Ducharme@MDSPS.com NR 29 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0163-4356 J9 THER DRUG MONIT JI Ther. Drug Monit. PD AUG PY 2004 VL 26 IS 4 BP 401 EP 407 DI 10.1097/00007691-200408000-00010 PG 7 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 845EN UT WOS:000223219300010 PM 15257070 ER PT J AU Pujols, L Xaubet, A Ramirez, J Mullol, J Roca-Ferrer, J Torrego, A Cidlowski, JA Picado, C AF Pujols, L Xaubet, A Ramirez, J Mullol, J Roca-Ferrer, J Torrego, A Cidlowski, JA Picado, C TI Expression of glucocorticoid receptors alpha and beta in steroid sensitive and steroid insensitive interstitial lung diseases SO THORAX LA English DT Article ID IDIOPATHIC PULMONARY-FIBROSIS; ALVEOLAR MACROPHAGES; ORGANIZING PNEUMONIA; CELLS; ISOFORM; SARCOIDOSIS; PATHOGENESIS; THERAPY; ASTHMA AB Background: Sensitivity to glucocorticoids may be related to the concentration of glucocorticoid receptors alpha (GRalpha) and beta (GRbeta). A study was undertaken to assess GRalpha and GRbeta expression in steroid insensitive interstitial lung disease ( idiopathic pulmonary fibrosis (IPF)) and steroid sensitive interstitial lung diseases ( sarcoidosis and cryptogenic organising pneumonia ( COP)). Methods: Lung tissue was obtained from control subjects and from patients with IPF, sarcoidosis, and COP. Pulmonary function tests were carried out at the time of lung biopsy and every 3 months. GRalpha and GRbeta expression was evaluated by both competitive RT-PCR and immunohistochemistry. Data are presented as median and 25 - 75th percentile. Results: GRalpha mRNA expression (10(5) cDNA copies/mug total RNA) was higher in patients with steroid sensitive interstitial lung diseases ( 10.0; 7.8 - 14.9; n = 11) than in patients with IPF (4.4; 3.2 - 6.6; n = 19; p< 0.001). GRβ expression was at least 1000 times lower than that of GRα and did not differ between the three groups. A negative correlation was found between GRa mRNA levels and the fibrotic pathology score of the tissue ( r = -0.484, p< 0.01) and a positive correlation was found between GRalpha mRNA levels and improvement in forced vital capacity ( r = 0.633; p< 0.01) after treatment of patients with glucocorticoids. Immunoreactivity for GR protein was also higher in patients with sarcoidosis and COP than in those with IPF. Conclusion: The variable response of some interstitial lung diseases to steroid treatment may be the result of differences in the expression of GRα. C1 Inst Invest Biomed August Pi & Sunyer, Barcelona, Spain. Univ Barcelona, Dept Med, Hosp Clin,Inst Clin Pneumol & Cirurgia Torac, Serv Pneumol & Allergia Resp, Barcelona, Spain. Hosp Clin Barcelona, Serv Anat Patol, Barcelona, Spain. Hosp Clin Barcelona, Serv Otorinolaringol, Barcelona, Spain. NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Picado, C (reprint author), Hosp Clin Barcelona, ICPCT, Serv Pneumol, Villarroel 170, Barcelona 08036, Spain. EM cpicado@ub.edu RI Pujols, Laura/G-8920-2015 OI Pujols, Laura/0000-0003-3708-5098 NR 32 TC 30 Z9 42 U1 1 U2 3 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 J9 THORAX JI Thorax PD AUG PY 2004 VL 59 IS 8 BP 687 EP 693 DI 10.1136/thx.2003.013268 PG 7 WC Respiratory System SC Respiratory System GA 841UD UT WOS:000222956200013 PM 15282390 ER PT J AU Angelov, N Moutsopoulos, N Jeong, MJ Nares, S Ashcroft, G Wahl, SM AF Angelov, N Moutsopoulos, N Jeong, MJ Nares, S Ashcroft, G Wahl, SM TI Aberrant mucosal wound repair in the absence of secretory leukocyte protease inhibitor SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE wound healing; oral; mucosa; cutaneous; inflammation; SLPI ID GROWTH-FACTOR-BETA; INFLAMMATORY RESPONSE; EXTRACELLULAR-MATRIX; GENE-EXPRESSION; AGED HUMANS; IN-VITRO; ELASTASE; FIBROBLASTS; FETAL; MODEL AB Secretory leukocyte protease inhibitor (SLPI) is a cationic serine protease inhibitor with anti-microbial and anti-inflammatory properties found in large quantities in mucosal fluids, including saliva. SLPI is expressed during cutaneous wound healing, however, its role in oral wound repair is unknown. We have used a novel approach involving a murine buccal mucosal acute wound model to investigate the role of SLPI in oral healing. In parallel to the observed cutaneous healing phenotype, an absence of SLPI results in markedly impaired oral wound healing associated with increased inflammation and raised elastase activity. Moreover, matrix deposition was decreased, while MMP activity was enhanced in the oral SLPI null wounds suggesting deregulated proteolysis. Intriguingly, regardless of genotype, reduced collagen deposition was observed in oral compared to dermal wounds, associated with reduced TGF-beta expression and decreased fibroblast collagen expression in vitro. We propose that SLPI is a pivotal endogenous factor necessary for optimal tissue repair including intra-oral wound healing. In addition, our model provides a unique opportunity to delineate the cellular and molecular mechanisms underlying the differences between dermal scarring and oral scar-free healing. C1 Natl Inst Dent & Craniofacial Res, Oral Infect & Immunn Branch, NIH, Bethesda, MD 20892 USA. RP Wahl, SM (reprint author), Natl Inst Dent & Craniofacial Res, Oral Infect & Immunn Branch, NIH, Bldg 30,30 Convent Dr,MSC 4352, Bethesda, MD 20892 USA. EM smwahl@dir.nidcr.nih.gov NR 50 TC 43 Z9 46 U1 1 U2 2 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD AUG PY 2004 VL 92 IS 2 BP 288 EP 297 DI 10.1160/TH03-07-0446 PG 10 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 847VT UT WOS:000223426700010 PM 15269824 ER PT J AU Smith, MV Nyska, A Portier, C AF Smith, MV Nyska, A Portier, C TI Application of a statistical dynamic model investigating the short-term cellular kinetics induced by riddelliine, a hepatic endothelial carcinogen SO TOXICOLOGICAL SCIENCES LA English DT Article DE riddelliine; mathematical model; cellular kinetics; hemangiosarcoma ID UNSCHEDULED DNA-SYNTHESIS; S-PHASE SYNTHESIS; INVIVO TREATMENT; RAT-LIVER; HEPATOCARCINOGENESIS; PROLIFERATION; ANGIOGENESIS; HEPATOCYTES; APOPTOSIS; GROWTH AB In recent studies, riddelliine, a pyrrolizidine alkaloid, was found to increase rates of replication and apoptosis and induce hemangiosarcoma in the liver of rats and mice. To analyze DNA replication and apoptosis data taken from the same animals, we have developed a predictive mathematical model for describing BrdU labeling and apoptotic processes. The model allows the incorporation of simple diurnal patterns in cellular kinetics and is applied to data on hepatocytes and endothelial cells taken from riddelliine exposed rats. Predictions from the model were used with multivariable nonlinear regression techniques to estimate replication and apoptotic rate constants for both cell types and all treatment groups. Hypothesis tests were used with the predicted rates to separate the competing effects of riddelliine on replication and apoptosis of hepatocytes and endothelial cells as well as compare replication rates between cell types. That estimated replication rates were found to be significantly higher for endothelial cells supports the supposition of induction of hemangiosarcoma by riddelliine in the liver. C1 Constella Hlth Sci, Durham, NC 27713 USA. NIEHS, NIH, Res Triangle Pk, NC 27713 USA. RP Smith, MV (reprint author), Constella Hlth Sci, 2605 Meridian Pkwy, Durham, NC 27713 USA. EM msmith@constellagroup.com RI Portier, Christopher/A-3160-2010 OI Portier, Christopher/0000-0002-0954-0279 NR 18 TC 2 Z9 3 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD AUG PY 2004 VL 80 IS 2 BP 258 EP 267 DI 10.1093/toxsci/kfh157 PG 10 WC Toxicology SC Toxicology GA 836LQ UT WOS:000222557600008 PM 15129021 ER PT J AU Yamauchi, H Aminaka, Y Yoshida, K Sun, GF Pi, JB Waalkes, MP AF Yamauchi, H Aminaka, Y Yoshida, K Sun, GF Pi, JB Waalkes, MP TI Evaluation of DNA damage in patients with arsenic poisoning: urinary 8-hydroxydeoxyguanine SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE DNA damage; arsenic poisoning; 8-OHdG ID ADMINISTERED DIMETHYLARSINIC ACID; ENVIRONMENTAL TOBACCO-SMOKE; DRINKING-WATER; SKIN TUMORIGENESIS; MAIN METABOLITE; LUNG-CANCER; WEST-BENGAL; INDUCTION; TRIVALENT; CHILE AB The relationship between arsenic exposure and DNA damage in patients with acute or chronic arsenic poisoning was analyzed. Urinary 8-hydroxydeoxyguanine (8-OHdG) concentrations were measured as an indication of oxidative DNA damage. A remarkable increase in 8-OHdG in the urine was observed in 60% of 52 patients with acute arsenic poisoning from the accidental oral intake of the arsenic trioxide. This was two- to threefold higher than levels in normal healthy subjects (n = 248). There was a clear relationship between arsenic concentrations in urine after acute poisoning and elevated levels of 8-OHdG. Levels of urinary 8-OHdG returned to normal within 180 days after the acute arsenic poisoning event. In patients chronically poisoned by the consumption of well water with elevated levels of arsenate [As(V)], elevated 8-OHdG concentrations in urine were also observed. A significant correlation between the 8-OHdG levels and arsenic levels in the urine was observed in 82 patients with chronic poisoning. Thus, evidence of oxidative DNA damage occurred in acute arsenic poisoning by arsenite [As(III)] and in chronic arsenic poisoning by As(V). In chronic poisoning patients provided low-arsenic drinking water, evidence of DNA damage subsided between 9 months and 1 year after the high levels of arsenic intake were reduced. The initial level of arsenic exposure appeared to dictate the length of this recovery period. These data indicate that some aspects of chronic and acute arsenic poisoning may be reversible with the cessation of exposure. This knowledge may contribute to our understanding of the risk elevation from arsenic carcinogenesis and perhaps be used in a prospective fashion to assess individual risk. (C) 2004 Elsevier Inc. All rights reserved. C1 St Marianna Univ, Sch Med, Dept Prevent Med, Kawasaki, Kanagawa 2168511, Japan. China Med Univ, Sch Publ Hlth, Shenyang 110001, Peoples R China. NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27709 USA. RP Yamauchi, H (reprint author), St Marianna Univ, Sch Med, Dept Prevent Med, 2-16-1 Sugano, Kawasaki, Kanagawa 2168511, Japan. EM h2yama@marianna-ti.ac.jp NR 33 TC 74 Z9 88 U1 4 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 AUG 1 PY 2004 VL 198 IS 3 BP 291 EP 296 DI 10.1016/j.taap.2003.10.021 PG 6 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 844GR UT WOS:000223146600006 PM 15276408 ER PT J AU Sakurai, T Ochiai, M Kojima, C Ohta, T Sakurai, MH Takada, NO Qu, W Waalkes, MP Fujiwara, K AF Sakurai, T Ochiai, M Kojima, C Ohta, T Sakurai, MH Takada, NO Qu, W Waalkes, MP Fujiwara, K TI Role of glutathione in dimethylarsinic acid-induced apoptosis SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Review DE dimethylarsinic acid; glutathione; apoptosis; caspase; arsenic ID HAMSTER OVARY CELLS; MALE F344 RATS; IN-VITRO; REDUCED GLUTATHIONE; ARSENIC COMPOUNDS; SODIUM ARSENITE; HUMAN URINE; LIVER; METHYLATION; EXPOSURE AB Inorganic arsenicals are clearly toxicants and carcinogens in humans. In mammals, including humans, inorganic arsenicals often undergo methylation, forming compounds such as dimethylarsinic acid (DMAsV). Recent evidence indicates that DMAsV is a complete carcinogen in rodents although evidence for inorganic arsenicals as carcinogens in rodents remains equivocal. Thus, we studied the molecular mechanisms of in vitro cytolethality of DMAsV using a rat liver epithelial cell line (TRL 1215). DMAsV selectively induced apoptosis in TRL 1215 cells; its LC50 value after 48 h exposure was 4.5 mM. The addition of a glutathione synthase inhibitor, L-buthionine-[S,R]-sulfoximine (BSO), actually decreased DMAsV-induced apoptosis. DMAsV exposure temporarily decreased cellular reduced glutathione (GSH) levels and enhanced cellular glutathione S-transferase (GST) activity from 6 h after the exposure when the cells were still alive. Also, DMAsV exposure activated cellular caspase 3 activity with a peak at 18 h after the exposure when apoptosis began, and BSO treatment completely inhibited this enzyme activity. The additions of inhibitors of caspase 3, caspase 8, and caspase 9 significantly reduced DMAsV-induced apoptosis. Taken together, these data indicate that cellular GSH was required for DMAsV-induced apoptosis to occur, and activation of cellular caspases after conjugation of DMAsV with cellular GSH appears to be of mechanistic significance. Further research will be required to determine the role of intracellular GSH and methylation in the toxicity of arsenicals in chronic arsenic poisoning or in cases where arsenicals are used as chemotherapeutics. (C) 2004 Published by Elsevier Inc. C1 Tokyo Univ Pharm & Life Sci, Environm Chem Lab, Sch Life Sci, Hachioji, Tokyo 1920392, Japan. Azabu Univ, Dept Environm Hlth, Lab Environm Hyg, Sagamihara, Kanagawa 2298501, Japan. NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. RP Sakurai, T (reprint author), Tokyo Univ Pharm & Life Sci, Environm Chem Lab, Sch Life Sci, Horinouchi 1432-1, Hachioji, Tokyo 1920392, Japan. EM sakurai@ls.toyaku.ac.jp NR 43 TC 18 Z9 19 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD AUG 1 PY 2004 VL 198 IS 3 BP 354 EP 365 DI 10.1016/j.taap.2003.10.015 PG 12 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 844GR UT WOS:000223146600013 PM 15276415 ER PT J AU Waalkes, MP Liu, J Ward, JM Diwan, BA AF Waalkes, MP Liu, J Ward, JM Diwan, BA TI Animal models for arsenic carcinogenesis: inorganic arsenic is a transplacental carcinogen in mice SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE inorganic arsenic; carcinogenesis; animal models; transplacental exposure ID MALE F344 RATS; DIMETHYLARSINIC ACID; TRANSGENIC MICE; DRINKING-WATER; CHRONIC STIMULATION; GENETIC TOXICOLOGY; INTERNAL CANCERS; SKIN NEOPLASIA; GROWTH-FACTORS; ADULT MICE AB Inorganic arsenic is a known human carcinogen causing tumors of the skin, urinary bladder, lung, liver, kidney, and possibly other organs. However, the animal models for inorganic arsenic carcinogenesis have been limited and development has been problematic. Gestation is often a period of high sensitivity to carcinogenesis so we investigated inorganic arsenite as a transplacental carcinogen in mice. Pregnant C3H mice were exposed to sodium arsenite (0, 42.5, and 85 ppm as arsenic) in the drinking water for a brief period during gestation (from Gestation day 8 to 18), with no further arsenic exposure or other treatments. The offsprings were monitored up to 90 weeks. Transplacental inorganic arsenic exposure produced a dose-dependent induction of tumors in the liver, adrenal, lung, and ovary in the offsprings after they had reached adulthood. This included hepatocellular carcinoma (HCC), a tumor associated with arsenic exposure in humans. These tumors Occurred when mice became adults in the absence of any other treatments and well after arsenic exposure had ended. Genomic analysis of liver tumors and tumor-surrounding tissues revealed several patterns of aberrant gene expression associated with transplacental arsenic carcinogenesis. This animal model demonstrated that inorganic arsenic could act as a "complete" transplacental carcinogen in mice. In addition, other important animal models for inorganic arsenic as a skin tumor co-promoter or as a co-carcinogen are discussed. The development of these animal models should advance our understanding of the mechanisms of inorganic arsenic carcinogenesis. (C) 2004 Elsevier Inc. All rights reserved. C1 NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, Natl Canc Inst, Res Triangle Pk, NC 27709 USA. NCI, Vet & Tumor Pathol Sect, Basic Res Lab, Frederick, MD 21702 USA. NCI, SAIC, Basic Res Program, Frederick, MD 21702 USA. RP Waalkes, MP (reprint author), NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, Natl Canc Inst, 111 Alexander Dr,POB 12233,MD F0-09, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov FU NCI NIH HHS [N01-CO-12400] NR 54 TC 65 Z9 69 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 AUG 1 PY 2004 VL 198 IS 3 BP 377 EP 384 DI 10.1016/j.taap.2003.10.028 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 844GR UT WOS:000223146600015 PM 15276417 ER PT J AU Patterson, R Vega, L Trouba, K Bortner, C Germolec, D AF Patterson, R Vega, L Trouba, K Bortner, C Germolec, D TI Arsenic-induced alterations in the contact hypersensitivity response in Balb/c mice SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE arsenic; contact hypersensitivity; local lymph node assay; flow cytometry ID NECROSIS-FACTOR-ALPHA; LYMPH-NODE ASSAY; ALVEOLAR MACROPHAGE FUNCTION; LANGERHANS CELL-MIGRATION; FEMALE B6C3F1 MICE; GALLIUM-ARSENIDE; ICCVAM EVALUATION; HUMAN KERATINOCYTES; MURINE MACROPHAGES; GROWTH-FACTORS AB Previous studies in our laboratory indicate that arsenic alters secretion of growth promoting and inflammatory cytokines in the skin that can regulate the migration and maturation of Langerhans cells (LC) during allergic contact dermatitis. Therefore, we hypothesized that arsenic may modulate hypersensitivity responses to cutaneous sensitizing agents by altering cytokine production, LC migration, and T-cell proliferation. To investigate this hypothesis, we examined the induction and elicitation phases of dermal sensitization. Mice exposed to 50 mg/l arsenic in the drinking water for 4 weeks demonstrated a reduction in lymph node cell (LNC) proliferation and ear swelling following sensitization with 2,4-dinitrofluorobenzene (DNFB), compared to control mice. LC and T-cell populations in the draining lymph nodes of DNFB-sensitized mice were evaluated by fluorescence-activated cell sorting; activated LC were reduced in cervical lymph nodes, suggesting that LC migration may be altered following arsenic exposure. Lymphocytes from arsenic-treated animals sensitized with fluorescein isothiocyanate (FITC) exhibited reduced proliferative responses following T-cell mitogen stimulation in vitro; however, lymphocyte proliferation from nonsensitized, arsenic-treated mice was comparable to controls. Arsenic exposure also reduced the number of thioglycollate-induced peritoneal macrophages and circulating neutrophils. These studies demonstrate that repeated, prolonged exposure to nontoxic concentrations of sodium arsenite alters immune cell populations and results in functional changes in immune responses, specifically attenuation of contact hypersensitivity. (C) 2004 Published by Elsevier Inc. C1 NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. CINVESTAV, Natl Polytech Inst, Mexico City 07360, DF, Mexico. RP Germolec, D (reprint author), NIEHS, Environm Immunol Lab, 111 TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM germolec@niehs.nih.gov RI Vega, Libia/C-3391-2013 OI Vega, Libia/0000-0002-4993-5267 NR 73 TC 37 Z9 38 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 AUG 1 PY 2004 VL 198 IS 3 BP 434 EP 443 DI 10.1016/j.taap.2003.10.012 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 844GR UT WOS:000223146600022 PM 15276424 ER PT J AU Conry-Cantilena, C Klein, HG AF Conry-Cantilena, C Klein, HG TI Training physicians in the discipline of transfusion medicine-2004 SO TRANSFUSION LA English DT Editorial Material ID GRADUATE MEDICAL-EDUCATION; STUDENTS; CHOICE; FUTURE; TRENDS C1 NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Conry-Cantilena, C (reprint author), NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bldg 10,Room 1C711, Bethesda, MD 20892 USA. EM cathyc@mail.cc.nih.gov NR 20 TC 6 Z9 8 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD AUG PY 2004 VL 44 IS 8 BP 1252 EP 1256 DI 10.1111/j.1537-2995.2004.04094.x PG 5 WC Hematology SC Hematology GA 841CU UT WOS:000222907700020 PM 15265132 ER PT J AU Finkelstein, LD Schwartzberg, PL AF Finkelstein, LD Schwartzberg, PL TI Tec kinases: shaping T-cell activation through actin SO TRENDS IN CELL BIOLOGY LA English DT Review ID ALDRICH-SYNDROME PROTEIN; BRUTONS TYROSINE KINASE; X-LINKED AGAMMAGLOBULINEMIA; FACTOR-INDUCED RECRUITMENT; APC CONTACT SITE; FAMILY KINASES; ANTIGEN RECEPTOR; CYTOSKELETAL ORGANIZATION; IMMUNOLOGICAL SYNAPSE; INTEGRIN ACTIVATION AB Following stimulation, T cells undergo marked actin-dependent changes in shape that are required for productive cellular interactions and movement during immune responses. Reorganization of the actin cytoskeletal is also necessary for the formation of an immunological synapse - the convergence of several signaling molecules at the plasma membrane that occurs after effective T-cell receptor (TCR) signaling. Much emerging evidence indicates that the Tec family of tyrosine kinases has a role in actin cytoskeleton reorganization. Specifically, T cells that lack or express mutant versions of the Tec kinase Itk show impaired TCR-induced actin polymerization, cell polarization and regulation of the signaling events involved in cytoskeletal reorganization. These data, as well as other findings, support roles for Tec kinases in actin cytoskeleton regulation. C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Schwartzberg, PL (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM pams@nhgri.nih.gov NR 73 TC 35 Z9 39 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD AUG PY 2004 VL 14 IS 8 BP 443 EP 451 DI 10.1016/j.tcb.2003.07.001 PG 9 WC Cell Biology SC Cell Biology GA 851PM UT WOS:000223697100008 PM 15308211 ER PT J AU Shah, BH Catt, KJ AF Shah, BH Catt, KJ TI Matrix metalloproteinase-dependent EGF receptor activation in hypertension and left ventricular hypertrophy SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID EPIDERMAL-GROWTH-FACTOR; ANGIOTENSIN-II; CARDIAC-HYPERTROPHY; TRANSACTIVATION; INHIBITOR; HEART AB Agonist stimulation of certain G protein-coupled receptors (GPCRs) causes shedding of heparin-binding epidermal growth factor (HB-EGF) through activation of matrix metalloproteinases (MMPs), with subsequent transactivation of the EGF receptor. MMPs are widely expressed, and their dysregulated expression is crucial in cancer, inflammation, and cardiovascular remodeling. Recent studies in hypertensive animals have shown enhanced expression and activation of MMPs and EGF receptors, and their inhibition attenuates cardiac hypertrophy, vasoconstriction and hypertension induced by GPCR agonists such as angiotensin II, endothelin-1 and phenylepherine. These findings suggest that selective inhibition of MMPs might have therapeutic potential in hypertension and other cardiovascular diseases. C1 NICHD, Sect Hormonal Regulat, ERRB, NIH, Bethesda, MD 20892 USA. RP Shah, BH (reprint author), NICHD, Sect Hormonal Regulat, ERRB, NIH, Bethesda, MD 20892 USA. EM shahb@mail.nih.gov NR 20 TC 47 Z9 52 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD AUG PY 2004 VL 15 IS 6 BP 241 EP 243 DI 10.1016/j.tem.2004.06.011 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 847SY UT WOS:000223416400001 PM 15358274 ER PT J AU Paz, R Wise, SP Vaadia, E AF Paz, R Wise, SP Vaadia, E TI Viewing and doing: similar cortical mechanisms for perceptual and motor learning SO TRENDS IN NEUROSCIENCES LA English DT Review ID PRIMARY AUDITORY-CORTEX; SUPPLEMENTARY EYE FIELD; VISUAL-CORTEX; INTERNAL-MODELS; POPULATION CODES; VISUOMOTOR TRANSFORMATIONS; FREQUENCY MAP; PLASTICITY; ORIENTATION; CONTEXT AB Historically, different groups of researchers have investigated the mechanisms of perceptual learning and motor learning. For sensory cortex, neurophysiological and psychophysical findings have linked changes in perception with altered neuronal tuning properties. However, less information has been forthcoming from motor cortex. This review compares recent findings on perceptual and motor learning, and suggests that similar mechanisms govern both. These mechanisms involve changes in both the center of neuronal tuning functions and their width or slope. The former reflects the values of the sensory or motor parameters that a neuron encodes, and the latter adjusts the encoding sensitivity. These similarities suggest that specific unifying principles for neural coding and computation exist across sensory and motor domains. C1 Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Physiol, IL-91120 Jerusalem, Israel. Hebrew Univ Jerusalem, Interdisciplinary Ctr Neural Computat, IL-91904 Jerusalem, Israel. NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. RP Paz, R (reprint author), Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Physiol, IL-91120 Jerusalem, Israel. EM ronyp@hbf.huji.ac.il RI Vaadia, Eilon/E-9347-2011 NR 65 TC 26 Z9 27 U1 2 U2 5 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD AUG PY 2004 VL 27 IS 8 BP 496 EP 503 DI 10.1016/j.tins.2004.04.013 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 847AK UT WOS:000223360800012 PM 15271498 ER PT J AU Goncalves, LF Espinoza, J Mazor, M Romero, R AF Goncalves, LF Espinoza, J Mazor, M Romero, R TI Newer imaging modalities in the prenatal diagnosis of skeletal dysplasias SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Editorial Material ID FETAL LUNG-VOLUME; CONGENITAL DIAPHRAGMATIC-HERNIA; RHIZOMELIC CHONDRODYSPLASIA PUNCTATA; ABDOMINAL CIRCUMFERENCE RATIO; HELICAL COMPUTED-TOMOGRAPHY; LETHAL PULMONARY HYPOPLASIA; 3-DIMENSIONAL ULTRASOUND; ULTRASONOGRAPHIC PREDICTION; OSTEOGENESIS IMPERFECTA; PTS2 RECEPTOR C1 NICHHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. RP Romero, R (reprint author), NICHHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. EM warfiela@mail.nih.gov NR 98 TC 10 Z9 10 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0960-7692 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD AUG PY 2004 VL 24 IS 2 BP 115 EP 120 DI 10.1002/uog.1712 PG 6 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA 846FL UT WOS:000223300900002 PM 15287046 ER PT J AU Stevens, J Nichelson, E Linehan, WM Thompson, N Liewehr, D Venzon, D Walther, MM AF Stevens, J Nichelson, E Linehan, WM Thompson, N Liewehr, D Venzon, D Walther, MM TI Risk factors for skin breakdown after renal and adrenal surgery SO UROLOGY LA English DT Article AB Objectives. To perform a retrospective review in patients undergoing urologic operations during a 10-year period. Patient positioning is important before surgery to avoid pressure sores and other iatrogenic injuries. The reported risk factors have included a long operative time, diabetes, and malignancy. We have noted skin breakdown in patients placed on stabilizing devices and in patients with germline von Hippel-Lindau (VHL) gene mutations (a gene important in angiogenesis). Methods. We performed a retrospective review in patients undergoing urologic operations during a 10-year period. Patient sex, age, blood loss, position, use of belt or Vac Pac, and diagnosis of VHL were correlated with skin breakdown. Results. During a 10-year period, 382 patients underwent primarily renal and adrenal surgery. Fifty-five patients (14.4%) developed skin breakdown after surgery. Ninety-six patients had VHL gene mutations. Patient position and operative time were both significantly related to skin breakdown (both P < 0.0001). The odds ratio for the position effect indicated that patients in the lateral position were at much greater risk than patients in the supine position (estimated odds ratio 8.1, P < 0.0001). The odds ratio for operative time confirmed that patients experiencing longer operative times were also at increased risk of skin breakdown (estimated odds ratio 3.7 for each doubling of the operative time, P < 0.0001). Patient sex, patient age, estimated blood loss, diagnosis of VHL, and use of belt or Vac Pac were not associated with an increased risk of skin breakdown. Conclusions. Patients with longer operative times were at greater risk of skin breakdown and required greater care during preoperative positioning. The other factors studied were not significantly associated with skin breakdown. (C) 2004 Elsevier Inc. C1 NCI, Urol Oncol Branch, DCS, NIH, Bethesda, MD 20892 USA. RP Walther, MM (reprint author), NCI, Urol Oncol Branch, DCS, NIH, 10 Ctr Dr,MSC 1502,Bldg 10,Room 2B-43, Bethesda, MD 20892 USA. RI Venzon, David/B-3078-2008 NR 10 TC 10 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD AUG PY 2004 VL 64 IS 2 BP 246 EP 249 DI 10.1016/j.urology.2004.03.024 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 848UH UT WOS:000223492800013 PM 15302471 ER PT J AU Linehan, WM AF Linehan, WM TI Gene expression profiling of mesoblastic nephroma and wilms tumors - Comparison and clinical implications - Editorial comment SO UROLOGY LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Bethesda, MD 20892 USA. NR 4 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 0090-4295 J9 UROLOGY JI Urology PD AUG PY 2004 VL 64 IS 2 BP 368 EP 368 DI 10.1016/j.urology.2004.04.053 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 848UH UT WOS:000223492800039 ER PT J AU Saetta, AA Papanastasiou, P Michalopoulos, NV Gigelou, F Korkolopoulou, P Bei, T Patsouris, E AF Saetta, AA Papanastasiou, P Michalopoulos, NV Gigelou, F Korkolopoulou, P Bei, T Patsouris, E TI Mutational analysis of BRAF in gallbladder carcinomas in association with K-ras and p53 mutations and microsatellite instability SO VIRCHOWS ARCHIV LA English DT Article DE B-raf; gallbladder cancer; K-ras ID CANCER; GENE; EXPRESSION; NEOPLASIA AB Background. Little is known about the genetic changes involved in the pathogenesis of gallbladder cancer. The aim of this study was to examine the presence of mutations in exon 15 of the B-raf gene to investigate its role in gallbladder carcinogenesis. Materials and methods. We examined the mutational status in exon 15 of B-raf gene in 21 gallbladder carcinoma specimens and investigated its association with the presence of K-ras and p53 alterations, microsatellite instability and the clinicopathological features of tumors. Results. B-raf mutations were observed in 7 of 21 (33%) gallbladder carcinomas examined, and all were located at the hot spot codon 599 of exon 15. K-ras and B-raf mutations were never in the same specimens. Conclusions. B-raf gene mutations seem to be a quite common event in gallbladder carcinomas, implying that B-raf may play an important role in the pathogenesis of this tumor. C1 NICHHD, NIH, Dev Endocrinol Branch, Sect Endocrinol & Genet, Bethesda, MD 20892 USA. Natl & Kapodistrian Univ Athens, Dept Pathol, Goudi 11527, Greece. RP Saetta, AA (reprint author), 10 Pirrou Str, Athens 14564, Greece. EM asaetta@med.uoa.gr NR 15 TC 35 Z9 36 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0945-6317 J9 VIRCHOWS ARCH JI Virchows Arch. PD AUG PY 2004 VL 445 IS 2 BP 179 EP 182 DI 10.1007/s00428-004-1046-9 PG 4 WC Pathology SC Pathology GA 845TL UT WOS:000223267100010 PM 15221372 ER PT J AU Jiang, JG Tang, JB Chen, CL Liu, BX Fu, XN Zhu, ZH Qu, W Cianflone, K Waalkes, MP Wang, DW AF Jiang, Jian-Gang Tang, Jiang-Bo Chen, Chun-Lian Liu, Bao-Xing Fu, Xiang-Ning Zhu, Zhi-Hui Qu, Wei Cianflone, Katherine Waalkes, Michael P. Wang, Dao-Wen TI Expression of cyclooxygenase-2 in human esophageal squamous cell carcinomas SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article AB AIM: To determine whether cyclooxygenase-2 (COX-2) was expressed in human esophageal squamous cell carcinoma. METHODS: Quantitative reverse transcription-polymerase chain reaction (RT-PCR), western blotting, immunohistochemistry and immunofluorescence were used to assess the expression level of COX-2 in esophageal tissue. RESULT: COX-2 mRNA levels were increased by > 80-fold in esophageal squamous cell carcinoma when compared to adjacent noncancerous tissue. COX-2 protein in 21 of 30 cases of esophageal squamous cell carcinoma tissues, but was undetectable in noncancerous tissue. Immunohistochemistry was performed to directly show expression of COX-2 in tumor tissue. CONCLUSION: These results suggest that COX-2 may be an important factor for esophageal cancer and inhibition of COX-2 may be helpful for prevention and possibly treatment of this cancer. Jiang JG, Tang JB, Chen CL, Liu BX, Fu XN, Zhu ZH, Qu W, Cianflone K, Waalkes MP, Wang DW. Expression of cyclooxygenase-2 in human esophageal squamous cell carcinomas. World J Gastroenterol 2004; 10(15): 2168-2173 http://www.wjgnet.com/1007-9327/10/2168.asp C1 [Jiang, Jian-Gang; Tang, Jiang-Bo; Chen, Chun-Lian; Liu, Bao-Xing; Fu, Xiang-Ning; Zhu, Zhi-Hui; Wang, Dao-Wen] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Internal Med, Wuhan 430030, Hubei Province, Peoples R China. [Qu, Wei; Waalkes, Michael P.] NIEHS, Inorgan Carcinognenesis Sect, Lab Comparat Carcinogenesis, NCI, Res Triangle Pk, NC 27709 USA. [Cianflone, Katherine] McGill Univ, Ctr Hlth, Mike Rosenbloom Lab Cardiovasc Res, Montreal, PQ H3A 1A1, Canada. [Jiang, Jian-Gang; Tang, Jiang-Bo; Chen, Chun-Lian; Liu, Bao-Xing; Fu, Xiang-Ning; Zhu, Zhi-Hui; Wang, Dao-Wen] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Gene Therapy Ctr, Wuhan 430030, Hubei Province, Peoples R China. RP Wang, DW (reprint author), Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Internal Med, Wuhan 430030, Hubei Province, Peoples R China. EM dwwang@tjh.tjmu.edu.cn NR 45 TC 10 Z9 13 U1 0 U2 2 PU BAISHIDENG PUBL GRP CO LTD PI BEIJING PA RM 903, BLDG D, OCEAN INTERNATIONAL CTR, NO 62 DONGSIHUAN ZHONGLU, BEIJING, CHAOYANG DISTRICT 100025, PEOPLES R CHINA SN 1007-9327 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD AUG 1 PY 2004 VL 10 IS 15 BP 2168 EP 2173 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA V23BE UT WOS:000208317500003 PM 15259059 ER PT J AU Ross, ED Wickner, RB AF Ross, ED Wickner, RB TI Prions of yeast fail to elicit a transcriptional response SO YEAST LA English DT Article DE prion; microarray; nitrogen regulation; Ure2p; [URE3] ID SACCHAROMYCES-CEREVISIAE; NITROGEN REGULATION; GATA FACTORS; URE3 PRION; PROPAGATION; GENE; MUTATION; SCRAPIE; PROTEIN; REGIONS AB Amyloid deposits are associated with numerous human diseases. The [URE3] prion of Saccharomyces is an infectious, inactive, amyloid form of the Ure2p protein. Despite the presence of large prion aggregates in [URE3] yeast, the only apparent phenotypes associated with the prion are attributable to loss of Ure2p function. We used cDNA microarrays to look for genes in yeast that are differentially expressed in the presence of the [URE3] prion and which might act to mitigate the detrimental effects of the prion aggregates. On comparing [URE3] vs. ure2 yeast, we were surprised to find that the only expression changes detected were attributable to the low level of residual Ure2p activity in the [URE3] cells. Interestingly, in addition to repressing the activity of genes required for utilization of poor nitrogen sources when yeast are grown in the presence of a good nitrogen source, Ure2p appears to be involved in stimulating some of these same genes in the absence of a good nitrogen source. Copyright (C) 2004 John Wiley Sons, Ltd. C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP NIDDKD, Lab Biochem & Genet, NIH, Bldg 8,Room 225,8 Ctr Dr,MSC 0830, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov OI Ross, Eric/0000-0002-6473-9977 NR 36 TC 6 Z9 6 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0749-503X EI 1097-0061 J9 YEAST JI Yeast PD AUG PY 2004 VL 21 IS 11 BP 963 EP 972 DI 10.1002/yea.1143 PG 10 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology GA 849TP UT WOS:000223564100005 PM 15334559 ER PT J AU Kass, NE Hull, SC Natowicz, MR Faden, RR Plantinga, L Gostin, LO Slutsman, J AF Kass, NE Hull, SC Natowicz, MR Faden, RR Plantinga, L Gostin, LO Slutsman, J TI Medical privacy and the disclosure of personal medical information: The beliefs and experiences of those with genetic and other clinical conditions SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE confidentiality; disclosure; family members; hereditary disease; cross sectional survey ID DISCRIMINATION; INSURANCE; AIDS; PERSPECTIVES; POLICY; ACT; LAW AB There has been heightened legislative attention to medical privacy and to protections from genetic discrimination, without large-scale studies to document privacy concerns or analysis of whether experiences differ by whether the condition is genetic (defined here as a single-gene disorder) or non-genetic. To determine whether experiences regarding privacy, disclosure, and consequences of disclosure differ by whether one's medical condition is genetic, we conducted a descriptive study with one-time, structured quantitative and qualitative interviews. We interviewed approximately 100 adults or parents of children with each of the following medical conditions: sickle cell disease, cystic fibrosis, diabetes, and HIV, and 200 adults with or at risk for breast cancer or colon cancer. The percentages of the total 597 respondents experiencing positive or negative consequences of disclosure and the degree to which experiences differed by whether the condition was genetic were the outcomes of interest. Seventy-four percent were glad and 13% regretted others knew about their condition; these findings did not differ significantly by genetic vs. non-genetic condition. Reports of job and health insurance discrimination were not uncommon for the overall study population (19 and 27%, respectively) but were more likely among those with genetic conditions (30 and 37%, respectively). Legislation and other policy-making should target the needs of persons with all conditions and not focus exclusively on genetic discrimination, given that experiences and concerns generally do not differ based on the genetic etiology of the condition. (C) 2004 Wiley-Liss, Inc. C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Phoebe R Berman Bioeth Inst, Dept Hlth Policy & Management, Baltimore, MD 21205 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Ctr Law & Publ Hlth, Baltimore, MD 21205 USA. Cleveland Clin Fdn, Dept Neurol, Cleveland, OH 44195 USA. Georgetown Univ, Washington, DC 20057 USA. Johns Hopkins Univ, Sch Med, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. NCI, Bethesda, MD 20892 USA. RP Kass, NE (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Phoebe R Berman Bioeth Inst, Dept Hlth Policy & Management, 624 N Broadway,Hampton House 344, Baltimore, MD 21205 USA. EM nkass@jhsph.edu FU Intramural NIH HHS [Z99 HG999999] NR 27 TC 18 Z9 18 U1 2 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-7299 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUL 30 PY 2004 VL 128A IS 3 BP 261 EP 270 DI 10.1002/ajmg.a.30057 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 835FV UT WOS:000222467400007 PM 15216547 ER PT J AU Howard, OMZ Turpin, JA Goldman, R Modi, WS AF Howard, OMZ Turpin, JA Goldman, R Modi, WS TI Functional redundancy of the human CCL4 and CCL4L1 chemokine genes SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID NON-ALLELIC VARIANT; HIV-1 INFECTION; ANTI-HIV-1 ACTIVITY; MIP-1-BETA; INDIVIDUALS; MIP-1-ALPHA; RESISTANCE; CORECEPTOR; LD78-BETA; BINDING AB CCL4 and CCL4L1 are two CC chemokine genes located at chromosome 17q21 whose mature proteins differ at only a single amino acid. Abundant functional information exists for CCL4, however, CCL4L1 has only recently been recognized as a distinct gene, thus information describing it is wanting. The CCL4L1 protein was synthesized in Escherichia coli and compared with the CCL4 protein. Competitive binding studies using HEK-293/CCR5 cells produced comparable EC50 values for the two proteins. Similarly, chemotaxis assays with cells expressing CCR1, CCR3, or CCR5 revealed no substantial differences. CCL4L1 was somewhat more effective at inhibiting HIV-1 replication in PBMCs than was CCL4, however the difference was not statistically significant. These data combined with the observation of individual variation in CCL4L1 gene copy number [Eur. J. Immunol. 