FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Coronado, LL AF Coronado, LL TI An overview: IND, NDA, RDRC, and IRBs for the HP. SO HEALTH PHYSICS LA English DT Meeting Abstract C1 NIH, Off Director, Radiat Safety Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD JUN PY 2003 VL 84 IS 6 SU 2 BP S204 EP S204 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 683QE UT WOS:000183160000161 ER PT J AU Redmond, GR AF Redmond, GR TI X-ray exposure measurement using electret ion chamber. SO HEALTH PHYSICS LA English DT Meeting Abstract C1 Natl Inst Hlth, Mitchellville, MD 20721 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD JUN PY 2003 VL 84 IS 6 SU 2 BP S167 EP S167 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 683QE UT WOS:000183160000057 ER PT J AU Simon, SL Bouville, A Weinstock, R Land, C Lafond, C Farrell, C AF Simon, SL Bouville, A Weinstock, R Land, C Lafond, C Farrell, C TI A web-based calculator for estimating individual thyroid radiation dose and cancer risk from Nevada test site fallout. SO HEALTH PHYSICS LA English DT Meeting Abstract C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD JUN PY 2003 VL 84 IS 6 SU 2 BP S225 EP S225 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 683QE UT WOS:000183160000220 ER PT J AU West, JL AF West, JL TI Pediatric head computerized tomography in pediatric patients SO HEALTH PHYSICS LA English DT Meeting Abstract C1 NIH, Gaithersburg, MD 20879 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD JUN PY 2003 VL 84 IS 6 SU 2 BP S259 EP S259 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 683QE UT WOS:000183160000313 ER PT J AU Hampton, LL Wright, CG Alagramam, KN Battey, JF Noben-Trauth, K AF Hampton, LL Wright, CG Alagramam, KN Battey, JF Noben-Trauth, K TI A new spontaneous mutation in the mouse Ames waltzer gene, Pcdh15 SO HEARING RESEARCH LA English DT Article DE deafness; Ames waltzer; protocadherin 15 (Pcdh15) ID PROTOCADHERIN GENE; DEAFNESS; MICE; DEFECTS; MDFW AB A recessive deafness mutation in the mouse arose spontaneously and was identified in a colony segregating a null allele of the gastrin-releasing peptide receptor (Grpr) locus. Auditory-evoked brain stem response measurements revealed deafness in 7-week-old affected mice. By linkage analyses, the mutant phenotype was mapped near marker D10Mit186 and the protocadherin gene Pcdh15. As shown by complementation testing, the new mutation is allelic with Ames waltzer (Pcdh15(av)). Sequencing mutant-derived brain Pcdh15 cDNAs identified the insertion of a cytosine residue at nucleotide position c2099 (2099insC), which results in a frame-shift and premature stop codon. Abnormal stereocilia on inner and outer hair cells of the organ of Corti were identified by scanning electron microscopy as early as postnatal day 0 and cross-sectional histology revealed severe neuroepithelial degeneration in cochleas of 30-50-day-old mutants. The new allele of Ames waltzer, designated Pcdh15(av-Jfb), may aid in studying the histopathology associated with Usher syndrome type IF, which is caused by a functional null allele of PCDH15. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Natl Inst Deafness & Other Commun Disorders, Neurogenet Sect, Mol Biol Lab, NIH, Rockville, MD 20850 USA. NINDS, G Prot Coupled Receptors Sect, NIH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dept Otolaryngol Head & Neck Surg, Dallas, TX 75390 USA. Univ Hosp Cleveland, Inst Res, Dept Otolaryngol Head & Neck Surg, Cleveland, OH 44106 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Noben-Trauth, K (reprint author), Natl Inst Deafness & Other Commun Disorders, Neurogenet Sect, Mol Biol Lab, NIH, 5 Res Court,Room 2A3I, Rockville, MD 20850 USA. FU NIDCD NIH HHS [Z01 DC000026-06, DC00036-02] NR 18 TC 17 Z9 17 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 J9 HEARING RES JI Hear. Res. PD JUN PY 2003 VL 180 IS 1-2 BP 67 EP 75 DI 10.1016/S0378-5955(03)00107-2 PG 9 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 690WU UT WOS:000183574100007 PM 12782354 ER PT J AU Mbulaiteye, SM Parkin, DM Rabkin, CS AF Mbulaiteye, SM Parkin, DM Rabkin, CS TI Epidemiology of AIDS-related malignancies - An international perspective SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; SARCOMA-ASSOCIATED HERPESVIRUS; NON-HODGKINS-LYMPHOMA; ACTIVE ANTIRETROVIRAL THERAPY; SQUAMOUS INTRAEPITHELIAL LESIONS; EPSTEIN-BARR-VIRUS; MULTICENTRIC KAPOSIS-SARCOMA; HIV-INFECTED INDIVIDUALS; NERVOUS-SYSTEM LYMPHOMA; HEPATITIS-C VIRUS AB Patients with HIV infection are at increased risk for developing Kaposi's sarcoma, non-Hodgkin's lymphoma, and several other cancers. The relative risks for the most common epithelial cancers in the general population-lung, breast, colon/rectum, stomach, liver, and prostate-are not increased substantially in people with AIDS, however. Accumulating data suggest that HIV-infected patients also are at increased risk for developing Hodgkin's lymphoma, cervical carcinoma in situ (CIS), other anogenital neoplasms (invasive cancer and CIS), leiomyosarcoma, and conjunctival squamous cell carcinoma. There is inconclusive evidence, however, with regard to HIV infection being associated with invasive cervical cancer, testicular seminoma, or hepatocellular carcinoma. Notably, other viral infections have been implicated in the etiology of many of these conditions. The introduction of highly active antiretroviral therapy (HAART) has decreased the incidence of AIDS-associated cancers in Western countries, but less than 1% of AIDS patients are receiving HAART in the HIV epicenter of sub-Saharan Africa. Further therapeutic advances that extend survival with HIV infection with varying reconstitution of immune competence may lead to additional alterations in cancer risk. C1 Natl Canc Inst, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Int Agcy Res Canc, Univ Descript Epidemiol, F-69372 Lyon 08, France. RP Mbulaiteye, SM (reprint author), MSC 7248,6120 Execut Bldg,EPS Room 8007, Rockville, MD 20852 USA. NR 132 TC 66 Z9 69 U1 0 U2 4 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD JUN PY 2003 VL 17 IS 3 BP 673 EP + DI 10.1016/S0889-8588(03)00048-0 PG 25 WC Oncology; Hematology SC Oncology; Hematology GA 696VQ UT WOS:000183908600002 PM 12852650 ER PT J AU Lutchman, G Hoofnagle, JH AF Lutchman, G Hoofnagle, JH TI Viral kinetics in hepatitis C SO HEPATOLOGY LA English DT Editorial Material ID DYNAMICS IN-VIVO; VIRUS-INFECTION; INTERFERON-ALPHA; RIBAVIRIN; RESPONSES; THERAPY; PEGINTERFERON C1 NIDDKD, Liver Dis Sect, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Lutchman, G (reprint author), NIDDKD, Liver Dis Sect, Digest Dis Branch, NIH, Bldg 10,Room 9B16,10 Ctr Dr, Bethesda, MD 20892 USA. NR 13 TC 15 Z9 16 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUN PY 2003 VL 37 IS 6 BP 1257 EP 1259 DI 10.1053/jhep.2003.50238 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 684ZQ UT WOS:000183236700006 PM 12774002 ER PT J AU Kamiya, A Inoue, Y Gonzalez, FJ AF Kamiya, A Inoue, Y Gonzalez, FJ TI Role of the hepatocyte nuclear factor 4 alpha in control of the pregnane X receptor during fetal liver development SO HEPATOLOGY LA English DT Article ID ENRICHED TRANSCRIPTION FACTORS; HEMATOPOIETIC STEM-CELLS; ONCOSTATIN-M; GENE-EXPRESSION; TYROSINE AMINOTRANSFERASE; HEPATIC DEVELOPMENT; SIGNALING PATHWAY; BONE-MARROW; IN-VITRO; INDUCTION AB The fetal liver, the major site of hematopoiesis during embryonic development, acquires additional functions near birth. Among the important liver functions is the response to xenobiotic exposure due to expression of several cytochromes P450 (CYP) and drug efflux transporters. Expression of these genes is regulated by nuclear receptors such as the pregnane X receptor (PXR). In this study, regulation of xenobiotic responses during fetal liver development was analyzed using a fetal hepatocyte primary culture system derived from embryonic day 15 (E15) livers. Hepatocyte nuclear factor (HNF) 4alpha regulates the expression of many genes preferentially in the liver. Expression of several xenobiotic response genes as well as HNF4alpha was increased in fetal hepatocytes stimulated by the hepatic maturation factors oncostatin M (OSM) and Matrigel. To determine the contribution of HNF4alpha to xenobiotic responses in the fetal liver, fetal hepatocytes containing floxed HNF4alpha alleles were cultured and the HNF4alpha gene was inactivated by infection with an adenovirus containing the Cre gene. Expression of CYP3A11 and PXR was suppressed by inactivation of HNF4alpha. An HNF4alpha binding site was characterized in the PXR promoter and found to be required for activation of the PXR promoter in fetal hepatocytes. In conclusion, HNF4alpha is the key transcription factor regulating responses to xenobiotics through activation of the PXR gene during fetal liver development. C1 NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, NIH, Bldg 37,Room 2A19,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 42 TC 102 Z9 103 U1 1 U2 4 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUN PY 2003 VL 37 IS 6 BP 1375 EP 1384 DI 10.1053/jhep.2003.50212 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 684ZQ UT WOS:000183236700021 PM 12774017 ER PT J AU Marsh, SGE Parham, P Dupont, B Geraghty, DE Trowsdale, J Middleton, D Vilches, C Carrington, M Witt, C Guethlein, LA Shilling, H Garcia, CA Hsu, KC Wain, H AF Marsh, SGE Parham, P Dupont, B Geraghty, DE Trowsdale, J Middleton, D Vilches, C Carrington, M Witt, C Guethlein, LA Shilling, H Garcia, CA Hsu, KC Wain, H TI Killer-cell immunoglobulin-like receptor (KIR) nomenclature report, 2002 SO HUMAN IMMUNOLOGY LA English DT Article ID INHIBITORY RECEPTORS; ALLELIC POLYMORPHISM; GENOMIC ORGANIZATION; GENE CONTENT; HLA-C; NK; DOMAINS; HAPLOTYPES; DIVERSITY; VARIANTS C1 Royal Free Hosp, Anthony Nolan Res Inst, London NW3 2QG, England. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Cambridge, Cambridge, England. No Ireland Tissue Typing Lab, Belfast, Antrim, North Ireland. Hosp Puerta de Hierro, Madrid, Spain. Frederick Canc Res & Dev Ctr, Frederick, MD USA. Royal Perth Hosp, Perth, WA, Australia. Univ Washington, Seattle, WA 98195 USA. UCL, London, England. RP Marsh, SGE (reprint author), Royal Free Hosp, Anthony Nolan Res Inst, Pond St, London NW3 2QG, England. EM marsh@ebi.ac.uk RI Vilches, Carlos/G-1471-2012 OI Vilches, Carlos/0000-0002-0300-9225 NR 36 TC 59 Z9 69 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0198-8859 J9 HUM IMMUNOL JI Hum. Immunol. PD JUN PY 2003 VL 64 IS 6 BP 648 EP 654 DI 10.1016/S1098-8859(03)00067-3 PG 7 WC Immunology SC Immunology GA 687TN UT WOS:000183393200012 PM 12770798 ER PT J AU Marx, FP Holzmann, C Strauss, KM Li, L Eberhardt, O Gerhardt, E Cookson, MR Hernandez, D Farrer, MJ Kachergus, J Engelender, S Ross, CA Berger, K Schols, L Schulz, JB Riess, O Kruger, R AF Marx, FP Holzmann, C Strauss, KM Li, L Eberhardt, O Gerhardt, E Cookson, MR Hernandez, D Farrer, MJ Kachergus, J Engelender, S Ross, CA Berger, K Schols, L Schulz, JB Riess, O Kruger, R TI Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson's disease SO HUMAN MOLECULAR GENETICS LA English DT Article ID ALPHA-SYNUCLEIN; BODY FORMATION; PATHWAY; ASSOCIATION; DISORDERS; SYSTEM; SCREEN AB Synphilin-1 is linked to the pathogenesis of Parkinson's disease (PD) based on its identification as an alpha-synuclein (PARK1) and parkin (PARK2) interacting protein. Moreover, synphilin-1 is a component of Lewy bodies (LB) in brains of sporadic PD patients. Therefore, we performed a detailed mutation analysis of the synphilin-1 gene in 328 German familial and sporadic PD patients. In two apparently sporadic PD patients we deciphered a novel C to T transition in position 1861 of the coding sequence leading to an amino acid substitution from arginine to cysteine in position 621 (R621C). This mutation was absent in a total of 702 chromosomes of healthy German controls. To define a possible role of mutant synphilin-1 in the pathogenesis of PD we performed functional analyses in SH-SY5Y cells. We found synphilin-1 capable of producing cytoplasmic inclusions in transfected cells. Moreover we observed a significantly reduced number of inclusions in cells expressing C621 synphilin-1 compared with cells expressing wild-type (wt) synphilin-1, when subjected to proteasomal inhibition. C621 synphilin-1 transfected cells were more susceptible to staurosporine-induced cell death than cells expressing wt synphilin-1. Our findings argue in favour of a causative role of the R621C mutation in the synphilin-1 gene in PD and suggest that the formation of intracellular inclusions may be beneficial to cells and that a mutation in synphilin-1 that reduces this ability may sensitize neurons to cellular stress. C1 Univ Tubingen, Dept Neurol, Lab Neurodegenerat, D-72076 Tubingen, Germany. Univ Rostock, Dept Med Genet, Rostock, Germany. Tongji Med Univ, Union Hosp, Dept Tradit Chinese Med, Wuhan, Peoples R China. NIA, Neurogenet Lab, Bethesda, MD 20892 USA. Mayo Clin, Neurogenet Lab, Jacksonville, FL USA. Technion Israel Inst Technol, Bruce Rappaport Fac Med, Dept Pharmacol, IL-31096 Haifa, Israel. Johns Hopkins Univ, Sch Med, Dept Psychiat, Div Neurobiol, Baltimore, MD 21205 USA. Univ Munster, Dept Epidemiol & Social Med, D-4400 Munster, Germany. Univ Bochum, Bochum, Germany. Univ Tubingen, Dept Med Genet, Tubingen, Germany. RP Kruger, R (reprint author), Univ Tubingen, Dept Neurol, Lab Neurodegenerat, Hoppe Seyler Str 3, D-72076 Tubingen, Germany. RI Holzmann, Carsten/B-9254-2008; Schulz, Jorg/D-9786-2012; Ross, Christopher/H-8395-2013 OI Holzmann, Carsten/0000-0001-7977-9093; Schulz, Jorg/0000-0002-8903-0593; FU NINDS NIH HHS [NS 38377] NR 28 TC 107 Z9 109 U1 0 U2 4 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 JUN 1 PY 2003 VL 12 IS 11 BP 1223 EP 1231 DI 10.1093/hmg/ddg134 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 684YA UT WOS:000183233000002 PM 12761037 ER PT J AU Ning, Y Xu, JF Li, Y Chavez, L Riethman, HC Lansdorp, PM Weng, NP AF Ning, Y Xu, JF Li, Y Chavez, L Riethman, HC Lansdorp, PM Weng, NP TI Telomere length and the expression of natural telomeric genes in human fibroblasts SO HUMAN MOLECULAR GENETICS LA English DT Article ID SENESCENT HUMAN-CELLS; REPLICATIVE SENESCENCE; GROWTH ARREST; YEAST TELOMERES; BREAST-CANCER; INHIBITORS; SEQUENCE; DOMAINS; 16Q24.3; REGION AB Progressive telomere shortening occurs with division of normal human cells, and eventually leads to replicative senescence. The mechanism by which the shortened telomeres cause growth arrest is largely unknown. Transcriptional silencing of genes adjacent to telomeres, also called telomere position effect, has been hypothesized as a possible mechanism of telomere-mediated senescence. However, there is no report regarding telomere position effect on natural telomeric genes in human cells. To address whether the expression of natural telomeric genes is regulated by telomere length, we combined quantitative RT-PCR with quantitative fluorescence in situ hybridization to comparatively analyze the expression of 34 telomeric genes and telomere length of their 24 corresponding chromosome ends in young and senescent human fibroblasts. We have demonstrated here that telomere length alone is not sufficient to determine the expression status of natural telomeric genes. An extended analysis of a tandem of eight telomeric genes on a single chromosome end revealed a discontinuous pattern of changed expression during telomere shortening and some of the changes are senescence-specific rather than non-dividing-related. These results suggest that the expression of natural telomeric genes may be influenced by alteration of local heterochromatin structure. C1 Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. British Columbia Canc Res Ctr, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada. Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. RP Ning, Y (reprint author), Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. FU NIA NIH HHS [AG21208] NR 28 TC 30 Z9 35 U1 1 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 JUN 1 PY 2003 VL 12 IS 11 BP 1329 EP 1336 DI 10.1093/hmg/ddg139 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 684YA UT WOS:000183233000013 PM 12761048 ER PT J AU Nelson, KB AF Nelson, KB TI Perinatal pathology, the placenta, and litigation: An open forum SO HUMAN PATHOLOGY LA English DT Editorial Material C1 NINDS, Bethesda, MD 20892 USA. RP Nelson, KB (reprint author), NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0046-8177 EI 1532-8392 J9 HUM PATHOL JI Hum. Pathol. PD JUN PY 2003 VL 34 IS 6 BP 522 EP 523 DI 10.1016/S0046-8177(03)00230-2 PG 2 WC Pathology SC Pathology GA 692UA UT WOS:000183677600003 ER PT J AU Lenfant, C Chobanian, AV Jones, DW Roccella, EJ AF Lenfant, C Chobanian, AV Jones, DW Roccella, EJ TI Seventh report of the Joint National Committee on the prevention, detection, evaluation, and treatment of high blood pressure (JNC 7) resetting the hypertension sails SO HYPERTENSION LA English DT Editorial Material C1 Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. NHLBI, Bethesda, MD 20892 USA. Boston Univ, Med Ctr, Boston, MA USA. RP Jones, DW (reprint author), Univ Mississippi, Med Ctr, 2500 N State St, Jackson, MS 39216 USA. RI Lakic, Dragana/F-8688-2011 NR 4 TC 194 Z9 213 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD JUN PY 2003 VL 41 IS 6 BP 1178 EP 1179 DI 10.1161/01.HYP.0000075790.33892.AE PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 686YK UT WOS:000183348400002 PM 12756222 ER PT J AU Wang, MY Takagi, G Asai, K Resuello, RG Natividad, FF Vatner, DE Vatner, SF Lakatta, EG AF Wang, MY Takagi, G Asai, K Resuello, RG Natividad, FF Vatner, DE Vatner, SF Lakatta, EG TI Aging increases aortic MMP-2 activity and angiotensin II in nonhuman primates SO HYPERTENSION LA English DT Article DE aging; vasculature; enzymes; angiotensin II; monkeys ID CONVERTING ENZYME-INHIBITOR; SMOOTH-MUSCLE CELLS; TISSUE INHIBITOR; HYPERCHOLESTEROLEMIC RABBITS; MATRIX METALLOPROTEINASES; ENDOTHELIAL DYSFUNCTION; ATHEROSCLEROTIC AORTA; IN-VITRO; ACTIVATION; EXPRESSION AB To seek evidence that the nonhuman primate arterial wall, as it ages in the absence of atherosclerosis, exhibits alterations in pathways that are involved in the pathogenesis of experimental atherosclerosis, we assessed aortic matrix metalloproteinase-2 (MMP-2) and its regulators, ie, membrane type-1 of matrix metalloproteinase (MT1-MMP) and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2), and the expression of angiotensin II (Ang II), angiotensin-converting enzyme (ACE), and chymase in young (6.4+/-0.7 years) and old (20.0+/-1.9 years) male monkeys. With advancing age, (1) the intimal thickness increased 3-fold and contained numerous vascular smooth muscle cells and matrix, but no inflammatory cells; (2) the intimal MMP-2 antibody-staining fraction increased by 80% (P<0.01); (3) in situ zymography showed that MMP-2 activity, mainly confined to the intima, increased 3-fold (P<0.01); (4) the MT1-MMP antibody-staining fraction increased by 150% (P<0.001), but the TIMP-2 antibody-staining fraction did not significantly change; (5) steady levels of the mRNA-staining fraction (via in situ hybridization) for MMP-2 increased 7-fold, for MT1-MMP increased 9-fold, and for TIMP-2 increased 2-fold (all P<0.001); and (6) intimal Ang II and ACE immunofluorescence were increased 5-fold and 5.6-fold, respectively, and colocalized with MMP-2. Thus, age-associated arterial remodeling and the development and progression of experimental atherosclerosis in young animals share common mechanisms, ie, MMP-2 activation and increased Ang II signaling. This might explain, in part, the dramatically exaggerated prevalence and severity of vascular diseases with aging. C1 NIA, Intramural Res Program, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Cell Biol & Mol Med, Newark, NJ 07103 USA. St Lukes Hosp, Manila, Philippines. Siconbrec, Manila, Philippines. RP Lakatta, EG (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 38 TC 121 Z9 125 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD JUN PY 2003 VL 41 IS 6 BP 1308 EP 1316 DI 10.1161/01.HYP.0000073843.56046.45 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 686YK UT WOS:000183348400023 PM 12743015 ER PT J AU Jun, SC Pearlmutter, BA Nolte, G AF Jun, SC Pearlmutter, BA Nolte, G TI MEG source localization using an MLP with a distributed output representation SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE distributed representation; magnetoencephalography; multilayer perceptron; source localization ID MAGNETOENCEPHALOGRAPHY; BRAIN; SYSTEM AB We present a system that takes realistic magnetoencephalographic (MEG) signals and localizes a single dipole to reasonable accuracy in real time. At its heart is a multilayer perceptron (MLP) which takes the sensor measurements as inputs, uses one hidden layer, and generates as outputs the amplitudes of receptive fields holding a distributed representation of the dipole location. We trained this Soft-MLP on dipolar sources with real brain noise and converted the network's output into an explicit Cartesian coordinate representation of the dipole location using two different decoding strategies. The proposed Soft-MLPs are much more accurate than previous networks which output source locations in Cartesian coordinates. Hybrid Soft-MLP-start-LM systems, in which the Soft-MLP output initializes Levenberg-Marquardt, retained their accuracy of 0.28 cm with a decrease in computation time from 36 ins to 30 ms. We apply the Soft-MLP localizer to real MEG data separated by a blind source separation algorithm, and compare the Soft-MLP dipole locations to those of a conventional system. C1 Los Alamos Natl Lab, Biol & Quantum Phys Grp, Los Alamos, NM 87545 USA. NUI Maynooth, Hamilton Inst, Maynooth, Kildare, Ireland. Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Jun, SC (reprint author), Los Alamos Natl Lab, Biol & Quantum Phys Grp, MS-D454, Los Alamos, NM 87545 USA. RI Pearlmutter, Barak/M-8791-2014; OI Pearlmutter, Barak/0000-0003-0521-4553; JUN, SUNG CHAN/0000-0001-5357-4436 NR 13 TC 2 Z9 2 U1 0 U2 1 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 0018-9294 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD JUN PY 2003 VL 50 IS 6 BP 786 EP 789 DI 10.1109/TBME.2003.812154 PG 4 WC Engineering, Biomedical SC Engineering GA 688BU UT WOS:000183413100016 PM 12814246 ER PT J AU Milanesi, L Rogozin, IB AF Milanesi, L Rogozin, IB TI ESTMAP: A system for expressed sequence tags mapping on genomic sequences SO IEEE TRANSACTIONS ON NANOBIOSCIENCE LA English DT Article DE alignment; database searches; expressed sequence tag (EST); gene prediction; genomic DNA; repetitive elements ID GENE STRUCTURE PREDICTION; HUMAN MESSENGER-RNAS; DNA; ALIGNMENT; DISCOVERY; ESTS; TOOL AB The completion of a number of large genome sequencing projects emphasizes the importance of protein-coding gene predictions. Most of the problems associated with gene prediction are caused by the complex exon-intron structures commonly found in eukaryotic genomes. However, information from homologous sequences can significantly improve the accuracy of the prediction. In particular, expressed sequence tags (ESTs) are very useful for this purpose, since currently existing EST collections are very large. We developed an ESTMAP system, which utilizes homology searches against a database of repetitive elements using the RepeatView program and the EST Division of GenBank using the BLASTN program. ESTMAP extracts "exact" matches with EST sequences (> 95% of homology) from BLASTN output file and predicts introns in DNA comparing ESTs and a query sequence. ESTMAP is implemented as a part of the WebGene system. C1 Natl Ctr Biotechnol Informat, Natl Lib Med, NIH, Bethesda, MD 20894 USA. ITB, CNR, I-20090 Segrate, MI, Italy. RP Milanesi, L (reprint author), ITB, CNR, Via Frotelli Corni 93, I-20090 Segrate, MI, Italy. OI Milanesi, Luciano/0000-0002-1201-3939 NR 30 TC 4 Z9 5 U1 0 U2 0 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 1536-1241 J9 IEEE T NANOBIOSCI JI IEEE Trans. Nanobiosci. PD JUN PY 2003 VL 2 IS 2 BP 75 EP 78 DI 10.1109/TNB.2003.813928 PG 4 WC Biochemical Research Methods; Nanoscience & Nanotechnology SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA 780QK UT WOS:000189392700005 PM 15382662 ER PT J AU Vaughan, TM Heetderks, WJ Trejo, LJ Rymer, WZ Weinrich, M Moore, MM Kubler, A Dobkin, BH Birbaumer, N Donchin, E Wolpaw, EW Wolpaw, JR AF Vaughan, TM Heetderks, WJ Trejo, LJ Rymer, WZ Weinrich, M Moore, MM Kubler, A Dobkin, BH Birbaumer, N Donchin, E Wolpaw, EW Wolpaw, JR TI Brain-computer interface technology: A review of the second international meeting SO IEEE TRANSACTIONS ON NEURAL SYSTEMS AND REHABILITATION ENGINEERING LA English DT Editorial Material DE terms-augmentative communication; brain-computer interface (BCI); electroencephalography (EEG); rehabilitation ID EVENT-RELATED POTENTIALS; MENTAL PROSTHESIS; COMMUNICATION; PATIENT; SIGNAL; CORTEX AB This paper summarizes the Brain-Computer Interfaces for Communication and Control, The Second International Meeting, held in Rensselaerville, NY, in June 2002. Sponsored by the National Institutes of Health and organized by the Wadsworth Center of the New York State Department of Health, the meeting addressed current work and future plans in brain-computer interface (BCI) research. Ninety-two researchers representing 38 different research groups from the United States, Canada, Europe, and China participated. The BCIs discussed at the meeting use electroencephalographic activity recorded from the scalp or single-neuron activity recorded within cortex to control cursor movement, select letters or icons, or operate neuroprostheses. The central element in each BCI is a translation algorithm that converts electrophysiological input from the user into output that controls external devices. BCI operation depends on effective interaction between two adaptive controllers, the user who encodes his or her commands in the electrophysiological input provided to the BCI, and the BCI that recognizes the commands contained in the input and expresses them in device control. Current BCIs have maximum information transfer rates of up to 25 b/min. Achievement of greater speed and accuracy requires improvements in signal acquisition and processing, in translation algorithms, and in user training. These improvements depend on interdisciplinary cooperation among neuroscientists, engineers computer programmers, psychologists, and rehabilitation specialists, and on adoption and widespread application of objective criteria for evaluating alternative methods. The practical use of BCI technology will be determined by the development of appropriate applications and identification of appropriate user groups, and will require careful attention to the needs and desires of individual users. C1 New York State Dept Hlth, Lab Nervous Syst Disorders, Wadsworth Ctr, Albany, NY 12201 USA. Natl Inst Nervous Syst Disorders, NIH, Bethesda, MD 20892 USA. NASA, Ames Res Ctr, Moffett Field, CA 94035 USA. Rehabil Inst Chicago, Chicago, IL 60611 USA. Northwestern Univ, Chicago, IL 60611 USA. NICHHD, Natl Ctr Med Rehabil Res, NIH, Bethesda, MD 20892 USA. Georgia State Univ, Atlanta, GA 30302 USA. Univ Tubingen, Inst Med Psychol & Behav Neurobiol, D-72074 Tubingen, Germany. Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90095 USA. Univ S Florida, Dept Psychol, Tampa, FL 33620 USA. RP Vaughan, TM (reprint author), New York State Dept Hlth, Lab Nervous Syst Disorders, Wadsworth Ctr, Albany, NY 12201 USA. OI Kubler, Andrea/0000-0003-4876-0415 FU NICHD NIH HHS [HD41991-01] NR 54 TC 176 Z9 200 U1 4 U2 37 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 1534-4320 J9 IEEE T NEUR SYS REH JI IEEE Trans. Neural Syst. Rehabil. Eng. PD JUN PY 2003 VL 11 IS 2 BP 94 EP 109 DI 10.1109/TNSRE.2003.814799 PG 16 WC Engineering, Biomedical; Rehabilitation SC Engineering; Rehabilitation GA 705EL UT WOS:000184382700001 PM 12899247 ER PT J AU Modi, WS O'Brien, TR Vlahov, D Buchbinder, S Gomperts, E Phair, J O'Brien, SJ Winkler, C AF Modi, WS O'Brien, TR Vlahov, D Buchbinder, S Gomperts, E Phair, J O'Brien, SJ Winkler, C TI Haplotype diversity in the interleukin-4 gene is not associated with HIV-1 transmission and AIDS progression SO IMMUNOGENETICS LA English DT Article DE HIV-1; AIDS; interleukin-4; haplotype diversity; recombination hotspot ID LINKAGE DISEQUILIBRIUM; DISEASE PROGRESSION; DRUG-USERS; INFECTION; POLYMORPHISM; TYPE-1; EXPRESSION; IL-4; PATHOGENESIS; RESTRICTION AB Interleukin-4 (IL-4) is a pleiotropic cytokine produced primarily by activated CD4(+) T lymphocytes, mast cells, and basophils. It modulates the functions of a variety of cell types involved with the immune response. This cytokine differentially regulates two major HIV-1 coreceptors and activates viral expression, and is thus a reasonable candidate gene for analyses in HIV-1/AIDS cohort studies. Population genetic variation in five single nucleotide polymorphisms (SNPs) in the 5' region of the IL-4 gene was assessed in five racial groups. Neutrality tests reveal that the populations are evolving in accord with the infinite-sites model. However, coalescent simulations suggest greater haplotype diversity among African Americans than expected. This increased variation is presumably attributable to recombination or gene conversion. Genetic epidemiological analyses were conducted among European American and African American participants enrolled in five USA-based HIV-1/AIDS cohorts. One SNP, -589T, known to influence IL-4 transcription was previously shown to be associated with HIV-1/AIDS in both Japanese and French populations. Present analyses failed to identify any significant associations with HIV-1 infection or progression to AIDS. C1 Natl Canc Inst, Basic Res Program, SAIC Frederick, FCRDC, Frederick, MD 21702 USA. NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Johns Hopkins Sch Hyg & Publ Hlth, AIDS Link Intravenous Experience, Baltimore, MD 21205 USA. San Francisco Dept Publ Hlth, San Francisco, CA 94102 USA. Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. Northwestern Univ, Sch Med, Dept Med, Chicago, IL 60611 USA. NCI, Lab Genom Divers, FCRDC, Frederick, MD 21702 USA. RP Winkler, C (reprint author), Natl Canc Inst, Basic Res Program, SAIC Frederick, FCRDC, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-124000] NR 45 TC 9 Z9 9 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0093-7711 J9 IMMUNOGENETICS JI Immunogenetics PD JUN PY 2003 VL 55 IS 3 BP 157 EP 164 DI 10.1007/s00251-003-0541-5 PG 8 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 691ZY UT WOS:000183636900004 PM 12715242 ER PT J AU Khaled, AR Durum, SK AF Khaled, AR Durum, SK TI Death and Baxes: mechanisms of lymphotrophic cytokines SO IMMUNOLOGICAL REVIEWS LA English DT Review ID RECEPTOR-DEFICIENT MICE; T-CELL DEVELOPMENT; FORKHEAD TRANSCRIPTION FACTOR; GAMMA GENE REARRANGEMENT; APOPTOTIC PROTEIN BAK; FAMILY MEMBER BIM; MHC CLASS-I; INTERLEUKIN-7 RECEPTOR; BCL-2 FAMILY; HOMEOSTATIC PROLIFERATION AB In this review, we briefly cover the critical requirements for interleukin-7 (IL-7) in thymocyte development and peripheral T-cell homeostasis. Part of the IL-7 effect is antiapoptotic or 'trophic' and we have studied the intracellular pathways involved in lymphocyte survival and death regulated by this cytokine. We review the evidence for a role of the JAK signal transducers and activators of transcription protein (STAT) pathway and phosphoinositide 3-kinase (PI3K)-AKT pathways in survival. The death pathway following IL-7 withdrawal is discussed in terms of the balance of BCL-2 vs. BAX and other death proteins and the role of metabolic disturbances involving glucose metabolism and intracellular pH. The IL-7 survival and death pathways in lymphocytes may be representative of many trophic factors in different cell types; yet we conclude that much of the mechanism remains to be discovered. C1 NCI, Sect Cytokines & Immun, Mol Immunoregulat Lab, Ctr Canc Res, Frederick, MD 21702 USA. Univ Cent Florida, Dept Mol Biol & Microbiol, Biomol Sci Ctr, Orlando, FL 32816 USA. RP Durum, SK (reprint author), NCI, Sect Cytokines & Immun, Mol Immunoregulat Lab, Ctr Canc Res, Bldg 560,Room 31-71, Frederick, MD 21702 USA. NR 92 TC 49 Z9 49 U1 1 U2 3 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 JUN PY 2003 VL 193 IS 1 BP 48 EP 57 DI 10.1034/j.1600-065X.2003.00050.x PG 10 WC Immunology SC Immunology GA 677XE UT WOS:000182833700006 PM 12752670 ER PT J AU Luckhart, S Crampton, AL Zamora, R Lieber, MJ Dos Santos, PC Peterson, TML Emmith, N Lim, J Wink, DA Vodovotz, Y AF Luckhart, S Crampton, AL Zamora, R Lieber, MJ Dos Santos, PC Peterson, TML Emmith, N Lim, J Wink, DA Vodovotz, Y TI Mammalian transforming growth factor beta 1 activated after ingestion by Anopheles stephensi modulates mosquito immunity SO INFECTION AND IMMUNITY LA English DT Article ID OXIDE SYNTHASE GENE; NITRIC-OXIDE; TGF-BETA; IN-VITRO; MALARIA; CELLS; EXPRESSION; GROWTH-FACTOR-BETA-1; FIBROBLASTS; CYTOKINES AB During the process of bloodfeeding by Anopheles stephensi, mammalian latent transforming growth factor beta1 (TGF-beta1) is ingested and activated rapidly in the mosquito midgut. Activation may involve heme and nitric oxide (NO), agents released in the midgut during blood digestion and catalysis Of L-arginine oxidation by A. stephensi NO synthase (AsNOS). Active TGF-beta1 persists in the mosquito midgut to extended times postingestion and is recognized by mosquito cells as a cytokine. In a manner analogous to the regulation of vertebrate inducible NO synthase and malaria parasite (Plasmodium) infection in mammals by TGF-beta1, TGF-beta1 regulates AsNOS expression and Plasmodium development in A. stephensi. Together, these observations indicate that, through conserved immunological cross talk, mammalian and mosquito immune systems interface with each other to influence the cycle of Plasmodium development. C1 Virginia Polytech Inst & State Univ, Dept Biochem, Blacksburg, VA 24061 USA. Univ Pittsburgh, Dept Surg, Pittsburgh, PA 15260 USA. NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. RP Luckhart, S (reprint author), Virginia Polytech Inst & State Univ, Dept Biochem, Mail Stop 0308,306 Engel Hall, Blacksburg, VA 24061 USA. RI Crampton, Andrea/A-7018-2008 OI Crampton, Andrea/0000-0001-9656-3059 FU NIAID NIH HHS [AI41027, AI50663, R01 AI050663, R21 AI050663, R29 AI041027] NR 62 TC 47 Z9 47 U1 1 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 JUN PY 2003 VL 71 IS 6 BP 3000 EP 3009 DI 10.1128/IAI.71.6.3000-3009.2003 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 682WX UT WOS:000183116300004 PM 12761076 ER PT J AU Grimm, D Elias, AF Tilly, K Rosa, PA AF Grimm, D Elias, AF Tilly, K Rosa, PA TI Plasmid stability during in vitro propagation of Borrelia burgdorferi assessed at a clonal level SO INFECTION AND IMMUNITY LA English DT Article ID LYME-DISEASE SPIROCHETE; OUTER-SURFACE-PROTEIN; WHITE-FOOTED MICE; STRAIN B31; INFECTIVITY; TICKS; TRANSFORMATION; INACTIVATION; CULTIVATION; POPULATIONS AB Borrelia burgdorferi causes Lyme disease in humans. The genome of the sequenced type strain B31 MI consists of a linear chromosome, 12 linear plasmids, and 9 circular plasmids. Previous studies by other investigators indicated that some of these plasmids are essential for the survival of the spirochetes in vivo but not in vitro. We have studied plasmid stability during in vitro growth at 23 and 35degreesC, conditions that approximate the temperatures of the tick vector and the mammalian host, respectively. Starting with two clones that have all 21 plasmids, we investigated plasmid maintenance within the population and on a clonal level. After three passages (27 generations), the cultures were no longer homogeneous and some derivative clones had already lost multiple plasmids. Despite this, one of six clones analyzed after 25 passages (225 generations) retained all but one plasmid (cp9) and was able to complete the mouse-tick-mouse infectious cycle. We analyzed protein composition and regulation of gene expression of clones differing in plasmid content after serial passages. All clones tested exhibited temperature-regulated expression of several proteins, including OspC. In addition, analysis of cultures inoculated from frozen stocks suggests that freezing and/or thawing contributes to heterogeneity in the outgrowth population with respect to plasmid content. Our investigations show that in vitro propagation of a clone leads to a heterogeneous population but that virulent clones can persist through extended passage. We therefore conclude that isogenicity of clones must be confirmed irrespective of their in vitro passage history. C1 NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. RP Grimm, D (reprint author), NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 39 TC 49 Z9 50 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 JUN PY 2003 VL 71 IS 6 BP 3138 EP 3145 DI 10.1128/IAI.71.6.3138-3145.2003 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 682WX UT WOS:000183116300020 PM 12761092 ER PT J AU Simons-Morton, BG Hartos, JL Beck, KH AF Simons-Morton, BG Hartos, JL Beck, KH TI Persistence of effects of a brief intervention on parental restrictions of teen driving privileges SO INJURY PREVENTION LA English DT Article ID MOTOR-VEHICLE CRASHES; DRIVER EDUCATION; RISK; PASSENGERS; LICENSURE AB Objective: The purpose of this study was to determine the extent to which effects of exposure to a brief intervention designed to increase parental restrictions on teen driving privileges persisted over time. Design: A total of 658 parents and their 16 year old adolescents were recruited from a local motor vehicle administration (MVA) site as adolescents successfully tested for provisional licenses. At the MVA, parents completed written surveys about expected teen driving during the first month of provisional licensure. Afterwards, on weeks assigned as intervention, parents watched a video and were given the video and a driving agreement to take home. Both parents and teens completed follow up telephone interviews about communication, amounts, and limits on teen driving at one month (579 dyads), four months (529 dyads), and nine months (528 dyads). Results: The results indicated that both intervention parents and teens were much more likely to report using a driving agreement at each follow up during the nine month period. Significant treatment group differences persisted for communication about driving, but effects related to limits on teen driving that were evident at one month declined over time. Reports for passenger, road, and overall limits remained significant at four months; fewer were present at nine months. There were no differences in amounts of teen driving at four or nine months. Conclusions: It is possible to reach parents through brief interventions at the MVA and successfully promote increases in initial parental restrictions on teen driving with modest persistence for at least four months. C1 NICHHD, Prevent Res Branch, Bethesda, MD 20892 USA. Univ Maryland, Dept Publ & Community Hlth, College Pk, MD 20742 USA. RP Simons-Morton, BG (reprint author), NICHHD, Prevent Res Branch, 6100 Execut Blvd,Rm 7B05, Bethesda, MD 20892 USA. OI Simons-Morton, Bruce/0000-0003-1099-6617 NR 29 TC 37 Z9 37 U1 0 U2 1 PU B M J PUBLISHING INC PI SAN FRANCISCO PA 221 MAIN ST, PO BOX 7690, SAN FRANCISCO, CA 94120-7690 USA SN 1353-8047 J9 INJ PREV JI Inj. Prev. PD JUN PY 2003 VL 9 IS 2 BP 142 EP 146 DI 10.1136/ip.9.2.142 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 690JW UT WOS:000183546000012 PM 12810741 ER PT J AU Manolio, TA Barnes, KC Naidu, RP Levett, PN Beaty, TH Wilson, AF AF Manolio, TA Barnes, KC Naidu, RP Levett, PN Beaty, TH Wilson, AF TI Correlates of sensitization to Blomia tropicalis and Dermatophagoides pteronyssinus in asthma in Barbados SO INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY LA English DT Article DE asthma; IgE; dust mites; Barbados ID TOTAL SERUM IGE; DER-P-I; DOMESTIC MITES; SKIN-TEST; ENVIRONMENT; ASSOCIATION; ALLERGENS; GENETICS; SMOKING; REACTIVITY AB Background: Sensitivity to the mite Blomia tropicalis is related to asthma in tropical climates, but correlates of sensitivity to B. tropicalis and its relationship to Dermatophagoides pteronyssinus sensitivity have not been widely examined in families with asthma. The main objective of this study was to determine prevalence and correlates of sensitivity to these mites in families with asthma and characteristics of persons sensitized to both. Methods: Antibodies to major antigens (Blo t 5 and Der p 1) of these mites were measured by immunochemiluminescent assay in 481 members of 29 families from Barbados ascertained through two asthmatic siblings. Results: Blo t 5 sensitivity was present in 261 subjects (46%) and was associated with younger age, higher total serum IgE level, and more than a three-fold increased prevalence of asthma (42 vs. 13%). Der p 1 sensitivity was less common (27%) and showed similar associations with age, IgE, and asthma. Of the 261 subjects sensitized to Blo t 5, 116 were also sensitized to Der p 1; they were younger, had higher total and Blo t 5 specific IgE levels, and had more than twice the asthma prevalence as those sensitized to Blo t 5 alone (59 vs. 29%). Der p 1 sensitivity without Blo t 5 sensitivity was uncommon; 90% of those sensitized to Der p 1 were also sensitized to Blo t 5. Geometric mean total IgE levels were lowest in the 207 participants without any mite sensitization (102 U/ml), intermediate in 158 sensitized to either Blo t 5 or Der p 1 (609 U/ml), and highest in 116 sensitized to both (1,869 U/ml). Conclusions: Blo t 5 is the predominant sensitizing mite allergen in these Barbadian families with correlates similar to Der p 1. Concomitant sensitization to Der p 1 appears to identify a more reactive subgroup of individuals at a higher risk of asthma. Copyright (C) 2003 S. Karger AG, Basel. C1 NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. Natl Human Genome Res Inst, Inherited Dis Res Branch, Baltimore, MD USA. Univ W Indies, Sch Clin Med & Res, Bridgetown, Barbados. RP Manolio, TA (reprint author), NHLBI, Div Epidemiol & Clin Applicat, 6701 Rockledge Dr,Room 8160, Bethesda, MD 20892 USA. RI Wilson, Alexander/C-2320-2009 FU NIAID NIH HHS [1 R01 AI20059] NR 27 TC 11 Z9 11 U1 1 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1018-2438 J9 INT ARCH ALLERGY IMM JI Int. Arch. Allergy Immunol. PD JUN PY 2003 VL 131 IS 2 BP 119 EP 126 DI 10.1159/000070927 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 696PG UT WOS:000183894800007 PM 12811020 ER PT J AU Mihalik, B Gaborik, Z Varnai, P Clark, AJL Catt, KJ Hunyady, L AF Mihalik, B Gaborik, Z Varnai, P Clark, AJL Catt, KJ Hunyady, L TI Endocytosis of the AT(1A) angiotensin receptor is independent of ubiquitylation of its cytoplasmic serine/threonine-rich region SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY LA English DT Article DE AT(1A) angiotensin receptor; carboxyl-terminal tail; internalisation; receptor regulation; ubiquitin ID PROTEIN-COUPLED RECEPTOR; AGONIST-INDUCED INTERNALIZATION; GROWTH-HORMONE RECEPTOR; BETA-ARRESTIN; II RECEPTOR; BETA(2)-ADRENERGIC RECEPTOR; DEPENDENT ENDOCYTOSIS; SIGNAL-TRANSDUCTION; CARBOXYL-TERMINUS; TYROSINE KINASES AB Agonist-induced internalisation of the rat type IA (AT(1A)) angiotensin II receptor is associated with phosphorylation of a serine/threonine-rich region in its cytoplasmic tail. In yeast, hyperphosphorylation of the a-factor pheromone receptor regulates endocytosis of the receptor by facilitating the monoubiquitylation of its cytoplasmic tail on lysine residues. The role of receptor ubiquitylation in AT(1A) receptor internalisation was evaluated by deletion or replacement of lysine residues in its agonist-sensitive scrine/threonine-rich region. Expression of such receptor mutants in CHO cells showed that these modifications had no detectable effect on the angiotensin II-induced endocytosis of the AT(1A) receptor. Furthermore, fusion of ubiquitin in-frame to an internalisation-deficient AT(1A) receptor mutant with a truncated carboxyl-terminal tail did not restore the endocytosis of the resulting chimeric receptor. No impairment of receptor internalisation was observed after substitution of all lysine residues in the scrine/threonine-rich region at saturating angiotensin II concentrations, where endocytosis occurs by a beta-arrestin and dynamin independent mechanism. Taken together, these data demonstrate that ubiquitylation of the cytoplasmic serine/threonine-rich region of the AT(1A) receptor on lysine residues is not required for its agonist-induced internalisation, and suggest that endocytosis of mammalian G protein-coupled receptors (GPCRs) occurs by a different mechanism than that of yeast GPCRs. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 Semmelweis Univ, Fac Med, Dept Physiol, H-1444 Budapest, Hungary. St Bartholomews & Royal London Sch Med & Dent, Dept Endocrinol, London, England. NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Hunyady, L (reprint author), Semmelweis Univ, Fac Med, Dept Physiol, POB 259, H-1444 Budapest, Hungary. EM hunyady@puskin.sote.hu NR 51 TC 5 Z9 5 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1357-2725 J9 INT J BIOCHEM CELL B JI Int. J. Biochem. Cell Biol. PD JUN PY 2003 VL 35 IS 6 BP 992 EP 1002 AR PII S1357-2725(02)00277-7 DI 10.1016/S1357-2725(02)00277-7 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 672BP UT WOS:000182501200025 PM 12676183 ER PT J AU Kogevinas, M AF Kogevinas, M TI Commentary: Standardized coding of occupational data in epidemiological studies SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material ID CANCER; QUESTIONNAIRES; EXPOSURE C1 Inst Municipal Invest Med, Resp & Environm Hlth Res Unit, E-08003 Barcelona, Spain. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Kogevinas, M (reprint author), Inst Municipal Invest Med, Resp & Environm Hlth Res Unit, 80 Dr Aiguader Rd, E-08003 Barcelona, Spain. RI Kogevinas, Manolis/C-3918-2017 NR 9 TC 3 Z9 3 U1 2 U2 3 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 JUN PY 2003 VL 32 IS 3 BP 428 EP 429 DI 10.1093/ije/dyg087 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 696EY UT WOS:000183874800021 PM 12777431 ER PT J AU Troisi, R Potischman, N Roberts, JM Ness, R Crombleholme, W Lykins, D Siiteri, P Hoover, RN AF Troisi, R Potischman, N Roberts, JM Ness, R Crombleholme, W Lykins, D Siiteri, P Hoover, RN TI Maternal serum oestrogen and androgen concentrations in preeclamptic and uncomplicated pregnancies SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE hormones; preeclampsia; cancer; oestrogens; androgens; in utero ID BREAST-CANCER RISK; URINARY ESTRIOL EXCRETION; HUMAN PLACENTAL-LACTOGEN; PRE-ECLAMPSIA; FETAL GROWTH; WOMEN; HYPERTENSION; ENVIRONMENT; ESTRADIOL; MARKERS AB Background Epidemiological studies show a substantially reduced risk of breast cancer in adult daughters of preeclamptic pregnancies, and modest risk reductions have been demonstrated for mothers also. Alterations in pregnancy hormone concentrations, particularly lower in utero exposure to oestrogen, are hypothesized to mediate this association. Methods Pregnancy hormone concentrations were measured in maternal sera collected at hospital admission for labour and delivery from 86 preeclamptic and 86 uncomplicated, singleton pregnancies matched on length of gestation, maternal age, parity, and type of delivery. Results Case and control pregnancies were similar in several maternal and pregnancy factors. Serum unconjugated oestradiol, oestrone, and oestriol concentrations were not lower in preeclamptic pregnancies in a matched analysis with adjustment for race and whether blood was collected before or after labour commenced. Serum unconjugated androstenedione (506.3 versus 316.0 ng/dl; P = 0.0007) and testosterone concentrations (214.5 versus 141.9 ng/dl; P = 0.004), however, were significantly higher in preeclamptic compared with control pregnancies, whereas dehydroepiandrosterone (DHEA) and DHEA sulphate did not differ. Conclusions These data do not support the hypothesis that cancer risk in mothers and offspring of preeclamptic pregnancies is explained by exposure to lower maternal blood oestrogen concentrations, but raise the possibility that androgens play a role. C1 NCI, Div Canc Epidemiol & Genet, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Univ Pittsburgh, Magee Womens Res Inst, Pittsburgh, PA USA. Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. Univ Calif San Francisco, Sch Med, San Francisco, CA 94143 USA. RP Troisi, R (reprint author), NCI, Div Canc Epidemiol & Genet, Epidemiol & Biostat Program, 6120 Execut Blvd, Bethesda, MD 20892 USA. FU NICHD NIH HHS [2 P01 HD30367] NR 35 TC 68 Z9 69 U1 1 U2 4 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 JUN PY 2003 VL 32 IS 3 BP 455 EP 460 DI 10.1093/ije/dyg094 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 696EY UT WOS:000183874800026 PM 12777436 ER PT J AU Hansen, AL Johnsen, BH Thayer, JE AF Hansen, AL Johnsen, BH Thayer, JE TI Vagal influence on working memory and attention SO INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY LA English DT Article DE heart rate variability; working memory; continuous performance test ID HEART-RATE-VARIABILITY; SUSTAINED ATTENTION; PREFRONTAL CORTEX; PERFORMANCE; MECHANISMS; WORKLOAD; DIFFICULTY; DEPRESSION; INDEXES; NETWORK AB The aim of the present study was to investigate the effect of vagal tone on performance during executive and non-executive tasks, using a working memory and a sustained attention test. Reactivity to cognitive tasks was also investigated using heart rate (HR) and heart rate variability (HRV). Fifty-three male sailors from the Royal Norwegian Navy participated in this study. Inter-beat-intervals were recorded continuously for 5 min of baseline, followed by randomized presentation of a working memory test (WMT) based on Baddeley and Hitch's research (1974) and a continuous performance test (CPT). The session ended with a 5-min recovery period. High HRV and low HRV groups were formed based on a median split of the root mean squared successive differences during baseline. The results showed that the high HRV group showed more correct responses than the low HRV group on the WMT. Furthermore, the high HRV group showed faster mean reaction time (mRT), more correct responses and less error, than the low HRV group on the CPT. Follow-up analysis revealed that this was evident only for components of the CPT where executive functions were involved. The analyses of reactivity showed a suppression of HRV and an increase in HR during presentation of cognitive tasks compared to recovery. This was evident for both groups. The present results indicated that high HRV was associated with better performance on tasks involving executive function. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Univ Bergen, Dept Psychosocial Sci, N-5015 Bergen, Norway. Norway & Royal Norwegian Naval Acad, N-5886 Bergen, Norway. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Hansen, AL (reprint author), Univ Bergen, Dept Psychosocial Sci, Christiesgt 12, N-5015 Bergen, Norway. NR 57 TC 230 Z9 232 U1 8 U2 34 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 JUN PY 2003 VL 48 IS 3 BP 263 EP 274 DI 10.1016/S0167-8760(03)00073-4 PG 12 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 691JE UT WOS:000183602100002 PM 12798986 ER PT J AU Clark, N Coleman, C Figure, K Mailhot, T Zeigler, J AF Clark, N Coleman, C Figure, K Mailhot, T Zeigler, J TI Food for trans-Atlantic rowers: A menu planning model and case study SO INTERNATIONAL JOURNAL OF SPORT NUTRITION AND EXERCISE METABOLISM LA English DT Article DE ultra-distance athletes; sports nutrition; ocean rowing; menu planning; food exchanges; Altantic Rowing Race AB Every 4 years, rowers from around the world compete in a 50- to 60-day trans-Atlantic rowing challenge. These ultra-distance rowers require a diet that provides adequate calories, protein, vitamins, minerals, and fluids so they can perform well day after day, minimize fatigue, and stay healthy. Yet, the rowers are confronted with menu planning challenges. The food needs to be lightweight, compact, sturdy, non-spoiling in tropical temperatures, calorie dense, easy to prepare, quick to cook, and good tasting. Financial concerns commonly add another menu planning challenge. The purpose of this case study is to summarize the rowers' food experiences and to provide guidance for sports nutrition professionals who work with ultra-endurance athletes embarking on a physical challenge with similar food requirements. The article provides food and nutrition recommendations as well as practical considerations for ultra-distance athletes. We describe an 8,000 calorie per day menu planning model that uses food exchanges based on familiar, tasty, and reasonably priced supermarket foods that provide the required nutrients and help contain financial costs. C1 Sports Med Assoc, Nutr Serv, Brookline, MA 02467 USA. NIDDKD, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Clark, N (reprint author), Sports Med Assoc, Nutr Serv, 830 Boylston St,Suite 205, Brookline, MA 02467 USA. NR 10 TC 3 Z9 3 U1 0 U2 7 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, CHAMPAIGN, IL 61820-2200 USA SN 1050-1606 J9 INT J SPORT NUTR EXE JI Int. J. Sport Nutr. Exerc. Metab. PD JUN PY 2003 VL 13 IS 2 BP 227 EP 243 PG 17 WC Nutrition & Dietetics; Sport Sciences SC Nutrition & Dietetics; Sport Sciences GA 691JK UT WOS:000183602700007 PM 12945831 ER PT J AU Tomarev, SI Wistow, G Raymond, V Dubois, S Malyukova, I AF Tomarev, SI Wistow, G Raymond, V Dubois, S Malyukova, I TI Gene expression profile of the human trabecular meshwork: NEIBank sequence tag analysis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID RETINAL-PIGMENT EPITHELIUM; OPEN-ANGLE GLAUCOMA; 6000 NONREDUNDANT TRANSCRIPTS; MYOTONIC-DYSTROPHY TYPE-2; ENDOTHELIAL CDNA LIBRARY; IN-SITU HYBRIDIZATION; EXTRACELLULAR-MATRIX; AQUEOUS-HUMOR; SPLICE VARIANTS; HUMAN CORNEA AB PURPOSE. To characterize the gene expression pattern in the human trabecular meshwork (TM) and identify candidate genes for glaucoma by expressed sequence tag (EST) analysis as part of the NEIBank project. METHODS. RNA was extracted from dissected human TM and used to construct unamplified, un-normalized cDNA libraries in the pSPORTI vector. More than 4000 clones were sequenced from the 5' end. Clones were clustered and identified using GRIST software. In addition, the expression patterns of genes encoding olfactomedin-domain proteins were analyzed by RT-PCR. RESULTS. After non-mRNA contaminants were removed, 3459 independent TM-expressed clones were obtained. These were grouped in 1888 clusters, potentially representing individual expressed genes. Transcripts for the myocilin gene, a locus for inherited glaucoma, formed the third most abundant cluster in the TM collection, and several other genes implicated in glaucoma (PITX2, CYP1B1, and optineurin) were also represented. One abundant TM transcript was from the gene for the angiopoietin-like factor CTD6, which is located at on the long arm of chromosome 1, area 36.2-36.1 in the region of the glaucoma locus GLC3B, whereas other transcripts were from genes close to known glaucoma loci. The TM collection contains for genes that are preferentially expressed in the lymphatic endothelium (matrix Gla protein, apolipoprotein D precursor, and selenoprotein P precursor). In addition to EST profiling, RT-PCR was used to detect transcripts of the olfactomedin-domain proteins latrotoxin receptor Lec3 and optimedin in the TM. CONCLUSIONS. The TM libraries are a good source of molecular markers for TM and candidate genes for glaucoma. The abundance of myocilin cDNAs corresponds to the critical role of this gene in glaucoma and contrasts with libraries derived from cultured tissue. The expression profile raises the possibility that cells of the TM and Schlemm's canal may be more similar to lymphatic, rather than blood vascular endothelium. C1 NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. NEI, Sect Mol Struct & Funct, NIH, Bethesda, MD 20892 USA. Univ Laval, Med Res Ctr, Quebec City, PQ, Canada. RP Tomarev, SI (reprint author), NEI, Mol & Dev Biol Lab, NIH, Bldg 6,Room 2A04,6 Ctr Dr MSC 2730, Bethesda, MD 20892 USA. NR 66 TC 104 Z9 110 U1 0 U2 5 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUN PY 2003 VL 44 IS 6 BP 2588 EP 2596 DI 10.1167/iovs.02-1099 PG 9 WC Ophthalmology SC Ophthalmology GA 682FU UT WOS:000183081700031 PM 12766061 ER PT J AU Folkers, GK Fauci, AS AF Folkers, GK Fauci, AS TI AIDS agenda still daunting SO ISSUES IN SCIENCE AND TECHNOLOGY LA English DT Article C1 NIAID, Bethesda, MD 20892 USA. RP Folkers, GK (reprint author), NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0748-5492 J9 ISSUES SCI TECHNOL JI Issues Sci. Technol. PD SUM PY 2003 VL 19 IS 4 BP 37 EP 39 PG 3 WC Engineering, Multidisciplinary; Engineering, Industrial; Multidisciplinary Sciences; Social Issues SC Engineering; Science & Technology - Other Topics; Social Issues GA 702HD UT WOS:000184217700012 ER PT J AU Anthony, KB Yoder, C Metcalf, JA DerSimonian, R Orenstein, JM Stevens, RA Falloon, J Polis, MA Lane, HC Sereti, I AF Anthony, KB Yoder, C Metcalf, JA DerSimonian, R Orenstein, JM Stevens, RA Falloon, J Polis, MA Lane, HC Sereti, I TI Incomplete CD4 T cell recovery in HIV-1 infection after 12 months of highly active antiretroviral therapy is associated with ongoing increased CD4 T cell activation and turnover SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article; Proceedings Paper CT 14th International AIDS Conference CY JUL 07-12, 2002 CL BARCELONA, SPAIN DE human-T lymphocytes; AIDS; cellular activation; cellular proliferation ID IMMUNE ACTIVATION; LYMPHOCYTE-ACTIVATION; HLA-DR; ANTIGEN; KINETICS; PROLIFERATION; CD38; REPLICATION; DEPLETION; IMPACT AB To evaluate the relationship between T cell turnover, immune activation, and CD4 recovery in HIV infection, 32 antiretroviral-naive HIV-1-infected patients were studied before and after initiation of highly active antiretroviral therapy (HAART). Elevated CD4 and CD8 T cell turnover (measured by Ki67) in HIV infection decreased with HAART in blood and lymphoid tissue. Increased peripheral CD4 T cell turnover was strongly associated with immune activation even after viral suppression to less than 50 copies/mL (R = 0.8; p <.001). Increased CD4 T cell turnover correlated strongly with CD4 cell counts both before (R = -0.6; p <.001) and after (R = -0.4; p =.05) HAART. In patients with baseline CD4 cell counts of less than 350/muL, decreases in CD4 T cell turnover with HAART significantly correlated with increases in CD4 cell counts. In addition, persistently elevated levels of CD4 T cell turnover after HAART were associated with incomplete CD4 T cell recovery despite HIV RNA levels of less than 50 copies/mL. These data suggest that immune activation is central to CD4 cell depletion in HIV infection and immune reconstitution with HAART. C1 NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NIAID, Div AIDS, Rockville, MD USA. George Washington Univ, Med Ctr, Dept Pathol, Washington, DC 20037 USA. NCI, Sci Applicat Int Corp, Frederick, MD 21701 USA. RP Sereti, I (reprint author), NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, NIH, 10 Ctr Dr,Bldg 10,Room 11B05, Bethesda, MD 20892 USA. OI Polis, Michael/0000-0002-9151-2268 FU NCI NIH HHS [N01 CO 56000] NR 30 TC 90 Z9 92 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUN 1 PY 2003 VL 33 IS 2 BP 125 EP 133 DI 10.1097/00126334-200306010-00002 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 695DG UT WOS:000183815400002 PM 12794543 ER PT J AU Mirochnick, M Dorenbaum, A Blanchard, S Cunningham, CK Gelber, RD Mofenson, L Culnane, M Sullivan, JL AF Mirochnick, M Dorenbaum, A Blanchard, S Cunningham, CK Gelber, RD Mofenson, L Culnane, M Sullivan, JL TI Predose infant nevirapine concentration with the two-dose intrapartum neonatal nevirapine regimen: Association with timing of maternal intrapartum nevirapine dose SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article; Proceedings Paper CT 9th Conference on Retroviruses and Opportunistic Infection CY FEB 24-28, 2002 CL SEATTLE, WASHINGTON DE HIV; pregnancy; nevirapine; placentaI transfer ID PREGNANT-WOMEN; HIV TRANSMISSION; RANDOMIZED TRIAL; PHARMACOKINETICS; PREVENTION AB Objective: To evaluate cord blood and predose nevirapine concentrations in infants exposed to the two-dose intrapartum neonatal nevirapine regimen. Methods: The authors obtained plasma samples for nevirapine assay from cord blood and just prior to the 48-hours to 72-hours after birth neonatal nevirapine dose from a subset of infants participating in PACTG 316, a randomized, placebo-controlled trial of the two-dose intrapartum neonatal nevirapine regimen added to standard antiretroviral therapy. Results: Nevirapine concentrations were measured in 109 cord blood samples and 149 predose samples. Cord blood nevirapine concentrations were below the target concentration of 100 ng/mL (10-times the in vitro IC50 of nevirapine against wild-type HIV) in eight (7%) of 109 infants (95% confidence interval [CI], 3%-14%); the concentrations in six of these infants were below the assay limit of quantitation. Predose infant nevirapine concentrations were below 100 ng/mL in 23 (15%) of 149 infants (95% CI, 10%-22%); the concentrations in 13 of these infants were below the assay limit of quantitation. Lower predose nevirapine concentrations were associated with lower cord blood concentrations and a shorter interval between maternal dosing and delivery. All but one of the infants with predose nevirapine concentrations below the assay limit of quantitation were born less than 2 hours after maternal dosing. Conclusion: Infants born less than 2 hours after maternal nevirapine dosing during labor should receive a dose of nevirapine immediately after birth in addition to the standard infant dose at 48 to 72 hours. C1 Boston Univ, Sch Med, Boston, MA 02215 USA. Chiron Corp, Emeryville, CA 94608 USA. Univ Calif San Diego, San Diego, CA 92103 USA. Harvard Univ, Sch Publ Hlth, SDAC, Boston, MA 02115 USA. SUNY Upstate Med Univ, Syracuse, NY USA. NICHHD, Rockville, MD USA. NIAID, NIH, Rockville, MD USA. Univ Massachusetts, Sch Med, Worcester, MA USA. RP Mirochnick, M (reprint author), Boston Med Ctr, 91 E Concord St,6th Floor, Boston, MA 02118 USA. OI Mofenson, Lynne/0000-0002-2818-9808 NR 8 TC 29 Z9 29 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 JUN 1 PY 2003 VL 33 IS 2 BP 153 EP 156 DI 10.1097/00126334-200306010-00006 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 695DG UT WOS:000183815400006 PM 12794547 ER PT J AU Poirier, MC Divi, RL Al-Harthi, L Olivero, OA Nguyen, V Walker, B Landay, AL Walker, VE Charurat, M Blattner, WA AF Poirier, MC Divi, RL Al-Harthi, L Olivero, OA Nguyen, V Walker, B Landay, AL Walker, VE Charurat, M Blattner, WA CA WITS Grp TI Long-term mitochondrial toxicity in HIV-uninfected infants born to HIV-infected mothers SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE lymphocytes; Women and Infants Transmission Study; nucleoside reverse transcriptase inhibitor; telomere; mitochondrial DNA ID IMMUNODEFICIENCY-VIRUS TYPE-1; 3'-AZIDO-2',3'-DIDEOXYTHYMIDINE AZT; PREFERENTIAL INCORPORATION; ANTIRETROVIRAL THERAPY; ZIDOVUDINE TREATMENT; NUCLEOSIDE ANALOGS; IN-UTERO; MYOPATHY; EXPOSURE; DNA AB Although children born to HIV-infected (HIV+) women receiving antiretroviral therapy during pregnancy show virtually no adverse clinical effects at birth, the antiretroviral nucleoside analog drugs are known to damage nuclear and mitochondrial DNA. In this study, biomarkers of mitochondrial toxicity and genotoxicity have been examined in a well-characterized sample set consisting of infants born to HIV-uninfected (HIV-) mothers (n = 30), and HIV- infants (n = 20) born to HIV-infected (HIV+) mothers who received either no antiretroviral therapy (n = 10) or zidovudine (3'-azido-3'-deoxythymidine [AZT]) during pregnancy (n = 10). DNA from cord blood leukocytes and peripheral blood leukocytes taken at 1 and 2 years of age was examined for loss of mitochondrial DNA (mtDNA) and telomere integrity. Telomere length, a measure of nuclear DNA damage, was the same in all infants at birth and at age 1 year. The quantity of mtDNA was assessed relative to nuclear DNA using a polymerase chain reaction-based chemiluminescence detection (PCR-CID) method that determined mitochondrial D Loop gene copies relative to nuclear 18S RNA gene copies by comparison with a standard curve. MtDNA quantity was expressed as a ratio of gene copy numbers. In infants of uninfected mothers (AZT-/HIV-) at the three time points, the ratios were 442 to 515, whereas in infants of untreated AZT-/HIV+ mothers the ratios were 261 to 297, and in infants of AZT-treated (AZT(+)/HIV+) mothers the ratios were 146 to 203. At all three time points, differences between the AZT-/HIV group and the two HIV+ groups were statistically significant (p <.05), and differences between the AZT-/HIV+ and AZT(+)/HIV+ groups were also statistically significant (p <.05), demonstrating that AZT exposure causes a persistent depletion of mtDNA. The study shows that children of HIV+ mothers are at risk for mitochondrial damage that is further increased in infants of mothers receiving AZT during pregnancy. C1 NCI, Carcinogen DNA Interact Sect, NIH, Bethesda, MD 20892 USA. Rush Med Coll, Dept Microbiol Immunol, Chicago, IL 60612 USA. Lovelace Resp Res Inst, Inhalat Toxciol Lab, Albuquerque, NM USA. Inst Human Virol, Baltimore, MD USA. RP Poirier, MC (reprint author), NCI, Carcinogen DNA Interact Sect, NIH, Bldg 37,Room 4032,37 Convent Dr,MSC-4255, Bethesda, MD 20892 USA. FU NCRR NIH HHS [RR 00188, RR 00645]; NIAID NIH HHS [1U01 AI 50274-01, N01 AI 85339, U01 AI 34841, U01 AI 34856, U01 AI 34858]; NICHD NIH HHS [U01 HD 36117, U01 HD 41983]; NIDA NIH HHS [U01 DA 15053] NR 43 TC 118 Z9 125 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUN 1 PY 2003 VL 33 IS 2 BP 175 EP 183 DI 10.1097/00126334-200306010-00010 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 695DG UT WOS:000183815400010 PM 12794551 ER PT J AU Chesney, MA Chambers, DB Taylor, JM Johnson, LM AF Chesney, MA Chambers, DB Taylor, JM Johnson, LM TI Social support, distress, and well-being in older men living with HIV infection SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV-positive; AIDS; social support; depression; positive influence ID QUALITY-OF-LIFE; IMMUNODEFICIENCY-VIRUS-INFECTION; HEALTH SURVEY SF-36; DEPRESSIVE SYMPTOMS; PSYCHOLOGICAL DISTRESS; AGE-DIFFERENCES; AIDS; SURVIVAL; DISEASE; STRESS AB Older men with HIV infection/AIDS, having often lived with the condition longer, are more likely to confront the stress of managing more advanced HIV disease than their younger counterparts. Meanwhile, they also are more likely to have less social support and experience more distress than younger persons with HIV infection. The moderating effect of social support on health functioning and distress is unknown for persons with HIV infection, particularly those who are older. Study objectives were to assess whether the association between perceived health functioning and psychological distress and well-being is moderated (or influenced) by social support and age and if the impact of social support on distress and well-being is more pronounced for older than for younger men living with HIV infection/AIDS. In this cross-sectional study of HIV-positive adult men (n = 199) who have sex with men, participants completed self-report assessments of perceived health functioning, social support, and psychological distress and well-being. Measures of health functioning and overall social support were significantly associated with outcome measures of distress and positive affect (all p <.05). However, the main effect for social support was qualified by a significant age-by-social support interaction for both outcomes (beta = -.190, p <.01 for distress; beta =.172, p <.05 for positive affect), indicating that the impact of social support on decreasing distress and increasing well-being was more pronounced in older men. The relationships between perceived health functioning and distress and well-being were not moderated by social support or age. The influence of social support on negative and positive moods in this population of HIV-infected men who have sex with men was significantly greater among older than among younger participants. With an increasing number of older people with HIV infection/AIDS, special efforts to create effective and sustainable social support interventions may be particularly beneficial to older persons living with HIV infection. C1 NCCAM, Div Extamural Res & Training, NIH, Bethesda, MD 20982 USA. Univ Calif San Francisco, Ctr AIDS Prevent Studies, Dept Med, Div Gen Internal Med, San Francisco, CA 94143 USA. RP Chesney, MA (reprint author), NCCAM, Div Extamural Res & Training, NIH, 31 Ctr Dr,2B11, Bethesda, MD 20982 USA. EM chesneym@mail.nih.gov FU NIMH NIH HHS [R01-MH57233] NR 57 TC 40 Z9 40 U1 1 U2 4 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 JUN 1 PY 2003 VL 33 SU 2 BP S185 EP S193 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 696QT UT WOS:000183898800016 PM 12853868 ER PT J AU Coon, DW Lipman, PD Ory, MG AF Coon, DW Lipman, PD Ory, MG TI Designing effective HIV/AIDS social and behavioral interventions for the population of those age 50 and older SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE middle-aged and older adults; HIV/AIDS prevention; social and behavioral interventions ID RESEARCH SYNTHESIS PROJECT; HIV PREVENTION RESEARCH; RISK-FACTORS; ADULTS; AIDS; AMERICANS; PEOPLE; STATES; CARE AB Social and behavioral HIV/AIDS prevention interventions designed to test their effects on older cohorts are sorely lacking in the scientific literature even though middle-aged and older people represent a significant minority of both existing and new AIDS cases. This article raises key issues relevant in developing and evaluating HIV/AIDS social and behavioral interventions for older cohorts. These interventions must build on our current understanding of behavior change and HIV prevention successes with younger populations while considering important intervention principles gathered from work with older populations in other health arenas. In addition, the authors expand on recent national panels and published reviews relevant to the topic and provide a set of intervention recommendations for use in tandem with these intervention principles. The article also calls for additional research into the sociocultural contexts that influence risk-taking among older cohorts and for the development of interventions at multiple levels. Pragmatic considerations such as identifying and dismantling ageism in interventions, delineating intervention outcomes, and planning for intervention transferability, dissemination, and sustainability also are raised. C1 Inst Aging, San Francisco, CA 94118 USA. Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. Vet Affairs Palo Alto Hlth Care Syst, Older Adult & Family Ctr, Palo Alto, CA USA. Aspen Syst, Rockville, MD USA. Texas A&M Univ, Syst Hlth Sci Ctr, Sch Rural Publ Hlth, College Stn, TX USA. NIA, Bethesda, MD 20892 USA. RP Coon, DW (reprint author), Inst Aging, 3330 Geary Blvd, San Francisco, CA 94118 USA. EM dcoon@ioaging.org FU NIA NIH HHS [R21 AG20419] NR 76 TC 25 Z9 25 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUN 1 PY 2003 VL 33 SU 2 BP S194 EP S205 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 696QT UT WOS:000183898800017 PM 12853869 ER PT J AU Levy, JA Ory, MG Crystal, S AF Levy, JA Ory, MG Crystal, S TI HIV/AIDS interventions for midlife and older adults: Current status and challenges SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV/AIDS and aging; AIDS and older adults; AIDS prevention in older population AB Drawing on both domestic and global international perspectives, this special issue is devoted to articles that confront the challenges of understanding, preventing, and intervening, with HIV/AIDS as an epidemic that carries increasingly serious consequences for a growing number of adults who are 50 years of age or older. This issue builds on papers first presented at an HIV/AIDS and aging conference sponsored in the fall of 2000 by the National Institute on Aging of the National Institutes of Health. The editors have selected articles that focus dually on what is currently known and what needs to be known to successfully address the needs of persons 50 years of age or older who are vulnerable to the virus's effects. This special issue is organized around a series of subsections representing key issues and research findings related to HIV/AIDS and aging issues, including the epidemiology of HIV/AIDS and aging, HIV/AIDS risk and risk behavior, settings and situations as social contexts of risk, clinical challenges with older populations, living with and managing HIV/AIDS, interventions and research methods, new frontiers and challenges, and strategies for action. Some articles are data driven, whereas others are reflective pieces that recount personal experiences in living with the virus or point to new directions for research and practice. In this introduction, the editors highlight findings and approaches from each article and further add to our knowledge by setting these articles within the context of major themes relevant to the study of HIV/AIDS in an aging population. C1 Univ Illinois, Sch Publ Hlth, Chicago, IL 60612 USA. Texas A&M Univ, Syst Hlth Sci Ctr, Sch Rural Publ Hlth, College Stn, TX USA. NIH, Bethesda, MD 20892 USA. Rutgers State Univ, Inst Hlth Hlth Care Policy & Aging Res, New Brunswick, NJ 08903 USA. RP Levy, JA (reprint author), Univ Illinois, Sch Publ Hlth, 1603 W Taylor,Room 768, Chicago, IL 60612 USA. NR 34 TC 24 Z9 27 U1 1 U2 4 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 JUN 1 PY 2003 VL 33 SU 2 BP S59 EP S67 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 696QT UT WOS:000183898800002 PM 12853854 ER PT J AU Zingmond, DS Kilbourne, AM Justice, AC Wenger, NS Rodriguez-Barradas, M Rabeneck, L Taub, D Weissman, S Briggs, J Wagner, J Smola, S Bozzette, SA AF Zingmond, DS Kilbourne, AM Justice, AC Wenger, NS Rodriguez-Barradas, M Rabeneck, L Taub, D Weissman, S Briggs, J Wagner, J Smola, S Bozzette, SA TI Differences in symptom expression in older HIV-positive patients: The veterans aging cohort 3 site study and HIV cost and service utilization study experience SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE AIDS; HIV; symptoms; older individuals ID QUALITY-OF-LIFE; IMMUNODEFICIENCY-VIRUS INFECTION; NATIONAL PROBABILITY SAMPLES; LOW-PREVALENCE DISEASES; AGE-RELATED DIFFERENCES; AMERICANS; CARE AB Symptom recognition is critical for patient care but has been little studied in older HIV-infected individuals. The authors examined differences in symptom expression between younger (younger than age 50 years) and older (older than age 50 years) HIV-infected individuals. The authors analyzed data from two cross-sectional studies of HIV-infected individuals: 2864 individuals from the HIV Cost and Service Utilization Study (HCSUS) and 881 individuals from the Veterans Aging Cohort 3 Site Study (VACS 3). The authors compared the prevalence of eight symptoms common to both studies and 10 symptoms examined only in the VACS 3 population, stratified by age and race. Disease severity was assessed by CD4 count and 18 HIV-related diseases reported. Multivariate logistic regression models were used to account for demographics and severity differences. VACS 3 versus HCSUS participants were more likely nonwhite and older. In unadjusted comparisons, older nonwhites were less likely to report experiencing symptoms than younger whites. They reported the fewest total number of symptoms and the fewest individual symptoms common to both studies (headache, fever, nausea/vomiting, and diarrhea) or in the VACS 3 only (dizziness, sleeping difficulty, fatigue, rashes, bloating, and myalgias/arthalgias). Multivariate regression estimates suggest older age predicts a greater likelihood of reporting peripheral neuropathy, weight loss, or hair loss, but a lower likelihood of reporting headaches, depressed mood, white oral patches, or diarrhea. Nonwhites appeared less likely to report symptoms. Age is a determinant of reporting certain symptoms in HIV disease but may be masked or accentuated by other factors such as race. C1 Univ Calif Los Angeles, Div Gen Internal Med & Hlth Serv Res, Sch Med, Dept Med, Los Angeles, CA 90095 USA. Univ So Calif, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA USA. Vet Adm Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Vet Adm Hlth Serv Res & Dev Ctr Excellence, Houston, TX USA. NIA, NIH, Baltimore, MD 21224 USA. Yale Univ, Sch Med, Dept Internal Med, Infect Dis Sect, New Haven, CT 06510 USA. Hosp St Raphael, New Haven, CT USA. Cleveland Vet Adm Healthcare Syst, Cleveland, OH USA. Vet Adm San Diego Healthcare Syst, San Diego, CA USA. RAND Corp, Santa Monica, CA USA. Univ Calif San Diego, San Diego, CA 92103 USA. RP Zingmond, DS (reprint author), Univ Calif Los Angeles, Div Gen Internal Med & Hlth Serv Res, Sch Med, Dept Med, 911 Broxton Pl, Los Angeles, CA 90095 USA. NR 24 TC 45 Z9 46 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUN 1 PY 2003 VL 33 SU 2 BP S84 EP S92 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 696QT UT WOS:000183898800005 PM 12853857 ER PT J AU Shaywitz, SE Shaywitz, BA AF Shaywitz, SE Shaywitz, BA TI The science of reading and dyslexia SO JOURNAL OF AAPOS LA English DT Article ID WORD FORM AREA; DEVELOPMENTAL DYSLEXIA; CEREBRAL MECHANISMS; PHONOLOGICAL-CORE; ADULT DYSLEXICS; CHILDREN; DISABILITY; BRAIN; FMRI; CHROMOSOME-6 C1 NICHD, Yale Ctr Study Learning & Attent, New Haven, CT USA. RP Shaywitz, SE (reprint author), Yale Univ, Sch Med, Dept Pediat, POB 333, New Haven, CT 06510 USA. NR 70 TC 17 Z9 18 U1 6 U2 11 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 1091-8531 J9 J AAPOS JI J. AAPOS PD JUN PY 2003 VL 7 IS 3 BP 158 EP 166 DI 10.1016/S1091-8531(03)0002-8 PG 9 WC Ophthalmology; Pediatrics SC Ophthalmology; Pediatrics GA 696QB UT WOS:000183897000003 PM 12825054 ER PT J AU Visser, M Pahor, M Tylavsky, F Kritchevsky, SB Cauley, JA Newman, AB Blunt, BA Harris, TB AF Visser, M Pahor, M Tylavsky, F Kritchevsky, SB Cauley, JA Newman, AB Blunt, BA Harris, TB TI One- and two-year change in body composition as measured by DXA in a population-based cohort of older men and women SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE lean soft tissue; longitudinal study; sarcopenia; race; gender; dual-energy X-ray absorptiometry ID X-RAY ABSORPTIOMETRY; SKELETAL-MUSCLE MASS; FAT-FREE MASS; SOFT-TISSUE; LIMB MUSCLE; STRENGTH; WEIGHT; SARCOPENIA; DEXA; AGE AB Changing body composition has been suggested as a pathway to explain age-related functional decline. No data are available on the expected changes in body composition as measured by dual-energy X-ray absorptiometry (DXA) in a population-based cohort of older persons. Body composition data at baseline, 1-yr follow-up, and 2-yr follow-up was measured by DXA in 2,040 well-functioning black and white men and women aged 70 - 79 yr, participants of the Health, Aging, and Body Composition Study. After 2 yr, a small decline in total body mass was observed ( men: - 0.3%, women: -0.4%). Among men, fat-free mass and appendicular lean soft tissue mass (ALST) decreased by -1.1 and -0.8%, respectively, which was masked by a simultaneous increase in total fat mass (+2.0%). Among women, a decline in fat-free mass was observed after 2 yr only (-0.6%) with no change in ALST and body fat mass. After 2 yr, the decline in ALST was greater in blacks than whites. Change in total body mass was associated with change in ALST (r = +0.58 to +0.70; P < 0.0001). Among participants who lost total body mass, men lost relatively more ALST than women, and blacks lost relatively more ALST than whites. In conclusion, the mean change in body composition after a 1- to 2-yr follow- up was 1-2% with a high interindividual variability. Loss of ALST was greater in men compared with women, and greater in blacks compared with whites, suggesting that men and blacks may be more prone to muscle loss. C1 Free Univ Amsterdam, Inst Res Extramural Med, Med Ctr, NL-1081 BT Amsterdam, Netherlands. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Wake Forest Univ, Sticht Ctr Aging, Dept Internal Med, Sch Med, Winston Salem, NC 27157 USA. Univ Tennessee, Dept Prevent Med, Memphis, TN 38105 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Dept Med, Pittsburgh, PA 15261 USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94105 USA. RP Visser, M (reprint author), Free Univ Amsterdam, Inst Res Extramural Med, Med Ctr, Boechorststr 7, NL-1081 BT Amsterdam, Netherlands. RI Newman, Anne/C-6408-2013; Cauley, Jane/N-4836-2015 OI Newman, Anne/0000-0002-0106-1150; Cauley, Jane/0000-0003-0752-4408 FU NIA NIH HHS [P60-AG-10484, N01-AG-62101, N01-AG-62103, N01-AG-62106] NR 27 TC 96 Z9 97 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD JUN PY 2003 VL 94 IS 6 BP 2368 EP 2374 DI 10.1152/japplphysiol.00124.2002 PG 7 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 675MU UT WOS:000182699800035 PM 12598481 ER PT J AU Palmer, RJ Gordon, SM Cisar, JO Kolenbrander, PE AF Palmer, RJ Gordon, SM Cisar, JO Kolenbrander, PE TI Coaggregation-mediated interactions of streptococci and actinomyces detected in initial human dental plaque SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ROOT SURFACES INVIVO; SCANNING ELECTRON-MICROSCOPY; EARLY MICROBIAL COLONIZATION; CELL-WALL POLYSACCHARIDES; HUMAN PERIODONTAL POCKETS; HUMAN-ENAMEL; BIOFILM BACTERIA; DEFECTIVE MUTANT; VISCOSUS T14V; SP-NOV AB Streptococci and actinomyces that initiate colonization of the tooth surface frequently coaggregate with each other as well as with other oral bacteria. These observations have led to the hypothesis that interbacterial adhesion influences spatiotemporal development of plaque. To assess the role of such interactions in oral biofilm formation in vivo, antibodies directed against bacterial surface components that mediate coaggregation interactions were used as direct immunofluorescent probes in conjunction with laser confocal microscopy to determine the distribution and spatial arrangement of bacteria within intact human plaque formed on retrievable enamel chips. In intrageneric coaggregation, streptococci such as Streptococcus gordonii DL1 recognize receptor polysaccharides (RPS) borne on other streptococci such as Streptococcus oralis 34. To define potentially interactive subsets of streptococci in the developing plaque, an antibody against RPS (anti-RPS) was used together with an antibody against S. gordonii DL1 (anti-DL1). These antibodies reacted primarily with single cells in 4-h-old plaque and with mixed-species microcolonies in 8-h-old plaque. Anti-RPS-reactive bacteria frequently formed microcolonies with anti-DL1-reactive bacteria and with other bacteria distinguished by general nucleic acid stains. In intergeneric coaggregation between streptococci and actinomyces, type 2 fimbriae of actinomyces recognize RPS on the streptococci. Cells reactive with antibody against type 2 fimbriae of Actinomyces naeslundii T14V (anti-type-2) were much less frequent than either subset of streptococci. However, bacteria reactive with anti-type-2 were seen in intimate association with anti-RPS-reactive cells. These results are the first direct demonstration of coaggregation-mediated interactions during initial plaque accumulation in vivo. Further, these results demonstrate the spatiotemporal development and prevalence of mixed-species communities in early dental plaque. C1 NIDCR, NIH, Bethesda, MD 20892 USA. RP Kolenbrander, PE (reprint author), NIDCR, NIH, Bldg 30,Room 310,30 Convent Dr,MSC 4350, Bethesda, MD 20892 USA. NR 33 TC 157 Z9 164 U1 2 U2 16 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 JUN PY 2003 VL 185 IS 11 BP 3400 EP 3409 DI 10.1128/JB.185.11.3400.3409.2003 PG 10 WC Microbiology SC Microbiology GA 682PN UT WOS:000183100900018 PM 12754239 ER PT J AU Weis, RM Hirai, T Chalah, A Kessel, M Peters, PJ Subramaniam, S AF Weis, RM Hirai, T Chalah, A Kessel, M Peters, PJ Subramaniam, S TI Electron microscopic analysis of membrane assemblies formed by the bacterial chemotaxis receptor Tsr SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ESCHERICHIA-COLI CHEMOTAXIS; LIGAND-BINDING DOMAIN; ASPARTATE RECEPTOR; SIGNAL-TRANSDUCTION; CYTOPLASMIC DOMAIN; KINASE; CHEMORECEPTOR; COMPLEX; METHYLATION; PROTEIN AB The serine receptor (Tsr) from Escherichia coli is representative of a large family of transmembrane receptor proteins that mediate bacterial chemotaxis by influencing cell motility through signal transduction pathways: Tsr and other chemotaxis receptors form patches in the inner membrane that are often localized at the poles of the bacteria. In an effort to understand the structural constraints that dictate the packing of receptors in the plane of the membrane, we have used electron microscopy to examine ordered assemblies of Tsr in membrane extracts isolated from cells engineered to overproduce the receptor. Three types of assemblies were observed: ring-like "micelles" with a radial arrangement of receptor subunits, two-dimensional crystalline arrays with approximate hexagonal symmetry, and "zippers," which are receptor bilayers that result from the antiparallel interdigitation of cytoplasmic domains. The registration among Tsr molecules in the micelle and zipper assemblies was sufficient for identification of the receptor domains and for determination of their contributions to the total receptor length. The overall result of this analysis is compatible with an atomic model of the receptor dimer that was constructed primarily from the X-ray crystal structures of the periplasmic and cytoplasmic domains. Significantly, the micelle and zipper structures were also observed in fixed, cryosectioned cells expressing the Tsr receptor at high abundance, suggesting that the modes of Tsr assembly found in vitro are relevant to the situation in the cell. C1 Univ Massachusetts, Dept Chem, Amherst, MA 01003 USA. NCI, Biochem Lab, NIH, Bethesda, MD 20817 USA. Netherlands Canc Inst, Div Tumor Biol, NL-1066 CX Amsterdam, Netherlands. RP Weis, RM (reprint author), Univ Massachusetts, Dept Chem, LGRT 701,701 N Pleasant St, Amherst, MA 01003 USA. RI Hirai, Teruhisa/G-2105-2015 OI Hirai, Teruhisa/0000-0002-2114-8149 FU NIGMS NIH HHS [R01 NIGMS53210] NR 46 TC 52 Z9 53 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 JUN PY 2003 VL 185 IS 12 BP 3636 EP 3643 DI 10.1128/JB.185.12.3636-3643.2003 PG 8 WC Microbiology SC Microbiology GA 687FC UT WOS:000183364700018 PM 12775701 ER PT J AU Wu, YB Migliorini, M Yu, P Strickland, DK Wang, YX AF Wu, YB Migliorini, M Yu, P Strickland, DK Wang, YX TI Letter to the editor: H-1, C-13 and N-15 resonance assignments of domain 1 of receptor associated protein SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE domain 1; RAP; receptor associated protein ID C-13-LABELED PROTEINS; SPECTROSCOPY AB The 39 kDa receptor associated protein (RAP) is a modular protein consisting of multiple domains. There has been no x-ray crystal structure of RAP available and the full-length protein does not behave well in a NMR tube. To elucidate the 3D structure of the RAP, we undertook structure determination of individual domains of the RAP. As the first step, here we report the nearly complete assignments of the H-1, C-13 and N-15 chemical shift signals of domain 1 of the RAP. C1 Amer Red Cross, Jerome H Holland Lab Biomed Sci, Dept Vasc Biol, Rockville, MD 20855 USA. NCI, Prot Nucleic Acid NMR Sect, Struct Biophys Lab, NIH, Frederick, MD 21702 USA. RP Strickland, DK (reprint author), Amer Red Cross, Jerome H Holland Lab Biomed Sci, Dept Vasc Biol, Rockville, MD 20855 USA. NR 9 TC 5 Z9 6 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD JUN PY 2003 VL 26 IS 2 BP 187 EP 188 DI 10.1023/A:1023534107920 PG 2 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 671RU UT WOS:000182478500009 PM 12766414 ER PT J AU Ganesh, SK Nass, CM Blumenthal, RS AF Ganesh, SK Nass, CM Blumenthal, RS TI Anti-atherosclerotic effects of statins: lessons from prevention trials SO JOURNAL OF CARDIOVASCULAR RISK LA English DT Article DE atherosclerosis; cholesterol; prevention; lipids ID CORONARY-HEART-DISEASE; LIPID-LOWERING THERAPY; AVERAGE CHOLESTEROL LEVELS; GROWTH EVALUATION STATIN; ARTERY DISEASE; MYOCARDIAL-INFARCTION; VASOMOTOR FUNCTION; RANDOMIZED TRIAL; CLINICAL EVENTS; PRAVASTATIN AB Statins are best-known for their lipid-lowering effects and have been shown to significantly impact the natural progression of coronary atherosclerosis. The mechanism through which they exert this effect is thought to be primarily due to their ability to reduce low-density lipoprotein cholesterol levels. However, there is increasing evidence that statins exert a myriad of other beneficial effects on the vascular wall, thus altering the course of atherosclerotic disease. This article will review the prevention trial literature as it pertains to the effects of statin therapy on atherosclerosis. J Cardiovasc Risk 10:155-159 (C) 2003 Lippincott Williams Wilkins. C1 Johns Hopkins Univ Hosp, Ciccarone Prevent Cardiol Ctr, Div Cardiol, Baltimore, MD 21205 USA. NHLBI, Cardiovasc Branch, Baltimore, MD USA. RP Blumenthal, RS (reprint author), Johns Hopkins Univ Hosp, Ciccarone Prevent Cardiol Ctr, Div Cardiol, 600 N Wolfe St,Carnegie 538, Baltimore, MD 21205 USA. NR 35 TC 11 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1350-6277 J9 J CARDIOVASC RISK JI J. Cardiovasc. Risk PD JUN PY 2003 VL 10 IS 3 BP 155 EP 159 DI 10.1097/01.hjr.0000072574.13775.6d PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 693YX UT WOS:000183746900002 PM 12775947 ER PT J AU Davis, J Duncan, MK Robison, WG Piatigorsky, J AF Davis, J Duncan, MK Robison, WG Piatigorsky, J TI Requirement for Pax6 in corneal morphogenesis: a role in adhesion SO JOURNAL OF CELL SCIENCE LA English DT Review DE Pax6; cornea; adhesion; SEY mice; development ID EPIDERMAL GROWTH-FACTOR; SMALL-EYE; CELL-ADHESION; MOUSE EYE; ANTERIOR SEGMENT; STEM-CELLS; INTERMEDIATE FILAMENTS; TRANSCRIPTION FACTOR; DESMOSOMAL CADHERIN; BOUNDARY FORMATION AB The Pax6 transcription factor functions early during embryogenesis to control key steps in brain, pancreas, olfactory and ocular system development. A. requirement for Pax6 in proper formation of lens, iris and retina is well documented. By examining the corneas of heterozygous Small eye (SEY) mice, this report shows that Pax6 is also necessary for normal corneal morphogenesis. In particular, the epithelial component of the postnatal and adult SEY (+/-) cornea is thinner owing to a reduction in the number of cell layers, despite a tenfold increase in the proliferative index and no change in TUNEL labeling. Ultrastructural views revealed large gaps between corneal epithelial cells and a change in the appearance of desmosomes, suggesting that adhesion abnormalities contribute to the corneal phenotype of SEY (+/-) mice. Western blot analysis and immunofluorescence showed equivalent amounts and normal localization of E-cadherin in SEY (+/-) corneas, and the actin cytoskeleton appeared normal as judged by phalloidin staining. By contrast, the levels of desmoglein, beta-catenin and gamma-catenin were reduced in the SEY (+/-) cornea. In addition, the amount of keratin-12 mRNA and protein, the major intermediate filament, was reduced in SEY (+/-) corneal epithelium as shown by in situ hybridization and immunohistochemistry. Finally, the SEY (+/-) corneal epithelium adheres less well than wild-type when challenged with gentle rubbing using a microsponge. In conclusion, our results indicate that cellular adhesion is compromised in the SEY (+/-) corneal epithelium and suggests a role for Pax6 in the proper generation and maintenance of the adult cornea. C1 NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Delaware, Dept Biol Sci, Newark, DE 19716 USA. NEI, Lab Mech Ocular Dis, NIH, Bethesda, MD 20892 USA. RP Piatigorsky, J (reprint author), NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. OI Duncan, Melinda/0000-0003-1570-322X NR 104 TC 87 Z9 91 U1 1 U2 6 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 JUN 1 PY 2003 VL 116 IS 11 BP 2157 EP 2167 DI 10.1242/jcs.00441 PG 11 WC Cell Biology SC Cell Biology GA 689RU UT WOS:000183507400005 PM 12692153 ER PT J AU Lu, SJ Carroll, SL Herrera, AH Ozanne, B Horowits, R AF Lu, SJ Carroll, SL Herrera, AH Ozanne, B Horowits, R TI New N-RAP-binding partners alpha-actinin, filamin and Krp1 detected by yeast two-hybrid screening: implications for myofibril assembly SO JOURNAL OF CELL SCIENCE LA English DT Article DE N-RAP; alpha-actinin; filamin; Krp1; myofibril ID CULTURED CHICK CARDIOMYOCYTES; NEBULIN-RELATED PROTEIN; INTERCALATED DISKS; SKELETAL-MUSCLE; STRIATED-MUSCLE; CELL-ADHESION; LIM PROTEIN; LOCALIZATION; FILAMENTS; SEQUENCE AB N-RAP, a muscle-specific protein concentrated at myotendinous junctions in skeletal muscle and intercalated disks in cardiac muscle, has been implicated in myofibril assembly. To discover more about the role of N-RAP in myofibril assembly, we used the yeast two-hybrid system to screen a mouse skeletal muscle cDNA library for proteins capable of binding N-RAP in a eukaryotic cell. From yeast two-hybrid experiments we were able to identify three new N-RAP binding partners: alpha-actinin, filamin-2, and Krp1 (also called sarcosin). In vitro binding assays were used to verify these interactions and to identify the N-RAP domains involved. Three regions of N-RAP were expressed as His-tagged recombinant proteins, including the nebulin-like super repeat region (N-RAP-SR), the N-terminal LIM domain (N-RAP-LIM), and the region of N-RAP in between the super repeat region and the LIM domain (N-RAP-1B). We detected significant alpha-actinin binding to N-RAP-IB and N-RAP-LIM, filamin binding to N-RAP-SR, and Krp1 binding to N-RAP-SR and N-RAP-IB. During myofibril assembly in cultured chick cardiomyocytes, N-RAP and filamin appear to co-localize with alpha-actinin in the earliest myofibril precursors found near the cell periphery, as well as in the nascent myofibrils that form as these structures fuse laterally. In contrast, Krp1 is not localized until late in the assembly process, when it appears at the periphery of myofibrils that appear to be fusing laterally. The results suggest that sequential recruitment of N-RAP binding partners may serve an important role during myofibril assembly. C1 NIAMSD, Muscle Biol Lab, NIH, Bethesda, MD 20892 USA. Beatson Inst Canc Res, Glasgow G61 1BD, Lanark, Scotland. RP Horowits, R (reprint author), NIAMSD, Muscle Biol Lab, NIH, Bethesda, MD 20892 USA. NR 40 TC 38 Z9 40 U1 0 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD JUN 1 PY 2003 VL 116 IS 11 BP 2169 EP 2178 DI 10.1242/jcs.00425 PG 10 WC Cell Biology SC Cell Biology GA 689RU UT WOS:000183507400006 PM 12692149 ER PT J AU Rallapalli, R Strachan, G Tuan, RS Hall, DJ AF Rallapalli, R Strachan, G Tuan, RS Hall, DJ TI Identification of a domain within MDMX-S that is responsible for its high affinity interaction with p53 and high-level expression in mammalian cells SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE MDMX; MDMX-S; p53; interaction ID E2F1 TRANSCRIPTION FACTOR; P53-BINDING PROTEIN; DNA-DAMAGE; DEGRADATION; ONCOPROTEIN; ACTIVATION; INHIBITORS; GROWTH AB The MDMX gene product is related to the MDM2 oncoprotein, both of which interact with the p53 tumor suppressor. A novel transcript of the MDMX gene has been previously identified that has a short internal deletion of 68 base pairs, producing a shift in the reading frame after codon 114, resulting in the inclusion of 13 novel amino acids (after residue 114) followed by a stop codon at amino acid residue 127. This truncated MDMX protein, termed MDMX-S, represents only the p53 binding domain and binds and inactivates p53 better than full-length MDMX or MDM2. Here we show that when expressed in cells, MDMX-S is targeted more efficiently to the nucleus than MDMX. MDMX-S suppresses p53-mediated transcription from a p53 target promoter better than full-length MDMX. The DNA damage inducibility of these p53 responsive promoters was suppressed better by MDMX-S than by MDMX. Analysis of the MDMX-S protein indicated that the 13 novel amino acids at its carboxy terminus was responsible for high affinity binding to p53 in vitro and for high level expression of the protein in cells. Deletion of this 13 amino acid sequence resulted in a protein that was not able to bind p53 and was not able to be expressed well in cells. Taken together, these data point to an important domain within MDMX-S that enables it to function well in vivo to block p53 activity. C1 NIAMS, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. Univ Penn, Sch Dent Med, Dept Pathol, Philadelphia, PA 19104 USA. RP Hall, DJ (reprint author), NIAMS, Cartilage Biol & Orthopaed Branch, NIH, 13 South Dr,Rm 3W17,MSC 5755, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA67032]; NIAMS NIH HHS [AR39740, AR42887]; NIDCR NIH HHS [DE16864]; NIEHS NIH HHS [ES07005] NR 34 TC 27 Z9 29 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD JUN 1 PY 2003 VL 89 IS 3 BP 563 EP 575 DI 10.1002/jcb.10535 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 683EU UT WOS:000183135500014 PM 12761890 ER PT J AU Kim, BC Kim, HT Park, SH Cha, JS Yufit, T Kim, SJ Falanga, V AF Kim, BC Kim, HT Park, SH Cha, JS Yufit, T Kim, SJ Falanga, V TI Fibroblasts from chronic wounds show altered TGF-beta-signaling and decreased TGF-beta type II receptor expression SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID EXTREMITY DIABETIC ULCERS; VENOUS LEG ULCERS; GROWTH-FACTORS; DERMAL FIBROBLASTS; EFFICACY; PROLIFERATION; STIMULATION; ULCERATION; INHIBITORS; BINDING AB Chronic wounds are characterized by failure to heal in a defined time frame. However, the pathogenic steps leading from the etiological factors to failure to heal are unknown. Recently, increasing evidence suggests that resident cells in chronic wounds display a number of critical abnormalities, including senescence and unresponsiveness to the stimulatory action of transforming growth factor-beta1 (TGF-beta1). in this study, we have determined some of the mechanisms that might be responsible for unresponsiveness to TGF-beta1. Using Northern analysis and affinity labeling, we show that venous ulcer fibroblasts have decreased TGF-beta Type II receptor expression. This finding is not the result of genetic mutation, as shown by experiments with Type II receptor satellite instability. Decreased Type II receptor expression was accompanied by failure of ulcer fibroblasts to phosphorylate Smad 2, Smad 3, and p42/44 mitogen activating protein kinase (MAPK), and was associated with a slower proliferative rate in response to TGF-beta1. We conclude that venous ulcer fibroblasts show decreased Type II receptor expression and display abnormalities in the downstream signaling pathway involving MAPK and the early Smad pathway. These findings suggest ways to address and treat the abnormal cellular phenotype of cells in chronic wounds. (C) 2003 Wiley-Liss, Inc. C1 NCI, NIH, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Dept Dermatol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA. Roger Williams Med Ctr, Dept Dermatol, Providence, RI USA. RP Kim, SJ (reprint author), NCI, NIH, Lab Cell Regulat & Carcinogenesis, 9000 Rockville Pike,Bldg 41,Room B 1106, Bethesda, MD 20892 USA. FU NIAMS NIH HHS [AR42936, AR46557] NR 37 TC 71 Z9 75 U1 1 U2 9 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD JUN PY 2003 VL 195 IS 3 BP 331 EP 336 DI 10.1002/jcp.10301 PG 6 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 675BV UT WOS:000182673900001 PM 12704642 ER PT J AU Chen, Y Hallenbeck, JM Ruetzler, C Bol, D Thomas, K Berman, NEJ Vogel, SN AF Chen, Y Hallenbeck, JM Ruetzler, C Bol, D Thomas, K Berman, NEJ Vogel, SN TI Overexpression of monocyte chemoattractant protein 1 in the brain exacerbates ischemic brain injury and is associated with recruitment of inflammatory cells SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE mouse; MCAO; MBP-JE; ischemia; macrophages ID FOCAL CEREBRAL-ISCHEMIA; NEONATAL RAT-BRAIN; MESSENGER-RNA EXPRESSION; ACUTE EXCITOTOXIC INJURY; CYTOKINE; MOUSE; MCP-1; MICE; CHEMOKINES; CHEMOTAXIS AB Brain cells produce cytokines and chemokines during the inflammatory process after stroke both in animal models and in patients. Monocyte chemoattractant protein I (MCP-1), one of the proinflammatory chemokines, can attract monocytes to the tissue where MCP-1 is overexpressed. However, the role of MCP-1 elevation in stroke has not been explored in detail. The authors hypothesized that elevated MCP-1 levels would lead to increased influx of monocytes and increased brain infarction size in stroke induced by middle cerebral artery occlusion with partial reperfusion. There were no differences in blood pressure, blood flow, or vascular architecture between wild-type mice and transgenic MBP-JE mice. Twenty-four to 48 hours after middle cerebral artery occlusion, brain infarction volumes after ischemia were significantly larger in MBP-JE mice than in wild-type controls and were accompanied by increased local transmigration and perivascular accumulation of macrophages and neutrophils. These results indicate that MCP-1 can contribute to inflammatory injury in stroke. C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. Bristol Myers Squibb Co, Princeton, NJ 08543 USA. Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. Univ Kansas, Med Ctr, Dept Anat & Cell Biol, Kansas City, KS 66103 USA. RP Hallenbeck, JM (reprint author), NINDS, Stroke Branch, NIH, 36 Convent Dr MSC 4128,Bldg 36,Room 4A03, Bethesda, MD 20892 USA. NR 44 TC 145 Z9 150 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUN PY 2003 VL 23 IS 6 BP 748 EP 755 DI 10.1097/01.WCB.0000071885.63724.20 PG 8 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 689JY UT WOS:000183489900013 PM 12796723 ER PT J AU Ghosh, SP Kumar, M Koley, AP Ghosh, MC AF Ghosh, SP Kumar, M Koley, AP Ghosh, MC TI First direct detection of chromium(IV) as a long lived intermediate in the oxidation of methanol by chromium(VI) SO JOURNAL OF CHEMICAL RESEARCH-S LA English DT Article DE chromiun(VI); chromium(IV); alcohol oxidation ID ELECTRON-TRANSFER; AQUEOUS CHROMIUM(IV); ACID; REDUCTION; COMPLEXES; CHROMATE AB Reduction of chromium(VI) by excess methanol in solutions buffered by 2-ethyl-2-hydroxy butanoic acid and its sodium salt proceeds through a 2-electron path to produce pink chromium(IV). With the progress of this reaction, a slow oxidation of the product chromium(IV) by reactant chromium(VI) takes place. When all the chromium(VI) is consumed, the chromium(IV) undergoes very slow disproportionation to chromium(V) and chromium(III). The formation of chromium(IV) is accelerated by both 2-ethyl-2-hydroxy butanoate ion and hydrogen ion. C1 Birla Inst Technol, Chem Grp, Pilani 333031, Rajasthan, India. Birla Inst Technol, Chem Engn Grp, Pilani 333031, Rajasthan, India. RP Ghosh, MC (reprint author), NICHD, Cell Biol & Metab Branch, NIH, Bldg 18T,Room 101,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 20 TC 1 Z9 1 U1 0 U2 1 PU SCIENCE REVIEWS LTD PI NORTHWOOD PA 40 THE FAIRWAY, NORTHWOOD HA6 3DY, MIDDX, ENGLAND SN 0308-2342 J9 J CHEM RES-S JI J. Chem. Res.-S PD JUN PY 2003 IS 6 BP 346 EP 347 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 726BN UT WOS:000185578300013 ER PT J AU Eisenhofer, G Goldstein, DS Walther, MM Friberg, P Lenders, JWM Keiser, HR Pacak, K AF Eisenhofer, G Goldstein, DS Walther, MM Friberg, P Lenders, JWM Keiser, HR Pacak, K TI Biochemical diagnosis of pheochromocytoma: How to distinguish true- from false-positive test results SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CLONIDINE-SUPPRESSION TEST; SYMPATHETIC NERVOUS-SYSTEM; PLASMA NOREPINEPHRINE; LIQUID-CHROMATOGRAPHY; METANEPHRINES; CATECHOLAMINES; URINARY; DESIPRAMINE; MANAGEMENT; METABOLISM AB Measurements of plasma normetanephrine and metanephrine provide a highly sensitive test for diagnosis of pheochromocytoma, but false-positive results remain a problem. We therefore assessed medication-associated false-positive results and use of supplementary tests, including plasma normetanephrine responses to clonidine, to distinguish true-from false-positive results. The study included 208 patients with pheochromocytoma and 648 patients in whom pheochromocytoma was excluded. Clonidine-suppression tests were carried out in 48 patients with and 49 patients without the tumor. Tricyclic antidepressants and phenoxybenzamine accounted for 41% of false-positive elevations of plasma normetanephrine and 44-45% those of plasma and urinary norepinephrine. High plasma normetanephrine to norepinephrine or metanephrine to epinephrine ratios were strongly predictive of pheochromocytoma. Lack of decrease and elevated plasma levels of norepinephrine or normetanephrine after clonidine also confirmed pheochromocytoma with high specificity. However, 16 of 48 patients with pheochromocytoma had normal levels or decreases of norepinephrine after clonidine. In contrast, plasma normetanephrine remained elevated in all but 2 patients, indicating more reliable diagnosis using normetanephrine than norepinephrine responses to clonidine. Thus, in patients with suspected pheochromocytoma and positive biochemical results, false-positive elevations due to medications should first be eliminated. Patterns of biochemical test results and responses of plasma normetanephrine to clonidine can then help distinguish true-from false-positive results. C1 NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Hypertens Endocrine Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Sahlgrens Univ Hosp, Dept Clin Physiol, S-41345 Gothenburg, Sweden. Univ Nijmegen St Radboud Hosp, Dept Gen Internal Med, NL-6525 GA Nijmegen, Netherlands. RP Eisenhofer, G (reprint author), NINDS, Clin Neurocardiol Sect, NIH, Bldg 10,Room 6N252,10 Ctr Dr, Bethesda, MD 20892 USA. EM ge@box-g.nih.gov RI Lenders, J.W.M./L-4487-2015 NR 41 TC 207 Z9 217 U1 0 U2 5 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2003 VL 88 IS 6 BP 2656 EP 2666 DI 10.1210/jc.2002-030005 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 686JL UT WOS:000183318200043 PM 12788870 ER PT J AU Lindsay, RS Wake, DJ Nair, S Bunt, J Livingstone, DEW Permana, PA Tataranni, PA Walker, BR AF Lindsay, RS Wake, DJ Nair, S Bunt, J Livingstone, DEW Permana, PA Tataranni, PA Walker, BR TI Subcutaneous adipose 11 beta-hydroxysteroid dehydrogenase type 1 activity and messenger ribonucleic acid levels are associated with adiposity and insulinemia in Pima Indians and Caucasians SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID OBESE ZUCKER RATS; CORTISOL METABOLISM; GLUCOCORTICOID ACTION; RISK-FACTORS; TISSUE; EXPRESSION; SECRETION; RESISTANCE; GLUCOSE; DYSREGULATION AB Metabolic effects of cortisol may be critically modulated by glucocorticoid metabolism in tissues. Specifically, active cortisol is regenerated from inactive cortisone by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11-HSD1) in adipose and liver. We examined activity and mRNA levels of 11-HSD1 and tissue cortisol and cortisone levels in sc adipose tissue biopsies from 12 Caucasian (7 males and 5 females) and 19 Pima Indian (10 males and 9 females) nondiabetic subjects aged 28+/-7.6 yr (mean+/-SD; range, 18-45). Adipose 11-HSD1 activity and mRNA levels were highly correlated (r=0.51, P=0.003). Adipose 11-HSD1 activity was positively related to measures of total (body mass index, percentage body fat) and central waist circumference) adiposity (P<0.05 for all) and fasting glucose (r=0.43, P=0.02), insulin (r=0.60, P=0.0005), and insulin resistance by the homeostasis model (r=0.70, P<0.0001) but did not differ between sexes or ethnic groups. Intra-adipose cortisol was positively associated with fasting insulin (r=0.37, P=0.04) but was not significantly correlated with 11-HSD1 mRNA or activity or with other metabolic variables. In this cross-sectional study, higher adipose 11-HSD1 activity is associated with features of the metabolic syndrome. Our data support the hypothesis that increased regeneration of cortisol in adipose tissue influences metabolic sequelae of human obesity. C1 NIDDKD, NIH, US Dept HHS, Phoenix, AZ 85016 USA. Univ Edinburgh, Western Gen Hosp, Endocrinol Unit, Dept Med Sci, Edinburgh EH4 2XU, Midlothian, Scotland. RP Tataranni, PA (reprint author), NIDDKD, NIH, US Dept HHS, 4212 N 16th St,Room 541A, Phoenix, AZ 85016 USA. EM antoniot@mail.nih.gov NR 40 TC 169 Z9 177 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2003 VL 88 IS 6 BP 2738 EP 2744 DI 10.1210/jc.2002-030017 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 686JL UT WOS:000183318200055 PM 12788882 ER PT J AU Caldwell, HD Wood, H Crane, D Bailey, R Jones, RB Mabey, D Maclean, I Mohammed, Z Peeling, R Roshick, C Schachter, J Solomon, AW Stamm, WE Suchland, RJ Taylor, L West, SK Quinn, TC Belland, RJ McClarty, G AF Caldwell, HD Wood, H Crane, D Bailey, R Jones, RB Mabey, D Maclean, I Mohammed, Z Peeling, R Roshick, C Schachter, J Solomon, AW Stamm, WE Suchland, RJ Taylor, L West, SK Quinn, TC Belland, RJ McClarty, G TI Polymorphisms in Chlamydia trachomatis tryptophan synthase genes differentiate between genital and ocular isolates SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID OUTER-MEMBRANE PROTEIN; PELVIC INFLAMMATORY DISEASE; BACTERIAL VAGINOSIS; INTERFERON-GAMMA; CELL-CULTURE; INDOLEAMINE 2,3-DIOXYGENASE; TOXOPLASMA-GONDII; HOST-CELLS; INFECTIONS; PATHOGENESIS AB We previously reported that laboratory reference strains of Chlamydia trachomatis differing in infection organotropism correlated with inactivating mutations in the pathogen's tryptophan synthase (trpBA) genes. Here, we have applied functional genomics to extend this work and find that the paradigm established for reference serovars also applies to clinical isolates - specifically, all ocular trachoma isolates tested have inactivating mutations in the synthase, whereas all genital isolates encode a functional enzyme. Moreover, functional enzyme activity was directly correlated to IFN-gamma resistance through an indole rescue mechanism. Hence, a strong selective pressure exists for genital strains to maintain a functional synthase capable of using indole for tryptophan biosynthesis. The fact that ocular serovars (serovar B) isolated from the genital tract were found to possess a functional synthase provided further persuasive evidence of this association. These results argue that there is an important host-parasite relationship between chlamydial genital strains and the human host that determines organotropism of infection and the pathophysiology of disease. We speculate that this relationship involves the production of indole by components of the vaginal microbial flora, allowing chlamydiae to escape IFN-gamma-mediated eradication and thus establish persistent infection. C1 NIAID, Rocky Mt Labs, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. Hlth Canada, Natl Microbiol Lab, Winnipeg, MB, Canada. London Sch Hyg & Trop Med, Dept Infect & Trop Dis, London WC1, England. Indiana Univ, Sch Med, Dept Med, Div Infect Dis, Indianapolis, IN 46204 USA. Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. Univ Washington, Sch Med, Div Allergy & Infect Dis, Seattle, WA 98195 USA. Johns Hopkins Univ, Wilmer Eye Inst, Baltimore, MD 21218 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP McClarty, G (reprint author), Univ Manitoba, Dept Med Microbiol, 730 William Ave, Winnipeg, MB R3E 0W3, Canada. EM mcclart@cc.umanitoba.ca NR 63 TC 165 Z9 167 U1 0 U2 7 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN PY 2003 VL 111 IS 11 BP 1757 EP 1769 DI 10.1172/JCI200317993 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 686GQ UT WOS:000183313400019 PM 12782678 ER PT J AU Nishigaki, Y Marti, R Copeland, WC Hirano, M AF Nishigaki, Y Marti, R Copeland, WC Hirano, M TI Site-speciflic somatic mitochondrial DNA point mutations in patients with thymidine phosphorylase deficiency SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID PERFORMANCE LIQUID-CHROMATOGRAPHY; UV-ABSORBING COMPOUNDS; MOUSE L-CELLS; NEUROGASTROINTESTINAL ENCEPHALOMYOPATHY; MULTIPLE DELETIONS; CONTROL REGION; AUTOSOMAL-DOMINANT; POLYMERASE-GAMMA; GENE; FIDELITY AB Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by loss-of-function mutations in the gene encoding thymidine phosphorylase (TP). This deficiency of TP leads to increased circulating levels of thymidine (deoxythymidine, dThd) and deoxyuridine (dUrd) and has been associated with multiple deletions and depletion of mitochondrial DNA (mtDNA). Here we describe 36 point mutations in mtDNA of tissues and cultured cells from MNGIE patients. Thirty-one mtDNA point mutations (86%) were T-to-C transitions, and of these, 25 were preceded by 5'-AA sequences. In addition, we identified a single base-pair mtDNA deletion and a TT-to-AA mutation. Next-nucleotide effects and dislocation mutagenesis may contribute to the formation of these mutations. These results provide the first demonstration that alterations of nucleoside metabolism can induce multiple sequence-specific point mutations in humans. We hypothesize that, in patients with TP deficiency, increased levels of dThd and dUrd cause mitochondrial nucleotide pool imbalances, which, in turn, lead to mtDNA abnormalities including site-specific point mutations. C1 Columbia Univ Coll Phys & Surg, Dept Neurol, New York, NY 10032 USA. NIEHS, Genet Mol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Hirano, M (reprint author), Columbia Univ Coll Phys & Surg, Dept Neurol, 630 W 168th St,Phys & Surg 4-443, New York, NY 10032 USA. FU NICHD NIH HHS [R01 HD-37529] NR 41 TC 118 Z9 122 U1 0 U2 2 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 JUN PY 2003 VL 111 IS 12 BP 1913 EP 1921 DI 10.1172/JCI200317828 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 691UH UT WOS:000183623600015 PM 12813027 ER PT J AU Conville, PS Brown, JM Steigerwalt, AG Lee, JW Byrer, DE Anderson, VL Dorman, SE Holland, SM Cahill, B Carroll, KC Witebsky, FG AF Conville, PS Brown, JM Steigerwalt, AG Lee, JW Byrer, DE Anderson, VL Dorman, SE Holland, SM Cahill, B Carroll, KC Witebsky, FG TI Nocardia veterana as a pathogen in North American patients SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID RESTRICTION-ENDONUCLEASE ANALYSIS; RIBOSOMAL-RNA GENE; SP-NOV; RAPID IDENTIFICATION; DNA; BRASILIENSIS; STREPTOMYCES; RHODOCOCCUS; ASTEROIDES; DISEASE AB The molecular methodologies used in our laboratories have allowed us to define a group of Nocardia isolates from clinical samples which resemble the type strain of Nocardia veterana. Three patient isolates and the type strain of N. veterana gave identical and distinctive restriction fragment length polymorphisms (RFLPs) for an amplified portion of the 16S rRNA gene. These three isolates and the N. veterana type strain also gave identical RFLPs for an amplified portion of the 65-kDa heat shock protein gene, but this pattern was identical to that obtained for the Nocardia nova type strain. Sequence analysis of both a 1,359-bp region of the 16S rRNA gene and a 441-bp region of the heat shock protein gene of the patient isolates showed 100% identities with the same regions of the N. veterana type strain. DNA-DNA hybridization of the DNA of one of the patient isolates with the DNA of the N. veterana type strain showed a relative binding ratio of 82%, with 0% divergence, confirming that the isolate was N. veterana. Biochemical and susceptibility testing showed no significant differences among the patient isolates and the N. veterana type strain. Significantly, the results of antimicrobial susceptibility testing obtained for our isolates were similar to those obtained for N. nova, indicating that susceptibility testing alone cannot discriminate between these species. We present two case studies which show that N. veterana is a causative agent of pulmonary disease in immunocompromised patients residing in North America. We also describe difficulties encountered in using 16S rRNA gene sequences alone for discrimination of N. veterana from the related species Nocardia africana and N. nova because of the very high degree of 16S rRNA gene similarity among them. C1 US Dept HHS, Warren G Magnuson Clin Ctr, Microbiol Serv, Dept Lab Med,NIH, Bethesda, MD 20892 USA. US Dept HHS, NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. US Dept HHC, CDCP, Natl Ctr Infect Dis,Meningitis & Special Pathogen, Div Bacterial & Mycot Dis, Atlanta, GA USA. Amer Type Culture Collect, Manassas, VA USA. Univ Utah, Sch Med, Div Pulm & Crit Care Med, Salt Lake City, UT USA. Univ Utah, Dept Pathol, Salt Lake City, UT USA. RP Conville, PS (reprint author), US Dept HHS, Warren G Magnuson Clin Ctr, Microbiol Serv, Dept Lab Med,NIH, 10 Ctr Dr,MSC 1508, Bethesda, MD 20892 USA. NR 32 TC 29 Z9 29 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD JUN PY 2003 VL 41 IS 6 BP 2560 EP 2568 DI 10.1128/JCM.41.6.2560-2568.2003 PG 9 WC Microbiology SC Microbiology GA 688ZB UT WOS:000183466200047 PM 12791881 ER PT J AU Tang, YW Johnson, JE Browning, PJ Cruz-Gervis, RA Davis, A Graham, BS Brigham, KL Oates, JA Loyd, JE Stecenko, AA AF Tang, YW Johnson, JE Browning, PJ Cruz-Gervis, RA Davis, A Graham, BS Brigham, KL Oates, JA Loyd, JE Stecenko, AA TI Herpesvirus DNA is consistently detected in lungs of patients with idiopathic pulmonary fibrosis SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID EPSTEIN-BARR-VIRUS; HEPATITIS-C VIRUS; KAPOSIS-SARCOMA; DISEASE PROGRESSION; CYTOMEGALOVIRUS; INFECTION; CELLS; PREVALENCE; ALVEOLITIS; ANTIBODIES AB On the basis of earlier reports associating Epstein-Barr Virus (EBV) with half of the cases of idiopathic pulmonary fibrosis (IPF), we hypothesized that chronic infection with EBV or a closely related herpesvirus would be detected in all cases of IPF. We tested lung specimens from 33 IPF patients (8 patients with familial IPF and 25 patients with sporadic IPF) and 25 patients with other diseases as controls for the presence of eight herpesviruses using PCR-based techniques. One or more of four herpesviruses (cytomegalovirus [CMV], EBV, human herpesvirus 7 [HHV-7], and HHV-8) were detected in 32 of 33 (97%) subjects with IPF and in 9 of 25 (36%) controls (P < 0.0001). CMV, EBV, and HHV-8 were found more frequently in IPF patients than in controls (P < 0.05, P < 0.001, and P < 0.01 respectively). Two or more herpesviruses were detected in 19 of 33 (57%) IPF patients and in 2 of 25 (8%) controls (P < 0.001). Two or more herpesviruses and HHV-8 were found more frequently in patients with sporadic IPF than in patients with familial IPF (P < 0.05 for both comparisons), and CMV was found less frequently in patients with sporadic IPF than in patients with familial IPF (P < 0.05). Immunohistochemistry for EBV or HHV-8 antigen showed viral antigen primarily in airway epithelial cells. These data support the concept that a herpesvirus could be a source of chronic antigenic stimulation in IPF. C1 Vanderbilt Univ, Med Ctr, Div Infect Dis, Dept Med, Nashville, TN 37232 USA. Vanderbilt Univ, Med Ctr, Dept Pathol, Nashville, TN 37232 USA. Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA. Meharry Med Coll, Dept Med, Nashville, TN 37208 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. Emory Univ, Sch Med, Dept Med, Atlanta, GA USA. RP Tang, YW (reprint author), Vanderbilt Univ, Med Ctr, Div Infect Dis, Dept Med, A3310 Med Ctr N, Nashville, TN 37232 USA. NR 33 TC 145 Z9 149 U1 0 U2 12 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD JUN PY 2003 VL 41 IS 6 BP 2633 EP 2640 DI 10.1128/JCM.41.6.2633-2640.2003 PG 8 WC Microbiology SC Microbiology GA 688ZB UT WOS:000183466200057 PM 12791891 ER PT J AU Douglas, JT Qian, LS Montoya, JC Musser, JM Van Embden, JDA Van Soolingen, D Kremer, K AF Douglas, JT Qian, LS Montoya, JC Musser, JM Van Embden, JDA Van Soolingen, D Kremer, K TI Characterization of the Manila family of Mycobacterium tuberculosis SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID EPIDEMIOLOGY; NETHERLANDS; RESISTANT; STRAINS AB Forty-eight Mycobacterium tuberculosis strains were obtained from patients living in metropolitan Manila, Republic of the Philippines. Three molecular typing methods, IS6110 restriction fragment length polymorphism, spoligotyping, and DNA sequencing of the oxyR, gyrA, and katG loci, established that these strains have restricted diversity and are members of a related genetic group of organisms. Comparison of the DNA fingerprint patterns with those in international databases confirmed the uniqueness of this group of isolates, which we designate the Manila family of M. tuberculosis. C1 Univ Hawaii Manoa, Dept Microbiol, Honolulu, HI 96822 USA. Univ Philippines, Res Inst Trop Med, Manila, Philippines. Univ Philippines, Philippine Gen Hosp, Manila, Philippines. NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT USA. Natl Inst Publ Hlth & Environm, Bilthoven, Netherlands. RP Douglas, JT (reprint author), Univ Hawaii Manoa, Dept Microbiol, 2538 The Mall,Snyder Hall 207, Honolulu, HI 96822 USA. RI van Embden, Joel/P-4925-2014 NR 16 TC 34 Z9 35 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD JUN PY 2003 VL 41 IS 6 BP 2723 EP 2726 DI 10.1128/JCM.41.6.2723-2726.2003 PG 4 WC Microbiology SC Microbiology GA 688ZB UT WOS:000183466200081 PM 12791915 ER PT J AU Post, RM Denicoff, KD Leverich, GS Altshuler, LL Frye, MA Suppes, TM Rush, AJ Keck, PE McElroy, SL Luckenbaugh, DA Pollio, C Kupka, R Nolen, WA AF Post, RM Denicoff, KD Leverich, GS Altshuler, LL Frye, MA Suppes, TM Rush, AJ Keck, PE McElroy, SL Luckenbaugh, DA Pollio, C Kupka, R Nolen, WA TI Morbidity in 258 bipolar outpatients followed for 1 year with daily prospective ratings on the NIMH Life Chart Method SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID LOW SERUM LEVELS; AFFECTIVE-DISORDER; LITHIUM TREATMENT; WORKSHOP REPORT; NETWORK I; ILLNESS; EPISODE; DEMOGRAPHICS; PROPHYLAXIS; RECURRENCE AB Background. A number of recent longitudinal outcome studies have found substantial long-term morbidity in patients with bipolar disorder. The detailed course and pattern of illness emerging despite comprehensive treatment with mood stabilizers and adjunctive agents have previously not been well delineated. Method: 258 consecutive outpatients admitted from 1996 to 1999 to the Stanley Foundation Bipolar Network who had a full year of prospective daily clinician ratings on the National Institute of Mental Health-Life Chart Method were included in the analysis. Patients were diagnosed by the Structured Clinical Interview for DSM-IV, with the majority (76%) having bipolar I disorder. They completed a questionnaire on demographics and prior illness course, and variables associated with outcome were examined in a hierarchical multinomial logistic regression analysis. Patients were treated naturalistically with a mean of 4.1 psychotropic medications during the year. Results: Despite comprehensive pharmacologic treatment, mean time depressed (33.2% of the year) was 3-fold higher than time manic (10.8%); 62.8% of patients had 4 or more mood episodes per year. Two thirds of the patients were substantially impacted by their illness; 26.4% were ill for more than three fourths of the year, and 40.7% were intermittently ill with major affective episodes. After logistic regression analysis, those who were ill most of the year, compared with the largely well group, had a significantly greater family history of substance abuse, 10 or more depressive episodes, and limited occupational functioning prior to Network entry. Conclusion: A majority of outpatients with bipolar illness, even with intense monitoring and treatment in specialty clinics, have a considerable degree of residual illness-related morbidity, including a 3-fold greater amount of time spent depressed versus time spent manic. A personal or family history of substance abuse, 10 or more prior depressions, and limited occupational functioning predicted the poorest outcomes. Additional interventions, particularly those targeted at treating depressive phases of bipolar illness, are greatly needed. C1 NIMH, Biol Psychiat Branch, NIH, Bethesda, MD 20892 USA. NIMH, Stanley Fdn Bipolar Network, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Ambulatory Clin Res Ctr, Los Angeles, CA USA. Univ Calif Los Angeles, VA Med Ctr, Los Angeles, CA USA. Univ Texas, SW Med Ctr, Dallas, TX 75230 USA. Univ Cincinnati, Coll Med, Cincinnati, OH USA. Univ Utrecht, Ctr Med, Utrecht, Netherlands. Altrecht Inst Mental Hlth Care, Utrecht, Netherlands. RP NIMH, Biol Psychiat Branch, NIH, 10 Ctr Dr MSC 1272,Bldg 10,Room 3s239, Bethesda, MD 20892 USA. EM robert.post@nih.gov RI Nolen, Willem/E-9006-2014; OI Rush, Augustus/0000-0003-2004-2382 FU NIMH NIH HHS [R01 MH079261] NR 45 TC 261 Z9 272 U1 0 U2 9 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD JUN PY 2003 VL 64 IS 6 BP 680 EP 690 PG 11 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 693YR UT WOS:000183746400010 PM 12823083 ER PT J AU Post, RM Keck, PE Rush, AJ AF Post, RM Keck, PE Rush, AJ TI Bipolar disorder and crossover design - Reply to Curtin letter SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Letter ID GABAPENTIN MONOTHERAPY; ILLNESS; PLACEBO; ISSUES; CARBAMAZEPINE; LAMOTRIGINE C1 NIMH, Biol Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP Post, RM (reprint author), NIMH, Biol Psychiat Branch, NIH, Bethesda, MD 20892 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD JUN PY 2003 VL 23 IS 3 BP 320 EP 320 DI 10.1097/00004714-200306000-00018 PG 1 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 697GM UT WOS:000183934200018 ER PT J AU Owens, EB Hinshaw, SP Kraemer, HC Arnold, LE Abikoff, HB Cantwell, DP Conners, CK Elliott, G Greenhill, LL Hechtman, L Hoza, B Jensen, PS March, JS Newcorn, JH Pelham, WE Severe, JB Swanson, JM Vitiello, B Wells, KC Wigal, T AF Owens, EB Hinshaw, SP Kraemer, HC Arnold, LE Abikoff, HB Cantwell, DP Conners, CK Elliott, G Greenhill, LL Hechtman, L Hoza, B Jensen, PS March, JS Newcorn, JH Pelham, WE Severe, JB Swanson, JM Vitiello, B Wells, KC Wigal, T TI Which treatment for whom for ADHD? Moderators of treatment response in the MTA SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article ID MULTIMODAL TREATMENT; ANTISOCIAL CHILDREN; DECISION-MAKING; FOLLOW-UP; PARENT; PREDICTORS; METHYLPHENIDATE; DESIGN; RISK; RATIONALE AB Using receiver operating characteristics, the authors examined outcome predictors (variables associated with outcome regardless of treatment) and moderators (variables identifying subgroups with differential treatment effectiveness) in the Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (ADHD; MTA). Treatment response was determined using parent- and teacher-reported ADHD and oppositional defiant symptoms, with levels near or within the normal range indicating excellent response. Among 9 baseline child and family characteristics, none predicted but 3 moderated treatment response. In medication management and combined treatments, parental depressive symptoms and severity of child ADHD were associated with decreased rates of excellent response; when these 2 characteristics were present, below-average child IQ was an additional moderator. No predictors or moderators emerged for behavioral and community comparison treatments. The authors discuss conceptual and clinical implications of research on treatment moderators. C1 Univ Calif Berkeley, Inst Human Dev, Berkeley, CA 94720 USA. Univ Calif Berkeley, Dept Psychol, Berkeley, CA 94720 USA. Stanford Univ, Dept Psychiat, Stanford, CA 94305 USA. Ohio State Univ, Dept Psychiat, Columbus, OH 43210 USA. NYU, Ctr Child Study, New York, NY USA. Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. Duke Univ, Dept Psychiat & Behav Sci, Durham, NC 27706 USA. Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. Columbia Univ, New York, NY 10027 USA. McGill Univ, Dept Psychiat & Pediat, Montreal, PQ H3A 2T5, Canada. Montreal Childrens Hosp, Dept Psychiat, Montreal, PQ H3H 1P3, Canada. Purdue Univ, Dept Psychol, W Lafayette, IN 47907 USA. Univ Buffalo, Dept Psychol, Buffalo, NY USA. NIMH, Div Serv & Intervent Res, Bethesda, MD USA. Univ Calif Irvine, Dept Pediat, Irvine, CA 92717 USA. RP Owens, EB (reprint author), Univ Calif Berkeley, Inst Human Dev, Tolman Hall,MC 1690, Berkeley, CA 94720 USA. OI Jensen, Peter/0000-0003-2387-0650; Newcorn, Jeffrey /0000-0001-8993-9337 FU NIMH NIH HHS [U01 MH50453, MH50467, U01 MH50440, U01 MH50447, U01 MH50454, U01 MH50461, U01 MH50467, U01-MH50453, U01-MH50461] NR 62 TC 135 Z9 135 U1 6 U2 15 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD JUN PY 2003 VL 71 IS 3 BP 540 EP 552 DI 10.1037/0022-006X.71.3.540 PG 13 WC Psychology, Clinical SC Psychology GA 681JB UT WOS:000183032100013 PM 12795577 ER PT J AU Csako, G Zheng, C Limaye, A Costello, R Sreenath, T Ambudkar, I Brady, RO Kulkarni, AB AF Csako, G. Zheng, C. Limaye, A. Costello, R. Sreenath, T. Ambudkar, I. Brady, R. O. Kulkarni, A. B. TI Sialochemical changes in a fabry mouse model indicate impaired salivary gland function. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 NIH, DHHS, Ctr Clin, Bethesda, MD 20892 USA. NIH, Natl Inst Dent & Craniofacial Res, DHHS, Bethesda, MD 20892 USA. NIH, Natl Inst Neurol Disorders & Stroke, DHHS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUN PY 2003 VL 82 SI B MA 3103 BP B397 EP B397 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA V42UY UT WOS:000202893603763 ER PT J AU Dohke, Y Oh, YS Ambudkar, I Turner, RJ AF Dohke, Y. Oh, Y. S. Ambudkar, I. Turner, R. J. TI Topology of the transient receptor potential Ca2+ channel Trp1. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Nihon Univ, Sch Dent, Matsudo, Chiba 271, Japan. NIH, NIDCR, DHHS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUN PY 2003 VL 82 SI B MA 1099 BP B150 EP B150 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA V42UY UT WOS:000202893601311 ER PT J AU Gao, C Shi, S Li, W Liu, H Denbesten, PK AF Gao, C. Shi, S. Li, W. Liu, H. Denbesten, P. K. TI Enhancement of proliferation of odontoblast progenitor cells by emdogain. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. NIDCR, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUN PY 2003 VL 82 SI B MA 0511 BP B76 EP B76 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA V42UY UT WOS:000202893600509 ER PT J AU Gordon, SM Dionne, RA Picco, C Wahl, SM AF Gordon, S. M. Dionne, R. A. Picco, C. Wahl, S. M. TI Dose-finding study: Topical thalidomide for aphthous ulcers. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 NIH, NIDCR, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUN PY 2003 VL 82 SI B MA 0127 BP B28 EP B28 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA V42UY UT WOS:000202893600126 ER PT J AU Gordon, SM Wahl, SM Picco, C Sonies, B Miller, J Castillo, J Dionne, RA AF Gordon, S. M. Wahl, S. M. Picco, C. Sonies, B. Miller, J. Castillo, J. Dionne, R. A. TI Etanercept demonstrates acute anti-inflammatory effects. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 NIH, NIDCR, Washington, DC USA. Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUN PY 2003 VL 82 SI B MA 0129 BP B28 EP B28 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA V42UY UT WOS:000202893600128 ER PT J AU Hoffman, MP Steinberg, ZL Myers, CR Larsen, M AF Hoffman, M. P. Steinberg, Z. L. Myers, C. R. Larsen, M. TI FGF7 and FGF10 regulate branching morphogenesis of developing mouse submandibular glands in vitro through FGFR2b and FGFR1b. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Natl Inst Mental & Craniofacial Res, NIH, US Dept HHS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUN PY 2003 VL 82 SI B MA 2471 BP B319 EP B319 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA V42UY UT WOS:000202893603137 ER PT J AU Koontongkaew, S Yapong, B Amornphimoltham, P AF Koontongkaew, S. Yapong, B. Amornphimoltham, P. TI Cytokine responses of primary and metastatic oral cancer cells to fibroblasts. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Thammasat Univ, Pathum Thani, Thailand. Prince Songkla Univ, Hat Yai, Thailand. NIDCR, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUN PY 2003 VL 82 SI B MA 1201 BP B162 EP B162 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA V42UY UT WOS:000202893601413 ER PT J AU Kulkarni, GV Hatakeyama, J Yavuz, I Rosca, G Khadivi, A Gibson, CW Kulkarni, AB AF Kulkarni, G. V. Hatakeyama, J. Yavuz, I. Rosca, G. Khadivi, A. Gibson, C. W. Kulkarni, A. B. TI Amelogenin knockout mice mimic physical tooth characteristics of human amelogenesis imperfecta. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Univ Toronto, Fac Dent, Toronto, ON, Canada. NIH, Natl Inst Dent & Craniofacial Res, Funct Genom Unit, Bethesda, MD 20892 USA. Dicle Univ, Diyarbakir, Turkey. Univ Penn, Philadelphia, PA 19104 USA. Natl Inst Hlth, Natl Inst Dent & Craniofacial Res, Funct Genom Unit, Bethesda, MD USA. EM g.kulkarni@utoronto.ca RI yavuz, izzet/A-6758-2016 OI yavuz, izzet/0000-0001-6953-747X NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUN PY 2003 VL 82 SI B MA 0080 BP B22 EP B22 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA V42UY UT WOS:000202893600079 ER PT J AU Li, W Pugach, M Shi, S Gao, C Machule, D Denbesten, P AF Li, W. Pugach, M. Shi, S. Gao, C. Machule, D. Denbesten, P. TI Co-culture of pre-odontoblasts and ameloblasts promotes ameloblast differentiation and enamel matrix formation. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. NIDCR, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUN PY 2003 VL 82 SI B MA 1065 BP B145 EP B145 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA V42UY UT WOS:000202893601277 ER PT J AU Liu, H Li, W Shi, S Gao, C Denbesten, PK AF Liu, H. Li, W. Shi, S. Gao, C. Denbesten, P. K. TI Dentonin, a fragment of MEPE, enhanced dental pulp stem cell proliferation in vitro. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. NIDCR, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUN PY 2003 VL 82 SI B MA 1865 BP B244 EP B244 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA V42UY UT WOS:000202893602303 ER PT J AU Miura, M Gronthos, S Zhao, M Lu, B Fisher, LW Robey, PG Shi, S AF Miura, M. Gronthos, S. Zhao, M. Lu, B. Fisher, L. W. Robey, P. G. Shi, S. TI SHED - Stem cells from human exfoliated deciduous teeth. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 3 Z9 4 U1 1 U2 4 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUN PY 2003 VL 82 SI B MA 2358 BP B305 EP B305 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA V42UY UT WOS:000202893603026 ER PT J AU Myers, CR Steinberg, ZL Hoffman, MP AF Myers, C. R. Steinberg, Z. L. Hoffman, M. P. TI Matrix metalloproteinase (MMP) activity is required for branching morphogenesis of developing mouse submandibular glands. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 NIH, Natl Inst Dent & Craniofacial Res, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUN PY 2003 VL 82 SI B MA 1104 BP B150 EP B150 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA V42UY UT WOS:000202893601316 ER PT J AU Ogbureke, KUE Fisher, LW AF Ogbureke, K. U. E. Fisher, L-W. TI Dentin sialophosphoprotein and osteopontin are expressed in salivary glands. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 NIDCR, NIH, HHS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUN PY 2003 VL 82 SI B MA 1864 BP B244 EP B244 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA V42UY UT WOS:000202893602302 ER PT J AU Pihlstrom, BL AF Pihlstrom, B. L. TI Clinical research opportunities for dental researchers in the international setting. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUN PY 2003 VL 82 SI B MA 1374 BP B184 EP B184 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA V42UY UT WOS:000202893601585 ER PT J AU Sreenath, T Thyagarajan, T Hall, B Longenecker, G D'Souza, RN Hong, S Wright, JT MacDougall, M Sauk, JJ Kulkarni, AB AF Sreenath, T. Thyagarajan, T. Hall, B. Longenecker, G. D'Souza, R. N. Hong, S. Wright, J. T. MacDougall, M. Sauk, J. J. Kulkarni, A. B. TI Dentin sialophosphoprotein is critical for tooth mineralization. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Natl Inst Dent & Craniofacial Res, NIH, DHHS, Bethesda, MD USA. Univ Texas, Hlth Sci Ctr Houston, Dent Branch, Houston, TX USA. Univ Texas, Hlth Sci Ctr San Antonio, San Antonio, TX USA. Univ N Carolina, Sch Dent, Chapel Hill, NC USA. Univ Maryland, Baltimore, MD 21201 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUN PY 2003 VL 82 SI B MA 1868 BP B244 EP B244 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA V42UY UT WOS:000202893602306 ER PT J AU Thyagarajan, T Sreenath, T Wrighti, JT Septier, D Goldberg, M Kulkarni, AB AF Thyagarajan, T. Sreenath, T. Wrighti, J. T. Septier, D. Goldberg, M. Kulkarni, A. B. TI Transient over-expression of TGF-beta 1 in pre-ameloblasts and ameloblasts results in defective enamel. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. NIH, Dept Hlth Human Serv, Bethesda, MD USA. Univ N Carolina, Chapel Hill, NC USA. Univ Paris 05, Grp Matrices Extracellullaires Biomineralisat, Montrouge, France. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUN PY 2003 VL 82 SI B MA 1318 BP B177 EP B177 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA V42UY UT WOS:000202893601529 ER PT J AU Wadhwa, S Young, MF AF Wadhwa, S. Young, M. F. TI Biglycan and decorin: Potential role in controlling suture maturation and craniofacial development. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Natl Inst Hlth, US Dept HHS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUN PY 2003 VL 82 SI B MA 0039 BP B17 EP B17 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA V42UY UT WOS:000202893600039 ER PT J AU Watson, MR Winn, DM Samet, J AF Watson, M. -R. Winn, D. M. Samet, J. TI Fetal growth patterns and ECC among a low-income preschool population. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Univ Maryland, Sch Dent, Baltimore, MD 21201 USA. NIH, Natl Canc Inst, Bethesda, MD 20892 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUN PY 2003 VL 82 SI B MA 0436 BP B67 EP B67 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA V42UY UT WOS:000202893600434 ER PT J AU Watt, R Harnett, R Nowjack-Raymer, RE Treasure, E Kay, EJ Daly, B Munday, P Fuller, S Morgan, A AF Watt, R. Harnett, R. Nowjack-Raymer, R. E. Treasure, E. Kay, E. J. Daly, B. Munday, P. Fuller, S. Morgan, A. TI A review and assessment of oral health promotion outcome evaluation measures. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 UCL, London, England. Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. Cardiff Univ, Cardiff, Wales. Univ Manchester, Manchester, Lancs, England. Kings Coll London, London WC2R 2LS, England. Hlth Dev Agcy, London, England. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUN PY 2003 VL 82 SI B MA 2715 BP B350 EP B350 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA V42UY UT WOS:000202893603380 ER PT J AU Axelrod, DA Fendrick, AM Carlos, RC Lederman, RJ Froehlich, JB Weder, AB Abrahamse, PH Stanley, JC AF Axelrod, DA Fendrick, AM Carlos, RC Lederman, RJ Froehlich, JB Weder, AB Abrahamse, PH Stanley, JC TI Percutaneous stenting of incidental unilateral renal artery stenosis: Decision analysis of costs and benefits SO JOURNAL OF ENDOVASCULAR THERAPY LA English DT Article DE decision analysis; balloon angioplasty; stent; renal artery stenosis; cost comparison; Markov modeling ID ATHEROSCLEROTIC RENOVASCULAR DISEASE; BALLOON ANGIOPLASTY; BLOOD-PRESSURE; CARDIAC-CATHETERIZATION; ISCHEMIC NEPHROPATHY; RANDOMIZED TRIAL; VASCULAR-DISEASE; FOLLOW-UP; HYPERTENSION; REVASCULARIZATION AB Purpose: To determine the incremental cost-effectiveness of prophylactic percutaneous transluminal angioplasty with stent placement (PTA-S) in patients with incidentally discovered, asymptomatic renal artery stenosis (RAS) compared to delaying PTA-S until patients develop refractory hypertension or renal insufficiency (therapeutic PTA-S). Methods: The Markov decision analysis model was used to determine the incremental cost per quality adjusted life year (QALY) saved for prophylactic PTA-S as compared to therapeutic PTA-S in a hypothetical cohort of patients with 50% unilateral atherosclerotic RAS followed from age 61 to death. Results: Prophylactic PTA-S compared to therapeutic PTA-S results in more QALYs/patient (10.9 versus 10.3) at higher lifetime costs ($23,664 versus $16,558). The incremental cost effectiveness of prophylactic PTA-S was estimated to be $12,466/QALY. Prophylactic stenting was not cost effective (>$50,000/QALY) if the modeled incidence of stent restenosis exceeded 15%/year and the incidence of progression in the contralateral renal artery was <2% of arteries/year. Conclusions: PTA-S of incidental, asymptomatic unilateral RAS may improve patients' quality of life at an acceptable incremental cost. However, this technology should be used hesitantly until a randomized comparison confirms its effectiveness. C1 Univ Michigan, Med Ctr, Dept Surg, Ann Arbor, MI 48109 USA. Univ Michigan, Med Ctr, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Michigan, Med Ctr, Dept Radiol, Ann Arbor, MI 48109 USA. Univ Michigan, Med Ctr, Consortium Hlth Outcomes Innovat & Cost Effective, Ann Arbor, MI 48109 USA. NIH, Washington, DC USA. Univ Massachusetts, Sect Vasc Med, Worcester, MA USA. RP Axelrod, DA (reprint author), 6312 Med Sci Bldg 1,1150 W Med Ctr Dr, Ann Arbor, MI USA. NR 35 TC 7 Z9 8 U1 0 U2 0 PU ALLIANCE COMMUNICATIONS GROUP DIVISION ALLEN PRESS PI LAWRENCE PA 810 EAST 10TH STREET, LAWRENCE, KS 66044 USA SN 1526-6028 J9 J ENDOVASC THER JI J. Endovascular Ther. PD JUN PY 2003 VL 10 IS 3 BP 546 EP 556 DI 10.1583/1545-1550(2003)010<0546:PSOIUR>2.0.CO;2 PG 11 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 721FK UT WOS:000185306200021 PM 12932167 ER PT J AU Kelly, JB Lamb, ME AF Kelly, JB Lamb, ME TI Developmental issues in relocation cases involving young children: When, whether, and how? SO JOURNAL OF FAMILY PSYCHOLOGY LA English DT Review ID POSTDIVORCE ADJUSTMENT; INTERPARENTAL CONFLICT; RESIDENTIAL-MOBILITY; PARENTAL SEPARATION; NONRESIDENT FATHERS; JOINT-CUSTODY; DIVORCE; ATTACHMENT; METAANALYSIS; ARRANGEMENTS AB Many divorced parents seek the court's permission each year to move their children to a new location away from their other parents. Such moves stress and often disrupt psychologically important parent-child relationships, and this may in turn have adverse consequences for children. This article discusses the development of attachment relationships in infants and toddlers and the ways in which relocation is likely to affect young children of different ages; recent trends in judicial decisions regarding relocation; factors to consider when deciding whether or not to permit relocation; ways of promoting long-distance relationships between young children and their nonmoving parents; and implications for legal policy and clinical practice. C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP Kelly, JB (reprint author), POB 7063, Corte Madera, CA 94976 USA. NR 101 TC 30 Z9 30 U1 4 U2 16 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0893-3200 J9 J FAM PSYCHOL JI J. Fam. Psychol. PD JUN PY 2003 VL 17 IS 2 BP 193 EP 205 DI 10.1037/0893-3200.17.2.193 PG 13 WC Psychology, Clinical; Family Studies SC Psychology; Family Studies GA 691GM UT WOS:000183597700004 PM 12828016 ER PT J AU Ershow, AG AF Ershow, AG TI Research science, regulatory science, and nutrient databases: achieving an optimal convergence SO JOURNAL OF FOOD COMPOSITION AND ANALYSIS LA English DT Editorial Material DE nutrient databases; regulatory science; peer review; food composition research; National Food and Nutrient Analysis Program AB The compelling practical applications of nutrient databases, and the technical challenges in their development, often divert attention from their underlying research basis. Nutrient databases are, in fact, the publications of research projects that draw on the methodology of analytical chemistry, sampling statistics, and information technology in order to answer a core question: "What is the nutrient content of the food supply?" The responsibility for addressing this question, and for conducting the ensuing research, is typically assigned to governmental entities, especially for databases that are reflective of national food supplies. This responsibility reflects the key role of nutrient data in public health decision-making. At their best, nutrient databases can represent an optimal convergence of the characteristics of both "research science," which seeks to increase knowledge of natural phenomena and processes, and "regulatory science," which provides the knowledge base needed for policy-making and other government work. These two categories of research have many commonalities, such as their scientific methodology, even though they differ in their sites of performance and affiliated institutions, their operational procedures, and their standards of accountability. A good example of this convergence is found in the National Food and Nutrient Analysis Program and its various ancillary projects (databases on fluoride, choline, phytonutrients, Native American/Alaska Native foods, commodity foods, and dietary supplements). Confirmed validity of the findings, enhanced trust in the results, strengthened political and public support, and funding that underwrites the capacity for high scientific standards, are all potential benefits of acknowledging the simultaneous research and regulatory science aspects of nutrient databases. C1 US Dept HHS, NHLBI, Div Heart & Vasc Dis, NIH, Bethesda, MD 20892 USA. RP Ershow, AG (reprint author), US Dept HHS, NHLBI, Div Heart & Vasc Dis, NIH, 6701 Rockledge Dr,Suite 10-193,MSC 7956, Bethesda, MD 20892 USA. NR 23 TC 4 Z9 4 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1575 J9 J FOOD COMPOS ANAL JI J. Food Compos. Anal. PD JUN PY 2003 VL 16 IS 3 BP 255 EP 268 DI 10.1016/S0889-1575(03)00054-1 PG 14 WC Chemistry, Applied; Food Science & Technology SC Chemistry; Food Science & Technology GA 692NQ UT WOS:000183667500002 ER PT J AU Dixon, LB Zimmerman, TP Kahle, LL Subar, AF AF Dixon, LB Zimmerman, TP Kahle, LL Subar, AF TI Adding carotenoids to the NCI Diet History Questionnaire Database SO JOURNAL OF FOOD COMPOSITION AND ANALYSIS LA English DT Article DE carotenoids; diet assessment; Diet History Questionnaire; food frequency questionnaire; nutrient database ID FOOD FREQUENCY QUESTIONNAIRES; VALIDATION; VEGETABLES; FRUITS; CANCER; WOMEN AB Food frequency questionnaires (FFQ), like the Diet History Questionnaire (DHQ) developed by researchers at the National Cancer Institute (NCI), are commonly used to estimate long-term total daily energy and nutrient intake. However, the methodology used to create the database to determine dietary intake varies by FFQ and is often a "black box" to researchers. This brief communication discusses how we added values for carotenoids (alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein/zeaxanthin, lycopene) to the NCI DHQ database. The NCI DHQ database is based on intake of 4220 foods from 24-h dietary recalls of adult participants in the 1994-96 Continuing Survey of Food Intakes by Individuals (CSFII). These 4220 foods are categorized into 255 food groups consistent with line items on the NCI DHQ. Given the extensive number of foods from CSFII used to create the NCI DHQ database, we used the University of Minnesota Nutrition Data System for Research (NDS-R) that has values for the carotenoids in mug/100g units for approximately 18,000 foods, 8000 brand name products, and many ethnic foods. We matched foods in the NDS-R database to the 4220 CSFII foods according to the detailed description of the foods and their energy and nutrient content. We re-evaluated the matches of certain foods that had estimates of energy, fat, and other nutrients from the NDS-R that differed from the respective CSFII values. Data files with the latest NCI DHQ database that contains the carotenoids are now available at http://riskfactor.cancer.gov/DHQ. C1 NYU, Dept Nutr & Food Studies, New York, NY 10012 USA. Westat Corp, Rockville, MD USA. Informat Management Serv Inc, Silver Spring, MD USA. NCI, NIH, Bethesda, MD 20892 USA. RP Dixon, LB (reprint author), NYU, Dept Nutr & Food Studies, 35 W,4th St,10th Floor, New York, NY 10012 USA. NR 17 TC 21 Z9 21 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 0889-1575 J9 J FOOD COMPOS ANAL JI J. Food Compos. Anal. PD JUN PY 2003 VL 16 IS 3 BP 269 EP 280 DI 10.1016/S0889-1575(03)00051-6 PG 12 WC Chemistry, Applied; Food Science & Technology SC Chemistry; Food Science & Technology GA 692NQ UT WOS:000183667500003 ER PT J AU Pennington, JAT AF Pennington, JAT TI National Institutes of Health (NIH) activities concerning nutrition research related to food composition databases SO JOURNAL OF FOOD COMPOSITION AND ANALYSIS LA English DT Article DE nutrition research; NIH; food composition databases AB Approximately 4% of the research expenditures for the US National Institutes of Health (NIH) is used to support nutrition research and training within NIH laboratories (intramural program) and in research institutions in the US and abroad (extramural program). In fiscal year (FY) 2000, the funding for NIH nutrition research and training was $694.9 million for 3150 projects. The research areas are broad and include the functions of nutrients and other food components in biological systems, the dietary intakes needed to prevent disease and/or promote optimal health, variables that affect nutrient functions and requirements, and genetic differences in needs and responses. The results of the many nutrition research projects and programs may help the Agriculture Research Service (ARS) of the US Department of Agriculture (USDA) establish priorities for analyzing food components and including them in USDA food composition databases. NIH research projects are described and tracked through the Human Nutrition Research Information Management (HNRIM) system. A recent search for the key word antioxidants, food components of great interest to database developers and users, identified 131 projects, many with direct relevance to specific foods. NIH, along with other government agencies, provides financial support for the ARS, USDA National Food and Nutrient Analysis Program (NFNAP), which began in 1997. NIH support for NFNAP amounted to $1850000 in FY 2001. NIH is currently providing support for four NFNAP complementary databases: Native American foods, USDA commodity foods, choline, and fluoride. NIH provides support for segments of the National Health and Nutrition Examination Survey (NHANES) conducted by the National Center for Health Statistics (NCHS). NIH support for NHANES was about $5.3 million in FY 2001 (about 12.4% of FY 2001 costs for the survey), and discussions are underway to assure continued NIH support for this survey. C1 NIH, Div Nutr Res Coordinat, Bethesda, MD 20892 USA. RP Pennington, JAT (reprint author), NIH, Div Nutr Res Coordinat, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 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 0889-1575 J9 J FOOD COMPOS ANAL JI J. Food Compos. Anal. PD JUN PY 2003 VL 16 IS 3 BP 359 EP 364 DI 10.1016/S0889-1575(03)00027-9 PG 6 WC Chemistry, Applied; Food Science & Technology SC Chemistry; Food Science & Technology GA 692NQ UT WOS:000183667500014 ER PT J AU McDermott, MM Greenland, P Guralnik, JM Liu, K Criqui, MH Pearce, WH Chan, C Schneider, J Sharma, L Taylor, LM Arseven, A Quann, M Celic, L AF McDermott, MM Greenland, P Guralnik, JM Liu, K Criqui, MH Pearce, WH Chan, C Schneider, J Sharma, L Taylor, LM Arseven, A Quann, M Celic, L TI Depressive symptoms and lower extremity functioning in men and women with peripheral arterial disease SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT National Meeting of the Society-of-General-Internal-Medicine CY MAY 04, 2002 CL ATLANTA, GEORGIA SP Soc General Internal Med DE depression; peripheral vascular disease; physical functioning ID CHRONIC HEART-FAILURE; PRIMARY-CARE PATIENTS; PHYSICAL-DISABILITY; OLDER ADULTS; CARDIOVASCULAR HEALTH; TREADMILL WALKING; IMMUNE-SYSTEM; 6-MINUTE WALK; ASSOCIATION; CRITERIA AB OBJECTIVE: Factors associated with impaired functioning in patients with lower extremity peripheral arterial disease (PAD) are not fully understood. The purpose of this study was to determine the relationship between depressive symptoms and objective measures of lower extremity functioning in persons with PAD. DESIGN: Cross-sectional. PATIENTS/PARTICIPANTS: Four hundred twenty-three men and women with PAD identified from 3 Chicago area medical centers. MEASUREMENTS AND MAIN RESULTS: PAD was defined as ankle brachial index (ABI) <0.90. The Geriatric Depression Scale short form (GDS-S) (0-15 scale, 15 = worst) was completed by all participants. A clinically significant number of depressive symptoms was defined as a GDS-S score &GE;6. Six-minute walk distance and usual-and fast-pace walking velocity were determined for all participants. A GDS-S score &GE;6 was present in 21.7% of participants with PAD. Adjusting for age, increasing numbers of depressive symptoms were associated with an increasing prevalence of leg pain on exertion and rest (P = .004). Adjusting for age, sex, race, ABI, number of comorbidities, current smoking, and antidepressant medications, increasing numbers of depressive symptoms were associated with shorter 6-minute walk distance (P < .001), slower usual-pace walking velocity (P = .005), and slower fast-pace walking velocity (P = .005). These relationships were attenuated slightly after additional adjustment for presence versus absence of leg pain on exertion and rest and severity of exertional leg symptoms. CONCLUSIONS: Among men and women with PAD, the prevalence of a clinically significant number of depressive symptoms is high. Greater numbers of depressive symptoms are associated with greater impairment in lower extremity functioning. Further study is needed to determine whether identifying and treating depressive symptoms in PAD is associated with improved lower extremity functioning. C1 Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. Northwestern Univ, Div Vasc Surg, Feinberg Sch Med, Dept Surg, Chicago, IL 60611 USA. NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. Northwestern Univ, Evanston Hosp, Div Vasc Surg, Dept Surg, Evanston, IL 60201 USA. Oregon Hlth Sci Med Ctr, Div Vasc Surg, Dept Surg, Portland, OR USA. RP McDermott, MM (reprint author), 675 N St Clair,Suite 18-200, Chicago, IL 60611 USA. FU NCRR NIH HHS [M01 RR000048, RR-00048]; NHLBI NIH HHS [R01-HL58099] NR 36 TC 56 Z9 56 U1 0 U2 7 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 JUN PY 2003 VL 18 IS 6 BP 461 EP 467 DI 10.1046/j.1525-1497.2003.20527.x PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 694VP UT WOS:000183796100007 PM 12823653 ER PT J AU Nyska, A Glovinsky, Y Belkin, M Epstein, Y AF Nyska, A Glovinsky, Y Belkin, M Epstein, Y TI Biocompatibility of the Ex-PRESS miniature glaucoma drainage implant SO JOURNAL OF GLAUCOMA LA English DT Article DE aqueous shunts; biocompatibility; drainage device; glaucoma ID DIFFERENT BIOMATERIALS; REFRACTORY GLAUCOMA; FILTERING SURGERY; MOLTENO IMPLANT; DEVICES; TRABECULECTOMY; TITANIUM; MODEL AB Purpose: Based on lessons learned from earlier attempts, a novel miniature glaucoma implant, Ex-PRESS, was developed in 1998. The current study summarizes the histopathologic evaluation of this device implanted in the eyes of rabbits. Methods: The device was implanted into the anterior chamber at the corneoscleral junction in 1 eye each of 8 white New Zealand rabbits, while the contralateral eye served as control. Three and 6 months after implantation, the rabbits were killed and their eyes were enucleated and processed histologically, leaving the device in situ when sectioning. Results: Three and 6 months postoperatively, the local tissue reaction typically consisted of an enveloping, thin, mature, fibrotic capsule (thickness <0.04 mm), devoid of inflammatory cells. This capsule surrounded approximately 25% of the implant surface area present in the sections. The lumina of the devices were devoid of inflammatory exudates or other obstructions in all specimens examined, suggesting free flow of fluid. Conclusions: The implantation of the Ex-PRESS miniature glaucoma shunt resulted in minimal capsular reaction. Considering the high reactivity of the rabbit eye, it is possible that this implant will induce a smaller cellular inflammatory reaction in the human eye. C1 NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. Tel Aviv Univ, Goldshleger Eye Res Inst, Tel Hashomer, Israel. Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. RP Belkin, M (reprint author), NIEHS, Lab Expt Pathol, POB 12233, Res Triangle Pk, NC 27709 USA. NR 22 TC 48 Z9 56 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1057-0829 J9 J GLAUCOMA JI J. Glaucoma PD JUN PY 2003 VL 12 IS 3 BP 275 EP 280 DI 10.1097/00061198-200306000-00017 PG 6 WC Ophthalmology SC Ophthalmology GA 690UH UT WOS:000183568000017 PM 12782849 ER PT J AU Scuteri, A Najjar, S Lakatta, EG AF Scuteri, A Najjar, S Lakatta, EG TI Metabolic alterations in isolated systolic hypertension in the elderly SO JOURNAL OF HYPERTENSION LA English DT Meeting Abstract CT 13th European Meeting on Hypertension CY JUN 13-17, 2003 CL MILAN, ITALY SP European Soc Hypertens C1 INRCA, Rome, Italy. NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 2003 VL 21 SU 4 BP S279 EP S280 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 705QT UT WOS:000184406700985 ER PT J AU Sharabi, Y Pacak, K Eisenhofer, G McElroy, B Chun, J Goldstein, DS AF Sharabi, Y Pacak, K Eisenhofer, G McElroy, B Chun, J Goldstein, DS TI Blood pressure and hemodynamics profile of pheochromocytoma: Lessons from 24 hour blood pressure monitoring and pulse wave form analysis SO JOURNAL OF HYPERTENSION LA English DT Meeting Abstract CT 13th European Meeting on Hypertension CY JUN 13-17, 2003 CL MILAN, ITALY SP European Soc Hypertens C1 Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 2003 VL 21 SU 4 BP S214 EP S214 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 705QT UT WOS:000184406700747 ER PT J AU Sharabi, Y Zimlichman, R Huynh, T Mansouri, R Chun, J Eisenhofer, G Alesci, S Pacak, K Goldstein, DS AF Sharabi, Y Zimlichman, R Huynh, T Mansouri, R Chun, J Eisenhofer, G Alesci, S Pacak, K Goldstein, DS TI Epinephrine response to glucagon characterizes pheochrmocytoma cells and not normal chromaffin cells: Study of primary bovine adrenomedullary cells SO JOURNAL OF HYPERTENSION LA English DT Meeting Abstract CT 13th European Meeting on Hypertension CY JUN 13-17, 2003 CL MILAN, ITALY SP European Soc Hypertens C1 NIH, Bethesda, MD 20892 USA. E Wolfson Med Ctr, Holon, Israel. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 2003 VL 21 SU 4 BP S142 EP S143 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 705QT UT WOS:000184406700489 ER PT J AU Yang, XY Jiang, HG Hartmann, WK Mitra, G Soman, G AF Yang, XY Jiang, HG Hartmann, WK Mitra, G Soman, G TI Development of a quantitative antigen-specific cell-based ELISA for the 7G7/B6 monoclonal antibody directed toward IL-2R alpha SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE IL-2R alpha; antibody; 7G7/B6; CbELISA; assay validation ID LINKED-IMMUNOSORBENT-ASSAY; INTERLEUKIN-2 RECEPTOR TAC; CARDIAC ALLOGRAFT SURVIVAL; HUMAN IL-2 RECEPTOR; HUMANIZED ANTIBODY; SURFACE-ANTIGENS; BETA-CHAIN; VIABLE CELLS; GAMMA-CHAIN; LEUKEMIA AB Interleukin-2 receptor alpha (IL-2Ralpha, CD25) has been identified as a valuable target for immunotherapy. The 7G7/136 monoclonal antibody, a mouse IgG2alpha kappa, recognizes an epitope of the IL-2Ralpha peptide, other than that identified by anti-Tac. This antibody is currently being explored for potential therapeutic and diagnostic applications. Here, we show a cell-based enzyme-linked immunosorbent assay (CbELISA) method for quantitative measurement of the binding activity of the 7G7/B6 antibody to the Kit-225-iG3 cell line expressing IL-2Ralpha antigen on the cell surface. The cell- and antigen-specificity of the assay was established using specific cell lines and irrelevant control antibodies. Satisfactory binding curves were demonstrated with Kit-225-iG3 cells grown between 3 and 25 passages in culture and at seed densities of 2 x 10(5)-4 X 10(6) cells/well. The assay shows reproducible dose-response curves in the concentration range of 10-1000 ng/ml. The assay validation data presented here indicate that this CbELISA assay is quantitative, reproducible, robust, precise, and can be used to test the biological activity, lot to lot comparison, and stability of 7G7/B6 monoclonal antibody. (C) 2003 Elsevier Science B.V. All rights reserved. C1 SAIC Frederick Inc, Natl Canc Inst, Biopharmaceut Dev Program, Bioanalyt Dev Lab, Frederick, MD 21702 USA. RP Soman, G (reprint author), SAIC Frederick Inc, Natl Canc Inst, Biopharmaceut Dev Program, Bioanalyt Dev Lab, Bldg 458,Room 17,POB B, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400] NR 51 TC 8 Z9 11 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD JUN 1 PY 2003 VL 277 IS 1-2 BP 87 EP 100 DI 10.1016/S0022-1759(03)00178-9 PG 14 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 692LD UT WOS:000183661800008 PM 12799042 ER PT J AU Aliberti, J Viola, JPB Vieira-de-Abreu, A Bozza, PT Sher, A Scharfstein, J AF Aliberti, J Viola, JPB Vieira-de-Abreu, A Bozza, PT Sher, A Scharfstein, J TI Cutting edge: Bradykinin induces IL-12 production by dendritic cells: A danger signal that drives Th1 polarization SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TRYPANOSOMA-CRUZI; IMMUNE-SYSTEM; RECEPTOR; KININS; FAMILY AB Dendritic cells play a major role in the induction of both innate and acquired immune responses against pathogenic invaders. These cells are also able to sense endogenous activation signals liberated by injured tissues even in the absence of infection. In the present work, we demonstrate. that kinins mobilize dendritic cells to produce IL-12 through activation of the B-2 bradykinin receptor subtype and that bradykinin-induced IL-12 responses are tightly regulated both by angiotensin-converting enzyme, a kinin-degrading peptidase, and by endogenous IL-10. Using a mouse model of allergic inflammation, we further show that addition of bradykinin to OVA during immunization results in decreased eosinophil infiltration on Ag challenge. The latter effect was demonstrated to be due to IL-12-driven skewing of Ag-specific T cell responses to a type 1 cytokine profile. Our data thus indicate that kinin peptides can serve as danger signals that trigger dendritic cells to produce IL-12 through activation of B-2 bradykinin receptors. C1 Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Lab Mol Immunol, BR-21944900 Rio De Janeiro, Brazil. NIAID, Parasit Dis Lab, Immunobiol Sect, NIH, Bethesda, MD 20892 USA. Fdn Osawaldo Cruz, Inst Nacl Canc, Div Expt Med, Rio De Janeiro, Brazil. Fdn Osawaldo Cruz, Inst Oswaldo Cruz, Dept Fisiol L& Farmacodinam, Rio De Janeiro, Brazil. RP Scharfstein, J (reprint author), Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Lab Mol Immunol, BR-21944900 Rio De Janeiro, Brazil. RI Aliberti, Julio/G-4565-2012; Aliberti, Julio/I-7354-2013; OI Aliberti, Julio/0000-0003-3420-8478; Bozza, Patricia/0000-0001-8349-9529 NR 18 TC 66 Z9 68 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 JUN 1 PY 2003 VL 170 IS 11 BP 5349 EP 5353 PG 5 WC Immunology SC Immunology GA 681UY UT WOS:000183055000002 PM 12759407 ER PT J AU Kopp, T Lenz, P Bello-Fernandez, C Kastelein, RA Kupper, TS Stingl, G AF Kopp, T Lenz, P Bello-Fernandez, C Kastelein, RA Kupper, TS Stingl, G TI IL-23 production by cosecretion of endogenous p19 and transgenic p40 in keratin 14/p40 transgenic mice: Evidence for enhanced cutaneous immunity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EPIDERMAL LANGERHANS CELLS; DENDRITIC CELLS; IN-VIVO; T-CELLS; INTERLEUKIN-12; IL-12; RESPONSES; CYTOKINE; SKIN; INFLAMMATION AB p40, the common subunit of the proinflammatory cytokines IL-12 and IL-23, is produced by resident skin cells. Whereas the in vivo effects of IL-12 are well established, little is known about the role of IL-23 in cutaneous immune responses. In this study we show that p40 transgenic TG mice constitutively produce IL-23 (p19/p40), but not IL-12 (p35/p40), in basal keratinocytes by cosecretion of TG p40 with endogenous p19. Repeated injections of rIL-23 in littermate (LM) mice result in an inflammatory skin disease similar to that of p40 TG mice, confirming the proinflammatory activity of IL-23. Furthermore, IL-23 secretion by p40 TG keratinocytes induces elevated numbers of Langerhans cells (LC) with a marked up-regulation of costimulatory molecules, indicating advanced maturation of keratin 14 (K14)/p40 LC when compared with LM LC. At the functional level, freshly isolated K14/p40 LC greatly exceeded LC from LM animals in their capacity to stimulate allogeneic T cell proliferation. To assess whether IL-23 regulates cutaneous immune responses in vivo, we used an allogeneic skin transplantation model. Full thickness skin grafts from K14/p40 donors (H-2(q)) transplanted across a MHC class I and class II barrier onto BALB/c (H-2(d)) recipients were rejected in a significantly accelerated fashion (mean survival time: 8.8 days) when compared with skin grafts from non-TG LM (H-2(q)) (mean survival time: 10.7 days,p < 0.01). Based on these results we propose that IL-23-induced changes of LC may be an important mechanism in directing the outcome of cutaneous immune responses. C1 Univ Vienna, Sch Med,Vienna Int Res Cooperat Ctr, Dept Dermatol, Div Immunol Allergy & Infect Dis, A-1090 Vienna, Austria. Univ Vienna, Sch Med,Vienna Int Res Cooperat Ctr, Vienna Int Res Cooperat Ctr, Inst Immunol, A-1090 Vienna, Austria. NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. DNAX Res Inst Mol & Cellular Biol Inc, Palo Alto, CA 94304 USA. Harvard Skin Dis Res Ctr, Boston, MA 02115 USA. RP Kopp, T (reprint author), Univ Vienna, Sch Med,Vienna Int Res Cooperat Ctr, Dept Dermatol, Div Immunol Allergy & Infect Dis, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. NR 37 TC 76 Z9 78 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 JUN 1 PY 2003 VL 170 IS 11 BP 5438 EP 5444 PG 7 WC Immunology SC Immunology GA 681UY UT WOS:000183055000014 PM 12759419 ER PT J AU Winter, DB Phung, QH Zeng, XM Seeberg, E Barnes, DE Lindahl, T Gearhart, PJ AF Winter, DB Phung, QH Zeng, XM Seeberg, E Barnes, DE Lindahl, T Gearhart, PJ TI Normal somatic hypermutation 8-hydroxyguanine-DNA of Ig genes in the absence of glycosylase SO JOURNAL OF IMMUNOLOGY LA English DT Article ID DOUBLE-STRAND BREAKS; B-CELL LINE; IMMUNOGLOBULIN VARIABLE GENES; 8-OXOGUANINE DNA GLYCOSYLASE; MISMATCH REPAIR PROTEIN; CYTIDINE DEAMINASE AID; MUTATIONAL SPECTRA; DEFICIENT MICE; BASE DAMAGE; OGG1 GENE AB The hypermutation cascade in Ig V genes can be initiated by deamination of cytosine in DNA to uracil by activation-induced cytosine deaminase and its removal by uracil-DNA glycosylase. To determine whether damage to guanine also contributes to hypermutation, we examined the glycosylase that removes oxidized guanine from DNA, 8-hydroxyguanine-DNA glycosylase (OGG1). OGG1 has been reported to be overexpressed in human B cells from germinal centers, where mutation occurs, and could be involved in initiating Ab diversity by removing modified guanines. In this study, mice deficient in Ogg1 were immunized, and V genes from the H and kappa L chain loci were sequenced. Both the frequency of mutation and the spectra of nucleotide substitutions were similar in ogg1(-/-) and Ogg1(+/+) clones. More importantly, there was no significant increase in G:C to T:A transversions in the ogg1(-/-) clones, which would be expected if 8-hydroxyguanine remained in the DNA. Furthermore, Ogg1 was not up-regulated in murine B cells from germinal centers. These findings show that hypermutation is unaffected in the absence of Ogg1 activity and indicate that 8-hydroxyguanine lesions most likely do not cause V gene mutations. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Univ Oslo, Natl Hosp, Inst Med Microbiol, Dept Biol Mol, Oslo, Norway. Canc Res UK, Clare Hall Labs, London Res Inst, London, England. RP Gearhart, PJ (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 52 TC 15 Z9 15 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 JUN 1 PY 2003 VL 170 IS 11 BP 5558 EP 5562 PG 5 WC Immunology SC Immunology GA 681UY UT WOS:000183055000028 PM 12759433 ER PT J AU Gasche, C Grundtner, P Zwirn, P Reinisch, W Shaw, SH Zdanov, A Sarma, U Williams, LM Foxwell, BM Gangl, A AF Gasche, C Grundtner, P Zwirn, P Reinisch, W Shaw, SH Zdanov, A Sarma, U Williams, LM Foxwell, BM Gangl, A TI Novel variants of the IL-10 receptor 1 affect inhibition of monocyte TNF-alpha production SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; RECOMBINANT HUMAN INTERLEUKIN-10; ACTIVE CROHNS-DISEASE; CHRONIC ENTEROCOLITIS; CRYSTAL-STRUCTURE; HUMAN GUT; GENE; MICE; MACROPHAGES; EXPRESSION AB IL-10-deficient mice exhibit spontaneous enterocolitis and other symptoms akin to Crohn's disease, indicating that IL-10 might regulate normal physiology in the gut. However, clinical trials with IL-10 in Crohn's disease were disappointing, although some patients showed healing of intestinal mucosa. This study searched for genetic polymorphisms within the IL-10 pathway. We decided to screen for mutations of the IL-10R1 cDNA in healthy volunteers and Crohn's disease patients and identified two novel variants: a serine 138-to-glycine (S138G) and a glycine 330-to-arginine (G330R) substitution. The allelic frequency in a European cohort was relatively high (16% for the S138G and 33% for the G330R), and S138G was in strong linkage disequilibrium with G330R. A similar allele frequency was found in a group of Crohn's patients. In IL-10R1 G330R-expressing monocytes, the inhibitory effect of IL-10 on TNF-alpha production was diminished, indicating that this variant may be a loss-of-function allele. No such difference was observed between haplotypes 4 (G330R only) and 7 (S138G and G330R). In addition, these IL-10R1 variants had no influence on the IL-10R1 expression density. Structural analysis of the S138G variant revealed that the substitution of S138G may interfere with binding of IL-10 to IL-10R1. C1 Univ Vienna, Dept Med 4, Div Gastroenterol & Hepatol, Vienna, Austria. DNA Sci Inc, Fremont, CA 94555 USA. NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. Univ London Imperial Coll Sci Technol & Med, Kennedy Inst Rheumatol, London, England. RP Gasche, C (reprint author), Gen Hosp Vienna, Dept Med 4, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. RI Gasche, Christoph/A-5139-2013 NR 40 TC 50 Z9 54 U1 1 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 JUN 1 PY 2003 VL 170 IS 11 BP 5578 EP 5582 PG 5 WC Immunology SC Immunology GA 681UY UT WOS:000183055000031 PM 12759436 ER PT J AU Boyaka, PN Tafaro, A Fischer, R Leppla, SH Fniihashi, K McGhee, JR AF Boyaka, PN Tafaro, A Fischer, R Leppla, SH Fniihashi, K McGhee, JR TI Effective mucosal immunity to anthrax: Neutralizing antibodies and Th cell responses following nasal immunization with protective antigen SO JOURNAL OF IMMUNOLOGY LA English DT Article ID BACILLUS-ANTHRACIS; INHALATIONAL ANTHRAX; CHOLERA-TOXIN; CPG DNA; B-CELL; RHESUS MACAQUES; LETHAL TOXIN; ORAL VACCINE; EDEMA FACTOR; GUINEA-PIGS AB Mucosal, but not parenteral, immunization induces immune responses in both systemic and secretory immune compartments. Thus, despite the reports that Abs to the protective Ag of anthrax (PA) have both anti-toxin and anti-spore activities, a vaccine administered parenterally, such as the aluminum-adsorbed anthrax vaccine, will most likely not induce the needed mucosal immunity to efficiently protect the initial site of infection with inhaled anthrax spores. We therefore took a nasal anthrax vaccine approach to attempt to induce protective immunity both at mucosal surfaces and in the peripheral immune compartment. Mice nasally immunized with recombinant PA (rPA) and cholera toxin (CT) as mucosal adjuvant developed high plasma PA-specific IgG Ab responses. Plasma IgA Abs as well as secretory IgA anti-PA Abs in saliva, nasal washes, and fecal extracts were also induced when a higher dose of rPA was used. The anti-PA IgG subclass responses to nasal rPA plus CT consisted of IgG1 and IgG2b Abs. A more balanced profile of IgG subclasses with IgG1, IgG2a, and IgG2b Abs was seen when rPA was given with a CpG oligodeoxynucleotide as adjuvant, suggesting a role for the adjuvants in the nasal rPA-induced immunity. The PA-specific CD4(+) T cells from mice nasally immunized with rPA and CT as adjuvant secreted low levels of CD4(+) Th1-type cytokines in vitro, but exhibited elevated IL-4, IL-5, IL-6, and IL-10 responses. The functional significance of the anti-PA Ab responses was established in an in vitro macrophage toxicity assay in which both plasma and mucosal secretions neutralized the lethal effects of Bacillus anthracis toxin. C1 Univ Alabama, Dept Oral Biol, Birmingham, AL 35294 USA. NIAID, Microbial Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. RP Boyaka, PN (reprint author), Univ Alabama, Vaccine Ctr, Dept Microbiol & Immunol, BBRB 761,845,19th St South, Birmingham, AL 35294 USA. FU NIAID NIH HHS [N01AI65299, AI43197, AI18958]; NIDCD NIH HHS [DC04976]; NIDCR NIH HHS [DE098837, DE12242]; NIDDK NIH HHS [P30DK54781, DK44240] NR 55 TC 100 Z9 105 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 JUN 1 PY 2003 VL 170 IS 11 BP 5636 EP 5643 PG 8 WC Immunology SC Immunology GA 681UY UT WOS:000183055000039 PM 12759444 ER PT J AU Singer, LM Mirel, LB ter Kuile, FO Branch, OH Vulule, JM Kolczak, MS Hawley, WA Kariuki, SK Kaslow, DC Lanar, DE Lal, AA AF Singer, LM Mirel, LB ter Kuile, FO Branch, OH Vulule, JM Kolczak, MS Hawley, WA Kariuki, SK Kaslow, DC Lanar, DE Lal, AA TI The effects of varying exposure to malaria transmission on development of antimalarial antibody responses in preschool children. XVI. Asembo Bay Cohort Project SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 10th International Congress on Infectious Diseases CY MAR, 2002 CL SINGAPORE, SINGAPORE ID MEROZOITE SURFACE PROTEIN-1; TREATED BED NETS; PLASMODIUM-FALCIPARUM TRANSMISSION; CARBOXYL-TERMINAL FRAGMENT; B-CELL EPITOPES; CIRCUMSPOROZOITE PROTEIN; WESTERN KENYA; 19-KILODALTON DOMAIN; LONGITUDINAL COHORT; INOCULATION RATES AB In areas of intense malaria transmission, malaria morbidity and mortality is highest in children 3-18 months old. Interventions that reduce malaria exposure early in life reduce morbidity but may also delay development of clinical immunity. We assessed the relationship between intensity of malaria exposure and development of antibody responses. Thirty-nine children were monitored monthly, from birth to greater than or equal to2.5 years old (1238 observations), and were divided into 3 exposure categories, on the basis of parasitemic episodes or entomological data. Children with low exposure during the first 2 years of life had higher subsequent levels of antibody to merozoite surface protein-1(19-kDa) (a marker of blood-stage responses) by months 24-35 (P<.05). This inverse relationship decreased as children aged. There was no consistent relationship between exposure early in life and subsequent levels of antibody to circumsporozoite protein (a marker of sporozoite-stage responses). These data suggest that, in areas of intense malaria transmission, during the first 3 years of life, interventions that either reduce the number of asexual parasitemic episodes or lower entomological exposure do not delay the development of antibody responses to blood-stage malarial antigens. C1 Ctr Dis Control & Prevent, Mol Vaccine Sect, Div Parasit Dis, Natl Ctr Infect Dis, Atlanta, GA 30341 USA. Kenya Govt Med Res Ctr, Ctr Vector Biol & Control Res, Kisumu, Kenya. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Walter Reed Army Inst Res, Dept Immunol, Silver Spring, MD USA. RP Lal, AA (reprint author), Ctr Dis Control & Prevent, Mol Vaccine Sect, Div Parasit Dis, Natl Ctr Infect Dis, 4700 Buford Hwy, Chamblee, GA 30341 USA. EM alal@cdc.gov RI Lanar, David/B-3560-2011 NR 42 TC 14 Z9 14 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 1 PY 2003 VL 187 IS 11 BP 1756 EP 1764 DI 10.1086/375241 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 685TK UT WOS:000183279200010 PM 12751033 ER PT J AU Mbulaiteye, SM Pfeiffer, RM Whitby, D Brubaker, GR Shao, J Biggar, RJ AF Mbulaiteye, SM Pfeiffer, RM Whitby, D Brubaker, GR Shao, J Biggar, RJ TI Human herpesvirus 8 infection within families in rural Tanzania SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 5th International Workshop on Kaposi-Sarcoma-Associated Herpesvirus and Related Agents CY AUG 07-11, 2002 CL KLOSTER IRSEE, GERMANY ID SARCOMA-ASSOCIATED HERPESVIRUS; KAPOSIS-SARCOMA; HUMAN-HERPESVIRUS-8 INFECTION; SEXUAL TRANSMISSION; DNA-SEQUENCES; POPULATION; ANTIBODIES; CHILDREN; AFRICA; WOMEN AB Human herpesvirus 8 (HHV-8) infection is common in Africa. We examined the distribution of HHV-8 within families in rural Tanzania to determine routes of spread. HHV-8 infection was assessed by measuring antibody reactivity with a K8.1 (lytic-phase antigen) immunoassay. The prevalence increased from 3.7% (1/27) among infants to 58.1% (36/62) among children aged 3-4 years and 89.0% (65/73) among adults aged greater than or equal to45 years. Women with HHV-8-seropositive husbands had a 7-fold risk for infection (odds ratio [OR], 6.9; 95% confidence interval [CI], 1.9-25.3). HHV-8 seropositivity in children was associated with having at least 1 seropositive first-degree relative (OR, 14.7; 95% CI, 5.9-43.1), a seropositive mother (OR, 7.4; 95% CI, 3.2-16.8), a seropositive father (OR, 4.8; 95% CI, 2.3-10.1), or a seropositive next-older sibling (OR, 4.2; 95% CI, 1.9-9.4). Our data are consistent with the occurrence of HHV-8 transmission within families, from mothers and other relatives to children via nonsexual routes and between spouses via sexual routes. C1 NCI, Div Can Epidemiol & Genet, Bethesda, MD 20892 USA. Sci Applicat Int Corp, Viral Epidemiol Sect, AIDS Vaccine Program, Frederick, MD USA. NCI, Frederick, MD 21701 USA. Shirati Hosp, Shirati, Tanzania. Kilimanjaro Christian Med Ctr, Moshi, Tanzania. RP Mbulaiteye, SM (reprint author), 6120 Execut Blvd,Execut Plaza S,Rm 8007,Mail Sto, Rockville, MD 20852 USA. RI Pfeiffer, Ruth /F-4748-2011 FU NCI NIH HHS [N01-CO-12400] NR 31 TC 87 Z9 94 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 JUN 1 PY 2003 VL 187 IS 11 BP 1780 EP 1785 DI 10.1086/374973 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 685TK UT WOS:000183279200013 PM 12751036 ER PT J AU Chandrasekharappa, SC Teh, BT AF Chandrasekharappa, SC Teh, BT TI Functional studies of the MEN1 gene SO JOURNAL OF INTERNAL MEDICINE LA English DT Article DE Jun D; menin; multiple endocrine neoplasia type 1 (MEN1); nuclear localization; protein interaction; tumour suppressor ID MULTIPLE ENDOCRINE NEOPLASIA; JUND-ACTIVATED TRANSCRIPTION; METASTASIS SUPPRESSOR NM23; TYPE-1 GENE; EXPRESSION ANALYSIS; MURINE HOMOLOG; PROTEIN; PRODUCT; INTERACTS; TRANSACTIVATION AB Multiple endocrine neoplasia type 1 is an autosomal dominant cancer syndrome affecting primarily parathyroid, enteropancreatic endocrine and pituitary tissues. The inactivating germline and somatic mutations spread throughout the gene and the accompanying loss of the second allele in tumours show that the MEN1 gene is a tumour suppressor. The MEN1 -encoded protein, menin, is a novel nuclear protein. Menin binds and alters JunD-, NF-kappaB-, Smad3-mediated transcriptional activation. The mouse Men1 knockout model mimicks the human MEN1 condition contributing to the understanding of tumorigenesis in MEN1. C1 NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Van Andel Res Inst, Canc Genet Lab, Grand Rapids, MI USA. RP Chandrasekharappa, SC (reprint author), NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NR 40 TC 46 Z9 54 U1 2 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 2003 VL 253 IS 6 BP 606 EP 615 DI 10.1046/j.1365-2796.2003.01165.x PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 680ZY UT WOS:000183011000004 PM 12755956 ER PT J AU Chen, JD Morrison, C Zhang, C Kahnoski, K Carpten, JD Teh, BT AF Chen, JD Morrison, C Zhang, C Kahnoski, K Carpten, JD Teh, BT TI Hyperparathyroidism-jaw tumour syndrome SO JOURNAL OF INTERNAL MEDICINE LA English DT Article DE HRPT2; hyperparathyroidism; jaw tumour; Parafibromin ID FAMILIAL ISOLATED HYPERPARATHYROIDISM; MULTIPLE ENDOCRINE NEOPLASIA; HEREDITARY HYPERPARATHYROIDISM; PARATHYROID CARCINOMA; STROMAL TUMOR; FIBROMA; KIDNEY; HRPT2; 1Q21-Q32; SPECTRUM AB Amongst hyperparathyroidism-related syndromes, hyperparathyroidism-jaw tumour syndrome is one of the least common and relatively unknown but its clinical and genetic aspects are not less interesting or important. With the recent identification of its genes, we can now better characterize the disease, both clinically and genetically, which will certainly impact the field of endocrinology and oncology. In this article, we review the clinico-pathological features and genetic basis of this syndrome with the hope that it will create awareness and interest in this disease amongst clinicians and basic scientists. C1 Van Andel Res Inst, Canc Genet Lab, Grand Rapids, MI 49503 USA. Ohio State Univ, Dept Pathol, Ctr Comprehens Canc, Columbus, OH 43210 USA. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Teh, BT (reprint author), Van Andel Res Inst, Canc Genet Lab, 333 Bostwick NE, Grand Rapids, MI 49503 USA. NR 36 TC 57 Z9 57 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 2003 VL 253 IS 6 BP 634 EP 642 DI 10.1046/j.1365-2796.2003.01168.x PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 680ZY UT WOS:000183011000007 PM 12755959 ER PT J AU Gabel, SA Chen, J Petranka, JG Yamamura, K Walker, VR London, RE Korach, KS Steenbergen, C Murphy, E AF Gabel, SA Chen, J Petranka, JG Yamamura, K Walker, VR London, RE Korach, KS Steenbergen, C Murphy, E TI Estrogen receptor beta mediates gender differences in ischemia reperfusion injury SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Meeting Abstract CT 25th Annual Meeting of the North American Section of the International-Society-for-Heart-Research CY JUN 28-JUL 01, 2003 CL MYSTIC, CT SP Int Soc Heart Res, N Amer Sect C1 NIEHS, Lab Signal Transduct & Reprod, Res Triangle Pk, NC 27709 USA. NIEHS, Dev Biol Lab, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. NR 0 TC 1 Z9 1 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD JUN PY 2003 VL 35 IS 6 MA L55 BP A16 EP A16 PG 1 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 692QZ UT WOS:000183672900072 ER PT J AU Imahashi, K Schneider, M Steenbergen, C Murphy, E AF Imahashi, K Schneider, M Steenbergen, C Murphy, E TI Transgenic expression of Bcl-2 reduces cytosolic acidification in ischemic myocardium and promotes restoration of creatine phosphate after reperfusion SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Meeting Abstract CT 25th Annual Meeting of the North American Section of the International-Society-for-Heart-Research CY JUN 28-JUL 01, 2003 CL MYSTIC, CT SP Int Soc Heart Res, N Amer Sect C1 NIEHS, Res Triangle Pk, NC 27709 USA. Baylor Coll Med, Houston, TX 77030 USA. Duke Univ, Durham, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD JUN PY 2003 VL 35 IS 6 MA P84 BP A40 EP A40 PG 1 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 692QZ UT WOS:000183672900170 ER PT J AU Steenbergen, C Tong, HY Murphy, E AF Steenbergen, C Tong, HY Murphy, E TI Role of phosphatidylinositol-3-kinase (PI3K) in cardioprotection. SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Meeting Abstract CT 25th Annual Meeting of the North American Section of the International-Society-for-Heart-Research CY JUN 28-JUL 01, 2003 CL MYSTIC, CT SP Int Soc Heart Res, N Amer Sect C1 Duke Univ, Dept Pathol, Durham, NC 27706 USA. NIEHS, LST, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD JUN PY 2003 VL 35 IS 6 MA L29 BP A10 EP A10 PG 1 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 692QZ UT WOS:000183672900047 ER PT J AU Tong, HY Steenbergen, C Koch, WJ Murphy, E AF Tong, HY Steenbergen, C Koch, WJ Murphy, E TI G beta gamma-dependent signaling pathway in ischemic preconditioning: A role for endosomal signaling SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Meeting Abstract CT 25th Annual Meeting of the North American Section of the International-Society-for-Heart-Research CY JUN 28-JUL 01, 2003 CL MYSTIC, CT SP Int Soc Heart Res, N Amer Sect C1 NIEHS, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27706 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD JUN PY 2003 VL 35 IS 6 MA P118 BP A49 EP A49 PG 1 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 692QZ UT WOS:000183672900205 ER PT J AU Noskov, VN Leem, SH Solomon, G Mullokandov, M Chae, JY Yoon, YH Shin, YS Kouprina, N Larionov, V AF Noskov, VN Leem, SH Solomon, G Mullokandov, M Chae, JY Yoon, YH Shin, YS Kouprina, N Larionov, V TI A novel strategy for analysis of gene homologues and segmental genome duplications SO JOURNAL OF MOLECULAR EVOLUTION LA English DT Article DE isolation of orthologues; isolation of homologues; transformation-associated recombination; cloning; Saccharomyces cerevisiae ID TRANSFORMATION-ASSOCIATED RECOMBINATION; YEAST ARTIFICIAL CHROMOSOMES; DOUBLE-STRAND BREAKS; SACCHAROMYCES-CEREVISIAE; MISMATCH REPAIR; TAR CLONING; DNA; SEQUENCE; CONSTRUCTION; IDENTITY AB Transformation-associated recombination (TAR) cloning allows selective isolation of a desired chromosomal region or gene from complex genomes. The method exploits a high level of recombination between homologous DNA sequences during transformation in the yeast Saccharomyces cerevisiae. We investigated the effect of nonhomology on the efficiency of gene capture and found that up to 15% DNA divergence did not prevent efficient gene isolation. Such tolerance to DNA divergence greatly expands the potential applications of TAR cloning for comparative genomics. In this study, we were able to use the technique to isolate nonidentical chromosomal duplications and gene homologues. C1 NCI, Lab Biosyst & Canc, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Dong A Univ, Dept Biol, Pusan 604714, South Korea. NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Larionov, V (reprint author), NCI, Lab Biosyst & Canc, Ctr Canc Res, NIH, Bldg 37,Room 5032, Bethesda, MD 20892 USA. FU NIDCR NIH HHS [DE-AI02-01ER63079] NR 35 TC 8 Z9 9 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0022-2844 J9 J MOL EVOL JI J. Mol. Evol. PD JUN PY 2003 VL 56 IS 6 BP 702 EP 710 DI 10.1007/s00239-002-2442-x PG 9 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 683CG UT WOS:000183129100007 PM 12911033 ER PT J AU Chalimoniuk, M Pederson, WA Mattson, MP Toborek, M AF Chalimoniuk, M Pederson, WA Mattson, MP Toborek, M TI PKC is involved in arachidonic acid-induced choline acetyltransferase activity in spinal cord neurons SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 14th Meeting of the European-Society-for-Neurochemistry CY JUN 01-04, 2003 CL WARSAW, POLAND SP European Soc Neurochem C1 Univ Kentucky, Dept Surg, Lexington, KY USA. Polish Acad Sci, Dept Cellular Signaling, Warsaw, Poland. NIA, Neurosci Lab, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUN PY 2003 VL 85 SU 2 BP 16 EP 16 DI 10.1046/j.1471-4159.85.s2.15_1.x PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 683NT UT WOS:000183156200052 ER PT J AU Cohen, RI Rottkamp, DM Maric, D Barker, JL Hudson, LD AF Cohen, RI Rottkamp, DM Maric, D Barker, JL Hudson, LD TI A role for semaphorins and neuropilins in oligodendrocyte guidance SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE fluorescent activated cell sorting; guidance; microarray; neuropilin; oligodendrocyte; semaphorin ID SPINAL-CORD OLIGODENDROCYTES; GROWTH CONE COLLAPSE; AXON GUIDANCE; SONIC HEDGEHOG; HUMAN BRAIN; IN-VIVO; RECEPTORS; EXPRESSION; PROTEINS; SIGNALS AB Oligodendrocytes develop in defined CNS regions as progenitor cells, which migrate to their final destinations, encountering soluble and membrane-bound signals that influence their differentiation and potential to myelinate axonal projections. To identify the regulatory genes that may be involved in this process, microarray analysis of developing oligodendroglia was performed. Several neural guidance genes, including members of the neuropilin (NP) and semaphorin families were detected. These findings were verified and expanded upon using RT-PCR with RNA from fluorescent activated cell sorted A2B5(+) oligodendrocyte progenitors and O4(+) pro-oligodendrocytes isolated from in vitro and in vivo sources. RT-PCR, western and immunocytochemical analyses revealed that oligodendrocytes expressed NP1, several alternatively spliced isoforms of NP2, and a broad spectrum of both soluble (Class 3), membrane-spanning (Class 4-6), and membrane-tethered (Class 7) semaphorin ligands. Class 3 semaphorins, in a modified stripe assay, caused the collapse of oligodendrocyte progenitor growth cones, redirection of processes, and altered progenitor migration. Our data support a role for neuropilins and semaphorins in orchestrating the migration patterns of developing oligodendrocytes in the CNS. C1 Coriell Inst Med Res, Lab Cellular Genet & Dev, Richard D Satell Lab Canc Res, Camden, NJ 08103 USA. NINDS, Lab Dev Neurogenet, NIH, Bethesda, MD 20892 USA. NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Cohen, RI (reprint author), Stanford Univ, Coriell Inst Med Res, Palo Alto, CA 94304 USA. NR 54 TC 58 Z9 59 U1 0 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUN PY 2003 VL 85 IS 5 BP 1262 EP 1278 DI 10.1046/j.1471-4159.2003.01722.x PG 17 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 678FR UT WOS:000182855400018 PM 12753085 ER PT J AU Bahia, DS Sartania, N Ward, RJ Cavalli, A Jones, TLZ Druey, KM Milligan, G AF Bahia, DS Sartania, N Ward, RJ Cavalli, A Jones, TLZ Druey, KM Milligan, G TI Concerted stimulation and deactivation of pertussis toxin-sensitive G proteins by chimeric G protein-coupled receptor-regulator of G protein signaling 4 fusion proteins: analysis of the contribution of palmitoylated cysteine residues to the GAP activity of RGS4 SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE alpha(2A)-adrenoceptor; G protein; GTPase activity; palmitoylation; regulator of G protein signaling ID GTPASE-ACTIVATING PROTEIN; HETEROTRIMERIC G-PROTEINS; CLATHRIN-COATED VESICLES; ALPHA-SUBUNITS; G-ALPHA(I) SUBUNITS; PLASMA-MEMBRANE; GAIP; BINDING; ALPHA(2A)-ADRENOCEPTOR; IDENTIFICATION AB Agonists stimulated high-affinity GTPase activity in membranes of HEK293 cells following coexpression of the alpha(2A) -adrenoceptor and a pertussis toxin-resistant mutant of G(o1) alpha. Enzyme kinetic analysis of V (max) and K (m) failed to detect regulation of the effect of agonist by a GTPase activating protein. This did occur, however, when cells were also transfected to express RGS4. Both elements of a fusion protein in which the N-terminus of RGS4 was linked to the C-terminal tail of the alpha(2A) -adrenoceptor were functional, as it was able to provide concerted stimulation and deactivation of the G protein. By contrast, the alpha(2A) -adrenoceptor-RGS4 fusion protein stimulated but did not enhance deactivation of a form of G(o1) alpha that is resistant to the effects of regulator of G protein signaling (RGS) proteins. Employing this model system, mutation of Asn128 but not Asn88 eliminated detectable GTPase activating protein activity of RGS4 against G(o1) alpha. Mutation of all three cysteine residues that are sites of post-translational acylation in RGS4 also eliminated GTPase activating protein activity but this was not achieved by less concerted mutation of these sites. These studies demonstrate that a fusion protein between a G protein-coupled receptor and an RGS protein is fully functional in providing both enhanced guanine nucleotide exchange and GTP hydrolysis of a coexpressed G protein. They also provide a direct means to assess, in mammalian cells, the effects of mutation of the RGS protein on function in circumstances in which the spatial relationship and orientation of the RGS to its target G protein is defined and maintained. C1 Univ Glasgow, Mol Pharmacol Grp, Div Biochem & Mol Biol, Inst Biomed & Life Sci, Glasgow G12 8QQ, Lanark, Scotland. NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. NIH, Mol Signal Transduct Sect, Lab Allerg Dis, Rockville, MD USA. RP Milligan, G (reprint author), Univ Glasgow, Mol Pharmacol Grp, Div Biochem & Mol Biol, Inst Biomed & Life Sci, Davidson Bldg, Glasgow G12 8QQ, Lanark, Scotland. RI Milligan, Graeme/F-9426-2011 OI Milligan, Graeme/0000-0002-6946-3519 NR 50 TC 11 Z9 11 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 JUN PY 2003 VL 85 IS 5 BP 1289 EP 1298 DI 10.1046/j.1471-4159.2003.01769.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 678FR UT WOS:000182855400020 PM 12753087 ER PT J AU Kim, JY Koh, HC Lee, JY Chang, MY Kim, YC Chung, HY Son, H Lee, YS Studer, L McKay, R Lee, SH AF Kim, JY Koh, HC Lee, JY Chang, MY Kim, YC Chung, HY Son, H Lee, YS Studer, L McKay, R Lee, SH TI Dopaminergic neuronal differentiation from rat embryonic neural precursors by Nurr1 overexpression SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE CNS precursor; differentiation; dopamine neuron; Nurr1; Parkinson's disease; tyrosine hydroxylase expression ID CENTRAL-NERVOUS-SYSTEM; EXPANDED MESENCEPHALIC PRECURSORS; FETAL VENTRAL MESENCEPHALON; PARKINSONS-DISEASE; STEM-CELLS; TYROSINE-HYDROXYLASE; FUNCTIONAL RECOVERY; SONIC HEDGEHOG; INDUCTION; MIDBRAIN AB In vitro expanded CNS precursors could provide a renewable source of dopamine (DA) neurons for cell therapy in Parkinson's disease. Functional DA neurons have been derived previously from early midbrain precursors. Here we demonstrate the ability of Nurr1, a nuclear orphan receptor essential for midbrain DA neuron development in vivo , to induce dopaminergic differentiation in naive CNS precursors in vitro . Independent of gestational age or brain region of origin, Nurr1-induced precursors expressed dopaminergic markers and exhibited depolarization-evoked DA release in vitro . However, these cells were less mature and secreted lower levels of DA than those derived from mesencephalic precursors. Transplantation of Nurr1-induced DA neuron precursors resulted in limited survival and in vivo differentiation. No behavioral improvement in apomorphine-induced rotation scores was observed. These results demonstrate that Nurr1 induces dopaminergic features in naive CNS precursors in vitro . However, additional factors will be required to achieve in vivo function and to unravel the full potential of neural precursors for cell therapy in Parkinson's disease. C1 Hanyang Univ, Coll Med, Dept Biochem, Seoul 133791, South Korea. Hanyang Univ, Coll Med, Dept Pharmacol, Seoul 133791, South Korea. Hanyang Univ, Coll Med, Dept Microbiol, Seoul 133791, South Korea. Hanyang Univ, Inst Mental Hlth, Seoul 133791, South Korea. Sloan Kettering Canc Inst, Lab Stem Cell & Tumor Biol, New York, NY USA. NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Lee, SH (reprint author), Hanyang Univ, Coll Med, Dept Biochem, Seoul 133791, South Korea. NR 42 TC 102 Z9 122 U1 0 U2 6 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 JUN PY 2003 VL 85 IS 6 BP 1443 EP 1454 DI 10.1046/j.1471-4159.2003.01780.x PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 686EK UT WOS:000183308300010 PM 12787064 ER PT J AU Basselin, M Chang, L Seemann, R Bell, JM Rapoport, SI AF Basselin, M Chang, L Seemann, R Bell, JM Rapoport, SI TI Chronic lithium administration potentiates brain arachidonic acid signaling at rest and during cholinergic activation in awake rats SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE arachidonic acid; brain; lithium; muscarinic; phospholipase A(2); stimulation ID MUSCARINIC ACETYLCHOLINE-RECEPTORS; INOSITOL PHOSPHOLIPID HYDROLYSIS; HUMAN CEREBRAL METABOLISM; CELL-DEATH; IN-VIVO; HIPPOCAMPAL-NEURONS; INDUCED CONVULSIONS; HEALTHY-SUBJECTS; PRIMARY CULTURE; ALBINO-RAT AB Studies were performed to determine if the reported 'proconvulsant' action of lithium in rats given cholinergic drugs is related to receptor-initiated phospholipase A2 signaling via arachidonic acid. Regional brain incorporation coefficients k* of intravenously injected [1-(14) C]arachidonic acid, which represent this signaling, were measured by quantitative autoradiography in unanesthetized rats at baseline and following administration of subconvulsant doses of the cholinergic muscarinic agonist, arecoline. In rats fed LiCl for 6 weeks to produce a therapeutically relevant brain lithium concentration, the mean baseline values of k* in brain auditory and visual areas were significantly greater than in rats fed control diet. Arecoline at doses of 2 and 5 mg/kg intraperitoneally increased k* in widespread brain areas in rats fed the control diet as well as the LiCl diet. However, the arecoline-induced increments often were significantly greater in the LiCl-fed than in the control diet-fed rats. Lithium's elevation of baseline k* in auditory and visual regions may correspond to its ability in humans to increase auditory and visual evoked responses. Additionally, its augmentation of the k* responses to arecoline may underlie its reported 'proconvulsant' action with cholinergic drugs, as arachidonic acid and its eicosanoid metabolites can increase neuronal excitability and seizure propagation. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP NIA, Brain Physiol & Metab Sect, NIH, Bldg 10,Room 6 N202, Bethesda, MD 20892 USA. EM mirvasln@mail.nih.gov NR 76 TC 35 Z9 36 U1 0 U2 2 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD JUN PY 2003 VL 85 IS 6 BP 1553 EP 1562 DI 10.1046/j.1471-4159.2003.01811.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 686EK UT WOS:000183308300020 PM 12787074 ER PT J AU Lu, L Grimm, JW Shaham, Y Hope, BT AF Lu, L Grimm, JW Shaham, Y Hope, BT TI Molecular neuroadaptations in the accumbens and ventral tegmental area during the first 90 days of forced abstinence from cocaine self-administration in rats SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE adenylate cyclase; cAMP-dependent protein kinase; cocaine self-administration; cyclin-dependent kinase 5; glutamate receptors; tyrosine hydroxylase ID TIME-DEPENDENT CHANGES; TYROSINE-HYDROXYLASE; NUCLEUS-ACCUMBENS; BEHAVIORAL SENSITIZATION; SEEKING BEHAVIOR; GLUTAMATE TRANSMISSION; INDUCED REINSTATEMENT; EXTINCTION BEHAVIOR; RECEPTOR SUBUNITS; GENE-EXPRESSION AB Cocaine self-administration is associated with a propensity to relapse in humans and reinstatement of drug seeking in rats after prolonged withdrawal periods. These behaviors are hypothesized to be mediated by molecular neuroadaptations within the mesolimbic dopamine system. However, in most studies of drug-induced neuroadaptations, cocaine was experimenter-delivered and molecular measurements were performed after short withdrawal periods. In the present study, rats were trained to self-administer intravenous cocaine or oral sucrose (a control non-drug reward) for 10 days (6-h/day) and were killed following 1, 30, or 90 days of reward withdrawal. Tissues from the accumbens and ventral tegmental area (VTA) were assayed for candidate molecular neuroadaptations, including enzyme activities of cAMP-dependent protein kinase (PKA) and adenylate cyclase (AC), and protein expression of cyclin-dependent kinase 5 (cdk5), tyrosine hydroxylase (TH) and glutamate receptor subunits (GluR1, GluR2 and NMDAR1). In the accumbens of cocaine-trained rats, GluR1 and NMDAR1 levels were increased on days 1 and 90, while GluR2 levels were increased on days 1 and 30, but not day 90; PKA activity levels were increased on days 1 and 30, but not day 90, while AC activity, TH and cdk5 levels were unaltered. In the VTA of cocaine-trained rats, NMDAR1 levels were increased for up to 90 days, while GluR2 levels were increased only on day 1; TH and Cdk5 levels were increased only on day 1, while PKA and AC activity levels were unaltered. Cocaine self-administration produces long-lasting molecular neuroadaptations in the VTA and accumbens that may underlie cocaine relapse during periods of abstinence. C1 NIDA, Behav Neuosci Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. RP Hope, BT (reprint author), NIDA, Behav Neuosci Branch, Intramural Res Program, NIH,DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Hope, Bruce/A-9223-2010; shaham, yavin/G-1306-2014 OI Hope, Bruce/0000-0001-5804-7061; NR 60 TC 166 Z9 174 U1 0 U2 10 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 JUN PY 2003 VL 85 IS 6 BP 1604 EP 1613 DI 10.1046/j.1471-4159.2003.01824.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 686EK UT WOS:000183308300025 PM 12787079 ER PT J AU Nelson, PG Lanuza, MA Jia, M Li, MX Tomas, J AF Nelson, PG Lanuza, MA Jia, M Li, MX Tomas, J TI Phosphorylation reactions in activity-dependent synapse modification at the neuromuscular junction during development SO JOURNAL OF NEUROCYTOLOGY LA English DT Review ID PROTEIN-KINASE-C; CENTRAL-NERVOUS-SYSTEM; ACETYLCHOLINE-RECEPTORS; MUSCLE-CELLS; NEONATAL-RAT; IN-VITRO; ELIMINATION; THROMBIN; MOUSE; DESENSITIZATION AB We have studied developmental activity-dependent synapse diminution in both an in vitro tissue culture chamber system and at the intact rodent neuromuscular junction (nmj). In both types of preparations, pre- and postsynaptic alterations in synapse structure and function are produced by manipulations of thrombin (Thr) and protein kinase C (PKC) activity. An opposing postsynaptic effect of PKC and protein kinase A (PKA) action on the acetycholine receptor (AChR) can be shown in vitro with PKA stabilizing and PKC destabilizing the nmj synapses. In vivo studies of normal junctional maturation show that changes in axonal inputs and postsynaptic receptor cluster morphology occur, to a substantial degree, independently of one another. Presynaptic actions of PKA are involved in the activity dependent synapse modulation that can be demonstrated in vitro. Late in the elimination process, (>12 days in vivo) the process becomes independent of PKC, implying that diverse, redundant mechanisms are involved in this important developmental process. C1 NICHHD, Neurobiol Sect, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. Univ Rovira & Virgili, Fac Med & Ciencies Salut, Unitat Histol & Neurobiol, E-43201 Reus, Spain. RP Nelson, PG (reprint author), NICHHD, Neurobiol Sect, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. EM pgnelson@codon.nih.gov NR 38 TC 27 Z9 27 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0300-4864 J9 J NEUROCYTOL JI J. Neurocytol. PD JUN-SEP PY 2003 VL 32 IS 5-8 BP 803 EP 816 DI 10.1023/B:NEUR.0000020625.70284.a6 PG 14 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 805AY UT WOS:000220340400027 PM 15034269 ER PT J AU Lu, B Je, HS AF Lu, B Je, HS TI Neurotrophic regulation of the development and function of the neuromuscular synapses SO JOURNAL OF NEUROCYTOLOGY LA English DT Review ID INDUCED SYNAPTIC POTENTIATION; DEVELOPING MOTOR-NEURONS; LOCAL PROTEIN-SYNTHESIS; INDUCED CELL-DEATH; MICE LACKING GDNF; SIGNAL-TRANSDUCTION; NERVOUS-SYSTEM; IN-VIVO; POSTSYNAPTIC DIFFERENTIATION; DEVELOPING MOTONEURONS AB Recent studies have established that one of the major functions of neurotrophic factors is to regulate synaptic development and plasticity. This owes a great deal to the studies using the neuromuscular junction (NMJ) as a model system. In this review, we summarize the effects of various neurotrophic factors on the development and function of the neuromuscular synapses. We describe experiments addressing the role of neurotrophins, as well as that of other factors (GFLs, TGF-betas, and Wnts). The synaptic effects of neurotrophic factors are divided into two categories: acute effects on synaptic transmission and plasticity occurring within seconds or minutes after cells are exposed to a particular factor, and long-term regulation of synaptic structure and function that takes days to accomplish. We consider the presynaptic effects on the release of the neurotransmitter ACh, as well as the postsynaptic effects on the clustering of ACh receptors. Further studies of the mechanisms underlying these regulatory effects will help us better understand how neurotrophic factors can achieve diverse and synapse-specific modulation in the brain. C1 NICHD, Sect Neural Dev & Plast, NIH, Bethesda, MD 20892 USA. George Washington Univ, Genet Program, Washington, DC 20052 USA. RP Lu, B (reprint author), NICHD, Sect Neural Dev & Plast, NIH, Bethesda, MD 20892 USA. EM bailu@mail.nih.gov RI Lu, Bai/A-4018-2012; OI Je, hyunsoo/0000-0002-2924-5621 NR 90 TC 21 Z9 21 U1 0 U2 4 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0300-4864 J9 J NEUROCYTOL JI J. Neurocytol. PD JUN-SEP PY 2003 VL 32 IS 5-8 BP 931 EP 941 DI 10.1023/B:NEUR.0000020633.93430.db PG 11 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 805AY UT WOS:000220340400035 PM 15034277 ER PT J AU Emsley, HCA Smith, CJ Gavin, CM Georgiou, RF Vail, A Barberan, EM Hallenbeck, JM del Zoppo, GJ Rothwell, NJ Tyrrell, PJ Hopkins, SJ AF Emsley, HCA Smith, CJ Gavin, CM Georgiou, RF Vail, A Barberan, EM Hallenbeck, JM del Zoppo, GJ Rothwell, NJ Tyrrell, PJ Hopkins, SJ TI An early and sustained peripheral inflammatory response in acute ischaemic stroke: relationships with infection and atherosclerosis SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE stroke; acute; C-reactive protein; erythrocyte sedimentation rate; IL-6; inflammation; infection ID C-REACTIVE PROTEIN; ACUTE-PHASE RESPONSE; BLOOD-CELL COUNT; CEREBRAL INFARCTION; PROINFLAMMATORY CYTOKINES; BODY-TEMPERATURE; INTERLEUKIN-6; DISEASE; SEVERITY; RISK AB Central nervous system and peripheral inflammation is important in the responses to ischaemic stroke, and may also predispose to its development. We aimed to identify (1) the extent to which a peripheral inflammatory response is activated in patients following acute stroke, and (2) whether there was evidence for preexisting peripheral inflammation. Thirty-six patients with ischaemic stroke within 12 h of onset of symptoms had serial blood samples taken up to 12 months for analysis of markers of inflammation. Thirty-six control subjects, individually matched for age, sex and degree of atherosclerosis, were also studied. Median C-reactive protein (CRP) was elevated, relative to controls (2.08 mg/l), from admission (4.31 mg/l) (p less than or equal to 0.001) until 3 months (2.90 mg/l) (p less than or equal to 0.01), the greatest elevation occurring at 5-7 days (17.67 mg/l) (p less than or equal to 0.001). Elevations were also seen in erythrocyte sedimentation rate (ESR) and white blood cell (WBC) count until 3 months. Median plasma IL-6 was also elevated, relative to controls (9 pg/ml), by 24 h after onset of symptoms (22 pg/ml) (p less than or equal to 0.01), and remained elevated at 5-7 days (23 pg/ml) (p less than or equal to 0.01), but not at 3 months. Less marked elevations in these markers were seen in patients without evidence of infection except for IL-6, which was not increased in the absence of infection. These data provide evidence of an early and sustained peripheral inflammatory response to acute ischaemic stroke in patients with or without evidence of infection. The very early increase in concentrations of inflammatory markers after stroke may either be induced by stroke itself, or may indicate a preexisting inflammatory condition in stroke patients which may contribute to the development of stroke. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Hope Hosp, Stroke Serv, Salford M6 8HD, Lancs, England. Univ Manchester, Manchester, Lancs, England. Hope Hosp, Dept Emergency Med, Salford, Lancs, England. Univ Manchester, Hope Hosp, Biostat Grp, Salford M6 8HD, Lancs, England. NINDS, Stroke Branch, NIH, Bethesda, MD USA. Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA USA. Univ Manchester, Sch Biol Sci, Manchester M13 9PT, Lancs, England. Hope Hosp, NWIRC, Salford M6 8HD, Lancs, England. RP Emsley, HCA (reprint author), Hope Hosp, Stroke Serv, Clin Sci Bldg,Eccles old Rd, Salford M6 8HD, Lancs, England. RI Hopkins, Stephen/I-7363-2015; OI Hopkins, Stephen/0000-0001-7644-2823; Emsley, Hedley/0000-0003-0129-4488; Smith, Craig/0000-0002-9078-9919; Tyrrell, Pippa/0000-0001-9609-1231 FU NINDS NIH HHS [NS26945, NS38710] NR 47 TC 151 Z9 159 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD JUN PY 2003 VL 139 IS 1-2 BP 93 EP 101 DI 10.1016/S0165-5728(03)00134-6 PG 9 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 696RB UT WOS:000183899800013 PM 12799026 ER PT J AU Pigino, G Morfini, G Pelsman, A Mattson, MP Brady, ST Busciglio, J AF Pigino, G Morfini, G Pelsman, A Mattson, MP Brady, ST Busciglio, J TI Alzheimer's presenilin 1 mutations impair kinesin-based axonal transport SO JOURNAL OF NEUROSCIENCE LA English DT Article DE Alzheimer's disease; presenilin; GSK3 beta; kinesin; axonal transport; growth cones ID GLYCOGEN-SYNTHASE KINASE-3-BETA; AMYLOID PRECURSOR PROTEIN; HIPPOCAMPAL-NEURONS; IN-VITRO; TARGETED DISRUPTION; DOWNS-SYNDROME; LIGHT-CHAINS; BETA-CATENIN; HEAVY-CHAIN; DISEASE AB Several lines of evidence indicate that alterations in axonal transport play a critical role in Alzheimer's disease ( AD) neuropathology, but the molecular mechanisms that control this process are not understood fully. Recent work indicates that presenilin 1 (PS1) interacts with glycogen synthase kinase 3beta(GSK3beta). In vivo, GSK3beta phosphorylates kinesin light chains (KLC) and causes the release of kinesin-I from membrane-bound organelles (MBOs), leading to a reduction in kinesin-I driven motility (Morfini et al., 2002b). To characterize a potential role for PS1 in the regulation of kinesin-based axonal transport, we used PS1(-/-) and PS1 knock-in(M146V) (KIM146V) mice and cultured cells. We show that relative levels of GSK3beta activity were increased in cells either in the presence of mutant PS1 or in the absence of PS1 ( PS1(-/-)). Concomitant with increased GSK3beta activity, relative levels of KLC phosphorylation were increased, and the amount of kinesin-I bound to MBOs was reduced. Consistent with a deficit in kinesin-I-mediated fast axonal transport, densities of synaptophysin-and syntaxin-I-containing vesicles and mitochondria were reduced in neuritic processes of KIM146V hippocampal neurons. Similarly, we found reduced levels of PS1, amyloid precursor protein, and synaptophysin in sciatic nerves of KIM146V mice. Thus PS1 appears to modulate GSK3beta activity and the release of kinesin-I from MBOs at sites of vesicle delivery and membrane insertion. These findings suggest that mutations in PS1 may compromise neuronal function by affecting GSK-3 activity and kinesin-I-based motility. C1 Univ Connecticut, Ctr Hlth, Dept Neurosci, Farmington, CT 06030 USA. Univ Texas, SW Med Ctr, Dept Cell Biol, Dallas, TX 75390 USA. NIA, Neurosci Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Busciglio, J (reprint author), Univ Connecticut, Ctr Hlth, Dept Neurosci, 263 Farmington Ave, Farmington, CT 06030 USA. RI Mattson, Mark/F-6038-2012 FU NICHD NIH HHS [HD38466]; NINDS NIH HHS [R01 NS023868] NR 76 TC 200 Z9 210 U1 1 U2 16 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 JUN 1 PY 2003 VL 23 IS 11 BP 4499 EP 4508 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 688PD UT WOS:000183443700013 PM 12805290 ER PT J AU Perry, T Lahiri, DK Sambamurti, K Chen, DM Mattson, MP Egan, JM Greig, NH AF Perry, T Lahiri, DK Sambamurti, K Chen, DM Mattson, MP Egan, JM Greig, NH TI Glucagon-like peptide-1 decreases endogenous amyloid-beta peptide (A beta) levels and protects hippocampal neurons from death induced by A beta and iron SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE Alzheimer's disease; apoptosis; NGF; oxidative stress; PC12 cell ID HUMAN NEUROBLASTOMA-CELLS; PRECURSOR PROTEIN; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; GLUCOSE-TRANSPORT; BINDING-SITES; MESSENGER-RNA; RAT-BRAIN; SECRETION; EXENDIN-4 AB Glucagon-like peptide-1(7-36)-amide (GLP-1) is an endogenous insulinotropic peptide that is secreted from the gastrointestinal tract in response to food. It enhances pancreatic islet beta-cell proliferation and glucose-dependent insulin secretion and lowers blood glucose and food intake in patients with type 2 diabetes mellitus. GLP-1 receptors, which are coupled to the cyclic AMP second messenger pathway, are expressed throughout the brains of rodents and humans. It was recently reported that GLP-1 and exendin-4, a naturally occurring, more stable analogue of GLP-1 that binds at the GLP-1 receptor, possess neurotrophic properties and can protect neurons against glutamate-induced apoptosis. We report here that GLP-1 can reduce the levels of amyloid-beta peptide (Abeta) in the brain in vivo and can reduce levels of amyloid precursor protein (APP) in cultured neuronal cells. Moreover, GLP-1 and exendin-4 protect cultured hippocampal neurons against death induced by Abeta and iron, an oxidative insult. Collectively, these data suggest that GLP-1 can modify APP processing and protect against oxidative injury, two actions that suggest a novel therapeutic target for intervention in Alzheimer's disease. (C) 2003 Wiley-Liss, Inc. C1 NIA, Neurosci Lab, Sect Drug Design & Dev, NIH, Baltimore, MD 21224 USA. Mayo Clin, Dept Neurosci, Jacksonville, FL USA. Indiana Univ, Sch Med, Inst Psychiat Res, Indianapolis, IN 46202 USA. NIA, Sect Cellular & Mol Neurosci, Neurosci Lab, NIH, Baltimore, MD 21224 USA. NIA, Diabet Sect, Clin Invest Lab, Gerontol Res Ctr,NIH, Baltimore, MD 21224 USA. RP Perry, T (reprint author), NIA, Neurosci Lab, Sect Drug Design & Dev, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 57 TC 202 Z9 214 U1 2 U2 15 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD JUN 1 PY 2003 VL 72 IS 5 BP 603 EP 612 DI 10.1002/jnr.10611 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 679RZ UT WOS:000182936900007 PM 12749025 ER PT J AU Galey, D Becker, K Haughey, N Kalehua, A Taub, D Woodward, J Mattson, MP Nath, A AF Galey, D Becker, K Haughey, N Kalehua, A Taub, D Woodward, J Mattson, MP Nath, A TI Differential transcriptional regulation by human immunodeficiency virus type 1 and gp120 in human astrocytes SO JOURNAL OF NEUROVIROLOGY LA English DT Article DE astrocyte; chemokine; cytokine; gp120; HIV; microarray; RPA; transcription ID NECROSIS-FACTOR-ALPHA; GLIAL-CELLS; SYNERGISTIC NEUROTOXICITY; ENVELOPE GLYCOPROTEIN; INSULIN-RESISTANCE; GENE-EXPRESSION; HIV-1 INFECTION; TAT PROTEIN; REPLICATION; ACTIVATION AB Astrocytes may be infected with the human immunodeficiency virus type 1 (HIV-1) or exposed to the HIV protein gp120, yet their role in the pathogenesis of HIV dementia is largely unknown. To characterize the effects of HIV on astrocytic transcription, microarray analysis and ribonuclease protection assays (RPA) were performed. Infection of astrocytes by HIV or treatment with gp120 had differential and profound effects on gene transcription. Of the 1153 oligonucleotides on the immune-based array, the expression of 108 genes (53 up; 55 down) and 82 genes (32 up; 50 down) were significantly modulated by gp120 and HIV infection respectively. Of the 1153 oligonucleotides on the neuro-based array, 58 genes (25 up; 33 down) and 47 genes (17 up; 30 down) were significantly modulated by gp120 and HIV infection respectively. Chemokine and cytokine induction occurred predominantly by HIV infection, whereas gp120 had no significant effect. These results were confirmed by RPA. The authors conclude that profound alterations of astrocytic function occur in response to HIV infection or interaction with viral proteins, suggesting that astrocytes may play an important role in the pathogenesis of HIV dementia. C1 Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD 21287 USA. NIA, Baltimore, MD 21224 USA. Univ Kentucky, Dept Microbiol, Lexington, KY USA. Univ Kentucky, Dept Immunol, Lexington, KY USA. Univ Kentucky, Dept Mol Genet, Lexington, KY USA. RP Nath, A (reprint author), Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD 21287 USA. RI Mattson, Mark/F-6038-2012; OI Becker, Kevin/0000-0002-6794-6656 FU NCRR NIH HHS [RR15592]; NINDS NIH HHS [NS38428, NS39253] NR 32 TC 26 Z9 27 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD JUN PY 2003 VL 9 IS 3 BP 358 EP 371 DI 10.1080/13550280390201119 PG 14 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 683XJ UT WOS:000183176100008 PM 12775419 ER PT J AU Davis, MR Votaw, JR Bremner, JD Byas-Smith, MG Faber, TL Voll, RJ Hoffman, JM Grafton, ST Kilts, CD Goodman, MM AF Davis, MR Votaw, JR Bremner, JD Byas-Smith, MG Faber, TL Voll, RJ Hoffman, JM Grafton, ST Kilts, CD Goodman, MM TI Initial human PET imaging studies with the dopamine transporter ligand F-18-FECNT SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE dopamine transporter; PET; 2 beta-carbomethoxy-3 beta-(4-chlorophenyl)-8-(2-F-18-fluoroethyl)nortropane; Parkinson's disease ID SPECT BRAIN MEASUREMENT; I-123 BETA-CIT; PARKINSONS-DISEASE; EMISSION-TOMOGRAPHY; COCAINE; REPRODUCIBILITY; OCCUPANCY; BINDING; CFT; BIODISTRIBUTION AB The aim of this study was to do an initial assessment of the usefulness of 2(3-carbomethoxy-3(3-(4-chlorophenyl)-8-(2-F-18-fluoroethyl)nortropane (F-18-FECNT) PET scanning in determining in vivo brain dopamine transporter (DAT) density in healthy humans and subjects with Parkinson's disease (PD). Methods: We investigated 6 neurologically healthy subjects and 5 PD patients: 2 with mild unilateral disease, 1 with mild-to-moderate bilateral disease, and 2 with moderately severe bilateral disease. The healthy subjects underwent a 3-h PET scan (26 frames) and the PD subjects underwent a 2-h PET scan (23 frames) while F-18-FECNT was being injected over the first 5 min of the scan. Arterial blood samples were taken throughout scanning for well-counter and metabolite analysis to determine the presence of possible active metabolites. The scans were reconstructed; then we placed spheric regions of interest in the caudate nuclei, putamena, thalami, brain stem, cerebellum, and occipital cortex of each subject. The radioactivity level in each region was calculated for each frame of a subject's PET scan. Then we calculated target tissue-to-cerebellum ratios for each time frame. Results: The analysis of arterial blood samples revealed that metabolism of the tracer was rapid. The ether-extractable component of the arterial input was >98% pure F-18-FECNT. The caudate nucleus and putamen exhibited the highest uptake and prolonged retention of the radioligand. They both attained maximum uptake at similar to90 min, with the healthy subjects' average caudate- and putamen-to-cerebellum ratios (+/-SD) at that time being 9.0 +/- 1.2 and 7.8 +/- 0.7, respectively. The maximal caudate-to-cerebellum ratios for the healthy subjects ranged from 7.6 to 10.5 and their maximal putamen-to-cerebellum ratios ranged from 7.1 to 9.3. The 2 early-stage, unilateral PD patients had, at 90 min, an average right caudate-to-cerebellum ratio of 5.3 +/- 1.1 and a left ratio of 5.9 +/- 0.7 and an average right putamen-to cerebellum ratio of 2.8 +/- 0.1 and a left ratio of 3.0 +/- 0.6. The late-stage PD patients had, at 90 min, an average right caudate-to-cerebellum ratio of 3.7 +/- 0.4 and a left ratio of 3.9 +/- 0 and an average right putamen-to cerebellum ratio of 1.8 +/- 0.1 and a left ratio of 1.8 +/- 0. Conclusion: These results indicate that F-18-FECNT is an excellent candidate radioligand for in vivo imaging of the DAT system in humans. It has a much higher affinity for DAT than for the serotonin transporter and yields the highest peak striatum-to-cerebellum ratios and has among the most favorable kinetics of F-18-radiolabeled DAT ligands. Having picked up presymptomatic changes in the hemisphere opposite the unaffected side of the body in our earlystage (unilateral) PD patients, it appears that, like other DAT radioligands, it may be able to identify presymptomatic PD. C1 Emory Univ, PET Ctr, Atlanta, GA 30322 USA. Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. Emory Univ, Dept Radiol, Atlanta, GA 30322 USA. Emory Univ, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. Emory Univ, Dept Anesthesiol, Atlanta, GA 30322 USA. NCI, Biomed Imaging Program, NIH, Bethesda, MD 20892 USA. Dartmouth Coll, Ctr Cognit Neurosci, Hanover, NH 03755 USA. RP Goodman, MM (reprint author), Emory Univ Hosp, Dept Radiol, 1364 Clifton Rd,NE, Atlanta, GA 30322 USA. RI Bremner, James/B-1632-2013 NR 34 TC 57 Z9 60 U1 1 U2 5 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 JUN PY 2003 VL 44 IS 6 BP 855 EP 861 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 688GN UT WOS:000183426000011 PM 12791810 ER PT J AU Davis, CD AF Davis, CD TI Use of exfoliated cells from target tissues to predict responses to bioactive food components SO JOURNAL OF NUTRITION LA English DT Article DE exfoliated cells; biomarkers; cancer; colon; lung; breast ID EPITHELIAL-CELLS; COLORECTAL-CANCER; DNA ADDUCTS; MUCOSA; MICRONUCLEI; DAMAGE; BLOOD; INDIVIDUALS; STOOL; ASSAY AB A host of bioactive food components have been proposed to promote health and reduce the risk of disease states. It is clear that not all individuals respond identically to these essential and nonessential food components. Genetic polymorphisms may influence absorption, metabolism and accumulation of bioactive food components, thereby influencing their actions in target tissues. Unfortunately, serum concentrations of bioactive food components may not correlate with tissue concentrations and may therefore under- or overestimate the response in target tissues. Exfoliated cells may be useful to assess the actions of nutrients in specific tissues. Although not extensively examined, evidence already suggests the usefulness of these cells in predicting changes in gene expression, DNA methylation, DNA damage, protein expression and accumulation of dietary components. Although there are limitations on the collection of exfoliated cells, the inaccessibility of tissues they can represent raises intriguing possibilities for their ability to predict the outcome of nutritional intervention studies. J. Nutr. 133:1769-1772, 2003. C1 NCI, Nutr Sci Res Grp, NIH, Bethesda, MD 20892 USA. RP Davis, CD (reprint author), NCI, Nutr Sci Res Grp, NIH, Bethesda, MD 20892 USA. NR 45 TC 11 Z9 14 U1 2 U2 4 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD JUN PY 2003 VL 133 IS 6 BP 1769 EP 1772 PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 687BP UT WOS:000183356200001 PM 12771314 ER PT J AU Wan, RQ Camandola, S Mattson, MP AF Wan, RQ Camandola, S Mattson, MP TI Intermittent food deprivation improves cardiovascular and neuroendocrine responses to stress in rats SO JOURNAL OF NUTRITION LA English DT Article DE energy restriction; cardiovascular disease; glucose metabolism; hypertension; sympathetic nervous system ID TERM CALORIC RESTRICTION; ISCHEMIC BRAIN-DAMAGE; DIETARY RESTRICTION; INSULIN-RESISTANCE; BLOOD-PRESSURE; VOLUNTARY EXERCISE; DIABETES-MELLITUS; HYPERTENSION; DISEASE; RISK AB Stressful events may trigger disease processes in many different organ systems, with the cardiovascular system being particularly vulnerable. Five-mo-old male rats had ad libitum (AL) access to food or were deprived of food every other day [intermittent food deprivation (IF)] for 6 mo, during which time their heart rate (HR), blood pressure (BP), physical activity and body temperature were measured by radiotelemetry under nonstress and stress (immobilization or cold-water swim) conditions. IF rats had significantly lower basal HR and BP, and significantly lower increases in HR and BP after exposures to the immobilization and swim stressors. Basal levels of adrenocorticotropic hormone (ACTH) and corticosterone were greater in the IF rats. However, in contrast to large stress-induced increases in ACTH, corticosterone and epinephrine levels in AL rats, increases in these hormones in response to repeated immobilization stress sessions were reduced or absent in IF rats. Nevertheless, the IF rats exhibited robust hypothalamic/pituitary and sympathetic neuroendocrine responses to a different stress (swim). The IF treatment improved glucose metabolism, as indicated by lower basal levels of circulating glucose and insulin, but with maintenance of glucose and insulin responses to stress. We concluded that improvements in cardiovascular risk factors and cardiovascular and neuroendocrine stress adaptation occur in response to IF. C1 NIA, Gerontol Res Ctr, Neurosci Lab, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Gerontol Res Ctr, Neurosci Lab, 4940 Eastern Ave, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 42 TC 62 Z9 64 U1 2 U2 5 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD JUN PY 2003 VL 133 IS 6 BP 1921 EP 1929 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 687BP UT WOS:000183356200027 PM 12771340 ER PT J AU Picciano, MF Coates, PM Cohen, BE AF Picciano, MF Coates, PM Cohen, BE TI The National Nutrition Summit: History and continued commitment to the nutritional health of the US population SO JOURNAL OF NUTRITION LA English DT Article DE emerging research agenda; historical resources; National Nutrition Summit; nutrition policy ID UNITED-STATES; OBESITY AB Over the past several decades, great progress has been made in developing national nutrition policies and research agendas that address numerous problems faced by various segments of our population. Despite the success of these initiatives and our understanding of the importance of nutrition throughout the life cycle, ongoing nutrition-related problems have been identified and still need to be adequately addressed through research and policy. The recognition of these various issues inspired the development of an agenda for the National Nutrition Summit held in May 2000, jointly sponsored by the U.S. Departments of Agriculture and of Health and Human Services. The major goal of the Summit was to forge partnerships among policy makers and program planners at the federal, state, and community levels to examine what accomplishments were made since 1969 and to identify existing gaps in the areas of food, nutrition and health. This review provides an overview of the purpose and overarching themes that emerged from the Summit, along with a review of additional resources from the Summit available on a website sponsored by the U.S. Departments of Health and Human Services and Agriculture. C1 NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. Collaborat Consultants, Bethesda, MD 20817 USA. RP Picciano, MF (reprint author), NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. NR 8 TC 1 Z9 1 U1 0 U2 0 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD JUN PY 2003 VL 133 IS 6 BP 1949 EP 1952 PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 687BP UT WOS:000183356200031 PM 12771344 ER PT J AU Raiten, DJ Picciano, MF Coates, PM AF Raiten, DJ Picciano, MF Coates, PM TI Dietary supplement use in women: Current status and future directions - Introduction and conference summary SO JOURNAL OF NUTRITION LA English DT Article C1 US Dept Hlth & Human Serv, Off Dietary Supplements, NIH, Bethesda, MD 20892 USA. Natl Inst Child Hlth & Human Dev, Off Prevent Res & Int Programs, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Picciano, MF (reprint author), US Dept Hlth & Human Serv, Off Dietary Supplements, NIH, Bethesda, MD 20892 USA. NR 6 TC 7 Z9 8 U1 0 U2 2 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD JUN PY 2003 VL 133 IS 6 BP 1957S EP 1960S PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 687BP UT WOS:000183356200033 PM 12771345 ER PT J AU Picciano, MF AF Picciano, MF TI Pregnancy and lactation: Physiological adjustments, nutritional requirements and the role of dietary supplements SO JOURNAL OF NUTRITION LA English DT Article DE pregnancy; lactation; nutritional requirements; dietary supplements ID INTERVENTIONS AB Nutritional needs are increased during pregnancy and lactation for support of fetal and infant growth and development along with alterations in maternal tissues and metabolism. Total nutrient needs are not necessarily the sum of those accumulated in maternal tissues, products of pregnancy and lactation and those attributable to the maintenance of nonreproducing women. Maternal metabolism is adjusted through the elaboration of hormones that serve as mediators, redirecting nutrients to highly specialized maternal tissues specific to reproduction (i.e., placenta and mammary gland). It is most unlikely that the heightened nutrient needs for successful reproduction can always be met from the maternal diet. Requirements for energy-yielding macronutrients increase modestly compared with several micronutrients that are unevenly distributed among foods. Altered nutrient utilization and mobilization of reserves often offset enhanced needs but sometimes nutrient deficiencies are precipitated by reproduction. There are only limited data from well-controlled intervention studies with dietary supplements and with few exceptions (iron during pregnancy and folate during the periconceptional period), the evidence is not strong that nutrient supplements confer measurable benefit. More research is needed and in future studies attention must be given to subject characteristics that may influence ability to meet maternal and infant demands (genetic and environmental), nutrient-nutrient interactions, sensitivity and selectivity of measured outcomes and proper use of proxy measures. Consideration of these factors in future studies of pregnancy and lactation are necessary to provide an understanding of the links among maternal diet; nutritional supplementation; and fetal, infant and maternal health. C1 NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Picciano, MF (reprint author), NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. NR 35 TC 72 Z9 80 U1 2 U2 19 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD JUN PY 2003 VL 133 IS 6 BP 1997S EP 2002S PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 687BP UT WOS:000183356200041 PM 12771353 ER PT J AU Spouge, J Wan, H Wilbur, WJ AF Spouge, J Wan, H Wilbur, WJ TI Least squares isotonic regression in two dimensions SO JOURNAL OF OPTIMIZATION THEORY AND APPLICATIONS LA English DT Article DE quasiorders; partial orders; weighted least-square fits; network flows; grids; dynamic programming ID ALGORITHMS AB Given a finite partially-ordered set with a positive weighting function defined on its points, it is well known that any real-valued function defined on the set has a unique best order-preserving approximation in the weighted least squares sense. Many algorithms have been given for the solution of this isotonic regression problem. Most such algorithms either are not polynomial or they are of unknown time complexity. Recently, it has become clear that the general isotonic regression problem can be solved as a network flow problem in time O(n(4)) with a space requirement of O(n(2)), where n is the number of points in the set. Building on the insights at the basis of this improvement, we show here that, in the case of a general two-dimensional partial ordering, the problem can be solved in O(n(3)) time and, when the two-dimensional set is restricted to a grid, the time can be further improved to O(n(2)). C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. Natl Ctr Genome Resources, Santa Fe, NM USA. RP Spouge, J (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. NR 15 TC 12 Z9 12 U1 0 U2 2 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0022-3239 J9 J OPTIMIZ THEORY APP JI J. Optim. Theory Appl. PD JUN PY 2003 VL 117 IS 3 BP 585 EP 605 DI 10.1023/A:1023901806339 PG 21 WC Operations Research & Management Science; Mathematics, Applied SC Operations Research & Management Science; Mathematics GA 684KG UT WOS:000183205400009 ER PT J AU Goldstein, DS Eisenhofer, G Kopin, IJ AF Goldstein, DS Eisenhofer, G Kopin, IJ TI Sources and significance of plasma levels of catechols and their metabolites in humans SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID PHYSIOLOGICAL SIGNIFICANCE; CLINICAL PHENOTYPES; PHEOCHROMOCYTOMA; DOPA; NOREPINEPHRINE; DIAGNOSIS; DIHYDROXYPHENYLGLYCOL; DEFICIENCY; ACID; 3,4-DIHYDROXYPHENYLALANINE AB Human plasma contains several catechols, including the catecholamines norepinephrine, epinephrine, and dopamine, their precursor, L-3,4-dihydroxyphenylalanine (L-DOPA),and their deaminated metabolites, dihydroxyphenylglycol, the main neuronal metabolite of norepinephrine, and dihydroxyphenylacetic acid, a deaminated metabolite of dopamine. Products of metabolism of catechols include 3-methoxytyrosine (from L-DOPA), homovanillic acid and dopamine sulfate (from dopamine), normetanephrine, vanillylmandelic acid, and methoxyhydroxyphenylglycol (from norepinephrine), and metanephrine (from epinephrine). Plasma levels of catechols and their metabolites have related but distinct sources and therefore reflect different functions of catecholamine systems. This article provides an update about plasma levels of catechols and their metabolites and the relevance of those levels to some issues in human health and disease. C1 NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. RP Goldstein, DS (reprint author), NINDS, Clin Neurocardiol Sect, NIH, Bldg 10,Rm 6N252,10 Ctr Dr,MSC-1620, Bethesda, MD 20892 USA. NR 46 TC 180 Z9 181 U1 0 U2 13 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUN PY 2003 VL 305 IS 3 BP 800 EP 811 DI 10.1124/jpet.103.049270 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 680PF UT WOS:000182986000001 PM 12649306 ER PT J AU Rothman, RB Clark, RD Partilla, JS Baumann, MH AF Rothman, RB Clark, RD Partilla, JS Baumann, MH TI (+)-Fenfluramine and its major metabolite, (+)-norfenfluramine, are potent substrates for norepinephrine transporters SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID D-FENFLURAMINE; PREFRONTAL CORTEX; NERVOUS-SYSTEM; RAT-BRAIN; DEXFENFLURAMINE TREATMENT; EXTRACELLULAR DOPAMINE; PULMONARY-HYPERTENSION; NORADRENALINE CARRIER; D-NORFENFLURAMINE; 5-HT2B RECEPTORS AB (+/-)-Fenfluramine is an amphetamine analog that was once widely prescribed as an appetite suppressant. Although (+/-)-fenfluramine is no longer clinically available, the mechanisms underlying its anorectic properties are still of interest. Upon peripheral administration, stereoisomers of (+/-)-fenfluramine are N-deethylated to form the metabolites, (+)- and (-)-norfenfluramine. It is well accepted that isomers of (+/-)- fenfluramine and (+/-)-norfenfluramine interact with 5-hydroxytryptamine ( serotonin, 5-HT) transporters to release 5-HT from neurons. However, the effects of these drugs on other monoamine transporters are not well characterized. In this study, we examined the interaction of stereoisomers of (+/-)fenfluramine and (+/-)-norfenfluramine with transporters for 5-HT, norepinephrine ( NE), and dopamine (DA). Results from in vitro assays confirmed these drugs are potent substrates for 5-HT transporters: (+)- fenfluramine, (-)- fenfluramine, (+)- norfenfluramine, and (-)-norfenfluramine released [H-3] 5-HT from synaptosomes with EC50 values of 52, 147, 59, and 287 nM, respectively. Importantly, (+)-fenfluramine and (+)-norfenfluramine released [H-3] NE with EC50 values of 302 and 73 nM. Results from in vivo microdialysis experiments showed that intravenous injection of (+)-norfenfluramine elevates extracellular levels of 5-HT, NE, and DA in rat frontal cortex. The effects of (+)-norfenfluramine on NE and DA were antagonized by pretreatment with the NE uptake blocker nisoxetine. In summary, administration of fenfluramines can increase synaptic levels of 5-HT, NE, and DA in the cortex, and (+)-norfenfluramine likely contributes to these effects. Release of NE and DA evoked by (+)-norfenfluramine is at least partly mediated via NE transporters. Our results emphasize the potential involvement of noradrenergic mechanisms in the actions of fenfluramines. C1 NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Rothman, RB (reprint author), NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH, 5500 Nathan Shock Dr,POB 5180, Baltimore, MD 21224 USA. NR 43 TC 39 Z9 40 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUN PY 2003 VL 305 IS 3 BP 1191 EP 1199 DI 10.1124/jpet.103.049684 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 680PF UT WOS:000182986000046 PM 12649307 ER PT J AU Jin, BH Ma, DS Moon, HS Paik, DI Hahn, SH Horowitz, AM AF Jin, BH Ma, DS Moon, HS Paik, DI Hahn, SH Horowitz, AM TI Early childhood caries: Prevalence and risk factors in Seoul, Korea SO JOURNAL OF PUBLIC HEALTH DENTISTRY LA English DT Article; Proceedings Paper CT Annual Session of the American-Association-of-Public-Health-Dentistry CY APR 30, 2002 CL DANVERS, MASSACHUSETTS SP Amer Assoc Publ Hlth Dent DE early childhood caries; noncavitated lesion; caries risk factors ID HEAD-START CHILDREN; DENTAL-CARIES; PRESCHOOL-CHILDREN; HEALTH; PREDICTORS; DENTITION; PATTERNS; INFANT; ISSUES AB Objective: The purpose of this study was to determine the prevalence of early childhood caries (ECC), including noncavitated lesions (d(1)), in children 6-59 months of age in relation to socioeconomic factors, feeding practices, and oral health behaviors in Seoul, Korea. Methods: The children attended child care facilities and were selected from 32 primary sampling units. Two dentists examined 470 children. Parents of 383 of the subjects were interviewed by phone regarding caries risk factors. Results: For children 6-59 months of age, the prevalence of ECC and severe ECC were 56.5 percent and 47.0 percent respectively. In bivariate analysis, the children whose nursing bottle contained sweetened solution had higher severe ECC prevalence (P=.035), and children whose parents reported a lower frequency of between-meal snacks showed lower ECC prevalence (P=.046). By logistic regression analysis, age and frequency of between-meal snacks were associated with the prevalence of ECC (P<.05). Conclusion: This study demonstrates that the prevalence of ECC was high among children in Seoul. Early educational intervention programs for pregnant women and mothers of young children should be developed based on the risk factors identified in this study. C1 Kangnung Natl Univ, Coll Dent, Kangnungshi 210702, Kangwondo, South Korea. Shingu Coll, Dept Dent Hyt, Sungnam, Kyunggi, South Korea. Seoul Natl Univ, Coll Dent, Seoul 151, South Korea. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Ma, DS (reprint author), Kangnung Natl Univ, Coll Dent, 123 Chibyundong, Kangnungshi 210702, Kangwondo, South Korea. NR 32 TC 24 Z9 26 U1 3 U2 6 PU AAPHD NATIONAL OFFICE PI PORTLAND PA 3760 SW LYLE COURT, PORTLAND, OR 97221 USA SN 0022-4006 J9 J PUBLIC HEALTH DENT JI J. Public Health Dent. PD SUM PY 2003 VL 63 IS 3 BP 183 EP 188 DI 10.1111/j.1752-7325.2003.tb03497.x PG 6 WC Dentistry, Oral Surgery & Medicine; Public, Environmental & Occupational Health SC Dentistry, Oral Surgery & Medicine; Public, Environmental & Occupational Health GA 716JU UT WOS:000185025700007 PM 12962472 ER PT J AU Brennan, MT Sankar, V Leakan, RA Grisius, MM Collins, MT Fox, PC Baum, BJ Pillemer, SR AF Brennan, MT Sankar, V Leakan, RA Grisius, MM Collins, MT Fox, PC Baum, BJ Pillemer, SR TI Sex steroid hormones in primary Sjogren's syndrome SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE Sjogren's syndrome; androgens; estrogens; hormone replacement therapy ID DEHYDROEPIANDROSTERONE; CLASSIFICATION; METABOLITES; CRITERIA; THERAPY AB Objective. To investigate the relationships between concentrations of sex hormones and measures of disease activity in patients with primary Sjogren's Syndrome (pSS). Methods. Fifty-four women were evaluated: 39 patients (age, Q1,Q3: 57.0 yrs; 46, 66) diagnosed with pSS and 15 patients (49.0 yrs; 45, 60) who did not meet diagnostic criteria for pSS. The following measures of disease activity were assessed: serological data [antinuclear antibody, rheumatoid factor, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum immunoglobulin levels (IgG, IgA, IgM), serum protein, anti-SSA, and anti-SSB], labial minor salivary gland focus score, salivary flow rates, and objective measures of eye dryness (fluorescein corneal staining and unstimulated Schirmer's I test). Spearman correlations were calculated between these indices of disease activity and serum levels of sex hormones: dehydroepiandrosterone (DHEA), DHEA sulfate, androstenedione, testosterone, dihydrotestosterone (DHT), estrone, estradiol, and sex hormone binding globulin (SHBG). Results. Numerous differences were noted between cases and controls with disease activity measures. All median values of sex steroid hormones were within the range of normal for pSS cases. Positive correlations were noted between testosterone and ESR (r = 0.36, p = 0.03), testosterone and, serum protein (r = 0.37, p = 0.05), and testosterone and focus score (r = 0.44; p = 0.007). Negative correlations were present between SHBG and anti-SSA (r = -0.33, p = 0.05), SHBG and anti-SSB (r = -0.43, p = 0.009), and DHT and CRP (r = -0.41, p = 0.05). No correlations were noted between estrogens and measures of pSS disease activity. Conclusion. Higher levels of disease activity (ESR, serum protein, and focus score) were associated with higher concentrations of testosterone. No correlation between disease activity and estrogens was found. C1 Carolinas Med Ctr, Dept Oral Med, Charlotte, NC 28232 USA. NIDCR, GTTB, NIH, Bethesda, MD USA. Univ Penn, Dept Oral Med, Sch Dent Med, Philadelphia, PA 19104 USA. RP Brennan, MT (reprint author), Carolinas Med Ctr, Dept Oral Med, POB 32861, Charlotte, NC 28232 USA. RI Perez , Claudio Alejandro/F-8310-2010 OI Perez , Claudio Alejandro/0000-0001-9688-184X NR 18 TC 17 Z9 17 U1 0 U2 3 PU J RHEUMATOL PUBL CO PI TORONTO PA 365 BLOOR ST E, STE 901, TORONTO, ONTARIO M4W 3L4, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD JUN PY 2003 VL 30 IS 6 BP 1267 EP 1271 PG 5 WC Rheumatology SC Rheumatology GA 687BV UT WOS:000183356700024 PM 12784401 ER PT J AU Shah, M Kavanaugh, A Coyle, Y Huet, BA Lipsky, PE AF Shah, M Kavanaugh, A Coyle, Y Huet, BA Lipsky, PE TI Effect of a diet program on lipid and lipoproteins, body weight, nutrient intakes, and quality of life in patients with systemic lupus erythematosus - Drs. Shah, et al reply SO JOURNAL OF RHEUMATOLOGY LA English DT Letter C1 Texas Christian Univ, Dept Kinesiol, Ft Worth, TX 76129 USA. Univ Calif San Diego, Ctr Innovat Therapy, Div Rheumatol Allergy & Immunol, San Diego, CA 92103 USA. Univ Texas, SW Med Ctr, Dallas, TX 75230 USA. NIAMSD, Bethesda, MD 20892 USA. RP Shah, M (reprint author), Texas Christian Univ, Dept Kinesiol, Ft Worth, TX 76129 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD JUN PY 2003 VL 30 IS 6 BP 1394 EP 1394 PG 1 WC Rheumatology SC Rheumatology GA 687BV UT WOS:000183356700050 ER PT J AU Farsshori, PQ Shah, BH Arora, KK Martinez-Fuentes, A Catt, KJ AF Farsshori, PQ Shah, BH Arora, KK Martinez-Fuentes, A Catt, KJ TI Activation and nuclear translocation of PKC delta, Pyk2 and ERK1/2 by gonadotropin releasing hormone in HEK293 cells SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article; Proceedings Paper CT 11th International Congress on Hormonal Steroids/7th International Congress on Hormones and Cancer CY OCT 21-25, 2002 CL FUKUOKA, JAPAN DE GnRH; ERK 1/2 MAP kinases; HEK293 cells; nuclear translocation; Pyk2; PKC ID GROWTH-FACTOR RECEPTOR; PROTEIN-KINASE-C; SIGNAL-REGULATED KINASE; SMOOTH-MUSCLE-CELLS; 2ND INTRACELLULAR LOOP; RICH TYROSINE KINASE-2; ANGIOTENSIN-II; COUPLED RECEPTORS; FOCAL ADHESIONS; EGF RECEPTOR AB The mechanism of agonist-induced activation of Pyk2 and its relationship with ERK1/2 phosphorylation was analyzed in HEK293 cells stably expressing the gonadotropin releasing hormone (GnRH) receptor. GnRH stimulation caused rapid and sustained phosphorylation of ERK1/2 and Pyk2 that was accompanied by their nuclear translocation. Pyk2 was also localized on cell membranes and at focal adhesions. Dominant negative Pyk2 (PKM) had no effect on GnRH-induced ERK1/2 phosphorylation and c-fos expression. These actions of GnRH on ERK1/2 and Pyk2 were mimicked by activation of protein kinase C (PKC) and were abolished by its inhibition. GnRH caused translocation of PKCalpha and delta, but not of epsilon, iota and lambda, to the cell membrane, as well as phosphorylation of Raf at Ser338, a major site in the activation of MEK/ERK1/2. Stimulation of HEK293 cells by EGF caused marked ERK1/2 phosphorylation that was attenuated by the selective EGFR receptor (EGF-R) kinase inhibitor, AG1478. However, GnRH-induced ERK1/2 activation was independent of EGF-R activation. These results indicate that activation of PKC is responsible for GnRH-induced phosphorylation of both ERK1/2 and Pyk2, and that Pyk2 activation does not contribute to GnRH signaling. Moreover, GnRH-induced phosphorylation of ERK1/2 and expression of c-fos in HEK293 cells is independent of Src and EGF-R transactivation, and is mediated through the PKC/Raf/MEK cascade. Published by Elsevier Ltd. C1 NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Catt, KJ (reprint author), NICHHD, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Rm 6A-36, Bethesda, MD 20892 USA. NR 60 TC 27 Z9 27 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD JUN PY 2003 VL 85 IS 2-5 BP 337 EP 347 DI 10.1016/S0960-0760(03)00226-7 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 724NM UT WOS:000185493700029 PM 12943720 ER PT J AU Zhang, Y Dufau, ML AF Zhang, Y Dufau, ML TI Dual mechanisms of regulation of transcription of luteinizing hormone receptor gene by nuclear orphan receptors and histone deacetylase complexes SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article; Proceedings Paper CT 11th International Congress on Hormonal Steroids/7th International Congress on Hormones and Cancer CY OCT 21-25, 2002 CL FUKUOKA, JAPAN DE Sp1; Sp3; orphan receptors; EAR2; EAR3-COUP-TFI; histone; deacetylases ID CHORIONIC-GONADOTROPIN RECEPTOR; RETINOIC ACID RECEPTOR; COUP-TF; ESTROGEN-RECEPTOR; THYROID-HORMONE; GRANULOSA-CELLS; SIGNALING PATHWAYS; FLANKING SEQUENCES; MOLECULAR-CLONING; FACTOR FAMILY AB The luteinizing hormone receptor (LHR), a member of the G protein-coupled, seven transmembrane receptor family, is essential for normal sexual development and reproductive function. LHR are expressed primarily in the gonads, but also are found in non-gonadal and cancer tissues. LH acts through LH receptors in Leydig cells to maintain general metabolic processes and steroidogenic enzymes, and in the ovary enhances follicular development and steroidogenesis in granulosa and luteal cells. The major transcriptional start sites of the LHR gene are located within the 176 bp promoter domain. In the rat, the LHR gene is constitutively inhibited by upstream sequences (-176/-2056 bp) in several cell systems, while in the human only a minor inhibitory effect was observed in JAR and HeLa cells (>20%). The TATA-less human promoter is driven by Sp1 and Sp3 transactivators that bind to two Sp1 domains at -79 bp [Sp1 (I)] and -119 bp [Sp1 (II)] (from ATG) with additive effects. An imperfect estrogen receptor half-site response element direct-repeat within the LHR promoter is an inhibitory locus. Endogenous orphan receptors, EAR2 and EAR3/COUP-TFI, bind this motif and repress promoter activity by 70%. TR4 also binds this motif and stimulates promoter activity (up to 2.5-fold). This is reversed by coexpression of EAR2 or EAR3/COUP-TFI through competitive binding to this site. Comparative studies of hDR and rDR orphan receptors binding and function revealed sequence-specific requirements. The A/C mismatch between hDR and rDR is responsible for the lack of TR4 binding and function in the rat. The G 3'-adjacent to the hDR core is important for EAR2/EAR3-COUP-TFI high-affinity binding. The Sp1-1 site is critical for EAR3/COUP-TFI repression, with minor participation for EAR2, and is not involved in the TR4 effect. Interaction of EAR3/COUP-TFI with Sp1 perturbs association of TFIIB with Sp1, independently of HDACs, and caused impairment of LHR transcription. Other aspect of control is through HDAC/mSin3A mechanism. Inhibition of HDACs by TSA increases LHR promoter activity in JAR cells (40-fold), association of acetylated H3/H4 with the LHR promoter, recruitment of Pol II to the promoter, and LHR mRNA levels. A multiprotein complex is recruited to the hLHR promoter via interaction with Sp1/Sp3: HDACs dock directly to Sp1-1 bound DNA and indirectly to Sp3-1 bound DNA through RbAp48, while mSin3A interacts HDACs and potentiates HDAC1-mediated repression. Our studies have demonstrated that orphan receptor-ERE complexes, and the HDAC1-HDAC2-mSin3A complex have important roles in the regulation of LHR gene transcription by interaction with Sp1/Sp3, and by region-specific changes in histone acetylation and Pol II recruitment within the LHR promoter. Published by Elsevier Ltd. C1 NICHD, Endocrinol & Reprod Res Branch, Mol Endocrinol Sect, NIH, Bethesda, MD 20892 USA. RP Dufau, ML (reprint author), NICHD, Endocrinol & Reprod Res Branch, Mol Endocrinol Sect, NIH, 49 Convent Dr,Bldg 49,6A-36, Bethesda, MD 20892 USA. NR 74 TC 36 Z9 36 U1 0 U2 2 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 JUN PY 2003 VL 85 IS 2-5 BP 401 EP 414 DI 10.1016/S0960-0760(03)00230-9 PG 14 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 724NM UT WOS:000185493700038 PM 12943729 ER PT J AU Kino, T De Martino, MU Charmandari, E Mirani, M Chrousos, GR AF Kino, T De Martino, MU Charmandari, E Mirani, M Chrousos, GR TI Tissue glucocorticoid resistance/hypersensitivity syndromes SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article; Proceedings Paper CT 11th International Congress on Hormonal Steroids/7th International Congress on Hormones and Cancer CY OCT 21-25, 2002 CL FUKUOKA, JAPAN DE glucocorticoid; accessory proteins; HIV-1 ID HUMAN-IMMUNODEFICIENCY-VIRUS; PRIMARY CORTISOL RESISTANCE; PHOSPHOENOLPYRUVATE CARBOXYKINASE GENE; NUCLEAR RECEPTOR COACTIVATORS; NEGATIVE CROSS-TALK; FACTOR-KAPPA-B; TRANSCRIPTIONAL ACTIVATION; RESPONSE ELEMENT; DNA-BINDING; PROTEIN VPR AB Glucocorticoids have a broad array of life-sustaining functions and play an important role in the therapy of many diseases. Thus, changes of tissue sensitivity to glucocorticoids may be associated with and influence the course and treatment of many pathologic states. Such tissue sensitivity changes may present on either side of an optimal range, respectively as glucocorticoid resistance or hypersensitivity, and may be generalized or tissue-specific. Familial/sporadic glucocorticoid resistance syndrome caused by inactivating mutations of the glucocorticoid receptor (GR) gene is a classic monogenic disorder associated with congenital, generalized glucocorticoid insensitivity, while several autoimmune, inflammatory and allergic diseases are often associated with resistance of the inflamed tissues to glucocorticoids. On the other hand, glucocorticoid hypersensitivity has been suggested in visceral obesity-related insulin resistance associated with components of the metabolic syndrome, and in the acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus type-1 (HIV-1) infection. Here, we have reviewed the molecular analyses of five familial and three sporadic cases of the familial/sporadic glucocorticoid resistance syndrome and discussed the possible contribution of newly identified molecules, such as HIV-1 accessory proteins Vpr and Tat, FLICE-associated huge protein (FLASH) and chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), on the molecular regulation of GR activity, as well as their possible contribution to changes in tissue sensitivity to glucocorticoids in pathologic conditions. Published by Elsevier Science Ltd. C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Kino, T (reprint author), NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RI Charmandari, Evangelia/B-6701-2011 NR 93 TC 111 Z9 119 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 JUN PY 2003 VL 85 IS 2-5 BP 457 EP 467 DI 10.1016/S0960-0760(03)00218-8 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 724NM UT WOS:000185493700045 PM 12943736 ER PT J AU Mindell, JA Grigorieff, N AF Mindell, JA Grigorieff, N TI Accurate determination of local defocus and specimen tilt in electron microscopy SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE electron microscopy; contrast transfer function; algorithm; tilt determination ID FROZEN-HYDRATED SPECIMENS; CONTRAST TRANSFER; ANGSTROM RESOLUTION; PURPLE MEMBRANE; CRYOELECTRON MICROGRAPHS; 3-DIMENSIONAL STRUCTURE; ATOMIC-RESOLUTION; VIRUS; CRYSTALLOGRAPHY; CRYOMICROSCOPY AB Accurate knowledge of defocus and tilt parameters is essential for the determination of three-dimensional protein structures at high resolution using electron microscopy. We present two computer programs, CTFFIND3 and CTFTILT, which determine defocus parameters from images of untilted specimens, as well as defocus and tilt parameters from images of tilted specimens, respectively. Both programs use a simple algorithm that fits the amplitude modulations visible in a power spectrum with a calculated contrast transfer function (CTF). The background present in the power spectrum is calculated using a low-pass filter. The background is then subtracted from the original power spectrum, allowing the fitting of only the oscillatory component of the CTF. CTFTILT determines specimen tilt parameters by measuring the defocus at a series of locations on the image while constraining them to a single plane. We tested the algorithm on images of two-dimensional crystals by comparing the results with those obtained using crystallographic methods. The images also contained contrast from carbon support film that added to the visibility of the CTF oscillations. The tests suggest that the fitting procedure is able to determine the image defocus with an error of about 10 nm, whereas tilt axis and tilt angle are determined with an error of about 2degrees and P, respectively. Further tests were performed on images of single protein particles embedded in ice that were recorded from untilted or slightly tilted specimens. The visibility of the CTF oscillations from these images was reduced due to the lack of a carbon support film. Nevertheless, the test results suggest that the fitting procedure is able to determine image defocus and tilt angle with errors of about 100nm and 6degrees, respectively. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Brandeis Univ, Rosenstiel Basic Med Sci Res Ctr, Howard Hughes Med Inst, Waltham, MA 02454 USA. NINDS, Membrane Transport Biophys Unit, NIH, Bethesda, MD 20892 USA. RP Grigorieff, N (reprint author), Brandeis Univ, Rosenstiel Basic Med Sci Res Ctr, Howard Hughes Med Inst, MS029,415 S St, Waltham, MA 02454 USA. OI Mindell, Joseph/0000-0002-6952-8247 FU NIDDK NIH HHS [DK-2801]; NIGMS NIH HHS [GM-62580] NR 36 TC 693 Z9 695 U1 2 U2 38 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 JUN PY 2003 VL 142 IS 3 BP 334 EP 347 DI 10.1016/S1047-8477(03)00069-8 PG 14 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 689PK UT WOS:000183502000002 PM 12781660 ER PT J AU Greenhill, LL Vitiello, B Riddle, MA Fisher, P Shockey, E March, JS Levine, J Fried, J Abikoff, H Zito, JM McCracken, JT Findling, RL Robinson, J Cooper, TB Davies, M Varipatis, E Labellarte, MJ Scahill, L AF Greenhill, LL Vitiello, B Riddle, MA Fisher, P Shockey, E March, JS Levine, J Fried, J Abikoff, H Zito, JM McCracken, JT Findling, RL Robinson, J Cooper, TB Davies, M Varipatis, E Labellarte, MJ Scahill, L TI Review of safety assessment methods used in pediatric psychopharmacology SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Review ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; OBSESSIVE-COMPULSIVE DISORDER; CONTROLLED TRIAL; DOUBLE-BLIND; CHILDREN; METHYLPHENIDATE; ADOLESCENTS; VALPROATE; EFFICACY AB Objective: Elicitation is an essential and critical step in ascertaining adverse events (AEs). This report reviews elicitation methods used in published clinical trials of psychopharmacological agents in children. Method: Pediatric psychopharmacology reports were reviewed for safety methods in the Medline database. Studies were included if they were published 1980 or later, provided data on AEs, and described the ascertainment methodology used for determining them. Results: A review of 196 pediatric psychopharmacology articles depicting safety assessments in clinical studies over the past 22 years revealed that there was no common method used for eliciting or reporting AE data. Conclusion: The current inconsistency in safety data ascertainment is a major limitation that likely impairs the ability to promptly and accurately identify drug-induced AEs. Research on how best to standardize safety methods should be considered a priority in pediatric psychopharmacology. C1 Columbia Univ, Attent Deficit Disorder Res Program, New York State Psychiat Inst, New York, NY 10032 USA. NIMH, Div Serv & Intervent Res, Bethesda, MD USA. Johns Hopkins Univ, Div Child & Adolescent Psychiat, Baltimore, MD 21218 USA. Duke Univ, Med Ctr, Child & Family Study Ctr, Durham, NC 27706 USA. Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. NYU, Ctr Child Study, New York, NY USA. Univ Maryland, Sch Pharm, College Pk, MD 20742 USA. Univ Calif Los Angeles, Div Child & Adolescent Psychiat, Los Angeles, CA 90024 USA. Case Western Reserve Univ, Div Child & Adolescent Psychiat, Cleveland, OH 44106 USA. Yale Univ, Ctr Child Study, New Haven, CT 06520 USA. RP Greenhill, LL (reprint author), Columbia Univ, Attent Deficit Disorder Res Program, New York State Psychiat Inst, 1051 Riverside Dr, New York, NY 10032 USA. OI Scahill, Lawrence/0000-0001-5073-1707 FU NIMH NIH HHS [N01MH60016, N01MH60005] NR 37 TC 55 Z9 56 U1 2 U2 2 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 JUN PY 2003 VL 42 IS 6 BP 627 EP 633 DI 10.1097/01.CH1.0000046841.56865.37 PG 7 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 681DQ UT WOS:000183022000007 PM 12921469 ER PT J AU Vitiello, B Riddle, MA Greenhill, LL March, JS Levine, J Schachar, RJ Abikoff, H Zito, JM McCracken, JT Walkup, JT Findling, RL Robinson, J Cooper, TB Davies, M Varipatis, E Labellarte, MJ Scahill, L Capasso, L AF Vitiello, B Riddle, MA Greenhill, LL March, JS Levine, J Schachar, RJ Abikoff, H Zito, JM McCracken, JT Walkup, JT Findling, RL Robinson, J Cooper, TB Davies, M Varipatis, E Labellarte, MJ Scahill, L Capasso, L TI How can we improve the assessment of safety in child and adolescent psychopharmacology? SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE children; adverse events; treatment; psychopharmacology ID POSTMARKETING SURVEILLANCE; SUDDEN-DEATH; METHYLPHENIDATE; ASSOCIATION; RATS AB To identify approaches to improving methods for assessing tolerability and safety of psychotropic medications in children and adolescents. Method: Strengths and limitations of current methodology were reviewed and possible alternatives examined. Results: Research on the validity of safety evaluation has been extremely limited. No evidence-based "gold standard" exists. Clinical trials remain the best design to establish causality, but sample size limitations prevent the detection of infrequent, though serious, adverse events. Other designs, such as cohort and case-control studies, and approaches, such-as mining of large databases, must be considered. Conclusions: The current lack of methodological standardization across studies prevents generalizations and meta-analyses. Because the issues relevant to drug safety are diverse, a variety of methodological approaches and instruments are needed. It is, however, possible to adopt standard basic definitions of adverse events, degree of severity, ascertainment methods, and recording procedures, as a common "core," to which more specific assessment instruments can be added. Systematic empirical testing and validation of safety methodology is needed. C1 NIMH, Div Serv & Intervent Res, Bethesda, MD 20982 USA. Johns Hopkins Univ, Div Child & Adolescent Psychiat, Baltimore, MD 21218 USA. Columbia Univ, New York State Psychiat Inst, New York, NY 10027 USA. Duke Univ, Med Ctr, Child & Family Study Ctr, Durham, NC 27706 USA. Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. Univ Toronto, Div Child & Adolescent Psychiat, Toronto, ON, Canada. NYU, Ctr Child Study, New York, NY USA. Univ Maryland, Sch Pharm, College Pk, MD 20742 USA. Univ Calif Los Angeles, Div Child & Adolescent Psychiat, Los Angeles, CA 90024 USA. Case Western Reserve Univ, Div Child & Adolescent Psychiat, Cleveland, OH 44106 USA. Yale Univ, Ctr Child Study, New Haven, CT 06520 USA. RP Vitiello, B (reprint author), NIMH, Div Serv & Intervent Res, Room 7147,6001 Execut Blvd,MSC 9633, Bethesda, MD 20982 USA. OI Schachar, Russell/0000-0002-2015-4395; Scahill, Lawrence/0000-0001-5073-1707 FU NIMH NIH HHS [N01MH60016, N01MH60005] NR 37 TC 41 Z9 42 U1 1 U2 3 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 JUN PY 2003 VL 42 IS 6 BP 634 EP 641 DI 10.1097/01.CH1/0000046840.90931.36 PG 8 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 681DQ UT WOS:000183022000008 PM 12921470 ER PT J AU Greenhill, LL Vitiello, B Abikoff, H Levine, J March, JS Riddle, MA Capasso, L Cooper, TB Davies, M Fisher, P Findling, RL Fried, J Labellarte, MJ McCracken, JT Mcmahon, D Robinson, J Skrobala, A Scahill, L Varipatis, E Walkup, JT Zito, JM AF Greenhill, LL Vitiello, B Abikoff, H Levine, J March, JS Riddle, MA Capasso, L Cooper, TB Davies, M Fisher, P Findling, RL Fried, J Labellarte, MJ McCracken, JT Mcmahon, D Robinson, J Skrobala, A Scahill, L Varipatis, E Walkup, JT Zito, JM TI Developing methodologies for monitoring long-term safety of psychotropic medications in children: Report on the NIMH Conference, September 25, 2000 SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE children; psychopharmacology; treatment; adverse events; drug safety AB Objective: To improve the methods for long-term assessment of drug-associated side effects and advance knowledge of the safety profile of psychotropic medications in children and adolescents. Method: A multidisciplinary, interactive workshop was hosted by the National Institute of Mental Health (NIMH) and the Research Units on Pediatric Psychopharmacology network. Participants were experts in child and adolescent psychiatry, psychopharmacology, pharmacoepidemiology, and statistics from academia, the pharmaceutical industry, the Food and Drug Administration (FDA), and the NIMH. Evaluation of drug safety was examined from five perspectives: research design and methods, industry, regulatory requirements, bioethics, and practice settings. For each of these areas, special emphasis was placed on identifying barriers and generating solutions. Results: A major obstacle is the lack of standardization of the methods used for collecting safety data. The limitations of both randomized clinical trials and passive postmarketing surveillance in assessing long-term safety were recognized. The need to consider alternative approaches, such as registries and trend analysis of population-based databases, was highlighted. Recommendations were proposed together with possible approaches to implementation. Conclusions: A concerted effort by academic researchers, industry, FDA, practitioners, and NIMH is needed to standardize methods and lay the foundations for systematic research on the long-term safety of psychotropic medications in children. C1 New York State Psychiat Inst & Hosp, New York, NY 10032 USA. NIMH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD 21218 USA. Univ Calif Los Angeles, Div Child & Adolescent Psychiat, Los Angeles, CA 90024 USA. Duke Univ, Med Ctr, Durham, NC 27706 USA. Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. NYU, Ctr Child Study, New York, NY USA. Univ Maryland, College Pk, MD 20742 USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. Yale Univ, Ctr Child Study, New Haven, CT 06520 USA. RP Greenhill, LL (reprint author), New York State Psychiat Inst & Hosp, 1051 Riverside Dr, New York, NY 10032 USA. OI Scahill, Lawrence/0000-0001-5073-1707 FU NIMH NIH HHS [N01MH60016, N01MH60005] NR 3 TC 28 Z9 28 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 JUN PY 2003 VL 42 IS 6 BP 651 EP 655 DI 10.1097/01.CH1.0000046842.56865.EC PG 5 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 681DQ UT WOS:000183022000010 PM 12921472 ER PT J AU Most, MM Ershow, AG Clevidence, BA AF Most, MM Ershow, AG Clevidence, BA TI An overview of methodologies, proficiencies, and training resources for controlled feeding studies SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID TRIAL AB Dietary intervention studies of human beings produce valuable information regarding dietary effects on biological processes and risk factors for chronic diseases. Using the well-controlled feeding approach, participants consume only foods that have been precisely prepared in a research kitchen, whereas in behavioral counseling studies, participants self-select their foods within guidelines. Because controlled feeding studies meticulously control experimental diets, they are intellectually and logistically challenging to conduct. They afford exciting opportunities for dietetic professionals in designing protocols, developing budgets, and collaborating in multidisciplinary research teams. Research dietitians use food composition data and chemical analysis of menus to prepare research diets with precision. They determine the energy requirements of subjects and adjust diets as required, most often for weight maintenance, throughout the study. All people involved in research must be attentive to the ethical treatment of the study participants while motivating them to adhere to the protocol requirements. Dietitians possess many of these skills, but may require training specific to well-controlled feeding studies. Information related to the conduct of controlled feeding studies has recently become more accessible. We provide an overview of well-controlled feeding study methodologies, proficiencies for planning and implementing these studies, and training resources. C1 Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. Natl Heart Lung & Blood, Div Heart & Vasc Dis, NIH, Bethesda, MD USA. USDA, Beltsville Human Nutr Res Ctr, Phytonutrients Lab, Beltsville, MD USA. RP Most, MM (reprint author), Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. NR 14 TC 13 Z9 13 U1 0 U2 5 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD JUN PY 2003 VL 103 IS 6 BP 729 EP 735 DI 10.1053/jada.2003.50132 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 684PW UT WOS:000183216600016 PM 12778045 ER PT J AU de Rekeneire, N Visser, M Peila, R Nevitt, MC Cauley, JA Tylavsky, FA Simonsick, EM Harris, TB AF de Rekeneire, N Visser, M Peila, R Nevitt, MC Cauley, JA Tylavsky, FA Simonsick, EM Harris, TB TI Is a fall just a fall: Correlates of falling in healthy older persons. The health, aging and body composition study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE falls; risk factors; elderly ID MUSCLE STRENGTH; RISK-FACTORS; ELDERLY PERSONS; NURSING-HOME; COMMUNITY; WOMEN; INJURIES; SARCOPENIA; DISABILITY; PREDICTION AB OBJECTIVES: To identify factors associated with falling in well-functioning older people. DESIGN: Cross-sectional analyses of report of falls over the past 12 months using baseline data from the Health, Aging and Body Composition Study. SETTING: Clinic examinations in Pittsburgh, Pennsylvania, or Memphis, Tennessee. PARTICIPANTS: Three thousand seventy-five high-functioning black and white elderly aged 70 to 79 living in the community. MEASUREMENTS: Physical function assessed using self-report and performance measures. Health status indicators included diseases, medication use, and body composition measures. RESULTS: Almost one-quarter (24.1%) of women and 18.3% of men reported at least one fall within the year before the baseline examination. Fallers were more likely to be female; white; report more chronic diseases and medications; and have lower leg strength, poorer balance, slower 400-meter walk time, and lower muscle mass. In men, multivariate logistic regression models showed white race (adjusted odds ratio (OR) = 1.4, 95% confidence interval (CI) = 1.2-1.6), slower 6-meter walk speed (OR = 1.1, 95% CI = 1.0-1.3), poor standing balance (OR = 1.2, 95% CI = 1.0-1.4), inability to do 5 chair stands (OR = 1.7, 95% CI = 1.3-1.9), report of urinary incontinence (UI) (OR = 1.5, 95% CI = 1.1-2.0), and mid-quintile of leg muscle strength (OR = 0.6, 95% CI = 0.4-0.9) to be independently associated with report of falling. In women, benzodiazepine use (OR = 1.6, 95% CI = 1.0-2.6), UI (OR = 1.5, 95% CI = 1.2-1.9), and reported difficulty in rising from a chair (OR = 1.4, 95% CI = 1.2-1.6) were associated with past falls. CONCLUSION: Falls history needs to be screened in healthier older adults. Even for well-functioning older persons, specific correlates of falling can be identified to define those at risk. C1 NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. NIA, Gerontol Res Ctr, Bethesda, MD 20892 USA. Vrije Univ Amsterdam, Med Ctr, Fac Med, Inst Res Extramural Med, Amsterdam, Netherlands. Univ Calif San Francisco, Prevent Sci Grp, San Francisco, CA 94143 USA. Univ Pittsburgh, Div Geriatr Med, Pittsburgh, PA USA. Univ Tennessee, Dept Prevent Med, Memphis, TN USA. RP de Rekeneire, N (reprint author), NIA, Lab Epidemiol Demog & Biometry, Gateway Bldg,Suite 3C-309,7201 Wisconsin Ave, Bethesda, MD 20892 USA. RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 FU NIA NIH HHS [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] NR 30 TC 136 Z9 143 U1 1 U2 10 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUN PY 2003 VL 51 IS 6 BP 841 EP 846 DI 10.1046/j.1365-2389.2003.51267.