32 (2002) 3016, Genomics 83 (2004) 735] support the contention that the CCL4 and CCL4L1 proteins have redundant functions. (C) 2004 Elsevier Inc. All rights reserved. C1 NCI, SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA. PeproTech Inc, Rocky Hill, NJ 08533 USA. Gene Log Inc, TherImmune Res, Infect Dis & Immunol Res, Gaithersburg, MD 20879 USA. NCI, Mol Immunoregulat Lab, Frederick, MD 21702 USA. RP Modi, WS (reprint author), NCI, SAIC Frederick, Ctr Adv Technol, Gaithersburg, MD 20877 USA. EM modiw@mail.nih.gov RI Howard, O M Zack/B-6117-2012 OI Howard, O M Zack/0000-0002-0505-7052 FU NCI NIH HHS [N01-CO-124000] NR 21 TC 11 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 JUL 30 PY 2004 VL 320 IS 3 BP 927 EP 931 DI 10.1016/j.bbrc.2004.06.039 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 838OR UT WOS:000222723200044 PM 15240137 ER PT J AU Jeang, KT Giam, CZ Majone, F Aboud, M AF Jeang, KT Giam, CZ Majone, F Aboud, M TI Life, death, and tax: Role of HTLV-I oncoprotein in genetic instability and cellular transformation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID VIRUS TYPE-I; NF-KAPPA-B; ONCOGENE PRODUCT TAX; DEPENDENT KINASE INHIBITORS; LONG TERMINAL REPEAT; CYCLIN D2 GENE; LEUKEMIA-VIRUS; TYPE-1 TAX; T-CELLS; RETINOBLASTOMA PROTEIN C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Microbiol, Bethesda, MD 20814 USA. Univ Padua, Dept Biol, Padua, Italy. Ben Gurion Univ Negev, Dept Microbiol, IL-84105 Beer Sheva, Israel. RP Jeang, KT (reprint author), NIAID, Mol Microbiol Lab, NIH, Bldg 4,Rm 306,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kj7e@nih.gov RI Jeang, Kuan-Teh/A-2424-2008 NR 113 TC 128 Z9 132 U1 0 U2 0 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 JUL 30 PY 2004 VL 279 IS 31 BP 31991 EP 31994 DI 10.1074/jbc.R400009200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 840HW UT WOS:000222849700001 PM 15090550 ER PT J AU Sekiya, F Poulin, B Kim, YJ Rhee, SG AF Sekiya, F Poulin, B Kim, YJ Rhee, SG TI Mechanism of tyrosine phosphorylation and activation of phospholipase C-gamma 1 - Tyrosine 783 phosphorylation is not sufficient for lipase activation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; CELL ANTIGEN RECEPTOR; PROTEIN-KINASE-C; SIGNAL-TRANSDUCTION; PHOSPHATIDYLINOSITOL 3-KINASE; EGF RECEPTOR; ARACHIDONIC-ACID; GENETIC-EVIDENCE; SH2 DOMAINS; C-GAMMA-1 AB Phospholipase C-gamma1 (PLC-gamma1) is phosphorylated on three tyrosine residues: Tyr-771, Tyr-783, and Tyr-1253. With the use of antibodies specific for each of these phosphorylation sites, we have now determined the kinetics and magnitude of phosphorylation at each site. Phosphorylation of Tyr-783, which is essential for lipase activation, was observed in all stimulated cell types examined. The extent of phosphorylation of Tyr-1253 was similar to50 to 70% of that of Tyr-783 in cells stimulated with platelet-derived growth factor ( PDGF) or epidermal growth factor (EGF), but Tyr-1253 phosphorylation was not detected in B or T cell lines stimulated through Band T-cell antigen receptors, respectively. Tyr-771 was phosphorylated only at a low level in all cells studied. In cells stimulated with PDGF, phosphorylation and dephosphorylation of Tyr-783 and of Tyr-1253 occurred with similar kinetics; the receptor kinase appeared to phosphorylate both sites, albeit with Tyr-783 favored over Tyr-1253, before the bound PLC-gamma1 was released, and phosphorylation at the two sites occurred independently. PDGF and EGF induced similar levels of phosphorylation of Tyr-783 and of Tyr-1253 in a cell line that expressed receptors for both growth factors. However, only PDGF, not EGF, elicited substantial PLC activity, suggesting that Tyr-783 phosphorylation was not sufficient for enzyme activation. Finally, concurrent production of phosphatidylinositol 3,4,5-trisphosphate was found to contribute to the activation of phosphorylated PLC-gamma1. C1 NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. Ewha Womans Univ, Ctr Cell Signaling Res, Seoul 120750, South Korea. Ewha Womans Univ, Div Mol Life Sci, Seoul 120750, South Korea. RP NHLBI, Lab Cell Signaling, NIH, Bldg 50,Rm 3523,South Dr,MSC 8015, Bethesda, MD 20892 USA. EM sgrhee@nih.gov NR 53 TC 43 Z9 44 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 30 PY 2004 VL 279 IS 31 BP 32181 EP 32190 DI 10.1074/jbc.M405116200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 840HW UT WOS:000222849700024 PM 15161916 ER PT J AU Leslie, EM Haimeur, A Waalkes, MP AF Leslie, EM Haimeur, A Waalkes, MP TI Arsenic transport by the human multidrug resistance protein 1 (MRP1/ABCC1) - Evidence that a tri-glutathione conjugate is required SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PURINE NUCLEOSIDE PHOSPHORYLASE; S-TRANSFERASE-PI; ORGANIC ANION TRANSPORT; CHARGED AMINO-ACIDS; SUBSTRATE-SPECIFICITY; MEMBRANE-VESICLES; TUMOR-CELLS; PHARMACOKINETIC MODEL; VINCRISTINE TRANSPORT; MONOCLONAL-ANTIBODIES AB Inorganic arsenic is an established human carcinogen, but its metabolism is incompletely defined. The ATP binding cassette protein, multidrug resistance protein (MRP1/ABCC1), transports conjugated organic anions (e.g. leukotriene C-4) and also co-transports certain unmodified xenobiotics ( e. g. vincristine) with glutathione (GSH). MRP1 also confers resistance to arsenic in association with GSH; however, the mechanism and the species of arsenic transported are unknown. Using membrane vesicles prepared from the MRP1-overexpressing lung cancer cell line, H69AR, we found that MRP1 transports arsenite (As-III) only in the presence of GSH but does not transport arsenate (As-V) ( with or without GSH). The non-reducing GSH analogs L-gamma-glutamyl-L-alpha-aminobutyryl glycine and S-methyl GSH did not support AsIII transport, indicating that the free thiol group of GSH is required. GSH-dependent transport of As-III was 2-fold higher at pH 6.5-7 than at a more basic pH, consistent with the formation and transport of the acid-stable arsenic triglutathione (As(GS)(3)). Immunoblot analysis of H69AR vesicles revealed the unexpected membrane association of GSH S-transferase P1-1 (GSTP1-1). Membrane vesicles from an MRP1-transfected HeLa cell line lacking membrane-associated GSTP1-1 did not transport AsIII even in the presence of GSH but did transport synthetic As(GS)(3). The addition of exogenous GSTP1-1 to HeLa-MRP1 vesicles resulted in GSH-dependent AsIII transport. The apparent K-m of As(GS)(3) for MRP1 was 0.32 muM, suggesting a remarkably high relative affinity. As(GS)(3) transport by MRP1 was osmotically sensitive and was inhibited by several conjugated organic anions ( MRP1 substrates) as well as the metalloid antimonite (K-i 2.8 muM). As(GS) 3 transport experiments using MRP1 mutants with substrate specificities differing from wild-type MRP1 suggested a commonality in the substrate binding pockets of As(GS)(3) and leukotriene C-4. Finally, human MRP2 also transported As(GS)(3). In conclusion, MRP1 transports inorganic arsenic as a tri-GSH conjugate, and GSTP1-1 may have a synergistic role in this process. C1 NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI,NIH, Res Triangle Pk, NC 27709 USA. Queens Univ, Canc Res Labs, Kingston, ON K7L 3N6, Canada. RP Waalkes, MP (reprint author), NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI,NIH, POB 12233,Mail Drop F0-09,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov NR 67 TC 150 Z9 158 U1 0 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 30 PY 2004 VL 279 IS 31 BP 32700 EP 32708 DI 10.1074/jbc.M404912200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 840HW UT WOS:000222849700089 PM 15161912 ER PT J AU Schelling, P Claus, MT Johner, R Marquez, VE Schulz, GE Scapozza, L AF Schelling, P Claus, MT Johner, R Marquez, VE Schulz, GE Scapozza, L TI Biochemical and structural characterization of (South)-methanocarbathymidine that specifically inhibits growth of herpes simplex virus type 1 thymidine kinase-transduced osteosarcoma cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SUICIDE GENE-THERAPY; HIV-1 REVERSE-TRANSCRIPTASE; IN-VIVO; QUANTITATIVE-DETERMINATION; BIOLOGICAL-ACTIVITY; NUCLEOSIDE ANALOGS; BRAIN-TUMORS; ACTIVE-SITE; GANCICLOVIR; ACYCLOVIR AB Two analogs of the natural nucleoside dT featuring a pseudosugar with fixed conformation in place of the deoxyribosyl residue ( carbathymidine analogs) were biochemically and structurally characterized for their acceptance by both human cytosolic thymidine kinase isoenzyme 1 (hTK1) and herpes simplex virus type 1 thymidine kinase (HSV1 TK) and subsequently tested in cell proliferation assays. 3'-exo-Methanocarbathymidine ((South)-methanocarbathymidine (S)-MCT), which is a substrate for HSV1 TK, specifically inhibited growth of HSV1 TK-transduced human osteosarcoma cells with an IC50 value in the range of 15 muM without significant toxicity toward both hTK1-negative (TK-) and non-transduced cells. 2'-exo-Methanocarbathymidine ((North)-methanocarbathymidine (N)-MCT), which is a weak substrate for hTK1 and a substantial one for HSV1 TK, induced a specific growth inhibition in HSV1 TK-transfected cells comparable to that of (S)-MCT and ganciclovir. A growth inhibition activity was also observed with (N)-MCT and ganciclovir in non-transduced cells in a cell line-dependent manner, whereas TK- cells were not affected. The presented 1.95-Angstrom crystal structure of the complex (S)-MCT.HSV1 TK explains both the more favorable binding affinity and catalytic turnover of (S)-MCT for HSV1 TK over the North analog. Additionally the plasticity of the active site of the enzyme is addressed by comparing the binding of (North)- and (South)- carbathymidine analogs. The presented study of these two potent candidate prodrugs for HSV1 TK gene-directed enzyme prodrug therapy suggests that (S)-MCT may be even safer to use than its North counterpart ( N)-MCT. C1 ETH, Inst Pharmaceut Sci, CH-8057 Zurich, Switzerland. Univ Freiburg, Inst Organ Chem & Biochem, D-79104 Freiburg, Germany. NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Scapozza, L (reprint author), ETH, Inst Pharmaceut Sci, Winterthurerstr 190, CH-8057 Zurich, Switzerland. EM Leonardo.Scapozza@pharma.ethz.ch NR 59 TC 26 Z9 27 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 30 PY 2004 VL 279 IS 31 BP 32832 EP 32838 DI 10.1074/jbc.M313343200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 840HW UT WOS:000222849700103 PM 15163659 ER PT J AU Boudsocq, F Kokoska, RJ Plosky, BS Vaisman, A Ling, H Kunkel, TA Yang, W Woodgate, R AF Boudsocq, F Kokoska, RJ Plosky, BS Vaisman, A Ling, H Kunkel, TA Yang, W Woodgate, R TI Investigating the role of the little finger domain of Y-family DNA polymerases in low fidelity synthesis and translesion replication SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SULFOLOBUS-SOLFATARICUS P2; SYN THYMINE DIMER; LESION-BYPASS; ERROR-PRONE; CRYSTAL-STRUCTURE; XERODERMA-PIGMENTOSUM; ADAPTIVE MUTATION; ESCHERICHIA-COLI; GENE ENCODES; ETA AB Dpo4 and Dbh are Y-family polymerases that originate from two closely related strains of Sulfolobaceae. Quite surprisingly, however, the two polymerases exhibit different enzymatic properties in vitro. For example, Dpo4 can replicate past a variety of DNA lesions, yet Dbh does so with a much lower efficiency. When replicating undamaged DNA, Dpo4 is prone to make base pair substitutions, whereas Dbh predominantly makes single-base deletions. Overall, the two proteins are 54% identical, but the greatest divergence is found in their respective little finger (LF) domains, which are only 41% identical. To investigate the role of the LF domain in the fidelity and lesion-bypassing abilities of Y-family polymerases, we have generated chimeras of Dpo4 and Dbh in which their LF domains have been interchanged. Interestingly, by replacing the LF domain of Dbh with that of Dpo4, the enzymatic properties of the chimeric enzyme are more Dpo4-like in that the enzyme is more processive, can bypass an abasic site and a thymine-thymine cyclobutane pyrimidine dimer, and predominantly makes base pair substitutions when replicating undamaged DNA. The converse is true for the Dpo4-LF-Dbh chimera, which is more Dbh-like in its processivity and ability to bypass DNA adducts and generate single-base deletion errors. Our studies indicate that the unique but variable LF domain of Y-family polymerases plays a major role in determining the enzymatic and biological properties of each individual Y-family member. C1 NICHD, Sect DNA Replicat Repair & Mutagenesis, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Woodgate, R (reprint author), NICHD, Sect DNA Replicat Repair & Mutagenesis, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. EM woodgate@nih.gov RI Ling, Hong/E-3729-2010; Yang, Wei/D-4926-2011; Vaisman, Alexandra/C-3766-2013 OI Yang, Wei/0000-0002-3591-2195; Vaisman, Alexandra/0000-0002-2521-1467 NR 35 TC 85 Z9 86 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 30 PY 2004 VL 279 IS 31 BP 32932 EP 32940 DI 10.1074/jbc.M405249200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 840HW UT WOS:000222849700113 PM 15155753 ER PT J AU Esser, L Quinn, B Li, YF Zhang, MQ Elberry, M Yu, L Yu, CA Xia, D AF Esser, L Quinn, B Li, YF Zhang, MQ Elberry, M Yu, L Yu, CA Xia, D TI Crystallographic studies of quinol oxidation site inhibitors: A modified classification of inhibitors for the cytochrome bc(1) complex SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE cytochrome bc(1); crystal structures; inhibitors; membrane protein; electron transport ID IRON-SULFUR PROTEIN; MITOCHONDRIAL RESPIRATORY-CHAIN; BOVINE HEART-MITOCHONDRIA; PROTONMOTIVE Q-CYCLE; ELECTRON-TRANSFER; C REDUCTASE; BC1 COMPLEX; SACCHAROMYCES-CEREVISIAE; RHODOBACTER-SPHAEROIDES; CRYSTAL-STRUCTURE AB Cytochrome bc(1) is an integral membrane protein complex essential for cellular respiration and photosynthesis; it couples electron transfer from quinol to cytochrome c to proton translocation across the membrane. Specific bc(1), inhibitors have not only played crucial roles in elucidating the mechanism of bc(1) function but have also provided leads for the development of novel antibiotics. Crystal structures of bovine bc(1) in complex with the specific Q(o) site inhibitors azoxystrobin, MOAS, myxothiazol, stigmatellin and 5-undecyl-6-hydroxy-4,7-dioxobenzothiazole were determined. Interactions, conformational changes and possible mechanisms of resistance, specific to each inhibitor, were defined. Residues and secondary structure elements that are capable of discriminating different classes of Q(o) site inhibitors were identified for the cytochrome b subunit. Directions in the displacement of the cd1 helix of cytochrome b subunit in response to various Q(o) site inhibitors were correlated to the binary conformational switch of the extrinsic domain of the iron-sulfur protein subunit. The new structural information, together with structures previously determined, provide a basis that, combined with biophysical and mutational data, suggest a modification to the existing classification of bc(1) inhibitors. bc(1) inhibitors are grouped into three classes: class P inhibitors bind to the Q(o) site, class N inhibitors bind to the Q(i) site and the class PN inhibitors target both sites. Class P contains two subgroups, Pm and Pf, that are distinct by their ability to induce mobile or fixed conformation of iron-sulfur protein. Published by Elsevier Ltd. C1 NCI, Cell Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. Oklahoma State Univ, Dept Biochem & Mol Biol, Stillwater, OK 74078 USA. RP Xia, D (reprint author), NCI, Cell Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. EM dixia@helix.nih.gov FU NIGMS NIH HHS [GM 30721] NR 64 TC 164 Z9 181 U1 1 U2 20 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 JUL 30 PY 2004 VL 341 IS 1 BP 281 EP 302 DI 10.1016/j.jmb.2004.05.065 PG 22 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 841JC UT WOS:000222925100023 PM 15312779 ER PT J AU Mkrtchian, V Parsegian, VA Podgornik, R Saslow, WM AF Mkrtchian, V Parsegian, VA Podgornik, R Saslow, WM TI Comment on "Universal thermal radiation drag on neutral objects" - Reply SO PHYSICAL REVIEW LETTERS LA English DT Editorial Material C1 Armenian Acad Sci, Inst Phys Res, Ashtarak 378410 2, Armenia. NIH, Lab Struct & Phys Biol, Bethesda, MD 20892 USA. Univ Ljubljana, Fac Math & Phys, SI-1000 Ljubljana, Slovenia. Texas A&M Univ, Dept Phys, College Stn, TX 77840 USA. RP Mkrtchian, V (reprint author), Armenian Acad Sci, Inst Phys Res, Ashtarak 378410 2, Armenia. RI Podgornik, Rudolf/C-6209-2008 OI Podgornik, Rudolf/0000-0002-3855-4637 NR 2 TC 4 Z9 4 U1 0 U2 0 PU AMERICAN PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 J9 PHYS REV LETT JI Phys. Rev. Lett. PD JUL 30 PY 2004 VL 93 IS 5 AR 059002 DI 10.1103/PhysRevLett.93.059002 PG 1 WC Physics, Multidisciplinary SC Physics GA 842IJ UT WOS:000222996800060 ER PT J AU Blasi, G Bertolino, A Brudaglio, F Sciota, D Altamura, M Antonucci, N Scarabino, T Weinberger, DR Nardini, M AF Blasi, G Bertolino, A Brudaglio, F Sciota, D Altamura, M Antonucci, N Scarabino, T Weinberger, DR Nardini, M TI Hippocampal neurochemical pathology in patients at first episode of affective psychosis: a proton magnetic resonance spectroscopic imaging study SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE N-acetylaspartate; hippocampus; proton magnetic resonance spectroscopic imaging ID CEREBRAL BLOOD-FLOW; N-ACETYL-ASPARTATE; SUBGENUAL PREFRONTAL CORTEX; TEMPORAL-LOBE EPILEPSY; BIPOLAR DISORDER; MAJOR DEPRESSION; IN-VIVO; MOOD DISORDERS; WHITE-MATTER; 1ST-EPISODE SCHIZOPHRENIA AB While several studies have suggested a relationship between the hippocampus and psychosis in schizophrenia, fewer studies have specifically investigated the presence of psychosis in mood disorders from a neurobiological perspective. Moreover, a limitation of these earlier studies is that the majority of them were performed in chronic patients. The present proton magnetic resonance spectroscopic imaging (H-1-MRSI) study assessed neuronal integrity (as assessed with N-acetylaspartate, NAA) in the hippocampus of patients with a first episode of mood disorders with psychotic symptoms. We studied 17 patients and 17 healthy subjects matched for age and sex. Subjects underwent H-1-MRSI, and measures of NAA, choline-containing compounds (CHO), and creatine+phosphocreatine (CRE) in 11 brain regions were obtained, i.e. hippocampus (HIPPO), dorsolateral prefrontal cortex, superior temporal gyrus, inferior frontal gyrus, occipital cortex, anterior and posterior cingulate, centrum semiovale, prefrontal white matter, thalamus and putamen. NAA/CRE ratios in HIPPO of patients were significantly lower than in controls. Sporadic and non-hypothesis-driven results were found in occipital cortex and prefrontal white matter as a main effect of diagnosis, and in superior temporal gyrus as a hemisphere by diagnosis interaction. These results would not survive a Bonferroni correction for the number of ROIs. No correlations were found with the available demographic and clinical data. Therefore, hippocampal neuronal abnormalities are present at the onset of mood disorders with psychotic symptoms. These data suggest that neuronal abnormalities in HIPPO may be associated with psychosis in mood disorders. Since these data were obtained in patients at first episode, they cannot be explained by chronicity of illness or pharmacological treatment. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 Univ Bari, Dipartimento Sci Neurol & Psichiatriche, Grp Neurosci Psichiatriche, Sez Clin Malattie Mentali, I-70124 Bari, Italy. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. IRCCS, Casa Sollievo Sofferenza, Dept Neuroradiol, San Giovanni Rotondo, Italy. RP Bertolino, A (reprint author), Univ Bari, Dipartimento Sci Neurol & Psichiatriche, Grp Neurosci Psichiatriche, Sez Clin Malattie Mentali, Piazza Giulio Cesare 9, I-70124 Bari, Italy. EM bertolia@psichiat.uniba.it NR 82 TC 46 Z9 48 U1 6 U2 8 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD JUL 30 PY 2004 VL 131 IS 2 BP 95 EP 105 DI 10.1016/j.pscychresns.2003.11.002 PG 11 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 852BK UT WOS:000223730000001 PM 15313516 ER PT J AU Kang, JH Kim, SY Lee, J Marquez, VE Lewin, NE Pearce, LV Blumberg, PM AF Kang, JH Kim, SY Lee, J Marquez, VE Lewin, NE Pearce, LV Blumberg, PM TI Macrocyclic diacylglycerol-bis-lactones as conformationally constrained analogues of diacylglycerol-lactones. Interactions with protein kinase C SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID 5-DISUBSTITUTED TETRAHYDRO-2-FURANONE TEMPLATE; PHORBOL ESTER; PK-C; BINDING MODES; DAG-LACTONES; LIGANDS; DOMAIN; DELTA AB A series of macrocyclic diacylglycerol (DAG)-bis-lactones were investigated as extreme conformationally constrained analogues of DAG-lactones in order to seek more potent protein kinase C (PKC) ligands with higher binding affinities and less lipophilicity than previous compounds. The additional constraint achieved the desired objective as exemplified by the macrocyclic DAG-bis-lactone 57, which exhibited a 6-fold higher binding affinity for PKCalpha (K-i = 6.07 nM) than the corresponding nonmacrocyclic 3-alkylidene DAG-lactone 6. A structure-activity relationship (SAR) analysis of the macrocyclic DAG-bis-lactones demonstrated a parabolic relationship between activity and lipophilicity, as well as a predilection for the Z-alkylidene isomers as the preferred ligands. Molecular docking studies revealed that macrocyclic DAG-bis-lactone 57 bound to the C1b domain of PKCalpha exclusively in the sn-1 binding mode in contrast to DAG-lactone 6, which showed both sn-1 and sn-2 binding modes. It is proposed that the high potency displayed by these macrocyclic DAG-bis-lactones results from a set of more favorable hydrogen bonding and hydrophobic interactions with PKCalpha as well as from a reduced entropy penalty due to conformational restriction. C1 Seoul Natl Univ, Coll Pharm, Res Inst Pharmaceut Sci, Seoul 151742, South Korea. NCI, Med Chem Lab, Canc Res Ctr, NIH, Frederick, MD 21701 USA. NCI, Lab Cellular Carcinogenesis & Tumor Promot, NIH, Bethesda, MD 20892 USA. RP Lee, J (reprint author), Seoul Natl Univ, Coll Pharm, Res Inst Pharmaceut Sci, Seoul 151742, South Korea. EM jeewoo@snu.ac.kr NR 22 TC 17 Z9 17 U1 0 U2 1 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 JUL 29 PY 2004 VL 47 IS 16 BP 4000 EP 4007 DI 10.1021/jm0497747 PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 840KF UT WOS:000222856800013 PM 15267238 ER PT J AU Jozwiak, K Ravichandran, S Collins, JR Wainer, IW AF Jozwiak, K Ravichandran, S Collins, JR Wainer, IW TI Interaction of noncompetitive inhibitors with an immobilized alpha 3 beta 4 nicotinic acetylcholine receptor investigated by affinity chromatography, quantitative-structure activity relationship analysis, and molecular docking SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID NONLINEAR CHROMATOGRAPHY; QUINACRINE BINDING; AUTOMATED DOCKING; OPEN-CHANNEL; LIGANDS; MODELS; PORE; DEXTROMETHORPHAN; ANTAGONISM; DIVERSITY AB A large number of drug substances act as noncompetitive inhibitors (NCIs) of the nicotinic acetylcholine receptor (nAChR) by blocking the ion flux through the channel. An affinity chromatography technique has been developed for investigating the interactions between NCIs and the alpha3beta4 subtype of neuronal nAChR. The data obtained from the chromatographic study were used to construct QSAR models of the NCI-nAChR binding with both electronic and steric parameters observed as important descriptors. A molecular model of the transmembrane domain of the alpha3beta4 subtype of nAChR was constructed and used to simulate the docking of a series of NCIs. A key aspect of the model was the discovery of the cleft produced by the incorporation of the bulky phenylalanine moiety into the nonpolar section of the lumen by the beta4 subunit. Quantitatively, the results of docking simulations modeled the experimental affinity data better than QSAR results. The computational approach, combined with the modeling of NCI-nAChR interaction by affinity chromatography, can be used to predict possible toxicities and adverse interactions. C1 NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. NCI, Adv Biomed Comp Ctr, Ft Detrick, MD 21702 USA. Med Univ Lublin, PL-20081 Lublin, Poland. RP Wainer, IW (reprint author), NIA, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM wainerir@gre.nia.nih.gov NR 62 TC 48 Z9 49 U1 1 U2 6 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 JUL 29 PY 2004 VL 47 IS 16 BP 4008 EP 4021 DI 10.1021/jm0400707 PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 840KF UT WOS:000222856800014 PM 15267239 ER PT J AU Balboni, G Salvadori, S Guerrini, R Negri, L Giannini, E Bryant, SD Jinsmaa, Y Lazarus, LH AF Balboni, G Salvadori, S Guerrini, R Negri, L Giannini, E Bryant, SD Jinsmaa, Y Lazarus, LH TI Direct influence of C-terminally substituted amino acids in the Dmt-Tic pharmacophore on delta-opioid receptor selectivity and antagonism SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HIGH-AFFINITY; ANALOGS; PEPTIDE; POTENT; MU; DELTORPHIN; DESIGN; AGONISTS; DERIVATIVES; DIPEPTIDES AB A series of 17 analogues were developed on the basis of the general formula H-Dmt-Tic-NH-*CH(R)-R' (* denotes chirality; R = charged, neutral, or aromatic functional group; R' = -OH or -NH2). These compounds were designed to test the following hypothesis: the physicochemical properties of third-residue substitutions C-terminal to Tic in the Dmt-Tic pharmacophore modify delta-opioid receptor selectivity and delta-opioid receptor antagonism through enhanced interactions with they-opioid receptor. The data substantiate the following conclusions: (i) all compounds had high receptor affinity [K-i(delta) = 0.034-1.1 nM], while that for the mu-opioid receptor fluctuated by orders of magnitude [K-i(mu) = 15.1-3966 nM]; (ii) delta-opioid receptor selectivity [K-i(mu)/Ki(delta)] declined 1000-fold from 22 600 to 21; (iii) a C-terminal carboxyl. group enhanced selectivity but only as a consequence of the specific residue; (iv) amidated, positive charged residues [Lys-NH2 (6), Arg-NH2 (7)], and a negatively charged aromatic residue [Trp-OH (11)] enhanced mu-opioid affinity [Ki(mu) = 17.0, 15.1, and 15.7 nM, respectively], while Gly-NH2 (8), Ser-NH2 (10), and His-OH (12) were nearly one-tenth as active; and M D-isomers exhibited mixed effects on mu-opioid receptor affinity (2' much less than 3' < 4' < 1' < 5') and decreased 6-selectivity in D-Asp-NH2 (1') and D-Lys(Ac)-OH (5'). The analogues exhibited delta-opioid receptor antagonism (pA(2) = 6.9-10.07) and weak mu-opioid receptor agonism (IC50 > 1 muM) except H-Dmt-Tic-Glu-NH2 (3), which was a partial delta-opioid receptor agonist (IC50 = 2.5 nM). Thus, these C-terminally extended analogues indicated that an amino acid residue containing a single charge, amino or guanidino functionality, or aromatic group substantially altered the delta-opioid receptor activity profile (selectivity and antagonism) of the Dmt-Tic pharmacophore, which suggests that the C-terminal constituent plays a major role in determining opioid receptor activity as an "address domain". C1 NIEHS, Med Chem Grp, LCBRA, Res Triangle Pk, NC 27709 USA. Univ Cagliari, Dept Toxicol, I-09126 Cagliari, Italy. Univ Ferrara, Dept Pharmaceut Sci, I-44100 Ferrara, Italy. Univ Ferrara, Ctr Biotechnol, I-44100 Ferrara, Italy. Univ Roma La Sapienza, Dept Human Physiol & Pharmacol Vittorio Erspamer, I-00185 Rome, Italy. RP Lazarus, LH (reprint author), NIEHS, Med Chem Grp, LCBRA, POB 12233, Res Triangle Pk, NC 27709 USA. EM lazarus@niehs.nih.gov OI Guerrini, Remo/0000-0002-7619-0918 NR 48 TC 15 Z9 16 U1 0 U2 0 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 JUL 29 PY 2004 VL 47 IS 16 BP 4066 EP 4071 DI 10.1021/jm040033f PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 840KF UT WOS:000222856800020 PM 15267245 ER PT J AU Ross, KE Cohen-Fix, O AF Ross, KE Cohen-Fix, O TI Molecular biology - Cohesins slip sliding away SO NATURE LA English DT Editorial Material ID SITES; CENTROMERES; BINDING; ARMS C1 NIDDKD, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ross, KE (reprint author), NIDDKD, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. EM kross@helix.nih.gov; ornacf@helix.nih.gov NR 10 TC 4 Z9 4 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 29 PY 2004 VL 430 IS 6999 BP 520 EP 521 DI 10.1038/430520b PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 841QI UT WOS:000222946100029 PM 15282594 ER PT J AU Xiong, KM Stewart, RR Hu, XQ Werby, E Peoples, RW Weight, FF Li, CY AF Xiong, KM Stewart, RR Hu, XQ Werby, E Peoples, RW Weight, FF Li, CY TI Role of extracellular histidines in agonist sensitivity of the rat P2X(4) receptor SO NEUROSCIENCE LETTERS LA English DT Article DE P2X; P2X(4) receptor; agonist affinity; channel gating; histidine ID MODULATION; ZINC; RESIDUES; BINDING; COPPER AB Relatively little information is available about the relationship between the molecular structure of each of the seven subtypes of P2X receptors and their function. Here, we investigated the possible function of three histidine residues in the extracellular loop of rat P2X(4) receptors. Mutation of histidine 241 to alanine (H241A) in the rat P2X(4) receptor decreased the EC50 value of the ATP concentration-response curve from 8.4 to 0.7 muM. In contrast, the histidine mutation H140A or H286A slightly increased the EC50 value. Maximal current responses were significantly larger in oocytes expressing rat H241A-mutated receptors compared to those expressing wildtype, H140A or H286A receptors. In addition, significantly less receptor protein was detected in H241A-expressing oocytes than in oocytes expressing wildtype, H140A or H286A receptors. Moreover, ATP-activated current in H241A-expressing cells activated faster than in wildtype receptor-expressing cells. The increased maximal current amplitude, the decrease in protein expression and the more rapid activation kinetics suggest that the H241A mutation facilitates opening of the receptor-channel (gating). (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 NIAAA, Mol & Cellular Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Li, CY (reprint author), AstraZeneca CNS Discovery, 1800 Concord Pike,A133,POB 15437, Wilmington, DE 19850 USA. EM chaoying.li@astrazeneca.com NR 16 TC 4 Z9 5 U1 1 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JUL 29 PY 2004 VL 365 IS 3 BP 195 EP 199 DI 10.1016/j.neulet.2004.04.078 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 840OT UT WOS:000222869500009 PM 15246547 ER PT J AU Chung, RT Andersen, J Volberding, P Robbins, GK Liu, T Sherman, KE Peters, MG Koziel, MJ Bhan, AK Alston, B Colquhoun, D Nevin, T Harb, G van der Horst, C AF Chung, RT Andersen, J Volberding, P Robbins, GK Liu, T Sherman, KE Peters, MG Koziel, MJ Bhan, AK Alston, B Colquhoun, D Nevin, T Harb, G van der Horst, C CA AIDS Clinical Trials Grp A5071 Stu TI Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; LIVER-DISEASE; COMBINATION THERAPY; INFECTION; REPLICATION; ANTAGONIZES; MORTALITY; EFFICACY; SAFETY; TRIAL AB BACKGROUND: Chronic hepatitis C virus (HCV) infection is a cause of major complications in persons who are also infected with the human immunodeficiency virus (HIV). However, the treatment of HCV infection in such persons has been associated with a high rate of intolerance and a low rate of response. We conducted a multicenter, randomized trial comparing peginterferon plus ribavirin with interferon plus ribavirin for the treatment of chronic hepatitis C in persons coinfected with HIV. METHODS: A total of 66 subjects were randomly assigned to receive 180 microg of peginterferon alfa-2a weekly for 48 weeks, and 67 subjects were assigned to receive 6 million IU of interferon alfa-2a three times weekly for 12 weeks followed by 3 million IU three times weekly for 36 weeks. Both groups received ribavirin according to a dose-escalation schedule. At week 24, subjects who did not have a virologic response (those who had an HCV RNA level greater than or equal to 60 IU per milliliter) underwent liver biopsy, and medications were continued in subjects with either a virologic response or histologic improvement. RESULTS: Treatment with peginterferon and ribavirin was associated with a significantly higher rate of sustained virologic response (an HCV RNA level of less than 60 IU per milliliter 24 weeks after completion of therapy) than was treatment with interferon and ribavirin (27 percent vs. 12 percent, P=0.03). In the group given peginterferon and ribavirin, only 14 percent of subjects with HCV genotype 1 infection had a sustained virologic response (7 of 51), as compared with 73 percent of subjects with an HCV genotype other than 1 (11 of 15, P<0.001). Histologic responses were observed in 35 percent of subjects with no virologic response who underwent liver biopsy. CONCLUSIONS: In persons infected with HIV, the combination of peginterferon and ribavirin is superior to the combination of interferon and ribavirin in the treatment of chronic hepatitis C. These regimens may provide clinical benefit even in the absence of virologic clearance. The marked discrepancy in the rates of sustained virologic response between HCV genotypes indicates that strategies are needed to improve the outcome in persons infected with HCV genotype 1. C1 Massachusetts Gen Hosp, Gastrointestinal Unit, GRJ 825, Boston, MA 02114 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Cincinnati, Cincinnati, OH USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NIAID, Bethesda, MD 20892 USA. Frontier Sci Technol & Res Fdn, Amherst, NY USA. Social & Sci Syst, Rockville, MD USA. Roche Labs, Nutley, NJ USA. Univ N Carolina, Chapel Hill, NC USA. RP Chung, RT (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, GRJ 825, Boston, MA 02114 USA. EM rtchung@partners.org RI Robbins, Gregory/F-7988-2011 FU NCRR NIH HHS [M01 RR000096, M01 RR000044, RR00044, RR00046, RR00096, M01 RR000046]; NIAID NIH HHS [AI046376, AI25868, AI25897, AI27659, AI27661, AI27670, AI27675, AI46370, AI50410, P30 AI027763, P30 AI050410, P30-AI27763D, U01 AI025868, U01 AI025897, U01 AI027659, U01 AI027661, U01 AI027670, U01 AI027675, U01 AI046370, U01 AI046376, U01 AI069502, UM1 AI068636] NR 15 TC 632 Z9 665 U1 0 U2 5 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 JUL 29 PY 2004 VL 351 IS 5 BP 451 EP 459 DI 10.1056/NEJMoa032653 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 841OJ UT WOS:000222939700008 PM 15282352 ER PT J AU Senchenko, VN Liu, J Loginov, W Bazov, I Angeloni, D Seryogin, Y Ermilova, V Kazubskaya, T Garkavtseva, R Zabarovska, VI Kashuba, VI Kisselev, LL Minna, JD Lerman, MI Klein, G Braga, EA Zabarovsky, ER AF Senchenko, VN Liu, J Loginov, W Bazov, I Angeloni, D Seryogin, Y Ermilova, V Kazubskaya, T Garkavtseva, R Zabarovska, VI Kashuba, VI Kisselev, LL Minna, JD Lerman, MI Klein, G Braga, EA Zabarovsky, ER TI Discovery of frequent homozygous deletions in chromosome 3p21.3 LUCA and AP20 regions in renal, lung and breast carcinomas SO ONCOGENE LA English DT Article DE breast cancer; human chromosome 3p; lung cancer; renal carcinoma; tumour suppressor genes; quantitative real-time PCR ID TUMOR-SUPPRESSOR GENE; SINGLE-NUCLEOTIDE POLYMORPHISM; HUMAN EPITHELIAL MALIGNANCIES; REAL-TIME PCR; MOLECULAR-GENETICS; CELL CARCINOMA; SHORT ARM; CANCER; 3P; HETEROZYGOSITY AB We searched for chromosome 3p homo- and hemizygous losses in 23 lung cancer cell lines, 53 renal cell and 22 breast carcinoma biopsies using 31 microsatellite markers located in frequently deleted 3p regions. In addition, two sequence-tagged site markers (NLJ-003 and NL3-001) located in the Alu-PCR clone 20 region (AP20) and lung cancer (LUCA) regions, respectively, were used for quantitative real-time PCR (QPCR). We found frequent (10-18%) homozygous deletions (HDs) in both 3p2l.3 regions in the biopsies and lung cancer cell lines. In addition, we discovered that amplification of 3p is a very common (15-42.5%) event in these cancers and probably in other epithelial malignancies. QPCR showed that aberrations of either NLJ-003 or NL3-001 were detected in more than 90% of all studied cases. HDs were frequently detected simultaneously both in NLJ-003 or NL3-001 loci in the same tumour (P < 3-10(-7)). This observation suggests that tumour suppressor genes (TSG) in these regions could have a synergistic effect. The exceptionally high frequency of chromosome aberrations in NLJ-003 and NL3-001 loci suggests that multiple TSG(s) involved in different malignancies are located very near to these markers. Precise mapping of 15 independent HDs in the LUCA region allowed us to establish the smallest HD region in 3p21.3C located between D3S1568 (CACNA2D2 gene) and D3S4604 (SEMA3F gene). This region contains 17 genes. Mapping of 19 HDs in the AP20 region resulted in the localization of the minimal region to the interval flanked by D3S1298 and D3S3623 markers. Only four genes were discovered in this interval, namely, APRG1, ITGA9, HYA22 and VILL. C1 Karolinska Inst, Ctr Microbiol & Tumor Biol, Ctr Genom & Bioinformat, S-17177 Stockholm, Sweden. Russian Acad Sci, Ctr Bioengn, Moscow 117312, Russia. Russian State Genet Ctr, Moscow 117545, Russia. Natl Canc Inst, Immunobiol Lab, Canc Causing Genes Sect, Ctr Canc Res, Frederick, MD 21702 USA. Russian Acad Med Sci, Blokhin Canc Res Ctr, Moscow 115478, Russia. Russian Acad Sci, Engelhardt Inst Mol Biol, Moscow 119991, Russia. Univ Texas, SW Med Ctr, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA. RP Zabarovsky, ER (reprint author), Karolinska Inst, Ctr Microbiol & Tumor Biol, Ctr Genom & Bioinformat, S-17177 Stockholm, Sweden. EM eugene.zabarovsky@mtc.ki.se RI Zabarovsky, Eugene/A-6645-2010; Senchenko, Vera/C-8992-2014; Braga, Eleonora/P-5574-2016 OI Senchenko, Vera/0000-0002-3119-515X; FU NCI NIH HHS [CA71618, P50CA70907, N01-CO-56000] NR 31 TC 70 Z9 86 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 JUL 29 PY 2004 VL 23 IS 34 BP 5719 EP 5728 DI 10.1038/sj.onc.1207760 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 837KW UT WOS:000222629800001 PM 15208675 ER PT J AU Summers, RM Bitter, I Petrick, N AF Summers, RM Bitter, I Petrick, N TI Virtual colonoscopy SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID COLORECTAL NEOPLASIA C1 NIH, Dept Radiol, Bethesda, MD 20892 USA. US FDA, Ctr Devices & Radiol Hlth, Rockville, MD 20857 USA. RP Summers, RM (reprint author), NIH, Dept Radiol, Bldg 10, Bethesda, MD 20892 USA. EM rms@nih.gov NR 4 TC 4 Z9 4 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 28 PY 2004 VL 292 IS 4 BP 432 EP 433 DI 10.1001/jama.292.4.432-b PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 841AA UT WOS:000222900500015 PM 15280337 ER PT J AU McDermott, MM Liu, K Greenland, P Guralnik, JM Criqui, MH Chan, CL Pearce, WH Schneider, JR Ferrucci, L Celic, L Taylor, LM Vonesh, E Martin, GJ Clark, E AF McDermott, MM Liu, K Greenland, P Guralnik, JM Criqui, MH Chan, CL Pearce, WH Schneider, JR Ferrucci, L Celic, L Taylor, LM Vonesh, E Martin, GJ Clark, E TI Functional decline in peripheral arterial disease - Associations with the ankle brachial index and leg symptoms SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CHRONIC HEART-FAILURE; 6-MINUTE WALK TEST; INTERMITTENT CLAUDICATION; CARDIOVASCULAR HEALTH; PHYSICAL-DISABILITY; TREADMILL WALKING; LOWER-EXTREMITIES; LONGITUDINAL DATA; VASCULAR-DISEASE; NATURAL COURSE AB Context Among individuals with lower-extremity peripheral arterial disease (PAD), specific leg symptoms and the ankle brachial index (ABI) are cross-sectionally related to the degree of functional impairment. However, relations between these clinical characteristics and objectively measured functional decline are unknown. Objective To define whether PAD, ABI, and specific leg symptoms predict functional decline at 2-year follow-up. Design, Setting, and Participants Prospective cohort study among 676 consecutively identified individuals (aged greater than or equal to55 years) with and without PAD (n=417 and n=259, respectively), with baseline functional assessments occurring between October 1, 1998, and January 31, 2000, and follow-up assessments scheduled 1 and 2 years thereafter. PAD was defined as ABI less than 0.90, and participants with PAD were categorized at baseline into 1 of 5 mutually exclusive symptom groups. Main Outcome Measures Mean annual changes in 6-minute walk performance and in usual-paced and fast-paced 4-m walking velocity, adjusted for age, sex, race, prior-year functioning, comorbid diseases, body mass index, pack-years of cigarette smoking, and patterns of missing data. Results Lower baseline ABI values were associated with greater mean (95% confidence interval) annual decline in 6-minute walk performance (-73.0 [-142 to -4.2] ft for ABI <0.50 vs -58.8 [-83.5 to -34.0] ft for ABI 0.50 to <0.90 vs -12.6 [-40.3 to 15.1] ft for ABI 0.90-1.50, P=.02). Compared with participants without PAD, PAD participants with leg pain on exertion and rest at baseline had greater mean annual decline in 6-minute walk performance (-111 [-173 to -50.0] ft vs -8.67 [-36.9 to 19.5] ft, P=.004), usual-pace 4-meter walking velocity (-0.06 [-0.09 to -0.02] m/sec vs -0.01 (-0.03 to 0.003] m/sec, P=.02), and fastest-pace 4-meter walking velocity (-0.07 [-0.11 to -0.031 m/sec vs -0.02 [-0.04 to -0.006] m/sec, P=.046). Compared with participants without PAD, asymptomatic PAD was associated with greater mean annual decline in 6-minute walk performance (-76.8 (-135 to -18.61 ft vs -8.67 (-36.9 to 19.51 ft, P=.04) and an increased odds ratio for becoming unable to walk for 6 minutes continuously (3.63; 95% confidence interval, 1.58-8.36; P=.002). Conclusions Baseline ABI and the nature of leg symptoms predict the degree of functional decline at 2-year follow-up. Previously reported lack of worsening in claudication symptoms over time in patients with PAD may be more related to declining functional performance to than lack of disease progression. C1 Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Dept Surg, Div Vasc Surg, Chicago, IL 60611 USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. NIA, Lab Clin Epidemiol, Bethesda, MD 20892 USA. Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. Evanston NW Hosp, Dept Surg, Div Vasc Surg, Evanston, IL USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. Catholic Hlth Partners, Dept Surg, Div Vasc Surg, Chicago, IL USA. RP McDermott, MM (reprint author), 675 N St Clair,Suite 18-200, Chicago, IL 60611 USA. EM mdm608@northwestern.edu FU NCRR NIH HHS [RR-00048]; NHLBI NIH HHS [R01-HL58099, R01-HL64739] NR 48 TC 283 Z9 296 U1 0 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 28 PY 2004 VL 292 IS 4 BP 453 EP 461 DI 10.1001/jama.292.4.453 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 841AA UT WOS:000222900500022 PM 15280343 ER PT J AU Windels, F Kiyatkin, EA AF Windels, F Kiyatkin, EA TI GABA, not glutamate, controls the activity of substantia nigra reticulata neurons in awake, unrestrained rats SO JOURNAL OF NEUROSCIENCE LA English DT Article DE substantia nigra; GABA; glutamate; bicuculline; single-unit recording; freely moving animals; iontophoresis; anesthesia; basal ganglia ID PARS-RETICULATA; BASAL GANGLIA; IN-VITRO; GLOBUS-PALLIDUS; STRIATAL STIMULATION; MEMBRANE-PROPERTIES; DOPAMINE NEURONS; MODULATION; IONTOPHORESIS; RECEPTORS AB Substantia nigra pars reticulata (SNr) receives both GABAergic and glutamatergic (GLU) inputs that are believed to act together to regulate neuronal activity in this structure. To examine the role of these inputs, single-unit recording was coupled with iontophoresis of GLU and GABA in rats under two conditions: awake, unrestrained and under chloral hydrate anesthesia. Although GABA potently inhibited SNr cells in both conditions, freely moving rats showed lower sensitivity than anesthetized animals. Likewise, GLU effectively induced excitations in most SNr neurons in anesthetized animals but was much less effective in awake, unrestrained animals in terms of both the number of sensitive cells and the magnitude of GLU-induced excitation. These findings, along with consistent excitations induced by bicuculline in awake, unrestrained rats, suggest that modulation of GABA inhibitory input, not the opposing actions of GLU and GABA, is the primary factor that regulates the activity state of SNr neurons. C1 NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Windels, F (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM fwindels@intra.nida.nih.gov RI Windels, Francois/G-5432-2010 NR 31 TC 31 Z9 32 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 28 PY 2004 VL 24 IS 30 BP 6751 EP 6754 DI 10.1523/JNEUROSCI.1528-04-2004 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 841RZ UT WOS:000222950400015 PM 15282278 ER PT J AU Read, JA Ahmed, RA Morrison, JP Coleman, WG Tanner, ME AF Read, JA Ahmed, RA Morrison, JP Coleman, WG Tanner, ME TI The mechanism of the reaction catalyzed by ADP-beta-L-glycero-D-manno-heptose 6-epimerase SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID D-MANNOHEPTOSE 6-EPIMERASE; UDP-GALACTOSE 4-EPIMERASE; NUCLEOTIDE-MODIFYING ENZYMES; ESCHERICHIA-COLI; OUTER-MEMBRANE; EPIMERIZATION; GLUCOSE; 4,6-DEHYDRATASE; INSIGHTS; BACTERIA C1 Univ British Columbia, Dept Chem, Vancouver, BC V5Z 1M9, Canada. NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Tanner, ME (reprint author), Univ British Columbia, Dept Chem, Vancouver, BC V5Z 1M9, Canada. EM mtanner@chem.ubc.ca NR 24 TC 20 Z9 20 U1 1 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUL 28 PY 2004 VL 126 IS 29 BP 8878 EP 8879 DI 10.1021/ja0485659 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 840JT UT WOS:000222855300009 PM 15264802 ER PT J AU Mueller, GA Pari, K DeRose, EF Kirby, TW London, RE AF Mueller, GA Pari, K DeRose, EF Kirby, TW London, RE TI Backbone dynamics of the RNase H domain of HIV-1 reverse transcriptase SO BIOCHEMISTRY LA English DT Article ID N-15 NMR RELAXATION; RIBONUCLEASE-H; CHEMICAL-EXCHANGE; CRYSTAL-STRUCTURE; PROTEIN DYNAMICS; ESCHERICHIA-COLI; TIME-SCALE; SPECTROSCOPY; MODEL; MACROMOLECULES AB Previous NMR relaxation studies of the isolated RNase H domain of HIV-1 reverse transcriptase at low pH have revealed that it is substantially more dynamic and less ordered than the relatively stable and catalytically active E. coli RNase HI. Using more recently developed techniques, we have investigated the dynamic behavior of the RNase H domain of HIV-1 reverse transcriptase at a more physiological pH (6.8), under a variety of solution conditions: no Mg2+, 80 mM Mg2+, and 80 mM Mg2+ plus AMP ligand. In addition, we have repeated the previous measurements on a sample containing 100 mM sodium acetate, pH 5.4. Under all conditions studied, the order parameters from NMR relaxation analysis are uniformly high (>0.8) for most of the domain with the exception of the C-terminal region. Subtle differences can be found among the conditions studied, although the statistical significance of the differences is marginal. Residues 71-114 show a slight increase in order parameter with the addition of 5'-AMP. Conformational exchange, measured with CPMG relaxation dispersion experiments in the presence of Mg and AMP, were detected for some NH sites, predominantly located in the N-terminal region of the protein near strands beta2 and beta3 and helix alpha(A) (residues 28-69). In contrast with earlier studies indicating pathologically extreme dynamic behavior that apparently correlated with inactivity of the isolated domain, the relaxation analysis under the conditions of the present study yielded parameters that are more similar to those of the active E. coli RNase HI. A comparison of the order parameters obtained from a model-free analysis of the relaxation data with the B-factors in the crystal structures of the RNase H domain, both for the isolated domain and for the full HIV-1 reverse transcriptase structure, suggests that the dynamic behavior is similar in all cases. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP London, RE (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM london@niehs.nih.gov NR 42 TC 16 Z9 16 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 27 PY 2004 VL 43 IS 29 BP 9332 EP 9342 DI 10.1021/bi049555n PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 841XG UT WOS:000222964900005 PM 15260476 ER PT J AU Thapar, R Mueller, GA Marzluff, WF AF Thapar, R Mueller, GA Marzluff, WF TI The N-terminal domain of the Drosophila histone mRNA binding protein, SLBP, is intrinsically disordered with nascent helical structure SO BIOCHEMISTRY LA English DT Article ID CELL-CYCLE; CAENORHABDITIS-ELEGANS; SECONDARY STRUCTURE; DENATURED PROTEINS; NMR ASSIGNMENTS; 3' END; EXPRESSION; DYNAMICS; STATES; 3'-END AB Stem-loop binding protein (SLBP) is a 31 kDa protein that is central to the regulation of histone mRNAs and is highly conserved in metazoans. In vertebrates, the N-terminal domain of SLBP has sequence determinants necessary for histone mRNA translation, SLBP degradation, cyclin binding, and histone mRNA import. We have used high-resolution NMR spectroscopy and circular dichroism to characterize the structural and dynamic features of this domain of SLBP from Drosophila (dSLBP). We report that the N-terminal domain of dSLBP is stably unfolded but has nascent helical structure at physiological pH and native-like solution conditions. The conformational and dynamic properties of the isolated domain are mimicked in a longer 175-residue region of the N-terminus, as well as in the full-length protein. Complete resonance assignments, secondary structure propensity, and motional properties of a 91-residue N-terminal domain (G17-K108) of dSLBP are reported here. The deviation of H-1(alpha), C-13(alpha), and C-13(beta) chemical shifts from random coil reveals that there are four regions between residues 128-A45, S50-L57, S66-G75, and F91-N96 that have helical propensity. These regions also have small but positive heteronuclear NOEs, interresidue d(NN) NOEs, and small but significant protection from solvent exchange. However the lack of medium- and long-range NOES in 3D N-15- and C-13-edited spectra, fast amide proton exchange rates (all greater than 1 s(-1)), and long N-15 relaxation (T-1, T-2) times suggest that the domain from dSLBP does not adopt a well-defined tertiary fold. The backbone residual dipolar couplings (RDCs) for this domain are small and lie close to 0 Hz (+/-2 Hz) for most residues with no well-defined periodicity. The implications of this unfolded state for the function of dSLBP in regulating histone metabolism are discussed. C1 Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. Univ N Carolina, Program Mol Biol & Biotechnol, Chapel Hill, NC 27599 USA. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Thapar, R (reprint author), Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. EM thapar@email.unc.edu; marzluff@med.unc.edu FU NIGMS NIH HHS [GM29832, GM58961] NR 45 TC 14 Z9 15 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 27 PY 2004 VL 43 IS 29 BP 9390 EP 9400 DI 10.1021/bi036314r PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 841XG UT WOS:000222964900011 PM 15260482 ER PT J AU Polgar, O Robey, RW Morisaki, K Dean, M Michejda, C Sauna, ZE Ambudkar, SV Tarasova, N Bates, SE AF Polgar, O Robey, RW Morisaki, K Dean, M Michejda, C Sauna, ZE Ambudkar, SV Tarasova, N Bates, SE TI Mutational analysis of ABCG2: Role of the GXXXG motif SO BIOCHEMISTRY LA English DT Article ID CANCER RESISTANCE PROTEIN; HUMAN P-GLYCOPROTEIN; HUMAN MULTIDRUG TRANSPORTER; ATP HYDROLYSIS; GLYCOPHORIN-A; TRANSMEMBRANE DOMAINS; SUBSTRATE-SPECIFICITY; ACQUIRED MUTATIONS; DIMERIZATION MOTIF; HELIX ASSOCIATION AB ABCG2 (BCRP/MXR/ABCP) is a half-transporter associated with multidrug resistance that presumably homodimerizes for function. It has a conserved GXXXG motif in its first transmembrane segment, a motif that has been linked with dimerization in other proteins, e.g., glycophorin A. We substituted either or both glycines of this GXXXG motif with leucines to evaluate the impact on drug transport, ATP hydrolysis, cross-linking, and susceptibility to degradation. All mutants also carried the R482G gain-of-function mutation, and all migrated to the cell surface. The mutations resulted in lost transport for rhodamine 123 and impaired mitoxantrone, pheophorbide a, and BODIPY-prazosin transport, particularly in the double leucine mutant (G406L/G410L). Basal ATPase activity of the G406L/G410L mutant was comparable to the empty vector transfected cells with no substrate induction. Despite impaired function, the mutants retained susceptibility to cross-linking using either disuccinimidyl suberate (DSS) or the reducible dithiobis(succinimidyl propionate) (DSP) and demonstrated a high molecular weight complex under nonreducing conditions. Mutations to alanine at the same positions yielded fully functional transporters. Finally, we exposed cells to mitoxantrone to promote folding and processing of the mutant proteins, which in the leucine mutants resulted in increased amounts detected on immunoblot and by immunofluorescence. These studies support a hypothesis that the GXXXG motif promotes proper packing of the transmembrane segments in the functional ABCG2 homodimer, although it does not solely arbitrate dimerization. C1 NCI, Canc Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Human Genet Sect, Lab Genom Divers, Frederick, MD 21702 USA. NCI, Mol Aspects Drug Design Sect, Struct Biophys Lab, Frederick, MD 21702 USA. RP Bates, SE (reprint author), NCI, Canc Therapeut Branch, Ctr Canc Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM sebates@helix.nih.gov RI Ambudkar, Suresh/B-5964-2008; Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 NR 49 TC 69 Z9 70 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 27 PY 2004 VL 43 IS 29 BP 9448 EP 9456 DI 10.1021/bi0497953 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 841XG UT WOS:000222964900016 PM 15260487 ER PT J AU Rutter, MK Meigs, JB Sullivan, LM D'Agostino, RB Wilson, PWF AF Rutter, MK Meigs, JB Sullivan, LM D'Agostino, RB Wilson, PWF TI C-reactive protein, the metabolic syndrome, and prediction of cardiovascular events in the Framingham Offspring Study SO CIRCULATION LA English DT Article DE C-reactive protein; cardiovascular diseases; insulin; prognosis; risk factors ID CORONARY-HEART-DISEASE; INSULIN-RESISTANCE ATHEROSCLEROSIS; DIABETES-MELLITUS; SUBCLINICAL INFLAMMATION; ADIPOSE-TISSUE; RISK-FACTORS; POPULATION; MEN; ASSOCIATION; CYTOKINES AB Background-Inflammation (assessed by C-reactive protein [CRP]) and the metabolic syndrome (MetS) are associated with cardiovascular disease (CVD), but population-based data are limited. Methods and Results-We assessed the cross-sectional relations of CRP to the MetS ( National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, Adult Treatment Panel III definition) in 3037 subjects ( 1681 women; mean age, 54 years) and the utility of CRP and the MetS to predict new CVD events (n = 189) over 7 years. MetS (greater than or equal to3 of 5 traits) was present in 24% of subjects; mean age-adjusted CRP levels for those with 0, 1, 2, 3, 4, or 5 MetS traits were 2.2, 3.5, 4.2, 6.0, or 6.6 mg/L, respectively (P trend < 0.0001). In persons with MetS, age-adjusted CRP levels were higher in women than men (7.8 versus 4.6 mg/L; P < 0.0001). MetS and baseline CRP were individually related to CVD events (for MetS: age-sex-adjusted hazard ratio [HR], 2.1; 95% CI, 1.5 to 2.8; for highest versus lowest CRP quartile: HR, 2.2; 95% CI, 1.4 to 3.5). Greater risk of CVD persisted for MetS and CRP even after adjustment in a model including age, sex, MetS (HR, 1.8; 95% CI, 1.4 to 2.5), and CRP (HR, 1.9; 95% CI, 1.2 to 2.9). The c-statistic associated with the age- and sex-adjusted model including CRP was 0.72; including MetS, 0.74; and including CRP and MetS, 0.74. Conclusions-Elevated CRP levels are related to insulin resistance and the presence of the MetS, especially in women. Although discrimination of subjects at risk of CVD events using both MetS and CRP is not better than using either phenotype alone, both CRP and MetS are independent predictors of new CVD events. C1 Countess Chester Hosp, Chester, Cheshire, England. Univ Manchester, Dept Med, Manchester M13 9PL, Lancs, England. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Dept Med, Gen Internal Med Unit, Boston, MA 02114 USA. Boston Univ, Sch Publ Hlth, Boston, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. NHLBI, Framingham Mass Heart Study, Boston, MA USA. RP Rutter, MK (reprint author), Countess Chester Hosp NHS Trust, Directorate Med, Liverpool Rd, Chester CH2 1UL, Cheshire, England. EM Martin.Rutter@coch.nhs.uk OI Rutter, Martin/0000-0001-6380-539X; Sullivan, Lisa/0000-0003-0726-7149 FU NHLBI NIH HHS [N01-HC-25195, R01-HL-073272-01] NR 34 TC 413 Z9 428 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 27 PY 2004 VL 110 IS 4 BP 380 EP 385 DI 10.1161/01.CIR.0000136581.59584.0E PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 841CW UT WOS:000222907900004 PM 15262834 ER PT J AU Wange, RL AF Wange, RL TI TCR signaling: Another Abl-bodied kinase joins the cascade SO CURRENT BIOLOGY LA English DT Editorial Material ID JURKAT T-CELLS; IMATINIB MESYLATE; TYROSINE 319; B-CELL; ZAP-70; ACTIVATION; MICE; PHOSPHORYLATION; PROTEINS; BINDING C1 NIA, Cellular & Mol Biol Lab, NIH, Ctr Gerontol Res, Baltimore, MD 21224 USA. RP Wange, RL (reprint author), NIA, Cellular & Mol Biol Lab, NIH, Ctr Gerontol Res, Baltimore, MD 21224 USA. EM WangeR@grc.nia.nih.gov NR 17 TC 13 Z9 13 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JUL 27 PY 2004 VL 14 IS 14 BP R562 EP R564 DI 10.1016/j.cub.2004.07.012 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 842XS UT WOS:000223038600011 PM 15268875 ER PT J AU Peila, R Rodriguez, BL White, LR Launer, LJ AF Peila, R Rodriguez, BL White, LR Launer, LJ TI Fasting insulin and incident dementia in an elderly population of Japanese-American men SO NEUROLOGY LA English DT Article ID CORONARY-HEART-DISEASE; ALZHEIMERS-DISEASE; CEREBROSPINAL-FLUID; GENERAL-POPULATION; APOLIPOPROTEIN-E; PLASMA-INSULIN; SPATIAL MEMORY; HYPERINSULINEMIA; PROTEIN; BRAIN AB Objective: To evaluate the association of fasting insulin level to incident dementia in a cohort of elderly men. Methods: Data are from the Honolulu-Asia Aging Study, a community-based study of Japanese-American men, aged 71 to 91 years in 1991. Serum insulin was measured in 1991 and participants were grouped based on their insulin levels. Dementia was ascertained in 1991, 1994, and 1996 according to international guidelines. The 2,568 men dementia-free in 1991 were reexamined in 1994 and 1996; 244 new cases of dementia were diagnosed. Survival analysis with age as the time scale was used to estimate the risk ( hazard ratio [HR] and 95% CI) for incident dementia associated with levels of insulin. Results: The risk of dementia was increased at the two extremes of the insulin distribution ( lower and upper 15th percentiles). Compared to the rest of the cohort subjects in the lowest 15th percentile and highest 15th percentile had an increased risk for dementia ( HR = 1.54, CI 1.11 to 2.11 and HR = 1.54, CI 1.05 to 2.26). In men with insulin levels < 22.2 mIU/L the risk for dementia decreased with increased levels of insulin ( HR = 0.76, CI 0.72 to 0.79 for each increase of one logarithmic unit - 2.72 mIU/L of insulin). In men with insulin levels &GE; 22.2 mIU/L the risk for dementia increased with increasing levels of insulin ( HR = 1.64, CI = 1.07 to 2.52 for each 2.72 mIU/L). Conclusions: Both low and high levels of insulin are associated with an increased risk of developing dementia. C1 NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. Univ Hawaii Manoa, John A Burns Sch Med, Dept Med, Clin Epidemiol & Geriatr Div, Honolulu, HI 96822 USA. Pacific Hlth Res Inst, Honolulu, HI USA. RP Peila, R (reprint author), NIA, Lab Epidemiol Demog & Biometry, NIH, Room 3C-309 Gateway Bldg,7201 Wisconsin Ave, Bethesda, MD 20892 USA. EM peilar@mail.nih.gov FU NHLBI NIH HHS [N01-HC-O5102]; NIA NIH HHS [N01-AG-4-2149] NR 48 TC 83 Z9 92 U1 3 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL 27 PY 2004 VL 63 IS 2 BP 228 EP 233 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 841CX UT WOS:000222908000008 PM 15277613 ER PT J AU Brenner, AV Linet, MS Shapiro, WR Selker, RG Fine, HA Black, PM Inskip, PD AF Brenner, AV Linet, MS Shapiro, WR Selker, RG Fine, HA Black, PM Inskip, PD TI Season of birth and risk of brain tumors in adults SO NEUROLOGY LA English DT Article ID CEREBRAL LATERALIZATION; BIOLOGICAL MECHANISMS; NERVOUS-SYSTEM; BREAST-CANCER; HAY-FEVER; HYPOTHESIS; DISEASE; SCHIZOPHRENIA; ASSOCIATIONS; PATHOLOGY AB Background: Recent studies demonstrated an excess of winter births in children with brain tumors and in adults with various neurologic or psychiatric diseases relative to the general population. Objective: To investigate a possible association between month of birth and risk of brain tumors in adults using data from a large, hospital-based case-control study. Methods: Cases were patients with incident glioma ( n = 489) or meningioma ( n = 197) diagnosed at hospitals in Boston, MA, Phoenix, AZ, and Pittsburgh, PA. Controls ( n = 799) were patients hospitalized for a variety of nonmalignant conditions and frequency matched to cases by hospital, age, sex, race/ethnicity, and distance of residence from hospital. Odds ratios (ORs) were calculated using multivariate unconditional logistic regression allowing for cyclic variation in risk with month of birth. Results: A relationship between month of birth and risk of adult glioma and meningioma was found, best described by a 12-month periodic function with peaks in February and January and troughs in August and July. The association between month of birth and risk of glioma differed significantly by handedness, with left-handed and ambidextrous subjects born during late fall through early spring being at particularly high risk of adult glioma as compared with those born at other times of the year. Conclusion: These findings suggest the importance of seasonally varying exposures during the pre- or postnatal period in the development of brain tumors in adults. C1 NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. NCI, Neurooncol Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. St Josephs Hosp, Barrow Neurol Inst, Phoenix, AZ USA. Western Penn Hosp, Div Neurosurg, Pittsburgh, PA 15224 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Brenner, AV (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM brennera@mail.nih.gov NR 37 TC 40 Z9 41 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL 27 PY 2004 VL 63 IS 2 BP 276 EP 281 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 841CX UT WOS:000222908000015 PM 15277620 ER PT J AU De Georgia, MA Krieger, DW Abou-Chebl, A Devlin, TG Jauss, M Davis, SM Koroshetz, WJ Rordorf, G Warach, S AF De Georgia, MA Krieger, DW Abou-Chebl, A Devlin, TG Jauss, M Davis, SM Koroshetz, WJ Rordorf, G Warach, S TI Cooling for acute ischemic brain damage (COOL AID) - A feasibility trial of endovascular cooling SO NEUROLOGY LA English DT Article ID TRANSIENT FOCAL ISCHEMIA; INDUCED HYPOTHERMIA; MILD HYPOTHERMIA; CARDIAC-ARREST; INDUCTION; INJURY; STROKE; RAT AB Objective: To report results of a randomized pilot clinical feasibility trial of endovascular cooling in patients with ischemic stroke. Methods: Forty patients with ischemic stroke presenting within 12 hours of symptom onset were enrolled in the study. An endovascular cooling device was inserted into the inferior vena cava of those randomized to hypothermia. A core body temperature of 33 degreesC was targeted for 24 hours. All patients underwent clinical assessment and MRI initially, at days 3 to 5 and days 30 to 37. Results: Eighteen patients were randomized to hypothermia and 22 to receive standard medical management. Thirteen patients reached target temperature in a mean of 77 +/- 44 minutes. Most tolerated hypothermia well. Clinical outcomes were similar in both groups. Mean diffusion-weighted imaging (DWI) lesion growth in the hypothermia group ( n = 12) was 90.0 +/- 83.5% compared with 108.4 +/- 142.4% in the control group ( n = 11) (NS). Mean DWI lesion growth in patients who cooled well ( n = 8) was 72.9 +/- 95.2% (NS). Conclusions: Induced moderate hypothermia is feasible using an endovascular cooling device in most patients with acute ischemic stroke. Further studies are needed to determine if hypothermia improves outcome. C1 Cleveland Clin Fdn, Dept Neurol, Cleveland, OH 44195 USA. Erlanger Med Ctr, Chattanooga, TN USA. Univ Giessen, Giessen, Germany. Royal Melbourne Hosp, Melbourne, Vic, Australia. Massachusetts Gen Hosp, Boston, MA 02114 USA. NIH, Bethesda, MD 20892 USA. RP De Georgia, MA (reprint author), Cleveland Clin Fdn, Dept Neurol, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM degeorm@ccf.org RI Davis, Stephen/L-5260-2013 OI Davis, Stephen/0000-0003-0962-2300 NR 16 TC 192 Z9 196 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL 27 PY 2004 VL 63 IS 2 BP 312 EP 317 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 841CX UT WOS:000222908000021 PM 15277626 ER PT J AU Shapiro, EM Skrtic, S Sharer, K Hill, JM Dunbar, CE Koretsky, AP AF Shapiro, EM Skrtic, S Sharer, K Hill, JM Dunbar, CE Koretsky, AP TI MRI detection of single particles for cellular imaging SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IN-VIVO TRACKING; MAGNETIC-RESONANCE; IRON-OXIDE; MAMMALIAN-CELLS; STEM-CELLS; MACROPHAGE INFILTRATION; ALLOGRAFT-REJECTION; CONTRAST AGENTS; RAT; NANOPARTICLES AB There is rapid growth in the use of MRI for molecular and cellular imaging. Much of this work relies on the high relaxivity of nanometer-sized, ultrasmall dextran-coated iron oxide particles. Typically, millions of dextran-coated ultrasmall iron oxide particles must be loaded into cells for efficient detection. Here we show that single, micrometer-sized iron oxide particles (MPIOs) can be detected by MRI in vitro in agarose samples, in cultured cells, and in mouse embryos. Experiments studying effects of MRI resolution and particle size from 0.76 to 1.63 mum indicated that T-2(*) effects can be readily detected from single MPIOs at 50-mum resolution and significant signal effects could be detected at resolutions as low as 200 mum. Cultured cells were labeled with fluorescent MPIOs such that single particles were present in individual cells. These single particles in single cells could be detected both by MRI and fluorescence microscopy. Finally, single particles injected into single-cell-stage mouse embryos could be detected at embryonic day 11.5, demonstrating that even after many cell divisions, daughter cells still carry individual particles. These results demonstrate that MRI can detect single particles and indicate that single-particle detection will be useful for cellular imaging. C1 NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Shapiro, EM (reprint author), NINDS, Lab Funct & Mol Imaging, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM shapiroe@ninds.nih.gov RI Koretsky, Alan/C-7940-2015; OI Koretsky, Alan/0000-0002-8085-4756; Skrtic, Stanko/0000-0002-1950-5418 FU Intramural NIH HHS [Z01 NS003047-01] NR 34 TC 320 Z9 331 U1 4 U2 59 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 JUL 27 PY 2004 VL 101 IS 30 BP 10901 EP 10906 DI 10.1073/pnas.0403918101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 842JM UT WOS:000223000200013 PM 15256592 ER PT J AU Vamosi, G Bodnar, A Vereb, G Jenei, A Goldman, CK Langowski, J Toth, K Matyus, L Szollosi, J Waldmann, TA Damjanovich, S AF Vamosi, G Bodnar, A Vereb, G Jenei, A Goldman, CK Langowski, J Toth, K Matyus, L Szollosi, J Waldmann, TA Damjanovich, S TI IL-2 and IL-15 receptor alpha-subunits are coexpressed in a supramolecular receptor cluster in lipid rafts of T cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID FLUORESCENCE CORRELATION SPECTROSCOPY; CROSS-CORRELATION SPECTROSCOPY; ENERGY-TRANSFER; INTERLEUKIN-2 RECEPTOR; CLASS-II; MOLECULES; BIOLOGY; CHAIN; ASSOCIATION; IL-2R-ALPHA AB The private alpha-chains of IL-2 and IL-15 receptors (IL-2R and IL-15R) share the signaling beta- and gamma(c)-subunits, resulting in both common and contrasting roles of IL-2 and IL-15 in T cell function. Knowledge of the cytokine-dependent subunit assembly is indispensable for understanding the paradox of distinct signaling capacities. By using fluorescence resonance energy transfer and confocal microscopy, we have shown that IL-2Ralpha, IL-115Ralpha, IL-2/15Rbeta and gamma(c)-subunits, as well as MHC class I and II glycoproteins formed supramolecular receptor clusters in lipid rafts of the T lymphoma line Kit 225 FT7.10. Fluorescence crosscorrelation microscopy demonstrated the comobility of IL-15Ralpha with IL-2Ralpha and MHC class I. A model was generated for subunit switching between IL-2Ralpha and IL-15Ralpha upon the binding of the appropriate cytokine resulting in the formation of high-affinity heterotrimeric receptors. This model suggests a direct role for the alpha-subunits, to which no definite function has been assigned so far, in tuning cellular responses to IL-2 or IL-15. In addition, both a-chains were at least partially homodimerized/oligomerized, which could be the basis of distinct signaling pathways by the two cytokines. C1 NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Hungarian Acad Sci, Cell Biophys Res Grp, H-4012 Debrecen, Hungary. Univ Debrecen, Res Ctr Mol Med, Dept Biophys & Cell Biol, H-4012 Debrecen, Hungary. Deutsch Krebsforschungszentrum, Div Biophys Macromol, D-69120 Heidelberg, Germany. RP Waldmann, TA (reprint author), NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM tawald@helix.nih.gov RI Vamosi, Gyorgy/C-9351-2009; Bodnar, Andrea/A-9286-2011; Damjanovich, Sandor/A-9284-2011; Vereb, Gyorgy/A-4241-2008; Langowski, Jorg/A-1843-2011 OI Vereb, Gyorgy/0000-0003-2157-3265; Langowski, Jorg/0000-0001-8600-0666 NR 30 TC 79 Z9 79 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 27 PY 2004 VL 101 IS 30 BP 11082 EP 11087 DI 10.1073/pnas.0403916101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 842JM UT WOS:000223000200044 PM 15263076 ER PT J AU Mura, M Murcia, P Caporale, M Spencer, TE Nagashima, K Rein, A Palmarini, M AF Mura, M Murcia, P Caporale, M Spencer, TE Nagashima, K Rein, A Palmarini, M TI Late viral interference induced by transdominant Gag of an endogenous retrovirus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID JAAGSIEKTE SHEEP RETROVIRUS; PFIZER-MONKEY-VIRUS; BETARETROVIRUSES; CELL; MYRISTYLATION; POLYPROTEIN; EXPRESSION; SUFFICIENT; PROTEINS; RELEASE AB The sheep genome harbors approximate to 20 copies of endogenous retroviruses (enJSRVs) closely related to the exogenous and oncogenic Jaagsiekte sheep retrovirus (JSRV). One of the enJSRV loci, enJ556A1, has a defect for viral exit. We report a previously uncharacterized mechanism of retroviral interference. The defect possessed by enJS56A1 is determined by its Gag protein and is transdominant over the exogenous JSRV. By electron microscopy, cells transfected by enJS56A1, with or without JSRV, show agglomerates of tightly packed intracellular particles most abundant in the perinuclear area. The defect in exit and ability to interfere with JSRV exit could be largely attributed to the presence of tryptophan, rather than arginine, at position 21 of enJS56A1 Gag; C98 and V102 also contribute to these properties. We found that enJS56A1 or similar loci containing W21, C98, and V102 are expressed in sheep endometrium. enJS56A1 is a previously unrecognized example of a naturally occurring endogenous retrovirus expressing a dominant negative Gag acting at a late step of the viral replication cycle. Understanding the late blockade exerted by enJS56A1 could unravel fundamental aspects of retroviral biology and help to devise new antiretroviral strategies. C1 Univ Georgia, Coll Vet Med, Dept Infect Dis, Athens, GA 30602 USA. Texas A&M Univ, Ctr Anim Biotechnol & Genom, College Stn, TX 77843 USA. NCI, HIV Drug Resistance Program, Ft Detrick, MD 21702 USA. NCI, Image Anal Lab, Ft Detrick, MD 21702 USA. RP Palmarini, M (reprint author), Univ Georgia, Coll Vet Med, Dept Infect Dis, Athens, GA 30602 USA. EM mpalmari@vet.uga.edu RI Palmarini, Massimo/H-5982-2011; Caporale, Marco/A-6153-2011; OI Caporale, Marco/0000-0002-4087-4971; Spencer, Thomas/0000-0003-2815-766X FU NCI NIH HHS [R01 CA095706, CA95706-01] NR 25 TC 60 Z9 65 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 27 PY 2004 VL 101 IS 30 BP 11117 EP 11122 DI 10.1073/pnas.0402877101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 842JM UT WOS:000223000200050 PM 15263098 ER PT J AU Risitano, AM Maciejewski, JP Green, S Plasilova, M Zeng, WH Young, NS AF Risitano, AM Maciejewski, JP Green, S Plasilova, M Zeng, WH Young, NS TI In-vivo dominant immune responses in aplastic anaemia: molecular tracking of putatively pathogenetic T-cell clones by TCR beta-CDR3 sequencing SO LANCET LA English DT Article ID PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; MYELIN BASIC-PROTEIN; MULTIPLE-SCLEROSIS; MYELODYSPLASTIC-SYNDROME; INTERFERON-GAMMA; STRUCTURAL BASIS; FLOW-CYTOMETRY; RECEPTOR; REPERTOIRE; ANTIGEN AB Background Aplastic anaemia is a bone-marrow-failure syndrome characterised by low blood-cell counts and fatty bone marrow. in most cases, no obvious aetiological factor can be identified. However, clinical responses to immunosuppression strongly suggest an immune pathophysiology. Methods To test the hypothesis that aplastic anaemia results from antigen-specific lymphocyte attack against haemopoietic tissue, we analysed effector immunity, seeking especially dominant specific T-cell responses. Blood samples from 54 patients with aplastic anaemia were subjected to flow cytometry to define T-cell-receptor Vbeta-chain usage and expansion of particular Vbeta subsets. We measured the size distribution of the complementarity-determining region 3 (CDR3) for expanded Vbeta subsets, then cloned and sequenced skewed, oligoclonal, or monoclonal peaks. Findings Expanded Vbeta subsets were identified in almost all the patients. Over-represented Vbeta subsets from CD8-positive cells showed oligoclonal or monoclonal CDR3 size patterns. The CDR3 sequence repertoire in aplastic anaemia showed much redundancy compared with healthy donors. We identified patient-specific putative pathogenetic clonotypes that were not detectable in controls. in selected patients who were assessed longitudinally, these clonotypes were quantitatively related to disease activity. Selective killing of autologous haemopoietic progenitors by the Vbeta-specific lymphocyte population was shown in one patient. These apparently pathogenetic CDR3 sequences showed homology between individuals, suggesting a role for a "semi-public" immune response in the pathophysiology of aplastic anaemia. Interpretation In-vivo dominant clonal immune response can be identified in many patients with aplastic anaemia, which is evidence for an underlying antigen-driven immune process. Longitudinal tracking by molecular techniques could inform individual clinical decisions and the development of new treatments in autoimmune diseases. Relevance to practice Although the target of the aberrant immune response is the haemopoietic stem cell, the triggering antigens remain unknown. We combined cell phenotypic, molecular biology, and functional analyses to study the effector arm of immunity in an attempt to establish an immune pathophysiology. Clinical application of such a model could broadly extend to other autoimmune diseases. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. Cleveland Clin Fdn, Expt Hematol & Hematopoiesis Sect, Taussig Canc Ctr, Cleveland, OH 44195 USA. RP Risitano, AM (reprint author), Univ Naples Federico II, Div Hematol, Via Pansini 5, I-80131 Naples, Italy. EM amrisita@unina.it FU NHLBI NIH HHS [HL73429] NR 40 TC 112 Z9 120 U1 0 U2 2 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUL 24 PY 2004 VL 364 IS 9431 BP 355 EP 364 DI 10.1016/S0140-6736(04)16724-X PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 840IZ UT WOS:000222853300034 PM 15276395 ER PT J AU Vitorino, R Lobo, MJC Duarte, J Ferrer-Correia, AJ Tomer, KB Dubin, JR Domingues, PM Amado, FML AF Vitorino, R Lobo, MJC Duarte, J Ferrer-Correia, AJ Tomer, KB Dubin, JR Domingues, PM Amado, FML TI In vitro hydroxyapatite adsorbed salivary proteins SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE hydroxyapatite; saliva; two-dimensional electrophoresis; MALDI-TOF/TOF ID ACQUIRED ENAMEL PELLICLE; ANHYDRASE ISOENZYME VI; PROLINE-RICH PROTEINS; HUMAN WHOLE SALIVA; IDENTIFICATION; SECRETIONS; AMYLASE; INVIVO; SA; SN AB in spite of the present knowledge about saliva components and their respective functions, the mechanism(s) of pellicle and dental plaque formation have hitherto remained obscure. This has prompted recent efforts on in vitro studies using hydroxyapatite (HA) as an enamel model. In the present study salivary proteins adsorbed to HA were extracted with TFA and EDTA and resolved by 2D electrophoresis over a pH range between 3 and 10, digested, and then analysed by MALDI-TOF/TOF mass spectrometry and tandem mass spectrometry. Nineteen different proteins were identified using automated MS and MS/MS data acquisition. Among them, cystatins, amylase, carbonic anhydrase, and calgranulin B, were identified. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Aveiro, Dept Chem, P-3810193 Aveiro, Portugal. NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. Univ Porto, Fac Sport Sci & Phys Educ, P-4200450 Oporto, Portugal. RP Amado, FML (reprint author), Univ Aveiro, Dept Chem, P-3810193 Aveiro, Portugal. EM famado@dq.ua.pt RI Tomer, Kenneth/E-8018-2013; Domingues, Pedro/E-5202-2010; Duarte, Jose/F-1443-2013; Vitorino, Rui/G-7356-2014; Amado, Francisco/M-5337-2015 OI Domingues, Pedro/0000-0002-8060-7675; Duarte, Jose/0000-0003-4756-5917; Vitorino, Rui/0000-0003-3636-5805; CALHEIROS-LOBO, MARIA JOAO/0000-0003-1692-9108; Amado, Francisco/0000-0001-8256-1749 NR 23 TC 23 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUL 23 PY 2004 VL 320 IS 2 BP 342 EP 346 DI 10.1016/j.bbrc.2004.05.169 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 836PJ UT WOS:000222567700009 PM 15219832 ER PT J AU Bolli, R Becker, L Gross, G Mentzer, R Balshaw, D Lathrop, DA AF Bolli, R Becker, L Gross, G Mentzer, R Balshaw, D Lathrop, DA TI Myocardial protection at a crossroads - The need for translation into clinical therapy SO CIRCULATION RESEARCH LA English DT Article DE basic science; myocardial ischemia; reperfusion injury; ischemic heart disease; cardiac surgery; cardioprotection; research translation ID GLUCOSE-INSULIN-POTASSIUM; NITRIC-OXIDE SYNTHASE; SUDDEN CARDIAC DEATH; INFARCT SIZE; GENE-THERAPY; INDUCED HYPOTHERMIA; PRIMARY ANGIOPLASTY; FREE-RADICALS; TRIAL; ADENOSINE AB Over the past 30 years, hundreds of experimental interventions (both pharmacologic and nonpharmacologic) have been reported to protect the ischemic myocardium in experimental animals; however, with the exception of early reperfusion, none has been translated into clinical practice. The National Heart, Lung, and Blood Institute convened a working group to discuss the reasons for the failure to translate potential therapies for protecting the heart from ischemia and reperfusion and to recommend new approaches to accomplish this goal. The Working Group concluded that cardioprotection in the setting of acute myocardial infarction, cardiac surgery, and cardiac arrest is at a crossroads. Present basic research approaches to identify cardioprotective therapies are inefficient and counterproductive. For 3 decades, significant resources have been invested in single-center studies that have often yielded inconclusive results. A new paradigm is needed to obviate many of the difficulties associated with translation of basic science findings. The Working Group urged a new focus on translational research that emphasizes efficacy and clinically relevant outcomes, and recommended the establishment of a system for rigorous preclinical testing of promising cardioprotective agents with clinical trial-like approaches (ie, blinded, randomized, multicenter, and adequately powered studies using standardized methods). A national preclinical research consortium would enable rational translation of important basic science findings into clinical use. The Working Group recommended that the National Institutes of Health proactively intervene to remedy current problems that impede translation of cardioprotective therapies. Their specific recommendations include the establishment of a preclinical consortium and the performance of 2 clinical studies that are likely to demonstrate effectiveness (phase III clinical trials of adenosine in acute myocardial infarction and cardiac surgery). C1 NHLBI, Sci Res Grp, Heart Res Program,Div Heart & Vasc Dis, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Lathrop, DA (reprint author), NHLBI, Sci Res Grp, Heart Res Program,Div Heart & Vasc Dis, NIH,US Dept Hlth & Human Serv, Bldg 10, Bethesda, MD 20892 USA. EM LathropD@nhlbi.nih.gov RI LATHROP, David/A-2758-2008 NR 49 TC 308 Z9 322 U1 0 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JUL 23 PY 2004 VL 95 IS 2 BP 125 EP 134 DI 10.1161/01.RES.0000137171.97172.d7 PG 10 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 840CW UT WOS:000222835600004 PM 15271864 ER PT J AU Niu, SL Mitchell, DC Lim, SY Wen, ZM Kim, HY Salem, N Litman, BJ AF Niu, SL Mitchell, DC Lim, SY Wen, ZM Kim, HY Salem, N Litman, BJ TI Reduced G protein-coupled signaling efficiency in retinal rod outer segments in response to n-3 fatty acid deficiency SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ALPHA-LINOLENIC ACID; DOCOSAHEXAENOIC ACID; TERM INFANTS; METARHODOPSIN-II; VISUAL-ACUITY; DISK MEMBRANES; BRAIN; PHOSPHOLIPIDS; ACTIVATION; RATS AB The fatty acid ( FA) docosahexaenoic acid ( DHA, 22: 6n-3) is highly enriched in membrane phospholipids of the central nervous system and retina. Loss of DHA because of n-3 FA deficiency leads to suboptimal function in learning, memory, olfactory-based discrimination, spatial learning, and visual acuity. G protein-coupled receptor (GPCR) signal transduction is a common signaling motif in these neuronal pathways. Here we investigated the effect of n-3 FA deficiency on GPCR signaling in retinal rod outer segment (ROS) membranes isolated from rats raised on n-3-adequate or -deficient diets. ROS membranes of second generation n-3 FA-deficient rats had similar to 80% less DHA than n-3-adequate rats. DHA was replaced by docosapentaenoic acid ( 22: 5n-6), an n-6 FA. This replacement correlated with desensitization of visual signaling in n-3 FA-deficient ROS, as evidenced by reduced rhodopsin activation, rhodopsin-ransducin (G(t)) coupling, cGMP phosphodiesterase activity, and slower formation of metarhodopsin II (MII) and the MII-G(t) complex relative to n-3 FA-adequate ROS. ROS membranes from n-3 FA-deficient rats exhibited a higher degree of phospholipid acyl chain order relative to n-3 FA-adequate rats. These findings reported here provide an explanation for the reduced amplitude and delayed response of the electroretinogram a-wave observed in n-3 FA deficiency in rodents and nonhuman primates. Because members of the GPCR family are widespread in signaling pathways in the nervous system, the effect of reduced GPCR signaling due to the loss of membrane DHA may serve as an explanation for the suboptimal neural signaling observed in n-3 FA deficiency. C1 NIAAA, Lab Membrane Biochem & Biophys, Rockville, MD 20852 USA. RP Litman, BJ (reprint author), NIAAA, Lab Membrane Biochem & Biophys, Rockville, MD 20852 USA. EM litman@helix.nih.gov NR 44 TC 153 Z9 160 U1 2 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 23 PY 2004 VL 279 IS 30 BP 31098 EP 31104 DI 10.1074/jbc.M404376200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 838QA UT WOS:000222726800025 PM 15145938 ER PT J AU Armesilla, AL Williams, JC Buch, MH Pickard, A Emerson, M Cartwright, EJ Oceandy, D Vos, MD Gillies, S Clark, GJ Neyses, L AF Armesilla, AL Williams, JC Buch, MH Pickard, A Emerson, M Cartwright, EJ Oceandy, D Vos, MD Gillies, S Clark, GJ Neyses, L TI Novel functional interaction between the plasma membrane Ca2+ pump 4b and the proapoptotic tumor suppressor Ras-associated factor 1 (RASSF1) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CALMODULIN-BINDING DOMAIN; ACTIVATED PROTEIN-KINASES; ION MOTIVE ATPASES; CALCIUM-PUMP; MOLECULAR-CLONING; CA-2+ PUMP; CA-2+-TRANSPORTING ATPASE; FAMILY-MEMBERS; ISOFORM 4B; APOPTOSIS AB Plasma membrane calmodulin-dependent calcium ATPases (PMCAs) are enzymatic systems implicated in the extrusion of calcium from the cell. We and others have previously identified molecular interactions between the cytoplasmic COOH-terminal end of PMCA and PDZ domain-containing proteins. These interactions suggested a new role for PMCA as a modulator of signal transduction pathways. The existence of other intracellular regions in the PMCA molecule prompted us to investigate the possible participation of other domains in interactions with different partner proteins. A two-hybrid screen of a human fetal heart cDNA library, using the region 652 - 840 of human PMCA4b ( located in the catalytic, second intracellular loop) as bait, revealed a novel interaction between PMCA4b and the tumor suppressor RASSF1, a Ras effector protein involved in H-Ras-mediated apoptosis. Immunofluorescence co-localization, immunoprecipitation, and glutathione S-transferase pull-down experiments performed in mammalian cells provided further confirmation of the physical interaction between the two proteins. The interaction domain has been narrowed down to region 74 - 123 of RASSF1C ( 144 - 193 in RASSF1A) and 652 - 748 of human PMCA4b. The functionality of this interaction was demonstrated by the inhibition of the epidermal growth factor-dependent activation of the Erk pathway when PMCA4b and RASSF1 were co-expressed. This inhibition was abolished by blocking PMCA/ RASSSF1 association with an excess of a green fluorescent protein fusion protein containing the region 50 - 123 of RASSF1C. This work describes a novel protein-protein interaction involving a domain of PMCA other than the COOH terminus. It suggests a function for PMCA4b as an organizer of macromolecular protein complexes, where PMCA4b could recruit diverse proteins through interaction with different domains. Furthermore, the functional association with RASSF1 indicates a role for PMCA4b in the modulation of Ras-mediated signaling. C1 Univ Manchester, Div Cardiol, Manchester M13 9PT, Lancs, England. NCI, Dept Cell & Canc Biol, NIH, Rockville, MD 20850 USA. RP Neyses, L (reprint author), Univ Manchester, Div Cardiol, Rm 1-302,Stopford Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England. EM ludwig.neyses@cmmc.nhs.uk RI Oceandy, Delvac/G-9911-2015 OI Oceandy, Delvac/0000-0002-6242-6491 FU Medical Research Council [G0200020] NR 46 TC 73 Z9 77 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 JUL 23 PY 2004 VL 279 IS 30 BP 31318 EP 31328 DI 10.1074/jbc.M307557200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 838QA UT WOS:000222726800052 PM 15145946 ER PT J AU Pal, S Nemeth, MJ Bodine, D Miller, JL Svaren, J Thein, SL Lowry, PJ Bresnick, EH AF Pal, S Nemeth, MJ Bodine, D Miller, JL Svaren, J Thein, SL Lowry, PJ Bresnick, EH TI Neurokinin-B transcription in erythroid cells - Direct activation by the hematopoietic transcription factor GATA-1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SUBSTANCE-K RECEPTOR; DNA-BINDING; TACHYKININ RECEPTORS; VASCULAR ENDOTHELIUM; CHROMATIN DOMAIN; PRECURSOR CELLS; NERVOUS-SYSTEM; IN-VITRO; GENE; EXPRESSION AB The GATA family of transcription factors establishes genetic networks that control developmental processes including hematopoiesis, vasculogenesis, and cardiogenesis. We found that GATA-1 strongly activates transcription of the Tac-2 gene, which encodes proneurokinin-B, a precursor of neurokinin-B (NK-B). Neurokinins function through G protein-coupled transmembrane receptors to mediate diverse physiological responses including pain perception and the control of vascular tone. Whereas an elevated level of NK-B was implicated in pregnancy-associated pre-eclampsia ( Page, N. M., Woods, R. J., Gardiner, S. M., Lomthaisong, K., Gladwell, R. T., Butlin, D. J., Manyonda, I. T., and Lowry, P. J. ( 2000) Nature 405, 797 - 800), the regulation of NK-B synthesis and function are poorly understood. Tac-2 was expressed in normal murine erythroid cells and was induced upon ex vivo erythropoiesis. An estrogen receptor fusion to GATA-1 (ER-GATA-1) and endogenous GATA-1 both occupied a region of Tac-2 intron-7, which contains two conserved GATA motifs. Genetic complementation analysis in GATA-1-null G1E cells revealed that endogenous GATA-2 occupied the same region of intron-7, and expression of ER-GATA-1 displaced GATA-2 and activated Tac-2 transcription. Erythroid cells did not express neurokinin receptors, whereas aortic and yolk sac endothelial cells differentially expressed neurokinin receptor subtypes. Since NK-B induced cAMP accumulation in yolk sac endothelial cells, these results suggest a new mode of vascular regulation in which GATA-1 controls NK-B synthesis in erythroid cells. C1 Univ Wisconsin, Sch Med, Dept Pharmacol, Mol & Cellular Pharmacol Program, Madison, WI 53706 USA. NHGI, NIH, Bethesda, MD 20892 USA. NIDDK, NIH, Bethesda, MD 20892 USA. Hematol Med, London SE5 9PJ, England. Univ Wisconsin, Dept Comparat Biosci, Madison, WI 53706 USA. Univ Reading, Sch Anim & Microbial Sci, Reading RG6 6AJ, Berks, England. RP Bresnick, EH (reprint author), Univ Wisconsin, Sch Med, Dept Pharmacol, Mol & Cellular Pharmacol Program, 1300 Univ Ave,383 Med Sci Ctr, Madison, WI 53706 USA. EM ehbresni@wisc.edu OI Svaren, John/0000-0003-2963-7921 FU NIDDK NIH HHS [DK50107, DK55700] NR 68 TC 25 Z9 25 U1 0 U2 0 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 JUL 23 PY 2004 VL 279 IS 30 BP 31348 EP 31356 DI 10.1074/jbc.M403475200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 838QA UT WOS:000222726800055 PM 15123623 ER PT J AU Mattera, R Puertollano, R Smith, WJ Bonifacino, JS AF Mattera, R Puertollano, R Smith, WJ Bonifacino, JS TI The trihelical bundle subdomain of the GGA proteins interacts with multiple partners through overlapping but distinct sites SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DOMAIN-CONTAINING PROTEIN; AMINO-TERMINAL DOMAIN; TRANS-GOLGI NETWORK; EAR HOMOLOGY DOMAIN; GAMMA-ADAPTIN; UBIQUITIN-BINDING; VHS DOMAINS; GAT DOMAIN; MEMBRANE-FUSION; CLATHRIN AB The Golgi-localized, gamma-adaptin ear-containing, ARF-binding (GGA) proteins are monomeric clathrin adaptors that mediate the sorting of cargo at the trans-Golgi network and endosomes. The GGAs contain four different domains named Vps27, Hrs, Stam (VHS); GGAs and TOM1 (GAT); hinge; and gamma-adaptin ear (GAE). The VHS domain recognizes transmembrane cargo, whereas the hinge and GAE regions bind clathrin and accessory proteins, respectively. The GAT domain is a polyfunctional module that interacts with various partners including the small GTPase ARF, the endosomal fusion regulator Rabaptin-5, ubiquitin, and the product of the tumor susceptibility gene 101 (TSG101). Previous x-ray crystallographic analyses showed that the GAT region is composed of two subdomains, an N-terminal helix-loop-helix containing the ARF binding site, and a C-terminal triple alpha-helical (trihelical) bundle. In this study, we define the Rabaptin-5 binding site on the GGA1-GAT domain and its relationship to the binding sites for ubiquitin and TSG101. Our observations show that Rabaptin-5, ubiquitin, and TSG101 bind to overlapping but distinct binding sites on the trihelical bundle. The different GAT binding partners engage in both competitive and cooperative interactions that may be important for the function of the GGAs in protein sorting. C1 NICHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), NICHD, Cell Biol & Metab Branch, NIH, Bldg 18T,Rm 101, Bethesda, MD 20892 USA. EM juan@helix.nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 NR 45 TC 26 Z9 29 U1 0 U2 0 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 JUL 23 PY 2004 VL 279 IS 30 BP 31409 EP 31418 DI 10.1074/jbc.M402183200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 838QA UT WOS:000222726800062 PM 15143060 ER PT J AU Koo, BM Yoon, MJ Lee, CR Nam, TW Choe, YJ Jaffe, H Peterkofsky, A Seok, YJ AF Koo, BM Yoon, MJ Lee, CR Nam, TW Choe, YJ Jaffe, H Peterkofsky, A Seok, YJ TI A novel fermentation/respiration switch protein regulated by enzyme IIA(Glc) in Escherichia coli SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SUGAR PHOSPHOTRANSFERASE SYSTEM; PHOSPHORYL TRANSFER COMPLEX; GLOBAL REPRESSOR MLC; GLUCOSE-TRANSPORTER; INDUCER EXCLUSION; TERMINAL DOMAIN; GLYCEROL KINASE; SALMONELLA-TYPHIMURIUM; GLYCOGEN-PHOSPHORYLASE; ALLOSTERIC REGULATION AB The bacterial phosphoenolpyruvate: sugar phosphotransferase system regulates a variety of physiological processes as well as effecting sugar transport. The crr gene product (enzyme IIA(Glc) (IIA(Glc))) mediates some of these regulatory phenomena. In this report, we characterize a novel IIA(Glc)-binding protein from Escherichia coli extracts, discovered using ligand-fishing with surface plasmon resonance spectroscopy. This protein, which we named FrsA ( fermentation/respiration switch protein), is the 47-kDa product of the yafA gene, previously denoted as "function unknown." FrsA forms a 1: 1 complex specifically with the unphosphorylated form of IIA(Glc), with the highest affinity of any protein thus far shown to interact with IIA(Glc). Orthologs of FrsA have been found to exist only in facultative anaerobes belonging to the gamma-proteobacterial group. Disruption of frsA increased cellular respiration on several sugars including glucose, while increased FrsA expression resulted in an increased fermentation rate on these sugars with the concomitant accumulation of mixed-acid fermentation products. These results suggest that IIA(Glc) regulates the flux between respiration and fermentation pathways by sensing the available sugar species via a phosphorylation state-dependent interaction with FrsA. C1 Seoul Natl Univ, Sch Biol Sci, Lab Macromol Interact, Seoul 151742, South Korea. Seoul Natl Univ, Inst Microbiol, Seoul 151742, South Korea. NINDS, NIH, Bethesda, MD 20892 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Seok, YJ (reprint author), Seoul Natl Univ, Sch Biol Sci, Lab Macromol Interact, Seoul 151742, South Korea. EM yjseok@plaza.snu.ac.kr NR 34 TC 46 Z9 47 U1 1 U2 6 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 JUL 23 PY 2004 VL 279 IS 30 BP 31613 EP 31621 DI 10.1074/jbc.M405048200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 838QA UT WOS:000222726800085 PM 15169777 ER PT J AU Golestaneh, N Fan, JG Fariss, RN Lo, WK Zelenka, PS Chepelinsky, AB AF Golestaneh, N Fan, JG Fariss, RN Lo, WK Zelenka, PS Chepelinsky, AB TI Lens major intrinsic Protein (MIP)/aquaporin expression in rat lens epithelia explants requires fibroblast growth factor-induced ERK and JNK signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FIBER CELL-DIFFERENTIATION; CATARACTOUS HUMAN LENSES; TRANSGENIC MICE; OCULAR LENS; MOUSE LENS; MIP; PROLIFERATION; GENE; AQUAPORIN-0; DISRUPTION AB Lens major intrinsic protein (MIP), exclusive to the vertebrate lens, otherwise known as MIP26 and Aquaporin 0, is abundantly expressed as a lens fiber membrane protein. Although relatively less efficient compared with other aquaporins, MIP is suggested to function as a water channel, as an adhesion molecule, and is required for lens transparency. Because MIP is specifically expressed in lens fiber cells, we investigated in this study the activation of Mip expression after triggering differentiation of rat lens epithelia explants by fibroblast growth factor (FGF)-2. Here, we show that Mip expression in the lens cells is regulated by FGF-2. Using Real time PCR we demonstrate that endogenous Mip levels in the explants were up-regulated upon FGF-2 stimulation, in a concentration-dependent manner. Up-regulation of Mip at the transcriptional level was simultaneous with the activation of the FGF downstream signaling components, ERK1/2 and JNK. Specific inhibitors, UO126 for ERK1/2 and SP600125 for JNK, abrogated Mip expression in response to FGF-2 in the explants. This inhibition pattern was recapitulated in reporter assays for transfection of the rat lens epithelia explants, driven by the Mip promoter ( -1648/ +44). Our studies show that ERK1/2 and JNK signaling pathways are required for Mip expression in lens epithelia explants induced to differentiate by FGF-2. C1 NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. Morehouse Sch Med, Dept Anat & Neurobiol, Atlanta, GA 30310 USA. RP Chepelinsky, AB (reprint author), NEI, Mol & Dev Biol Lab, NIH, 7 Mem Dr,MSC 0704 Bldg 7,Rm 105, Bethesda, MD 20892 USA. NR 49 TC 23 Z9 23 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 23 PY 2004 VL 279 IS 30 BP 31813 EP 31822 DI 10.1074/jbc.M403473200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 838QA UT WOS:000222726800108 PM 15145928 ER PT J AU Guan, RJ Malchiodi, EL Wang, Q Schuck, P Mariuzza, RA AF Guan, RJ Malchiodi, EL Wang, Q Schuck, P Mariuzza, RA TI Crystal structure of the C-terminal peptidoglycan-binding domain of human peptidoglycan recognition protein I alpha SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GRAM-POSITIVE BACTERIA; DROSOPHILA-MELANOGASTER; IMMUNE-RESPONSE; GENE; ACTIVATION; AMIDASE; SYSTEM; ARCHITECTURE; NEUTROPHILS; INFECTION AB Peptidoglycan recognition proteins (PGRPs) are pattern recognition receptors of the innate immune system that bind, and in some cases hydrolyze, peptidoglycans (PGNs) on bacterial cell walls. These molecules, which are highly conserved from insects to mammals, participate in host defense against both Gram-positive and Gram-negative bacteria. We report the crystal structure of the C-terminal PGN-binding domain of human PGRP-Ialpha in two oligomeric states, monomer and dimer, to resolutions of 2.80 and 1.65 Angstrom, respectively. In contrast to PGRPs with PGN-lytic amidase activity, no zinc ion is present in the PGN-binding site of human PGRP-Ialpha. The structure reveals that PGRPs exhibit extensive topological variability in a large hydrophobic groove, located opposite the PGN-binding site, which may recognize host effector proteins or microbial ligands other than PGN. We also show that full-length PGRP-Ialpha comprises two tandem PGN-binding domains. These domains differ at most potential PGN-contacting positions, implying different fine specificities. Dimerization of PGRP-Ialpha, which occurs through three-dimensional domain swapping, is mediated by specific binding of sodium ions to a flexible hinge loop, stabilizing the conformation found in the dimer. We further demonstrate sodium-dependent dimerization of PGRP-Ialpha in solution, suggesting a possible mechanism for modulating PGRP activity through the formation of multivalent adducts. C1 Univ Maryland, Biotechnol Inst, Ctr Adv Res Biotechnol, WM Keck Lab Struct Biol, Rockville, MD 20850 USA. UBA, FFyB, CONICET, IDEHU,Catedra Inmunol, Buenos Aires, DF, Argentina. NIH, Div Bioengn & Phys Sci, Off Res Serv, Bethesda, MD 20892 USA. RP Mariuzza, RA (reprint author), Univ Maryland, Biotechnol Inst, Ctr Adv Res Biotechnol, WM Keck Lab Struct Biol, 9600 Gudelsky Dr, Rockville, MD 20850 USA. EM mariuzza@carb.nist.gov OI Schuck, Peter/0000-0002-8859-6966 FU NIAID NIH HHS [AI47900] NR 50 TC 42 Z9 49 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 JUL 23 PY 2004 VL 279 IS 30 BP 31873 EP 31882 DI 10.1074/jbc.M404920200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 838QA UT WOS:000222726800114 PM 15140887 ER PT J AU Beard, WA Shock, DD Wilson, SH AF Beard, WA Shock, DD Wilson, SH TI Influence of DNA structure on DNA polymerase beta active site function - Extension of mutagenic DNA intermediates SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BASE EXCISION-REPAIR; REVERSE-TRANSCRIPTASE; NUCLEOTIDE INCORPORATION; CATALYTIC EFFICIENCY; DYNAMICS SIMULATIONS; REPLICATION FIDELITY; MISMATCH EXTENSION; CRYSTAL-STRUCTURES; TERNARY COMPLEXES; BINDING AB In the ternary substrate complex of DNA polymerase (pol) beta, the nascent base pair (templating and incoming nucleotides) is sandwiched between the duplex DNA terminus and polymerase. To probe molecular interactions in the dNTP-binding pocket, we analyzed the kinetic behavior of wild-type pol beta on modified DNA substrates that alter the structure of the DNA terminus and represent mutagenic intermediates. The DNA substrates were modified to 1) alter the sequence of the duplex terminus ( matched and mismatched), 2) introduce abasic sites near the nascent base pair, and 3) insert extra bases in the primer or template strands to mimic frameshift intermediates. The results indicate that the nucleotide insertion efficiency (k(cat)/K-m, dGTP-dC) is highly dependent on the sequence identity of the matched (i.e. Watson-Crick base pair) DNA terminus (template/primer, G/C similar to A/T > T/A similar to C/G). Mismatches at the primer terminus strongly diminish correct nucleotide insertion efficiency but do not affect DNA binding affinity. Transition intermediates are generally extended more easily than transversions. Most mismatched primer termini decrease the rate of insertion and binding affinity of the incoming nucleotide. In contrast, the loss of catalytic efficiency with homopurine mismatches at the duplex DNA terminus is entirely due to the inability to insert the incoming nucleotide, since K-d(dGTP) is not affected. Abasic sites and extra nucleotides in and around the duplex terminus decrease catalytic efficiency and are more detrimental to the nascent base pair binding pocket when situated in the primer strand than the equivalent position in the template strand. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov NR 46 TC 53 Z9 55 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 23 PY 2004 VL 279 IS 30 BP 31921 EP 31929 DI 10.1074/jbc.M404016200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 838QA UT WOS:000222726800119 PM 15145936 ER PT J AU Cherukuri, A Carter, RH Brooks, S Bornmann, W Finn, R Dowd, CS Pierce, SK AF Cherukuri, A Carter, RH Brooks, S Bornmann, W Finn, R Dowd, CS Pierce, SK TI B cell signaling is regulated by induced palmitoylation of CD81 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-TYROSINE KINASES; LIPID RAFTS; ANTIGEN RECEPTOR; SACCHAROMYCES-CEREVISIAE; ENRICHED MICRODOMAINS; MEMBRANE MICRODOMAIN; TETRASPANIN PROTEINS; CD19/CD21 COMPLEX; ANCHORED PROTEINS; FATTY-ACIDS AB Signaling through the B cell antigen receptor (BCR) is amplified and prolonged by coligation of the BCR to the CD19/CD21/CD81 coreceptor complex. Coligation is induced during immune responses by the simultaneous binding of complement-tagged antigens to the complement receptor, CD21, and to the BCR. Enhanced signaling is due in part to the ability of the CD19/CD21/CD81 complex to stabilize the BCR in sphingolipid- and cholesterol-rich membrane microdomains termed lipid rafts. The tetraspanin CD81 is essential for the raft-stabilizing function of the coreceptor. Here we show that coligation of the BCR and the CD19/CD21/CD81 complex leads to selective, rapid, and reversible palmitoylation of CD81 and that palmitoylation is necessary for the raft stabilizing function of the CD19/CD21/CD81 complex. Inducible palmitoylation may represent a novel mechanism by which tetraspanins function to facilitate lipid raft-dependent receptor signaling. C1 NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. Univ Alabama, Dept Med & Microbiol, Birmingham, AL 35294 USA. Mem Sloan Kettering Canc Ctr, Radiochem Core Facil, New York, NY 10021 USA. RP Pierce, SK (reprint author), NIAID, Immunogenet Lab, NIH, Twinbrook 2,12441 Parklawn Dr,Rm 200B,MSC 8180, Rockville, MD 20852 USA. EM spierce@nih.gov NR 51 TC 66 Z9 67 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 23 PY 2004 VL 279 IS 30 BP 31973 EP 31982 DI 10.1074/jbc.M404410200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 838QA UT WOS:000222726800126 PM 15161911 ER PT J AU Ollivault-Shiflett, M Kimball, DB Silks, LAP AF Ollivault-Shiflett, M Kimball, DB Silks, LAP TI Synthesis of chiral C-13,Se-77-labeled selones SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID DERIVATIZING AGENTS; OXAZOLIDINE-2-SELONES; STEREOSELECTIVITY; SPECTROSCOPY; ALCOHOLS; CENTERS; ACID AB Stable isotope-labeled N-acyl selones have been constructed in fewer than four steps from readily available starting materials. Site-specific labeling was achieved using the following synthons: bromo [2-C-13] acetic acid, [C-13]formic acid, and elemental Se-77. These labeled selones have been found to provide unique insights into enolate structure and may be useful in the detection and quantitation of remotely disposed chiral centers in compounds in short supply. C1 Los Alamos Natl Lab, Biosci Div, Biotechnol Spect & Isotope Chem Grp, NIH Natl Stable Isotope Resource, Los Alamos, NM 87545 USA. RP Silks, LAP (reprint author), Los Alamos Natl Lab, Biosci Div, Biotechnol Spect & Isotope Chem Grp, NIH Natl Stable Isotope Resource, MS E529, Los Alamos, NM 87545 USA. EM pete-silks@lanl.gov FU NCRR NIH HHS [RR 02231] NR 16 TC 3 Z9 3 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD JUL 23 PY 2004 VL 69 IS 15 BP 5150 EP 5152 DI 10.1021/jo049747o PG 3 WC Chemistry, Organic SC Chemistry GA 839CJ UT WOS:000222760600046 PM 15255756 ER PT J AU Souret, FF Kastenmayer, JP Green, PJ AF Souret, FF Kastenmayer, JP Green, PJ TI AtXRN4 degrades mRNA in Arabidopsis and its substrates include selected miRNA targets SO MOLECULAR CELL LA English DT Article ID ENDONUCLEOLYTIC CLEAVAGE; SACCHAROMYCES-CEREVISIAE; MAMMALIAN EXOSOME; RAPID DECAY; MICRORNA; DEGRADATION; YEAST; GENES; EXORIBONUCLEASE; TURNOVER AB Messenger RNA degradation is an essential step in gene expression that can be regulated by siRNAs or miRNAs. However, most of our knowledge of in vivo eukaryotic mRNA degradation mechanisms derives from Saccharomyces cerevisiae, which lacks miRNAs and RNAi capability. Using reverse genetic and microarray analyses, we have identified multiple substrates of AtXRN4, the Arabidopsis homolog of the major yeast mRNA degrading exoribonuclease, Xrn1p. Insertional mutation of AtXRN4 leads to accumulation of the 3' end of several mRNAs, in a manner that correlates with increased stability of the 3' end, and is reversed following complementation with AtXRN4. Moreover, 3' products of miRNA-mediated cleavage of SCARECROW-LIKE transcripts and several other miRNA target transcripts are among those that accumulate in xrn4 mutants. The demonstration that an Xrn1p homolog degrades mRNA in a multicellular eukaryote and contributes to the miRNA-mediated decay pathway of selected targets has implications for XRNs in other organisms. C1 Univ Delaware, Delaware Biotechnol Inst, Newark, DE 19711 USA. USN, Ctr Med, Natl Canc Inst, Genet Branch,Ctr Canc Res, Bethesda, MD 20889 USA. RP Green, PJ (reprint author), Univ Delaware, Delaware Biotechnol Inst, Newark, DE 19711 USA. EM green@dbl.udel.edu NR 59 TC 187 Z9 201 U1 5 U2 34 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JUL 23 PY 2004 VL 15 IS 2 BP 173 EP 183 DI 10.1016/j.molcel.2004.06.006 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 841UY UT WOS:000222958300006 PM 15260969 ER PT J AU Wiederhold, L Leppard, JB Kedar, P Karimi-Busheri, F Rasouli-Nia, A Weinfeld, M Tomkinson, AE Izumi, T Prasad, R Wilson, SH Mitra, S Hazra, TK AF Wiederhold, L Leppard, JB Kedar, P Karimi-Busheri, F Rasouli-Nia, A Weinfeld, M Tomkinson, AE Izumi, T Prasad, R Wilson, SH Mitra, S Hazra, TK TI AP endonuclease-independent DNA base excision repair in human cells SO MOLECULAR CELL LA English DT Article ID STRAND BREAK REPAIR; ESCHERICHIA-COLI; MAMMALIAN-CELLS; POLYMERASE-BETA; LIGASE-III; OXIDATIVE DAMAGE; 8-OXOGUANINE-DNA GLYCOSYLASE; HUMAN NTH1; IN-VITRO; PROTEIN AB The paradigm for repair of oxidized base lesions in genomes via the base excision repair (BER) pathway is based on studies in Escherichia coli, in which AP endonuclease (APE) removes all 3' blocking groups (including 3' phosphate) generated by DNA glycosylase/AP lyases after base excision. The recently discovered mammalian DNA glycosylase/AP lyases, NEIL1 and NEIL2, unlike the previously characterized OGG1 and NTH1, generate DNA strand breaks with 3' phosphate termini. Here we show that in mammalian cells , removal of the 3' phosphate is dependent on polynucleotide kinase (PNK), and not APE. NEIL1 stably interacts with other BER proteins, DNA polymerase beta (pol beta) and DNA ligase IIIalpha. The complex of NEIL1, pol beta, and DNA ligase IIIalpha together with PNK suggests coordination of NEIL1-initiated repair. That NEIL1/PNK could also repair the products of other DNA glycosylases suggests a broad role for this APE-independent BER pathway in mammals. C1 Univ Texas, Med Branch, Dept Human Biol Chem & Genet, Galveston, TX 77555 USA. Univ Texas, Med Branch, Sealy Ctr Mol Sci, Galveston, TX 77555 USA. Univ Texas, Hlth Sci Ctr, Dept Mol Med, San Antonio, TX 78245 USA. Univ Texas, Hlth Sci Ctr, Inst Biotechnol, San Antonio, TX 78245 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. Cross Canc Inst, Dept Expt Oncol, Edmonton, AB T6G 1Z2, Canada. Univ Maryland, Dept Radiat Oncol, Baltimore, MD 21201 USA. RP Mitra, S (reprint author), Univ Texas, Med Branch, Dept Human Biol Chem & Genet, Galveston, TX 77555 USA. EM samitra@utmb.edu FU NCI NIH HHS [CA53791, CA81063, CA92584]; NIEHS NIH HHS [ES06676]; NIGMS NIH HHS [GM47251, GM57479]; PHS HHS [T32-07254] NR 55 TC 276 Z9 285 U1 1 U2 14 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JUL 23 PY 2004 VL 15 IS 2 BP 209 EP 220 DI 10.1016/j.molcel.2004.06.003 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 841UY UT WOS:000222958300009 PM 15260972 ER PT J AU Isacson, O AF Isacson, O TI Problems and solutions for circuits and synapses in Parkinson's disease SO NEURON LA English DT Article ID EMBRYONIC STEM-CELLS; DEEP BRAIN-STIMULATION; DOPAMINERGIC-NEURONS; BASAL-GANGLIA; TRANSPLANTATION; MIDBRAIN; MODEL; INDUCTION; PRIMATE C1 Harvard Univ, Sch Med, Dept Neurol, NINDS,Udall Parkinsons Dis Res Ctr Excellence, Belmont, MA 02478 USA. McLean Hosp, Belmont, MA 02478 USA. RP Isacson, O (reprint author), Harvard Univ, Sch Med, Dept Neurol, NINDS,Udall Parkinsons Dis Res Ctr Excellence, Belmont, MA 02478 USA. EM isacson@hms.harvard.edu NR 34 TC 9 Z9 9 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL 22 PY 2004 VL 43 IS 2 BP 165 EP 168 DI 10.1016/j.neuron.2004.07.007 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 841BX UT WOS:000222905400005 PM 15260952 ER PT J AU Knutson, B Bjork, JM Fong, GW Hommer, D Mattay, VS Weinberger, DR AF Knutson, B Bjork, JM Fong, GW Hommer, D Mattay, VS Weinberger, DR TI Amphetamine modulates human incentive processing SO NEURON LA English DT Article ID NUCLEUS-ACCUMBENS; FUNCTIONAL MRI; BRAIN ACTIVITY; CORTICAL ACTIVATION; PREFRONTAL CORTEX; NEURAL RESPONSES; REWARD; DOPAMINE; FMRI; ANTICIPATION AB Research suggests that psychostimulants can physiologically alter dopamine kinetics in the ventral striatum (VS) and psychologically enhance mood and attention. Using event-related functional magnetic resonance imaging (fMRI), we conducted a within-subject, double-blind, placebo (PLAC)-controlled study of the effects of oral dextroamphetamine (AMPH, 0.25 mg/kg) treatment on brain activity and affect during incentive processing. In two counterbalanced scanning sessions 60-180 min after ingesting AMPH or PLAC, 8 healthy volunteers played a game involving anticipation and receipt of monetary gains and losses. Group and volume of interest analyses suggested that by enhancing tonic over phasic activation, AMPH treatment "equalized" levels of VS activity and positive arousal during anticipation of both gain and loss. These findings suggest that therapeutic effects of amphetamine on incentive processing may involve reducing the difference between anticipation of gains and losses. C1 Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. NIAAA, Clin Studies Lab, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. RP Knutson, B (reprint author), Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. EM knutson@psych.stanford.edu OI Knutson, Brian/0000-0002-7669-426X FU NIMH NIH HHS [MH066923] NR 39 TC 105 Z9 107 U1 6 U2 16 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL 22 PY 2004 VL 43 IS 2 BP 261 EP 269 DI 10.1016/j.neuron.2004.06.030 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 841BX UT WOS:000222905400014 PM 15260961 ER PT J AU Brower, RG Lanken, PN MacIntyre, N Matthay, MA Morris, A Ancukiewicz, M Schoenfeld, D Thompson, BT AF Brower, RG Lanken, PN MacIntyre, N Matthay, MA Morris, A Ancukiewicz, M Schoenfeld, D Thompson, BT CA Natl Heart Lung Blood Inst ARDS Cl TI Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article; Proceedings Paper CT 98th International Conference of the American-Thoracic-Society CY MAY 17-23, 2002 CL ATLANTA, GA SP Amer Thorac Soc ID ACUTE LUNG INJURY; PEAK AIRWAY PRESSURES; MECHANICAL VENTILATION; TIDAL VOLUME; CONTROLLED-TRIAL; PULMONARY-EDEMA; ADULTS; SURFACTANT; MORTALITY; SEPSIS AB Background: Most patients requiring mechanical ventilation for acute lung injury and the acute respiratory distress syndrome (ARDS) receive positive end-expiratory pressure (PEEP) of 5 to 12 cm of water. Higher PEEP levels may improve oxygenation and reduce ventilator-induced lung injury but may also cause circulatory depression and lung injury from overdistention. We conducted this trial to compare the effects of higher and lower PEEP levels on clinical outcomes in these patients. Methods: We randomly assigned 549 patients with acute lung injury and ARDS to receive mechanical ventilation with either lower or higher PEEP levels, which were set according to different tables of predetermined combinations of PEEP and fraction of inspired oxygen. Results: Mean (+/-SD) PEEP values on days 1 through 4 were 8.3+/-3.2 cm of water in the lower-PEEP group and 13.2+/-3.5 cm of water in the higher-PEEP group (P<0.001). The rates of death before hospital discharge were 24.9 percent and 27.5 percent, respectively (P=0.48; 95 percent confidence interval for the difference between groups, -10.0 to 4.7 percent). From day 1 to day 28, breathing was unassisted for a mean of 14.5+/-10.4 days in the lower-PEEP group and 13.8+/-10.6 days in the higher-PEEP group (P=0.50). Conclusions: These results suggest that in patients with acute lung injury and ARDS who receive mechanical ventilation with a tidal-volume goal of 6 ml per kilogram of predicted body weight and an end-inspiratory plateau-pressure-limit of 30 cm of water, clinical outcomes are similar whether lower or higher PEEP levels are used. C1 Johns Hopkins Univ, Baltimore, MD 21205 USA. Univ Penn, Philadelphia, PA 19104 USA. Duke Univ, Durham, NC USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Latter Day St Hosp, Salt Lake City, UT 84143 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NHLBI, ARDS, Clin Trials Network, Bethesda, MD 20892 USA. RP Brower, RG (reprint author), Johns Hopkins Univ, 1830 E Monument St,Rm 549, Baltimore, MD 21205 USA. FU NHLBI NIH HHS [N01-HR 46062, N01-HR 46054, N01-HR 46055, N01-HR 46056, N01-HR 46057, N01-HR 46058, N01-HR 46059, N01-HR 46060, N01-HR 46061, N01-HR 46063, N01-HR 46064] NR 37 TC 912 Z9 985 U1 2 U2 34 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 JUL 22 PY 2004 VL 351 IS 4 BP 327 EP 336 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 839RC UT WOS:000222801200006 PM 15269312 ER PT J AU Anderson, WF Chu, KC AF Anderson, WF Chu, KC TI Ductal carcinoma in situ of the breast SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID CANCER C1 NCI, Bethesda, MD 20892 USA. RP Anderson, WF (reprint author), NCI, Bethesda, MD 20892 USA. EM wanderso@mail.nih.gov NR 5 TC 0 Z9 0 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 JUL 22 PY 2004 VL 351 IS 4 BP 400 EP 401 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 839RC UT WOS:000222801200030 ER PT J AU Leitzmann, MF Giovannucci, E AF Leitzmann, MF Giovannucci, E TI Frequency of ejaculation and risk of prostate cancer - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Leitzmann, MF (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM leitzmann@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 21 PY 2004 VL 292 IS 3 BP 329 EP 329 DI 10.1001/jama.292.3.329-b PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 838DL UT WOS:000222693500016 ER PT J AU Thakur, P Stevens, DR Sheng, ZH Rettig, J AF Thakur, P Stevens, DR Sheng, ZH Rettig, J TI Effects of PKA-mediated phosphorylation of snapin on synaptic transmission in cultured hippocampal neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE calcium; hippocampus; neurotransmitter; synapse; presynaptic mechanism; SNARE complex ID SECRETORY MACHINERY; PROTEIN-KINASE; MODULATION; EXPRESSION; SYNAPSES; STEP; POOL AB Use-dependent activation of protein kinase A (PKA) modulates transmitter release, contributing to synaptic plasticity. Snapin, a PKA substrate in neurons, associates with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor ( SNARE) complex, and its phosphorylation leads to increased binding of synaptotagmin to the SNARE complex. We investigated the role of PKA-dependent phosphorylation of Snapin in hippocampal neurons. Overexpression of Snapin S50D, a mutant mimicking the phosphorylated state, resulted in a decreased number of readily releasable vesicles. In addition, both the release probability of individual vesicles and the depression rate during high-frequency stimulation were increased. Overexpression of Snapin S50A, a mutant that cannot be phosphorylated, did not alter the size of the pool or the probability of release. Furthermore, dialysis of Sp-cAMPS, a nonhydrolyzable analog of cAMP that will promote phosphorylation by PKA, also led to increased synaptic depression in cells overexpressing wild-type Snapin. These results establish Snapin as an important target of PKA in CNS synapses and indicate a role for Snapin in the plasticity of transmitter release. C1 Univ Saarland, Inst Physiol, D-66424 Homburg, Germany. NINDS, Synapt Funct Unit, Bethesda, MD 20892 USA. RP Rettig, J (reprint author), Univ Saarland, Inst Physiol, Gebaude 59, D-66424 Homburg, Germany. EM jrettig@uniklinik-saarland.de RI Rettig, Jens/K-5103-2013 OI Rettig, Jens/0000-0001-6160-3954 NR 15 TC 41 Z9 46 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 21 PY 2004 VL 24 IS 29 BP 6476 EP 6481 DI 10.1523/JNEUROSCI.0590-04.2004 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 839YS UT WOS:000222821800007 PM 15269257 ER PT J AU Shahar, T House, SB Gainer, H AF Shahar, T House, SB Gainer, H TI Neural activity protects hypothalamic magnocellular neurons against axotomy-induced programmed cell death SO JOURNAL OF NEUROSCIENCE LA English DT Article DE hypothalamus; vasopressin; oxytocin; magnocellular neuron; axotomy; apoptosis ID CILIARY NEUROTROPHIC FACTOR; CEREBELLAR GRANULE CELLS; OUTWARD POTASSIUM CURRENT; C-FOS IMMUNOREACTIVITY; RETINAL GANGLION-CELLS; RAT SUPRAOPTIC NUCLEUS; OXYTOCIN NEURONS; IN-VITRO; NEUROHYPOPHYSEAL SYSTEM; VASOPRESSINERGIC NEURONS AB Axotomy typically leads to retrograde neuronal degeneration in the CNS. Studies in the hypothalamo-neurohypophysial system (HNS) have suggested that neural activity is supportive of magnocellular neuronal (MCN) survival after axotomy. In this study, we directly test this hypothesis by inhibiting neural activity in the HNS, both in vivo and in vitro, by the use of tetrodotoxin (TTX). After median eminence compression to produce axonal injury, unilateral superfusion of 3 muM TTX into the rat supraoptic nucleus ( SON), delivered with the use of a miniature osmotic pump for 2 weeks in vivo, produced a decrease in the number of surviving MCNs in the TTX-treated SON, compared with the contralateral untreated side of the SON. In vitro application of 2.5 muM TTX for 2 weeks to the SON in organotypic culture produced a 73% decrease in the surviving MCNs, compared with untreated control cultures. Raising the extracellular KCl in the culture medium to 25 mM rescued the MCNs from the axotomy- and TTX-induced cell death. These data support the proposal that after axotomy, neural activity is neuroprotective in the HNS. C1 NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Gainer, H (reprint author), NINDS, Neurochem Lab, NIH, Bldg 36,Room 4D-04, Bethesda, MD 20892 USA. EM gainerh@ninds.nih.gov NR 71 TC 19 Z9 19 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 21 PY 2004 VL 24 IS 29 BP 6553 EP 6562 DI 10.1523/JNEUROSCI.0886-04.2004 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 839YS UT WOS:000222821800017 PM 15269267 ER PT J AU Du, J Gray, NA Falke, CA Chen, WX Yuan, PX Szabo, ST Einat, H Manji, HK AF Du, J Gray, NA Falke, CA Chen, WX Yuan, PX Szabo, ST Einat, H Manji, HK TI Modulation of synaptic plasticity by antimanic agents: The role of AMPA glutamate receptor subunit 1 synaptic expression SO JOURNAL OF NEUROSCIENCE LA English DT Article DE lithium; valproate; antidepressant; bipolar disorder; GluR1; phosphorylation; PKA ID BEHAVIORAL SENSITIZATION; NEUROTROPHIC FACTOR; SURFACE EXPRESSION; NUCLEUS-ACCUMBENS; SIGNALING PATHWAY; BIPOLAR DISORDER; MOOD DISORDERS; IN-VIVO; DEPRESSION; ANTIDEPRESSANT AB Increasing data suggest that impairments of cellular plasticity underlie the pathophysiology of bipolar disorder. In this context, it is noteworthy that AMPA glutamate receptor trafficking regulates synaptic plasticity, effects mediated by signaling cascades, which are targets for antimanic agents. The present studies were undertaken to determine whether two clinically effective, but structurally highly dissimilar, antimanic agents lithium and valproate regulate synaptic expression of AMPA receptor subunit glutamate receptor 1 (GluR1). Chronic ( but not acute) treatment of rats with therapeutically relevant concentrations of lithium or valproate reduced hippocampal synaptosomal GluR1 levels. The reduction in synaptic GluR1 by lithium and valproate was attributable to a reduction of surface GluR1 distribution onto the neuronal membrane as demonstrated by three independent assays in cultured hippocampal neurons. Furthermore, these agents induced a decrease in GluR1 phosphorylation at a specific PKA site (GluR1p845), which is known to be critical for AMPA receptor insertion. Sp-cAMP treatment reversed the attenuation of phosphorylation by lithium and valproate and also brought GluR1 back to the surface, suggesting that phosphorylation of GluR1p845 is involved in the mechanism of GluR1 surface attenuation. In addition, GluR1p845 phosphorylation also was attenuated in hippocampus from lithium-or valproate-treated animals in vivo. In contrast, imipramine, an antidepressant that can trigger manic episodes, increased synaptic expression of GluR1 in hippocampus in vivo. These studies suggest that regulation of glutamatergically mediated synaptic plasticity may play a role in the treatment of bipolar disorder and raise the possibility that agents more directly affecting synaptic GluR1 may represent novel therapies for this devastating illness. C1 NIMH, Mol Pathophysiol Lab, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Manji, HK (reprint author), NIMH, Mol Pathophysiol Lab, Mood & Anxiety Disorders Program, 49 Convent Dr MSC 4405,Bldg B1EE16, Bethesda, MD 20892 USA. EM manjih@intra.nimh.nih.gov RI Einat, Haim/A-7203-2009 NR 46 TC 107 Z9 111 U1 0 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 JUL 21 PY 2004 VL 24 IS 29 BP 6578 EP 6589 DI 10.1523/JNEUROSCI.1258-04.2004 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 839YS UT WOS:000222821800020 PM 15269270 ER PT J AU Hao, YL Creson, T Zhang, L Li, PP Du, F Yuan, PX Gould, TD Manji, HK Chen, G AF Hao, YL Creson, T Zhang, L Li, PP Du, F Yuan, PX Gould, TD Manji, HK Chen, G TI Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis SO JOURNAL OF NEUROSCIENCE LA English DT Article DE valproate; ERK; neurite outgrowth; neurogenesis; mania; mood disorders ID ACTIVATED PROTEIN-KINASE; DNA-BINDING ACTIVITY; CHRONIC ELECTROCONVULSIVE SEIZURE; CHRONIC ANTIDEPRESSANT TREATMENT; GLYCOGEN-SYNTHASE KINASE-3-BETA; FAMILY-BASED ASSOCIATION; TRKB MESSENGER-RNA; IN-VIVO EVIDENCE; RAT-BRAIN; NEUROTROPHIC FACTOR AB Manic-depressive illness has been conceptualized as a neurochemical illness. However, brain imaging and postmortem studies reveal gray-matter reductions, as well as neuronal and glial atrophy and loss in discrete brain regions of manic-depressive patients. The roles of such cerebral morphological deficits in the neuropathophysiology and therapeutic mechanisms of manic-depressive illness are unknown. Valproate (2-propylpentanoate) is a commonly used mood stabilizer. The ERK (extracellular signal-regulated kinase) pathway is used by neurotrophic factors to regulate neurogenesis, neurite outgrowth, and neuronal survival. We found that chronic treatment of rats with valproate increased levels of activated phospho-ERK44/42 in neurons of the anterior cingulate, a region in which we found valproate-induced increases in expression of an ERK pathway-regulated gene, bcl-2. Valproate time and concentration dependently increased activated phospho-ERK44/42 and phospho-RSK1 (ribosomal S6 kinase 1) levels in cultured cortical cells. These increases were attenuated by Raf and MEK (mitogen-activated protein kinase/ERK kinase) inhibitors. Although valproate affects the functions of GSK-3 (glycogen synthase kinase-3) and histone deacetylase ( HDAC), its effects on the ERK pathway were not fully mimicked by selective inhibitors of GSK-3 or HDAC. Similar to neurotrophic factors, valproate enhanced ERK pathway-dependent cortical neuronal growth. Valproate also promoted neural stem cell proliferation-maturation ( neurogenesis), demonstrated by bromodeoxyuridine ( BrdU) incorporation and double staining of BrdU with nestin, Tuj1, or the neuronal nuclei marker NeuN (neuronal-specific nuclear protein). Chronic treatment with valproate enhanced neurogenesis in the dentate gyrus of the hippocampus. Together, these data demonstrate that valproate activates the ERK pathway and induces ERK pathway-mediated neurotrophic actions. This cascade of events provides a potential mechanism whereby mood stabilizers alleviate cerebral morphometric deficits associated with manic-depressive illness. C1 NIMH, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. FD NeuroTechnol, Ellicott City, MD 21041 USA. RP Chen, G (reprint author), NIMH, Mol Pathophysiol Lab, NIH, Bldg 49,Room B1EE16,49 Convent Dr,MSC 4405, Bethesda, MD 20892 USA. EM cheng@intra.nimh.nih.gov RI Chen, Guang/A-2570-2017 NR 83 TC 271 Z9 285 U1 2 U2 14 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 21 PY 2004 VL 24 IS 29 BP 6590 EP 6599 DI 10.1523/JNEUROSCI.5747-03.2004 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 839YS UT WOS:000222821800021 PM 15269271 ER PT J AU Leitzmann, MF Giovannucci, E AF Leitzmann, MF Giovannucci, E TI Re: Zinc supplement use and risk of prostate cancer - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Leitzmann, MF (reprint author), NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, 6120 Execut Blvd,EPS MSC 7232, Bethesda, MD 20892 USA. EM leitzmann@mail.nih.gov NR 3 TC 2 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL 21 PY 2004 VL 96 IS 14 BP 1108 EP 1109 DI 10.1093/jnci/djh207 PG 2 WC Oncology SC Oncology GA 839RM UT WOS:000222802600017 ER PT J AU Bose-Basu, B DeRose, EF Kirby, TW Mueller, GA Beard, WA Wilson, SH London, RE AF Bose-Basu, B DeRose, EF Kirby, TW Mueller, GA Beard, WA Wilson, SH London, RE TI Dynamic characterization of a DNA repair enzyme: NMR studies of [methyl-C-13]methionine-labeled DNA polymerase beta SO BIOCHEMISTRY LA English DT Article ID CRYSTAL-STRUCTURES; DIHYDROFOLATE-REDUCTASE; KLENOW FRAGMENT; FIDELITY; BINDING; PROTEINS; DOMAIN; RELAXATION; MECHANISM; IDENTIFICATION AB Crystallographic characterization of DNA polymerase beta (pol beta) has suggested that multiple-domain and subdomain motions occur during substrate binding and catalysis. NMR studies of [methyl-C-13]methionine-labeled pol P were conducted to characterize the structural and dynamic response to ligand binding. The enzyme contains seven methionine residues, one of which is at the amino terminus and is partially removed by the expression system. Three of the methyl resonances were readily assigned using site-directed mutants. Assignment of the resonances of Met155, Met158, and Met191 was more difficult due to the spatial proximity of these residues, so that assignments were based on NOESY-HSQC data and on the response to paramagnetic Co2+ addition, as well as shift perturbations observed for the site-directed mutants. The response of the methyl resonances to substrate binding was evaluated by the serial addition of a template oligonucleotide, a downstream 5'-phosphorylated oligonucleotide, and a primer oligonucleotide to create a two-nucleotide-gapped DNA substrate. Addition of the single-stranded template DNA resulted in selective broadening of the methyl resonance of Met18 in the 8 kDa lyase domain, and this resonance then shifted and sharpened upon addition of a 5'-phosphate-terminated downstream complementary oligonucleotide. Conversion of the two-nucleotide-gapped DNA substrate to a single-nucleotide-gapped substrate by incorporation of ddCMP produced a small perturbation of the Met236 resonance, which makes contact with the primer strand in the crystal structure. The addition of a second equivalent of ddCTP to form the pol P-DNA-ddCTP ternary complex resulted in significant shifts for the resonances corresponding to Met155, Met191, Met236, and Met282. The Met155 methyl resonance is severely broadened, while the Met191 and Met:282 resonances exhibit significant but less extreme broadening. Since only Met236 makes contact with the substrate, the effects on Met155, Met236, and Met282 result from indirect conformational and dynamic perturbations. Previous crystallographic characterization of this abortive complex indicated that a polymerase subdomain or segment (alpha-helix N) repositions itself to form one face of the binding pocket for the nascent base pair. Met282 serves as a probe for motion in this segment. Addition of Mg2+-dATP to pol beta in the absence of DNA produced qualitatively similar but much smaller effects on Met191 and Met155, but did not strongly perturb Met282, leading to the conclusion that Mg2+-dATP alone is insufficient to produce the large conformational changes that are observed in the abortive complex involving the gapped DNA with a blocked primer and ddNTP. Thus, the NMR data indicate that the nucleotide-DNA interaction appears to be essential for conformational activation. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP London, RE (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM london@niehs.nih.gov NR 45 TC 43 Z9 43 U1 1 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 20 PY 2004 VL 43 IS 28 BP 8911 EP 8922 DI 10.1021/bi049641n PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 837VB UT WOS:000222668000004 PM 15248749 ER PT J AU Choi, JS Choi, YH Park, JS AF Choi, JS Choi, YH Park, JS TI Characterization of linear polymer-dendrimer block copolymer/plasmid DNA complexes: Formation of core-shell type nanoparticles with DNA and application to gene delivery in vitro SO BULLETIN OF THE KOREAN CHEMICAL SOCIETY LA English DT Article DE dendrimer; block copolymer; polyplex; cytotoxicity; gene delivery ID PLASMID DNA; OLIGONUCLEOTIDE; POLYETHYLENIMINE; MICELLES; THERAPY; VECTOR; CELLS AB A hybrid linear polymer-dendrimer block copolymer, poly(ethylene glycol)-block-poly(L-lysine) dendrimer, was synthesized and introduced to form polyionic complexes with DNA. The copolymer formed core-shell type nanoparticles with plasmid DNA. From dynamic light scattering experiments, the mean diameter of the polyplexes was observed to be 154.4 nm. The complex showed much increased water solubility compared to poly(L-lysine). The plasmid DNA in polyplexes was efficiently protected from the enzymatic digestion of DNase I. The cytotoxicity and transfection efficiency for 293 cells was measured in comparison with poly(L-lysine). C1 Seoul Natl Univ, Sch Chem & Mol Engn, Seoul 151742, South Korea. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. Chungnam Natl Univ, Dept Biochem, Taejon 305764, South Korea. RP Park, JS (reprint author), Seoul Natl Univ, Sch Chem & Mol Engn, Seoul 151742, South Korea. EM pfjspark@plaza.snu.ac.kr NR 24 TC 13 Z9 13 U1 0 U2 5 PU KOREAN CHEMICAL SOC PI SEOUL PA 635-4 YEOGSAM-DONG, KANGNAM-GU, SEOUL 135-703, SOUTH KOREA SN 0253-2964 J9 B KOR CHEM SOC JI Bull. Korean Chem. Soc. PD JUL 20 PY 2004 VL 25 IS 7 BP 1025 EP 1030 PG 6 WC Chemistry, Multidisciplinary SC Chemistry GA 844CW UT WOS:000223135900016 ER PT J AU Benjamin, EJ Larson, MG Keyes, MJ Mitchell, GF Vasan, RS Keaney, JF Vita, JA AF Benjamin, EJ Larson, MG Keyes, MJ Mitchell, GF Vasan, RS Keaney, JF Vita, JA TI Endothelial function in a large community - Response SO CIRCULATION LA English DT Letter ID VASODILATION; ARTERY C1 Boston Univ, Sch Med, Boston, MA 02118 USA. Cardiovasc Engn Inc, Holliston, MA USA. NHLBI, Framingham Study, Framingham, MA USA. RP Benjamin, EJ (reprint author), Boston Univ, Sch Med, Boston, MA 02118 USA. NR 4 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 20 PY 2004 VL 110 IS 3 BP E24 EP E24 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 839HQ UT WOS:000222775000029 ER PT J AU Lee, K KewalRamani, VN AF Lee, K KewalRamani, VN TI In defense of the cell: TRIM5 alpha interception of mammalian retroviruses SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID LEUKEMIA-VIRUS; CYCLOPHILIN-A; RESTRICTION; INFECTION; HIV-1; SUSCEPTIBILITY; SENSITIVITY; RESISTANCE; MONKEYS; FV1 C1 NCI, Model Dev Sect, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. RP KewalRamani, VN (reprint author), NCI, Model Dev Sect, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. EM vineet@ncifcrf.gov NR 25 TC 25 Z9 27 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 20 PY 2004 VL 101 IS 29 BP 10496 EP 10497 DI 10.1073/pnas.0404066101 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 840FN UT WOS:000222842700002 PM 15252204 ER PT J AU Shen, DW Su, A Liang, XJ Pai-Panandiker, A Gottesman, MM AF Shen, DW Su, A Liang, XJ Pai-Panandiker, A Gottesman, MM TI Reduced expression of small GTPases and hypermethylation of the folate binding protein gene in cisplatin-resistant cells SO BRITISH JOURNAL OF CANCER LA English DT Article DE small GTPases; endocytosis; FBP; DNA hypermethylation ID DRUG-RESISTANCE; CELLULAR PHARMACOLOGY; MULTIDRUG-RESISTANCE; ACQUIRED-RESISTANCE; CROSS-RESISTANCE; MISMATCH REPAIR; CARCINOMA CELLS; OVARIAN-CANCER; KB CELLS; LINES AB Reduced accumulation of cisplatin is the most consistent feature seen in cisplatin-resistant (CP-r) cells that are cross-resistant to other cytotoxic compounds, such as methotrexate. In this report, defective uptake of a broad range of compounds, including [C-14]-carboplatin, [H-3] MTX, [H-3] folic acid (FA), [I-125] epidermal growth factor, Fe-59, [H-3] glucose, and [H-3] proline, as well as As-73(5+) and As-73(3+), was detected in CP-r human hepatoma and epidermal carcinoma cells that we have previously shown are defective in fluid-phase endocytosis. Downregulation of several small GTPases, such as rab5, rac1, and rhoA, which regulate endocytosis, was found in CP-r cells. However, expression of an early endosomal protein and clathrin heavy chain was not changed, suggesting that the defective endocytic pathway is clathrin independent. Reduced expression of the cell surface protein, folate-binding protein (FBP), which is a carrier for the uptake of MTX, was also observed in the CP-r cells by confocal immunofluorescence microscopy and Real-Time PCR. Reactivation of the silenced FBP gene in the CP-r cells by a DNA demethylation agent, 2-deoxy-5-aza-cytidine (DAC) demonstrates that hypermethylation occurred in the CP-r cells. The uptake of [C-14] carboplatin, [H-3] FA, and [H-3] MTX increased in an early stage CP-r cell line (KB-CP1) after treatment with DAC. Both a defective endocytic pathway and DNA hypermethylation resulting in the downregulation of small regulatory GTPases and cell surface receptors contribute to the reduced accumulation of a broad range of compounds in CP-r cells. C1 NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM mgottesman@nih.gov NR 37 TC 37 Z9 40 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUL 19 PY 2004 VL 91 IS 2 BP 270 EP 276 DI 10.1038/sj.bjc.6601956 PG 7 WC Oncology SC Oncology GA 841LC UT WOS:000222930300015 PM 15199393 ER PT J AU Connell, S Karikari, C Hohmann, CF AF Connell, S Karikari, C Hohmann, CF TI Sex-specific development of cortical monoamine levels in mouse SO DEVELOPMENTAL BRAIN RESEARCH LA English DT Article DE mouse; ontogeny; high performance liquid chromatography; dimorphism; mental health ID CEREBRAL-CORTEX; RAT CORTEX; BRAIN; SYSTEMS; DIFFERENTIATION; PLASTICITY; NEURONS; SCHIZOPHRENIA; HYPOTHALAMUS; METABOLITES AB Several mental health disorders exhibit sex differences in monoamine levels associated with dimorphic cortical ontogeny. Studies in rodents support the notion that monoamines can profoundly modulate morphogenesis. Here, we show significant sex and hemisphere differences in BALB/cByJ mice on postnatal day 3 for dopamine (DA) and serotonin (5-TH), supporting the notion that sex differences in early monoaminergic ontogeny may result in dimorphic cortical development. Such sex differences may also influence differential behavioral and/or clinical outcomes. (C) 2004 Elsevier B.V. All rights reserved. C1 Morgan State Univ, Dept Biol, Baltimore, MD 21251 USA. Morgan State Univ, Doctoral Studies Program Math & Sci Educ, Baltimore, MD 21251 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Hohmann, CF (reprint author), Morgan State Univ, Dept Biol, 1700 E Cold Spring Ln, Baltimore, MD 21251 USA. EM Chohmann@morgan.edu NR 39 TC 20 Z9 20 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-3806 J9 DEV BRAIN RES JI Dev. Brain Res. PD JUL 19 PY 2004 VL 151 IS 1-2 BP 187 EP 191 DI 10.1016/j.devbrainres.2004.03.008 PG 5 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 841VQ UT WOS:000222960200018 ER PT J AU Chernyavsky, AI Arredondo, J Wess, J Karlsson, E Grando, SA AF Chernyavsky, AI Arredondo, J Wess, J Karlsson, E Grando, SA TI Novel signaling pathways mediating reciprocal control of keratinocyte migration and wound epithelialization through M-3 and M-4 muscarinic receptors SO JOURNAL OF CELL BIOLOGY LA English DT Article DE cyclic GMP; cyclic AMP; knockout mice; acetylcholine ID HAIR FOLLICLE MORPHOGENESIS; PROTEIN-COUPLED RECEPTORS; SMOOTH-MUSCLE-CELLS; BETA-GAMMA DIMERS; ACETYLCHOLINE-RECEPTOR; EXTRACELLULAR-MATRIX; CARCINOMA-CELLS; CALCIUM INFLUX; MOTILITY; GROWTH AB To test the hypothesis that keratinocyte (KC) migration is modulated by distinct muscarinic acetylcholine (ACh) receptor subtypes, we inactivated signaling through specific receptors in in vitro and in vivo models of reepithelialization by subtype-selective antagonists, small interfering RNA, and gene knockout in mice. KC migration and wound reepithelialization were facilitated by M-4 and inhibited by M-3. Additional studies showed that M-4 increases expression of "migratory" integrins alpha(5)beta(1), alpha(v)beta(5), and alpha(v)beta(6), whereas M-3 up-regulates "sedentary" integrins alpha(2)beta(1) and alpha(3)beta(1). Inhibition of migration by M-3 was mediated through Ca2+-dependent guanylyl cyclase-cyclic GMP-protein kinase G signaling pathway. The M-4 effects resulted from inhibition of the inhibitory pathway involving the adenylyl cyclase-cyclic AMP-protein kinase A pathway. Both signaling pathways intersected at Rho, indicating that Rho kinase provides a common effector for M-3 and M-4 regulation of cell migration. These findings offer novel insights into the mechanisms of ACh-mediated modulation of KC migration and wound reepithelialization, and may aid the development of novel methods to promote wound healing. C1 Univ Calif Davis, Dept Dermatol, Sacramento, CA 95817 USA. NIDDKD, Bioorgan Chem Lab, Mol Signaling Sect, NIH, Bethesda, MD 20892 USA. Karolinska Inst, Sect Expt Geriatr, Neurotec, S-14186 Huddinge, Sweden. RP Grando, SA (reprint author), Univ Calif Davis, Dept Dermatol, 4860 Y St 3400, Sacramento, CA 95817 USA. EM sagrando@ucdavis.edu FU NIDCR NIH HHS [DE14173, R01 DE014173]; NIGMS NIH HHS [GM62136, R01 GM062136] NR 62 TC 44 Z9 46 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD JUL 19 PY 2004 VL 166 IS 2 BP 261 EP 272 DI 10.1083/jcb.200401034 PG 12 WC Cell Biology SC Cell Biology GA 841JT UT WOS:000222926800012 PM 15263021 ER PT J AU Al-Shami, A Spolski, R Kelly, J Fry, T Schwartzberg, PL Pandey, A Mackall, CL Leonard, WJ AF Al-Shami, A Spolski, R Kelly, J Fry, T Schwartzberg, PL Pandey, A Mackall, CL Leonard, WJ TI A role for thymic stromal lymphopoietin in CD4(+) T cell development SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE thymocyte development; IL-7; SCID; CD8 T cells; knockout inice ID RECEPTOR-GAMMA CHAIN; MEDIATED SIGNAL-TRANSDUCTION; INTERLEUKIN-7 RECEPTOR; LYMPHOID HOMEOSTASIS; GROWTH-FACTOR; IN-VITRO; CYTOKINE; STAT5; MICE; TSLP AB Thymic stromal lymphopoietin (TSLP) signals via a receptor comprising the interleukin (IL)-7 receptor alpha chain and a distinctive subunit, TSLP receptor (TSLPR,), which is most related to the common cytokine receptor gamma chain, gamma(c). We have generated TSLPR knockout (KO) mice and found that although these mice had normal lymphocyte numbers, gamma(c)/TSLPR double KO mice had a greater lymphoid defect than gamma(c) KO mice. This indicates that TSLP contributes to lymphoid development and accounts for some of the residual lymphoid development in gamma(c) KO mice and presumably in patients with X-linked severe combined immunodeficiency. Injection of TSLP into gamma(c) KO mice induced the expansion of T and B cells. Moreover, sublethally irradiated TSLPR, KO mice showed weaker recovery of lymphocyte populations than wild-type (WT) littermates, even when neutralizing anti-IL-7 antibodies were injected. Interestingly, TSLP preferentially stimulated the proliferation and survival of CD4(+) single positive thymocytes and peripheral T cells in vitro. Additionally, CD4(+) T cells from TSLPR KO mice expanded less efficiently than WT CD4(+) T cells in irradiated hosts, and TSLP preferentially expanded CD4(+) T cells both in vitro and in vivo. Thus, as compared with other known cytokines, TSLP is distinctive in exhibiting a lineage preference for the expansion and survival of CD4(+) T cells. C1 NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD 21287 USA. RP Leonard, WJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10,Room 7N252, Bethesda, MD 20892 USA. EM wjl@helix.nih.gov RI Pandey, Akhilesh/B-4127-2009; Al-Shami, Amin/D-3889-2009 OI Pandey, Akhilesh/0000-0001-9943-6127; NR 37 TC 148 Z9 153 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 19 PY 2004 VL 200 IS 2 BP 159 EP 168 DI 10.1084/jem.20031975 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 841JL UT WOS:000222926000004 PM 15263024 ER PT J AU Warfield, KL Perkins, JG Swenson, DL Deal, EM Bosio, CM Aman, MJ Yokoyama, WM Young, HA Bavari, S AF Warfield, KL Perkins, JG Swenson, DL Deal, EM Bosio, CM Aman, MJ Yokoyama, WM Young, HA Bavari, S TI Role of natural killer cells in innate protection against lethal Ebola virus infection SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE virus-like particles; filoviruses; immunity; matrix protein; glycoprotein ID MATRIX PROTEIN VP40; DENDRITIC CELLS; NK CELLS; IN-VIVO; HEMORRHAGIC-FEVER; MARBURG VIRUSES; CYTOMEGALOVIRUS; ACTIVATION; RECOGNITION; PARTICLES AB Ebola virus is a highly lethal human pathogen and is rapidly driving many wild primate populations toward extinction. Several lines of evidence suggest that innate, nonspecific host factors are potentially critical for survival after Ebola virus infection. Here, we show that nonreplicating Ebola virus-like particles (VLPs), containing the glycoprotein (GP) and matrix protein virus protein (VP)40, administered 1-3 d before Ebola virus infection rapidly induced protective immunity. VLP injection enhanced the numbers of natural killer (NK) cells in lymphoid tissues. In contrast to live Ebola virus, VLP treatment of NK cells enhanced cytokine secretion and cytolytic activity against NK-sensitive targets. Unlike wild-type mice, treatment of NK-deficient or -depleted mice with VLPs had no protective effect against Ebola virus infection and NK cells treated with VLPs protected against Ebola virus infection when adoptively transferred to naive mice. The mechanism of NK cell-mediated protection clearly depended on perform, but not interferon-gamma secretion. Particles containing only VP40 were sufficient to induce NK cell responses and provide protection from infection in the absence of the viral GP. These findings revealed a decisive role for NK cells during lethal Ebola virus infection. This work should open new doors for better understanding of Ebola virus pathogenesis and direct the development of immunotherapeutics, which target the innate immune system, for treatment of Ebola virus infection. C1 USA, Med Res Inst Infect Dis, Frederick, MD 21702 USA. NCI, Expt Immunol Lab, Frederick, MD 21702 USA. Walter Reed Army Med Ctr, Dept Hematol & Oncol, Washington, DC 20307 USA. Washington Univ, Sch Med, Howard Hughes Med Inst, Div Rheumatol, St Louis, MO 63110 USA. RP Bavari, S (reprint author), USA, Med Res Inst Infect Dis, 1425 Porter St, Frederick, MD 21702 USA. EM sina.bavari@amedd.army.mil RI Young, Howard/A-6350-2008; Bosio, Catharine/D-7456-2015 OI Young, Howard/0000-0002-3118-5111; NR 53 TC 79 Z9 85 U1 0 U2 22 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 19 PY 2004 VL 200 IS 2 BP 169 EP 179 DI 10.1084/jem.20032141 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 841JL UT WOS:000222926000005 PM 15249592 ER PT J AU Mendez, S Reckling, SK Piccirillo, CA Sacks, D Belkaid, Y AF Mendez, S Reckling, SK Piccirillo, CA Sacks, D Belkaid, Y TI Role for CD4(+) CD25(+) regulatory T cells in reactivation of persistent Leishmaniasis and control of concomitant immunity SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE Leishmania; reactivation; CD4(+); CD25(+); regulatory T cells; memory; chronicity ID EXPERIMENTAL VISCERAL LEISHMANIASIS; CUTANEOUS LEISHMANIASIS; MUCOCUTANEOUS LEISHMANIASIS; RECEPTOR BLOCKADE; DENDRITIC CELLS; MAJOR INFECTION; NATURAL MODEL; BALB/C MICE; IN-VIVO; IL-10 AB Reactivation of dormant infections causes an immense burden of morbidity and mortality in the world at large. Reactivation can occur as a result of immunosuppression, environmental insult, or aging; however, the cause of reactivation of such infections is often not clear. We have previously shown that persistence of the parasite Leishmania major is controlled by endogenous CD4(+) CD25(+) regulatory T (T reg) cells. In this report, we show that despite efficient parasite clearance at secondary sites of infection, Leishmania superinfection can cause disease reactivation at the primary site. Our results strongly suggest that T reg cells, whose numbers increase in sites of reactivation, are directly responsible for such reactivation. Depletion of CD25(+) cells at the time of secondary challenge prevented disease reactivation at the site of persistent infection while strengthening the expression of immunity at the site of secondary challenge. Finally, transfer of T reg cells purified from infected mice into chronically infected mice was sufficient to trigger disease reactivation and prevent the expression of an effector memory response. Our results demonstrate that after persistence is achieved, an equilibrium between T reg cells and effector lymphocytes, which can be disturbed by superinfection, controls the efficiency of recall immune responses and disease reactivation. C1 Childrens Hosp Res Fdn, Div Mol Immunol, Cincinnati, OH 45229 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Belkaid, Y (reprint author), Childrens Hosp Res Fdn, Div Mol Immunol, 3333 Burnet Ave,TCHFR 1565, Cincinnati, OH 45229 USA. EM yasmine.belkaid@cchmc.org NR 50 TC 192 Z9 209 U1 1 U2 5 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 19 PY 2004 VL 200 IS 2 BP 201 EP 210 DI 10.1084/jem.20040298 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 841JL UT WOS:000222926000008 PM 15263027 ER PT J AU Stavrovskaya, IG Narayanan, MV Zhang, WH Krasnikov, BF Heemskerk, J Young, SS Blass, JP Brown, AM Beal, MF Friedlander, RM Kristal, BS AF Stavrovskaya, IG Narayanan, MV Zhang, WH Krasnikov, BF Heemskerk, J Young, SS Blass, JP Brown, AM Beal, MF Friedlander, RM Kristal, BS TI Clinically approved heterocyclics act on a mitochondrial target and reduce stroke-induced pathology SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE caspases; cell death; apoptosis; antidepressants; antipsychotics ID PERMEABILITY TRANSITION PORE; CEREBRAL-ARTERY OCCLUSION; NEURONAL CELL-DEATH; INTERLEUKIN-1-BETA CONVERTING-ENZYME; CEREBELLAR GRANULE CELLS; CENTRAL-NERVOUS-SYSTEM; FOCAL BRAIN ISCHEMIA; SPINAL-CORD-INJURY; CYCLOSPORINE-A; CYTOCHROME-C AB Substantial evidence indicates that mitochondria are a major checkpoint in several pathways leading to neuronal cell death, but discerning critical propagation stages from downstream consequences has been difficult. The mitochondrial permeability transition (mPT) may be critical in stroke-related injury. To address this hypothesis, identify potential therapeutics, and screen for new uses for established drugs with known toxicity, 1,040 FDA-approved drugs and other bioactive compounds were tested as potential mPT inhibitors. We report the identification of 28 structurally related drugs, including tricyclic antidepressants and antipsychotics, capable of delaying the mPT. Clinically achievable doses of one drug in this general structural class that inhibits mPT, promethazine, were protective in both in vitro and mouse models of stroke. Specifically, promethazine protected primary neuronal cultures subjected to oxygen-glucose deprivation and reduced infarct size and neurological impairment in mice subjected to middle cerebral artery occlusion/reperfusion. These results, in conjunction with new insights provided to older studies, (a) suggest a class of safe, tolerable drugs for stroke and neurodegeneration; (b) provide new tools for understanding mitochondrial roles in neuronal cell death; (c) demonstrate the clinical/experimental value of screening collections of bioactive compounds enriched in clinically available agents; and (d) provide discovery-based evidence that mPT is an essential, causative event in stroke-related injury. C1 Burke Med Res Inst, Dementia Res Serv, White Plains, NY 10605 USA. Brigham & Womens Hosp, Dept Neurosurg, Neuroapoptosis Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. NINDS, Raleigh, NC 27607 USA. CGStat LLC, Raleigh, NC 27607 USA. Cornell Univ, Weill Med Coll, Dept Neurol & Neurosci, New York, NY 10021 USA. Cornell Univ, Weill Med Coll, Dept Biochem, New York, NY 10021 USA. RP Kristal, BS (reprint author), Burke Med Res Inst, Dementia Res Serv, 785 Mamaroneck Ave, White Plains, NY 10605 USA. EM bkristal@burke.org RI Friedlander, Robert/A-2845-2016; OI Friedlander, Robert/0000-0003-4423-9219; Krasnikov, Boris/0000-0001-9525-4385 NR 93 TC 58 Z9 63 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 19 PY 2004 VL 200 IS 2 BP 211 EP 222 DI 10.1084/jem.20032053 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 841JL UT WOS:000222926000009 PM 15263028 ER PT J AU Quandt, JA Baig, M Yao, K Kawamura, K Huh, JB Ludwin, SK Bian, HJ Bryant, M Quigley, L Nagy, ZA McFarland, HE Muraro, PA Martin, R Ito, K AF Quandt, JA Baig, M Yao, K Kawamura, K Huh, JB Ludwin, SK Bian, HJ Bryant, M Quigley, L Nagy, ZA McFarland, HE Muraro, PA Martin, R Ito, K TI Unique clinical and pathological features in HLA-DRB1*0401-restricted MBP 111-129-specific humanized TCR transgenic mice SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE HLA-DR-131*0401; myelin basic protein; transgenic mouse; experimental autoimmune encephalomyelitis; multiple sclerosis ID MYELIN BASIC-PROTEIN; T-CELL-RECEPTOR; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MULTIPLE-SCLEROSIS; OLIGODENDROCYTE GLYCOPROTEIN; ENCEPHALITOGENIC DETERMINANT; IMMUNOLOGICAL ASPECTS; DISEASE; SUSCEPTIBILITY AB Amino acid residues 111-129 represent an immunodominant epitope of myelin basic protein (MBP) in humans with human leukocyte antigen (HLA)-DRB1(star)0401 allele(s). The MBP 111-129-specific T cell clone MS2-3C8 was repeatedly isolated from a patient with multiple sclerosis (MS), suggesting an involvement of MS2-3C8 T cells in the pathogenesis. To address the pathogenic potential of the MS2-3C8 T cell clone, we generated transgenic (Tg) mice expressing its T cell receptor and restriction element, HLA-DRB1(star)0401, to examine the pathogenic characteristics of MS2-3C8 Tg T cells by adoptive transfer into HLA-DRB1(star)0401 Tg mice. In addition to the ascending paralysis typical of experimental autoimmune encephalomyelitis, mice displayed dysphagia due to restriction in jaw and tongue movements and abnormal gait. In accordance with the clinical phenotype, infiltrates of MS2-3C8 Tg T cells and inflammatory lesions were predominantly located in the brainstem and the cranial nerve roots in addition to the spinal cord and spinal nerve roots. Together, these data suggest a pathogenic role of MBP-specific T cells in inflammatory demyelination within the brainstem and cranial nerve roots during the progression of MS. This notion may help to explain the clinical and pathological heterogeneity of MS. C1 NINDS, NIH, Bethesda, MD 20892 USA. NIH, Vet Resources Program, Off Director, Bethesda, MD 20892 USA. Hoffmann La Roche Inc, Nutley, NJ 07110 USA. GPC Biotech AG, D-82152 Martinsried, Germany. RP Ito, K (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurol, 683 Hoes Ln, Piscataway, NJ 08854 USA. EM itoko@umdnj.edu OI Muraro, Paolo/0000-0002-3822-1218 NR 37 TC 29 Z9 30 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 19 PY 2004 VL 200 IS 2 BP 223 EP 234 DI 10.1084/jem.20030994 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 841JL UT WOS:000222926000010 PM 15263029 ER PT J AU Fleeton, MN Contractor, N Leon, F Wetzel, JD Dermody, TS Kelsall, BL AF Fleeton, MN Contractor, N Leon, F Wetzel, JD Dermody, TS Kelsall, BL TI Peyer's patch dendritic cells process viral antigen from apoptotic epithelial cells in the intestine of reovirus-infected mice SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE antigen processing; apoptosis; epithelial cells; immunity, mucosal; reovirus infection ID CD8(+) T-CELLS; CYTOMEGALOVIRUS PP65 UL83; CROSS-PRESENTATION; IN-VIVO; CUTTING EDGE; SUBEPITHELIAL DOME; SIGMA-1 PROTEIN; NEONATAL MICE; LYMPH-NODES; DYING CELLS AB We explored the role of Peyer's patch (PP) dendritic cell (DC) populations in the induction of immune responses to reovirus strain type 1 Lang (T1L). Immunofluorescence staining revealed the presence of T1L structural (sigma1) and nonstructural (sigmaNS) proteins in PPs of T1L-infected mice. Cells in the follicle-associated epithelium contained both sigma1 and sigmaNS, indicating productive viral replication. In contrast, sigma1, but not sigmaNS, was detected in the subepithelial dome (SED) in association with CD11c(+)/CD8alpha(-)/CD11b(lo) DCs, suggesting antigen uptake by these DCs in the absence of infection. Consistent with this possibility, PP DCs purified from infected mice contained sigma1, but not sigmaNS, and PP DCs from uninfected mice could not be productively infected in vitro. Furthermore, sigma1 protein in the SED was associated with fragmented DNA by terminal deoxy-UTP nick-end labeling staining, activated caspase-3, and the epithelial cell protein cytokeratin, suggesting that DCs capture T1L antigen from infected apoptotic epithelial cells. Finally, PP DCs from infected mice activated T1L-primed CD4(+) T cells in vitro. These studies show that CD8alpha(-)/CD11b(lo) DCs in. the PP SED process T1L antigen from infected apoptotic epithelial cells for presentation to CD4(+) T cells, and therefore demonstrate the cross-presentation of virally infected cells by DCs in vivo during a natural viral infection. C1 NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37232 USA. Vanderbilt Univ, Sch Med, Dept Microbiol & Immunol, Nashville, TN 37232 USA. Vanderbilt Univ, Sch Med, Elizabeth B Lamb Ctr Pediat Res, Nashville, TN 37232 USA. RP Kelsall, BL (reprint author), NIAID, Lab Mol Immunol, NIH, Bldg 10,Room 11N228, Bethesda, MD 20892 USA. EM Kelsall@nihi.gov FU NCI NIH HHS [P30 CA068485, CA68485]; NIAID NIH HHS [AI50080, R01 AI050080]; NIDDK NIH HHS [DK20593, P30 DK020593, P60 DK020593] NR 62 TC 94 Z9 95 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 19 PY 2004 VL 200 IS 2 BP 235 EP 245 DI 10.1084/jem.20041132 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 841JL UT WOS:000222926000011 PM 15263030 ER PT J AU Hron, JD Caplan, L Gerth, AJ Schwartzberg, PL Peng, SL AF Hron, JD Caplan, L Gerth, AJ Schwartzberg, PL Peng, SL TI SH2131A regulates T-dependent humoral autoimmunity SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE autoimmunity; mice; knockout; hipus; T lymphocytes ID LINKED LYMPHOPROLIFERATIVE DISEASE; SYSTEMIC-LUPUS-ERYTHEMATOSUS; NF-KAPPA-B; CELLS; RESPONSES; MICE; ACTIVATION; RECEPTOR; SAP; DIFFERENTIATION AB The signaling lymphocytic activation molecule (SLAM)/CD150 family includes a family of chromosome 1-encoded cell surface molecules with costimulatory functions mediated in part by the adaptor protein SH2D1A (SLAM-associated protein, SAP). Deficiency in SH2D1A protects mice from an experimental model of lupus, including the development of hypergammaglobulinemia, autoantibodies including anti-double stranded DNA, and renal disease. This protection did not reflect grossly defective T or B cell function per se because SH2D1A-deficient juice were susceptible to experimental autoimmune encephalomyelitis, a T cell-dependent disease, and they were capable of mounting normal T-Independent antigen-specific immunoglobulin responses. Instead, T-dependent antibody responses were impaired in SH2D1A-deficient mice, reflecting defective germinal center formation. These findings demonstrate a specific role for the SLAM-SH2D1A system in the regulation of T-dependent humoral immune responses, implicating members of the CD150-SH2D1A family as targets in the pathogenesis and therapy of antibody-mediated autoimmune and allergic diseases. C1 Washington Univ, Sch Med, Dept Internal Med Rheumatol, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Peng, SL (reprint author), Washington Univ, Sch Med, Dept Internal Med Rheumatol, Campus Box 8045,CSRB 6617,660 S Euclid Ave, St Louis, MO 63110 USA. EM speng@im.wustl.edu FU NIAID NIH HHS [AI057471, R01 AI057471, AI01803] NR 22 TC 77 Z9 81 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 19 PY 2004 VL 200 IS 2 BP 261 EP 266 DI 10.1084/jem.20040526 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 841JL UT WOS:000222926000014 PM 15263031 ER PT J AU Bertini, G Buffalo, EA De Weerd, P Desimone, R Ungerleider, LG AF Bertini, G Buffalo, EA De Weerd, P Desimone, R Ungerleider, LG TI Visual responses to targets and distracters by inferior temporal neurons after lesions of extrastriate areas V4 and TEO SO NEUROREPORT LA English DT Article DE attention; electrophysiology; receptive field; rhesus monkey; visual cortex; visual perception ID INFEROTEMPORAL CORTEX; MACAQUE MONKEY; SELECTIVE ATTENTION; CONNECTIONS; DISCRIMINATION; PERFORMANCE; MECHANISMS; PARIETAL; PATHWAYS; OBJECTS AB While lesions of visual areas V4 and TEO only modestly affect discrimination of isolated objects, they significantly impair the ability to selectively attend to an object surrounded by distracters. To test whether such deficits result from a loss of inputs to higher order areas, we recorded from area TE neurons after removing portions of V4 and TEO in a monkey. Responses to isolated targets in a lesion-affected visual quadrant were substantially preserved, indicating that TE still receives information even after removing a major source of input. Distracters increased or decreased the response to targets more in the lesion-affected than in the normal quadrant, supporting the idea that V4 and/or TEO are sites where top-down attentional inputs filter out distracting stimuli. C1 NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. RP Bertini, G (reprint author), Univ Verona, Dept Morphol & Biomed Sci, Strada Grazie 8, I-37134 Verona, Italy. EM giuseppe.bertini@univr.it NR 25 TC 6 Z9 6 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JUL 19 PY 2004 VL 15 IS 10 BP 1611 EP 1615 DI 10.1097/01.wnr.0000134847.86625.15 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 871NP UT WOS:000225140700016 PM 15232293 ER PT J AU Kim, M Sgagias, M Deng, XY Jung, YJ Rikiyama, T Lee, K Ouellette, M Cowan, K AF Kim, M Sgagias, M Deng, XY Jung, YJ Rikiyama, T Lee, K Ouellette, M Cowan, K TI Apoptosis induced by adenovirus-mediated p14(ARF) expression in U2OS osteosarcoma cells is associated with increased Fas expression SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE p14ARF; apoptosis; Fas; p53; adenovirus ID BREAST-CANCER CELLS; CYCLE ARREST; TUMOR SUPPRESSION; INK4A LOCUS; P53; ACTIVATION; P27(KIP1); PRODUCT; GROWTH; FLICE AB The INK4A/ARF locus on chromosome 9 is a tumor suppressor gene frequently mutated in human cancers. In order to study the effects of p14ARF expression in tumor cells, we constructed a recombinant adenovirus containing p14ARF cDNA (Adp14(ARF)). Adp14(ARF) infection of U2OS osteosarcoma cells which has wild type p53 and mutant p14ARF revealed high levels of p14 (ARF) expression within 24 h. In addition, Adp14(ARF)-mediated expressing of p14 (ARF) was associated with increased levels of p53, p21, and mdm2 protein. Growth inhibition assays following Adp14(ARF) infection demonstrated that the growth of U2OS cells was inhibited relative to infection with control virus. Furthermore, TUNEL analysis as well as PARP cleavage assays demonstrated that Adp14(ARF) infection was associated with increased apoptosis in U2OS cell line and that it was associated with Adp14(ARF) induced overexpression of Fas and Fas-L. Addition of Fas-L neutralizing antibody NOK-1 decreased Adp14-mediated cell death, indicating that p14 (ARF) induction of the Fas pathway is associated with increased apoptosis. The finding that Adp14(ARF) infection did not induce Fas expression in U2OS/E6 and MCF/E6 cells suggests that wild type p53 expression may be necessary for Adp14(ARF)- mediated induction of Fas. The observation that overexpression of p53 by Adp53 infection in MCF-7 does not induce increased Fas protein levels nor apoptotic cell death suggests that p53 overexpression is required but not sufficient enough for apoptosis. These studies suggest there are other mechanisms other than induction of p53 in ARF-mediated apoptosis and gene therapy using Adp14(ARF) may be a promising treatment option for human cancers containing wild type p53 and mutant or deleted p 14 expression. (C) 2004 Elsevier Inc. All rights reserved. C1 Childrens Natl Med Ctr, Washington, DC 20010 USA. Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. Cent S Univ, Xiangya Sch Med, Inst Canc Res, Changsha 410078, Hunan, Peoples R China. NCI, NIH, Med Branch, Bethesda, MD 20892 USA. RP Kim, M (reprint author), Childrens Natl Med Ctr, Washington, DC 20010 USA. EM minkim@cnmc.org NR 25 TC 11 Z9 16 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUL 16 PY 2004 VL 320 IS 1 BP 138 EP 144 DI 10.1016/j.bbrc.2004.05.135 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 835PA UT WOS:000222494500021 PM 15207713 ER PT J AU Morrell, A Antony, S Kohlhagen, G Pommier, Y Cushman, M AF Morrell, A Antony, S Kohlhagen, G Pommier, Y Cushman, M TI Synthesis of nitrated indenoisoquinolines as topoisomerase I inhibitors SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE indenoisoquinoline; topoisomerase I inhibitor; anticancer; cytotoxicity ID BIOLOGICAL EVALUATION; CHLORIDE; DESIGN AB Indenoisoquinolines and dihydroindenoisoquinolines have been synthesized possessing a nitro-substituted isoquinoline ring in an effort to explore the effects of electron-withdrawing substituents on biological activity. The in vitro anticancer activities of these molecules have been tested in the National Cancer Institute's screen of 55 cell lines. The compounds have also been tested for topoisomerase I (topI) inhibition. The results indicate that these substances are a potent class of topI inhibitors with sub-micromolar cytotoxicity mean graph midpoints (MGM) and topI inhibition equal to camptothecin. (C) 2004 Elsevier Ltd. All rights reserved. C1 Purdue Univ, Sch Pharm & Pharmacal Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. NCI, Canc Res Ctr, Mol Pharmacol Lab, Bethesda, MD 20892 USA. RP Cushman, M (reprint author), Purdue Univ, Sch Pharm & Pharmacal Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. EM cushman@pharmacy.purdue.edu FU NCI NIH HHS [UO1 CA89566, N01-CO-56000]; OHS HRSA HHS [ST32 CA09634-12] NR 13 TC 45 Z9 45 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 JUL 16 PY 2004 VL 14 IS 14 BP 3659 EP 3663 DI 10.1016/j.bmcl.2004.05.022 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 833VB UT WOS:000222367300008 PM 15203138 ER PT J AU Fetterolf, B Bewley, CA AF Fetterolf, B Bewley, CA TI Synthesis of a bromotyrosine-derived natural product inhibitor of mycothiol-S-conjugate amidase SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE mycobacteria; marine natural products; deacetylase; enzyme ID MYCOBACTERIUM-TUBERCULOSIS; RESISTANT TUBERCULOSIS; PSAMMAPLIN-A; METABOLITES; SPONGE AB Recently we described the structures of two new bromotyrosine-derived alkaloids that inhibit the detoxification enzyme mycothiol-S-conjugate amidase (MCA) from Mycobacterium tuberculosis. Here we describe a concise total synthesis of bromotyrosine oxime 1. The six-step synthesis of 1 utilized a trifluoromethyloxazole intermediate, whose hydrolysis product underwent alkylation and coupling to agmatine to give the inhibitor in similar to40% overall yield. Oxime 1 inhibited MCA and its homolog AcGI deacetylase with IC50 values of 30 and 150 muM, respectively. (C) 2004 Elsevier Ltd. All rights reserved. C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Bewley, CA (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM cb194k@nih.gov NR 21 TC 20 Z9 23 U1 0 U2 0 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 JUL 16 PY 2004 VL 14 IS 14 BP 3785 EP 3788 DI 10.1016/j.bmcl.2004.04.095 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 833VB UT WOS:000222367300032 PM 15203162 ER PT J AU Anantharaman, V Aravind, L AF Anantharaman, V Aravind, L TI Novel conserved domains in proteins with predicted roles in eukaryotic cell-cycle regulation, decapping and RNA stability SO BMC GENOMICS LA English DT Article ID SM-LIKE PROTEINS; MULTIPLE SEQUENCE ALIGNMENT; SACCHAROMYCES-CEREVISIAE; CRYSTAL-STRUCTURES; BINDING DOMAIN; COMPARATIVE GENOMICS; MAXIMUM-LIKELIHOOD; ESCHERICHIA-COLI; SPLICING FACTORS; STABLE CORE AB Background: The emergence of eukaryotes was characterized by the expansion and diversification of several ancient RNA-binding domains and the apparent de novo innovation of new RNA-binding domains. The identification of these RNA-binding domains may throw light on the emergence of eukaryote-specific systems of RNA metabolism. Results: Using sensitive sequence profile searches, homology-based fold recognition and sequence-structure superpositions, we identified novel, divergent versions of the Sm domain in the Scd6p family of proteins. This family of Sm-related domains shares certain features of conventional Sm domains, which are required for binding RNA, in addition to possessing some unique conserved features. We also show that these proteins contain a second previously uncharacterized C-terminal domain, termed the FDF domain (after a conserved sequence motif in this domain). The FDF domain is also found in the fungal Dcp3p-like and the animal FLJ22128-like proteins, where it fused to a C-terminal domain of the YjeF-N domain family. In addition to the FDF domains, the FLJ22128-like proteins contain yet another divergent version of the Sm domain at their extreme N-terminus. We show that the YjeF-N domains represent a novel version of the Rossmann fold that has acquired a set of catalytic residues and structural features that distinguish them from the conventional dehydrogenases. Conclusions: Several lines of contextual information suggest that the Scd6p family and the Dcp3p-like proteins are conserved components of the eukaryotic RNA metabolism system. We propose that the novel domains reported here, namely the divergent versions of the Sm domain and the FDF domain may mediate specific RNA-protein and protein-protein interactions in cytoplasmic ribonucleoprotein complexes. More specifically, the protein complexes containing Sm-like domains of the Scd6p family are predicted to regulate the stability of mRNA encoding proteins involved in cell cycle progression and vesicular assembly. The Dcp3p and FLJ22128 proteins may localize to the cytoplasmic processing bodies and possibly catalyze a specific processing step in the decapping pathway. The explosive diversification of Sm domains appears to have played a role in the emergence of several uniquely eukaryotic ribonucleoprotein complexes, including those involved in decapping and mRNA stability. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM ananthar@mail.nih.gov; aravind@mail.nih.gov OI Anantharaman, Vivek/0000-0001-8395-0009 NR 66 TC 54 Z9 55 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUL 16 PY 2004 VL 5 AR 45 DI 10.1186/1471-2164-5-45 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 844UP UT WOS:000223186400001 PM 15257761 ER PT J AU Cai, DC McCarron, RM Yu, EZ Li, YY Hallenbeck, J AF Cai, DC McCarron, RM Yu, EZ Li, YY Hallenbeck, J TI Akt phosphorylation and kinase activity are down-regulated during hibernation in the 13-lined ground squirrel SO BRAIN RESEARCH LA English DT Article DE hibernation; Akt; dauer larva; Caenorhabditis elegans; tolerance; signaling ID FORKHEAD TRANSCRIPTION FACTOR; NEMATODE CAENORHABDITIS-ELEGANS; PROTEIN-KINASE; CEREBRAL-ISCHEMIA; CELL-DEATH; MOLECULAR-CLONING; BINDING-PROTEINS; FACTOR FOXO3A; C-ELEGANS; SURVIVAL AB Hibernation in mammals is a reversible state of suspended animation associated with tolerance to an otherwise lethal reduction of core body temperature and metabolism. An integral aspect of hibernation is tolerance to a profound decrease of cerebral perfusion. Identification of regulatory mechanisms that control hibernation in ground squirrels can guide efforts to develop improved treatment for stroke and brain trauma. In this study, we show in multiple tissues that S473 phosphorylation of Akt (Protein kinase B), a phosphatidylinositol-3 kinase-regulated serine/threonine kinase, was significantly reduced (P<0.001) as was its kinase activity (P=0.023) in the 13-lined ground squirrel, Spermophilus tridecemlineatus, during hibernation. T308 phosphorylation of Akt was relatively preserved. Brain immunohistochemical staining confirmed these results. In hibernating animals, reduction of immunoreactive phospho (S473)-Akt was noted throughout the brain. Akt is a key molecule in the insulin/insulin-like growth factor signal transduction pathway, which plays a critical role in the balance between survival and apoptosis. The data presented here raise the possibility that down-regulation of Akt phosphorylation plays a regulatory role in hibernation. This would resemble dauer larva formation in Caenorhabditis elegans where Akt inhibition is associated with energy conservation, fat storage, expression of antioxidant enzymes and growth arrest. Published by Elsevier B.V. C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. USN, Med Res Ctr, Resusciat Med Dept, Silver Spring, MD 20910 USA. Uniformed Serv Univ Hlth Sci, Dept Pathol, Bethesda, MD 20814 USA. RP Hallenbeck, J (reprint author), NINDS, Stroke Branch, NIH, Bldg 36-Room 4A03,36 Convent Dr,MSC 4128, Bethesda, MD 20892 USA. EM hallenbj@ninds.nih.gov NR 50 TC 35 Z9 36 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUL 16 PY 2004 VL 1014 IS 1-2 BP 14 EP 21 DI 10.1016/j.braines.2004.04.008 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 838PZ UT WOS:000222726700002 PM 15212987 ER PT J AU Hwang, JS Kim, CW Son, KN Han, KY Lee, KH Kleinman, HK Koe, J Na, DS Kwon, BS Gho, YS Kim, J AF Hwang, JS Kim, CW Son, KN Han, KY Lee, KH Kleinman, HK Koe, J Na, DS Kwon, BS Gho, YS Kim, J TI Angiogenic activity of human CC chemokine CCL15 in vitro and in vivo SO FEBS LETTERS LA English DT Article DE chemokine; CCL15; endothelial cells; angiogenesis; CCR1; CCR3 ID INTERCELLULAR-ADHESION MOLECULE-1; ENDOTHELIAL GROWTH-FACTOR; HEMOFILTRATE CC-CHEMOKINE-1; BIOLOGICAL-ACTIVITY; LEUKOTACTIN-1; CELLS; EXPRESSION; RECEPTORS; NEUTROPHILS; AGONIST AB CCL15 is a novel human CC chemokine and exerts its biological activities on immune cells through CCR1 and CCR3. Because a number of chemokines induce angiogenesis and endothelial cells express CCR1 and CCR3, we investigated the angiogenic activity of CCL15. Both CCL15(1-92) and N-terminal truncated CCL15(25-92) stimulate the chemotactic endothelial cell migration and differentiation, but CCL15(25-92) is at least 100-fold more potent than CCL15(1-92). Treatment with pertussis toxin (PTX), with anti-CCR1, or with anti-CCR3 antibody inhibits the CCL15(25-92)-induced endothelial cell migration. CCL15(25-92) also stimulates sprouting of vessels from aortic rings and mediates angiogenesis in the chick chorioallantoic membrane assay. Our findings demonstrate that CCL15(25-92) has in vitro and in vivo angiogenic activity, and suggest roles of the chemokine in angiogenesis. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 Pohang Univ Sci & Technol, Dept Life Sci, Pohang 790784, South Korea. Kyung Hee Univ, Grad Sch Biotechnol, Yongin 449701, South Korea. Kyung Hee Univ, Inst Life Sci & Resources, Yongin 449701, South Korea. Kyung Hee Univ, Grad Sch E W Med Sci, Dept Oncol, Yongin 449701, South Korea. Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, Bethesda, MD 20892 USA. Univ Ulsan, Coll Med, Dept Biochem, Seoul 138736, South Korea. Univ Ulsan, Immunomodulat Res Ctr, Ulsan 680749, South Korea. RP Gho, YS (reprint author), Pohang Univ Sci & Technol, Dept Life Sci, Pohang 790784, South Korea. EM ysgho@postech.ac.kr; jkim@khu.ac.kr NR 26 TC 42 Z9 43 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 JUL 16 PY 2004 VL 570 IS 1-3 BP 47 EP 51 DI 10.1016/j.febslet.2004.06.023 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 840UM UT WOS:000222885400009 PM 15251437 ER PT J AU Lin, HJ Wang, XT Shaffer, KM Sasaki, CY Ma, W AF Lin, HJ Wang, XT Shaffer, KM Sasaki, CY Ma, W TI Characterization of H2O2-induced acute apoptosis in cultured neural stem/progenitor cells SO FEBS LETTERS LA English DT Article DE oxidative stress; apoptosis; Akt; survival; neural stein cell; Erk1/2 ID PRECURSOR CELLS; STEM-CELLS; SIGNAL-TRANSDUCTION; OXIDATIVE STRESS; GROWTH-FACTOR; RADICALS AB In the present study, we characterized hydrogen peroxide (H2O2)-induced cell apoptosis and related cell signaling pathways in cultured embryonic neural stem/progenitor cells (NS/PCs). Our data indicated that H2O2 induced acute cell apoptosis in NS/PC in concentration- and time-dependent manners and selectively, it transiently increased PI3K-Akt and Mek-Erk1/2 in a dose-dependent manner. Inhibition of PI3K-Akt with wortmannin, a PI3-K inhibitor, was found to significantly increase H2O2-induced acute apoptosis and dramatically decrease basal pGSK3beta levels. The level of pGSK3beta remained unchanged with H2O2 exposure. We conclude that the transient activation of PI3K-Akt signaling delays the H2O2-induced acute apoptosis in cultured NSIPCs in part through maintaining the basal pGSK3beta level and activating other downstream effectors. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 USN, Res Lab, Ctr Biol Mol Sci & Engn, Washington, DC 20375 USA. NIA, Lab Cell & Mol Biol, NIH, Baltimore, MD 21224 USA. NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. RP Lin, HJ (reprint author), USN, Res Lab, Ctr Biol Mol Sci & Engn, Washington, DC 20375 USA. EM jlin@cbmse.nrl.navy.mil NR 20 TC 33 Z9 38 U1 2 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUL 16 PY 2004 VL 570 IS 1-3 BP 102 EP 106 DI 10.1016/j.febslet.2004.06.019 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 840UM UT WOS:000222885400020 PM 15251448 ER PT J AU Miles, EW Kraus, JP AF Miles, EW Kraus, JP TI Cystathionine beta-synthase: Structure, function, regulation, and location of homocystinuria-causing mutations SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID HEME PROTEIN; SACCHAROMYCES-CEREVISIAE; PYRIDOXAL 5'-PHOSPHATE; TRANSCRIPTION FACTORS; REACTION-MECHANISM; ACTIVE CORE; NF-Y; YEAST; DOMAIN; TRANSSULFURATION C1 Univ Colorado, Hlth Sci Ctr, Dept Pediat, Denver, CO 80262 USA. NIDDK, NIH, Bethesda, MD 20892 USA. RP Kraus, JP (reprint author), Univ Colorado, Hlth Sci Ctr, Dept Pediat, C233,4200 E 9th Ave, Denver, CO 80262 USA. EM Jan.Kraus@uchsc.edu NR 50 TC 113 Z9 121 U1 1 U2 12 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 JUL 16 PY 2004 VL 279 IS 29 BP 29871 EP 29874 DI 10.1074/jbc.R400005200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 836CD UT WOS:000222531900001 PM 15087459 ER PT J AU Sattlegger, E Swanson, MJ Ashcraft, EA Jennings, JL Fekete, RA Link, AJ Hinnebusch, AG AF Sattlegger, E Swanson, MJ Ashcraft, EA Jennings, JL Fekete, RA Link, AJ Hinnebusch, AG TI YIH1 is an actin-binding protein that inhibits protein kinase GCN2 and impairs general amino acid control when overexpressed SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID UNCHARGED TRANSFER-RNA; INITIATION FACTOR-II; SACCHAROMYCES-CEREVISIAE; TRANSLATIONAL ACTIVATOR; BUDDING YEAST; SHUTTLE VECTORS; STARVED CELLS; GI DOMAIN; ASSOCIATION; PHOSPHORYLATION AB The general amino acid control (GAAC) enables yeast cells to overcome amino acid deprivation by activation of the alpha subunit of translation initiation factor 2 (eIF2alpha) kinase GCN2 and consequent induction of GCN4, a transcriptional activator of amino acid biosynthetic genes. Binding of GCN2 to GCN1 is required for stimulation of GCN2 kinase activity by uncharged tRNA in starved cells. Here we show that YIH1, when overexpressed, dampens the GAAC response (Gcn(-) phenotype) by suppressing eIF2alpha phosphorylation by GCN2. The overexpressed YIH1 binds GCN1 and reduces GCN1-GCN2 complex formation, and, consistent with this, the Gcn(-) phenotype produced by YIH1 overexpression is suppressed by GCN2 overexpression. YIH1 interacts with the same GCN1 fragment that binds GCN2, and this YIH1-GCN1 interaction requires Arg-2259 in GCN1 in vitro and in full-length GCN1 in vivo, as found for GCN2-GCN1 interaction. However, deletion of YIH1 does not increase eIF2alpha phosphorylation or derepress the GAAC, suggesting that YIH1 at native levels is not a general inhibitor of GCN2 activity. We discovered that YIH1 normally resides in a complex with monomeric actin, rather than GCN1, and that a genetic reduction in actin levels decreases the GAAC response. This Gcn(-) phenotype was partially suppressed by deletion of YIH1, consistent with YIH1-mediated inhibition of GCN2 in actin-deficient cells. We suggest that YIH1 resides in a YIH1-actin complex and may be released for inhibition of GCN2 and stimulation of protein synthesis under specialized conditions or in a restricted cellular compartment in which YIH1 is displaced from monomeric actin. C1 NICHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Med Ctr, Dept Microbiol & Immunol, Nashville, TN 37232 USA. NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), NICHD, Lab Gene Regulat & Dev, NIH, Bldg 6A,Rm B1A-13, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov FU NCI NIH HHS [CA098131]; NHLBI NIH HHS [HL68744]; NIEHS NIH HHS [ES11993]; NIGMS NIH HHS [GM64779]; NINDS NIH HHS [NS43952] NR 45 TC 29 Z9 31 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 16 PY 2004 VL 279 IS 29 BP 29952 EP 29962 DI 10.1074/jbc.M404009200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 836CD UT WOS:000222531900012 PM 15126500 ER PT J AU Lusetti, SL Voloshin, ON Inman, RB Camerini-Otero, RD Cox, MM AF Lusetti, SL Voloshin, ON Inman, RB Camerini-Otero, RD Cox, MM TI The DinI protein stabilizes RecA protein filaments SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ESCHERICHIA-COLI-RECA; SINGLE-STRANDED-DNA; BINDING-PROTEIN; NUCLEOPROTEIN FILAMENTS; NUCLEOSIDE TRIPHOSPHATE; STABLE COMPLEXES; DUPLEX DNA; C-TERMINUS; EXCHANGE; REPAIR AB When DinI is present at concentrations that are stoichiometric with those of RecA or somewhat greater, DinI has a substantial stabilizing effect on RecA filaments bound to DNA. Exchange of RecA between free and bound forms was almost entirely suppressed, and highly stable filaments were documented with several different experimental methods. DinI-mediated stabilization did not affect RecA-mediated ATP hydrolysis and LexA co-protease activities. Initiation of DNA strand exchange was affected in a DNA structure-dependent manner, whereas ongoing strand exchange was not affected. Destabilization of RecA filaments occurred as reported in earlier work but only when DinI protein was present at very high concentrations, generally super-stoichiometric, relative to the RecA protein concentration. DinI did not facilitate RecA filament formation but stabilized the filaments only after they were formed. The interaction between the RecA protein and DinI was modulated by the C terminus of RecA. We discuss these results in the context of a new hypothesis for the role of DinI in the regulation of recombination and the SOS response. C1 Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Cox, MM (reprint author), Univ Wisconsin, Dept Biochem, 433 Babcock Dr, Madison, WI 53706 USA. EM cox@biochem.wisc.edu FU NIGMS NIH HHS [GM52725] NR 41 TC 60 Z9 62 U1 0 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 16 PY 2004 VL 279 IS 29 BP 30037 EP 30046 DI 10.1074/jbc.M403064200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 836CD UT WOS:000222531900022 PM 15138263 ER PT J AU Pan, YP Ma, BY Keskin, O Nussinov, R AF Pan, YP Ma, BY Keskin, O Nussinov, R TI Characterization of the conformational state and flexibility of HIV-1 glycoprotein gp120 core domain SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD4 RECEPTOR-BINDING; ENVELOPE GLYCOPROTEIN; CRYSTAL-STRUCTURE; VARIABLE REGIONS; ATOMIC-STRUCTURE; NEUTRALIZATION; IDENTIFICATION; ANTIBODY; RETROVIRUS AB gp120 is key to the human immunodeficiency virus type 1 viral cell entry. Knowledge of the detailed conformational states of gp120 is crucial to intervention, yet the unbound form is still resistant to structural characterization probably because of its flexibility. Toward this goal, we performed molecular dynamics simulations on the wild type gp120 core domain extracted from its ternary crystal structure and on a modeled mutant, S375W, that experimentally has a significantly different phenotype from the wild type. Although the mutant retained a bound-like conformation, the wild type drifted to a different conformational state. The wild type beta strands 2 and 3 of the bridging sheet were very mobile and partially unfolded, and the organization among the inner and outer domains and beta strands 20 and 21 of the bridging sheet, near the mutation site, was more open than in the bound form, although the overall structure was maintained. These differences were apparently a result of the strengthening of the hydrophobic core in the mutant. This stabilization further explains the experimentally significantly different thermodynamic properties between the wild type and the mutant. Taken together, our results suggest that the free form, although different from the bound state, shares many of the bound structural features. The observed loss of freedom near the binding site, rather than the previously hypothesized more dramatic conformational transition from the unbound to the bound state, appears to be the major contributor to the large entropy cost for the CD4 binding to the wild type. C1 NCI, Basic Res Program, Sci Applicat Int Corp Frederick Inc, Lab Expt & Computat Biol, Frederick, MD 21702 USA. Koc Univ, Ctr Computat Biol & Bioinformat, TR-34450 Istanbul, Turkey. Koc Univ, Coll Engn, TR-34450 Istanbul, Turkey. Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Basic Res Program, Sci Applicat Int Corp Frederick Inc, Lab Expt & Computat Biol, Bldg 469,Rm 151, Frederick, MD 21702 USA. EM ruthn@ncifcrf.gov RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU NCI NIH HHS [N01-CO-12400] NR 42 TC 29 Z9 30 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 JUL 16 PY 2004 VL 279 IS 29 BP 30523 EP 30530 DI 10.1074/jbc.M404364200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 836CD UT WOS:000222531900081 PM 15131118 ER PT J AU Bai, R Covell, DG Taylor, GF Kepler, JA Copeland, TD Nguyen, NY Pettit, GR Hamel, E AF Bai, R Covell, DG Taylor, GF Kepler, JA Copeland, TD Nguyen, NY Pettit, GR Hamel, E TI Direct photoaffinity labeling by dolastatin 10 of the amino-terminal peptide of beta-tubulin containing cysteine 12 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BINDING-SITE; ANTINEOPLASTIC AGENTS; VINCA DOMAIN; EXCHANGEABLE SITE; ACID-SEQUENCE; PORCINE BRAIN; CROSS-LINKING; ALPHA-TUBULIN; MICROTUBULE; PROTEIN AB Tubulin with bound [5-H-3] dolastatin 10 was exposed to ultraviolet light, and 8-10% of the bound drug crosslinked to the protein, most of it specifically. The primary cross-link was to the peptide spanning amino acid residues 2-31 of beta-tubulin, but the specific amino acid could not be identified. Indirect studies indicated that cross-link formation occurred between cysteine 12 and the thiazole moiety of dolastatin 10. An equipotent analog of dolastatin 10, lacking the thiazole ring, did not form an ultraviolet light-induced cross-link to beta-tubulin. Preillumination of tubulin with ultraviolet light, known to induce cross-link formation between cysteine 12 and exchangeable site nucleotide, inhibited the binding of [5-H-3] dolastatin 10 and cross-link formation more potently than it inhibited the binding of colchicine or vinblastine to tubulin. Conversely, binding of dolastatin 10 to tubulin inhibited formation of the cross-link between cysteine 12 and the exchangeable site nucleotide. Dithiothreitol inhibited formation of the beta-tubulin/dolastatin 10 cross-link but not the beta-tubulin/exchangeable site nucleotide cross-link. Modeling studies revealed a highly favored binding site for dolastatin 10 at the + end of beta-tubulin in proximity to the exchangeable site GDP. Computational docking of an energy-minimized dolastatin 10 conformation at this site placed the thiazole ring of dolastatin 10 8-9 Angstrom from the sulfur atom of cysteine 12. Dolastatin 15 and cryptophycin 1 could also be docked into positions that overlapped more extensively with the docked dolastatin 10 than with each other. This result was consistent with the observed binding properties of these peptides. C1 NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, NIH, Frederick, MD 21702 USA. US FDA, Facil Biotechnol Resources, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. Arizona State Univ, Dept Chem & Biochem, Tempe, AZ 85287 USA. Arizona State Univ, Canc Res Inst, Tempe, AZ 85287 USA. RP Hamel, E (reprint author), NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Bldg 469,Rm 104,POB B, Frederick, MD 21702 USA. EM hamele@mail.nih.gov NR 54 TC 20 Z9 21 U1 0 U2 0 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 JUL 16 PY 2004 VL 279 IS 29 BP 30731 EP 30740 DI 10.1074/jbc.M402110200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 836CD UT WOS:000222531900104 PM 15123603 ER PT J AU Ivanova, AV Ivanov, SV Zhang, X Ivanov, VN Timofeeva, OA Lerman, MI AF Ivanova, AV Ivanov, SV Zhang, X Ivanov, VN Timofeeva, OA Lerman, MI TI STRA13 interacts with STAT3 and modulates transcription of STAT3-dependent targets SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE apoptosis; fas; STAT3; STRA13; transcriptional regulation ID TUMOR-SUPPRESSOR PROTEIN; LOOP-HELIX PROTEIN; TRANSMEMBRANE CARBONIC-ANHYDRASES; ACUTE MYELOID-LEUKEMIA; PHASE RESPONSE FACTOR; C-MYC; MESSENGER-RNA; REPRESSES TRANSCRIPTION; FUNCTIONAL INTERACTION; NEGATIVE REGULATION AB STRA13 is a pVHL-dependent bHLH transcription factor up-regulated on the mRNA level in multiple cancer cell lines and implicated recently in the regulation of immune cell homeostasis and autoimmunity. In searching for STRA13-interacting proteins with oncogenic potential by the yeast two-hybrid screening, we identified STAT3beta as a STRA13-binding partner. We showed that STRA13 binds predominantly to phosphorylated (active) STAT3 alpha and beta isoforms via its HLH and C-terminal regions. We also found that STRA13 was able to activate transcription from STAT-dependent cis-elements. Expression of endogenous STRA13 was shown to be. cytokine-inducible, consistent with STRA13 involvement in STAT-dependent transcription regulation. We demonstrated that the STAT3-regulated promoter of the pro-apoptotic Fas gene was activated upon STRA13 over-expression and that co-expression of STRA13 with STAT3beta or STAT3alpha modulated the transcriptional outcome. Forced expression of STRA13 induced apoptosis, in agreement with the STRA13 activation effect on the Fas promoter. Simultaneous expression of STRA13 and STAT3beta resulted in alleviation of the STRA13 pro-apoptotic effect. Thus, for the first time, we identify STRA13 as a STAT3 partner and provide a consistent line of evidence for STRA13 involvement into regulation of apoptosis via the STAT pathways. (C) 2004 Elsevier Ltd. All rights reserved. C1 NCI, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. NCI, Cellular & Mol Immunol Sect, Expt Immunol Lab, Ctr Canc Res, Frederick, MD 21702 USA. Mt Sinai Sch Med, Ruttenberg Canc Ctr, New York, NY 10029 USA. NCI, Comparat Carcinogenesis Lab, Canc Res Ctr, Frederick, MD 21702 USA. RP Ivanova, AV (reprint author), NCI, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. EM ivanova@mail.ncifcrf.gov RI Zhang, Xia/B-8152-2008; Ivanov, Vladimir/A-3081-2008; OI Zhang, Xia/0000-0002-9040-1486; Ivanov, Vladimir/0000-0002-2933-6339; Ivanov, Sergey/0000-0001-9770-7237 FU NCI NIH HHS [N01-CO-12400, N01-CO-56000] NR 59 TC 34 Z9 35 U1 0 U2 3 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUL 16 PY 2004 VL 340 IS 4 BP 641 EP 653 DI 10.1016/J.Jmb.2004.05.025 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 838SU UT WOS:000222734300001 PM 15223310 ER PT J AU Cohen, HY Miller, C Bitterman, KJ Wall, NR Hekking, B Kessler, B Howitz, KT Gorospe, M de Cabo, R Sinclair, DA AF Cohen, HY Miller, C Bitterman, KJ Wall, NR Hekking, B Kessler, B Howitz, KT Gorospe, M de Cabo, R Sinclair, DA TI Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase SO SCIENCE LA English DT Article ID LIFE-SPAN EXTENSION; SACCHAROMYCES-CEREVISIAE; AGING PROCESS; APOPTOSIS; P53; SENESCENCE; LONGEVITY; KU70; NAD; BAX AB A major cause of aging is thought to result from the cumulative effects of cell loss over time. In yeast, caloric restriction (CR) delays aging by activating the Sir2 deacetylase. Here we show that expression of mammalian Sir2 (SIRT1) is induced in CR rats as well as in human cells that are treated with serum from these animals. Insulin and insulin-like growth factor 1 (IGF-1) attenuated this response. SIRT1 deacetylates the DNA repair factor Ku70, causing it to sequester the proapoptotic factor Bax away from mitochondria, thereby inhibiting stress-induced apoptotic cell death. Thus, CR could extend life-span by inducing SIRT1 expression and promoting the long-term survival of irreplaceable cells. C1 Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. BIOMOL Res Labs, Plymouth Meeting, PA 19462 USA. NIA, Cellular & Mol Biol Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. NIA, Lab Expt Gerontol, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Sinclair, DA (reprint author), Harvard Univ, Sch Med, Dept Pathol, 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM david_sinclair@hms.harvard.edu RI de Cabo, Rafael/E-7996-2010; Wall, Nathan/H-7368-2015; de Cabo, Rafael/J-5230-2016; OI Wall, Nathan/0000-0002-3235-4386; de Cabo, Rafael/0000-0002-3354-2442; Sinclair, David/0000-0002-9936-436X; , rafael/0000-0003-2830-5693; Kessler, Benedikt/0000-0002-8160-2446 FU NCI NIH HHS [F32 CA097802]; NIA NIH HHS [R01 AG019972, AG19719-03, AG19972-02, P01 AG027916, R01 AG019719, R01 AG028730, R37 AG028730]; NIGMS NIH HHS [R01 GM068072] NR 24 TC 1119 Z9 1187 U1 17 U2 119 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 16 PY 2004 VL 305 IS 5682 BP 390 EP 392 DI 10.1126/science.1099196 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 837TE UT WOS:000222662400036 PM 15205477 ER PT J AU Bray, GA Vollmer, WM Sacks, FM Obarzanek, E Svetkey, LP Appel, LI AF Bray, GA Vollmer, WM Sacks, FM Obarzanek, E Svetkey, LP Appel, LI CA DASH Collaborative Res Grp TI A further subgroup analysis of the effects of the DASH diet and three dietary sodium levels on blood pressure: Results of the DASH-sodium trial SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article AB This study presents an extensive analysis of the effects on blood pressure (BP) of changes in sodium intake over a wide array of subgroups, including joint subgroups defined by age and hypertension status, race or ethnicity and hypertension status, and gender and race or ethnicity. Participants were given 3 levels of sodium (50, 100, and 150 mmol/2,100 kcal) for 30 days while consuming the Dietary Approaches to Stop Hypertension (DASH) diet (rich in fruits, vegetables, and low-fat dairy) or a more typical American diet. Within each diet and subgroup, there was a general pattern such that the lower the sodium level, the greater the mean reduction in BP. Sodium reduction from 100 to 50 mmol/2,100 kcal generally had twice the effect on BP as reduction from 150 to 100 mmol/2,1100 kcal. Age had a strong and graded influence on the effect of sodium within the typical and DASH diets, respectively: -4.8 and -1.0 mm Hg systolic for 23 to 41 years, -5.9 and -1.8 mm Hg for 42 to 47 years, -7.5 and -4.3 mm Hg for 48 to 54 years, and -8.1 and -6.0 mm Hg for 55 to 76 years. The influence of age on the effect of sodium reduction was particularly strong in nonhypertensive patients: -3.7 mm Hg systolic for <45 years and -7.0 mm Hg for >45 years with the typical diet and -0.7 and -2.8 mm Hg with the DASH diet. Reduced sodium intake and the DASH diet should be advocated for the prevention and treatment of high BP, particularly because the benefits to BP strengthen as subjects enter middle age, when the rate of cardiovascular disease increases sharply. (C) 2004 by Excerpta Medica, Inc. C1 Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Natl Heart Lung & Blood Inst, NIH, Bethesda, MD USA. Duke Univ, Ctr Med, Durham, NC 27706 USA. Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. RP Bray, GA (reprint author), Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM brayga@pbrc.edu FU NCRR NIH HHS [RR00722, RR02635]; NHLBI NIH HHS [HL03857, HL57114, HL57139, HL57156, HL57173, HL57190] NR 5 TC 93 Z9 99 U1 1 U2 12 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 15 PY 2004 VL 94 IS 2 BP 222 EP 227 DI 10.1016/j.amjcard.2004.03.070 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 838LJ UT WOS:000222714500020 PM 15246908 ER PT J AU Gamm, JL Nussbaum, RL Biesecker, BB AF Gamm, JL Nussbaum, RL Biesecker, BB TI Genetics and alcoholism among at-risk relatives I: Perceptions of cause, risk, and control SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE alcoholism; genetics; fatalism; perceived personal control; perceived risk; genetic counseling; behavioral genetics ID IDENTIFICATION TEST AUDIT; FAMILY-HISTORY; PUBLIC CONCEPTIONS; MENTAL-ILLNESS; UNITED-STATES; HEALTH LOCUS; DEPENDENCE; DISEASE; DISORDERS; BEHAVIOR AB Genetic factors influence a person's risk for developing alcoholism. In other common disorders with a genetic component, a belief in a genetic cause can lead to less perceived control or fatalism among those at risk that may adversely affect undertaking health-promoting behaviors. This study explores beliefs about the cause of alcoholism and risk perception among individuals with affected relatives. In-depth interviews including both open-ended questions and several quantitative measures were conducted with participants to explore the relationships between causal beliefs and perceptions of personal risk and control. Twenty-seven individuals with at least one first-degree relative affected with alcoholism participated. Transcript analysis of interviews revealed that all participants attribute multiple factors to the cause of alcoholism in their families, often as a combination of biological, genetic, environmental factors, and personal characteristics. Many perceived themselves as being 'at-risk,' and this concern often stemmed from a belief in a genetic or biological cause of alcoholism. However, participants also had a strong sense of personal control, rooted in beliefs about environmental causes or personal characteristics influencing alcoholism risk. A participant's strong belief in a genetic cause was associated with a significantly increased risk perception, but not a fatalistic outlook towards developing alcoholism. Published 2004 Wiley-Liss, Inc. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Cincinnati Childrens Hosp, Ctr Med, Cincinnati, OH USA. NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Gamm, JL (reprint author), Div Human Genet, 3333 Burnet Ave,MLC 4006, Cincinnati, OH 45229 USA. EM Jennifer.Gamm@cchmc.org NR 37 TC 14 Z9 14 U1 1 U2 10 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-7299 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUL 15 PY 2004 VL 128A IS 2 BP 144 EP 150 DI 10.1002/ajmg.a.30082 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 836PL UT WOS:000222567900009 PM 15214005 ER PT J AU Gamm, JL Nussbaum, RL Biesecker, BB AF Gamm, JL Nussbaum, RL Biesecker, BB TI Genetics and alcoholism among at-risk relatives II: Interest and concerns about hypothetical genetic testing for alcoholism risk SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE alcoholism; genetics; fatalism; genetic testing; genetic counseling; privacy ID GENOME-WIDE SEARCH; FAMILY HISTORY; UNITED-STATES; HEALTH LOCUS; YOUNG-ADULTS; DEPENDENCE; CANCER; SAMPLE; ATTITUDES; CHILDREN AB One purpose of this study was to examine hypothetical interest in genetic predisposition testing for alcoholism among at-risk relatives. Qualitative interviews and several quantitative tools were administered to 27 individuals who had at least one first-degree relative affected by alcoholism. Data analysis revealed that participants' interest in genetic testing for susceptibility to alcoholism was moderate. Lower educational level and a stronger belief in 'others' influencing health were related to participants' having a stronger interest in genetic testing. Participants' concerns about future use of genetic testing ranged from doubts about its usefulness in affecting behavior to apprehension regarding detrimental societal effects such as breaches in confidentiality and fear of being labeled an 'alcoholic.' Younger age and stronger interest in genetic testing were associated with deterministic or fatalistic beliefs, while drinking behaviors, gender, and other demographics were not. Participants questioned the utility of this type of testing. Their interest in testing and concerns about its hypothetical use may prove important for at-risk relatives who may face decisions about genetic testing in the future. Data from this study can provide direction for researchers and health care providers as genetic testing for this and other behavioral conditions emerges. Scientists and the public should address the social concerns expressed by participants, including the fear of labeling. Also, we can begin to anticipate characteristics common in those who may have fatalistic responses, and who may possibly make adverse behavior choices, to results from alcoholism susceptibility testing. Published 2004 Wiley-Liss, Inc. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Childrens Hosp Med Ctr, Cincinnati, OH USA. NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Gamm, JL (reprint author), Div Human Genet, 3333 Burnet Ave,MLC 4006, Cincinnati, OH 45229 USA. EM Jennifer.Gamm@chmcc.org NR 26 TC 6 Z9 6 U1 2 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-7299 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUL 15 PY 2004 VL 128A IS 2 BP 151 EP 155 DI 10.1002/ajmg.a.30003 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 836PL UT WOS:000222567900010 PM 15214006 ER PT J AU Hollingsworth, JW Cook, DN Brass, DM Walker, JKL Morgan, DL Foster, WM Schwartz, DA AF Hollingsworth, JW Cook, DN Brass, DM Walker, JKL Morgan, DL Foster, WM Schwartz, DA TI The role of toll-like receptor 4 in environmental airway injury in mice SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE toll-like receptor; innate immunity; endotoxin; ozone; residual oil fly ash ID OIL FLY-ASH; INDUCED LUNG INFLAMMATION; 18-20 H POSTEXPOSURE; GRAIN DUST; ALVEOLAR MACROPHAGES; POLLUTION PARTICLES; CYTOKINE PRODUCTION; EPITHELIAL-CELLS; OZONE EXPOSURE; CUTTING EDGE AB Inhalation of toxins commonly found in air pollution contributes to the development and progression of asthma and environmental airway injury. In this study, we investigated the requirement of toll-like receptor 4 (TLR4) in mice for pulmonary responses to three environmental toxins: aerosolized lipopolysaccharide, particulate matter (residual oil fly ash), and ozone. The physiologic and biologic responses to these toxins were evaluated by the extent of airway responsiveness, neutrophil recruitment to the lower respiratory tract, changes in inflammatory cytokines, and the concentration of protein in the lavage fluid. Genetically engineered, TLR4-deficient mice (C57BL/6(TLR4-/-)) were unresponsive to inhaled lipopolysaccharide, except for minimal increases in some inflammatory cytokines. In contrast, C57BL/6(TLR4-/-) mice did not differ from wild-type mice in their airway response to instilled residual oil fly ash or acute ozone exposure; however, we found that, despite a robust inflammatory response, C57BL/6(TLR4-/-) mice are protected against the development of airway hyperresponsiveness after subchronic ozone exposure. These data demonstrate in the mouse that the requirement of TLR4 for pulmonary inflammation depends on the nature of the toxin and appears specific to toxin and exposure conditions. C1 Duke Univ, Med Ctr, Div Pulm & Crit Care Med, Durham, NC 27710 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Hollingsworth, JW (reprint author), Duke Univ, Med Ctr, Div Pulm & Crit Care Med, Durham, NC 27710 USA. EM holli017@mc.duke.edu FU NHLBI NIH HHS [HL66604, HL074518, HL07538, HL62641, HL66611]; NIEHS NIH HHS [ES00703, ES012496, ES012717, ES07498, ES11375, ES7031] NR 51 TC 105 Z9 107 U1 0 U2 2 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUL 15 PY 2004 VL 170 IS 2 BP 126 EP 132 DI 10.1164/rccm.200311-1499OC PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 837NU UT WOS:000222643000007 PM 15020293 ER PT J AU Miller, FG Silverman, HJ AF Miller, FG Silverman, HJ TI Ethics and standard of care in clinical trials SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Letter C1 NIH, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. RP Miller, FG (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUL 15 PY 2004 VL 170 IS 2 BP 199 EP 199 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 837NU UT WOS:000222643000026 ER PT J AU Boja, ES Sokoloski, EA Fales, HM AF Boja, ES Sokoloski, EA Fales, HM TI Divinyl sulfone as a postdigestion modifier for enhancing the a(1) ion in MS/MS and postsource decay: Potential applications in proteomics SO ANALYTICAL CHEMISTRY LA English DT Article ID TANDEM MASS-SPECTROMETRY; PEPTIDE SPECTRA; AMINO-ACIDS; PROTEINS; O-18 AB Divinyl sulfone reacts at pH 8-9 with the alpha-amino groups of N-terminal residues, proline, the epsilon-amino groups of lysine, and the histidine side chains of peptides. This reaction leads to great enhancement of the abundance of the normally weak or missing "a(1)" fragment ion in MS/MS analysis defining the N-terminal residue of a peptide in a digest This provides "one-step Edman-like" information that, together with a fairly accurately determined mass, often enables one to correctly identify a protein or family of proteins. The applicability of this procedure in proteomics was demonstrated with several peptides and tryptic digests of protein mixtures by LC-MS/MS experiments using a QTOF and MALDI-PSD analyses. Advantages of this approach are its simple chemistry, retention of charge multiplicity, and possibly, shortening of database search time. Used with other MS/MS data, it provides higher confidence in the scores and identification of a protein found in peptide mass fingerprinting. Moreover, this approach has an advantage in "de novo" sequencing due to its ability to decipher the first amino acid of a peptide whose information is normally unavailable in MS/MS spectra. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20592 USA. RP Fales, HM (reprint author), NHLBI, Biophys Chem Lab, NIH, 50 S Dr, Bethesda, MD 20592 USA. EM hmfales@helix.nih.gov NR 23 TC 9 Z9 9 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD JUL 15 PY 2004 VL 76 IS 14 BP 3958 EP 3970 DI 10.1021/ac049774e PG 13 WC Chemistry, Analytical SC Chemistry GA 838IH UT WOS:000222706400012 PM 15253630 ER PT J AU Gao, ZG Mamedova, L Tchilibon, S Gross, AS Jacobson, KA AF Gao, ZG Mamedova, L Tchilibon, S Gross, AS Jacobson, KA TI 2,2 '-pyridylisatogen tosylate antagonizes P2Y(1) receptor signaling without affecting nucleotide binding SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE P2Y receptors; allosteric modulation; ADP; ATP; PIT; GPCR; purines; nucleotides ID ALLOSTERIC MODULATOR; AMILORIDE ANALOGS; P2 RECEPTORS; ADENOSINE; AGONIST; QUANTITATION; POTENTIATION; DERIVATIVES; SCH-202676; RESPONSES AB The effect of 2,2'-pyridylisatogentosylate (PIT) on the human P2Y(1) receptor and on other recombinant P2Y receptors has been studied. We first examined the modulation by PIT of the agonist-induced accumulation of inositol phosphates. PIT blocked 2-methylthio-ADP (2-MeSADP)-induced accumulation of inositol phosphates in 1321N1 astrocytoma cells stably expressing human P2Y, receptors in a non-competitive and concentration-dependent manner. The IC50 for reduction of the maximal agonist effect was 0.14 muM. In contrast, MRS2179, a competitive P2Y, receptor antagonist, parallel-shifted the agonist concentration-response curve to the right. PIT also concentration-dependently blocked the P2Y(1) receptor signaling induced by the endogenous agonists, ADP and ATR A simple structural analogue of PIT was synthesized and found to be inactive as a P2Y, receptor antagonist, suggesting that the nitroxyl group of PIT is a necessary structural component for P2Y, receptor antagonism. We next examined the possible modulation of the binding of the newly available antagonist radioligand for the P2Y, receptor, [H-3] MRS2279. It was found that PIT (0.01-10 muM) did not inhibit [H-3] MRS2279 binding to the human P2Y, receptor. PIT (10 muM) had no effect on the competition for [3H] MRS2279 binding by agonists, ADP and ATP, suggesting that its antagonism of the P2Y, receptor may be allosteric. PIT had no significant effect on agonist activation of other P2Y receptors, including P2Y(2), P2Y(4), P2Y(6), P2Y(11) and P2Y(12) receptors. Thus, PIT selectively and non-competitively blocked P2Y(1) receptor signaling without affecting nucleotide binding. (C) 2004 Elsevier Inc. All rights reserved. C1 NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM kaiacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031116-20, Z99 DK999999] NR 28 TC 21 Z9 23 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD JUL 15 PY 2004 VL 68 IS 2 BP 231 EP 237 DI 10.1016/j.bcp.2004.02.039 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 833AG UT WOS:000222308200004 PM 15193995 ER PT J AU Peterson, TC Peterson, MR Wornell, PA Blanchard, MG Gonzalez, FJ AF Peterson, TC Peterson, MR Wornell, PA Blanchard, MG Gonzalez, FJ TI Role of CYP1A2 and CYP2E1 in the pentoxifylline ciprofloxacin drug interaction SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE PTX; CIPRO; Cyp1A2 knockout; CYP1A2; FURA; CYP2E1; proliferation ID LIVER-DISEASE; GROWTH-FACTOR; THEOPHYLLINE METABOLISM; HYDROXYLASE-ACTIVITY; ANIMAL-MODEL; INHIBITION; FIBROPROLIFERATION; PHARMACOKINETICS; CELL; DEPRESSION AB In this study the drug interaction between ciprofloxacin (CIPRO) and pentoxitylline (PTX) was investigated and the role of CYP1A2 in the drug interaction was determined with the aid of a selective CYP1A2 inhibitor, furafylline (FURA), and the Cyp1A2 knockout mouse. Serum concentrations of PTX (83.4 +/- 1 mumol/l) and metabolite-1 (M-1) (13.7 +/-2.8 [mumol/l) following a single injection of PTX (100 mg/kg i.p.) were significantly higher (P < 0.05) in mice treated with CIPRO (25 mg/kg i.p. 9 days) compared to serum concentrations of PTX (46.3 +/- 0.5 mumol/l) and M-1 (6.4 +/- 1.1 mumol/l) in mice administered saline. Murine hepatic microsomes were incubated with PTX alone or the combination of PTX and CIPRO. The metabolism of PTX in the murine hepatic microsomes containing both CIPRO and PTX was significantly decreased compared to microsomes incubated with PTX alone, suggesting that CIPRO may inhibit the metabolism of PTX. To further clarify the role of CYP1A2 in the metabolism of PTX in mice, the effect of a selective CYP1A2 mechanism based inhibitor, FURA, on the metabolism of PTX was investigated and our results indicate that FURA inhibited metabolism of PTX. We then investigated PTX elimination in the Cyp1A2 knockout mouse. Blood levels of PTX were assessed at 2 and 20 min following a single injection of PTX (32 mg/kg i.v). Serum concentration of PTX was determined in Cyp I A2 knockout mice compared to Cyp I A2 wild type control mice. The serum concentration of PTX in Cyp1A2 wild type mice (n = 9) was 22.2 +/- 3.2 mumol/l at 20 min following injection of PTX. The serum concentration of PTX in CypIA2 knockout mice (n = 11) was significantly elevated at 20 min following injection of PTX compared to Cyp1A2 wild type mice. These results clearly indicate that inhibition of CYP1A2 catalytic activity that occurs in the Cyp1A2 knockout mice is sufficient to alter metabolism of PTX and result in markedly elevated levels in serum of Cyp1A2 knockout mice. The results of Western analysis in murine microsomes suggest that CYP1A2 protein levels were not altered by CIPRO indicating that CIPRO did not downregulate Cyp1A2. The results of Western analysis also indicated that CIPRO treatment increased CYP2E1 in mouse microsomes and the implications of these will be discussed. (C) 2004 Elsevier Inc. All rights reserved. C1 Dalhousie Univ, Fac Med, Dept Med, Halifax, NS, Canada. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Peterson, TC (reprint author), Dalhousie Univ, Fac Med, Dept Med, Halifax, NS, Canada. EM tcpmed@dal.ca NR 40 TC 16 Z9 16 U1 1 U2 7 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 JUL 15 PY 2004 VL 68 IS 2 BP 395 EP 402 DI 10.1016/j.bcp.2004.03.035 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 833AG UT WOS:000222308200020 PM 15194011 ER PT J AU Teicher, MH Dumont, NL Ito, Y Vaituzis, C Giedd, JN Andersen, SL AF Teicher, MH Dumont, NL Ito, Y Vaituzis, C Giedd, JN Andersen, SL TI Childhood neglect is associated with reduced corpus callosum area SO BIOLOGICAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 30th Annual Meeting of the Society-for-Neuroscience CY NOV 04-09, 2000 CL NEW ORLEANS, LA SP Soc Neurosci, Taiwanese Bioscientists Amer DE abuse; neglect; corpus callosum; magnetic resonance imaging; sex differences; children ID POSTTRAUMATIC-STRESS-DISORDER; HIPPOCAMPAL VOLUME; SEX-DIFFERENCES; CORTICAL DEVELOPMENT; BRAIN-DEVELOPMENT; ABUSED-CHILDREN; AGE; MALTREATMENT; TRAUMA; SIZE AB Background: Childhood abuse has been associated with abnormalities in brain development, particularly corpus callosum (CC) morphology. The impact of neglect has not been assessed, though it is the most prevalent form of childhood maltreatment. Methods: Regional CC area was measured from magnetic resonance imaging scans in 26 boys and 25 girls admitted for psychiatric evaluation, (28 with abuse or neglect) and compared with CC area in 115 healthy control subjects. Data were analyzed by multivariate analysis of covariance, with age and midsagittal area as covariates. Results: Total CC area of the abused/neglected patients was 17% smaller than in control subjects (p = .0001) and 11% smaller than in psychiatric patients who had not been abused or neglected (contrast group; p = .01). Control subjects and the contrast group did not differ in total CC area. Neglect was the strongest experiential factor and was associated with a 15%-18% reduction in CC regions 3, 4, 5, and 7 (all p < .02). In contrast, sexual abuse seemed to be the strongest factor associated with reduced CC size in girls. Conclusions: These data are consistent with animal research that demonstrated reduced CC size in nursery-reared compared with semi-naturally reared primates. Early experience might also affect the development of the human CC. C1 McLean Hosp, Dev Biopsychiat Res Program, Belmont, MA 02478 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Teicher, MH (reprint author), McLean Hosp, Dev Biopsychiat Res Program, 115 Mill St, Belmont, MA 02478 USA. RI Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 FU NIDA NIH HHS [R01DA-016934]; NIMH NIH HHS [R01 MH-53636, R01 MH-66222] NR 25 TC 211 Z9 217 U1 4 U2 16 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 JUL 15 PY 2004 VL 56 IS 2 BP 80 EP 85 DI 10.1016/j.biopsych.2004.03.016 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 835OQ UT WOS:000222493500003 PM 15231439 ER PT J AU Fujita, M Southwick, SM Denucci, CC Zoghbi, SS Dillon, MS Baldwin, RM Bozkurt, A Kugaya, A Verhoeff, NPLG Seibyl, JP Innis, RB AF Fujita, M Southwick, SM Denucci, CC Zoghbi, SS Dillon, MS Baldwin, RM Bozkurt, A Kugaya, A Verhoeff, NPLG Seibyl, JP Innis, RB TI Central type benzodiazepine receptors in Gulf War veterans with posttraumatic stress disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE single photon emission computed tomography; iomazenil; reproducibility; childhood trauma; combat; statistical parametric mapping ID TEMPORAL GYRUS VOLUMES; SPECT; BRAIN; SCALE; ANXIETY; BINDING; TRAUMA; PTSD; MRI; SCHIZOPHRENIA AB Background: A previous single photon emission computed tomography study showed decreased central type benzodiazepine receptors in the prefrontal cortex in Vietnam War veterans with posttraumatic stress disorder. To assess the generalizability of this finding to patients with more recent history, we studied central type benzodiazepine receptors in Gulf War veterans with posttraumatic stress disorder. Methods: Nineteen Gulf War veterans with posttraumatic stress disorder and 19 age-matched, healthy, nondeployed veterans participated in a single photon emission computed tomography study using [I-123]iomazenil. Regional total distribution volume (V-T') was compared between two groups using Statistical Parametric Mapping 99 (Wellcome Department of Imaging Neuroscience, London, United Kingdom) and volumes of interest analysis. Results: Benzodiazepine receptor levels did not show regional differences between the two groups, either with or without global normalization. Average difference in V-T' was 2% across brain areas; however, by applying global normalization, V-T' in the patient group showed significant negative correlation with childhood trauma scores in the right superior temporal gyrus. Conclusions: less severe symptoms and shorter duration of the illness in the current group than the prior one may be the source of the difference in the results of the two studies. C1 NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. Yale Univ, Dept Psychiat, West Haven, CT 06516 USA. Yale Univ, Dept Radiol, West Haven, CT 06516 USA. Vet Affairs Connecticut Healthcare Syst, West Haven, CT USA. Inst Neurodegenerat Disorders, New Haven, CT USA. RP Fujita, M (reprint author), NIMH, Mol Imaging Branch, Bldg 1,Room B3-10,1 Ctr Dr,MSC-0135, Bethesda, MD 20892 USA. NR 41 TC 30 Z9 31 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUL 15 PY 2004 VL 56 IS 2 BP 95 EP 100 DI 10.1016/j.biopsych.2004.03.010 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 835OQ UT WOS:000222493500005 PM 15231441 ER PT J AU Vythilingam, M Vermetten, E Anderson, GM Luckenbaugh, D Anderson, ER Snow, J Staib, LH Charney, DS Bremner, JD AF Vythilingam, M Vermetten, E Anderson, GM Luckenbaugh, D Anderson, ER Snow, J Staib, LH Charney, DS Bremner, JD TI Hippocampal volume, memory, and cortisol status in major depressive disorder: Effects of treatment SO BIOLOGICAL PSYCHIATRY LA English DT Review DE antidepressants; cortisol; hippocampus; MDD; memory; MRI ID POSTTRAUMATIC-STRESS-DISORDER; TEMPORAL-LOBE EPILEPSY; GERIATRIC DEPRESSION; ANTIDEPRESSANT TREATMENT; CELL-PROLIFERATION; VERBAL MEMORY; COGNITIVE DEFICITS; DECLARATIVE MEMORY; MOOD DISORDERS; NEUROGENESIS AB Background: Depression has been linked to stress, memory deficits, and hypercortisolemia. However; the relationships between depression, hippocampal structure and function, and cortisol levels are unclear and the effects of antidepressant treatment on the measures are not well studied. Methods: Whole hippocampal volume, performance on verbal and visual declarative memory function. and cortisol status was evaluated in 38 subjects with major depressive disorder (MDD) and 33 healthy subjects. All measures were repeated in a subgroup (n = 22) of depressed patients after successful selective serotonin reuptake inhibitor (SSRI) treatment. Results: Hippocampal volume was riot significantly different between patients with untreated MMD and healthy subjects, after controlling for whole brain volume, age and gender. However, depressed subjects had significantly greater deficits in delayed memory and percent retention. on the verbal portion of the Wechsler Memory Scale-Revised (WMS-R) compared with healthy subjects, without significant differences in visual memory, attention, vigilance, or distractibility. Baseline plasma or urinary free cortisol (UFC) was not related to either hippocampal volume or memory deficits. Successful treatment with antidepressants did not change hippocampal volume but did result in a significant improvement in memory function and a reduction in UFC excretion.. Conclusions: Medication-free nonelderly depressed outpatients without alcohol dependence or adverse experiences in childhood had normal hippocampal volume. Focal declarative memory deficits in depression supported localized hippocampal dysfunction in depressed patients. Treatment with antidepressants significantly unproved memory and depression but did riot alter hippocampal volume, suggesting that antidepressants may improve hippocampal junction in the absence of detectable structural changes. C1 NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Univ Utrecht, Med Ctr, Rudolf Magnus Inst Neurosci, Dept Psychiat, Utrecht, Netherlands. Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06510 USA. Yale Univ, Sch Med, Biomed Engn Program, New Haven, CT 06510 USA. Boston Univ, Dept Cognit & Neural Syst, Boston, MA 02215 USA. Emory Univ, Sch Med, Dept Psychiat, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Dept Radiol, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Emory Ctr Positron Emiss Tomog, Atlanta, GA 30322 USA. RP Vythilingam, M (reprint author), NIMH, Mood & Anxiety Disorders Program, 15K North Dr,Room 111,MSC 2670, Bethesda, MD 20892 USA. RI Bremner, James/B-1632-2013; OI Vermetten, Eric/0000-0003-0579-4404; Staib, Lawrence/0000-0002-9516-5136 FU NIMH NIH HHS [MH-42088, MH-56120, MH-58922]; OMHHE CDC HHS [MN-51761] NR 113 TC 266 Z9 276 U1 5 U2 36 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 JUL 15 PY 2004 VL 56 IS 2 BP 101 EP 112 DI 10.1016/j.biopsych.2004.04.002 PG 12 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 835OQ UT WOS:000222493500006 PM 15231442 ER PT J AU Adams, BK Ferstl, EM Davis, MC Herold, M Kurtkaya, S Camalier, RF Hollingshead, MG Kaur, G Sausville, EA Rickles, FR Snyder, JP Liotta, DC Shoji, M AF Adams, BK Ferstl, EM Davis, MC Herold, M Kurtkaya, S Camalier, RF Hollingshead, MG Kaur, G Sausville, EA Rickles, FR Snyder, JP Liotta, DC Shoji, M TI Synthesis and biological evaluation of novel curcumin analogs as anti-cancer and anti-angiogenesis agents SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE synthetic curcumin analogs; anti-cancer agent in vitro and in vivo; anti-angiogenesis properties; 3D quantitative structure relationship (QSAR) ID TUMOR-CELL-LINES; NATIONAL-CANCER-INSTITUTE; DRUG DISCOVERY; DIFERULOYLMETHANE; ANTIOXIDANT; REACTIVITY; INHIBITION; ANTITUMOR; APOPTOSIS; MOLECULES AB A series of novel curcumin analogs were synthesized and screened for anti-cancer and anti-angiogenesis activities at Emory University and at the National Cancer Institute (NCI). These compounds are symmetrical alpha,beta-unsaturated and saturated ketones. The majority of the analogs demonstrated a moderate degree of anti-cancer activity. Compounds 10, 11, and 14 exhibited a high degree of cytotoxicity in the NCI in vitro anti-cancer cell line screen. In addition, this screen revealed that these compounds inhibit tumor cell growth with a higher potency than the commonly used chemotherapeutic drug, cisplatin. In independent in vitro screens conducted at Emory, the same compounds plus 4, 5, 8, 9, and 13 exhibited a high degree of cytotoxicity to tumor cells. Analogs that were effective in the anti-cancer screens were also effective in in vitro anti-angiogenesis assays. Compounds 4, 9, 11, and 14 were most effective in the anti-angiogenesis assays run at Emory. In the assays conducted by the NCI, compound 14 was almost as potent as the anti-angiogenic drug TNP-470, which has undergone clinical trials. Based on the favorable in vitro anti-cancer and anti-angiogenesis results with 14, further in vivo tests were conducted. This compound effectively reduced the size of human breast tumors grown in female athymic nude mice and showed little toxicity. This data, coupled with the remarkable in vitro data, suggests that compound 14 may potentially be an effective chemotherapeutic agent. As a follow-up, a 3D quantitative structure relationship based on 14 has been developed. It shows a cross-validated r(2)(q(2)) = 0.83 and a predictive r(2)(p(2)) = 0.71. COMPARE analysis suggests the compound to be a possible RNA/DNA antimetabolite, but also implies that the compound's cytotoxicity may arise from a presently unknown mechanism. (C) 2004 Elsevier Ltd. All rights reserved. C1 Emory Univ, Winship Canc Ctr, Atlanta, GA 30322 USA. Emory Univ, Dept Chem, Atlanta, GA 30322 USA. NCI, Frederick Canc Res & Dev Ctr, DCTD, Dev Therapeut Program, Frederick, MD 21702 USA. George Washington Univ, Sch Med & Hlth Sci, Dept Med, Washington, DC 20037 USA. George Washington Univ, Sch Med & Hlth Sci, Dept Pediat, Washington, DC 20037 USA. Emory Univ, Program Mol 7 Syst Pharmacol, Atlanta, GA 30322 USA. RP Snyder, JP (reprint author), Emory Univ, Winship Canc Ctr, Atlanta, GA 30322 USA. EM snyder@euch4e.chem.emory.edu FU NCI NIH HHS [CA82995, N01-CM-5600] NR 48 TC 228 Z9 240 U1 3 U2 35 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD JUL 15 PY 2004 VL 12 IS 14 BP 3871 EP 3883 DI 10.1016/j.bmc.2004.05.006 PG 13 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 836RI UT WOS:000222572900012 PM 15210154 ER PT J AU Holland, SM AF Holland, SM TI The WHIMs of leukocytes SO BLOOD LA English DT Editorial Material ID CHEMOKINES; CXCR4 C1 NIAID, Bethesda, MD 20892 USA. RP Holland, SM (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 15 PY 2004 VL 104 IS 2 BP 301 EP 302 DI 10.1182/blood-2004-05-1780 PG 2 WC Hematology SC Hematology GA 836QU UT WOS:000222571400006 ER PT J AU Rosenberg, PS Huang, Y Alter, BP AF Rosenberg, PS Huang, Y Alter, BP TI Individualized risks of first adverse events in patients with Fanconi anemia SO BLOOD LA English DT Article ID FALSE DISCOVERY RATE; SEQUENCE VARIATION; REGISTRY IFAR; GENE; MUTATIONS; SPECTRUM; CANCER; TRANSPLANTATION; MYELODYSPLASIA; POPULATION AB Fanconi anemia (FA) is an autosomal recessive condition associated with bone marrow failure (BMF) leading to death or hematopoietic stem cell transplantation, acute myeloid leukemia (AML), and solid tumors (STs). It is unclear which patients are most likely to develop each outcome. From a cohort of 144 North American patients with FA, we calculated individualized risks of each outcome, given the presence or absence of readily diagnosed congenital abnormalities that occur frequently in FA. Abnormal radii and a 5-item congenital abnormality score were significant risk factors for BMF. The cumulative incidence of BMF by age 10 years varied from 18% in the lowest BMF risk group to 83% In the highest. Because of competing risks, patients in the lowest BMF risk group were most likely to live long enough to develop AML or ST, and, conversely, patients in the highest BMF risk group were least likely to live long enough to develop AML or ST. By age 40, the cumulative incidence of ST ranged from 0.6% to 29% in the highest and lowest BMF risk groups, respectively. Abnormal radii are the strongest predictor of early BMF in FA; a congenital abnormality score separates patients with normal radii into distinct prognostic groups. (C) 2004 by The American Society of Hematology. C1 NCI, Div Canc Epidemiol & Genet, Biostat Branch, US Dept HHS,NIH, Rockville, MD 20852 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. NCI, Div Canc Epidemiol & Genet, Clin Genet Branch, Dept Hlth & Human Serv,NIH, Rockville, MD 20852 USA. RP Rosenberg, PS (reprint author), NCI, Div Canc Epidemiol & Genet, Biostat Branch, US Dept HHS,NIH, 6120 Execut Blvd,Execut Plaza S,Rm 7006, Rockville, MD 20852 USA. EM rosenbep@mai.nih.gov NR 44 TC 39 Z9 39 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 15 PY 2004 VL 104 IS 2 BP 350 EP 355 DI 10.1182/blood-2004-01-0083 PG 6 WC Hematology SC Hematology GA 836QU UT WOS:000222571400016 PM 15059844 ER PT J AU Gulino, AV Moratto, D Sozzani, S Cavadini, P Otero, K Tassone, L Imberti, L Pirovano, S Notarangelo, LD Soresina, R Mazzolari, E Nelson, DL Notarangelo, LD Badolato, R AF Gulino, AV Moratto, D Sozzani, S Cavadini, P Otero, K Tassone, L Imberti, L Pirovano, S Notarangelo, LD Soresina, R Mazzolari, E Nelson, DL Notarangelo, LD Badolato, R TI Altered leukocyte response to CXCL12 in patients with warts hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome SO BLOOD LA English DT Article; Proceedings Paper CT Symposium on Primary Immunodeficiencies CY MAY 15, 2003 CL Paris, FRANCE SP Federat Clin Immunol Soc ID HEMATOPOIETIC PROGENITOR CELLS; UP-REGULATING CXCR4; BONE-MARROW; FACTOR-I; T-CELLS; CHEMOKINE RECEPTORS; SEVERE NEUTROPENIA; DENDRITIC CELLS; B-LYMPHOCYTES; CUTTING EDGE AB The chemokine receptor CXCR4 and its functional ligand, CXCL12, are essential regulators of development and homeostasis of hematopoietic and lymphoid organs. Heterozygous truncating mutations in the CXCR4 intracellular tall cause a rare genetic disease known as WHIM syndrome (warts, hypogammaglobulinemia, infections, myelokathexis), whose pathophysiology remains unclear. We report CXCR4 function in 3 patients with WHIM syndrome carrying heterozygous truncating mutations of CXCR4. We show that CXCR4 gene mutations in WHIM patients do not affect cell surface expression of the chemokine receptor and its internalization upon stimulation with CXCL12. Moreover, no significant differences in calcium mobilization in response to CXCL12 are found. However, the chemotactic response of both polymorphonuclear cells and T lymphocytes in response to CXCL12 is increased. Furthermore, immunophenotypic analysis of circulating T and B lymphocytes reveals a decreased number of memory B cells and of naive T cells and an accumulation of effector memory T cells associated with a restricted T-cell repertoire. Based on our results, we suggest that the altered leukocyte response to CXCL12 may account for the pathologic. retention of mature polymorphonuclear cells in the bone marrow (myelokathexis) and for an altered lymphocyte trafficking, which may cause the immunophenotyping abnormalities observed in WHIM patients. C1 Univ Brescia, Spedali Civili, Ist Med Mol Angelo Nocivelli, Pediat Clin,Sect Gen Pathol & Immunol, I-25123 Brescia, Italy. Ist Ric Farmacol Mario Negri, Milan, Italy. Spedali Civil Brescia, Terzo Serv Anal, I-25125 Brescia, Italy. NIH, Metab Branch, NCI, Bethesda, MD 20892 USA. RP Badolato, R (reprint author), Univ Brescia, Spedali Civili, Ist Med Mol Angelo Nocivelli, Pediat Clin,Sect Gen Pathol & Immunol, I-25123 Brescia, Italy. EM badolato@med.unibs.it RI Sozzani, Silvano/C-1447-2009; Badolato, Raffaele/A-8081-2010; Notarangelo, Luigi/F-9718-2016 OI Sozzani, Silvano/0000-0002-3144-8743; Badolato, Raffaele/0000-0001-7375-5410; Notarangelo, Luigi/0000-0002-8335-0262 NR 54 TC 86 Z9 92 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 15 PY 2004 VL 104 IS 2 BP 444 EP 452 DI 10.1182/blood-2003-10-3532 PG 9 WC Hematology SC Hematology GA 836QU UT WOS:000222571400029 PM 15026312 ER PT J AU Nascimbeni, M Shin, EC Chiriboga, L Kleiner, DE Rehermann, B AF Nascimbeni, M Shin, EC Chiriboga, L Kleiner, DE Rehermann, B TI Peripheral CD4(+)CD8(+) T cells are differentiated effector memory cells with antiviral functions SO BLOOD LA English DT Article ID HEPATITIS-C VIRUS; CELLULAR IMMUNE-RESPONSES; PERSISTENT EXPANSIONS; CYTOTOXIC ACTIVITY; EXPRESS CD4; HUMAN LIVER; IN-VIVO; LYMPHOCYTES; BLOOD; INFECTION AB Although an increased frequency of CD4(+)CD8(+) T cells has been observed in the peripheral blood during viral infections, their role, function, and biologic significance are still poorly understood. Here we demonstrate that the circulating CD4+CD8+ T-cell population contains mature effector memory lymphocytes specific for antigens of multiple past, latent, and high-level persistent viral infections. Upon in vitro antigenic challenge, a higher frequency of CD4+CD8+ than single-positive cells displayed a T helper 1/T cytotoxic 1 (Th1/Tc1) cytokine profile and proliferated. Ex vivo, more double-positive than single-positive cells exhibited a differentiated phenotype. Accordingly, their lower T-cell receptor excision circles (TREC) content and shorter telomeres proved they had divided more frequently than single-positive cells. Consistent with expression of the tissue-homing marker CXCR3, CD4(+)CD8(+) T cells were demonstrated in situ at the site of persistent viral infection (le, in the liver during chronic hepatitis C). Finally, a prospective analysis of hepatitis C virus (HCV) infection in a chimpanzee, the only animal model for HCV infection, showed a close correlation between the frequency of activated CD4(+)CD8(+) T cells and viral kinetics. Collectively, these findings demonstrate that peripheral CD4(+)CD8(+) T cells take part in the adaptive immune response against infectious pathogens and broaden the perception of the T-cell populations involved in antiviral immune responses. (C) 2004 by The American Society of Hematology. C1 NIDDK, Liver Dis Sect, Digest Dis Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NYU, Bellevue Hosp, Sch Med, Dept Pathol, New York, NY USA. NCI, Pathol Lab, NIH, DHHS, Bethesda, MD 20892 USA. NYU, Bellevue Hosp, Sch Med, Dept Pathol, New York, NY USA. RP Rehermann, B (reprint author), NIDDK, Liver Dis Sect, Digest Dis Branch, NIH,Dept Hlth & Human Serv, 10 Ctr Dr,Bldg 10,Room 9B16, Bethesda, MD 20892 USA. EM rehermann@nih.gov RI Shin, Eui-Cheol/C-1690-2011; OI Kleiner, David/0000-0003-3442-4453; Chiriboga, Luis/0000-0002-2028-6873 NR 40 TC 106 Z9 112 U1 1 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 15 PY 2004 VL 104 IS 2 BP 478 EP 486 DI 10.1182/blood-2003-12-4395 PG 9 WC Hematology SC Hematology GA 836QU UT WOS:000222571400033 PM 15044252 ER PT J AU Weerasinghe, GR Rapoport, SI Bosetti, F AF Weerasinghe, GR Rapoport, SI Bosetti, F TI The effect of chronic lithium on arachidonic acid release and metabolism in rat brain does not involve secretory phospholipase A(2) or lipoxygenase/cytochrome P450 pathways SO BRAIN RESEARCH BULLETIN LA English DT Article DE prostaglandin; mood-stabilizer; bipolar disorder; prostaglandin E synthase ID CENTRAL-NERVOUS-SYSTEM; DOCOSAHEXAENOIC ACID; CYCLOOXYGENASE-2; EXPRESSION; CELLS AB The mood-stabilizer lithium, when chronically administered to rats at therapeutic concentrations, has been shown to downregulate brain arachidonic acid (AA) turnover and total phospholipase A(2) (PLA(2)) activity, as well as protein and mRNA levels of cytosolic cPLA(2). These effects are accompanied by a decrease in cyclooxygenase (COX)-2 protein level, COX activity, and brain prostaglandin E-2 (PGE(2)) concentration. The involvement of Ca2+-dependent secretory PLA(2) (sPLA(2)) in the mechanism of action of lithium has not been investigated. The purpose of this study was to examine, whether the effect of lithium is selectively directed to cPLA(2) or it also affects sPLA(2) protein and enzyme activity and whether other AA metabolizing enzymes (5-lipoxygenase and cytochrome P450 epoxygenase) were also altered. Furthermore, to determine if the reduction of brain PGE(2) concentration was due only to downregulation of COX-2 protein or if it also involves the terminal PGE synthase, we determined brain microsomal PGE synthase protein level. Male Fischer-344 rats were fed lithium chloride for 6 weeks, whereas, control rats were fed lithium-free chow under parallel conditions. We found that chronic lithium did not significantly change sPLA(2) activity or protein level. 5-Lipoxygenase and cytochrome P450 epoxygenase protein levels were unchanged, as were levels of the terminal PGE synthase. These results indicate that the effect of lithium selectively involves the cPLA(2)/COX-2 pathway, which might be responsible for the therapeutic effect in bipolar disorder. Published by Elsevier Inc. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Bosetti, F (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. EM frances@mail.nih.gov NR 19 TC 37 Z9 38 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD JUL 15 PY 2004 VL 63 IS 6 BP 485 EP 489 DI 10.1016/j.brainresbull.2004.04.005 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 841IJ UT WOS:000222923200006 PM 15249113 ER PT J AU Ursin, G Bernstein, L Wang, YP Lord, SJ Deapen, D Liff, JM Norman, SA Weiss, LK Daling, JR Marchbanks, PA Malone, KE Folger, SG McDonald, JA Burkman, RT Simon, MS Strom, BL Spirtas, R AF Ursin, G Bernstein, L Wang, YP Lord, SJ Deapen, D Liff, JM Norman, SA Weiss, LK Daling, JR Marchbanks, PA Malone, KE Folger, SG McDonald, JA Burkman, RT Simon, MS Strom, BL Spirtas, R TI Reproductive factors and risk of breast carcinoma in a study of white and African-American women SO CANCER LA English DT Article DE reproductive factors; breast carcinoma; white women; African-American women ID FULL-TERM PREGNANCY; CANCER RISK; PREMENOPAUSAL WOMEN; REDUCED RISK; BLACK-WOMEN; LACTATION; AGE; HISTORY; PARITY; EXPERIENCE AB BACKGROUND. Few studies have investigated the association between reproductive factors and the risk of breast carcinoma among African-American women. The authors assessed whether the number of full-term pregnancies, age at first fullterm pregnancy, and total duration of breastfeeding were associated with similar relative risk estimates in white and African-American women in a large multicenter, population-based case-control study of breast carcinoma. METHODS. Case patients were 4567 women (2950 white women and 1617 African-American women) ages 35-64 years with newly diagnosed invasive breast carcinoma between 1994 and 1998. Control patients were 4668 women (3012 white women and 1656 African-American women) who were identified by random-digit dialing and were frequency matched to case patients according to study center, race, and age. Adjusted odds ratios and 95% confidence intervals were estimated using unconditional logistic regression. RESULTS. For white women, the reduction in risk of breast carcinoma per full-term pregnancy was 13% among younger women (ages 35-49 years) and 10% among older women (ages 50-64 years). The corresponding risk reductions for African-American women were 10% and 6%, respectively. Risk decreased significantly with increasing number of full-term pregnancies for both races and both age categories. Duration of lactation was inversely associated with breast carcinoma risk among younger parous white (trend P = 0.0001) and African-American (trend P = 0.01) women. African-American women tended to have more children compared with women, but parity rates were lower in younger women than in older women in both racial groups. However, breastfeeding was substantially more common in young white women than in young African-American women. CONCLUSIONS. Overall, parity and lactation had similar effects on breast carcinoma risk in white and African-American women. If younger African-Arnerican women now are giving birth to fewer children than in the past, without a substantial increase in breastfeeding, breast carcinoma rates may continue to increase at a more rapid rate among these women compared with white women. Published 2004 by the American Cancer Society. C1 Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90089 USA. Univ Oslo, Dept Nutr, Oslo, Norway. Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. Natl Canc Inst, Off Ctr Training & Resources, Canc Ctr Branch, Bethesda, MD USA. Fred Hutchinson Canc Res Ctr, Div Publ Hlth, Seattle, WA 98104 USA. Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA USA. Baystate Med Ctr, Dept Obstet & Gynecol, Springfield, MA USA. Wayne State Univ, Karmanos Canc Inst, Dept Internal Med, Detroit, MI USA. NICHHD, Populat Res Ctr, Contracept & Reprod Hlth Branch, Bethesda, MD 20892 USA. RP Ursin, G (reprint author), Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Dept Prevent Med, Keck Sch Med, 1441 Eastlake Ave, Los Angeles, CA 90089 USA. EM gursin@usc.edu OI Lord, Sarah J/0000-0003-2763-5949 FU NCI NIH HHS [N01 PC-67006, N01-CN-0532, N01-CN-65064, N01-CN-67010]; NICHD NIH HHS [N01 HD 3-3168, N01 HD 2-3166, N01 HD 3-3174, N01 HD 3-3175, N01 HD 3-3176, Y01 HD 7022] NR 36 TC 50 Z9 50 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JUL 15 PY 2004 VL 101 IS 2 BP 353 EP 362 DI 10.1002/cncr.20373 PG 10 WC Oncology SC Oncology GA 835YD UT WOS:000222520500019 PM 15241834 ER PT J AU Hibino, S Shibuya, M Engbring, JA Mochizuki, M Nomizu, M Kleinman, HK AF Hibino, S Shibuya, M Engbring, JA Mochizuki, M Nomizu, M Kleinman, HK TI Identification of an active site on the laminin alpha 5 chain globular domain that binds to CD44 and inhibits malignancy SO CANCER RESEARCH LA English DT Article ID HUMAN ENDOTHELIAL-CELLS; SYNTHETIC PEPTIDES; GAMMA-1 CHAIN; TUMOR-GROWTH; BETA-1 CHAIN; IN-VIVO; ANGIOGENESIS; ADHESION; EXPRESSION; SEQUENCES AB The laminin alpha5 chain is a component of laminin-10 (alpha5beta1gamma1) and -11 (alpha5beta2gamma1). In this study, we have screened 113 overlapping synthetic peptides from the laminin alpha5 globular domain (G-domain) for cell attachment activity with B16-F10 cells using peptide-coated dishes. Eleven attachment-active peptides were identified. In vivo experimental B16-F10 pulmonary metastasis and primary tumor growth assays found that 4 of the 11 peptides inhibited tumor metastasis and growth and increased apoptosis. These four peptides also blocked tumor cell migration, invasion, and angiogenesis. Two of the peptides were highly homologous and showed significant similarity to sequences in collagens. We sought to identify the B16-F10 cell surface receptors for each of the four active peptides using peptide affinity chromatography. Only one peptide recognized a cell surface protein. Peptide A5G27 (RLVSYNGIIFFLK, residues 2892-2904) bound a diffuse M-r similar to120,000-180,000 band that eluted with 2 m NaCl. Glycosidase digestion of the 2 m eluate yielded protein bands of M, 90,000 and 60,000 that reacted in Western blot analysis with antibodies to CD44. Immunoprecipitation of the A5G27-bound membrane proteins with various cell surface proteoglycan antibodies confirmed CD44 as the surface receptor for A5G27. Finally, attachment assays to A5G27 in the presence of soluble glycosaminoglycans (GAGS) identified the GAGS of CD44 as the binding sites for A5G27. Our results suggest that A5G27 binds to the CD44 receptor of B16-F10 melanoma cells via the GAGS on CD44 and, thus, inhibits tumor cell migration, invasion, and angiogenesis in a dominant-negative manner. C1 Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. Nippon Med Coll, Dept Internal Med 4, Tokyo, Japan. Tokyo Metropolitan Komagome Hosp, Resp Div Internal Med, Tokyo, Japan. Hokkaido Univ, Grad Sch Environm Earth Sci, Sapporo, Hokkaido 060, Japan. RP Kleinman, HK (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bldg 30,Room 433,30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. EM hkleinman@dir.nidcr.nih.gov NR 36 TC 49 Z9 53 U1 3 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 JUL 15 PY 2004 VL 64 IS 14 BP 4810 EP 4816 DI 10.1158/0008-5472.CAN-04-0129 PG 7 WC Oncology SC Oncology GA 837XM UT WOS:000222674700020 PM 15256450 ER PT J AU Mocellin, S Wang, E Panelli, M Pilati, P Marincola, FM AF Mocellin, S Wang, E Panelli, M Pilati, P Marincola, FM TI DNA array-based gene profiling in tumor immunology SO CLINICAL CANCER RESEARCH LA English DT Review ID MESSENGER-RNA AMPLIFICATION; EXPRESSION DATA-ANALYSIS; RENAL-CELL CARCINOMA; CD8(+) T-CELLS; DENDRITIC CELLS; METASTATIC MELANOMA; IMMUNE RESPONSIVENESS; FUNCTIONAL GENOMICS; MICROARRAY ANALYSIS; ANTITUMOR IMMUNITY AB Recent advances in tumor immunology have fostered the clinical implementation of different immunotherapy modalities. However, the alternate success of such regimens underscores the fact that the molecular mechanisms underlying tumor immune rejection are still poorly understood. Given the complexity of the immune system network and the multidimensionality of tumor-host interactions, the comprehension of tumor immunology might greatly benefit from high-throughput DNA array analysis, which can portray the molecular kinetics of immune response on a genome-wide scale, thus accelerating the accumulation of knowledge and ultimately catalyzing the development of new hypotheses in cell biology. Although in its infancy, the implementation of DNA array technology in tumor immunology studies has already provided investigators with novel data and intriguing hypotheses on the cascade of molecular events leading to an effective immune response against cancer. Although the principles of DNA array-based gene profiling techniques have become common knowledge, the need for mastering this technique to produce meaningful data and correctly interpret this enormous output of information is critical and represents a tremendous challenge for investigators. In the present work, we summarize the main technical features and critical issues characterizing this powerful laboratory tool and review its applications in the fascinating field of cancer immunogenomics. C1 Univ Padua, Dipartimento Sci Oncologiche & Chirurg, I-35128 Padua, Italy. NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Mocellin, S (reprint author), Univ Padua, Dipartimento Sci Oncologiche & Chirurg, Via Giustiniani 2,6 Piano Policlin, I-35128 Padua, Italy. EM mocellins@hotmail.com NR 100 TC 17 Z9 19 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2004 VL 10 IS 14 BP 4597 EP 4606 DI 10.1158/1078-0432.CCR-04-0327 PG 10 WC Oncology SC Oncology GA 840ET UT WOS:000222840700002 PM 15269130 ER EF