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 681RM UT WOS:000183049200016 PM 12757573 ER PT J AU Abbott, KC Agodoa, LY O'Malley, PG AF Abbott, KC Agodoa, LY O'Malley, PG TI Hospitalized psychoses after renal transplantation in the United States: Incidence, risk factors, and prognosis SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID ACUTE POSTTRANSPLANT NEUROPSYCHOSIS; KIDNEY-TRANSPLANTATION; MEDICATION COMPLIANCE; PATIENT; CYCLOSPORINE; RECIPIENTS; DEPRESSION; SYMPTOMS; MORPHINE; OUTCOMES AB Although it is recommended that renal transplant (RT) candidates routinely undergo screening for mental health-related conditions, national statistics for psychoses after RT have not been reported. This is a historical cohort study of 39,628 renal transplant recipients in the United States Renal Data System between July 1, 1994, and June 30, 1998, and followed until December 31, 1999. Adjusted hazard ratios (AHR) for time to hospitalization for both a primary and secondary discharge diagnosis of psychoses (ICD-9 codes 290.x-299.x) after RT and mortality/graft loss after psychosis were assessed by Cox Regression. In addition, rates of psychosis were compared with 178,986 patients with Medicare as their primary payer who started chronic dialysis from April 1, 1995, to June 29, 1999. The incidence of psychoses was 7.5/1000 person-years (PY) after RT compared with 7.2/1000 PY for all patients on chronic dialysis and 9.6/1000 PY for dialysis patients aged 65 yr or younger. Among RT recipients, graft loss (AHR, 2.97; 95% CI, 2.19 to 4.02), allograft rejection, and cadaveric donation were independently associated with psychosis, which was associated with an increased risk of both death (AHR, 2.09; 95% CI, 1.71 to 2.56; P < 0.001) and graft loss (AHR, 1.79; 95% CI, 1.15 to 2.78; P = 0.01). Graft loss due to noncompliance was significantly more common after psychosis (9.0% versus 3.7% in patients not hospitalized for psychosis; P < 0.001). The incidence of hospitalized psychosis was not substantially higher after RT compared with chronic dialysis patients. Psychoses were independently associated with increased risk of death and graft loss after renal transplantation, possibly mediated through medical non-adherence. C1 Walter Reed Army Med Ctr, Dialysis Nephrol Serv, Washington, DC 20307 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NIDDKD, NIH, Bethesda, MD USA. Walter Reed Army Med Ctr, Gen Internal Med Serv, Washington, DC 20307 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD USA. RP Abbott, KC (reprint author), Walter Reed Army Med Ctr, Dialysis Nephrol Serv, Washington, DC 20307 USA. OI Abbott, Kevin/0000-0003-2111-7112 NR 26 TC 16 Z9 16 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUN PY 2003 VL 14 IS 6 BP 1628 EP 1635 DI 10.1097/01.ASN.0000069268.63375.4A PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 682MK UT WOS:000183095600025 PM 12761265 ER PT J AU Schnermann, J AF Schnermann, J TI The juxtaglomerular apparatus: From anatomical peculiarity to physiological relevance SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID MACULA DENSA CELLS; STIMULATED RENIN SECRETION; GLOMERULAR-FILTRATION RATE; EPITHELIAL SODIUM-CHANNEL; LUNG LIQUID CLEARANCE; TUBULOGLOMERULAR FEEDBACK; DEFICIENT MICE; CYCLOOXYGENASE-2 EXPRESSION; EFFECTOR MECHANISM; CHLORIDE TRANSPORT C1 NIDDKD, NIH, Bethesda, MD 20892 USA. RP Schnermann, J (reprint author), Bldg 10,Room 4 D51,10 Ctr Dr,MSC 1370, Bethesda, MD 20892 USA. NR 80 TC 29 Z9 31 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUN PY 2003 VL 14 IS 6 BP 1681 EP 1694 DI 10.1097/01.ASN.0000069221.69551.30 PG 14 WC Urology & Nephrology SC Urology & Nephrology GA 682MK UT WOS:000183095600031 PM 12761271 ER PT J AU Dodd, LE Pepe, MS AF Dodd, LE Pepe, MS TI Semiparametric regression for the area under the receiver operating characteristic curve SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE classification; classifier performance; diagnostic test; disease screening; prediction ID PREDICTION; FRAMEWORK AB Medical advances continue to provide new and potentially better means for detecting disease. Such is true in cancer, for example, where biomarkers are sought for early detection and where improvements in imaging methods may pick up the initial functional and molecular changes associated with cancer development. In other binary classification tasks, computational algorithms such as neural networks, support vector machines, and evolutionary algorithms have been applied to areas as diverse as credit scoring, object recognition, and peptide-binding prediction. Before a classifier becomes an accepted technology, it must undergo rigorous evaluation to determine its ability to discriminate between states. Characterization of factors influencing classifier performance is an important step in this process. Analysis of covariates may reveal subpopulations in which classifier performance is greatest or identify features of the classifier that improve accuracy. We develop regression methods for the nonparametric area under the receiver operating characteristic curve, a well-accepted summary measure of classifier accuracy. The estimating function generalizes standard approaches and, interestingly, is related to the two-sample Mann-Whitney U statistic. Implementation is straightforward, because it is an adaptation of binary regression methods. Asymptotic theory is nonstandard, because the regressor variables are cross-correlated. Nevertheless, simulation studies show that the method produces estimates with small bias and reasonable coverage probability. Application of the method to evaluate the covariate effects on a new device for diagnosing hearing impairment reveals that the device performs better in more severely impaired subjects and that certain test parameters, which are adjustable by the device operator, are key to test performance. C1 NCI, Biometr Res Branch, Bethesda, MD 20892 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP Dodd, LE (reprint author), NCI, Biometr Res Branch, Bethesda, MD 20892 USA. NR 19 TC 33 Z9 34 U1 0 U2 2 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 1429 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0162-1459 J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD JUN PY 2003 VL 98 IS 462 BP 409 EP 417 DI 10.1198/016214503000198 PG 9 WC Statistics & Probability SC Mathematics GA 700XX UT WOS:000184137400017 ER PT J AU Chatterjee, S Bish, LT Jayasankar, V Stewart, AS Woo, YJ Crow, MT Gardner, TJ Sweeney, HL AF Chatterjee, S Bish, LT Jayasankar, V Stewart, AS Woo, YJ Crow, MT Gardner, TJ Sweeney, HL TI Blocking the development of postischemic cardiomyopathy with viral gene transfer of the apoptosis repressor with caspase recruitment domain SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article; Proceedings Paper CT 82nd Annual Meeting of the American-Association-for-Thoracic-Surgery CY MAY 05-09, 2002 CL WASHINGTON, D.C. SP Amer Assoc Thorac Surg ID MYOCARDIAL-INFARCTION; HEART-FAILURE; CELL-DEATH; CYTOCHROME-C; BORDER ZONE; RATS; ARC; CARDIOMYOCYTES; MECHANISMS AB Objectives: Apoptosis caused by acute ischemia and subsequent ventricular remodeling is implicated as a mediator of heart failure. This study was designed to assess the efficacy of in vivo viral gene transfer of the antiapoptotic factor apoptosis repressor with caspase recruitment domain to block apoptosis and preserve ventricular geometry and function. Methods: In a rabbit model of regional ischernia followed by reperfusion, an experimental group treated with adenovirus-apoptosis repressor with caspase recruitment domain was compared with empty vector adenovirus-null controls. Cardiac function was assessed by echocardiography and sonomicrometry of the border zone compared with the normal left ventricle. Animals were killed at 6 weeks with measurements of ventricular geometry and apoptosis. Results: Animals with the apoptosis repressor with caspase recruitment domain (ARC group) maintained higher ejection fractions at 4 and 6 weeks, and sonomicrometry demonstrated greater protection of border zone fractional shortening at 6 weeks compared with the control group. The ARC group maintained superior preservation of left ventricular geometry with less ventricular dilation and wall thinning. Finally, there was reduced apoptosis in the rabbits treated with apoptosis repressor with caspase recruitment domain compared with the controls. Conclusions: Gene transfer of apoptosis repressor with caspase recruitment domain preserves left ventricular function after ischemia. The benefit at 6 weeks is postulated to result from an apoptosis repressor with caspase recruitment domain-mediated reduction in apoptosis and ventricular remodeling. Adenovirus-apoptosis repressor with caspase recruitment domain administration offers a potential strategy after myocardial ischernia to protect the heart from late postischemic cardiomyopathy. C1 Univ Penn, Sch Med, Div Cardiothorac Surg, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Physiol, Philadelphia, PA 19104 USA. NIA, NIH, Baltimore, MD 21224 USA. RP Gardner, TJ (reprint author), Univ Penn, Sch Med, Div Cardiothorac Surg, 6 Silverstein Pavilion,3400 Spruce St, Philadelphia, PA 19104 USA. RI Sweeney, H Lee/F-1862-2010 FU NHLBI NIH HHS [HL07843, HL59407] NR 27 TC 30 Z9 33 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD JUN PY 2003 VL 125 IS 6 BP 1461 EP 1469 DI 10.1016/S0022-5223(02)73229-7 PG 9 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 696BG UT WOS:000183864700036 PM 12830068 ER PT J AU Walther, MM Grubb, RL AF Walther, MM Grubb, RL TI Re: Chromophobe renal cell carcinoma in a patient with the Birt-Hogg-Dube syndrome SO JOURNAL OF UROLOGY LA English DT Letter ID TUMORS C1 NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Walther, MM (reprint author), NCI, Urol Oncol Branch, Bldg 10 Room 2B47, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JUN PY 2003 VL 169 IS 6 BP 2303 EP 2304 DI 10.1097/01.ju.0000065420.78483.d1 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 679NU UT WOS:000182929500088 PM 12771781 ER PT J AU Miller, DL Balter, S Cole, PE Lu, HT Schueler, BA Geisinger, M Berenstein, A Albert, R Georgia, JD Noonan, PT Cardella, JF George, JS Russell, EJ Malisch, TW Vogelzang, RL Miller, GL Anderson, J AF Miller, DL Balter, S Cole, PE Lu, HT Schueler, BA Geisinger, M Berenstein, A Albert, R Georgia, JD Noonan, PT Cardella, JF George, JS Russell, EJ Malisch, TW Vogelzang, RL Miller, GL Anderson, J TI Radiation doses in interventional radiology procedures: The RAD-IR Study - Part I: Overall measures of dose SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID UTERINE ARTERY EMBOLIZATION; FLUOROSCOPICALLY GUIDED PROCEDURES; INDUCED SKIN INJURIES; CARDIAC-CATHETERIZATION; NEURORADIOLOGICAL PROCEDURES; AREA PRODUCT; PATIENT; EXPOSURE; DOSIMETRY; CARDIOLOGY AB PURPOSE: To determine patient radiation doses for interventional radiology and neuroradiology procedures, to identify procedures associated with higher radiation doses, and to determine the effects of various parameters on patient doses. MATERIALS AND METHODS: A prospective observational study was performed at seven academic medical centers. Each site contributed demographic and radiation dose data for subjects undergoing specific procedures in fluoroscopic suites equipped with built-in cumulative dose (CD) and dose-area-product (DAP) measurement capability compliant with International Electrotechnical Commission standard 60601-2-43. The accuracy of the dosimetry was confirmed by comprehensive measurements and by frequent consistency checks performed over the course of the study. RESULTS: Data were collected on 2,142 instances of interventional radiology procedures, 48 comprehensive physics evaluations, and 581 periodic consistency checks from the 12 fluoroscopic units in the study. There were wide variations in dose and statistically significant differences in fluoroscopy time, number of images, DAP, and CD for different instances of the same procedure, depending on the nature of the lesion, its anatomic location, and the complexity of the procedure. For the 2,142 instances, observed CD and DAP correlate well overall (r = 0.83, P < .000001), but correlation in individual instances is poor. The same is true for the correlation between fluoroscopy time and CD (r = 0.79, P < .000001). The correlation between fluoroscopy time and DAP (r = 0.60, P < .000001) is not as good. In 6% of instances (128 of 2,142), which were principally embolization procedures, transjugular intrahepatic portosystemic shunt (TIPS) procedures, and renal/visceral artery stent placements, CD was greater than 5 Gy. CONCLUSIONS: Most procedures studied can result in clinically significant radiation dose to the patient, even when performed by trained operators with use of dose-reducing technology and modem fluoroscopic equipment. Embolization procedures, TIPS creation, and renal/visceral artery stent placement are associated with a substantial likelihood of clinically significant patient dose. At minimum, patient dose data should be recorded in the medical record for these three types of procedures. These data should include indicators of the risk of deterministic effects as well as the risk of stochastic effects. C1 Natl Naval Med Ctr, Dept Radiol, Bethesda, MD 20889 USA. Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Radiol & Nucl Med, Bethesda, MD 20814 USA. Natl Canc Inst, Med Oncol Clin Res Unit, Canc Res Ctr, Bethesda, MD USA. US FDA, Ctr Devices & Radiol Hlth, Rockville, MD 20857 USA. Lenox Hill Hosp, Dept Med, New York, NY 10021 USA. Beth Israel Deaconess Med Ctr, Hyman Newman Inst Neurol & Neurosurg, Ctr Endovasc Surg, New York, NY 10003 USA. SUNY Upstate Med Univ, Dept Radiol, Syracuse, NY USA. Yale Univ, Sch Med, Dept Diagnost Radiol, New Haven, CT 06510 USA. Mayo Clin, Dept Radiol, Rochester, MN USA. Cleveland Clin Fdn, Dept Radiol, Cleveland, OH 44195 USA. Northwestern Univ, Feinberg Sch Med, Northwestern Mem Hosp, Dept Radiol, Chicago, IL 60611 USA. Univ Texas, SW Med Ctr, Dept Radiol, Dallas, TX 75230 USA. RP Natl Naval Med Ctr, Dept Radiol, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM dm72v@nih.gov NR 52 TC 177 Z9 183 U1 0 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD JUN PY 2003 VL 14 IS 6 BP 711 EP 727 DI 10.1097/01.RVI.0000079980.80153.4B PG 17 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 691UV UT WOS:000183625000004 PM 12817038 ER PT J AU Baker, J Blackwell, M Buss, D Eyre, P Held, JR Ogilvie, T Pappaioanou, M Sawyer, L AF Baker, J Blackwell, M Buss, D Eyre, P Held, JR Ogilvie, T Pappaioanou, M Sawyer, L TI Strategies for educational action to meet veterinary medicine's role in biodefense and public health SO JOURNAL OF VETERINARY MEDICAL EDUCATION LA English DT Article; Proceedings Paper CT Conference on An Agenda for Action: Veterinary Medicines Role in Biodefense and Public Health CY NOV 01-03, 2002 CL WASHINGTON, D.C. AB It is clear that the profession is not well prepared to respond to society's needs in biodefense and public health. The imperatives that face the veterinary profession, as emphasized by the Agenda for Action Conference deliberations that are reported in this issue of the journal, require action on many fronts, but possibly none more essential than to address how veterinary education needs to change to meet these challenges. Addressing these needs, participants at the Agenda for Action conference met in groups of 30 to 50 to shape approaches that would address these key questions. The 161 participants were broadly representative of government, private practice, corporate practice, organized veterinary medicine, and academia (Appendix A). Reported here are the results of those deliberations, with each of the seven sections written up by the discussion leader. Included in the participants were 20 students, representative of eight different veterinary colleges, who both participated in the group discussions and have presented their own report.(1) C1 Univ Tennessee, Coll Vet Med, Sch Vet Med, Knoxville, TN 37996 USA. Univ Wisconsin, Coll Vet Med, Sch Vet Med, Madison, WI 53706 USA. VA MD Reg Coll, Coll Vet Med, Sch Vet Med, Blacksburg, VA USA. Univ Prince Edward Isl, Coll Vet Med, Sch Vet Med, Charlottetown, PE C1A 4P3, Canada. Michigan State Univ, Coll Vet Med, E Lansing, MI 48824 USA. US PHS, Washington, DC 20201 USA. Ctr Dis Control & Prevent, Off Global Hlth, Atlanta, GA 30333 USA. NIAID, Clin Trials & Invest Program, Enter & Hepat Dis Branch, Div Microbiol & Infect Dis,NIH, Bethesda, MD 20892 USA. RP Baker, J (reprint author), Univ Tennessee, Coll Vet Med, Sch Vet Med, Knoxville, TN 37996 USA. NR 1 TC 14 Z9 14 U1 0 U2 0 PU UNIV TORONTO PRESS INC PI TORONTO PA JOURNALS DIVISION, 5201 DUFFERIN ST, DOWNSVIEW, TORONTO, ON M3H 5T8, CANADA SN 0748-321X J9 J VET MED EDUC JI J. Vet. Med. Educ. PD SUM PY 2003 VL 30 IS 2 BP 164 EP 172 DI 10.3138/jvme.30.2.164 PG 9 WC Education, Scientific Disciplines; Veterinary Sciences SC Education & Educational Research; Veterinary Sciences GA 704WE UT WOS:000184363200020 PM 12970866 ER PT J AU Watanabe, T Sugaya, M Atkins, AM Aquilino, EA Yang, A Borris, DL Brady, J Blauvelt, A AF Watanabe, T Sugaya, M Atkins, AM Aquilino, EA Yang, A Borris, DL Brady, J Blauvelt, A TI Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen prolongs the life span of primary human umbilical vein endothelial cells SO JOURNAL OF VIROLOGY LA English DT Article ID MULTICENTRIC CASTLEMANS-DISEASE; PRIMARY EFFUSION LYMPHOMA; PROTEIN-COUPLED RECEPTOR; EPSTEIN-BARR-VIRUS; GENE-EXPRESSION; DNA-SEQUENCES; TUMOR-SUPPRESSOR; SPINDLE CELLS; CYCLIN D; HUMAN-HERPESVIRUS-8 AB Tumor spindle cells in all clinical types of Kaposi's sarcoma (KS) are infected with Kaposi's sarcoma-associated herpesvirus (KSHV). Although KSHV contains more than 80 genes, only a few are expressed in tumor spindle cells, including latency-associated nuclear antigen (LANA) and k-cyclin (kCYC). To assess the oncogenic potential of LANA and kCYC, primary human umbilical vein endothelial cells (HUVEC) and murine NIH 3T3 cells were stably transduced by using recombinant retroviruses expressing these genes or the known viral oncogene simian virus 40 large T antigen (LTAg). Interestingly, LANA-transduced HUVEC proliferated faster and demonstrated a greatly prolonged life span (mean +/- standard deviation, 38.3 +/- 11.0 passages) than untransduced cells and vector-transduced cells (<20 passages). By contrast, kCYC-transduced HUVEC did not proliferate faster or live longer than control cells. LANA- and kCYC-transduced HUVEC, but not LTAg-transduced HUVEC, retained the ability to form normal vessel-like structures in an in vitro model of angiogenesis. In cellular assays of transformation, LANA- and kCYC-transduced NIH 3T3 cells demonstrated minimal or no anchorage-independent growth in soft agar and no tumorigenicity when injected into nude mice, unlike LTAg-transduced NIH 3T3 cells. Lastly, gene expression profiling revealed down-regulation, or silencing, of a number of genes within LANA-transduced HUVEC. Taken together, these results suggest that KSHV LANA is capable of inducing prolonged life span, but not transformation, in primary human cells. These findings may explain why LANA-expressing spindle cells proliferate within KS tumors, yet most often do not demonstrate biologic characteristics of transformation or true malignant conversion. C1 NCI, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Virus Tumor Biol Sect, Basic Res Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Blauvelt, A (reprint author), NCI, Dermatol Branch, Ctr Canc Res, Bldg 10,Rm 12N238,10 Ctr Dr MSC 1908, Bethesda, MD 20892 USA. EM blauvelt@mail.nih.gov NR 68 TC 59 Z9 62 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2003 VL 77 IS 11 BP 6188 EP 6196 DI 10.1128/JVI.77.11.6188-6196.2003 PG 9 WC Virology SC Virology GA 679NL UT WOS:000182928800010 PM 12743275 ER PT J AU Dehghani, H Puffer, BA Doms, RW Hirsch, VM AF Dehghani, H Puffer, BA Doms, RW Hirsch, VM TI Unique pattern of convergent envelope evolution in simian immunodeficiency virus-infected rapid progressor macaques: Association with CD4-independent usage of CCR5 SO JOURNAL OF VIROLOGY LA English DT Article ID DISEASE PROGRESSION; TYPE-1 INFECTION; RHESUS-MONKEYS; MACROPHAGE TROPISM; VIRAL REPLICATION; VACCINIA VIRUS; NEUTRALIZATION SENSITIVITY; CHEMOKINE RECEPTORS; SEQUENCE VARIATION; HIV-1 INFECTION AB The rate of disease development in simian immunodeficiency virus (SIV) infection of macaques varies considerably among individual macaques. While the majority of macaques inoculated with pathogenic SIV develop AIDS within a period of 1 to 2 years, a minority exhibit a rapid disease course characterized by absence or transience of humoral and cellular immune responses and high levels of virus replication with widespread dissemination of SIV in macrophages and multinucleated giant cells. The goal of this study was to examine viral evolution in three SIVsmE543-3-inoculated rapid progressors to determine the contribution of viral evolution to the development of rapid disease and the effect of the absence of immune pressure upon viral evolution. PCR was used to amplify and clone the entire SIV genome from tissues collected at necropsy, and the course of viral evolution was assessed by env sequences cloned from sequential plasma samples of one rapid progressor (RP) macaque. The majority of sequence changes in RP macaques occurred in the envelope genes Substitutions were observed in all three animals at specific conserved residues in envelope, including loss of a glycosylation site in V1/V2, a D-to-N/V substitution in a highly conserved GDPE motif, and a P-to-V/H/T substitution in the V3 loop analog. A cell-cell fusion assay revealed that representative env clones utilized CCR5 as a coreceptor, independent of CD4. The selection of specific substitutions in envelope in RP macaques suggests novel selection pressures on virus in such animals and suggests that viral variants that evolve in these animals may play a role in disease progression. C1 NIAID, Mol Microbiol Lab, NIH, Rockville, MD 20852 USA. Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA. RP Hirsch, VM (reprint author), Twinbrook 2 Facil,12441 Parklawn Dr, Rockville, MD 20852 USA. NR 72 TC 32 Z9 32 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 JUN PY 2003 VL 77 IS 11 BP 6405 EP 6418 DI 10.1128/JVI.77.11.6405-6418.2003 PG 14 WC Virology SC Virology GA 679NL UT WOS:000182928800033 PM 12743298 ER PT J AU Conway, JF Watts, NR Belnap, DM Cheng, N Stahl, SJ Wingfield, PT Steven, AC AF Conway, JF Watts, NR Belnap, DM Cheng, N Stahl, SJ Wingfield, PT Steven, AC TI Characterization of a conformational epitope on hepatitis B virus core antigen and quasiequivalent variations in antibody binding SO JOURNAL OF VIROLOGY LA English DT Article ID X-RAY CRYSTALLOGRAPHY; CRYOELECTRON MICROSCOPY; NEUTRALIZING ANTIBODY; CAPSID PROTEIN; DENSITY MAPS; ELECTRON CRYOMICROSCOPY; MONOCLONAL-ANTIBODY; ICOSAHEDRAL VIRUS; PARTICLES; PEPTIDE AB We have characterized a conformational epitope on capsids of hepatitis B virus (HBV) by cryo-electron microscopy and three-dimensional image reconstruction of Fab-labeled capsids to similar to10-Angstrom resolution, combined with molecular modeling. The epitope straddles the interface between two adjacent subunits and is discontinuous, consisting of five peptides-two on one subunit and three on its neighbor. Together, the two icosahedral forms of the HBV capsid-T=3 and T=4 particles-present seven quasiequivalent variants of the epitope. Of these, only three bind this Fab. Occupancy ranges from similar to100 to similar to0%, reflecting conformational variations in the epitope and steric blocking effects. In the former, small shifts of the component peptides have large effects on binding affinity. This approach appears to hold general promise for elucidating conformational epitopes of HBV and other viruses, including those of neutralizing and diagnostic significance. C1 Inst Biol Struct JP Ebel, Lab Microscopie Elect, F-38027 Grenoble, France. NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. RP Steven, AC (reprint author), NIAMSD, Struct Biol Lab, NIH, Bldg 50,Rm 1517,MSC 8025, Bethesda, MD 20892 USA. RI Conway, James/A-2296-2010 OI Conway, James/0000-0002-6581-4748 NR 46 TC 50 Z9 53 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2003 VL 77 IS 11 BP 6466 EP 6473 DI 10.1128/JVI.77.11.6466-6473.2003 PG 8 WC Virology SC Virology GA 679NL UT WOS:000182928800038 PM 12743303 ER PT J AU Goila-Gaur, R Demirov, DG Orenstein, JM Ono, A Freed, EO AF Goila-Gaur, R Demirov, DG Orenstein, JM Ono, A Freed, EO TI Defects in human immunodeficiency virus budding and endosomal sorting induced by TSG101 overexpression SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; VESICULAR STOMATITIS-VIRUS; LATE DOMAIN FUNCTION; ROUS-SARCOMA VIRUS; UBIQUITIN-PROTEASOME SYSTEM; INFECTIOUS-ANEMIA VIRUS; LATE ASSEMBLY DOMAIN; PROLINE-RICH MOTIF; GAG PROTEIN; MULTIVESICULAR BODY AB Retrovirus budding is greatly stimulated by the presence of Gag sequences known as late or L domains. The L domain of human immunodeficiency virus type 1 (HIV-1) maps to a highly conserved Pro-Thr-Ala-Pro (PTAP) sequence in the p6 domain of Gag. We and others recently observed that the p6 PTAP motif interacts with the cellular endosomal sorting protein TSG101. Consistent with a role for TSG101 in virus release, we demonstrated that overexpressing the N-terminal, Gag-binding domain of TSG101 (TSG-5') suppresses HIV-1 budding by blocking L domain function. To elucidate the role of TSG101 in HIV-1 budding, we evaluated the significance of the binding between Gag and TSG-5' on the inhibition of HIV-1 release. We observed that a mutation in TSG-5' that disrupts the Gag/TSG101 interaction suppresses the ability of TSG-5' to inhibit HIV-1 release. We also determined the effect of overexpressing a panel of truncated TSG101 derivatives and full-length TSG101 (TSG-F) on virus budding. Overexpressing TSG-F inhibits HIV-1 budding; however, the effect of TSG-F on virus release does not require Gag binding. Furthermore, overexpression of the C-terminal portion of TSG101 (TSG-3') potently inhibits budding of not only HIV-1 but also murine leukemia virus. Confocal microscopy data indicate that TSG-F and TSG-3' overexpression induces an aberrant endosome phenotype; this defect is dependent upon the C-terminal, Vps-28-binding domain of TSG101. We propose that TSG-5' suppresses HIV-1 release by binding PTAP and blocking HIV-1 L domain function, whereas overexpressing TSG-F or TSG-3' globally inhibits virus release by disrupting the cellular endosomal sorting machinery. These results highlight the importance of TSG101 and the endosomal sorting pathway in virus budding and suggest that inhibitors can be developed that, like TSG-5', target HIV-1 without disrupting endosomal sorting. C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. George Washington Univ, Med Ctr, Dept Pathol, Washington, DC 20037 USA. RP Freed, EO (reprint author), NIAID, Mol Microbiol Lab, NIH, Bldg 4,Rm 307, Bethesda, MD 20892 USA. OI Ono, Akira/0000-0001-7841-851X NR 64 TC 69 Z9 71 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2003 VL 77 IS 11 BP 6507 EP 6519 DI 10.1128/JVI.77.11.6507-6519.2003 PG 13 WC Virology SC Virology GA 679NL UT WOS:000182928800042 PM 12743307 ER PT J AU Haque, M Davis, DA Wang, V Widmer, I Yarchoan, R AF Haque, M Davis, DA Wang, V Widmer, I Yarchoan, R TI Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) contains hypoxia response elements: Relevance to lytic induction by hypoxia SO JOURNAL OF VIROLOGY LA English DT Article ID INDUCIBLE FACTOR 1-ALPHA; LYMPHOMA CELL-LINE; FACTOR GENE-TRANSCRIPTION; PAS DOMAIN PROTEIN-1; EPSTEIN-BARR-VIRUS; DNA-SEQUENCES; EXPRESSION; FACTOR-1; IDENTIFICATION; ACTIVATION AB Kaposi's sarcoma (KS)-associated herpesvirus (KSHV), also known as human herpesvirus 8, is an etiologic agent of KS, primary effusion lymphoma (PEL), and multicentric Castleman's disease. We recently demonstrated that hypoxia can induce lytic replication of KSHV in PEL cell lines. Hypoxia induces the accumulation of hypoxia-inducible factors (HIF), and we hypothesized that the KSHV genome may respond to hypoxia through functional hypoxia response elements (HREs). Here, we demonstrate the presence of at least two promoters within the KSHV genome that are activated by hypoxia or hypoxia mimics. One is in the promoter region of the gene for Rta, the main lytic switch gene, and the other is within the promoter region of ORF34, a lytic gene of unknown function. The ORF34 promoter contains three putative consensus HREs oriented in the direction of the gene. Dissection and site-directed mutagenesis studies confirmed that one of the HREs of the ORF34 promoter is functional. Under conditions of hypoxia, the ORF34 promoter was strongly upregulated by HIF-1alpha and HIF-2alpha. By contrast, the promoter of the gene for Rta appeared to be preferentially upregulated by HIF-2alpha. Reverse transcription-PCR analysis revealed that specific messages for ORF34 and ORF50 are upregulated in BCBL-1 cells exposed to hypoxia. An HIF-1 binding and competition assay demonstrated that the HRE sequence from the ORF34 promoter can compete for HIF-1alpha binding to an erythropoietin HRE oligonucleotide while a mutant sequence cannot. Thus, we demonstrated that a viral gene can be activated by hypoxia through activation of a functional viral HRE. To our knowledge, this is the first example of a functional HRE in a viral promoter. C1 NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. RP Yarchoan, R (reprint author), NCI, HIV & AIDS Malignancy Branch, NIH, Bldg 10,Room 10S255,MSC 1868, Bethesda, MD 20892 USA. EM yarchoan@helix.nih.gov NR 40 TC 71 Z9 74 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 JUN PY 2003 VL 77 IS 12 BP 6761 EP 6768 DI 10.1128/JVI.77.12.6761-6768.2003 PG 8 WC Virology SC Virology GA 684LT UT WOS:000183209400018 PM 12767996 ER PT J AU Bossis, I Chiorini, JA AF Bossis, I Chiorini, JA TI Cloning of an avian adeno-associated virus (AAAV) and generation of recombinant AAAV particles SO JOURNAL OF VIROLOGY LA English DT Article ID INVERTED TERMINAL REPETITION; HUMAN GENE-THERAPY; ADENOASSOCIATED VIRUS; NUCLEOTIDE-SEQUENCE; ENDONUCLEASE ACTIVITY; MUTATIONAL ANALYSIS; DNA REPLICATION; PROTEIN-KINASE; REP68 PROTEIN; HUMAN-CELLS AB Recent studies have proposed that adeno-associated viruses (AAVs) are not evolutionarily linked to other mammalian autonomous parvoviruses but are more closely linked to the autonomous parvoviruses of birds. To better understand the relationship between primate and avian AAVs (AAAVs), we cloned and sequenced the genome of an AAAV (ATCC VR-865) and generated recombinant AAAV particles. The genome of AAAV is 4,694 nucleotides in length and has organization similar to that of other AAVs. The entire genome of AAAV displays 56 to 65% identity at the nucleotide level with the other known AAVs. The AAAV genome has inverted terminal repeats of 142 nucleotides, with the first 122 forming the characteristic T-shaped palindromic structure. The putative Rep-binding element consists of a tandem (GAGY)(4) repeat, and the putative terminal resolution site (trs), CCGGT/CG, contains a single nucleotide substitution relative to the AAV(2) trs. The Rep open reading frame of AAAV displays 50 to 54% identity at the amino acid level with the other AAVs, with most of the diversity clustered at the carboxyl and amino termini. Comparison of the capsid proteins of AAAV and the primate dependoviruses indicate that divergent regions are localized to surface-exposed loops. Despite these sequence differences, we were able to produce recombinant AAAV particles carrying a lacZ reporter gene by cotransfection in 293T cells and were able to examine transduction efficiency in both chicken primary cells and several cell lines. Our findings indicate that AAAV is the most divergent AAV described to date but maintains all the characteristics unique to the genera of dependovirus. C1 NIDCR, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Chiorini, JA (reprint author), NIDCR, Gene Therapy & Therapeut Branch, NIH, 10-1N113,10 Ctr Dr,MSC 1190, Bethesda, MD 20892 USA. NR 70 TC 36 Z9 47 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 JUN PY 2003 VL 77 IS 12 BP 6799 EP 6810 DI 10.1128/JVI.77.12.6799-6810.2003 PG 12 WC Virology SC Virology GA 684LT UT WOS:000183209400022 PM 12768000 ER PT J AU Alexander, L Illyinskii, PO Lang, SM Means, RE Lifson, J Mansfield, K Desrosiers, RC AF Alexander, L Illyinskii, PO Lang, SM Means, RE Lifson, J Mansfield, K Desrosiers, RC TI Determinants of increased replicative capacity of serially passaged simian immunodeficiency virus with nef deleted in rhesus monkeys SO JOURNAL OF VIROLOGY LA English DT Article ID T-CELL ACTIVATION; GLYCOPROTEIN CYTOPLASMIC DOMAIN; ATTENUATED VACCINE STRAINS; POLYMERASE CHAIN-REACTION; UPSTREAM U3 SEQUENCES; CD4 DOWN-REGULATION; HIV-1 NEF; INFECTED-CELLS; ENVELOPE GLYCOPROTEINS; LYMPHOCYTE-ACTIVATION AB Most rhesus macaques infected with simian immunodeficiency virus SIVmac239 with nef deleted (either Deltanef or DeltanefDeltavprDeltaUS [Delta3]) control viral replication and do not progress to AIDS. Some monkeys, however, develop moderate viral load set points and progress to AIDS. When simian immunodeficiency viruses (SIVs) recovered from two such animals (one Deltanef and the other Delta3) were serially passaged in rhesus monkeys, the SIVs derived from both lineages were found to consistently induce moderate viral loads and disease progression. Analysis of viral sequences in the serially passaged derivatives revealed interesting changes in three regions: (i) an unusually high number of predicted amino acid changes (12 to 14) in the cytoplasmic domain of gp41, most of which were in regions that are usually conserved; these changes were observed in both lineages; (ii) an extreme shortening of nef sequences in the region of overlap with U3; these changes were observed in both lineages; and (iii) duplication of the NF-kappaB binding site in one lineage only. Neither the polymorphic gp41 changes alone nor the U3 deletion alone appeared to be responsible for increased replicative capacity because recombinant SIVmac239Deltanef, engineered to contain either of these changes, induced moderate viral loads in only one of six monkeys. However, five of six monkeys infected with recombinant SIVmac239Deltanef containing both TM and U3 changes did develop persisting moderate viral loads. These genetic changes did not increase lymphoid cell-activating properties in the monkey interleukin-2-dependent T-cell line 221, but the gp41 changes did increase the fusogenic activity of the SIV envelope two- to threefold. These results delineate sequence changes in SIV that can compensate for the loss of the nef gene to partially restore replicative and pathogenic potential in rhesus monkeys. C1 Harvard Univ, New England Reg Primate Res Ctr, Sch Med, Southborough, MA 01772 USA. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. Chemgenom Inc, Medford, MA 02155 USA. NCI, SAIC Frederick, AIDS Vaccine Program, Frederick, MD 21702 USA. RP Desrosiers, RC (reprint author), Harvard Univ, New England Reg Primate Res Ctr, Sch Med, 1 Pine Hill Dr,Box 9102, Southborough, MA 01772 USA. FU NCI NIH HHS [N01-C0-012400, N01-CO-12400]; NCRR NIH HHS [K26 RR000168, P51 RR000168, RR00168]; NIAID NIH HHS [AI25328, AI35365, P01 AI035365, R01 AI025328, R37 AI025328, U01 AI035365] NR 73 TC 50 Z9 50 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2003 VL 77 IS 12 BP 6823 EP 6835 DI 10.1128/JVI.77.12.6823-6835.2003 PG 13 WC Virology SC Virology GA 684LT UT WOS:000183209400024 PM 12768002 ER PT J AU Migueles, SA Laborico, AC Imamichi, H Shupert, WL Royce, C McLaughlin, M Ehler, L Metcalf, J Liu, SY Hallahan, CW Connors, M AF Migueles, SA Laborico, AC Imamichi, H Shupert, WL Royce, C McLaughlin, M Ehler, L Metcalf, J Liu, SY Hallahan, CW Connors, M TI The differential ability of HLA b*5701(+) long-term nonprogressors and progressors to restrict human immunodeficiency virus replication is not caused by loss of recognition of autologous viral gag sequences SO JOURNAL OF VIROLOGY LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; ACTIVE ANTIRETROVIRAL THERAPY; RECOMBINANT VACCINIA VIRUS; CHORIOMENINGITIS VIRUS; CELL RESPONSES; HIV-INFECTION; CLASS-I; SLOW PROGRESSORS; ESCAPE VARIANTS; EPITOPE AB Although the HLA B*5701 class I allele is highly overrepresented among human immunodeficiency virus (HIV)-infected long-term nonprogressors (LTNPs), it is also present at the expected frequency (11%) in patients with progressive HIV infection. Whether B57(+) progressors lack restriction of viral replication because of escape from recognition of highly immunodominant B57-restricted gag epitopes by CD8(+) T cells remains unknown. In this report, we investigate the association between restriction of virus replication and recognition of autologous virus sequences in 27 B*57(+) patients (10 LTNPs and 17 progressors). Amplification and direct sequencing of single molecules of viral cDNA or proviral DNA revealed low frequencies of genetic variations in these regions of gag. Furthermore, CD8(+) T-cell recognition of autologous viral variants was preserved in most cases. In two patients, responses to autologous viral variants were not demonstrable at one epitope. By using a novel technique to isolate primary CD4(+) T cells expressing autologous viral gene products, it was found that 1 to 13% of CD8(+) T cells were able to respond to these cells by gamma interferon production. In conclusion, escape-conferring mutations occur infrequently within immunodominant B57-restricted gag epitopes and are not the primary mechanism of virus evasion from immune control in B*5701(+) HIV-infected patients. Qualitative features of the virus-specific CD8(+) T-cell response not measured by current assays remain the most likely determinants of the differential abilities of HLA B*5701(+) LTNPs and progressors to restrict virus replication. C1 NIAID, LIR, NIH, Bethesda, MD 20892 USA. NCI, Sci Applicat Int Corp, Canc Res & Dev Ctr, Frederick, MD 21701 USA. RP Connors, M (reprint author), NIAID, LIR, NIH, Bldg 10,Rom 11B-09,10 Ctr Dr,MSC 1876, Bethesda, MD 20892 USA. NR 53 TC 116 Z9 120 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 JUN PY 2003 VL 77 IS 12 BP 6889 EP 6898 DI 10.1128/JVI.77.12.6889-6898.2003 PG 10 WC Virology SC Virology GA 684LT UT WOS:000183209400030 PM 12768008 ER PT J AU Zhang, KY Rana, F Silva, C Ethier, J Wehrly, K Chesebro, B Power, C AF Zhang, KY Rana, F Silva, C Ethier, J Wehrly, K Chesebro, B Power, C TI Human immunodeficiency virus type 1 envelope-mediated neuronal death: Uncoupling of viral replication and neurotoxicity SO JOURNAL OF VIROLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; AIDS DEMENTIA COMPLEX; IN-SITU HYBRIDIZATION; CHEMOKINE RECEPTORS; HIV-INFECTION; CEREBROSPINAL-FLUID; NEUROLOGICAL DISEASE; MACROPHAGE TROPISM; MURINE RETROVIRUS; CEREBRAL-CORTEX AB Although brain tissue from patients with human immunodeficiency virus (HIV) and/or AIDS is consistently infected by HIV type 1 (HIV-1), only 20 to 30% of patients exhibit clinical or neuropathological evidence of brain injury. Extensive HIV-1 sequence diversity is present in the brain, which may account in part for the variability in the occurrence of HIV-induced brain disease. Neurological injury caused by HIV-1 is mediated directly by neurotoxic viral proteins or indirectly through excess production of host molecules by infected or activated glial cells. To elucidate the relationship between HIV-1 infection and neuronal death, we examined the neurotoxic effects of supernatants from human 293T cells or macrophages expressing recombinant HIV-1 virions or gp120 proteins containing the V1V3 or C2V3 envelope region from non-clade B, brain-derived HIV-1 sequences. Neurotoxicity was measured separately as apoptosis or total neuronal death, with apoptosis representing 30 to 80% of the total neuron death observed, depending on the individual virus. In addition, neurotoxicity was dependent on expression of HIV-1 gp120 and could be blocked by anti-gp120 antibodies, as well as by antibodies to the human CCR5 and CXCR4 chemokine receptors. Despite extensive sequence diversity in the recombinant envelope region (V1V3 or C2V3), there was limited variation in the neurotoxicity induced by supernatants from transfected 293T cells. Conversely, supernatants from infected macrophages caused a broader range of neurotoxicity levels that depended on each virus and was independent of the replicative ability of the virus. These findings underscore the importance of HIV-1 envelope protein expression in neurotoxic pathways associated with HIV-induced brain disease and highlight the envelope as a target for neuroprotective therapeutic interventions. C1 Univ Calgary, Dept Clin Neurosci, Neurosci Res Grp, Calgary, AB T2N 4N1, Canada. Univ Calgary, Dept Microbiol & Infect Dis, Calgary, AB T2N 4N1, Canada. Univ Nairobi, Nairobi, Kenya. NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. RP Power, C (reprint author), Univ Calgary, Dept Clin Neurosci, Neurosci Res Grp, HMRB 150,3330 Hosp Dr NW, Calgary, AB T2N 4N1, Canada. RI Power, Christopher/C-7181-2013; OI Power, Christopher/0000-0002-5131-9711 NR 85 TC 36 Z9 39 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2003 VL 77 IS 12 BP 6899 EP 6912 DI 10.1128/JVI.77.12.6899-6912.2003 PG 14 WC Virology SC Virology GA 684LT UT WOS:000183209400031 PM 12768009 ER PT J AU Cheslock, SR Poon, DTK Fu, W Rhodes, TD Henderson, LE Nagashima, K McGrath, CF Hu, WS AF Cheslock, SR Poon, DTK Fu, W Rhodes, TD Henderson, LE Nagashima, K McGrath, CF Hu, WS TI Charged assembly helix motif in murine leukemia virus capsid: an important region for virus assembly and particle size determination SO JOURNAL OF VIROLOGY LA English DT Article ID ROUS-SARCOMA VIRUS; MAJOR-HOMOLOGY-REGION; GAG PROTEIN; IN-VITRO; TYPE-1; HIV-1; DNA; DOMAIN; RNA; CORE AB We have identified a region near the C terminus of capsid (CA) of murine leukemia virus (MLV) that contains many charged residues. This motif is conserved in various lengths in most MLV-like viruses. One exception is that spleen necrosis virus (SNV) does not contain a well-defined domain of charged residues. When 33 amino acids of the MLV motif were deleted to mimic SNV CA, the resulting mutant produced drastically reduced amounts of virions and the virions were noninfectious. Furthermore, these viruses had abnormal sizes, often contained punctate structures resembling those in the cell cytoplasm, and packaged both ribosomal and viral RNA. When 11 or 15 amino acids were deleted to modify the MLV CA to resemble those from other gammaretroviruses, the deletion mutants produced virions at,levels comparable to those of the wild-type virus and were able to complete one round of virus replication without detectable defects. We generated 10 more mutants that displayed either the wild-type or mutant phenotype. The distribution of the wild-type or mutant phenotype did not directly correlate with the number of amino acids deleted, suggesting that the function of the motif is determined not simply by its length but also by its structure. Structural modeling of the wild-type and mutant proteins suggested that this region forms alpha-helices; thus, we termed this motif the "charged assembly helix." This is the first description of the charged assembly helix motif in MLV CA and demonstration of its role in virus budding and assembly. C1 NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. Sci Applicat Int Corp, AIDS Vaccine Program, Frederick, MD 21702 USA. Sci Applicat Int Corp, Image Anal Lab, Frederick, MD 21702 USA. Sci Applicat Int Corp, Struct Based Drug Discovery Grp, Frederick, MD 21702 USA. W Virginia Univ, Dept Microbiol Immunol & Cell Biol, Sch Med, Morgantown, WV 26506 USA. RP Hu, WS (reprint author), NCI, HIV Drug Resistance Program, Bldg 535,Rm 336, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400, N01CO12400] NR 41 TC 28 Z9 28 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2003 VL 77 IS 12 BP 7058 EP 7066 DI 10.1128/JVI.77.12.7058-7066.2003 PG 9 WC Virology SC Virology GA 684LT UT WOS:000183209400047 PM 12768025 ER PT J AU Lin, XX Derdeyn, CA Blumenthal, R West, J Hunter, E AF Lin, XX Derdeyn, CA Blumenthal, R West, J Hunter, E TI Progressive truncations C terminal to the membrane-spanning domain of simian immunodeficiency virus Env reduce fusogenicity and increase concentration dependence of Env for fusion SO JOURNAL OF VIROLOGY LA English DT Article ID ANCHORED INFLUENZA HEMAGGLUTININ; CELL-CELL FUSION; TYPE-1 ENVELOPE GLYCOPROTEIN; TRANSMEMBRANE PROTEIN; CYTOPLASMIC DOMAIN; PORE FORMATION; HIV-1 GP41; HEMIFUSION; ENTRY; TRANSITION AB The simian immunodeficiency virus (SIV) transmembrane (TM) protein, gp41, has multiple functions, which include anchoring the glycoprotein complex in the lipid envelope of the virus and mediating fusion of the virus and host cell membranes. Recently, a series of mutants of the SIVmac239 TM protein that have truncations at the carboxyl terminus of the membrane-spanning domain (MSD) have been characterized (J. T. West, P. Johnston, S. R. Dubay, and E. Hunter, J. Virol. 75:9601-9612, 2001). These mutants retained membrane anchorage but demonstrated reduced fusogenicity and infectivity as the MSD length was shortened. We have established a novel three-color fluorescence assay, which allows qualitative confocal and quantitative flow cytometric analyses, to further characterize the nature of the fusion defect in five of the MSD mutants: TM185, TM186, TM187, TM188, and TM189. Our analysis showed that each mutant could mediate complete lipid and aqueous dye transfer at early time points after effector and target cell mixing. No hemifusion with only lipid dye flux was detected. However, another intermediate fusion stage, which appears to involve small-fusion-pore formation that allowed small aqueous dye transfer but prevented the exchange of large cytoplasmic components, was identified infrequently in mutant-Env-expressing cell and target cell mixtures. Quantitative now cytometric analysis of these mutants demonstrated that the TM187, TM188, and TM189 mutants were significantly more fusogenic than TM185 and TM186 but remained significantly impaired compared to the wild type. Moreover, fusion efficiency showed an increased dependence on the expression level of glycoproteins, suggesting that, for these mutants, formation of an active fusion complex was an increasingly stochastic event. C1 Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. NCI, Frederick Canc Res & Dev Ctr, Sect Membrane Struct & Funct, Lab Expt & Computat Biol, Frederick, MD 21702 USA. RP Hunter, E (reprint author), Univ Alabama, Dept Microbiol, 256 Bevill Biomed Res Bldg,845 19th St S, Birmingham, AL 35294 USA. FU NIAID NIH HHS [AI33319, R37 AI033319, R01 AI033319, P30 AI27767, P30 AI027767] NR 47 TC 29 Z9 29 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2003 VL 77 IS 12 BP 7067 EP 7077 DI 10.1128/JVI.77.12.7067-7077.2003 PG 11 WC Virology SC Virology GA 684LT UT WOS:000183209400048 PM 12768026 ER PT J AU Sell, DR Lane, MA Obrenovich, ME Mattison, JA Handy, A Ingram, DK Cutler, RG Roth, GS Monnier, VM AF Sell, DR Lane, MA Obrenovich, ME Mattison, JA Handy, A Ingram, DK Cutler, RG Roth, GS Monnier, VM TI The effect of caloric restriction on glycation and glycoxidation in skin collagen of nonhuman primates SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID MAILLARD REACTION-PRODUCTS; MALE RHESUS-MONKEYS; DIETARY RESTRICTION; DIABETES-MELLITUS; SQUIRREL-MONKEYS; CROSS-LINKING; FOOD RESTRICTION; OXIDATIVE STRESS; SKELETAL-MUSCLE; BLOOD-GLUCOSE AB The accumulation of Maillard reaction products increases with age in long-lived proteins and can be retarded by caloric restriction. Here we determined whether caloric restriction inhibits fort-nation of glycation and glycoxidation products in skin collagen of squirrel and rhesus monkeys between 1990-1997. Restricted monkeys (n = 11, n = 30, respectively) were maintained at 70% of caloric intake of controls (n = 25, n = 32, respectively). Glycation was assessed by furosine and glycoxidation by pentosidine and carboxymethyl-lysine. With age, the rate of furosine formation moderately but nonsignificantly (p > .05) increased in both control monkey groups. It significantly (p = .011) decreased in the caloric-restricted rhesus, but not squirrel monkeys. Caloric restriction did not significantly decrease the pentosidine or carboxymethyl-lysine rates in either species of monkeys. These results suggest that caloric restriction, when maintained long-term in nonhuman primates, tends to decrease glycation, but not glycoxidation. C1 Case Western Reserve Univ, Inst Pathol, Cleveland, OH 44106 USA. NIA, Ctr Gerontol Res, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Natl Inst Hlth Anim Ctr, NIA, Poolesville, MD USA. RP Sell, DR (reprint author), Case Western Reserve Univ, Inst Pathol, 2085 Adelbert Rd, Cleveland, OH 44106 USA. RI Monnier, Vincent/B-1371-2009 FU NIA NIH HHS [AG 18625] NR 54 TC 32 Z9 33 U1 0 U2 3 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUN PY 2003 VL 58 IS 6 BP 508 EP 516 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 689QV UT WOS:000183505200004 PM 12807921 ER PT J AU Sollitto, S Hoffman, S Mehlman, M Lederman, RJ Youngner, SJ Lederman, MM AF Sollitto, S Hoffman, S Mehlman, M Lederman, RJ Youngner, SJ Lederman, MM TI Intrinsic conflicts of interest in clinical research: A need for disclosure SO KENNEDY INSTITUTE OF ETHICS JOURNAL LA English DT Article ID BIOMEDICAL-RESEARCH; TRIALS; POLICIES; CONSENT; BOARDS; CARE AB Protection of human subjects from investigators' conflicts of interest is critical to the integrity of clinical investigation. Personal financial conflicts of interest are addressed by university policies, professional society guidelines, publication standards, and government regulation, but "Intrinsic conflicts of interest"-conflicts of interest inherent in all clinical research-have received relatively less attention. Such conflicts arise in all clinical research endeavors as a result of the tension among professionals' responsibilities to their research and to their patients and both academic and financial incentives. These conflicts should be disclosed to research subjects and managed as assiduously as are financial conflicts of interest. C1 Case Western Reserve Univ, Sch Law, Law Med Ctr, Cleveland, OH 44106 USA. NHLBI, Cardiovasc Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. Case Western Reserve Univ, Sch Med, Ctr AIDS Res, Cleveland, OH 44106 USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. Case Western Reserve Univ, Dept Bioeth, Cleveland, OH USA. RP Sollitto, S (reprint author), Case Western Reserve Univ, Sch Law, Law Med Ctr, Cleveland, OH 44106 USA. FU NIAID NIH HHS [AI 36219, AI 25879] NR 27 TC 24 Z9 25 U1 0 U2 3 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4319 USA SN 1054-6863 J9 KENNEDY INST ETHIC J JI Kennedy Inst. Ethics J. PD JUN PY 2003 VL 13 IS 2 BP 83 EP 91 DI 10.1353/ken.2003.0015 PG 9 WC Ethics; Philosophy; Social Issues SC Social Sciences - Other Topics; Philosophy; Social Issues GA 706VT UT WOS:000184476300002 PM 14569995 ER PT J AU Levashova, ZB Plisov, SY Perantoni, AO AF Levashova, ZB Plisov, SY Perantoni, AO TI Conditionally immortalized cell line of inducible metanephric mesenchyme SO KIDNEY INTERNATIONAL LA English DT Article DE induction; kidney; tubulogenesis; cell line; FGF2; LIF; TGF-beta 2 ID COLLECTING DUCT ANLAGEN; GROWTH-FACTOR; EPITHELIAL TRANSFORMATION; DEVELOPING KIDNEY; DIFFERENTIATION; EXPRESSION; MULTIPLE; RECEPTOR; ACTIVATION; TGF-BETA-2 AB Background. The mesenchymal-epithelial conversion of metanephric mesenchyme (MM) in the formation of nephronic tubules has long served as a paradigm for inductive signaling in morphogenesis. However, the mechanisms underlying this differentiation have remained an enigma due to insufficient numbers of primary mesenchymal cells that must be isolated manually from animal embryos. To overcome this problem, we have established a conditionally immortalized cell line, the rat-inducible metanephric mesenchyme (RIMM-18) by transfection of primary mesenchymal cells with a vector, encoding an estradiol-dependent E1A-ER fusion protein. Methods. Reverse transcription-polymerase chain reaction (RT-PCR), luciferase reporter assay, electrophoretic mobility shift assay, immunocytochemical, and immunohistochemical stainings were used to characterize the established cell line. Results. We demonstrate that in the presence of estradiol, the RIMM-18 cell line proliferates continuously, maintaining mesenchymal characteristics for over 40 passages. These cells are vimentin-positive and cytokeratin-negative. Under inductive conditions in the absence of estradiol, they are responsive to a number of cytokines, which are established inducers of mesenchymal cells in vivo and in vitro [i.e., fibroblast growth factor 2 (FGF2), leukemia inhibitory factor (LIF), and transforming growth factor-beta2 (TGF-beta2)]. We show the presence in RIMM-18 cells of specific protein markers and functionally active signaling pathways required for induction of tubule formation in MM. Furthermore, induced RIMM-18 cells change morphology, acquiring epithelial-like features, and begin to express epithelial markers (e.g., E-cadherin, cytokeratin, gamma-glutamyl-transpeptidase, and secreted frizzled-related protein 2 (sFRP2). Conclusion. This preliminary characterization of the RIMM-18cell line suggests that it will be useful in the study of biochemical and molecular mechanisms of nephronic development and, possibly, of some types of renal cancer such as Wilms' tumor, which caricatures the normal process of kidney development. C1 NCI, Comparat Carcinogenesis Lab, NIH, Frederick, MD 21702 USA. RP Levashova, ZB (reprint author), NCI, Comparat Carcinogenesis Lab, NIH, Bldg 538,Room 221, Frederick, MD 21702 USA. NR 34 TC 11 Z9 21 U1 1 U2 2 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JUN PY 2003 VL 63 IS 6 BP 2075 EP 2087 DI 10.1046/j.1523-1755.2003.00010.x PG 13 WC Urology & Nephrology SC Urology & Nephrology GA 676ZF UT WOS:000182781900011 PM 12753294 ER PT J AU Ray, PE Liu, XH Robinson, LR Reid, W Xu, L Owens, JW Jones, OD Denaro, F Davis, HG Bryant, JL AF Ray, PE Liu, XH Robinson, LR Reid, W Xu, L Owens, JW Jones, OD Denaro, F Davis, HG Bryant, JL TI A novel HIV-1 transgenic rat model of childhood HIV-1-associated nephropathy SO KIDNEY INTERNATIONAL LA English DT Article DE childhood HIV-1 nephropathy; HIV-transgenic rats; basic FGF; captopril ID HUMAN-IMMUNODEFICIENCY-VIRUS; FIBROBLAST-GROWTH-FACTOR; FOCAL SEGMENTAL GLOMERULOSCLEROSIS; ACTIVE ANTIRETROVIRAL THERAPY; COAT PROTEIN GP120; RENAL-DISEASE; EPITHELIAL-CELLS; UP-REGULATION; MICE; CHILDREN AB Background. A characteristic finding of human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is the presence of heavy proteinuria, focal or global glomerulosclerosis, and microcystic tubular dilatation leading to renal enlargement, and rapid progression to end-stage renal disease (ESRD). Methods. We have recently developed the first HIV-1 transgenic rat model that carry a noninfectious HIV-1 DNA construct lacking 3.1 kb of sequence overlapping the gag and pol sequences, and develop many of the clinical lesions seen in HIV-infected patients, including HIVAN. To gain further insight into the pathogenesis of childhood HIVAN, we followed the clinical and renal pathologic outcome of 165 HIV-1 transgenic (HIV-Tg) rats and their respective control littermates for a period of 18 months. Results. HIV-1 Tg rats progressively developed proteinuria and renal histologic lesions similar to those seen in children with HIVAN, leading to chronic renal failure. By in situ hybridization, HIV-1 genes were detected in glomerular and tubular epithelial cells and infiltrating mononuclear cells, which also expressed the HIV-1 envelop protein gp120. The development of HIVAN was associated with the accumulation of basic fibroblast growth factor (bFGF) in the kidney. Conclusion. These data support the notion that HIV-1 plays a direct role in the pathogenesis of HIVAN, by affecting the function and growth of renal epithelial cells, inducing the recruitment of mononuclear cells, and accumulating bFGF in the kidney, even in the absence of viral replication. These rats may provide an excellent model system to study the pathogenesis of childhood HIVAN. C1 Childrens Natl Med Ctr, Childrens Res Inst, Ctr Med Genet, Washington, DC 20010 USA. George Washington Univ, Washington, DC USA. NIH, Vet Resources Program, Off Res Serv, Bethesda, MD USA. Univ Maryland, Anim Model Div, Inst Human Virol, Inst Biotechnol, Baltimore, MD 21201 USA. RP Ray, PE (reprint author), Childrens Natl Med Ctr, Childrens Res Inst, Ctr Med Genet, Room R-211,111 Michigan Ave NW, Washington, DC 20010 USA. FU NHLBI NIH HHS [2R0-1 HL 55605]; NIAID NIH HHS [1 K08 AI01792]; NIDDK NIH HHS [2R0-1 DK 49419, DK 49414-S1] NR 46 TC 45 Z9 45 U1 0 U2 1 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JUN PY 2003 VL 63 IS 6 BP 2242 EP 2253 DI 10.1046/j.1523-1755.2003.00028.x PG 12 WC Urology & Nephrology SC Urology & Nephrology GA 676ZF UT WOS:000182781900031 PM 12753314 ER PT J AU Li, Y Greiner, RS Salem, N Watkins, BA AF Li, Y Greiner, RS Salem, N Watkins, BA TI Impact of dietary n-3 FA deficiency on rat bone tissue FA composition SO LIPIDS LA English DT Article ID FATTY-ACIDS AB The effect of dietary n-3 FA deficiency on bone tissue FA composition was evaluated in growing rats. Two mixtures combining hydrogenated coconut oil with safflower oil served as the n-3-deficient dietary treatments and provided two levels of linoleic acid (LA). The n-3 treatments were formulated with added alpha-linolenic acid (LNA) from flaxseed oil (diet LNA) or LNA plus DHA, and both were balanced for LA. This study showed that bone is sensitive to changes in dietary n-3 FA an that DHA is more effective than LNA in maintaining DHA levels in these tissues. C1 Purdue Univ, Ctr Enhancing Foods Protect Hlth, Lipid Chem & Mol Biol Lab, W Lafayette, IN 47907 USA. NIAAA, Lab Membrane Biochem & Biophys, Div Intramural Clin & Biol Res, NIH, Rockville, MD 20852 USA. RP Watkins, BA (reprint author), Dept Food Sci, 745 Agr Mall Dr, W Lafayette, IN 47907 USA. NR 5 TC 19 Z9 19 U1 0 U2 1 PU AMER OIL CHEMISTS SOC A O C S PRESS PI CHAMPAIGN PA 1608 BROADMOOR DRIVE, CHAMPAIGN, IL 61821-0489 USA SN 0024-4201 J9 LIPIDS JI Lipids PD JUN PY 2003 VL 38 IS 6 BP 683 EP 686 DI 10.1007/s11745-003-1115-8 PG 4 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 709JP UT WOS:000184622300013 PM 12934680 ER PT J AU Thompson, RB McVeigh, ER AF Thompson, RB McVeigh, ER TI Fast measurement of intracardiac pressure differences with 2D breath-hold phase-contrast MRI SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE blood pressure measurement; MRI; phase contrast imaging; hemodynamics; systolic function; diastolic function ID FLOW; GRADIENTS; MECHANISM; PATTERNS; STENOSIS; SPACE AB Intracardiovascular blood pressure differences can be derived from velocity images acquired with phase-contrast (PC) MRI by evaluating the Navier-Stokes equations. Pressure differences within a slice of interest can be calculated using only the in-plane velocity components from that slice. This rapid exam is proposed as an alternative to the lengthy 3D velocity imaging exams. Despite their good spatial coverage, the 3D exams are prone to artifacts and errors from respiratory motion and insufficient temporal resolution, and are unattractive in the clinical setting due to their excessive scan times (>10 min of free breathing). The proposed single-slice approach requires only one or two breath-holds of acquisition time, and the velocity data can be processed for the calculation of pressure differences online with immediate feedback. The impact of reducing the pressure difference calculation to two dimensions is quantified by comparison with 3D data sets for the case of blood flow within the cardiac chambers. The calculated pressure differences are validated using high-fidelity pressure transducers both in a pulsatile flow phantom and in vivo in a dog model. There was excellent agreement between the transducer and PC-MRI results in all of the studies. Published 2003 Wiley-Liss, Inc.(dagger). C1 NIH, Cardiac Energet Lab, Bethesda, MD 20892 USA. RP Thompson, RB (reprint author), NIH, Cardiac Energet Lab, 10 Ctr Dr,Bldg 10,Rm B1D 416, Bethesda, MD 20892 USA. EM thompsor@nhlbi.nih.gov RI Thompson, Richard/E-9821-2011 FU Intramural NIH HHS [Z01 HL004608-08] NR 26 TC 43 Z9 45 U1 0 U2 2 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 JUN PY 2003 VL 49 IS 6 BP 1056 EP 1066 DI 10.1002/mrm.10486 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 685NY UT WOS:000183271200012 PM 12768584 ER PT J AU Zhan, W Gu, H Xu, S Silbersweig, DA Stern, E Yang, YH AF Zhan, W Gu, H Xu, S Silbersweig, DA Stern, E Yang, YH TI Circular spectrum mapping for intravoxel fiber structures based on high angular resolution apparent diffusion coefficients SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE apparent diffusion coefficient; diffusion tensor imaging; fiber crossing; high angular resolution; spectral decomposition ID HUMAN BRAIN; TENSOR DATA; WEIGHTED MRI; SPIN-ECHO; ANISOTROPY; SCHEMES; NMR; ORIENTATION; TRACKING; TISSUES AB A method is presented for mapping intravoxel fiber structures using spectral decomposition onto a circular distribution of measured apparent diffusion coefficients (ADCs). The zeroth-, second-, and fourth-order harmonic components of the ADC distribution on the circle spanned by the major and median eigenvectors of the diffusion tensor can be used to provide quantitative indices for isotropic, linear, and fiber-crossing diffusion, respectively. A diffusion-weighted MRI technique with 90 encoding orientations was implemented to estimate the circular ADC distribution and calculate the circular spectrum. A digital phantom was used to simulate various diffusion patterns. Comparisons were made between the circular spectrum and regular DTI-based index maps. The results indicated that the zeroth- and second-order circular spectrum maps exhibited a strong consistency with the DTI-based mean diffusivity and linear indices, respectively, and the fourth-order circular spectrum map was able to identify the fiber crossings. MRI experiments were performed on seven healthy human brains using a 3T scanner. The in vivo fourth-order maps showed significantly higher densities in several brain regions, including the corpus callosum, cingulum bundle, superior longitudinal fasciculus, corticospinal tract, and middle cerebellar peduncle, which indicated the existence of fiber crossings in these regions. (C) 2003 Wiley-Liss, Inc. C1 Cornell Univ, Weill Med Coll, Dept Psychiat, Funct Neuroimaging Lab, New York, NY USA. Mem Sloan Kettering Canc Ctr, Dept Med Phys, New York, NY 10021 USA. RP Yang, YH (reprint author), NIDA, MRI Phys Unit, Neuroimaging Res Branch, NIH, 5500 Nathan Shock Dr,Rm 383, Baltimore, MD 21224 USA. RI Stern, Emily/E-6035-2011 NR 37 TC 23 Z9 23 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 JUN PY 2003 VL 49 IS 6 BP 1077 EP 1088 DI 10.1002/mrm.10484 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 685NY UT WOS:000183271200014 PM 12768586 ER PT J AU Strudler, P Deye, J Rardin, R Fraass, B AF Strudler, P Deye, J Rardin, R Fraass, B TI Everything you wanted to know about getting research money from NIH and NSF SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Association-of-Physicists-in-Medicine CY AUG 10-14, 2003 CL SAN DIEGO, CALIFORNIA SP Amer Assoc Physicists Med C1 NIH, Bethesda, MD 20892 USA. Natl Sci Fdn, Arlington, VA 22230 USA. Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2003 VL 30 IS 6 BP 1411 EP 1412 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 692JT UT WOS:000183658500394 ER PT J AU Lo, J Floyd, C Chan, HP Giger, M McNitt-Gray, M Roehrig, J Summers, R AF Lo, J Floyd, C Chan, HP Giger, M McNitt-Gray, M Roehrig, J Summers, R TI Unanswered questions in CAD research SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Association-of-Physicists-in-Medicine CY AUG 10-14, 2003 CL SAN DIEGO, CALIFORNIA SP Amer Assoc Physicists Med C1 Duke Univ, Ctr Med, Durham, NC USA. Univ Michigan, Ann Arbor, MI 48109 USA. Univ Chicago, Chicago, IL 60637 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. R2 Technol Inc, Sunnyvale, CA USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2003 VL 30 IS 6 BP 1433 EP 1433 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 692JT UT WOS:000183658500493 ER PT J AU Aman, MJ Bosio, CM Panchal, RG Burnett, JC Schmaljohn, A Bavari, S AF Aman, MJ Bosio, CM Panchal, RG Burnett, JC Schmaljohn, A Bavari, S TI Molecular mechanisms of filovirus cellular trafficking SO MICROBES AND INFECTION LA English DT Review DE filovirus; assembly; budding; viral entry; rafts; endocytic pathway ID EBOLA-VIRUS GLYCOPROTEIN; LIPID RAFT MICRODOMAINS; MATRIX PROTEIN VP40; MARBURG-VIRUS; MEMBRANE ASSOCIATION; CRYSTAL-STRUCTURE; SENDAI VIRUS; DOMAIN; ENTRY; TSG101 AB The filoviruses, Ebola and Marburg, are two of the most pathogenic viruses, causing lethal hemorrhagic fever in humans. Recent discoveries suggest that filoviruses, along with other phylogenetically or functionally related viruses, utilize a complex mechanism of replication exploiting multiple cellular components including lipid rafts, endocytic compartments, and vacuolar protein sorting machinery. In this review, we summarize these recent findings and discuss the implications for vaccine and therapeutics development. (C) 2003 Editions scientifiques et medicales Elsevier SAS. All rights reserved. C1 Clin Res Management Inc, Frederick, MD 21702 USA. USA, Med Res Inst Infect Dis, Dept Cell Biol & Biochem, USAMRIID, Frederick, MD 21702 USA. NCI, SAIC, Target Struct Based Drug Discovery Grp, Dev Therapeut Program, Frederick, MD 21702 USA. RP Aman, MJ (reprint author), Clin Res Management Inc, 1425 Porter St, Frederick, MD 21702 USA. RI Bosio, Catharine/D-7456-2015 NR 69 TC 25 Z9 27 U1 2 U2 7 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS CEDEX 15 PA 23 RUE LINOIS, 75724 PARIS CEDEX 15, FRANCE SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD JUN PY 2003 VL 5 IS 7 BP 639 EP 649 DI 10.1016/S1286-4579(03)00095-9 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 701PX UT WOS:000184176900009 PM 12787740 ER PT J AU Levin, BC Holland, KA Hancock, DK Coble, M Parsons, TJ Kienker, LJ Williams, DW Jones, M Richie, KL AF Levin, BC Holland, KA Hancock, DK Coble, M Parsons, TJ Kienker, LJ Williams, DW Jones, M Richie, KL TI Comparison of the complete mtDNA genome sequences of human cell lines - HL-60 and GM 10742A - from individuals with pro-myelocytic leukemia and leber hereditary optic neuropathy, respectively, and the inclusion of HL-60 in the NIST human mitochondrial DNA standard reference material - SRM 2392-I SO MITOCHONDRION LA English DT Article; Proceedings Paper CT 13th International Symposium on Human Identification CY OCT, 2002 CL PHOENIX, ARIZONA DE forensic identification; GM10742A; haplogroup J; HL-60; leber hereditary optic neuropathy (LHON); medical diagnosis; mitochondrial DNA sequence; single nucleotide polymorphism (SNP); standard reference material (SRM) ID REGION SEQUENCES; EXPRESSION; NETWORK AB Forensic and clinical laboratories benefit from DNA standard reference materials (SRMs) that provide the quality control and assurance that their results from sequencing unknown samples are correct. Therefore, the mitochondrial DNA (mtDNA) genome of HL-60, a promyelocytic leukemia cell line, has been completely sequenced by four laboratories and will be available to the forensic and medical communities in the spring of 2003; it will be called National Institute of Standards and Technology (NIST) SRM 2392-I. NIST human mtDNA SRM 2392 will continue to be available and includes. the DNA from two apparently healthy individuals. Both SRM 2392 and 2392-I contain all the information (e.g. the sequences of 58 unique primer sets) needed to use these SRMs as positive controls for the amplification and sequencing any DNA. Compared to the templates in SRM 2392, the HL-60 mtDNA in SRM 2392-I has two tRNA differences and more polymorphisms resulting in amino acid changes. Four of these HL-60 mtDNA polymorphisms have been associated with Leber Hereditary Optic Neuropathy (LHON), one as an intermediate mutation and three as secondary mutations. The mtDNA from a cell line (GM10742A) from an individual with LHON was also completely sequenced for comparison and contained some of the same LHON mutations. The combination of these particular LHON associated mutations is also found in phylogenetic haplogroup J and its subset, J(2), and may only be indicative that HL-60 belongs to haplogroup J, one of nine haplogroups that characterize Caucasian individuals of European descent or may mean that haplogroup J is more prone to LHON. Both these mtDNA. SRMs will provide enhanced quality control in forensic identification, medical diagnosis, and single nucleotide polymorphism detection. (C) 2003 Published by Elsevier Science B.V. on behalf of Mitochondria Research Society. C1 Natl Inst Stand & Technol, Gaithersburg, MD 20899 USA. Gettysburg Coll, Gettysburg, PA 17325 USA. Armed Forces DNA Identificat Lab, Rockville, MD USA. George Washington Univ, Washington, DC USA. Fed Bur Invest Lab, Quantico, VA USA. Georgia Bur Invest, Decatur, GA USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Levin, BC (reprint author), Natl Inst Stand & Technol, 100 Bur Dr,Mail Stop 8311, Gaithersburg, MD 20899 USA. RI Coble, Michael/E-7540-2010 NR 15 TC 14 Z9 15 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1567-7249 J9 MITOCHONDRION JI Mitochondrion PD JUN PY 2003 VL 2 IS 6 BP 387 EP 400 DI 10.1016/S1567-7249(03)00010-2 PG 14 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 713FY UT WOS:000184847500001 PM 16120335 ER PT J AU Pogozelski, WK Hamel, CJC Woeller, CF Jackson, WE Zullo, SJ Fischel-Ghodsian, N Blakely, WF AF Pogozelski, WK Hamel, CJC Woeller, CF Jackson, WE Zullo, SJ Fischel-Ghodsian, N Blakely, WF TI Quantification of total mitochondrial DNA and the 4977-by common deletion in Pearson's syndrome lymphoblasts using a fluorogenic 5 '-nuclease (TaqMan (TM)) real-time polymerase chain reaction assay and plasmid external calibration standards SO MITOCHONDRION LA English DT Article DE mitochondrial DNA; common deletion; copy number; real-time polymerase chain reaction; TaqMan; Pearson's syndrome; lymphoblasts; quantitative polymerase chain reaction ID MARROW-PANCREAS-SYNDROME; HUMAN-CELLS; SKELETAL-MUSCLE; COPY NUMBER; PCR; FIBROBLASTS; INCREASE; MTDNA; REARRANGEMENTS; MUTATION AB This study describes a multiplex real-time polymerase chain reaction (PCR) assay that quantifies total mitochondrial DNA (mtDNA(total)) and mtDNA bearing the 4977-base pair 'common deletion' (DeltamtDNA(4977)) in lymphoblasts derived from an individual diagnosed with Pearson's syndrome. The method is unique in its use of plasmids as external quantification standards and its use of multiplex conditions. Standards are validated by comparison with purified mtDNA amplification curves and by the fact that curves are largely unaffected by nuclear DNA (nucDNA). Finally, slopes of standard curves and unknowns are shown to be similar to each other and to theoretical predictions. From these data, mtDNA(total) in these cells is calculated to be 3258 (+723/-592) copies per cell while DeltamtDNA(4977) averages 232 (+136/-86) copies per cell or 7% (+4.65/-2.81). (C) 2003 Mitochondria Research Society. Published by Elsevier Science B.V. All rights reserved. C1 SUNY Coll Geneseo, Dept Chem, Geneseo, NY 14454 USA. Armed Forces Radiobiol Res Inst, Biol Dosimetry Team, Bethesda, MD 20889 USA. NIMH, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. Cedars Sinai Med Ctr, Ahmanson Dept Pediat, Los Angeles, CA 90048 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90048 USA. RP Pogozelski, WK (reprint author), SUNY Coll Geneseo, Dept Chem, Geneseo, NY 14454 USA. NR 42 TC 25 Z9 25 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1567-7249 J9 MITOCHONDRION JI Mitochondrion PD JUN PY 2003 VL 2 IS 6 BP 415 EP 427 DI 10.1016/S1567-7249(03)00033-3 PG 13 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 713FY UT WOS:000184847500003 PM 16120337 ER PT J AU Lai, WS Kennington, EA Blackshear, PJ AF Lai, WS Kennington, EA Blackshear, PJ TI Tristetraprolin and its family members can promote the cell-free deadenylation of AU-rich element-containing mRNAs by poly(A) ribonuclease SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MESSENGER-RNA STABILITY; ZINC-FINGER PROTEINS; IN-VITRO; POLY(A)-SPECIFIC RIBONUCLEASE; TRANSCRIPTION FACTOR; MAMMALIAN-CELLS; DEGRADATION; BINDING; TAIL; IDENTIFICATION AB Eukaryotic mRNA stability can be influenced by AU-rich elements (AREs) within mRNA primary sequences. Tristetraprolin (TTP) is a CCCH tandem zinc finger protein that binds to ARE-containing transcripts and destabilizes them, apparently by first promoting the removal of their poly(A) tails. We developed a cell-free system in which TTP and its related proteins stimulated the deadenylation of ARE-containing, polyadenylated transcripts. Transcript deadenylation was not stimulated when a mutant TTP protein was used that was incapable of RNA binding, nor when a mutant ARE was present that did not bind TTP. The ability of TTP to promote transcript deadenylation required Mg2+, but not ATP or prior capping of the RNA substrate. Cotransfection and additivity studies with the poly(A) RNase (PARN) demonstrated that TTP promoted the ability of this enzyme to deadenylate ARE-containing, polyadenylated transcripts, while having no effect on transcripts lacking an ARE. There was no effect of TTP to act synergistically with enzymatically inactive PARN mutants. We conclude that TTP can promote the deadenylation of ARE-containing, polyadenylated substrates by PARN. This interaction may be responsible for the ability of TTP and its family members to promote the deadenylation of such transcripts in intact cells. C1 NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. NIEHS, Off Clin Res, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. RP Blackshear, PJ (reprint author), NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, A2-05,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 37 TC 159 Z9 170 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 2003 VL 23 IS 11 BP 3798 EP 3812 DI 10.1128/MCB.23.11.3798-3812.2003 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 681HZ UT WOS:000183031900008 PM 12748283 ER PT J AU Bulavin, DV Kovalsky, O Hollander, MC Fornace, AJ AF Bulavin, DV Kovalsky, O Hollander, MC Fornace, AJ TI Loss of oncogenic H-ras-induced cell cycle arrest and p38 mitogen-activated protein kinase activation by disruption of gadd45a SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PROLYL ISOMERASE PIN1; P53 TUMOR-SUPPRESSOR; P53-REGULATED PROTEIN; PREMATURE SENESCENCE; PANCREATIC-CANCER; HUMAN FIBROBLASTS; STRESS RESPONSES; TERMINAL KINASE; UV-RADIATION; DNA-DAMAGE AB The activation of p53 is a guardian mechanism to protect primary cells from malignant transformation; however, the details of the activation of p53 by oncogenic stress are still incomplete. In this report we show that in Gadd45a(-/-) mouse embryo fibroblasts (MEF), overexpression of H-ras activates extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) but not p38 kinase, and this correlates with the loss of H-ras-induced cell cycle arrest (premature senescence). Inhibition of p38 mitogen-activated protein kinase (MAPK) activation correlated with the deregulation of p53 activation, and both a p38 MAPK chemical inhibitor and the expression of a dominant-negative p38alpha inhibited p53 activation in the presence of H-ras in wild-type MEF. p38, but not ERK or JNK, was found in a complex with Gadd45 proteins. The region of interaction was mapped to amino acids 71 to 96, and the central portion (amino acids 71 to 124) of Gadd45a was required for p38 MAPK activation in the presence of H-ras. Our results indicate that this Gadd45/p38 pathway plays an important role in preventing oncogene-induced growth at least in part by regulating the p53 tumor suppressor. C1 NCI, Gene Response Sect, Ctr Canc Res, Bethesda, MD 20892 USA. RP Fornace, AJ (reprint author), NIH, Bldg 37,Room 6144, Bethesda, MD 20892 USA. RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X NR 63 TC 107 Z9 111 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 JUN PY 2003 VL 23 IS 11 BP 3859 EP 3871 DI 10.1128/MCB.23.11.3859-3871.2003 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 681HZ UT WOS:000183031900013 PM 12748288 ER PT J AU Yudt, MR Jewell, CM Bienstock, RJ Cidlowski, JA AF Yudt, MR Jewell, CM Bienstock, RJ Cidlowski, JA TI Molecular origins for the dominant negative function of human glucocorticoid receptor beta SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PROTEIN SECONDARY STRUCTURE; LIGAND-BINDING DOMAIN; STRUCTURE PREDICTION; ESTROGEN-RECEPTOR; NUCLEAR RECEPTORS; GENE-EXPRESSION; HORMONE-BINDING; C-TERMINUS; RESISTANCE; SEQUENCE AB This study molecularly elucidates the basis for the dominant negative mechanism of the glucocorticoid receptor (GR) isoform hGRbeta, whose overexpression is associated with human glucocorticoid resistance. Using a series of truncated hGRalpha mutants and sequential mutagenesis to generate a series of hGRalpha/beta hybrids, we find that the absence of helix 12 is neither necessary nor sufficient for the GR dominant negative phenotype. Moreover, we have localized the dominant negative activity of hGRbeta to two residues and found that nuclear localization, in addition to heterodimerization, is a critical feature of the dominant negative activity. Molecular modeling of wild-type and mutant hGRalpha and hGRbeta provides structural insight and a potential physical explanation for the lack of hormone binding and the dominant negative actions of hGRbeta. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, NIH, 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. OI Bienstock, Rachelle/0000-0001-5228-3610 NR 48 TC 95 Z9 108 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 JUN PY 2003 VL 23 IS 12 BP 4319 EP 4330 DI 10.1128/MCB.23.12.4319-4330.2003 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 686HP UT WOS:000183315600025 PM 12773573 ER PT J AU Heinloth, AN Shackelford, RE Innes, CL Bennett, L Li, LP Amin, RP Sieber, SO Flores, KG Bushel, PR Paules, RS AF Heinloth, AN Shackelford, RE Innes, CL Bennett, L Li, LP Amin, RP Sieber, SO Flores, KG Bushel, PR Paules, RS TI Identification of distinct and common gene expression changes after oxidative stress and gamma and ultraviolet radiation SO MOLECULAR CARCINOGENESIS LA English DT Article DE gene expression; DNA damage; oxidative stress ID CELL NUCLEAR ANTIGEN; NUCLEOTIDE EXCISION-REPAIR; DNA-REPLICATION; PROTEIN-KINASE; IONIZING-RADIATION; HELICASE ACTIVITY; DAMAGE; COMPLEX; PHOSPHORYLATION; CHECKPOINT AB The human genome is exposed to many different kinds of DNA-damaging agents. While most damage is detected and repaired through complex damage recognition and repair machineries, some damage has the potential to escape these mechanisms. Unrepaired DNA damage can give rise to alterations and mutations in the genome in an individual cell, which can result in malignant transformation, especially when critical genes are deregulated. In this study, we investigated gene expression changes in response to oxidative stress, gamma (gamma) radiation, and ultraviolet (UV) radiation and their potential implications in cancer development. Doses were selected for each of the three treatments, based on their ability to cause a similar G, checkpoint induction and slow down in early S-phase progression, as reflected by a comparable reduction in cyclin E-associated kinase activity of at least 75% in logarithmically growing human dermal diploid fibroblasts. To investigate gene expression changes, logarithmically growing dermal diploid fibroblasts were exposed to either gamma radiation (5 Gy), oxidative stress (75 muM of tert-butyl hydroperoxide (t-butyl-OOH)), or UV radiation (UVC) (7.5 J/m(2)) and RNA was harvested 6 h after treatment. Gene expression was analyzed using the NIEHS Human ToxChip 2.0 with approximately 1901 cDNA clones representing known genes and expressed sequence tags (ESTs). We were able to identify common and distinct responses in dermal diploid fibroblasts to the three different stimuli used. Within our analysis, gene expression profiles in response to gamma radiation and oxidative stress appeared to be more similar than profiles expressed after UV radiation. Interestingly, equivalent cyclin E-associated kinase activity reduction with all the three treatments was associated with greater transcriptional changes after UV radiation than after gamma radiation and oxidative stress. While samples treated with UV radiation displayed modulations of their mitogen activated protein kinase (MAPK) pathway, gamma radiation had its major influence on cell-cycle progression in S-phase and mitosis. In addition, cell cultures from different individuals displayed significant differences in their gene expression responses to DNA damage. Published 2003 Wiley-Liss, Inc. C1 NIEHS, Growth Control & Canc Grp, Res Triangle Pk, NC 27709 USA. NIEHS, Microarray Ctr, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Paules, RS (reprint author), NIEHS, Growth Control & Canc Grp, POB 12233,Mail Drop D2-03,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 47 TC 40 Z9 43 U1 0 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD JUN PY 2003 VL 37 IS 2 BP 65 EP 82 DI 10.1002/mc.10122 PG 18 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 686HK UT WOS:000183315200002 PM 12766906 ER PT J AU Li, SW Braverman, R Li, HZ Vass, WC Lowy, DR DeClue, JE AF Li, SW Braverman, R Li, HZ Vass, WC Lowy, DR DeClue, JE TI Regulation of cell morphology and adhesion by the tuberous sclerosis complex (TSC1/2) gene products in human kidney epithelial cells through increased E-cadherin/beta-catenin activity SO MOLECULAR CARCINOGENESIS LA English DT Article DE tumor suppressor gene; tuberous sclerosis complex; cell adhesion; E-cadherin ID HUMAN CANCER; TSC2 GENE; HAMARTIN COMPLEX; BETA-CATENIN; GROWTH; PROLIFERATION; EXPRESSION; PROTEIN; PHOSPHORYLATION; POLYCYSTIN-1 AB We investigated the effects of overexpression of the tuberous sclerosis-1 and -2 (TSC1/2) gene products (hamartin and tuberin, respectively) in the human kidney epithelial cell line 293 with an inducible expression system. As we had observed previously in fibroblasts, 293 cells overexpressing hamartin and/or tuberin grew more slowly in vitro. However, here we also observed that the 293 overexpressing cells underwent a dramatic morphological change in which groups of cells formed compact clusters. The overexpressing cells also displayed decreased dissociation and increased reaggregation in vitro. These changes were found to be associated with an increased level of E-cadherin, which is known to regulate cell-cell interactions in epithelial cells, and of its binding partner beta-catenin. Consistent with the role of E-cadherin in these effects, we found that the observed changes in 293 cell morphology, dissociation, and adhesion were calcium-dependent, and were reproduced by overexpression of E-cadherin. In contrast, overexpression of TSC1 in rat embryo fibroblasts, which lack E-cadherin, failed to elicit the same changes as in 293 cells. We conclude that the hamartin/tuberin complex exerted a direct effect on the morphology and adhesive properties of 293 cells through regulation of the level and/or activity of cellular E-cadherin/beta-catenin. (C) 2003 Wiley-Liss, Inc. C1 NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP DeClue, JE (reprint author), NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. NR 38 TC 10 Z9 11 U1 0 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD JUN PY 2003 VL 37 IS 2 BP 98 EP 109 DI 10.1002/mc.10125 PG 12 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 686HK UT WOS:000183315200005 PM 12766909 ER PT J AU Dubaele, S De Santis, LP Bienstock, RJ Keriel, A Stefanini, M Van Houten, B Egly, JM AF Dubaele, S De Santis, LP Bienstock, RJ Keriel, A Stefanini, M Van Houten, B Egly, JM TI Basal transcription defect discriminates between xeroderma pigmentosum and trichothiodystrophy in XPD patients SO MOLECULAR CELL LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; RNA-POLYMERASE-II; FACTOR TFIIH; DNA-REPAIR; RECEPTOR-ALPHA; RAR-ALPHA; IN-VIVO; MUTATIONS; MECHANISM; GENE AB Mutations in the XPD gene result in xeroderma pigmentosum (XP) and trichothiodystrophy (TTD), the phenotypes of which are often intricate. To understand the genotype/phenotype relationship, we engineered recombinant TFIIHs in which XPD subunits carry amino acid changes found in XPD patients. We demonstrate that all the XPD mutations are detrimental for XPD helicase activity, thus explaining the NER defect. We also show that TFIIH from TTD patients, but not from XP patients, exhibits a significant in vitro basal transcription defect in addition to a reduced intracellular concentration. Moreover, when XPD mutations prevent interaction with the p44 subunit of TFIIH, transactivation directed by certain nuclear receptors is inhibited, regardless of TTD versus XP phenotype, thus explaining the overlapping symptoms. The implications of these mutations are discussed using a structural model of the XPD protein. Our study provides explanations for the nature and the severity of the various clinical features. C1 Univ Strasbourg 1, CNRS, INSERM, Inst Genet & Biol Mol & Cellulaire, F-67404 Illkirch Graffenstaden, CU Strasbourg, France. Natl Inst Environm Hlth, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. Natl Inst Environm Hlth, Comp Sci Lab, NIH, Res Triangle Pk, NC 27709 USA. CNR, Ist Genet Mol, I-27100 Pavia, Italy. RP Egly, JM (reprint author), Univ Strasbourg 1, CNRS, INSERM, Inst Genet & Biol Mol & Cellulaire, BP 10142, F-67404 Illkirch Graffenstaden, CU Strasbourg, France. NR 43 TC 126 Z9 128 U1 1 U2 8 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JUN PY 2003 VL 11 IS 6 BP 1635 EP 1646 DI 10.1016/S1097-2765(03)00182-5 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 693LU UT WOS:000183719700022 PM 12820975 ER PT J AU Couse, JF Yates, MM Walker, VR Korach, KS AF Couse, JF Yates, MM Walker, VR Korach, KS TI Characterization of the hypothalamic-pituitary-gonadal axis in estrogen receptor (ER) null mice reveals hypergonadism and endocrine sex reversal in females lacking ER alpha but not ER beta SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID GONADOTROPIN-RELEASING-HORMONE; MESSENGER-RIBONUCLEIC-ACID; 17-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1; FOLLICLE-STIMULATING-HORMONE; POLYCYSTIC-OVARY-SYNDROME; RAT GRANULOSA-CELLS; LUTEINIZING-HORMONE; ANDROGEN PRODUCTION; KNOCKOUT MOUSE; REPRODUCTIVE PHENOTYPES AB To determine the role of each estrogen receptor (ER) form (ERalpha, ERbeta) in mediating the estrogen actions necessary to maintain proper function of the hypothalamic-pituitary-gonadal axis, we have characterized the hypothalamic-pituitary-gonadal axis in female ER knockout (ERKO) mice. Evaluation of pituitary function included gene expression assays for Gnrhr, Cga, Lhb, Fshb, and Prl. Evaluation of ovarian steroidogenic capacity included gene expression assays for the components necessary for estradiol synthesis: i.e. Star, Cyp11a, Cyp17, Cyp19, Hsd3b1, and Hsd17b1. These data were corroborated by assessing plasma levels of the respective peptide and steroid hormones. alphaERKO and alphabetaERKO females exhibited increased pituitary Cga and Lhb expression and increased plasma LH levels, whereas both were normal in betaERKO. Pituitary Fshb expression and plasma FSH were normal in all three ERKOs. In the ovary, all three ERKOs exhibited normal expression of Star, Cyp11a, and Hsd3b1. In contrast, Cyp17 and Cyp19 expression were elevated in alphaERKO but normal in betaERKO and alphabetaERKO. Plasma steroid levels in each ERKO mirrored the steroidogenic enzyme expression, with only the alphaERKO exhibiting elevated androstenedione and estradiol. Elevated plasma testosterone in alphaERKO and alphabetaERKO females was attributable to aberrant expression of Hsd17b3 in the ovary, representing a form of endocrine sex reversal, as this enzyme is unique to the testes. Enhanced steroidogenic capacity in alphaERKO ovaries was erased by treatment with a GnRH antagonist, indicating these phenotypes to be the indirect result of excess LH stimulation that follows the loss of ERalpha in the hypothalamic-pituitary axis. Overall, these findings indicate that ERalpha, but not ERbeta, is indispensable to the negative-feedback effects of estradiol that maintain proper LH secretion from the pituitary. The subsequent hypergonadism is illustrated as increased Cyp17, Cyp19, Hsd17b1, and ectopic Hsd17b3 expression in the ovary. C1 Natl Inst Environm Hlth Sci, Receptor Biol Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA. RP Korach, KS (reprint author), Natl Inst Environm Hlth Sci, Receptor Biol Sect, Reprod & Dev Toxicol Lab, NIH, B3-02,POB 12233, Res Triangle Pk, NC 27709 USA. OI Korach, Kenneth/0000-0002-7765-418X NR 66 TC 175 Z9 178 U1 2 U2 7 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD JUN PY 2003 VL 17 IS 6 BP 1039 EP 1053 DI 10.1210/me.2002-0398 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 683LY UT WOS:000183152000006 PM 12624116 ER PT J AU Jones, GW Song, Y Masison, DC AF Jones, GW Song, Y Masison, DC TI Deletion of the Hsp70 chaperone gene SSB causes hypersensitivity to guanidine toxicity and curing of the [PSI+] prion by increasing guanidine uptake in yeast SO MOLECULAR GENETICS AND GENOMICS LA English DT Article DE SSB; Hsp70; [PSI+] prion; guanidine ID SACCHAROMYCES-CEREVISIAE; TRANSLATION TERMINATION; MOLECULAR CHAPERONE; PROTEIN; PROPAGATION; HSP104; HYDROCHLORIDE; COMPLEX; MECHANISM; MUTANTS AB Yeast Ssb proteins (Ssbp) are ribosome-associated Hsp70 chaperones that function in translation. Elevated levels of Ssbp enhance the ability of over-expressed Hsp104 chaperone to eliminate the yeast [ PSI (+)] prion, while depletion of Ssbp reduces this effect. Millimolar concentrations of guanidine in the growth medium cure yeast cells of prions by inactivating Hsp104. Guanidine is also toxic to yeast, irrespective of the status of Hsp104 and [ PSI (+)]. Strains that lack Ssbp are hypersensitive to guanidine toxicity. Here we show that ssb (-) cells have normal numbers of [ PSI (+)] 'seeds', but can be cured of [ PSI (+)] using one-sixth of the guanidine concentration required to eliminate [ PSI (+)] from SSB cells. Correspondingly, the level of intracellular guanidine was eight-fold higher in ssb (-) cells than in wild-type cells, which explains all effects of Ssbp depletion on susceptibility to guanidine. The sensitivity of wild-type cells to the effects of guanidine also correlated with guanidine uptake, which was enhanced at low temperature. Guanidine sensitivity of strains mutated in any of 16 ABC membrane transporters, which are implicated in multidrug resistance, was normal. We found that an erg6mutant that has an altered membrane lipid composition was hypersensitive to guanidine toxicity, but the lipid composition of ssb (-) cells was identical to that of wild-type cells. Our results suggest that Ssbp depletion does not affect prion seed regeneration, and that elevated guanidine uptake by ssb (-) cells may be due to increased retention rather than to an alteration in active or passive transport of the compound. C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP NIDDKD, Lab Biochem & Genet, NIH, 8 Ctr Dr,Rm 407,MSC 0851, Bethesda, MD 20892 USA. EM masisond@helix.nih.gov NR 42 TC 12 Z9 12 U1 1 U2 3 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1617-4615 EI 1617-4623 J9 MOL GENET GENOMICS JI Mol. Genet. Genomics PD JUN PY 2003 VL 269 IS 3 BP 304 EP 311 DI 10.1007/s00438-003-0838-y PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 698UE UT WOS:000184016600002 PM 12684878 ER PT J AU Somers, KL Royals, MA Carstea, ED Rafi, MA Wenger, DA Thrall, MA AF Somers, KL Royals, MA Carstea, ED Rafi, MA Wenger, DA Thrall, MA TI Mutation analysis of feline Niemann-Pick C1 disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE NPC; NPC1; feline; cat; cholesterol; lysosomal storage; neurodegeneration ID PROTEIN; COMPARTMENT; LINKAGE AB Niemann-Pick C (NPC) disease is an autosomal recessive neurovisceral lysosomal storage disorder that results in defective intracellular transport of cholesterol. The major form of human NPC (NPC1) has been mapped to chromosome 18, the NPCI gene (NPC1) has been sequenced and several mutations have been identified in NPC1 patients. A feline model of NPC has been characterized and is phenotypically, morphologically, and biochemically similar to human NPC1. Complementation studies using cultured fibroblasts from NPC affected cats and NPC1 affected humans support that the gene responsible for the NPC phenotype in this colony of cats is orthologous to human NPC1 Using human-based PCR primers, initial fragments of the feline NPC cDNA were amplified and sequenced. From these sequences, feline-specific PCR primers were generated and designed to amplify six overlapping bands that span the entire feline NPCI open reading frame. A single base substitution (2864G-C) was identified in NPC1 affected cats. Obligate carriers are heterozygous at the same allele and a PCR-based assay was developed to identify the geneotype of all cats in the colony. The mutation results in an amino acid change from cysteine to serine (C955S). Several of the mutations identified in people occur in the same region. Marked similarity exists between the human and feline NPC1 cDNA sequences, and is greater than that between the human and murine NPC1 sequences. The human cDNA sequence predicts a 1278aa protein with a lysosomal targeting sequence, several trans-membrane domains and extensive homology with other known mediators of cholesterol homeostasis. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Colorado State Univ, Ft Collins, CO 80523 USA. NINDS, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Jefferson Med Coll, Dept Neurol, Philadelphia, PA 19107 USA. RP Somers, KL (reprint author), Colorado State Univ, Ft Collins, CO 80523 USA. OI Royals, Michael/0000-0003-3639-3101 NR 13 TC 32 Z9 32 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JUN PY 2003 VL 79 IS 2 BP 99 EP 103 DI 10.1016/S1096-7192(03)00074-X PG 5 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 692GF UT WOS:000183652500004 PM 12809639 ER PT J AU Tayebi, N Walker, J Stubblefield, B Orvisky, E LaMarca, ME Wong, K Rosenbaum, H Schiffmann, R Bembi, B Sidransky, E AF Tayebi, N Walker, J Stubblefield, B Orvisky, E LaMarca, ME Wong, K Rosenbaum, H Schiffmann, R Bembi, B Sidransky, E TI Gaucher disease with parkinsonian manifestations: does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism? SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Gaucher disease; glucocerebrosidase; Parkinsonism; metaxin; genotype/phenotype correlation; Lewy body; moditier gene ID MUTATIONS; GENE; PHENOTYPE; GENOTYPE; COMPLEX; TRAITS; TYPE-1 AB Among the phenotypes associated with Gaucher disease, the deficiency of glucocerebrosidase, are rare patients with early onset, treatment-refractory parkinsonism. Sequencing of glucocerebrosidase in 17 such patients revealed 12 different genotypes. Fourteen patients had the common "non-neuronopathic" N370S mutation, including five N370S homozygotes. While brain glucosylsphingosine levels were not elevated, Lewy bodies were seen in the four brains available for study. The shared clinical and neuropathologic findings in this subgroup suggest that the deficiency in glucocerebrosidase may contribute to a vulnerability to parkinsonism. Published by Elsevier Science (USA). C1 NIMH, Sect Mol Neurogenet, NIH, Bethesda, MD 20892 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Armed Forces Inst Pathol, Dept Neuropathol & Ophthalm Pathol, Washington, DC 20306 USA. Rambam Med Ctr, Dept Hematol, Haifa, Israel. Technion Israel Inst Technol, Bruce Rappaport Fac Med, IL-31096 Haifa, Israel. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. IRCCS, VO Metab Disorders, Trieste, Italy. RP Sidransky, E (reprint author), NIMH, Sect Mol Neurogenet, NIH, 49 Convent Dr MSC4405,49-B1EE16, Bethesda, MD 20892 USA. NR 21 TC 138 Z9 142 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JUN PY 2003 VL 79 IS 2 BP 104 EP 109 DI 10.1016/S1096-7192(03)00071-4 PG 6 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 692GF UT WOS:000183652500005 PM 12809640 ER PT J AU O'Leary, VB Mills, JL Kirke, PN Parle-McDermott, A Swanson, DA Weiler, A Pangilinan, F Conley, M Molloy, AM Lynch, M Cox, C Scott, JM Brody, LC AF O'Leary, VB Mills, JL Kirke, PN Parle-McDermott, A Swanson, DA Weiler, A Pangilinan, F Conley, M Molloy, AM Lynch, M Cox, C Scott, JM Brody, LC TI Analysis of the human folate receptor P gene for an association with neural tube defects SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE folate receptor; neural tube defects; polymorphism; folate; spina bifida ID 5,10-METHYLENETETRAHYDROFOLATE REDUCTASE; METHYLENETETRAHYDROFOLATE REDUCTASE; BINDING-PROTEINS; SPINA-BIFIDA; RISK FACTOR; EXPRESSION; CELLS; CLONING; CDNA; IDENTIFICATION AB The folate receptor beta (FRbeta) gene encodes a receptor that binds and transports 5-methyltetrahydrofolate. FRbeta polymorphisms may potentially alter folate delivery and are likely candidates for an association with neural tube defect (NTD) risk. To look for association between FRbeta polymorphisms we studied NTD-affected children and their parents (254 triads) recruited throughout Ireland and a control population of 296 pregnant women who did not give birth to an NTD-affected child. Five potential single nucleotide polymorphisms (SNPs) were examined. These were located within the coding, intronic and 3'-untranslated regions of the FRbeta gene. Four of these SNPs were not found to be variable within our Irish cohort. SNP rs651646 (A --> T), located upstream of exon 2 within an intronic region, is polymorphic and is thus a marker for an FRbeta NTD association study. The frequency of the SNP rs651646 "A" allele was not significantly different in cases (odds ratio [OR] 1.07, 95% Cl. 0.84-1.36; P = 0.60), their mothers (odds ratio [OR] 1.09, 95% Cl. 0.86-1.38; P = 0.51) or fathers (odds ratio [OR] 1.09, 95% CI. 0.86-1.38; P = 0.50) when compared to controls. Comparisons of allele transmission from 255 informative heterozygous parents of NTD cases showed no preferential transmission of either the A or T alleles (A: 50.2%, n = 128; T: 49.8%, n = 127; P = 1.00, McNemar X-2 0.0). We also measured allele frequencies in a sample of American-Caucasians and African-Americans. Highly significant allele frequency differences were observed between populations. In conclusion, SNP rs651646 within the FRbeta gene is polymorphic but is not associated with neural tube defects within the Irish population. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Trinity Coll Dublin, Dept Biochem, Dublin, Ireland. NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. Hlth Res Board, Child Hlth Epidemiol Div, Dublin, Ireland. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Trinity Coll Dublin, Dept Clin Med, Dublin, Ireland. RP O'Leary, VB (reprint author), Trinity Coll Dublin, Dept Biochem, Dublin, Ireland. FU NICHD NIH HHS [N01 HD 23163] NR 26 TC 15 Z9 17 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JUN PY 2003 VL 79 IS 2 BP 129 EP 133 DI 10.1016/S1096-7192(03)00075-1 PG 5 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 692GF UT WOS:000183652500009 PM 12809644 ER PT J AU Hansen, AM Lehnherr, H Wang, XD Mobley, V Jin, DJ AF Hansen, AM Lehnherr, H Wang, XD Mobley, V Jin, DJ TI Escherichia coli SspA is a transcription activator for bacteriophage P1 late genes SO MOLECULAR MICROBIOLOGY LA English DT Article ID STRINGENT STARVATION PROTEIN; RNA-POLYMERASE; MIDDLE TRANSCRIPTION; PROMOTER RECOGNITION; LAMBDA-REPRESSOR; NULL MUTATION; SIGMA-FACTOR; TAIL-FIBER; EXPRESSION; DNA AB The stringent starvation protein A (SspA), an Escherichia coli RNA polymerase (RNAP)-associated protein, has been reported to be essential for lytic growth of bacteriophage P1. Unlike P1 early promoters, P1 late promoters are not recognized by RNAP alone. A phage-encoded early protein, Lpa ((l) under bar ate (p) under bar romoter (a) under bar ctivator protein, formerly called gp10), has been shown to be required for P1 late transcription in vivo . Here, we demonstrate that SspA is a transcription activator for P1 late genes. Our results indicated that Lpa is not limiting in an sspA mutant. However, the transcription of P1 late genes was deficient in an sspA mutant in vivo. We demonstrated that SspA/Lpa are required for transcription activation of the P1 late promoter Ps in vitro . In addition, SspA and Lpa were shown to facilitate the binding of RNAP to Ps late promoter DNA. Activation of late transcription by SspA/Lpa was dependent on holoenzyme containing sigma(70) but not sigma(S), indicating that the two activators discriminate between the two forms of the holoenzyme. Furthermore, P1 early gene expression was downregulated in the wild-type background, whereas it persisted in the sspA mutant background, indicating that SspA/Lpa mediate the transcriptional switch from the early to the late genes during P1 lytic growth. Thus, this work provides the first evidence for a function of the E. coli RNAP-associated protein SspA. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Odense Univ, Dept Biochem & Mol Biol, Univ So Denmark, DK-5230 Odense, Denmark. Univ Greifswald, Inst Microbiol, Dept Biochem & Genet, D-17487 Greifswald, Germany. RP Jin, DJ (reprint author), NCI, Mol Biol Lab, NIH, 37 Convent Dr,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 65 TC 27 Z9 27 U1 0 U2 5 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 JUN PY 2003 VL 48 IS 6 BP 1621 EP 1631 DI 10.1046/j.1365-2958.2003.03533.x PG 11 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 687GZ UT WOS:000183369500015 PM 12791143 ER PT J AU Ghosh, J Basu, A Pal, S Chowdhuri, S Bhattacharya, A Pal, D Chattoraj, DK DasGupta, C AF Ghosh, J Basu, A Pal, S Chowdhuri, S Bhattacharya, A Pal, D Chattoraj, DK DasGupta, C TI Ribosome-DnaK interactions in relation to protein folding SO MOLECULAR MICROBIOLOGY LA English DT Article ID ESCHERICHIA-COLI; IN-VITRO; HEAT-SHOCK; DOMAIN-V; MOLECULAR CHAPERONES; DENATURED PROTEINS; TRIGGER FACTOR; RNA; HSP70; BINDING AB Bacterial ribosomes or their 50S subunit can refold many unfolded proteins. The folding activity resides in domain V of 23S RNA of the 50S subunit. Here we show that ribosomes can also refold a denatured chaperone, DnaK, in vitro , and the activity may apply in the folding of nascent DnaK polypeptides in vivo . The chaperone was unusual as the native protein associated with the 50S subunit stably with a 1:1 stoichiometry in vitro . The binding site of the native protein appears to be different from the domain V of 23S RNA, the region with which denatured proteins interact. The DnaK binding influenced the protein folding activity of domain V modestly. Conversely, denatured protein binding to domain V led to dissociation of the native chaperone from the 50S subunit. DnaK thus appears to depend on ribosomes for its own folding, and upon folding, can rebind to ribosome to modulate its general protein folding activity. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. Univ Calcutta, Dept Biophys Mol Biol & Genet, Kolkata, W Bengal, India. Univ Kalyani, Dept Biochem & Biophys, Kalyani 741235, W Bengal, India. Uluberia Coll, Dept Zool, Uluberia, W Bengal, India. RP Chattoraj, DK (reprint author), NCI, Biochem Lab, NIH, 37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM chattoraj@nih.gov NR 46 TC 17 Z9 19 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X EI 1365-2958 J9 MOL MICROBIOL JI Mol. Microbiol. PD JUN PY 2003 VL 48 IS 6 BP 1679 EP 1692 DI 10.1046/j.1365-2958.2003.03538.x PG 14 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 687GZ UT WOS:000183369500019 PM 12791147 ER PT J AU Manganiello, V AF Manganiello, V TI Cyclic nucleotide phosphodiesterase 5 and sildenafil: Promises realized SO MOLECULAR PHARMACOLOGY LA English DT Article ID PHOSPHORYLATION C1 NHLBI, Sect Biochem Physiol, Crit Care Med Branch, NIH,DHHS, Bethesda, MD 20892 USA. RP Manganiello, V (reprint author), NHLBI, Sect Biochem Physiol, Crit Care Med Branch, NIH,DHHS, Bldg 10,Room 5N307,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 9 TC 15 Z9 16 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUN PY 2003 VL 63 IS 6 BP 1209 EP 1211 DI 10.1124/mol.63.6.1209 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 681AN UT WOS:000183013900004 PM 12761329 ER PT J AU Setola, V Hufeisen, SJ Grande-Allen, KJ Vesely, I Glennon, RA Blough, B Rothman, RB Roth, BL AF Setola, V Hufeisen, SJ Grande-Allen, KJ Vesely, I Glennon, RA Blough, B Rothman, RB Roth, BL TI 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro SO MOLECULAR PHARMACOLOGY LA English DT Article ID 5-HYDROXYTRYPTAMINE 2B RECEPTOR; APPETITE-SUPPRESSANT DRUGS; HEART-DISEASE; PULMONARY-HYPERTENSION; 5-HT2B RECEPTORS; SEROTONIN; VALVE; RELEASE; RISK AB Recent findings have implicated the 5-hydroxytryptamine 2B (5-HT 2B) serotonin receptor in mediating the heart valve fibroplasia [ valvular heart disease ( VHD)] and primary pulmonary hypertension observed in patients taking the now-banned appetite suppressant fenfluramine (Pondimin, Redux). Via large-scale, random screening of a portion of the receptorome, we have discovered that the amphetamine derivative 3,4-methylenedioxymethamphetamine ( MDMA, "Ecstasy") and its N-demethylated metabolite 3,4-methylenedioxyamphetamine (MDA) each preferentially bind to and activate human recombinant 5-HT2B receptors. We also demonstrate that MDMA and MDA, like fenfluramine and its N-deethylated metabolite norfenfluramine, elicit prolonged mitogenic responses in human valvular interstitial cells via activation of 5-HT2B receptors. We also report that pergolide and dihydroergotamine, two drugs recently demonstrated to induce VHD in humans, potently activate 5-HT2B receptors, thus validating this assay system for its ability to predict medications that might induce VHD. Our discovery that MDMA and a major metabolite, MDA, induce prolonged mitogenic responses in vitro similar to those induced by fenfluramine and norfenfluramine in vivo ( i.e., valvular interstitial cell fibroplasia) predict that long-term MDMA use could lead to the development of fenfluramine-like VHD. Because of the widespread abuse of MDMA, these findings have major public health implications. These findings also underscore the necessity of screening current and future drugs at h5-HT2B receptors for agonist actions before their use in humans. C1 Case Western Reserve Univ, Sch Med, Dept Biochem, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, NIMH, Psychoact Drug Screening Program, Cleveland, OH 44106 USA. Case Western Reserve Univ, Lerner Res Inst, Dept Biomed Engn, Cleveland, OH 44106 USA. Virginia Commonwealth Univ, Dept Med Chem, Richmond, VA 23298 USA. Res Triangle Inst Int, Chem & Life Sci Grp, Res Triangle Pk, NC USA. NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH, Baltimore, MD USA. RP Roth, BL (reprint author), Case Western Reserve Univ, Sch Med, Dept Biochem, RM W438,2109 Adelbert Rd, Cleveland, OH 44106 USA. RI Roth, Bryan/F-3928-2010; Grande-Allen, Kathryn/P-4042-2014 OI Grande-Allen, Kathryn/0000-0003-1533-3767 FU NIMH NIH HHS [K02 MH 01366, N01 MH 80002, R01 MH 57635] NR 22 TC 166 Z9 171 U1 0 U2 7 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUN PY 2003 VL 63 IS 6 BP 1223 EP 1229 DI 10.1124/mol.63.6.1223 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 681AN UT WOS:000183013900006 PM 12761331 ER PT J AU Cruz-Monserrate, Z Vervoort, HC Bai, RL Newman, DJ Howell, SB Los, G Mullaney, JT Williams, MD Pettit, GR Fenical, W Hamel, E AF Cruz-Monserrate, Z Vervoort, HC Bai, RL Newman, DJ Howell, SB Los, G Mullaney, JT Williams, MD Pettit, GR Fenical, W Hamel, E TI Diazonamide A and a synthetic structural analog: Disruptive effects on mitosis and cellular microtubules and analysis of their interactions with tubulin SO MOLECULAR PHARMACOLOGY LA English DT Article ID ANTINEOPLASTIC AGENTS; NOMINAL DIAZONAMIDES; ANTIMITOTIC AGENTS; CELOSIA-ARGENTEA; DOLASTATIN 10; BINDING; DEPSIPEPTIDE; NUCLEOTIDE; MECHANISM; PEPTIDE AB The marine ascidian Diazona angulata was the source organism for the complex cytotoxic peptide diazonamide A. The molecular structure of this peptide was recently revised after synthesis of a biologically active analog of diazonamide A in which a single nitrogen atom was replaced by an oxygen atom. Diazonamide A causes cells to arrest in mitosis, and, after exposure to the drug, treated cells lose both interphase and spindle microtubules. Both diazonamide A and the oxygen analog are potent inhibitors of microtubule assembly, equivalent in activity to dolastatin 10 and therefore far more potent than dolastatin 15. This inhibition of microtubule assembly is accompanied by potent inhibition of tubulin-dependent GTP hydrolysis, also comparable with the effects observed with dolastatin 10. However, the remaining biochemical properties of diazonamide A and its analog differ markedly from those of dolastatin 10 and closely resemble the properties of dolastatin 15. Neither diazonamide A nor the analog inhibited the binding of [H-3] vinblastine, [H-3] dolastatin 10, or [8-C-14] GTP to tubulin. Nor were they able to stabilize the colchicine binding activity of tubulin. These observations indicate either that diazonamide A and the analog have a unique binding site on tubulin differing from the vinca alkaloid and dolastatin 10 binding sites, or that diazonamide A and the analog bind weakly to unpolymerized tubulin but strongly to microtubule ends. If the latter is correct, diazonamide A and its oxygen analog should have uniquely potent inhibitory effects on the dynamic properties of microtubules. C1 NCI, Screening Technol Branch, NIH, Frederick, MD 21702 USA. NCI, Nat Prod Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. Univ Calif San Diego, Scripps Inst Oceanog, Ctr Marine Biotechnol & Biomed, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. Univ Calif San Diego, Ctr Canc, La Jolla, CA 92093 USA. Arizona State Univ, Dept Chem & Biochem, Tempe, AZ USA. Arizona State Univ, Canc Res Inst, Tempe, AZ USA. RP Hamel, E (reprint author), NCI, Screening Technol Branch, NIH, Bldg 469,Room 104, Frederick, MD 21702 USA. RI Cruz-Monserrate, Zobeida/H-2290-2013; Cruz, Zobeida/J-2714-2013 NR 37 TC 69 Z9 75 U1 2 U2 10 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUN PY 2003 VL 63 IS 6 BP 1273 EP 1280 DI 10.1124/mol.63.6.1273 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 681AN UT WOS:000183013900011 PM 12761336 ER PT J AU Braun, FJ Aziz, O Putney, JW AF Braun, FJ Aziz, O Putney, JW TI 2-aminoethoxydiphenyl borane activates a novel calcium-permeable cation channel SO MOLECULAR PHARMACOLOGY LA English DT Article ID INS(1,4,5)P-3-INDUCED CA2+ RELEASE; INOSITOL TRISPHOSPHATE RECEPTOR; PANCREATIC ACINAR-CELLS; CURRENT I-CRAC; INTRACELLULAR CA2+; MIC CHANNELS; MAST-CELLS; ENTRY; MODULATOR; MECHANISM AB The membrane-permeable, noncompetitive inositol 1,4,5-trisphosphate (IP3)- receptor inhibitor 2-aminoethoxydiphenyl borane (2-APB) has been widely used to probe for IP3-receptor involvement in calcium signaling pathways. However, a number of recent studies in different cell types revealed other sites of action of 2-APB. In this study, we examined the influence of 2-APB on capacitative calcium entry and intracellular Ca2+ concentrations in rat basophilic leukemia (RBL-2H3 m1) cells. 2-APB was found to inhibit capacitative calcium entry, but at concentrations greater than 50 muM, a new effect of 2-APB was observed. When capacitative calcium entry was blocked with Gd3+, 2-APB caused an increase in cytoplasmic Ca2+. This increase in intracellular Ca2+ was not caused by altered buffering of cytoplasmic Ca2+ and was not caused by or in any way affected by the depletion of intracellular Ca2+ stores. Associated with the increase in intracellular Ca2+, in the presence of 2 mM Ca2+, 2-APB activated single channels in the plasma membrane with a conductance of similar to50 pS. These channels seem to be nonselective cation channels; monovalent cations are the major carriers of current, but finite permeability to Ca2+ leads to a significant intracellular Ca2+ signal. Experiments with excised patches indicate that 2-APB activates these channels from the outer aspect of the cell membrane. This effect of 2-APB further illustrates the complex actions of this compound and reveals the presence in RBL-2H3 m1 cells of a novel, ligand-gated calcium-permeable channel. C1 NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), NIEHS, Lab Signal Transduct, POB 12233, Res Triangle Pk, NC 27709 USA. NR 30 TC 41 Z9 42 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUN PY 2003 VL 63 IS 6 BP 1304 EP 1311 DI 10.1124/mol.63.6.1304 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 681AN UT WOS:000183013900015 PM 12761340 ER PT J AU Corbin, JD Blount, MA Weeks, JL Beasley, A Kuhn, KP Ho, YSJ Saidi, LF Hurley, JH Kotera, J Francis, SH AF Corbin, JD Blount, MA Weeks, JL Beasley, A Kuhn, KP Ho, YSJ Saidi, LF Hurley, JH Kotera, J Francis, SH TI [H-3]Sildenafil binding to phosphodiesterase-5 is specific, kinetically heterogeneous, and stimulated by cGMP SO MOLECULAR PHARMACOLOGY LA English DT Article ID CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES; DEPENDENT PROTEIN-KINASE; CORPUS CAVERNOSUM; SMOOTH-MUSCLE; HIGH-AFFINITY; GENE FAMILY; IN-VITRO; PHOSPHORYLATION; CAMP; PDE5 AB Sildenafil ( Viagra) potentiates penile erection by acting as a nonhydrolyzable analog of cGMP and competing with this nucleotide for catalysis by phosphodiesterase-5 (PDE5), but the characteristics of direct binding of radiolabeled sildenafil to PDE5 have not been determined. [H-3] Sildenafil binding to PDE5 was retained when filtered through nitrocellulose or glass-fiber membranes. Binding was inhibited by excess sildenafil, 2-(2-methylpyridin- 4-yl) methyl-4-(3,4,5-trimethoxyphenyl)-8-(pyrimidin-2- yl) methoxy-1,2-dihydro-1-oxo-2,7-naphthyridine-3-carboxylic acid methyl ester hydrochloride (T-0156), 3-isobutyl-1- methylxanthine, EDTA, or cGMP, but not by cAMP or 5'-GMP. PDE5 was the only [H-3] sildenafil binding protein detected in human lung extract. Using purified recombinant PDE5, [H-3] sildenafil exchange dissociation yielded two components with t(1/2) values of 1 and 14 min and corresponding calculated K-D values of 12 and 0.83 nM, respectively. This implied the existence of two conformers of the PDE5 catalytic site. [H-3] Sildenafil binding isotherm of PDE5 indicated K-D was 8.3 to 13.3 nM, and low cGMP decreased the K-D to 4.8 nM but only slightly increased B-max to a maximum of 0.61 mol/mol-subunit. Results suggest that these effects occur via cGMP binding to the allosteric cGMP binding sites of PDE5. Results imply that by inhibiting PDE5 and thereby increasing cGMP, sildenafil accentuates its own binding affinity for PDE5, which further elevates cGMP. The data also indicate that after physiological elevation, cGMP may directly stimulate the catalytic site by binding to the allosteric cGMP-binding sites of PDE5, thus causing negative feedback on this pathway. C1 Vanderbilt Univ, Dept Mol Physiol & Biophys, Sch Med, Nashville, TN 37232 USA. Vanderbilt Univ, Ctr Lung Res, Div Allergy Pulm & Crit Care Med, Sch Med, Nashville, TN 37232 USA. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Corbin, JD (reprint author), Vanderbilt Univ, Dept Mol Physiol & Biophys, Sch Med, 702 Light Hall, Nashville, TN 37232 USA. FU NIDDK NIH HHS [DK 40029, DK 58277] NR 44 TC 50 Z9 52 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUN PY 2003 VL 63 IS 6 BP 1364 EP 1372 DI 10.1124/mol.63.6.1364 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 681AN UT WOS:000183013900022 PM 12761347 ER PT J AU Morris, JC AF Morris, JC TI Cancer gene therapy: Lessons learned from experiences with chemotherapy SO MOLECULAR THERAPY LA English DT Review ID TUMOR ANGIOGENESIS; RECURRENT HEAD; OVARIAN-CANCER; BLADDER-CANCER; NECK-CANCER; PHASE-I; ADENOVIRUS; CISPLATIN; CELLS; ANGIOSTATIN C1 NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Morris, JC (reprint author), NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NR 38 TC 2 Z9 2 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD JUN PY 2003 VL 7 IS 6 BP 717 EP 719 DI 10.1016/mthe.2003.1000 PG 3 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 687PF UT WOS:000183385100003 PM 12803174 ER PT J AU Maraganore, DM de Andrade, M Lesnick, TG Farrer, MJ Bower, JH Hardy, JA Rocca, WA AF Maraganore, DM de Andrade, M Lesnick, TG Farrer, MJ Bower, JH Hardy, JA Rocca, WA TI Complex interactions in Parkinson's disease: A two-phased approach SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; susceptibility genes; ubiquitin proteasome system; recursive partitioning; epistasis; interactions ID TERMINAL HYDROLASE-L1 GENE; ALPHA-SYNUCLEIN; S18Y POLYMORPHISM; L1 GENE; ASSOCIATION; ESTROGEN; MUTATION; SUSCEPTIBILITY; GENOTYPE; RISK AB The identification of pathogenic mutations in the three genes alpha-synuclein, parkin, and ubiquitin carboxy-terminal hydrolase L1 (UCHL1) has elucidated the ubiquitin proteasome system (UPS) and its potential role as a causal pathway in Parkinson's disease (PD). In addition, polymorphisms of these three genes have been shown to be independently associated with PD. In a sample of 298 unrelated PD cases and 185 controls, we applied a two-phased approach of recursive partitioning and logistic regression analyses to explore complex interactions. For women only, we observed an epistatic interaction of UCHL1 and alpha-synuclein genotypes with significant effects on PD risk (odds ratio = 2.42; P = 0.003). Our findings are consistent with the hypothesis that PD is a multigenic disorder of the UPS. (C) 2003 Movement Disorder Society. C1 Mayo Clin & Mayo Fdn, Dept Neurol, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Dept Hlth Sci Res, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Dept Neurosci, Jacksonville, FL USA. NIA, Neurogenet Lab, Bethesda, MD 20892 USA. RP Maraganore, DM (reprint author), Mayo Clin & Mayo Fdn, Dept Neurol, 200 1st St SW, Rochester, MN 55905 USA. RI Hardy, John/C-2451-2009; OI de Andrade, Mariza/0000-0003-2329-2686 FU NIEHS NIH HHS [ES10751]; NINDS NIH HHS [NS33978, NS40256] NR 39 TC 25 Z9 27 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUN PY 2003 VL 18 IS 6 BP 631 EP 636 DI 10.1002/mds.10431 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 687ZR UT WOS:000183407800003 PM 12784265 ER PT J AU Dagvadorj, A Goudeau, B Hilton-Jones, D Blancato, JK Shatunov, A Simon-Casteras, M Squier, W Nagle, JW Goldfarb, LG Vicart, P AF Dagvadorj, A Goudeau, B Hilton-Jones, D Blancato, JK Shatunov, A Simon-Casteras, M Squier, W Nagle, JW Goldfarb, LG Vicart, P TI Respiratory insufficiency in desminopathy patients caused by introduction of proline residues in desmin C-terminal alpha-helical segment SO MUSCLE & NERVE LA English DT Article DE cardiomyopathy; desmin gene mutation; desminopathy; distal myopathy; myofibrillar myopathy ID INTERMEDIATE FILAMENTS; SKELETAL MYOPATHY; COILED COILS; MISSENSE MUTATION; GENE CAUSES; CARDIOMYOPATHY AB Mutations in desmin gene have been identified in patients with cardiac and skeletal myopathy characterized by intracytoplasmic accumulation of desmin-reactive deposits and electron-dense granular aggregates. We characterized two new desminopathy families with unusual features of adult-onset, slowly progressive, diffuse skeletal myopathy and respiratory insufficiency. Progressive reduction of respiratory muscle strength became clinically detectable between the 3rd and the 8th years of illness and led to recurrent chest infections and death in one of the patients. Novel mutations, A357P and L370P, predicted to introduce proline residue into a highly conserved a-helical region of desmin, were identified, Proline is known to disrupt the a-helix. In addition, the A357P mutation distorts a unique stutter sequence that is considered to be critically important for proper filament assembly. Functional assessment in two cell-lines, one of which does and the other of which does not constitutively produce type III intermediate filaments, demonstrated the inability of mutant desmin carrying either the A357P or the L370P mutation to polymerize and form an intracellular filamentous network. The results of this study indicate that respiratory insufficiency is an intrinsic feature of disease associated with specific desmin mutations; in some patients, respiratory weakness may present as a dominant clinical manifestation and a major cause of disability and death. C1 NINDS, Clin Neurogenet Unit, NIH, Bethesda, MD 20892 USA. Univ Paris 06, CNRS, UMR 7000, Paris, France. Radcliffe Infirm, Dept Clin Neurol, Oxford OX2 6HE, England. Georgetown Univ, Med Ctr, Dept Neurol, Washington, DC 20007 USA. RP Goldfarb, LG (reprint author), NINDS, Clin Neurogenet Unit, NIH, Bldg 10,Room 4B37,10 Cent Dr,MSC 1361, Bethesda, MD 20892 USA. RI Shatunov, Aleksey/E-6946-2011 NR 26 TC 31 Z9 35 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-639X J9 MUSCLE NERVE JI Muscle Nerve PD JUN PY 2003 VL 27 IS 6 BP 669 EP 675 DI 10.1002/mus.10370 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 687NY UT WOS:000183384400004 PM 12766977 ER PT J AU Johnson, FM AF Johnson, FM TI How many high production chemicals are rodent carcinogens? Why should we care? What do we need to do about it? SO MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH LA English DT Article DE cancer; carcinogens; National Toxicology Program; Environmental Protection Agency; high production chemicals; rodent bioassay; NTP; EPA; HPV ID NATIONAL-TOXICOLOGY-PROGRAM; HUMAN CANCER HAZARDS; PREVENTION; BIOASSAY; MUTAGENICITY; PERSPECTIVE; PREDICTION; TESTS; NTP AB High production volume (HPV) chemicals are produced in or imported to the US in amounts greater than I million pounds per chemical per year. The EPA has identified thousands of HPVs. Due to their abundance, such chemicals bring a substantial risk for human exposure, and as a result some level of adverse consequences to health are to be expected. In order to examine the potential for cancer risk associated with HPVs, this paper examines HPVs that have been tested in the National Toxicology Program's rodent cancer bioassay. The chemicals tested in the bioassay represent a small sample of the universe of environmental chemicals to which people are exposed. Unexpectedly, 60% of the 128 HPVs evaluated in the bioassay proved to be rodent carcinogens. This value compares to a predicted prevalence of only 16.5% carcinogens in a previous study. The previous study concluded that HPVs were less likely to be toxic by a variety of other test criteria as well. However, the approach involved identifying putative carcinogens using quantitative chemical structure-activity relationships QSAR) in contrast to the direct tabulation of bioassay test results performed here. Detailed examination of bioassay results reveals that test outcomes depend heavily on route of administration as well as on dose level, sex, strain, and species used. Since most of these factors have little or no apparent relationship to chemical structure, results of this study suggest that QSAR, as well as virtually all other alternative methods, may not generally provide accurate predictions of carcinogenic potential. As we wait for efficient and effective methods for predicting carcinogens to be developed, people continue to be exposed to environmental carcinogens. Progress on regulating environmental carcinogens as well as on developing more effective test methods has been minimal since "war on cancer" began approximately 30 years ago. The present study questions whether the current strategy for dealing with environmental carcinogens will ever be successful. Close examination of rodent cancer test results seems to suggest that almost all chemicals may have carcinogenic potential in some genotypes under some exposure circumstances. If this hypothesis is correct, it would explain the general lack of progress in developing methods to differentiate carcinogens from noncarcinogens. A completely new strategy for dealing with cancer caused by exposures to environmental chemicals seems to be needed. Published by Elsevier Science B.V. C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Johnson, FM (reprint author), NIEHS, Mail Drop EC-31, Res Triangle Pk, NC 27709 USA. NR 42 TC 6 Z9 6 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5742 J9 MUTAT RES-REV MUTAT JI Mutat. Res.-Rev. Mutat. Res. PD JUN PY 2003 VL 543 IS 3 BP 201 EP 215 AR PII S1383-5742(02)00091-1 DI 10.1016/S1383-5742(02)00091-1 PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 690GF UT WOS:000183538800004 PM 12787813 ER PT J AU Sans, N Prybylowski, K Petralia, RS Chang, K Wang, YX Racca, C Vicini, S Wenthold, RJ AF Sans, N Prybylowski, K Petralia, RS Chang, K Wang, YX Racca, C Vicini, S Wenthold, RJ TI NMDA receptor trafficking through an interaction between PDZ proteins and the exocyst complex SO NATURE CELL BIOLOGY LA English DT Article ID ER RETENTION SIGNAL; IONOTROPIC GLUTAMATE RECEPTORS; CEREBELLAR GRANULE NEURONS; SEC6/8 COMPLEX; PLASMA-MEMBRANE; AMPA RECEPTORS; HIPPOCAMPAL SYNAPSES; BIOCHEMICAL-EVIDENCE; SUBUNIT COMPOSITION; SURFACE EXPRESSION AB NMDA (N-methyl-D-aspartate) receptors (NMDARs) are targeted to dendrites and anchored at the post-synaptic density (PSD) through interactions with PDZ proteins. However, little is known about how these receptors are sorted from the endoplasmic reticulum and Golgi apparatus to the synapse. Here, we find that synapse-associated protein 102 (SAP102) interacts with the PDZ-binding domain of Sec8, a member of the exocyst complex. Our results show that interactions between SAP102 and Sec8 are involved in the delivery of NMDARs to the cell surface in heterologous cells and neurons. Furthermore, they suggest that an exocyst-SAP102-NMDAR complex is an important component of NMDAR trafficking. C1 Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Dept Physiol & Biophys, Med Ctr, Washington, DC 20057 USA. RP Sans, N (reprint author), Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Bldg 50,Room 4146,50 South Dr, Bethesda, MD 20892 USA. NR 47 TC 196 Z9 208 U1 0 U2 6 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 JUN PY 2003 VL 5 IS 6 BP 520 EP 530 DI 10.1038/ncb990 PG 11 WC Cell Biology SC Cell Biology GA 684JP UT WOS:000183202800012 PM 12738960 ER PT J AU Bulavin, DV Higashimoto, Y Demidenko, ZN Meek, S Graves, P Phillips, C Zhao, H Moody, SA Appella, E Piwnica-Worms, H Fornace, AJ AF Bulavin, DV Higashimoto, Y Demidenko, ZN Meek, S Graves, P Phillips, C Zhao, H Moody, SA Appella, E Piwnica-Worms, H Fornace, AJ TI Dual phosphorylation controls Cdc25 phosphatases and mitotic entry SO NATURE CELL BIOLOGY LA English DT Article ID PROTEIN-KINASE; NUCLEAR EXPORT; P38 KINASE; CHECKPOINT; MITOSIS; RADIATION; BINDING; LOCALIZATION; INITIATION; ACTIVATION AB Negative regulation of the Cdc25C protein phosphatase by phosphorylation on Ser 216, the 14-3-3-binding site, is an important regulatory mechanism used by cells to block mitotic entry under normal conditions and after DNA damage. During mitosis, Cdc25C is not phosphorylated on Ser 216 and ionizing radiation (IR) does not induce either phosphorylation of Ser 216, or binding to 14-3-3. Here, we show that Cdc25C is phosphorylated on Ser 214 during mitosis, which in turn prevents phosphorylation of Ser 216. Mutation of Ser 214 to Ala reconstitutes Ser 216 phosphorylation and 14-3-3 binding during mitosis. Introduction of exogenous Cdc25C(S214A) into HeLa cells depleted of endogenous Cdc25C results in a substantial delay to mitotic entry. This effect was fully reversed in a S214A/S216A double-mutant, implying that the inhibitory effect of S214A mutant was entirely dependent on Ser 216 phosphorylation. A similar regulatory mechanism may also apply to another mitotic phosphatase, Cdc25B, as well as mitotic phosphatases of other species, including Xenopus laevis. We propose that this pathway ensures that Cdc2 remains active once mitosis is initiated and is a key control mechanism for maintaining the proper order of cell-cycle transitions. C1 NCI, Gene Response Sect, NIH, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. George Washington Univ, Med Ctr, Dept Anat & Cell Biol, Washington, DC 20037 USA. Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA. Washington Univ, Sch Med, Howard Hughes Med Inst, St Louis, MO 63110 USA. RP Bulavin, DV (reprint author), NCI, Gene Response Sect, NIH, Bethesda, MD 20892 USA. RI Fornace, Albert/A-7407-2008; Piwnica-Worms, Helen/C-5214-2012; OI Fornace, Albert/0000-0001-9695-085X; Moody, Sally/0000-0003-4192-1087 NR 17 TC 118 Z9 120 U1 1 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 JUN PY 2003 VL 5 IS 6 BP 545 EP 551 DI 10.1038/ncb994 PG 7 WC Cell Biology SC Cell Biology GA 684JP UT WOS:000183202800016 PM 12766774 ER PT J AU Nelson, SJ AF Nelson, SJ TI MEDLINE definitions of race and ethnicity and their application to genetic research - In reply SO NATURE GENETICS LA English DT Letter C1 Natl Lib Med, Med Subject Headings Sect, Bethesda, MD 20894 USA. RP Nelson, SJ (reprint author), Natl Lib Med, Med Subject Headings Sect, Bethesda, MD 20894 USA. NR 0 TC 0 Z9 0 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 JUN PY 2003 VL 34 IS 2 BP 120 EP 120 DI 10.1038/ng0603-120 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 684HZ UT WOS:000183200500005 ER PT J AU Park, KY Pfeifer, K AF Park, KY Pfeifer, K TI Epigenetic interplay SO NATURE GENETICS LA English DT Editorial Material ID DNA METHYLATION; MAMMALIAN DEVELOPMENT; HISTONE CODE; CPG ISLAND; DIFFERENTIATION; CHROMATIN AB In a new study, the presence of a CpG island transgene protects neighboring sequence from DNA methylation during development leading to an open chromatin state that persists in the adult animal. This study suggests the importance of DNA methylation in setting up the epigenome. C1 NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Park, KY (reprint author), NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. OI Pfeifer, Karl/0000-0002-0254-682X NR 16 TC 3 Z9 4 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 JUN PY 2003 VL 34 IS 2 BP 126 EP 128 DI 10.1038/ng0603-126 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 684HZ UT WOS:000183200500008 PM 12776111 ER PT J AU Hashimshony, T Zhang, JM Keshet, I Bustin, M Cedar, H AF Hashimshony, T Zhang, JM Keshet, I Bustin, M Cedar, H TI The role of DNA methylation in setting up chromatin structure during development SO NATURE GENETICS LA English DT Article ID H3 LYSINE-4 METHYLATION; MOUSE EMBRYO; HISTONE H1; BINDING; TRANSCRIPTION; COMPLEX AB DNA methylation inhibits gene expression in animal cells, probably by affecting chromatin structure. Biochemical studies suggest that this process may be mediated by methyl-specific binding proteins that recruit enzymatic machinery capable of locally altering histone modification(1). To test whether DNA methylation actually has a role in the assembly of chromatin during normal development, we used cell transfection and a transgene construct genetically programmed to be either methylated or unmethylated in all cell types of the mouse(2). Chromatin immunoprecipitation (ChIP) analysis shows that the presence of DNA methylation brings about the deacetylation of histone H4 and methylation of Lys9 of histone H3 (H3 Lys9) and prevents methylation of Lys4 of histone H3 (H3 Lys4), thus generating a structure identical to that of methylated sequences in the genome. These results indicate that the methylation pattern established in early embryogenesis is profoundly important in setting up the structural profile of the genome. C1 Hebrew Univ Jerusalem, Dept Cellular Biochem & Human Genet, IL-91120 Jerusalem, Israel. Hebrew Univ Jerusalem, Dept Expt Med & Canc Res, IL-91120 Jerusalem, Israel. NCI, Prot Sect, Mol Carcinogenesis Lab, Div Basic Sci,NIH, Bethesda, MD 20892 USA. RP Cedar, H (reprint author), Hebrew Univ Jerusalem, Dept Cellular Biochem & Human Genet, POB 12272, IL-91120 Jerusalem, Israel. RI Bustin, Michael/G-6155-2015 NR 24 TC 184 Z9 193 U1 7 U2 18 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 JUN PY 2003 VL 34 IS 2 BP 187 EP 192 DI 10.1038/ng1158 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 684HZ UT WOS:000183200500025 PM 12740577 ER PT J AU Johnston, JA O'Shea, JJ AF Johnston, JA O'Shea, JJ TI Matching SOCS with function SO NATURE IMMUNOLOGY LA English DT Editorial Material ID CYTOKINE AB Overexpression studies suggest that SOCS3 is a pleiotropic negative regulator of cytokines. The generation of Socs3(-/-) mice indicates that SOCS3 actually functions in a remarkably specific manner. C1 Queens Univ Belfast, Dept Immunol, Belfast, Antrim, North Ireland. NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP Johnston, JA (reprint author), Queens Univ Belfast, Dept Immunol, Belfast, Antrim, North Ireland. NR 10 TC 46 Z9 47 U1 0 U2 1 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 JUN PY 2003 VL 4 IS 6 BP 507 EP 509 DI 10.1038/ni0603-507 PG 3 WC Immunology SC Immunology GA 683XC UT WOS:000183175500005 PM 12774070 ER PT J AU Durum, SK AF Durum, SK TI Bcl11: sibling rivalry in lymphoid development SO NATURE IMMUNOLOGY LA English DT Editorial Material ID TRANSCRIPTIONAL REPRESSION; PATHWAY; FAMILY; GENE AB Lymphocyte development is a complex process that involves the coordinated action of many transcription factors. The puzzle of B cell and T cell development gains an additional clue with the discovery of two critical factors. C1 NCI, NIH, Bethesda, MD 20892 USA. RP Durum, SK (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 12 TC 7 Z9 8 U1 0 U2 1 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 JUN PY 2003 VL 4 IS 6 BP 512 EP 514 DI 10.1038/ni0603-512 PG 4 WC Immunology SC Immunology GA 683XC UT WOS:000183175500008 PM 12774073 ER PT J AU Liu, PT Keller, JR Ortiz, M Tessarollo, L Rachel, RA Nakamura, T Jenkins, NA Copeland, NG AF Liu, PT Keller, JR Ortiz, M Tessarollo, L Rachel, RA Nakamura, T Jenkins, NA Copeland, NG TI Bcl11a is essential for normal lymphoid development SO NATURE IMMUNOLOGY LA English DT Article ID T-CELL DEVELOPMENT; HEMATOPOIETIC STEM-CELLS; MOUSE BONE-MARROW; CHROMOSOMAL TRANSLOCATIONS; LINEAGE DECISION; FETAL LIVER; B-CELLS; GENE; TRANSCRIPTION; NOTCH1 AB Bcl11a (also called Evi9) functions as a myeloid or B cell proto-oncogene in mice and humans, respectively. Here we show that Bcl11a is essential for postnatal development and normal lymphopoiesis. Bcl11a mutant embryos lack B cells and have alterations in several types of T cells. Phenotypic and expression studies show that Bcl11a functions upstream of the transcription factors Ebf1 and Pax5 in the B cell pathway. Transplantation studies show that these defects in Bcl11a mutant mice are intrinsic to fetal liver precursor cells. Mice transplanted with Bcl11a-deficient cells died from T cell leukemia derived from the host. Thus, Bcl11a may also function as a non-autonomous T cell tumor suppressor gene. C1 NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. NCI, SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. Japanese Fdn Canc Res, Toshima Ku, Tokyo 1708455, Japan. RP Copeland, NG (reprint author), NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400] NR 51 TC 160 Z9 167 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 JUN PY 2003 VL 4 IS 6 BP 525 EP 532 DI 10.1038/ni925 PG 8 WC Immunology SC Immunology GA 683XC UT WOS:000183175500010 PM 12717432 ER PT J AU Tscharke, DC Yewdell, JW AF Tscharke, DC Yewdell, JW TI T cells bite the hand that feeds them SO NATURE MEDICINE LA English DT Editorial Material ID MALARIA LIVER STAGES; ANTIGEN PRESENTATION; DIFFERENTIATION; INFECTION C1 NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Tscharke, DC (reprint author), NIAID, Viral Dis Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. RI yewdell, jyewdell@nih.gov/A-1702-2012; Tscharke, David/C-9133-2009 OI Tscharke, David/0000-0001-6825-9172 NR 8 TC 6 Z9 6 U1 0 U2 0 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 JUN PY 2003 VL 9 IS 6 BP 647 EP 648 DI 10.1038/nm0603-647 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 688PH UT WOS:000183444100016 PM 12778158 ER PT J AU McDonald, DM Choyke, PL AF McDonald, DM Choyke, PL TI Imaging of angiogenesis: from microscope to clinic SO NATURE MEDICINE LA English DT Review ID ENDOTHELIAL GROWTH-FACTOR; HUMAN BREAST-CANCER; ULTRASOUND CONTRAST AGENTS; IN-VIVO ASSESSMENT; MICROVESSEL DENSITY; VASCULAR-PERMEABILITY; TUMOR VASCULARITY; BLOOD-VESSELS; CELL PROLIFERATION; PROSTATE-CANCER AB Advances in imaging are transforming our understanding of angiogenesis and the evaluation of drugs that stimulate or inhibit angiogenesis in preclinical models and human disease. Vascular imaging makes it possible to quantify the number and spacing of blood vessels, measure blood flow and vascular permeability, and analyze cellular and molecular abnormalities in blood vessel walls. Microscopic methods ranging from fluorescence, confocal and multiphoton microscopy to electron microscopic imaging are particularly useful for elucidating structural and functional abnormalities of angiogenic blood vessels. Magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), ultrasonography and optical imaging provide noninvasive, functionally relevant images of angiogenesis in animals and humans. An ongoing dilemma is, however, that microscopic methods provide their highest resolution on preserved tissue specimens, whereas clinical methods give images of living tissues deep within the body but at much lower resolution and specificity and generally cannot resolve vessels of the microcirculation. Future challenges include developing new imaging methods that can bridge this resolution gap and specifically identify angiogenic vessels. Another goal is to determine which microscopic techniques are the best benchmarks for interpreting clinical images. The importance of angiogenesis in cancer, chronic inflammatory diseases, age-related macular degeneration and reversal of ischemic heart and limb disease provides incentive for meeting these challenges. C1 Univ Calif San Francisco, Ctr Comprehens Canc, Cardiovasc Res Inst, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. NIH, Imaging Sci Program, Bethesda, MD 20892 USA. RP McDonald, DM (reprint author), Univ Calif San Francisco, Ctr Comprehens Canc, Cardiovasc Res Inst, 513 Parnassus Ave, San Francisco, CA 94143 USA. FU NCI NIH HHS [P50-CA90270]; NHLBI NIH HHS [HL-24136, HL-59157] NR 140 TC 598 Z9 619 U1 13 U2 115 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 JUN PY 2003 VL 9 IS 6 BP 713 EP 725 DI 10.1038/nm0603-713 PG 13 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 688PH UT WOS:000183444100026 PM 12778170 ER PT J AU Siliciano, JD Kajdas, J Finzi, D Quinn, TC Chadwick, K Margolick, JB Kovacs, C Gange, SJ Siliciano, RF AF Siliciano, JD Kajdas, J Finzi, D Quinn, TC Chadwick, K Margolick, JB Kovacs, C Gange, SJ Siliciano, RF TI Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4(+) T cells SO NATURE MEDICINE LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; IMMUNODEFICIENCY-VIRUS INFECTION; COMBINATION THERAPY; VIRAL LOAD; REPLICATION; PERSISTENCE; INDINAVIR; PLASMA; ADULTS; DECAY AB Latent HIV-1 persists in resting memory CD4(+) T cells, even in patients receiving highly active antiretroviral therapy (HAART). It has been unclear how stable this latent reservoir is and whether its persistence reflects replenishment by low-level viremia. Here we show that even in treated patients who have had no detectable viremia for as long as 7 years, the reservoir decays so slowly (t(1/2) = 44 months) that eradication is unlikely. C1 Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. NIAID, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. Univ Toronto, Dept Med, Toronto, ON M5B 1L6, Canada. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. RP Siliciano, RF (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. RI Quinn, Thomas/A-2494-2010; OI Gange, Stephen/0000-0001-7842-512X FU NIAID NIH HHS [AI43222] NR 15 TC 638 Z9 657 U1 3 U2 21 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 JUN PY 2003 VL 9 IS 6 BP 727 EP 728 DI 10.1038/nm880 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 688PH UT WOS:000183444100027 PM 12754504 ER PT J AU Merril, C Scholl, D Adhya, SL AF Merril, C Scholl, D Adhya, SL TI The prospect for bacteriophage therapy in Western medicine SO NATURE REVIEWS DRUG DISCOVERY LA English DT Article ID ESCHERICHIA-COLI; PHAGE THERAPY; MYCOBACTERIUM-TUBERCULOSIS; STREPTOCOCCUS-PNEUMONIAE; MASS-SPECTROMETRY; FOREIGN DNA; MICE; INFECTIONS; PROTEIN; CELL C1 NIMH, Sect Biochem Genet, NIH, Bethesda, MD 20892 USA. NCI, Sect Dev Genet, NIH, Bethesda, MD 20892 USA. RP Merril, C (reprint author), NIMH, Sect Biochem Genet, NIH, Bethesda, MD 20892 USA. NR 87 TC 173 Z9 187 U1 2 U2 64 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 JUN PY 2003 VL 2 IS 6 BP 489 EP 497 DI 10.1038/nrd1111 PG 9 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 683BZ UT WOS:000183128300018 PM 12776223 ER PT J AU Strausberg, RL Simpson, AJG Wooster, R AF Strausberg, RL Simpson, AJG Wooster, R TI Sequence-based cancer genomics: Progress, lessons and opportunities SO NATURE REVIEWS GENETICS LA English DT Review ID TUMOR-SUPPRESSOR LOCUS; GENE-EXPRESSION; HUMAN TRANSCRIPTOME; ANATOMY PROJECT; SERIAL ANALYSIS; PROSTATE-CANCER; MESSENGER-RNA; BREAST-CANCER; ORAL-CANCER; DATABASE AB Technologies that provide a genome-wide view offer an unprecedented opportunity to scrutinize the molecular biology of the cancer cell. The information that is derived from these technologies is well suited to the development of public databases of alterations in the cancer genome and its expression. Here, we describe the synergistic efforts of research programmes in Brazil, the United Kingdom and the United States towards building integrated databases that are widely accessible to the research community, to enable basic and applied applications in cancer research. C1 NCI, Bethesda, MD 20892 USA. Ludwig Inst Canc Res, New York, NY 10158 USA. Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. RP Strausberg, RL (reprint author), NCI, 31 Ctr Dr,Room 10A07, Bethesda, MD 20892 USA. NR 73 TC 44 Z9 50 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 EI 1471-0064 J9 NAT REV GENET JI Nat. Rev. Genet. PD JUN PY 2003 VL 4 IS 6 BP 409 EP 418 DI 10.1038/nrg1085 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 684JM UT WOS:000183202600011 PM 12776211 ER PT J AU Li, YL Li, HM Yang, F Smith-Gill, SJ Mariuzza, RA AF Li, YL Li, HM Yang, F Smith-Gill, SJ Mariuzza, RA TI X-ray snapshots of the maturation of an antibody response to a protein antigen SO NATURE STRUCTURAL BIOLOGY LA English DT Article ID EGG-WHITE LYSOZYME; 3-DIMENSIONAL STRUCTURES; IMMUNE-RESPONSE; MOLECULAR RECOGNITION; BINDING INTERACTIONS; AFFINITY MATURATION; MUTATIONAL ANALYSIS; COMBINING SITE; COMPLEX; INTERFACES AB The process whereby the immune system generates antibodies of higher affinities during a response to antigen ( affinity maturation) is a prototypical example of molecular evolution. Earlier studies have been confined to antibodies specific for small molecules (haptens) rather than for proteins. We compare the structures of four antibodies bound to the same site on hen egg white lysozyme (HEL) at different stages of affinity maturation. These X-ray snapshots reveal that binding is enhanced, not through the formation of additional hydrogen bonds or van der Waals contacts or by an increase in total buried surface, but by burial of increasing amounts of apolar surface at the expense of polar surface, accompanied by improved shape complementarity. The increase in hydrophobic interactions results from highly correlated rearrangements in antibody residues at the interface periphery, adjacent to the central energetic hot spot. This first visualization of the maturation of antibodies to protein provides insights into the evolution of high affinity in other protein protein interfaces. C1 Univ Maryland, Maryland Biotechnol Inst, Ctr Adv Res Biotechnol, WM Keck Lab Struct Biol, Rockville, MD 20850 USA. New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12201 USA. NCI, Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA. RP Mariuzza, RA (reprint author), Univ Maryland, 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 Li, Hongmin/0000-0002-8684-5308 NR 37 TC 105 Z9 107 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1072-8368 J9 NAT STRUCT BIOL JI Nat. Struct. Biol. PD JUN PY 2003 VL 10 IS 6 BP 482 EP 488 DI 10.1038/nsb930 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 683GT UT WOS:000183140600016 PM 12740607 ER PT J AU Ulloa, A Bullock, D Rhodes, BJ AF Ulloa, A Bullock, D Rhodes, BJ TI Adaptive force generation for precision-grip lifting by a spectral timing model of the cerebellum SO NEURAL NETWORKS LA English DT Article; Proceedings Paper CT INNS/IEEE International Joint Conference on Neural Network (IJCNN 03) CY JUL 20-24, 2003 CL PORTLAND, OREGON SP Int Neural Network Soc, IEEE, Neural Network Soc DE adaptive timing; neural model; synaptic plasticity; prehension; learning; force ID MOSSY FIBER; MOTOR; RESPONSES; PLASTICITY; MOVEMENTS; AFFERENTS; OBJECTS; SYSTEM; MEMORY; CORTEX AB We modeled adaptive generation of precision grip forces during object lifting. The model presented adjusts reactive and anticipatory grip forces to a level just above that needed to stabilize lifted objects in the hand. The model obeys principles of cerebellar structure and function by using slip sensations as error signals to adapt phasic motor commands to tonic force generators associated with output synergies controlling grip aperture. The learned phasic commands are weight- and texture-dependent. Simulations of the new circuit model reproduce key aspects of experimental observations of force application. Over learning trials, the onset of grip force buildup comes to lead the load force buildup, and the rate-of-rise of grip force, but not load force, scales inversely with the friction of the object. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 Boston Univ, Dept Cognit & Neural Syst, Boston, MA 02215 USA. RP Ulloa, A (reprint author), NIH, Brain Imaging & Modeling Sect, 9000 Rockville Pike,10-3C716, Bethesda, MD 20892 USA. OI Ulloa, Antonio/0000-0002-7554-4542 FU NIDCD NIH HHS [R01 DC02852] NR 28 TC 7 Z9 7 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0893-6080 J9 NEURAL NETWORKS JI Neural Netw. PD JUN-JUL PY 2003 VL 16 IS 5-6 BP 521 EP 528 DI 10.1016/S0893-6080(03)00094-7 PG 8 WC Computer Science, Artificial Intelligence SC Computer Science GA 698RE UT WOS:000184011900002 PM 12850003 ER PT J AU Deutsch, J Rapoport, SI Rosenberger, TA AF Deutsch, J Rapoport, SI Rosenberger, TA TI Valproyl-CoA and esterified valproic acid are not found in brains of rats treated with valproic acid, but the brain concentrations of CoA and acetyl-CoA are altered SO NEUROCHEMICAL RESEARCH LA English DT Article DE valproic acid; coenzyme A; acetyl-CoA; phospholipid; fatty acid; arachidonic acid; brain ID ACTIVATED RECEPTOR-ALPHA; CENTRAL-NERVOUS-SYSTEM; FATTY-ACID; ANTICONVULSANT EFFICACY; ARACHIDONIC-ACID; METABOLISM; DELTA; PHOSPHOLIPIDS; DERIVATIVES; BETA AB Sodium valproate and lithium are used to treat bipolar disorder. In rats, both reduce the turnover of arachidonic acid in several brain phospholipids, suggesting that arachidonate turnover is a common target of action of these mood stabilizers. However, the mechanisms by which these drugs reduce arachidonate turnover in brain are not the same. Lithium decreases turnover by reducing the activity and expression of the 85-kDa type IVA cytosolic phospholipase A(2) (cPLA(2)); valproate does not affect cPLA(2) activity or expression. To test whether valproate alters neural membrane order by direct esterification into phospholipid or by interrupting intermediary CoA metabolism, we measured valproyl-CoA, esterified valproate, and short chain acyl-CoAs in brains from control rats and rats treated chronically with sodium valproate. Valproyl-CoA and esterified forms of valproate were not found in brain with detection limits of 25 and 37.5 pmol/g brain(-1), respectively. Valproate treatment did result in a 1.4-fold decrease and 1.5-fold increase in the brain concentrations of free CoA and acetyl-CoA when compared to control. Therefore the reduction of brain arachidonic acid turnover by chronic valproate in rats is not related to the formation of valproyl-CoA or esterified valproate, but may involve changes in the intermediary metabolism of CoA and short chain acyl-CoA. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. Hebrew Univ Jerusalem, David R Bloom Ctr Pharm, Dept Med Chem, Sch Pharm, Jerusalem, Israel. RP Rosenberger, TA (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 10,Room 6N202, Bethesda, MD 20892 USA. NR 37 TC 15 Z9 15 U1 0 U2 2 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD JUN PY 2003 VL 28 IS 6 BP 861 EP 866 DI 10.1023/A:1023267224819 PG 6 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 665BN UT WOS:000182099900010 PM 12718439 ER PT J AU Liang, HL Bressler, SL Ding, MZ Desimone, R Fries, P AF Liang, HL Bressler, SL Ding, MZ Desimone, R Fries, P TI Temporal dynamics of attention-modulated neuronal synchronization in macaque V4 SO NEUROCOMPUTING LA English DT Article DE selective visual attention; multivariate autoregressive modeling; gamma synchronization; coherence; bottom-up; top-down AB It was recently observed that neurons in area V4 exhibited enhanced gamma band (35-90 Hz) synchronization when monkeys attended to a visual stimulus as compared to when they were not attending to the same stimulus (Science 291 (2001) 1560). Spike-triggered averaging of local field potentials (LFPs) was used to show attentional modulation in an early period from 50 to 150 ms after stimulus onset (Science 291 (2001) 1560). In this work we further studied the fine temporal structure in the same data by focusing only on the LFPs without reference to the concurrent spike trains. With the method of adaptive multivariate autoregressive (AMVAR) modeling, we discovered that attentional modulation of gamma power (similar to65 Hz) in V4 can be as brief as about 25 ms. Gamma coherence between two V4 recording sites revealed similar attention effects, as well as a second peak around 45 Hz. Directional influences between two V4 populations revealed that one can play a more dominant role than another. These results implicate gamma oscillation as a possible agent in carrying out attention-biased competition among visual stimuli in favor of those that are behaviorally relevant. The AMVAR method was instrumental in revealing the dynamics of gamma frequency synchronization with high temporal and frequency resolution. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Univ Texas, Hlth Sci Ctr, Sch Hlth Informat Sci, Houston, TX 77030 USA. Florida Atlantic Univ, Ctr Complex Syst & Brain Sci, Boca Raton, FL 33431 USA. NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. Univ Nijmegen, FC Donders Ctr Cognit Neuroimaging, NL-6525 EK Nijmegen, Netherlands. RP Liang, HL (reprint author), Univ Texas, Hlth Sci Ctr, Sch Hlth Informat Sci, Houston, TX 77030 USA. RI Fries, Pascal/E-3196-2010 OI Fries, Pascal/0000-0002-4270-1468 NR 8 TC 11 Z9 11 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-2312 J9 NEUROCOMPUTING JI Neurocomputing PD JUN PY 2003 VL 52-4 BP 481 EP 487 DI 10.1016/S0925-2312(02)00741-5 PG 7 WC Computer Science, Artificial Intelligence SC Computer Science GA 689VU UT WOS:000183514300071 ER PT J AU Hertz, J Richmond, B Nilsen, K AF Hertz, J Richmond, B Nilsen, K TI Anomalous response variability in a balanced cortical network model SO NEUROCOMPUTING LA English DT Article DE response variability; cortical dynamics; asynchronous firing ID NEURONAL NETWORKS; SPIKING NEURONS; DYNAMICS AB We use mean field theory to study the response properties of a simple randomly connected model cortical network of leaky integrate-and-fire neurons with balanced excitation and inhibition. The formulation permits arbitrary temporal variation of the input to the network and takes exact account of temporal firing correlations. We find that neuronal firing statistics depend sensitively on the firing threshold. In particular, spike count variances can be either significantly greater than or significantly less than those for a Poisson process. These findings may help in understanding the variability observed experimentally in cortical neuronal responses. Published by Elsevier Science B.V. C1 NORDITA, DK-2100 Copenhagen, Denmark. NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. RP Hertz, J (reprint author), NORDITA, Blegdamsvej 17, DK-2100 Copenhagen, Denmark. NR 9 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-2312 J9 NEUROCOMPUTING JI Neurocomputing PD JUN PY 2003 VL 52-4 BP 787 EP 792 DI 10.1016/S0925-2312(02)00775-0 PG 6 WC Computer Science, Artificial Intelligence SC Computer Science GA 689VU UT WOS:000183514300113 ER PT J AU Hanakawa, T Honda, M Okada, T Fukuyama, H Shibasaki, H AF Hanakawa, T Honda, M Okada, T Fukuyama, H Shibasaki, H TI Neural correlates underlying mental calculation in abacus experts: a functional magnetic resonance imaging study SO NEUROIMAGE LA English DT Article ID PARIETAL LOBE; DIGIT MEMORY; BRAIN; AREAS; IMAGERY; FMRI; ACTIVATION; ACALCULIA; ANATOMY; CONNECTIVITY AB Experts of abacus operation demonstrate extraordinary ability in mental calculation. There is psychological evidence that abacus experts utilize a mental image of an abacus to remember and manipulate large numbers in solving problems; however, the neural correlates underlying this expertise are unknown. Using functional magnetic resonance imaging, we compared the neural correlates associated with three mental-operation tasks (numeral, spatial, verbal) among six experts in abacus operations and eight nonexperts. In general, there was more involvement of neural correlates for visuospatial processing (e.g., right premotor and parietal areas) for abacus experts during the numeral mental-operation task. Activity of these areas and the fusiform cortex was correlated with the size of numerals used in the numeral mental-operation task. Particularly, the posterior superior parietal cortex revealed significantly enhanced activity for experts compared with controls during the numeral mental-operation task. Comparison with the other mental-operation tasks indicated that activity in the posterior superior parietal cortex was relatively specific to computation in 2-dimensional space. In conclusion, mental calculation of abacus experts is likely associated with enhanced involvement of the neural resources for visuospatial information processing in 2-dimensional space. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Nalt Inst Physiol Sci, Lab Cerebral Integrat, Okazaki, Aichi 4448585, Japan. PRESTO, Japan Sci & Technol Corp, Kawaguchi, Japan. Kyoto Univ, Grad Sch Med, Dept Nucl Med, Kyoto, Japan. Kyoto Univ, Grad Sch Med, Human Brain Res Ctr, Kyoto, Japan. NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Honda, M (reprint author), Nalt Inst Physiol Sci, Lab Cerebral Integrat, 38 Nishigonaka Myodaiji Cho, Okazaki, Aichi 4448585, Japan. NR 49 TC 65 Z9 74 U1 0 U2 15 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 JUN PY 2003 VL 19 IS 2 BP 296 EP 307 DI 10.1016/S1053-8119(03)00050-8 PN 1 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 690UP UT WOS:000183568900009 PM 12814580 ER PT J AU Foltys, H Meister, IG Weidemann, J Sparing, R Thron, A Willmes, K Topper, R Hallett, M Boroojerdi, B AF Foltys, H Meister, IG Weidemann, J Sparing, R Thron, A Willmes, K Topper, R Hallett, M Boroojerdi, B TI Power grip disinhibits the ipsilateral sensorimotor cortex: a TMS and fMRI study SO NEUROIMAGE LA English DT Article DE fMRI; TMS; ipsilateral motor cortex; facilitating maneuver; power grip ID HUMAN MOTOR CORTEX; CEREBRAL BLOOD-FLOW; VOLUNTARY CONTRACTION; INTERHEMISPHERIC INHIBITION; MAGNETIC STIMULATION; FINGER MOVEMENTS; HUMAN-BRAIN; CORTICOCORTICAL INHIBITION; MUSCLE RESPONSES; CORPUS-CALLOSUM AB Electrophysiological studies have shown that forceful activation of the hand muscles (power grip) is accompanied by an increased excitability of the ipsilateral corticospinal system. This increase in excitability may be due to spinal or cortical mechanisms. Here we show with fMRI that this phenomenon is at least in part mediated at a cortical level. We used TMS to show that the increased ipsilateral excitability during a forceful maneuver leads to enhanced stimulus-response curves. fMRI was used to compare the activation during a repetitive hand movement with or without an accompanying power grip on the opposite site. The power grip reduced movement-related activation in the ipsilateral sensorimotor cortex. Peak deactivation was located in the left postcentral gyrus extending into the adjacent precentral gyrus. This finding suggests that a forceful activation of the hand muscles disinhibits a distinct functional representation in the ipsilateral sensorimotor cortex. Consequently, the excitability of the corticospinal system increases and less neuronal excitatory activity is needed to perform a given task. The results may be important for a variety of studies as they suggest that fMRI may show decreased hemodynamic response under conditions in which other neurophysiological methods have shown increased functional activity. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Univ Aachen, Dept Neurol, D-5100 Aachen, Germany. Univ Aachen, Dept Neuroradiol, D-5100 Aachen, Germany. Univ Aachen, CNS, Interdisciplinary Ctr Clin Res, D-5100 Aachen, Germany. NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Boroojerdi, B (reprint author), Univ Hosp Aachen, Dept Neurol, Pauwelsstr 30, D-52057 Aachen, Germany. RI Meister, Ingo/A-3642-2008 NR 59 TC 19 Z9 20 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUN PY 2003 VL 19 IS 2 BP 332 EP 340 DI 10.1016/S1053-8119(03)00107-1 PN 1 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 690UP UT WOS:000183568900012 PM 12814583 ER PT J AU Calamante, F Yim, PJ Cebral, JR AF Calamante, F Yim, PJ Cebral, JR TI Estimation of bolus dispersion effects in perfusion MRI using image-based computational fluid dynamics SO NEUROIMAGE LA English DT Article DE perfusion; computational fluid dynamics; quantification; cerebral blood flow ID CEREBRAL-BLOOD-FLOW; CAROTID-ARTERY STENOSIS; WEIGHTED MRI; ISCHEMIC PENUMBRA; DWI/PWI MISMATCH; GRID GENERATION; ACUTE STROKE; DIFFUSION; QUANTIFICATION; TRIANGULATIONS AB Bolus tracking magnetic resonance imaging (MRI) is a powerful technique for measuring perfusion, and is playing an increasing role in the investigation of acute stroke. However, limitations have been reported when assessing patients with steno-occlusive disease. The presence of a steno-occlusive disease in the artery may cause bolus dispersion, which has been shown to introduce significant errors in cerebral blood flow (CBF) quantification. Bolus dispersion is commonly described by a vascular transport function, but the function that properly characterizes the dispersion is unknown. A novel method to quantify bolus dispersion errors on perfusion measurements is presented. A realistic patient-specific model is constructed from anatomical and physiologic MR data, and the arterial blood flow pattern and the transport of the bolus of contrast agent are computed using finite element analysis. The methodology presented was used also to evaluate the accuracy of three simple vascular models. The methodology was tested on MR data from two normal subjects and two subjects with mild carotid artery stenosis. The estimated CBF errors were of the order of 15% to 20%. However, the presence of stenosis did not necessarily introduce larger dispersion (not only the geometrical model but also the particular physiologic conditions influence the degree of bolus dispersion). The method described will contribute to a better understanding of errors introduced by dispersion effects, to the assessment and validation of vascular models, and to the development of new methods for the correction of dispersion errors in CBF quantification. (C) 2003 Elsevier Science (USA). All rights reserved. C1 UCL, Inst Child Hlth, Radiol & Phys Unit, London WC1N 1EH, England. NIH, Imaging Sci Program, Bethesda, MD 20892 USA. George Mason Univ, Fairfax, VA 22030 USA. RP Calamante, F (reprint author), UCL, Inst Child Hlth, Radiol & Phys Unit, 30 Guildford St, London WC1N 1EH, England. EM cfernan@ich.ucl.ac.uk NR 41 TC 65 Z9 65 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUN PY 2003 VL 19 IS 2 BP 341 EP 353 DI 10.1016/S1053-8119(03)00090-9 PN 1 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 690UP UT WOS:000183568900013 PM 12814584 ER PT J AU Horwitz, B AF Horwitz, B TI The elusive concept of brain connectivity SO NEUROIMAGE LA English DT Article ID GLUCOSE METABOLIC RATES; FUNCTIONAL CONNECTIVITY; VISUAL PATHWAYS; NETWORK ANALYSIS; REGIONS; CORTEX; PET; 2-DEOXYGLUCOSE; DYNAMICS; ADULTS AB Neurons and neural populations do not function as islands onto themselves. Rather, they interact with other such elements through their afferent and efferent connections in an orchestrated manner so as to enable different sensorimotor and cognitive tasks to be performed. The concept of functional connectivity and the allied notion of effective connectivity were introduced to designate the functional strengths of such interactions. Functional neuroimaging methods, especially PET and fMRI, have been used extensively to evaluate the functional connectivity between different brain regions. After providing a brief historical review of these notions of brain connectivity, I argue that the conceptual formulations of functional and effective connectivity are far from clear. Specifically, the terms functional and effective connectivity are applied to quantities computed on types of functional imaging data (e.g., PET, fMRI, EEG) that vary in spatial, temporal, and other features, using different definitions (even for data of the same modality) and employing different computational algorithms. Until it is understood what each definition means in terms of an underlying neural substrate, comparisons of functional and/or effective connectivity across studies may appear inconsistent and should be performed with great caution. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NIDCD, Brain Imaging & Modeling Sect, NIH, Bethesda, MD 20892 USA. RP Horwitz, B (reprint author), NIDCD, Brain Imaging & Modeling Sect, NIH, Bldg 10,Rm 6C420,MSC 1591, Bethesda, MD 20892 USA. EM horwitz@helix.nih.gov NR 44 TC 352 Z9 361 U1 2 U2 28 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 JUN PY 2003 VL 19 IS 2 BP 466 EP 470 DI 10.1016/S1053-8119(03)00112-5 PN 1 PG 5 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 690UP UT WOS:000183568900024 PM 12814595 ER PT J AU Amin, R Kamitani, H Sultana, H Taniura, S Islam, A Sho, A Ishibashi, M Eling, TE Watanabe, T AF Amin, R Kamitani, H Sultana, H Taniura, S Islam, A Sho, A Ishibashi, M Eling, TE Watanabe, T TI Aspirin and indomethacin exhibit antiproliferative effects and induce apoptosis in T98G human glioblastoma cells SO NEUROLOGICAL RESEARCH LA English DT Article DE NSAIDs; T98G; COX; apoptosis; chemoprevention ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; COLORECTAL-CANCER; GROWTH-INHIBITION; GLIOMA-CELLS; IN-VITRO; CYCLOOXYGENASE-2 EXPRESSION; MALIGNANT GLIOMA; SULINDAC SULFIDE; THERAPY; TUMORS AB The in vitro antiproliferative and apoptosis inducing properties of the nonsteroidal anti-inflammatory drugs (NSAIDs) like acetyl salicylic acid (aspirin) and indomethacin were investigated in T98G human glioblastoma cells to explore their potential role in the chemoprevention of human glioma. The biological effects induced by aspirin and indomethacin on T98G cells, in which the expression of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) were confirmed by RT-PCR and immunostaining, were investigated by studying cell proliferation and apoptosis assays. The antiproliferative effects occurred in a dose- and time-dependent manner on T98G cells by the treatment with 0.1 -2 mM aspirin and 25-100 muM indomethacin. Moreover, aspirin displayed the greatest growth inhibition within 24 h. Approximately 90% growth inhibition occurred following treatment either with 2 mM aspirin or 100 muM indomethacin by 72 h and induction of apoptosis was confirmed by DNA laddering and TUNEL assay. Our in vitro findings indicate that aspirin and indomethacin have an antiproliferative effect on T98G human glioblastoma cells at toxic concentrations. C1 Tottori Univ, Sch Med, Dept Neurosurg, Inst Neurol Sci,Fac Med, Tottori 6838504, Japan. Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, Res Triangle Pk, NC USA. RP Kamitani, H (reprint author), Tottori Univ, Sch Med, Dept Neurosurg, Inst Neurol Sci,Fac Med, 36-1 Nishi Cho, Tottori 6838504, Japan. NR 33 TC 20 Z9 23 U1 0 U2 2 PU FOREFRONT PUBL GROUP PI WILTON PA C/O MARY J RAWLINS, 5 RIVER RD, STE 113, WILTON, CT 06897 USA SN 0161-6412 J9 NEUROL RES JI Neurol. Res. PD JUN PY 2003 VL 25 IS 4 BP 370 EP 376 DI 10.1179/016164103101201706 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 703EL UT WOS:000184267000009 PM 12870263 ER PT J AU Kumari, D Mital, A Gupta, M Goyle, S AF Kumari, D Mital, A Gupta, M Goyle, S TI Deletion analysis of the dystrophin gene in Duchenne and Becker muscular dystrophy patients: Use in carrier diagnosis SO NEUROLOGY INDIA LA English DT Article DE carrier diagnosis; dystrophin; deletions; multiplex PCR ID POLYMERASE CHAIN-REACTION; CDNA; HYBRIDIZATION; PATTERN; PCR; DMD AB The dystrophin gene was analyzed in 8 Duchenne muscular dystrophy (DMD) and 10 Becker muscular dystrophy (BMD) unrelated families (22 subjects: 18 index cases and 4 sibs) for the presence of deletions by multiplex polymerase chain reaction (mPCR; 27 exons) and Southern hybridization using 8 cDMD probes. Deletions were identified in 5 DMD and 7 BMD patients (6 index cases and 1 sib). The concordance between the clinical phenotype and "reading frame hypothesis" was observed in 11/12 patients (92%). The female relatives of DMD/BMD patients with identifiable deletions were examined by quantitative mPCR. Carriers were identified in 7 families. We also describe a variation in the Hindlll pattern with cDNA probe 8 and 11-14. Molecular. characterization of the dystrophin gene in this study has been helpful in advising the patients concerning the inheritance of the condition, and carrier diagnosis of female relatives, and should also prove useful for prenatal diagnosis. C1 GB Pant Hosp, Dept Neurol, New Delhi, India. Jawaharlal Nehru Univ, Sch Life Sci, Human Mol Genet Lab, New Delhi 110067, India. RP Kumari, D (reprint author), NIDDKD, Mol & Cellular Biol Lab, NIH, Bldg 8,Room 202, Bethesda, MD 20892 USA. NR 18 TC 5 Z9 6 U1 0 U2 2 PU NEUROL SOC INDIA PI CHANDIGARH PA C/O J S CHOPRA, PGIMER, DEPT NEUROLOGY, CHANDIGARH 160 012, INDIA SN 0028-3886 J9 NEUROL INDIA JI Neurol. India PD JUN PY 2003 VL 51 IS 2 BP 223 EP 226 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 743BT UT WOS:000186553100014 PM 14571009 ER PT J AU Li, JL Gould, TD Yuan, PX Manji, HK Chen, G AF Li, JL Gould, TD Yuan, PX Manji, HK Chen, G TI Post-mortem interval effects on the phosphorylation of signaling proteins SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Alzheimer's disease; bipolar disorder; depression; schizophrenia; two-dimensional gel electrophoresis; protein phosphorylation ID HUMAN POSTMORTEM BRAIN; ALZHEIMERS-DISEASE; BIPOLAR DISORDER; RAT-BRAIN; TAU-PHOSPHORYLATION; SENILE DEMENTIA; MESSENGER-RNAS; AGONAL STATUS; SCHIZOPHRENIA; NEUROPATHOLOGY AB Post-mortem brain tissue provides a unique opportunity to uncover the genes or proteins involved in the pathophysiology of neuropsychiatric disorders. Protein phosphorylation is a common protein modification within intracellular signaling pathways that affects the distribution and function of protein, and has been hypothesized to be of major importance in both the pathophysiology and treatment of major neuropsychiatric disorders. Thus, we were interested in ascertaining the stability of the phosphorylated forms of proteins that are involved in cellular signaling. Antibodies against phospho-tyrosine, phospho-threonine, and phospho-PKA substrates were used to examine the PMI effects on the general amounts of proteins in their phosphorylated form. Phospho-specific antibodies for ERK, JNK, RSK, CREB, and ATF-2 were used to test the effects of PMI on specific proteins whose functioning are known to be regulated markedly by phosphorylation. We found that PMI rapidly decreased the levels of proteins in their phosphorylated states and also decreased the total levels of certain proteins. The PMI effects were observed in the samples stored at both 4degreesC and room temperature, in both frontal cortex and hippocampus. Thus, it appears that measurements (such as two-dimensional gel electrophoresis and functional assays) that rely on the phosphorylation state of proteins would be extremely sensitive to PMI. C1 NIMH, Mol Pathophysiol Lab, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. Wayne State Univ, Mol Pathophysiol Lab, Sch Med, Detroit, MI USA. RP Chen, G (reprint author), NIMH, Mol Pathophysiol Lab, Mood & Anxiety Disorders Program, NIH, Bldg 49,Room B1EE16, Bethesda, MD 20892 USA. RI Chen, Guang/A-2570-2017 NR 60 TC 51 Z9 51 U1 1 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 JUN PY 2003 VL 28 IS 6 BP 1017 EP 1025 DI 10.1038/sj.npp.1300112 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 686HT UT WOS:000183316100001 PM 12637955 ER PT J AU Holmes, A Kinney, JW Wrenn, CC Li, Q Yang, RJ Ma, L Vishwanath, J Saavedra, MC Innerfield, CE Jacoby, AS Shine, J Iismaa, TP Crawley, JN AF Holmes, A Kinney, JW Wrenn, CC Li, Q Yang, RJ Ma, L Vishwanath, J Saavedra, MC Innerfield, CE Jacoby, AS Shine, J Iismaa, TP Crawley, JN TI Galanin GAL-R1 receptor null mutant mice display increased anxiety-like behavior specific to the elevated plus-maze SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE galanin; GAL-R1 receptor; mouse; anxiety; stress; norepinephrine ID LOCUS-COERULEUS NEURONS; OVEREXPRESSING TRANSGENIC MICE; PREPROGALANIN MESSENGER-RNA; CHRONIC RESTRAINT STRESS; HORMONE RECEPTOR-2; TEST BATTERY; NEUROENDOCRINE RESPONSES; TYROSINE-HYDROXYLASE; ANXIOLYTIC EFFICACY; CERULEUS NEURONS AB The neuropeptide galanin coexists with norepinephrine and serotonin in neural systems mediating emotion. Previous findings suggested that galanin modulates anxiety-related behaviors in rodents. Three galanin receptor subtypes have been cloned; however, understanding their functions has been limited by the lack of galanin receptor subtype-selective ligands. To study the role of the galanin GAL-RI receptor subtype in mediating anxiety-related behavior, we generated mice with a null mutation in the Galrl gene, GAL-Rl -/- are viable and show no abnormalities in health, neurological reflexes, motoric functions, or sensory abilities. On a battery of tests for anxiety-like behavior, GAL-R I -/- showed increased anxiety-like behavior on the elevated plus-maze test. Anxiety-related behaviors on the light/dark exploration, emergence, and open field tests were normal in GAL-RI -/-. This test-specific anxiety-like phenotype was confirmed in a second, independent cohort of GAL-RI null mutant mice and +/+ controls, Principal components factor analysis of behavioral scores from 279 mice suggested that anxiety-like behavior on the elevated plus-maze was qualitatively distinct from behavior on other tests in the battery, In addition, exposure to the elevated plus-maze produced a significantly greater neuroendocrine response than exposure to the light/dark exploration test, as analyzed in normal C57BU6J mice. These behavioral findings in the first galanin receptor null mutant mouse are consistent with the hypothesis that galanin exerts anxiolytic actions via the GAL-R I receptor under conditions of relatively high stress. C1 NIMH, Sect Behav Genom, Bethesda, MD 20892 USA. NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. Garvan Inst Med Res, Sydney, NSW, Australia. RP Holmes, A (reprint author), NIMH, Sect Behav Genom, Bldg 10,Room 4D11, Bethesda, MD 20892 USA. NR 96 TC 121 Z9 126 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUN PY 2003 VL 28 IS 6 BP 1031 EP 1044 DI 10.1038/sj.npp.1300164 PG 14 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 686HT UT WOS:000183316100003 PM 12700679 ER PT J AU Westergaard, GC Suomi, SJ Chavanne, TJ Houser, L Hurley, A Cleveland, A Snoy, PJ Higley, JD AF Westergaard, GC Suomi, SJ Chavanne, TJ Houser, L Hurley, A Cleveland, A Snoy, PJ Higley, JD TI Physiological correlates of aggression and impulsivity in free-ranging female primates SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE serotonin; 5-HIAA; aggression; Macaca mulatta; females; impulsivity ID FLUID AMINE METABOLITES; 5-HYDROXYINDOLEACETIC ACID CONCENTRATIONS; CEREBROSPINAL-FLUID; CSF 5-HIAA; SEROTONERGIC RESPONSIVITY; HEALTHY-VOLUNTEERS; VIOLENT OFFENDERS; RHESUS-MONKEYS; FIRE SETTERS; INTERINDIVIDUAL DIFFERENCES AB We examined the relations among cerebrospinal fluid (CSF) monoamine metabolite concentrations, plasma hormone concentrations, aggression, and impulsive risk-taking behavior in a free-ranging population of female rhesus macaques. We selected 44 juvenile female rhesus macaques as subjects from a population of approximately 3000 macaques that inhabit a 475-acre Sea Island. We obtained CSF and blood samples, and recorded behavioral observations over a subsequent 18-month period. Our results indicate an inverse correlation between CSF concentrations of the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), and the frequency of low-intensity restrained aggression typically associated with matrilineal defense of social status. In contrast, previous research with males has shown an inverse correlation between CSF 5-HIAA concentrations and levels of violent unstrained aggression typically associated with traumatic injury and death. We also noted a negative correlation between plasma concentrations of the stress hormone cortisol and the frequency of low-intensity aggressive acts, a finding not reported in our previous studies with males. Further examination revealed a negative correlation between CSF 5-HIAA concentrations and the rate of long dangerous leaps through the forest canopy, suggesting that the relation between low serotonergic functioning and impulsivity may generalize to both female and male primates. These results indicate that females with low CSF 5-HIAA concentrations, like their male counterparts, are at increased risk for impulsive temperament, but that unlike males, females may be buffered from this risk through intersexual differences in life history patterns and social affiliation. C1 LABS Virginia Inc, Div Res & Dev, Yemassee, SC 29945 USA. NICHHD, Comparat Ethol Lab, Bethesda, MD 20892 USA. NIAAA, Clin Studies Lab, Bethesda, MD 20892 USA. US FDA, Div Vet Serv, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. RP Westergaard, GC (reprint author), LABS Virginia Inc, Div Res, 95 Castle Hall Rd,POB 557, Yemassee, SC 29945 USA. FU NIAAA NIH HHS [N01AA02018] NR 59 TC 55 Z9 55 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUN PY 2003 VL 28 IS 6 BP 1045 EP 1055 DI 10.1038/sj.npp.1300171 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 686HT UT WOS:000183316100004 PM 12700686 ER PT J AU Chen, KC AF Chen, KC TI Insensitivity of the microdialysis zero-net-flux method to nonlinear uptake and release processes SO NEUROSCIENCE RESEARCH LA English DT Article DE Michaelis-Menten uptake; autoinhibitory release; extracellular diffusion; neurotransmitters ID QUANTITATIVE MICRODIALYSIS; EXTRACELLULAR CONCENTRATION; EXTRACTION FRACTION; DOPAMINE; VOLTAMMETRY; INHIBITION; RECEPTORS; DIFFUSION AB In the microdialysis zero-net-flux (ZNF) method the extraction efficiency is conventionally obtained by linear regression. The linear analysis may become invalid for certain analytes that have nonlinear uptake/release processes in the tissue. To examine this hypothesis, a nonlinear model was used to numerically investigate the nonlinearity of the ZNF plot caused by nonlinear uptake and release processes. Three findings from this analysis are: (i) the ZNF method is markedly insensitive to the nonlinear active processes; (ii) a slow infusion rate or a long probe membrane can suppress the nonlinearity; (iii) the release under autoreceptor control does not affect the slope and linearity of the concentration difference plot. It is concluded that in the nM infusion range, the ZNF method is unable to distinguish whether or not the tissue clearance process is nonlinear. During electrical stimulation, neurotransmitter overflow may cause the microdialysis ZNF method to exhibit nonlinearity. (C) 2003 Elsevier Science Ireland Ltd and the Japan Neuroscience Society. All rights reserved. C1 NCI, Mol Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Chen, KC (reprint author), NCI, Mol Biol Lab, Canc Res Ctr, NIH, 37 Convent Dr,MSC 4264,Bldg 37,Room 5120, Bethesda, MD 20892 USA. NR 25 TC 8 Z9 8 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0168-0102 J9 NEUROSCI RES JI Neurosci. Res. PD JUN PY 2003 VL 46 IS 2 BP 251 EP 256 DI 10.1016/S0168-0102(03)00091-9 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 687GR UT WOS:000183368600014 PM 12767488 ER PT J AU Harry, GJ d'Hellencourt, CL AF Harry, GJ d'Hellencourt, CL TI Dentate gyrus: Alterations that occur with hippocampal injury SO NEUROTOXICOLOGY LA English DT Review DE hippocampal injury; ischemia; hypoglycemia ID TEMPORAL-LOBE EPILEPSY; DELAYED NEURONAL DEATH; TRANSIENT FOREBRAIN ISCHEMIA; GRANULE CELL DEGENERATION; PILOCARPINE-INDUCED SEIZURES; PERFORANT PATH STIMULATION; INDUCED STATUS EPILEPTICUS; GLUTAMATE BINDING-SITES; MULTIPLE SYSTEM ATROPHY; TRAUMATIC BRAIN-INJURY AB Injury to the brain usually manifests not in a diffuse uniform manner but rather with selective sites of damage indicative of differential vulnerability. This question of neuronal susceptibility has been one of major interest both in disease processes as well as damage induced by environmental factors. For experimental examination, brain structures with obvious neuronal subpopulations and organization such as the cerebellum and the hippocampus have offered the most promise. In the hippocampus distinct neuronal populations exist that demonstrate differential vulnerability to various forms of insult including ischemia, excitotoxicity, and environmental factors. The more recent data regarding the presence of neuronal progenitor cells in the subgranular zone of the dentate offers the opportunity to expand such experimental examination to the process of injury-induced neurogenesis. Thus, more recent studies have expanded the examination of the hippocampus to include models of damage to the dentate neurons in addition to the highly vulnerable pyramidal neurons. A number of these models are presented for both human disease and experimental animal conditions. Examination of the responses between these distinct cell populations offers the potential for understanding factors that are critical in neuronal death and survival. (C) 2003 Elsevier Science Inc. All rights reserved. C1 NIEHS, Res Triangle Inst, Neurotoxicol Grp, Lab Mol Toxicol, Res Triangle Pk, NC 27709 USA. RP Harry, GJ (reprint author), NIEHS, Res Triangle Inst, Neurotoxicol Grp, Lab Mol Toxicol, POB 12233, Res Triangle Pk, NC 27709 USA. NR 199 TC 49 Z9 51 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X J9 NEUROTOXICOLOGY JI Neurotoxicology PD JUN PY 2003 VL 24 IS 3 BP 343 EP 356 DI 10.1016/S0161-813X(03)00039-1 PG 14 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 691CK UT WOS:000183587100003 PM 12782100 ER PT J AU Veronesi, B Wei, GW Zeng, JQ Oortgiesen, M AF Veronesi, B Wei, GW Zeng, JQ Oortgiesen, M TI Electrostatic charge activates inflammatory vanilloid (VR1) receptors SO NEUROTOXICOLOGY LA English DT Article DE particulate matter; physicochemistry; particle number; surface charge; zeta potential; vanilloid receptors; VR1; ASICs; neurogenic inflammation; airway inflammation; bronchial epithelial cells; BEAS-2B ID EPITHELIAL-CELL LINE; NEUROGENIC INFLAMMATION; SCAVENGER RECEPTORS; CYTOKINE RELEASE; SURFACE-CHARGE; NEUTRAL RED; MAST-CELLS; RAT; CAPSAICIN; ACID AB The pathophysiology of neurogenic inflammation culminates in the overt symptoms of tissue inflammation through a series of events which are initiated by the activation of vanilloid receptors (VR1). This study was designed to test the hypothesis that a sufficiently negative, electrostatic charge carried on a particulate matter (PM) particle, could acquire a cloud of protons sufficient to activate proton-sensitive VR1 receptors and acid-sensitive ionic channels (ASICs) pathways. For this, nanometer-sized, synthetic polystyrene micells (SPM) or those charged with chemical groups (e.g. diamino, carboxyl) were used. These chemical groups imparted either a net positive (i.e. diamino) or negative (i.e. carboxyl) charge on the SPM when suspended in a neutral ionic medium. The zeta potential, a measure of the SPM's electronegativity, was taken in both cell culture nutrient medium and in ultraviolet light-distilled water (UV-DW). In both vehicles, the rank order of electronegativity (most to least negative) was carboxyl > polystyrene > diamino-SPM. Individual types of SPM were exposed to human, immortalized bronchial-tracheal epithelial cells (i.e. BEAS-2B) and endpoints of biological activation (i.e. membrane depolarization, increases in intracellular calcium (i.e. [Ca2+](i)) levels, IL-6 release) were measured. Cells loaded with a fluorescent probe for membrane depolarization (3,3'-dihexyloxacarbocyanine iodide, DiOC-6-3) showed a positive reaction when exposed to carboxyl-SPM but not to diamino-SPM. BEAS-2B cells exposed to carboxyl-SPM responded with significant increases in [Ca2+](i), and IL-6 release relative to uncharged SPM or diamino-SPM. This IL-6 release could be reduced by pretreatment with antagonists to the VR1 receptor (i.e. capsazepine) or to acid-sensitive ionc channels (i.e. amiloride). Although both diamino and carboxyl-SPM groups stimulated increases in IL-6 transcript, only the more electronegatively charged carboxyl-SPM stimulated mRNA-VR1 receptor These data suggest that measurable inflammatory changes can be stimulated in human epithelial target cells by the electrostatic charge carried on an inert particle. Further these changes appear to be mediated through acid-sensitive VRI receptors and ASICs. (C) 2003 Elsevier Science Inc. All rights reserved. C1 US EPA, Div Neurotoxicol, Off Res & Dev, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. CNR, Washington, DC 20418 USA. Univ Calif San Francisco, Dept Pathol, San Francisco, CA USA. NIEHS, Res Triangle Pk, NC 27709 USA. Wenzhou Med Coll, Zhejiang, Peoples R China. Cato Res Ltd, Res Triangle Pk, NC USA. RP Veronesi, B (reprint author), US EPA, Div Neurotoxicol, Off Res & Dev, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. NR 48 TC 23 Z9 24 U1 2 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X J9 NEUROTOXICOLOGY JI Neurotoxicology PD JUN PY 2003 VL 24 IS 3 BP 463 EP 473 DI 10.1016/S0161-813X(03)00022-6 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 691CK UT WOS:000183587100014 PM 12782111 ER PT J AU de Simone, G Devereux, RB Palmieri, V Roman, M Celentano, A Welty, TK Fabsitz, RR Contaldo, E Howard, BV AF de Simone, G Devereux, RB Palmieri, V Roman, M Celentano, A Welty, TK Fabsitz, RR Contaldo, E Howard, BV CA String Heart Study Investigation TI Relation of insulin resistance to markers of preclinical cardiovascular disease: the Strong Heart Study SO NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES LA English DT Article DE echocardiography; epidemiology; ventricular mass; obesity; arterial compliance ID LEFT-VENTRICULAR MASS; M-MODE ECHOCARDIOGRAPHY; BETA-CELL FUNCTION; BLOOD-PRESSURE; AMERICAN-INDIANS; ESSENTIAL-HYPERTENSION; ARTERIAL-HYPERTENSION; SKELETAL-MUSCLE; RISK-FACTOR; GLUCOSE AB Background and Aims: To investigate whether insulin-resistance influences echocardiographic markers of preclinical disease, independent of significant confounders. Methods and Results: We examined 1,471 (59 8 years) non-diabetic individuals (WHO criteria) with available echocardiograms from the Strong Heart Study cohort. Among them, 530 subjects had arterial hypertension (62% on medications), 152 had impaired glucose tolerance (GT) and 460 were normotensive, non-obese with normal GT Insulin resistance was estimated by the Homeostasis Model Assessment (HOMA). LV mass, systolic function measured at the endocardium and the midwall (also correcting for circumferential wall stress) and arterial compliance (stroke volume/pulse pressure as a percent of predicted from body weight, age and heart rate [Delta%SV/PP]) were measured by echocardiography, as prognostically validated markers of preclinical disease. HOMA-index was related positively to body mass index (BMI), waist/hip ratio (WHR), blood pressure, left ventricular (LV) mass, and negatively to arterial compliance (all p<0.005) in the whole population, as well as in separate normotensive or hypertensive groups. In multiple regression models, relation of HOMA-index with the markers of risk was adjusted for age, sex, WHR, body mass index, presence of hypertension and number of antihypertensive medications. In this analysis, neither LV mass nor indices of systolic function were independently related to HOMA-index. In contrast, HOMA-index maintained a significant negative association with Delta%SV/PP, independent of demographics, hypertension, treatment and body fat distribution. Also, HOMA-index maintained an independent relation with LV mass, when WHR and BMI were not included in the regression model. Conclusions: After accounting for relevant biological covariates, including body mass and fat distribution, insulin-resistance measured by HOMA is not an independent correlate of LV mass and function, but negatively influences arterial compliance. (C)2003, Medikal Press. C1 Cornell Univ, Weill Med Coll, New York Presbyterian Hosp, Div Cardiol, New York, NY 10021 USA. Univ Naples Federico II, Naples, Italy. Aberdeen Area Tribal Chairmens Hlth Board, Rapid City, SD USA. NHLBI, Bethesda, MD 20892 USA. Medstar Res Inst, Washington, DC USA. RP de Simone, G (reprint author), Cornell Univ, Weill Med Coll, New York Presbyterian Hosp, Div Cardiol, 525 E 68th St, New York, NY 10021 USA. RI de Simone, Giovanni/D-1767-2011; OI de Simone, Giovanni/0000-0001-8567-9881; Contaldo, Franco/0000-0002-3657-3922 FU NCRR NIH HHS [M10RR0047-34]; NHLBI NIH HHS [U01-HL41642, U01-HL41652, U01-HL41654, U01-HL65521] NR 48 TC 11 Z9 11 U1 0 U2 0 PU MEDIKAL PRESS S R L PI MILAN PA VIA LUIGI ZOJA, 30, 20153 MILAN, ITALY SN 0939-4753 J9 NUTR METAB CARDIOVAS JI Nutr. Metab. Carbiovasc. Dis. PD JUN PY 2003 VL 13 IS 3 BP 140 EP 147 DI 10.1016/S0939-4753(03)80173-4 PG 8 WC Cardiac & Cardiovascular Systems; Endocrinology & Metabolism; Nutrition & Dietetics SC Cardiovascular System & Cardiology; Endocrinology & Metabolism; Nutrition & Dietetics GA 705UM UT WOS:000184413500005 PM 12955795 ER PT J AU Bonne, O Avraham, Y Bachar, E Katz, M Berry, EM AF Bonne, O Avraham, Y Bachar, E Katz, M Berry, EM TI Does short-term diet restriction in mice precipitate the development of anorexia? SO NUTRITIONAL NEUROSCIENCE LA English DT Article DE short term diet restriction; anorexia; mice; serotonin ID BULIMIA-NERVOSA; FOOD-INTAKE; SEROTONIN; DISORDERS; WEIGHT; WOMEN AB Anorexia nervosa (AN) inevitably begins with dieting. Yet, it is unknown whether anyone who will ultimately suffer from anorexia is already ill upon "going on a diet", or whether disease begins during, and is perhaps triggered by, dieting. The objective of the following study was to precipitate anorexia by imposing diet restriction on animals, as a model for generating AN in humans. Three hundred young female Sabra mice were diet restricted to 40% of daily nutrient requirements for 12 days, lost 17% of body weight and were then re-fed ad-lib. All mice regained appetite and weight. Our conclusions are that diet restriction does not precipitate anorexia in mice. Our findings do not support a role for diet restriction per se in triggering AN. C1 Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Psychiat, IL-91120 Jerusalem, Israel. Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Human Nutr & Metab, IL-91120 Jerusalem, Israel. RP Bonne, O (reprint author), NIMH, Mood & Anxiety Disorders Program, 15K North Dr,Room 200, Bethesda, MD 20892 USA. NR 14 TC 1 Z9 1 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1028-415X J9 NUTR NEUROSCI JI Nutr. Neurosci. PD JUN PY 2003 VL 6 IS 3 BP 197 EP 199 DI 10.1080/1028415031000094282 PG 3 WC Neurosciences; Nutrition & Dietetics SC Neurosciences & Neurology; Nutrition & Dietetics GA 684YL UT WOS:000183234000008 PM 12793525 ER PT J AU Stanford, JB Smith, KR Dunson, DB AF Stanford, JB Smith, KR Dunson, DB TI Vulvar mucus observations and the probability of pregnancy SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID FERTILITY CARE SYSTEM; MENSTRUAL-CYCLE; OVULATION METHOD; CERVICAL-MUCUS; CONTRACEPTIVE FAILURE; CONCEPTION; INTERCOURSE; DURATION; LEVEL; WOMEN AB OBJECTIVE: To assess the day-specific and cycle-specific probabilities of conception leading to clinical pregnancy, in relation to the timing of intercourse and vulvar mucus observations. METHODS: This was a retrospective cohort study of women beginning use of the Creighton Model Fertility Care System in Missouri, Nebraska, Kansas, and California. Data were abstracted from Creighton Model Fertility Care System records, including women's daily standardized vulvar observations of cervical mucus discharge, days of intercourse, and clinically evident pregnancy (conception). Established statistical models were used to estimate day-specific probabilities of conception. RESULTS: Data were analyzed from 1681 cycles with 81 conceptions from 309 normally fertile couples (initially seeking to avoid pregnancy) and from 373 cycles with 30 conceptions from 117 subfertile couples (who were initially trying to achieve pregnancy). The highest probability of pregnancy occurred on the peak day of vulvar mucus observation (.38 for normally fertile couples and .14 for subfertile couples). The probability of pregnancy was greater than .05 for normally fertile couples from 3 days before to 2 days after the peak, and for subfertile couples from 1 day before to 1 day after the peak. The cycle-specific probability of conception correlated with the quality of mucus discharge in normally fertile couples but not in subfertile couples. CONCLUSION: Standardized vulvar observations of vaginal mucus discharge identify the days with the greatest likelihood of conception from intercourse in normal fertility and subfertility and provide an indicator of the overall potential for conception in a given menstrual cycle in normal fertility. (C) 2003 by The American College of Obstetricians and Gynecologists. C1 Univ Utah, Hlth Res Ctr, Dept Family & Prevent Med, Salt Lake City, UT USA. Univ Utah, Hlth Res Ctr, Dept Family & Consumer Studies, Salt Lake City, UT USA. Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC USA. RP Stanford, JB (reprint author), 375 Chipeta Way,Suite A, Salt Lake City, UT 84108 USA. NR 38 TC 44 Z9 44 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JUN PY 2003 VL 101 IS 6 BP 1285 EP 1293 DI 10.1016/S0029-7844(03)00358-2 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 685YY UT WOS:000183293300025 PM 12798538 ER PT J AU Navazesh, M Mulligan, R Barron, Y Redford, M Greenspan, D Alves, M Phelan, J AF Navazesh, M Mulligan, R Barron, Y Redford, M Greenspan, D Alves, M Phelan, J TI A 4-year longitudinal evaluation of xerostomia and salivary gland hypofunction in the Women's Interagency HIV Study participants SO ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY AND ENDODONTICS LA English DT Article ID ORAL CANDIDIASIS; DRY MOUTH; SJOGRENS-SYNDROME; DENTAL EROSION; FLOW; SYMPTOMS; DISEASE; ADULTS; HEALTH; MEDICATION AB Objectives. Our purpose was to conduct a longitudinal investigation of xerostomia and salivary gland hypofunction in a national cohort of HIV-positive and at-risk HIV-negative participants in the Women's Interagency HIV Study. Study design. Data included responses to a dry mouth questionnaire, clinical evaluations of major salivary glands, and unstimulated and chewing-stimulated whole salivary flow rates. Repeated measures regression models were used to determine factors associated with xerostomia and salivary gland hypofunction. Results. Significant univariate associations were found between HIV status and reports of "too little saliva" (P < .0001), : 0.1 mL/min, unstimulated saliva (P = .01), and lack of saliva upon palpation of parotid (P = .02) and submandibular/sublingual salivary glands (P = .03). Adjusted odds of reports of "too little saliva" were significantly higher for HIV-positive participants (odds ratio [OR] = 2.44; 95% CI, 1.49 - 3.97; P = .0004) than for HIV-negative participants. Among HIV-positive women, adjusted odds of reports of "too little saliva" and of less than or equal to 0.7 mL/min chewing-stimulated saliva were significantly higher for those with CD4 < 200 (OR = 1.58; 95% CI, 1.07-2.34; P = .022; and OR = 1.53; 95% CI, 1.05-2.23; P = .027, respectively) and for those with CD4 200-500 (OR = 1.47; 95% CI, 1.072.02; P = 0.016; and OR = 1.37; 95% CI, 1.01-2.31; P = .001, respectively) than for those with CD4 > 500. Also, adjusted odds of less than or equal to 0.1 mL/min unstimulated saliva and less than or equal to0.7 mL/min chewing-stimulated saliva were significantly higher in women on highly active antiretroviral therapy (HAART) (OR = 1.25; 95% CI, 1.05 - 1.50; P = .014) than in women not on HAART (OR = 1.34; 95% CI, 1.01 - 1.79; P = .044). Conclusions. HIV-positive women are at a significantly higher risk for xerostomia and salivary gland hypofunction than HIV-negative women, and low CD4 cell counts and HAART use are significant risk factors for these conditions. C1 Univ So Calif, Sch Dent, Div Hlth Promot Dis Prevent & Epidemiol, Los Angeles, CA 90089 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. NEI, Collaborat Clin Res, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Stomatol, San Francisco, CA 94143 USA. Univ Illinois, Coll Dent, Chicago Dept Periodont, Chicago, IL 60680 USA. NYU, Dept Oral Pathol, New York, NY USA. RP Navazesh, M (reprint author), Univ So Calif, Sch Dent, Div Diagnost Sci, Room 4320,925 W 34th St, Los Angeles, CA 90089 USA. FU NIAID NIH HHS [U01-AI34994, U01-AI-31834, U01-AI-34993, U01-AI34989, U01-AI-42590, U01-AI-35004]; NICHD NIH HHS [U01-HD-32632] NR 43 TC 20 Z9 21 U1 1 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 1079-2104 J9 ORAL SURG ORAL MED O JI Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. PD JUN PY 2003 VL 95 IS 6 BP 693 EP 698 DI 10.1067/moe.2003.230 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 687GA UT WOS:000183367000015 PM 12789150 ER PT J AU Kipnes, J Carlberg, AL Loredo, GA Lawler, J Tuan, RS Hall, DJ AF Kipnes, J Carlberg, AL Loredo, GA Lawler, J Tuan, RS Hall, DJ TI Effect of cartilage oligomeric matrix protein on mesenchymal chondrogenesis in vitro SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article DE cartilage oligomeric matrix protein; cartilage; arthritis; chondrogenesis ID MULTIPLE EPIPHYSEAL DYSPLASIA; BONE MORPHOGENETIC PROTEIN-2; E2F1 TRANSCRIPTION FACTOR; PROGRAMMED CELL-DEATH; GENE-EXPRESSION; EXTRACELLULAR-MATRIX; MICROMASS CULTURES; COMP; PSEUDOACHONDROPLASIA; MUTATIONS AB Objective: Cartilage oligomeric matrix protein (COMP) mutations have been identified as responsible for two arthritic disorders, multiple epiphyseal dysplasia (MED) and pseudoachondroplasia (PSACH). However, the function of COMP in chondrogenic differentiation is largely unknown. Our investigation focuses on analyzing the function of normal COMP protein in cartilage biology. Methods and results: To explore the function of COMP we make use of an In vitro model system for chondrogenesis, consisting of murine C3H10T1/2 mesenchymal cells maintained as a high-density micromass culture and stimulated with bone morphogenetic protein 2 (BMP-2). Under these culture conditions, C3H10T1/2 cells undergo active chondrogenesis in a manner analogous to that of embryonic limb mesenchymal cells, and have been shown to serve as a valid model system to investigate the mechanisms regulating mesenchymal chondrogenesis. Our results indicate that ectopic COMP expression enhances several early aspects of chondrogenesis induced by BMP-2 in this system, indicating that COMP functions in part to positively regulate chondrogenesis. Additionally, COMP has inhibitory effects on proliferation of cells in monolayer. However, at later times in micromass culture, ectopic COMP expression in the presence of BMP-2 causes an increase in apoptosis, with an accompanying reduction in cell numbers in the micromass culture. However, the remaining cells retain their chondrogenic phenotype. Conclusions: These data suggest that COMP and BMP-2 signaling converge to regulate the fate of these cells in vitro by affecting both early and late stages of chondrogenesis. (C) 2003 Published by Elsevier Science Ltd on behalf of OsteoArthritis Research Society International. C1 NIAMSD, Cartilage & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02115 USA. RP Hall, DJ (reprint author), NIAMSD, Cartilage & Orthopaed Branch, NIH, MSC 5755,Bldg 13,Rm 3W17, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [HL49081]; NIAMS NIH HHS [AR39740] NR 55 TC 35 Z9 37 U1 0 U2 1 PU W B SAUNDERS CO LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD JUN PY 2003 VL 11 IS 6 BP 442 EP 454 DI 10.1016/S1063-4584(03)00055-4 PG 13 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 690UM UT WOS:000183568500007 PM 12801484 ER PT J AU Dvorak, JA Kobayashi, S Nozaki, T Takeuchi, T Matsubara, C AF Dvorak, JA Kobayashi, S Nozaki, T Takeuchi, T Matsubara, C TI Induction of permeability changes and death of vertebrate cells is modulated by the virulence of Entamoeba spp. isolates SO PARASITOLOGY INTERNATIONAL LA English DT Article DE Entamoeba histolytica; E. dispar; vertebrate cells; ethidium homodimer; cell death ID HISTOLYTICA SCHAUDINN; IN-VITRO; DISPAR; AMEBIASIS; PARASITE; CULTIVATION; INVASION; DISEASE; LECTIN; HOST AB Although Entamoeba histolytica is capable of inducing an apoptotic response in vertebrate cells in vitro (Cell. Microbiol. 2 (2000) 617), it is not known whether vertebrate cell death requires direct amoeba-vertebrate cell contact or simply the presence of amoebae in the area of the vertebrate cells. In addition, Entamoeba spp. vary in their virulence and pathogenicity. The potential effects of these critical parameters also have not been elucidated. We tested the virulent HM-1:IMSS isolate and the non-virulent Rahman isolate of E. histolytica, and the non-virulent E. dispar CYNO16:TPC isolate against two vertebrate cell lines, HeLa and Chinese hamster ovary cells in vitro using ethidium homodimer as a fluorescent indicator of changes in vertebrate cell permeability. Fluorescence appeared in vertebrate cell nuclei within approximately 2-3 min of contact between HM-1 amoebae and vertebrate cells independent of vertebrate cell type. However, vertebrate cells in the immediate vicinity of but not contacted by HM-1 amoebae were not affected. In contrast, although both E. histolytica Rahman and E. dispar CYNO16 amoebae moved freely among and contacted vertebrate cells, the nuclei of the vertebrate cells never fluoresced implying that the cells remained alive and impermeant to the ethidium homodimer. This is the first demonstration that direct contact between virulent amoebae and vertebrate cells is required-to kill vertebrate cells and that the process is restricted to virulent Entamoeba isolates. An understanding at the molecular level of the processes involved could help to reduce the pathology associated with this parasite. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 NIAID, Lab Malaria & Vector Biol, NIH, Bethesda, MD 20892 USA. Keio Univ, Sch Med, Dept Trop Med & Parasitol, Shinjuku Ku, Tokyo 1608582, Japan. Natl Inst Infect Dis, Dept Parasitol, Shinjuku Ku, Tokyo 1608640, Japan. Japan Sci & Technol Corp, Precurs Res Embryon Sci & Technol, Kawaguchi, Japan. Leica Microsyst KK, Shinagawa Ku, Tokyo 1410032, Japan. RP Dvorak, JA (reprint author), NIAID, Lab Malaria & Vector Biol, NIH, Bethesda, MD 20892 USA. RI Kobayashi, seiki/L-4026-2013 NR 22 TC 10 Z9 11 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1383-5769 J9 PARASITOL INT JI Parasitol. Int. PD JUN PY 2003 VL 52 IS 2 BP 169 EP 173 DI 10.1016/S1383-5769(02)00090-9 PG 5 WC Parasitology SC Parasitology GA 693QD UT WOS:000183729100008 PM 12798929 ER PT J AU Lukoschek, P Fazzari, M Marantz, P AF Lukoschek, P Fazzari, M Marantz, P TI Patient and physician factors predict patients' comprehension of health information SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE patient-physician communication; health information exchange; comprehension; self-assessment; attitudes ID STANDARDIZED PATIENTS; DECISION-MAKING; COMMUNICATION; LITERACY; CARE; EDUCATION; CANCER; SATISFACTION; PARTNERSHIP; PROGRAM AB While patients frequently do not comprehend health information, little is known about patient and physician factors that influence lack of comprehension. To assess effectiveness of health information exchange, 19 physicians and 145 patients were given post-encounter questionnaires to evaluate the preceding visit. We analyzed differences in beliefs between patients who comprehended health information and patients who did not, and whether physicians' attitudes and self-assessment of their educational abilities influenced this comprehension. Patients with insufficient comprehension were more likely to have schooling below college and cited language as a barrier. Physicians who believed health information delivery to be important had fewer patients with comprehension difficulties, while physicians who assessed themselves as very effective educators had significantly more patients with lack of comprehension, compared with physicians who did not feel as effective. Patients' comprehension of health information was associated not only with patient factors but also with physicians' attitude and self-assessment. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Albert Einstein Coll Med, Dept Epidemiol & Social Med, Bronx, NY 10461 USA. Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA. Albert Einstein Coll Med, NIH, Designated Canc Res Ctr, Bronx, NY 10461 USA. RP Lukoschek, P (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Social Med, Room 1306,Belfer Bldg,1300 Morris Pk Ave, Bronx, NY 10461 USA. NR 50 TC 27 Z9 28 U1 1 U2 6 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD JUN PY 2003 VL 50 IS 2 BP 201 EP 210 AR PII S0738-3991(02)00128-3 DI 10.1016/S0738-3991(02)00128-3 PG 10 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 691FZ UT WOS:000183596500011 PM 12781935 ER PT J AU Chrousos, G AF Chrousos, G TI Hormonal mediators of stress and human development: Potential usefulness of antalarmins as research and therapeutic means SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT 2nd World Congress on Dietal Origins of Adult Disease CY JUN 07-10, 2003 CL BRIGHTON, ENGLAND C1 Univ Southampton, Southampton, Hants, England. NICHD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD JUN PY 2003 VL 53 IS 6 SU S BP 1A EP 2A PN 2 PG 2 WC Pediatrics SC Pediatrics GA 686RB UT WOS:000183333800007 ER PT J AU Newbold, R AF Newbold, R TI Developmental exposure to environmental chemicals with estrogenic activity plays a role in reproductive tract disease dysfunction later in life SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT 2nd World Congress on Dietal Origins of Adult Disease CY JUN 07-10, 2003 CL BRIGHTON, ENGLAND C1 Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD JUN PY 2003 VL 53 IS 6 SU S BP 11A EP 11A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 686RB UT WOS:000183333800077 ER PT J AU Skjaerven, R Wilcox, AJ Melve, KK Ronning, T Vatten, LJ AF Skjaerven, R Wilcox, AJ Melve, KK Ronning, T Vatten, LJ TI Mothers' and fathers' own birth weight. Relation to their reproduction and perinatal survival of their offspring SO PEDIATRIC RESEARCH LA English DT Meeting Abstract CT 2nd World Congress on Dietal Origins of Adult Disease CY JUN 07-10, 2003 CL BRIGHTON, ENGLAND C1 Univ Bergen, Bergen, Norway. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD JUN PY 2003 VL 53 IS 6 SU S BP 38A EP 38A PN 2 PG 1 WC Pediatrics SC Pediatrics GA 686RB UT WOS:000183333800299 ER PT J AU Cope, JU Askling, J Gridley, G Mohr, A Ekbom, A Nyren, O Linet, MS AF Cope, JU Askling, J Gridley, G Mohr, A Ekbom, A Nyren, O Linet, MS TI Appendectomy during childhood and adolescence and the subsequent risk of cancer in Sweden SO PEDIATRICS LA English DT Article DE childhood appendectomy; appendicitis; Sweden; cancer incidence; cancer risk ID RECURRENT ABDOMINAL-PAIN; POPULATION-BASED COHORT; ACUTE APPENDICITIS; HELICOBACTER-PYLORI; HODGKINS-DISEASE; GASTRIC-CANCER; TONSILLECTOMY; CALIFORNIA; NEOPLASIA; ETIOLOGY AB Objective. Researchers have speculated that surgical excision of lymphoid tissue, such as appendectomy, early in life might confer an increased risk of cancer. In this study, we determined the risks of cancer for people who had appendectomy performed during childhood. Methods. We studied the risk of cancer in a large Swedish cohort of children who had appendectomy performed during the period of 1965-1993. Standardized incidence ratios (SIRs) were computed using age-, gender, and period-specific incidence rates derived from the entire Swedish population as comparison. Hospital discharge diagnosis data were used to examine cancer risks by categories of surgery, medical conditions, and type of appendicitis. The average length of follow-up was 11.2 years. Results. We found no excess overall cancer risk but noted a significant excess for stomach cancer (SIR: 2.45; 95% confidence interval [CI]: 1.1-4.8) and a borderline increase of non-Hodgkin's lymphoma (NHL; SIR: 1.55; 95% CI: 1.0-2.3). The elevated risks for both cancers were only evident 15 or more years after appendectomy (stomach cancer, SIR: 3.82; 95% CI: 1.7-7.5; NHL, SIR: 2.49; 95% CI: 1.4-4.2). Conclusions. It is reassuring that there was no overall increase of cancer several years after childhood appendectomy. Increased risks for NHL and stomach cancer, occurring 15 or more years after appendectomy, were based on small absolute numbers of excess cancers. As 95% of the subjects were younger than 40 years at exit, this cohort requires continuing follow-up and monitoring. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Karolinska Inst, Dept Med Epidemiol, Stockholm, Sweden. RP Gridley, G (reprint author), NCI, Div Canc Epidemiol & Genet, EPS Rm 8034,MSC 7244,6120 Execut Blvd, Bethesda, MD 20892 USA. NR 41 TC 13 Z9 13 U1 0 U2 2 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 JUN PY 2003 VL 111 IS 6 BP 1343 EP 1350 DI 10.1542/peds.111.6.1343 PG 8 WC Pediatrics SC Pediatrics GA 693CA UT WOS:000183696000030 PM 12777551 ER PT J AU Blackmon, LR Batton, DG Bell, EF Engle, WA Kanto, WP Martin, GI Rosenfeld, W Stark, A Miller, C Barrington, KJ Ecord, J Iyasu, S Riley, LE Wright, LL Couto, J AF Blackmon, LR Batton, DG Bell, EF Engle, WA Kanto, WP Martin, GI Rosenfeld, W Stark, A Miller, C Barrington, KJ Ecord, J Iyasu, S Riley, LE Wright, LL Couto, J CA Comm Fetus Newborn TI Advanced practice in neonatal nursing SO PEDIATRICS LA English DT Article AB The advanced practice neonatal nurse's participation in newborn care continues to be accepted and supported by the American Academy of Pediatrics. Recognized categories of advanced practice neonatal nurse are the neonatal clinical nurse specialist and the neonatal nurse practitioner. Training and credentialing requirements have been updated recently and are endorsed in this revised statement. C1 Canadian Paediat Soc, Ottawa, ON, Canada. Amer Nurses Assoc, Washington, DC 20024 USA. Assoc Womens Hlth Obstet & Neonatal Nurses, Washington, DC 20036 USA. Natl Assoc Neonatal Nurses, Glenview, IL 60025 USA. Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. Amer Coll Obstetricians & Gynecologists, Washington, DC 20090 USA. Natl Inst Hlth, Bethesda, MD 20892 USA. RP Blackmon, LR (reprint author), Canadian Paediat Soc, Ottawa, ON, Canada. NR 4 TC 6 Z9 6 U1 0 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUN PY 2003 VL 111 IS 6 BP 1453 EP 1454 PG 2 WC Pediatrics SC Pediatrics GA 693CA UT WOS:000183696000050 ER PT J AU Balk, SJ Best, D Johnson, CL Kim, JJ Mazur, LJ Reynolds, DW Roberts, JR Shannon, MW Weil, WB Amler, RW Blackburn, E Linet, M Miller, RW Rogan, W Spire, P AF Balk, SJ Best, D Johnson, CL Kim, JJ Mazur, LJ Reynolds, DW Roberts, JR Shannon, MW Weil, WB Amler, RW Blackburn, E Linet, M Miller, RW Rogan, W Spire, P CA Comm Environm Hlth TI Radiation disasters and children SO PEDIATRICS LA English DT Article ID ATOMIC-BOMB SURVIVORS; THREE-MILE-ISLAND; BREAST-CANCER; CHERNOBYL DISASTER; RISK-FACTORS; ACCIDENT; ADOLESCENTS; STRESS; PREPAREDNESS; TERRORISM AB The special medical needs of children make it essential that pediatricians be prepared for radiation disasters, including 1) the detonation of a nuclear weapon; 2) a nuclear power plant event that unleashes a radioactive cloud; and 3) the dispersal of radionuclides by conventional explosive or the crash of a transport vehicle. Any of these events could occur unintentionally or as an act of terrorism. Nuclear facilities (eg, power plants, fuel processing centers, and food irradiation facilities) are often located in highly populated areas, and as they age, the risk of mechanical failure increases. The short- and long-term consequences of a radiation disaster are significantly greater in children for several reasons. First, children have a disproportionately higher minute ventilation, leading to greater internal exposure to radioactive gases. Children have a significantly greater risk of developing cancer even when they are exposed to radiation in utero. Finally, children and the parents of young children are more likely than are adults to develop enduring psychologic injury after a radiation disaster. The pediatrician has a critical role in planning for radiation disasters. For example, potassium iodide is of proven value for thyroid protection but must be given before or soon after exposure to radioiodines, requiring its placement in homes, schools, and child care centers. Pediatricians should work with public health authorities to ensure that children receive full consideration in local planning for a radiation disaster. C1 Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. Agcy Tox Substances & Dis Registry, Atlanta, GA 30333 USA. US EPA, Washington, DC 20460 USA. Natl Canc Inst, Bethesda, MD 20892 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Balk, SJ (reprint author), Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. NR 69 TC 26 Z9 26 U1 2 U2 10 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUN PY 2003 VL 111 IS 6 BP 1455 EP 1466 PG 12 WC Pediatrics SC Pediatrics GA 693CA UT WOS:000183696000051 ER PT J AU Shea, KM AF Shea, KM CA Comm Environm Hlth TI Pediatric exposure and potential toxicity of phthalate plasticizers SO PEDIATRICS LA English DT Article ID EXTRACORPOREAL MEMBRANE-OXYGENATION; DI(2-ETHYLHEXYL) PHTHALATE; MONO-(2-ETHYLHEXYL) PHTHALATE; DI-(2-ETHYLHEXYL) PHTHALATE; NEWBORN-INFANTS; DI-2-ETHYLHEXYL PHTHALATE; GASTROINTESTINAL-TRACT; EXCHANGE-TRANSFUSION; RISK ASSESSMENT; SERTOLI CELLS AB Phthalates are plasticizers that are added to polyvinyl chloride (PVC) products to impart flexibility and durability. They are produced in high volume and generate extensive though poorly defined human exposures and unique childhood exposures. Phthalates are animal carcinogens and can cause fetal death, malformations, and reproductive toxicity in laboratory animals. Toxicity profiles and potency vary by specific phthalate. The extent of these toxicities and their applicability to humans remains incompletely characterized and controversial. Two phthalates, diethylhexyl phthalate (DEHP) and diisononyl phthalate (DINP), have received considerable attention recently because of specific concerns about pediatric exposures. Like all phthalates, DEHP and DINP are ubiquitous contaminants in food, indoor air, soils, and sediments. DEHP is used in toys and medical devices. DINP is a major plasticizer used in children's toys. Scientific panels, advocacy groups, and industry groups have analyzed the literature on DEHP and DINP and have come to different conclusions about their safety. The controversy exists because risk to humans must be extrapolated from animal data that demonstrate differences in toxicity by species, route of exposure, and age at exposure and because of persistent uncertainties in human exposure data. This report addresses sensitive endpoints of reproductive and developmental toxicity and the unique aspects of pediatric exposures to phthalates that generate concern. DEHP and DINP are used as specific examples to illustrate the controversy. C1 Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. Agcy Tox Substances & Dis Registry, Atlanta, GA 30333 USA. US EPA, Washington, DC 20460 USA. NCI, Bethesda, MD 20892 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Shea, KM (reprint author), Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. NR 72 TC 144 Z9 156 U1 2 U2 30 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 JUN PY 2003 VL 111 IS 6 BP 1467 EP 1474 DI 10.1542/peds.111.6.1467 PG 8 WC Pediatrics SC Pediatrics GA 693CA UT WOS:000183696000052 PM 12777573 ER PT J AU Havens, PL AF Havens, PL CA Comm Pediat AIDS TI Postexposure prophylaxis in children and adolescents for nonoccupational exposure to human immunodeficiency virus SO PEDIATRICS LA English DT Review ID HEALTH-CARE WORKERS; MOTHER-TO-CHILD; RECENT SEXUAL EXPOSURE; INJECTION-DRUG USE; PERINATAL TRANSMISSION; HIV-INFECTION; ZIDOVUDINE PROPHYLAXIS; HOMOSEXUAL MEN; OCCUPATIONAL TRANSMISSION; ANTIRETROVIRAL TREATMENT AB Exposure to human immunodeficiency virus (HIV) can occur in a number of situations unique to, or more common among, children and adolescents. Guidelines for postexposure prophylaxis (PEP) for occupational and nonoccupational (eg, sexual, needle-sharing) exposures to HIV have been published by the US Public Health Service, but they do not directly address nonoccupational HIV exposures unique to children (such as accidental exposure to human milk from a woman infected with HIV or a puncture wound from a discarded needle on a playground), and they do not provide antiretroviral drug information relevant to PEP in children. This clinical report reviews issues of potential exposure of children and adolescents to HIV and gives recommendations for PEP in those situations. The risk of HIV transmission from nonoccupational, nonperinatal exposure is generally low. Transmission risk is modified by factors related to the source and extent of exposure. Determination of the HIV infection status of the exposure source may not be possible, and data on transmission risk by exposure type may not exist. Except in the setting of perinatal transmission, no studies have demonstrated the safety and efficacy of postexposure use of antiretroviral drugs for the prevention of HIV transmission in nonoccupational settings. Antiretroviral therapy used for PEP is associated with significant toxicity. The decision to initiate prophylaxis needs to be made in consultation with the patient, the family, and a clinician with experience in treatment of persons with HIV infection. If instituted, therapy should be started as soon as possible after an exposure-no later than 72 hours-and continued for 28 days. Many clinicians would use 3 drugs for PEP regimens, although 2 drugs may be considered in certain circumstances. Instruction for avoiding secondary transmission should be given. Careful follow-up is needed for psychologic support, encouragement of medication adherence, toxicity monitoring, and serial HIV antibody testing. C1 Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. NICHHD, Bethesda, MD 20892 USA. RP Havens, PL (reprint author), Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. NR 121 TC 39 Z9 41 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 JUN PY 2003 VL 111 IS 6 BP 1475 EP 1489 DI 10.1542/peds.111.6.1475 PG 15 WC Pediatrics SC Pediatrics GA 693CA UT WOS:000183696000053 PM 12777574 ER PT J AU Pbert, L Moolchan, ET Muramoto, M Winickoff, JP Curry, S Lando, H Ossip-Klein, D Prokhorov, AV DiFranza, J Klein, JD AF Pbert, L Moolchan, ET Muramoto, M Winickoff, JP Curry, S Lando, H Ossip-Klein, D Prokhorov, AV DiFranza, J Klein, JD CA Ctr Child Hlth Res Am Acad Pediat TI The state of office-based interventions for youth tobacco use SO PEDIATRICS LA English DT Review DE tobacco; youth; treatment; primary care providers ID PRIMARY-CARE PHYSICIANS; COMMUNITY-HEALTH CENTERS; CIGARETTE-SMOKING; NICOTINE DEPENDENCE; ADOLESCENT SMOKERS; PREVENTIVE SERVICES; CONTROLLED TRIAL; SUBSTANCE USE; CESSATION INTERVENTION; COUNSELING ADOLESCENTS AB Tobacco use is a serious pediatric health issue as dependence begins during childhood or adolescence in the majority of tobacco users. Primary care settings provide tremendous opportunities for delivering tobacco treatment to young tobacco users. Although evidence-based practice guidelines for treating nicotine dependence in youths are not yet available, professional organizations and the current clinical practice guideline for adults provide recommendations based on expert opinion. This article reports on the current tobacco treatment practices of pediatric and family practice clinicians, discusses similarities and differences between adolescent and adult tobacco use, summarizes research efforts to date and current cutting-edge research that may ultimately help to inform and guide clinicians, and presents existing recommendations regarding treating tobacco use in youths. Finally, recommendations are made for the primary care clinician, professional organizations, and health care systems and policies. Pediatricians and other clinicians can and should play an important role in treating tobacco dependence in youths. C1 Univ Massachusetts, Sch Med, Div Prevent & Behav Med, Worcester, MA 01655 USA. NIDA, Teen Tobacco Addict Treatment Res Ctr, NIH, Baltimore, MD USA. Univ Arizona, Arizona Hlth Sci Ctr, Tucson, AZ USA. MassGen Hosp Children, Div Gen Pediat, MGH Ctr Child & Adolescent Hlth Policy, Boston, MA USA. Tobacco Res & Treatment Ctr, Boston, MA USA. Univ Illinois, Hlth Res Ctr, Chicago, IL USA. Univ Illinois, Policy Ctr, Chicago, IL USA. Univ Minnesota, Div Epidemiol, Minneapolis, MN 55455 USA. Univ Rochester, Dept Community & Prevent Med, Rochester, NY USA. Univ Rochester, James P Wilmot Canc Ctr, Rochester, NY USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Massachusetts, Sch Med, Worcester, MA USA. RP Pbert, L (reprint author), Univ Massachusetts, Sch Med, Div Prevent & Behav Med, 55 Lake Ave N, Worcester, MA 01655 USA. NR 127 TC 25 Z9 25 U1 4 U2 5 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUN PY 2003 VL 111 IS 6 BP E650 EP E660 DI 10.1542/peds.111.6.e650 PG 11 WC Pediatrics SC Pediatrics GA 693CA UT WOS:000183696000003 PM 12777581 ER PT J AU Yu, AM Idle, JR Herraiz, T Kupfer, A Gonzalez, FJ AF Yu, AM Idle, JR Herraiz, T Kupfer, A Gonzalez, FJ TI Screening for endogenous substrates reveals that CYP2D6 is a 5-methoxyindolethylamine O-demethylase SO PHARMACOGENETICS LA English DT Article DE phenylethylamines; tryptamines; beta-carbolines; hydroxylation; oxidoreductases; O-demethylating; cytochrome P-450CYP2D6 ID CYTOCHROME-P450 2D6; DEBRISOQUINE HYDROXYLATION; BETA-CARBOLINES; 5-METHYLTETRAHYDROFOLIC ACID; PERHEXILINE NEUROPATHY; PSYCHOACTIVE COMPOUNDS; METABOLIZER PHENOTYPE; MONOCLONAL-ANTIBODIES; POOR METABOLIZERS; MAMMALIAN BODY AB The objective of this investigation was to screen for potential endogenous substrates for CYP2D6. Using recombinant CYP2D6, together with hepatic microsomes from CYP2D6-transgenic mice, human liver microsomes, and a specific anti-CYP2D6 monoclonal antibody, it was ascertained that CYP2D6 does not significantly metabolize the endogenous phenylethylamines 2-phenylethylamine, octopamine, synephrine, 3-methoxy-p-tyramine, 4-methoxy-m-tyramine, metanephrine, and normetanephrine, nor the indolethylamines tryptamine, serotonin, 6-methoxytryptamine, and melatonin, nor the carbolines harman, norharman and tryptoline. However, the indolethylamines 5-methoxy-N,N-dimethyltryptamine (5-MDMT) and pinoline (6-methoxy-1,2,3,4-tetrahydro-beta-carboline) showed relatively high affinity for CYP2D6 in a spectral binding assay (K-s 28 +/- 5, and 0.5 +/- 0.3 muM (mean +/- SEM), respectively) and were O-demethylated only by CYP2D6 in a panel of 15 recombinant common human P450s. Pinoline and 5-MDMT O-demethylase activities were 35- and 11-fold greater in liver microsomes from CYP2D6-humanized mice, respectively, than those in liver microsomes from control mice. Moreover, the increased activities were completely inhibited by an anti-CYP2D6 monoclonal antibody. Kinetic analysis with recombinant CYP2D6 gave K-m and k(cat) values for 5-MDMT and pinoline O-demethylations of 12 +/- 1 muM and 65 +/- 1 min(-1) and 1.8 +/- 0.3 muM and 26 +/- 1 min(-1), respectively. These two substrates can be added to 5-methoxytryptamine, which we have recently reported to be an endogenous CYP2D6 substrate. CYP2D6 is therefore a relatively highly specific, high-affinity, high-capacity 5-methoxyindolethylamine O-demethylase. Polymorphic cytochrome CYP2D6 may therefore exert an influence on mood and behavior by the O-demethylation of these 5-methoxyindolethylamines found in the brain and pineal gland. These processes may also impact on mental and neurological health. The findings may open new vistas for the determination of CYP2D6 phenotype. (C) 2003 Lippincott Williams Wilkins. C1 NCI, Met Lab, NIH, Bethesda, MD 20892 USA. Inst Clin Pharmacol, CH-3010 Bern, Switzerland. CSIC, Inst Fermentac Ind, E-28006 Madrid, Spain. RP Gonzalez, FJ (reprint author), NCI, Met Lab, NIH, Bldg 37,Rm 2A19, Bethesda, MD 20892 USA. RI Herraiz, Tomas/K-9958-2014; OI Herraiz, Tomas/0000-0003-3682-9227; Idle, Jeff/0000-0002-6143-1520 NR 81 TC 83 Z9 87 U1 1 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0960-314X J9 PHARMACOGENETICS JI Pharmacogenetics PD JUN PY 2003 VL 13 IS 6 BP 307 EP 319 DI 10.1097/01.fpc.0000054094.48725.b7 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 696JL UT WOS:000183883800002 PM 12777961 ER PT J AU Choi, JY Lee, KM Cho, SH Kim, SW Choi, HY Lee, SY Im, HJ Yoon, KJ Choi, H Choi, I Hirvonen, A Hayes, RB Kang, D AF Choi, JY Lee, KM Cho, SH Kim, SW Choi, HY Lee, SY Im, HJ Yoon, KJ Choi, H Choi, I Hirvonen, A Hayes, RB Kang, D TI CYP2E1 and NQO1 genotypes, smoking and bladder cancer SO PHARMACOGENETICS LA English DT Article DE CYP2E1; NQO1; combined effect; genetic polymorphisms; bladder cancer ID QUINONE OXIDOREDUCTASE POLYMORPHISM; S-TRANSFERASES M1; LUNG-CANCER; NAD(P)H-QUINONE OXIDOREDUCTASE; GENETIC POLYMORPHISMS; C-609->T POLYMORPHISM; CYTOCHROME-P450 2E1; DT-DIAPHORASE; SUSCEPTIBILITY; RISK AB Background Cytochrome P450 2E1 (CYP2E1) and NAD(P)H:quinone oxidoreductase (NQO1) catalyze the activation of some environmental procarcinogens present in tobacco smoke (i.e. nitrosoamines and heterocyclic amines). We conducted a hospital based case-control study to evaluate the potential association between genetic polymorphisms of CYP2E1 ((CT)-T-1019 in the 5' flanking region) and NQO1 ((CT)-T-609 in exon 6) and bladder cancer risk in Asian population. Methods The study population was comprised of 218 histologically confirmed prevalent bladder cancer cases and 199 controls without cancer or systemic illness. PCR-restriction fragment length polymorphism based methods were used for the genotyping analyses and unconditional logistic regression model for the statistical evaluations. Results The risk of bladder cancer increased with the amount of smoking (P for trend < 0.01). The frequency of CYP2E1 c1/c1 genotype was significantly higher in bladder cancer patients (57.9%) than in the controls (47.9%) (OR = 1.8, 95% Cl = 1.1-2.9). Similarly, the NQO1 C/C genotypes were significantly more prevalent in the patients (45.8%) than in the controls (37.6%) (OR = 1.6, 95% Cl = 1.0-2.7). The risk for bladder cancer increased with the number of the putative risk genotypes (P for trend = 0.03); the most remarkable risk was observed for heavy smokers with both CYP2E1 c1/c1 and NQO1 C/C genotypes (OR = 13.8, 95% Cl = 3.9-48-6) when compared to non/light smokers with other genotypes. Conclusion Our findings suggest that CYP2E1 and NQO1 genotypes may play an important role in development of smoking related bladder cancer among Korean men. (C) 2003 Lippincott Williams Wilkins. C1 Seoul Natl Univ, Coll Med, Canc Res Inst, Dept Prevent Med, Seoul 110799, South Korea. Seoul Natl Univ, Coll Med, Canc Res Inst, Dept Urol, Seoul 110799, South Korea. Sungkyunkwan Univ, Coll Med, Dept Urol, Suwon 440746, South Korea. Inst Occupat Hlth, Dept Ind Hyg & Toxicol, Helsinki 00250, Finland. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Kang, D (reprint author), Seoul Natl Univ, Coll Med, Canc Res Inst, Dept Prevent Med, 28 Yongon Dong, Seoul 110799, South Korea. EM dhkang@snu.ac.kr RI Kang, Dae Hee/E-8631-2012; Choi, Ji-Yeob/J-2796-2012; Kim, Soo Woong/J-5411-2012; Cho, Soo-Hun/J-5668-2012; OI Hayes, Richard/0000-0002-0918-661X NR 45 TC 51 Z9 53 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0960-314X J9 PHARMACOGENETICS JI Pharmacogenetics PD JUN PY 2003 VL 13 IS 6 BP 349 EP 355 DI 10.1097/01.fpc.0000054096.48725.25 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 696JL UT WOS:000183883800006 PM 12777965 ER PT J AU Lee, CR Pieper, JA Hinderliter, AL Blaisdell, JA Goldstein, JA AF Lee, CR Pieper, JA Hinderliter, AL Blaisdell, JA Goldstein, JA TI Losartan and E3174 pharmacokinetics in cytochrome P4502C9*1/*1,*1/*2, and*1/*3 individuals SO PHARMACOTHERAPY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-College-of-Clinical-Pharmacy CY OCT 21-24, 2001 CL TAMPA, FLORIDA SP Amer Coll Clin Pharmacy ID II RECEPTOR ANTAGONIST; HEALTHY-VOLUNTEERS; METABOLITE E-3174; DOSE REQUIREMENT; GLUCOSE RESPONSE; AMINO-ACID; IN-VITRO; CYP2C9; POLYMORPHISMS; P4502C9 AB Study Objective. To determine if differences in the pharmacokinetics of losartan and its pharmacologically active E3174 metabolite exist among individuals expressing the cytochrome P450 (CYP) 2C9*1/*1, *1/*2, and *1/*3 genotypes. Design. Single-dose pharmacokinetic study. Setting. University general clinical research center. Subjects. Fifteen healthy volunteers, five from each genotype: CYP2C9*1/*1, *1/*2, and *1/*3. Intervention. A single oral dose of losartan 50 mg. Measurements and Main Results. Plasma and urine samples were collected for 24 hours, and losartan and E3174 pharmacokinetic data were compared across the three genotypes. Orthostatic blood pressure was measured over 12 hours after dosing. No significant differences were observed among the three groups in losartan or E3174 area under the plasma concentration-time curve, losartan or E3174 elimination half-life, or losartan oral clearance. A significant association between CYP2C9 genotype and losartan to E3174 formation clearance was observed, such that 50% of the variability was accounted for by the genotype. No significant relationship between that genotype and blood pressure was observed at any time. Conclusion. Differences in the pharmacokinetics of losartan and its active E3174 metabolite were not observed in healthy subjects with the genotype of CYP2C9*1/*2 and *1/*3 compared with those expressing *1/*1. Alterations in losartan dosing in CYP2C9*1/*2 and *1/*3 individuals does not appear necessary. C1 Univ N Carolina, Div Pharmacol, Chapel Hill, NC 27599 USA. Univ N Carolina, Div Cardiol, Chapel Hill, NC 27599 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Lee, CR (reprint author), Univ N Carolina, Div Pharmacol, CB 7360,Beard Hall, Chapel Hill, NC 27599 USA. RI Goldstein, Joyce/A-6681-2012; OI Lee, Craig/0000-0003-3595-5301 FU NCRR NIH HHS [RR00046] NR 28 TC 24 Z9 27 U1 0 U2 0 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER, 806, 750 WASHINGTON ST, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD JUN PY 2003 VL 23 IS 6 BP 720 EP 725 DI 10.1592/phco.23.6.720.32187 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 684UH UT WOS:000183224600004 PM 12820813 ER PT J AU He, YY Ramirez, DC Detweiler, CD Mason, RP Chignell, CF AF He, YY Ramirez, DC Detweiler, CD Mason, RP Chignell, CF TI UVA-ketoprofen-induced hemoglobin radicals detected by immuno-spin trapping SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID HYDROGEN-PEROXIDE; BENZOPHENONE CHROMOPHORE; HUMAN ERYTHROCYTES; HUMAN MYOGLOBIN; IDENTIFICATION; PHOTOCHEMISTRY; PHOTOHEMOLYSIS; INVOLVEMENT; MECHANISMS; DRUGS AB Ketoprofen (3-benzoyl-alpha-methylbenzeneacetic acid, KP) is a widely used nonsteroidal anti-inflammatory drug (NSAID) that causes both phototoxicity and photoallergy. Here, we investigated the formation of hemoglobin radicals, in both purified hemoglobin and red blood cells (RBC), induced by ultraviolet A (UVA)-KP by using "immuno-spin trapping," a novel approach that combines the specificity of spin trapping with the sensitivity of antigen-anti body interactions. The methemoglobin (metHb) radicals react covalently with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) to form nitroxyl radical adducts that are oxidized to the corresponding nitrone adducts, which in turn are specifically recognized by antiserum against DMPO nitrone. We found that the formation of nitrone adducts in metHb depended on the UVA dose, the KP concentration and the presence of DNIPO, as determined by enzyme-linked immunosorbent assay and Western blotting. Adduct formation decreased when irradiation was carried out in the presence of catalase or nitrogen, suggesting that H2O2 plays a key role in KP-UVA-induced metHb radical formation. KP in the dark did not generate metHb radical-derived nitrone adducts, whereas UVA alone resulted in the formation of metHb radical-derived nitrone adducts that increased with UVA dose from 4 to 10 J/cm(2). However, KP (25 and 200 muM) plus UVA (4 and 10 J/cm(2)) resulted in a significant increase in the formation of metHb radical-derived nitrone adducts as compared with UVA or KP alone, indicating that KP photosensitized the production of the metHb radicals in the presence of UVA. In contrast, no metHb radical-derived nitrone adduct was detected in the absence of DMPO, even though KP and UVA were present. We also detected the hemoglobin radical formation in RBC as well as in hemolysates. The endogenous antioxidants and exogenous reduced glutathione inhibited the protein radical formation. These studies have shown that the immuno-spin-trapping technique can be used to detect radical damage in proteins as a result of photosensitizing reactions. The successful detection of protein radical formation caused by KP photosensitization could help further understand the photoallergic effect of this NSAID. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP He, YY (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, POB 12233,MD F0-06, Res Triangle Pk, NC 27709 USA. RI RAMIREZ, DARIO/K-3312-2013 OI RAMIREZ, DARIO/0000-0001-6725-3326 NR 25 TC 17 Z9 17 U1 0 U2 5 PU AMER SOC PHOTOBIOLOGY PI AUGUSTA PA BIOTECH PARK, 1021 15TH ST, SUITE 9, AUGUSTA, GA 30901-3158 USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD JUN PY 2003 VL 77 IS 6 BP 585 EP 591 DI 10.1562/0031-8655(2003)077<0585:UHRDBI>2.0.CO;2 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 693RC UT WOS:000183731300002 PM 12870842 ER PT J AU Egli, M AF Egli, M TI Peptides: their role in excess alcohol drinking and their promise as a therapeutic tool SO PHYSIOLOGY & BEHAVIOR LA English DT Editorial Material ID NONPREFERRING NP RATS; VENTRAL TEGMENTAL AREA; NEUROPEPTIDE-Y LEVELS; RHESUS-MONKEYS; ETHANOL-CONSUMPTION; BETA-ENDORPHIN; SATIATED RATS; PREFERRING P; FOOD-INTAKE; OPIOID RECEPTORS C1 NIAAA, Div Basic Res, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Egli, M (reprint author), NIAAA, Div Basic Res, NIH, Dept Hlth & Human Serv, 6000 Execut Blvd, Bethesda, MD 20892 USA. NR 80 TC 9 Z9 9 U1 2 U2 2 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 JUN PY 2003 VL 79 IS 1 BP 89 EP 93 DI 10.1016/S0031-9384(03)00108-2 PG 5 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 695TQ UT WOS:000183846800010 PM 12818713 ER PT J AU Winters, WD Huo, YS Ya, DL AF Winters, WD Huo, YS Ya, DL TI Inhibition of the progression of type 2 diabetes in the C57BL/6J mouse model by an anti-diabetes herbal formula SO PHYTOTHERAPY RESEARCH LA English DT Article DE herbal formula; diet induced diabetes; NIDDM ID IMPAIRED GLUCOSE-TOLERANCE; 10-YEAR FOLLOW-UP; INSULIN RESISTANCE; PANCREAS; MICE; EXPRESSION; MELLITUS AB The effects of a specifically prepared anti-diabetic herbal formula (ADHF) on the course of established diet-induced type 2 diabetes in animal subjects has been studied. In a C57BL/6J mouse model for diet induced type 2 diabetes, intervention for 12 weeks using ADHF as a diet supplement resulted in a significant inhibition of diabetes related changes in major organs usually targeted by type 2 diabetes and a significant reduction in circulating levels of glucose and insulin. Young male mice were randomly assigned to receive ad libitum exposure to either a standard rodent chow diet or to a high fat, high simple sugar, low fibre diet (diabetes induction diet), respectively for 8 weeks. All mice fed the induction diet developed abnormally high blood glucose levels at 8 weeks. Animals with confirmed diet induced diabetic blood glucose levels were again randomly assigned into one of three groups (10 subjects per group), one group was thereafter fed only the diabetes induction diet and the other two groups were thereafter fed the diabetes induction diet into which ADHF had been mixed at 4% or at 8% final concentrations. Normal mice were also randomized into two groups that were fed either a regular diet alone or 8% ADHF mixed in the regular diet. Blood glucose levels markedly increased over the 20 weeks of study in the diabetic mice fed the diabetes induction diet only. In contrast, diabetic mice fed induction diet into which 4% or 8% ADHF had been incorporated showed significantly decreased blood glucose and insulin levels over the time of the study. Additional parameters significantly reduced in diabetic mice fed ADHF included insulin resistance and histopathological changes in the pancreas and liver. This is the first report to our knowledge to show in vivo evidence for significantly decreased circulating glucose and insulin levels and a significant reduction of progressive damage to major target organs by the addition of an herbal diet supplement to a diabetes induction diet proven to be capable of causing and maintaining type 2 diabetes. Copyright (C) 2003 John Wiley Sons, Ltd. C1 Univ Texas, Hlth Sci Ctr, Dept Microbiol, San Antonio, TX 78229 USA. NINDS, Expt Neuropathol Lab, NIH, Bethesda, MD 20892 USA. RP Winters, WD (reprint author), Univ Texas, Hlth Sci Ctr, Dept Microbiol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. NR 28 TC 4 Z9 4 U1 0 U2 2 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0951-418X J9 PHYTOTHER RES JI Phytother. Res. PD JUN PY 2003 VL 17 IS 6 BP 591 EP 598 DI 10.1002/ptr.1079 PG 8 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 693QY UT WOS:000183730900002 PM 12820223 ER PT J AU Weeraratna, AT AF Weeraratna, AT TI Serial analysis of gene expression (SAGE): Advances, analysis and applications to pigment cell research SO PIGMENT CELL RESEARCH LA English DT Review DE SAGE; melanoma; pigment; gene expression profiling ID HUMAN EPIDERMIS; OVARIAN-CANCER; MELANOMA; TISSUE; INDEX; TRANSCRIPTOMES; EPITHELIUM; CARCINOMA; LIBRARIES; PROFILES AB As cells progress from normal to diseased states, they may undergo a series of gene expression changes. Advances in molecular biology allow us to examine a host of these changes at once, in a high throughput fashion. Serial analysis of gene expression (SAGE) allows for the expression profiling of the complete transcriptome of a given cell, and has the potential for identifying novel genes as well as those in low abundance. In this review, we will outline the technique, how one analyzes the massive amounts of data generated, and describe pigment cell libraries currently in the making. C1 NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Weeraratna, AT (reprint author), NHGRI, Canc Genet Branch, NIH, 50 South Dr,Room 5146, Bethesda, MD 20892 USA. EM aweerara@nhgri.nih.gov NR 37 TC 8 Z9 8 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-5785 J9 PIGM CELL RES JI Pigm. Cell. Res. PD JUN PY 2003 VL 16 IS 3 BP 183 EP 189 DI 10.1034/j.1600-0749.2003.00042.x PG 7 WC Cell Biology; Dermatology SC Cell Biology; Dermatology GA 678FV UT WOS:000182856000003 PM 12753384 ER PT J AU Tadokoro, T Rouzaud, F Itami, S Hearing, VJ Yoshikawa, K AF Tadokoro, T Rouzaud, F Itami, S Hearing, VJ Yoshikawa, K TI The inhibitory effect of androgen and sex-hormone-binding globulin on the intracellular cAMP level and tyrosinase activity of normal human melanocytes SO PIGMENT CELL RESEARCH LA English DT Article DE androgen; melanocyte; sex hormone; tyrosinase ID CULTURED HUMAN MELANOCYTES; STEROID-HORMONES; PROTEIN SBP; CYCLIC-AMP; RECEPTOR; CELLS; MELANOGENESIS; ACCUMULATION; HETEROGENEITY; PIGMENTATION AB The effect of androgens on human melanocytes has not been well clarified. We studied the effects of androgens on normal human melanocytes in the presence or absence of sex-hormone-binding globulin (SHBG), which complexes with those hormones. Immunohistochemically, testosterone and SHBG co-localized on the cell membrane. Androgens such as testosterone, 5alpha -dihydrotestosterone, and methyltrienolone (R1881, a potent synthetic androgen), reduced intracellular cAMP levels after treatment with SHBG, but hydrocortisone had no effect. We also found that testosterone and R1881 slightly suppressed tyrosinase activity in melanocytes when treated with SHBG, although they had no effect on the expression of tyrosinase at the transcriptional or translational level, as measured by semi-quantitative reverse transcriptase-polymerase chain reaction and by Western blot analysis, respectively. Our results suggest that androgens may modulate tyrosinase activity at the posttranslational level through the cell membrane signaling pathway. C1 Osaka Univ, Grad Sch Med, Dept Dermatol, Suita, Osaka 5650871, Japan. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Tadokoro, T (reprint author), Osaka Univ, Grad Sch Med, Dept Dermatol, C5,2-2 Yamadaoka, Suita, Osaka 5650871, Japan. RI Perez , Claudio Alejandro/F-8310-2010 OI Perez , Claudio Alejandro/0000-0001-9688-184X NR 49 TC 14 Z9 17 U1 1 U2 2 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 JUN PY 2003 VL 16 IS 3 BP 190 EP 197 DI 10.1034/j.1600-0749.2003.00019.x PG 8 WC Cell Biology; Dermatology SC Cell Biology; Dermatology GA 678FV UT WOS:000182856000004 PM 12753385 ER PT J AU Kushimoto, T Valencia, JC Costin, GE Toyofuku, K Watabe, H Yasumoto, KI Rouzaud, F Vieira, WD Hearing, VJ AF Kushimoto, T Valencia, JC Costin, GE Toyofuku, K Watabe, H Yasumoto, KI Rouzaud, F Vieira, WD Hearing, VJ TI The melanosome: An ideal model to study cellular differentiation SO PIGMENT CELL RESEARCH LA English DT Article; Proceedings Paper CT 18th International Pigment Cell Conference CY SEP, 2002 CL LEIDEN, NETHERLANDS DE melanosome; pigmentation; proteomics; biogenesis ID HERMANSKY-PUDLAK-SYNDROME; PINK-EYED DILUTION; OCULOCUTANEOUS ALBINISM TYPE-1; MELANOCYTE-STIMULATING HORMONE; LYSOSOME-RELATED ORGANELLES; AGOUTI SIGNAL PROTEIN; MELANOCORTIN-1 RECEPTOR; MELANIN FORMATION; TYROSINASE GENE; MYOSIN-VA AB Melanosomes provide an intriguing model for study at many levels. In part this is due to their unique structure and function, but also in part to their involvement in pigmentary diseases and as a model to study basic cellular mechanisms of organelle biogenesis. Recent studies have elucidated the full proteome of the melanosome and the metabolic and molecular lesions involved in a number of pigmentary diseases have been resolved. This paper summarizes recent advances in the field in these areas. C1 NCI, Pigment Cell Biol Sect, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hearing, VJ (reprint author), NCI, Pigment Cell Biol Sect, Cell Biol Lab, NIH, Bldg 37,Room 1B25, Bethesda, MD 20892 USA. NR 49 TC 63 Z9 63 U1 2 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 JUN PY 2003 VL 16 IS 3 BP 237 EP 244 DI 10.1034/j.1600-0749.2003.00034.x PG 8 WC Cell Biology; Dermatology SC Cell Biology; Dermatology GA 678FV UT WOS:000182856000012 PM 12753396 ER PT J AU Kato, H Takeuchi, Y Tsumuraya, Y Hashimoto, Y Nakano, H Kovac, P AF Kato, H Takeuchi, Y Tsumuraya, Y Hashimoto, Y Nakano, H Kovac, P TI In vitro biosynthesis of galactans by membrane-bound galactosyltransferase from radish (Raphanus sativus L.) seedlings SO PLANTA LA English DT Article DE arabinogalactan-protein; galactan; galactosyltransferase; Golgi apparatus; Raphanus ID CELL-WALL POLYSACCHARIDES; SUSPENSION-CULTURED CELLS; RYEGRASS ENDOSPERM CELLS; ARABINO-D-GALACTAN; ARABINOGALACTAN-PROTEINS; RHAMNOGALACTURONAN-I; UDP-GALACTOSE; IDENTIFICATION; GLYCOPROTEINS; PURIFICATION AB We investigated a galactosyltransferase (GalT) involved in the synthesis of the carbohydrate portion of arabinogalactan-proteins (AGPs), which consist of a beta-(1-->3)-galactan backbone from which consecutive (1-->6)-linked beta-Galp residues branch off. A membrane preparation from 6-day-old primary roots of radish (Raphanus sativus L.) transferred [(14)C]Gal from UDP-[(14)C]Gal onto a beta-(1-->3)-galactan exogenous acceptor. The reaction occurred maximally at pH 5.9-6.3 and 30 degreesC in the presence of 15 mM Mn(2+) and 0.75% Triton X-100. The apparent K(m) and V(max) values for UDP-Gal were 0.41 mM and 1,000 pmol min(-1) (mg protein)(-1), respectively. The reaction with beta-(1-->3)-galactan showed a bi-phasic kinetic character with K(m) values of 0.43 and 2.8 mg ml(-1). beta-(1-->3)-Galactooligomers were good acceptors and enzyme activity increased with increasing polymerization of Gal residues. In contrast, the enzyme was less efficient on beta-(1-->6)-oligomers. The transfer reaction for an AGP from radish mature roots was negligible but could be increased by prior enzymatic or chemical removal of alpha-L-arabinofuranose (alpha-L-Araf) residues or both alpha-L-Araf residues and (1-->6)-linked beta-Gal side chains. Digestion of radiolabeled products formed from beta-(1-->3)-galactan and the modified AGP with exo-beta-(1-->3)-galactanase released mainly radioactive beta-(1-->6)-galactobiose, indicating that the transfer of [(14)C]Gal occurred preferentially onto consecutive (1-->3)-linked beta-Gal chains through beta-(1-->6)-linkages, resulting in the formation of single branching points. The enzyme produced mainly a branched tetrasaccharide, Galbeta(1-->3)[Galbeta(1-->6)] Galbeta(1-->3)Gal, from beta-(1-->3)-galactotriose by incubation with UDP-Gal, confirming the preferential formation of the branching linkage. Localization of the GalT in the Golgi apparatus was revealed on a sucrose density gradient. The membrane preparation also incorporated [(14)C]Gal into beta-(1-->4)-galactan, indicating that the membranes contained different types of GalT isoform catalyzing the synthesis of different types of galactosidic linkage. C1 Saitama Univ, Dept Biochem & Mol Biol, Fac Sci, Saitama 3388570, Japan. Osaka Municipal Tech Res Inst, Jyoto Ku, Osaka 5368553, Japan. NIDDK, NIH, Bethesda, MD 20892 USA. RP Tsumuraya, Y (reprint author), Saitama Univ, Dept Biochem & Mol Biol, Fac Sci, 255 Shimookubo, Saitama 3388570, Japan. EM tsumura@molbiol.saitama-u.ac.jp RI Tsumuraya, Yoichi/C-7903-2012 NR 41 TC 12 Z9 13 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0032-0935 J9 PLANTA JI Planta PD JUN PY 2003 VL 217 IS 2 BP 271 EP 282 DI 10.1007/s00425-003-0978-7 PG 12 WC Plant Sciences SC Plant Sciences GA 688TF UT WOS:000183451700011 PM 12783335 ER PT J AU Wewers, ME Stillman, FA Hartman, AM Shopland, DR AF Wewers, ME Stillman, FA Hartman, AM Shopland, DR TI Distribution of daily smokers by stage of change: Current Population Survey results SO PREVENTIVE MEDICINE LA English DT Article DE stage of change; tobacco; current population survey; smoking ID EXPERT-SYSTEM INTERVENTION; SMOKING CESSATION; CIGARETTE-SMOKING; UNITED-STATES; PREVALENCE; MODEL AB Background. Population-based national estimates of stage of change among daily smokers are unknown. This study described the proportion of U.S. daily smokers, 18 and older, by stage of change. Selected sociodemographic characteristics were delineated. Methods. Cross-sectional data were collected via telephone or face-to-face interview in daily smokers who responded to the Current Population Survey in 1992-1993 (n = 39,706), 1995-1996 (n = 34,865), or 1998-1999 (n = 30,153). Main outcomes included stage of change: (1) Precontemplation-not interested in quitting smoking in next 6 months; (2) Contemplation-interested in quitting smoking in next 6 months but not next 30 days; (3) Preparation-interested in quitting smoking in next 30 days and stopped at least 1 day during past year. Results. During 1992-1993, 59.1% of respondents were precontemplators, 33.2% contemplators, and 7.7% in preparation stage. This distribution was similar in subsequent surveys (1995-1996; 1998-1999). Gender differences were not apparent. Whites were more likely to be precontemplators. As education and income increased, the percentage in precontemplation decreased. Rural residents were more likely in precontemplation and less frequently in preparation. Conclusions. Among daily smokers, little movement in stage of change was apparent in the United States during the 1990s. Tobacco control efforts must receive high priority to address these static patterns. (C) 2003 American Health Foundation and Elsevier Science (USA). All rights reserved. C1 Ohio State Univ, Coll Nursing, Columbus, OH 43210 USA. Ohio State Univ, Sch Publ Hlth, Columbus, OH 43210 USA. NCI, Div Canc Control & Populat Sci, Tobacco Control Res Branch, Bethesda, MD USA. NCI, Div Canc Control & Populat Sci, Risk Factor Monitoring & Methods Branch, Bethesda, MD USA. RP Wewers, ME (reprint author), Ohio State Univ, Coll Nursing, Newton Hall Room 38,1585 Neil Ave, Columbus, OH 43210 USA. NR 33 TC 92 Z9 92 U1 1 U2 3 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 JUN PY 2003 VL 36 IS 6 BP 710 EP 720 DI 10.1016/S0091-7435(03)00044-6 PG 11 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 683QM UT WOS:000183160700010 PM 12744915 ER PT J AU Augustson, EM Vadaparampil, ST Paltoo, DN Kidd, LR O'Malley, AS AF Augustson, EM Vadaparampil, ST Paltoo, DN Kidd, LR O'Malley, AS TI Association between CBE, FOBT, and Pap smear adherence and mammography adherence among older low-income women SO PREVENTIVE MEDICINE LA English DT Article; Proceedings Paper CT 8th Biennial Symposium on Minorities and the Medically Underserved and Cancer CY FEB 06-10, 2002 CL WASHINGTON, D.C. DE adherence; African American women; breast cancer; cancer screening; clinical breast exam; fecal occult blood test; low income; mammography; older women; Pap smear ID CANCER SCREENING PRACTICES; AFRICAN-AMERICAN WOMEN; BREAST-CANCER; PRIMARY-CARE; HEALTH; GUIDELINES; BEHAVIOR; POPULATION; COMMUNITY; SERVICES AB Background. Adherence to regular and timely mammography screening, especially in older low-income women, continues to fall below objectives. The primary aim of this study was to examine whether engaging in other cancer screenings was associated with mammography adherence for older women. Method. Women, ages 52 and over, without a self-reported history of breast cancer (N = 862) were selected from a larger sample of women residing in Washington, DC, census tracts with greater than or equal to30% of households below 200% of the federal poverty threshold. A computer-assisted telephone survey was used to collect data on health care system factors, demographics, cultural beliefs, clinical breast exam (CBE), Pap smear, fecal occult blood testing (FOBT), and mammography. Adherence was defined as receipt of the last two screening tests within recommended intervals for age. Results. After controlling for other variables, adherence to CBE (OR = 4.15; 95% CI, 2.55-6.73) and Pap smear (OR = 1.82; 95% CI, 1.07-3.12) were highly predictive of mammography adherence. Adherence to FOBT (OR = 1.66; 95% CI, 0.97-2.84) was marginally predictive. Conclusions. Results of this study indicate that nonadherence to other cancer screenings can help identify women in need of additional interventions to improve mammography adherence. (C) 2003 American Health Foundation and Elsevier Science (USA). All rights reserved. C1 NCI, DCCPS TCRB, Bethesda, MD 20892 USA. NCI, Canc Prevent Studies Branch, Canc Res Ctr, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC USA. Georgetown Univ, Med Ctr, Dept Internal Med, Washington, DC USA. RP Augustson, EM (reprint author), NCI, DCCPS TCRB, EPN-4087B,6130 Execut Blvd MSC 7337, Bethesda, MD 20892 USA. FU NCI NIH HHS [R01 CA 83338-02] NR 46 TC 14 Z9 15 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 0091-7435 J9 PREV MED JI Prev. Med. PD JUN PY 2003 VL 36 IS 6 BP 734 EP 739 DI 10.1016/S0091-7435(03)00050-1 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 683QM UT WOS:000183160700013 PM 12744918 ER PT J AU Blanchet, PJ Konitsiotis, S Mochizuki, H Pluta, R Emerich, DF Chase, TN Mouradian, MM AF Blanchet, PJ Konitsiotis, S Mochizuki, H Pluta, R Emerich, DF Chase, TN Mouradian, MM TI Complications of atrophic xenotransplant approach in parkinsonian monkeys SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Review DE glial cell line-derived neurotrophic factor (GDNF); gene therapy; xenotransplantation; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); Parkinson's disease; monkeys; neurorestoration ID GDNF-PRODUCING CELLS; NEUROTROPHIC FACTOR; DOPAMINERGIC-NEURONS; FUNCTIONAL RECOVERY; MESENCEPHALIC TISSUE; RAT MODEL; IN-VIVO; DISEASE; LINE; TRANSPLANTATION AB Various restorative cell transplantation strategies have been investigated to substitute for lost dopamine (DA) neurons or to enhance DA synthesis in Parkinson's disease. Intracerebral implantation of engineered cells encapsulated in a semipermeable polymer membrane constitutes one way to deliver bioactive substances unable to cross the blood-brain barrier while avoiding the need for long-term immuno suppression. Glial cell line-derived neurotrophic factor (GDNF) has shown trophic effects on DA neurons but effective and sustained delivery within the brain parenchyma remains problematic. The long-term efficacy and late complications of a xenotransplant approach utilizing GDNF-expressing encapsulated baby hamster kidney (BHK) cells were examined. Each of five MPTP-lesioned parkinsonian cynomolgus monkeys received five devices containing active or inert cells grafted bilaterally in the striatum in a two-stage procedure 9 months apart and animals were sacrificed 4 months later for analyses. No definite motor benefit was observed, DA levels were comparable between GDNF- and control cell-implanted striata, and tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra showed no consistent recovery. Cell viability and GDNF synthesis in the explanted devices were negligible. The brain tissue surrounding all implants showed an intense immune reaction with prominent "foreign body" inflammatory infiltrates. Membrane biophysics, the cell type used, and the extended period of time the devices remained in situ may have contributed to the negative outcome and should be addressed in future investigations using this approach. (C) 2003 Elsevier Science Inc. All rights reserved. C1 NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. Univ Montreal, Fac Med Dent, Dept Stomatol, Montreal, PQ, Canada. CHUM, Neurosci Res Unit, Montreal, PQ, Canada. Univ Ioannina, Sch Med, Dept Neurol, GR-45110 Ioannina, Greece. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. Juntendo Univ, Sch Med, Dept Neurol, Tokyo 113, Japan. NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Cyto Therapeut Inc, Providence, RI USA. Sertoli Technol Inc, Cranston, RI USA. RP Mouradian, MM (reprint author), NINDS, Expt Therapeut Branch, NIH, 10 Ctr Dr,MSC 1406, Bethesda, MD 20892 USA. OI Mouradian, M. Maral/0000-0002-9937-412X NR 32 TC 8 Z9 8 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD JUN PY 2003 VL 27 IS 4 BP 607 EP 612 DI 10.1016/S0278-5846(03)00048-4 PG 6 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 691FW UT WOS:000183596200007 PM 12787846 ER PT J AU Haspel, N Tsai, CJ Wolfson, H Nussinov, R AF Haspel, N Tsai, CJ Wolfson, H Nussinov, R TI Reducing the computational complexity of protein folding via fragment folding and assembly SO PROTEIN SCIENCE LA English DT Article DE protein folding; building blocks; protein structure prediction; hierarchical folding; folding complexity ID MULTIPLE STRUCTURE ALIGNMENT; ALPHA-LACTALBUMIN; GLOBULAR-PROTEINS; STRUCTURE PREDICTION; LIMITED PROTEOLYSIS; LOCAL-STRUCTURE; MOLTEN GLOBULE; COMPACT UNITS; DOMAINS; CLASSIFICATION AB Understanding, and ultimately predicting, how a I-D protein chain reaches its native 3-D fold has been one of the most challenging problems during the last few decades. Data increasingly indicate that protein folding is a hierarchical process. Hence, the question arises as to whether we can use the hierarchical concept to reduce the practically intractable computational times. For such a scheme to work, the first step is to cut the protein sequence into fragments that form local minima on the polypeptide chain. The conformations of such fragments in solution are likely to be similar to those when the fragments are embedded in the native fold, although alternate conformations may be favored during the mutual stabilization in the combinatorial assembly process. Two elements are needed for such cutting: (1) a library of (clustered) fragments derived from known protein structures and (2) an assignment algorithm that selects optimal combinations to "cover" the protein sequence. The next two steps in hierarchical folding schemes, not addressed here, are the combinatorial assembly of the fragments and finally, optimization of the obtained conformations. Here, we address the first step in a hierarchical protein-folding scheme. The input is a target protein sequence and a library of fragments created by clustering building blocks that were generated by cutting all protein structures. The output is a set of cutout fragments. We briefly outline a graph theoretic algorithm that automatically assigns building blocks to the target sequence, and we describe a sample of the results we have obtained. C1 Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. SAIC, Sci Applicat Int Corp Frederick Inc, Basic Res Program, Lab Expt & Computat Biol, Frederick, MD 21702 USA. Tel Aviv Univ, Fac Exact Sci, Sch Comp Sci, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Bldg 469,Room 151, Frederick, MD 21702 USA. RI Wolfson, Haim/A-1837-2011; Haspel, Nurit/D-1961-2017 FU NCI NIH HHS [N01CO12400, N01-CO-12400] NR 47 TC 38 Z9 38 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 JUN PY 2003 VL 12 IS 6 BP 1177 EP 1187 DI 10.1110/ps.0232903 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 681LC UT WOS:000183036800004 PM 12761388 ER PT J AU Jones, K Colson, PW Holter, MC Lin, S Valencia, E Susser, E Wyatt, RJ AF Jones, K Colson, PW Holter, MC Lin, S Valencia, E Susser, E Wyatt, RJ TI Cost-effectiveness of critical time intervention to reduce homelessness among persons with mental illness SO PSYCHIATRIC SERVICES LA English DT Article ID ASSERTIVE COMMUNITY TREATMENT; NET HEALTH-BENEFITS; INTENSIVE CASE-MANAGEMENT; ILL CLIENTS; CARE; SERVICES; PROGRAM; PEOPLE; OUTCOMES; IMPACT AB Objectives: Cost-effective programs are needed to assist homeless persons with severe mental illness in their transition from shelters to community living. The authors investigated the cost-effectiveness of the critical time intervention program, a time-limited adaptation of intensive case management, which has been shown to significantly reduce recurrent homelessness among men with severe mental illness. Methods: Ninety-six study participants recruited from a psychiatric program in a men's public shelter from 1991 to 1993 were randomly assigned to the critical time intervention program or to usual services. Costs and housing outcomes for the two groups were examined over IS months. Results: Over the study period, the critical time intervention group and the usual services group incurred mean costs of $52,374 and $51,649, respectively, for acute care services, outpatient services, housing and shelter services, criminal justice services, and transfer income. During the same period, the critical time intervention group experienced significantly fewer homeless nights than the usual care group (32 nights versus 90 nights). For each willingness-to-pay value-the additional price society is willing to spend for an additional nonhomeless night-greater than $152, the critical time intervention group exhibited a significantly greater net housing stability benefit, indicating cost-effectiveness, compared with usual care. Conclusions: Although difficult to conduct, studies of the cost-effectiveness of community mental health programs can yield rich information for policy makers and program planners. The critical time intervention program is not only an effective method to reduce recurrent homelessness among persons with severe mental illness but also represents a cost-effective alternative to the status quo. C1 Nathan S Kline Inst Psychiat Res, Ctr Study Issues Publ Mental Hlth, Orangeburg, NY 10962 USA. Harlem Hosp Med Ctr, Charles P Felton Natl TB Ctr, New York, NY USA. Univ Michigan, Sch Social Work, Ann Arbor, MI 48109 USA. Parnassia Psychiat Inst, The Hague, Netherlands. Columbia Univ, Joseph L Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10027 USA. NIMH, Neuropsychiat Branch, Bethesda, MD 20892 USA. RP Jones, K (reprint author), Nathan S Kline Inst Psychiat Res, Ctr Study Issues Publ Mental Hlth, 140 Old Orangeburg Rd, Orangeburg, NY 10962 USA. EM jones@nki.rfmh.org FU NIMH NIH HHS [MH-48041, MH-51359, MH-56299-01] NR 39 TC 36 Z9 36 U1 3 U2 10 PU AMER PSYCHIATRIC PRESS, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD JUN PY 2003 VL 54 IS 6 BP 884 EP 890 DI 10.1176/appi.ps.54.6.884 PG 7 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 839BM UT WOS:000222758300017 PM 12773605 ER PT J AU Rowland, JH AF Rowland, JH TI Defining and delivering care: Where is the research taking us? SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 NCI, Off Canc Survivorship, NIH, DHHS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD JUN PY 2003 VL 12 IS 4 SU S MA 646 BP S265 EP S265 PG 1 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 684UR UT WOS:000183225400559 ER PT J AU Varricchio, C AF Varricchio, C TI Single item versus summated scale scores and patient versus clinician versus population perspectives of clinical significance SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD JUN PY 2003 VL 12 IS 4 SU S MA 26 BP S77 EP S78 PG 2 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 684UR UT WOS:000183225400013 ER PT J AU Desai, RI Barber, DJ Terry, P AF Desai, RI Barber, DJ Terry, P TI Dopaminergic and cholinergic involvement in the discriminative stimulus effects of nicotine and cocaine in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE nicotine; cocaine; drug discrimination; mecamyjamine; flupentixol; cholinergic agonists; dopamine reuptake blockers ID CIGARETTE-SMOKING; H-3 DOPAMINE; INTRAVENOUS NICOTINE; NUCLEUS-ACCUMBENS; SQUIRREL-MONKEYS; STRIATAL SLICES; RECEPTOR; MEDIATION; ANTAGONIST; BUPROPION AB Rationale: Previous work has demonstrated asymmetrical cross-generalization between the discriminative stimulus effects of nicotine and cocaine: nicotine fully substitutes for cocaine, whereas cocaine only partially substitutes for nicotine. The factors responsible for the similarities and differences between the two drugs remain unclear. Objective: The study tested the involvement of dopaminergic and/or cholinergic mechanisms in the discriminative stimulus effects of nicotine and cocaine. Methods: One set of rats was trained to discriminate cocaine (8.9 mg/kg) from saline, and two other sets of rats were trained to discriminate nicotine (0.1 mg/kg) from saline. Results: In cocaine-trained rats, among the cholinergic agonists studied only nicotine (0.01-0.56 mg/kg) produced full, dose-related substitution; nornicotine (1-5.6 mg/kg) substituted only partially, and lobeline (2.71-15.34 mg/kg) and pilocarpine (0.26-2.55 mg/kg) failed to engender any cocaine-appropriate responding. The nicotinic antagonist mecamylamine (1-5.6 mg/kg) failed to block cocaine's discriminative stimulus effects. The dopamine antagonist cis-flupentixol (0.48 mg/kg) blocked the substitution of nicotine for cocaine. In nicotine-trained rats, the dopamine uptake blockers cocaine, bupropion and nomifensine (0.2-26.1 mg/kg) each substituted only partially for nicotine, and cis-flupentixol (0.48-0.86 mg/kg) antagonized the discriminative stimulus effects of nicotine. Conclusions: Nicotine fully substitutes for cocaine because of its effects on dopamine transmission, and not because the discriminative stimulus effects of cocaine incorporate a cholinergic component. Substitution of nicotine for cocaine may depend more on nicotine-induced dopamine release than does the nicotine-trained discriminative stimulus; there may be differential dopaminergic involvement after acute and repeated treatment with nicotine or cocaine. C1 NIDA, Medicat Discovery Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Univ Birmingham, Sch Psychol, Birmingham B15 2TT, W Midlands, England. RP Desai, RI (reprint author), NIDA, Medicat Discovery Res Branch, Intramural Res Program, NIH, POB 5180, Baltimore, MD 21224 USA. NR 64 TC 41 Z9 41 U1 1 U2 5 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUN PY 2003 VL 167 IS 4 BP 335 EP 343 DI 10.1007/s00213-003-1426-x PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 696MC UT WOS:000183889800001 PM 12684733 ER PT J AU Shilnikova, NS Preston, DL Ron, E Gilbert, ES Vassilenko, EK Romanov, SA Kuznetsova, IS Sokolnikov, ME Okatenko, PV Kreslov, VV Koshurnikova, NA AF Shilnikova, NS Preston, DL Ron, E Gilbert, ES Vassilenko, EK Romanov, SA Kuznetsova, IS Sokolnikov, ME Okatenko, PV Kreslov, VV Koshurnikova, NA TI Cancer mortality risk among workers at the Mayak nuclear complex SO RADIATION RESEARCH LA English DT Article ID ATOMIC-BOMB SURVIVORS; LUNG-CANCER; PRODUCTION-ASSOCIATION; RADIATION; PLUTONIUM; LEUKEMIA; ENTERPRISE AB At present, direct data on risk from protracted or fractionated radiation exposure at low dose rates have been limited largely to studies of populations exposed to low cumulative doses with resulting low statistical power. We evaluated the cancer risks associated with protracted exposure to external whole-body gamma radiation at high cumulative doses (the average dose is 0.8 Gy and the highest doses exceed 10 Gy) in Russian nuclear workers. Cancer deaths in a cohort of about 21,500 nuclear workers who began working at the Mayak complex between 1948 and 1972 were ascertained from death certificates and autopsy reports with follow-up through December 1997. Excess relative risk models were used to estimate solid cancer and leukemia risks associated with external gamma-radiation dose with adjustment for effects of plutonium exposures. Both solid cancer and leukemia death rates increased significantly with increasing gamma-ray dose (P < 0.001). Under a linear dose-response model, the excess relative risk for lung, liver and skeletal cancers as a group (668 deaths) adjusted for plutonium exposure is 0.30 per gray (P < 0.001) and 0.08 per gray (P < 0.001) for all other solid cancers (1062 deaths). The solid cancer dose-response functions appear to be nonlinear, with the excess risk estimates at doses of less than 3 Gy being about twice those predicted by the linear model. Plutonium exposure was associated with increased risks both for lung, liver and skeletal cancers (the sites of primary plutonium deposition) and for other solid cancers as a group. A significant dose response, with no indication of plutonium exposure effects, was found for leukemia. Excess risks for leukemia exhibited a significant dependence on the time since the dose was received. For doses received within 3 to 5 years of death the excess relative risk per gray was estimated to be about 7 (P < 0.001), but this risk was only 0.45 (P = 0.02) for doses received 5 to 45 years prior to death. External gamma-ray exposures significantly increased risks of both solid cancers and leukemia in this large cohort of men and women with occupational radiation exposures. Risks at doses of less than 1 Gy may be slightly lower than those seen for doses arising from acute exposures in the atomic bomb survivors. As dose estimates for the Mayak workers are improved, it should be possible to obtain more precise estimates of solid cancer and leukemia risks from protracted external radiation exposure in this cohort. (C) 2003 by Radiation Research Society. C1 Radiat Effects Res Fdn, Dept Stat, Minami Ku, Hiroshima 7300045, Japan. So Urals Biophys Inst, Ozyorsk, Russia. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Mayak Prod Assoc, Dept Radiat Safety, Ozyorsk, Russia. RP Preston, DL (reprint author), Radiat Effects Res Fdn, Dept Stat, Minami Ku, 5-2 Hijiyama Koen, Hiroshima 7300045, Japan. FU NCI NIH HHS [N01-CP-51025, N01-CP-81034] NR 37 TC 90 Z9 100 U1 0 U2 4 PU RADIATION RESEARCH SOC PI OAK BROOK PA 820 JORIE BOULEVARD, OAK BROOK, IL 60523 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD JUN PY 2003 VL 159 IS 6 BP 787 EP 798 DI 10.1667/0033-7587(2003)159[0787:CMRAWA]2.0.CO;2 PG 12 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 685YH UT WOS:000183291800012 PM 12751962 ER PT J AU Choyke, PL Knopp, MV AF Choyke, PL Knopp, MV TI Pseudohypocalcemia with MR imaging contrast agents: A cautionary tale SO RADIOLOGY LA English DT Editorial Material DE calcium; contrast media; contrast media, effects; editorials; magnetic resonance (MR), contrast media ID SERUM-CALCIUM; INTERFERENCE C1 NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. Ohio State Univ, Coll Med & Publ Hlth, Dept Radiol, Columbus, OH 43210 USA. RP Choyke, PL (reprint author), NIH, Dept Diagnost Radiol, 10 Ctr Dr,MSC 1182,Bldg 10,Rm 1C660, Bethesda, MD 20892 USA. NR 4 TC 18 Z9 18 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUN PY 2003 VL 227 IS 3 BP 627 EP 628 DI 10.1148/ PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 679LW UT WOS:000182924800003 PM 12773668 ER PT J AU Huff, J AF Huff, J TI Does exposure to bisphenol A represent a human health risk? SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Letter ID CELL-TRANSFORMATION; MICE; CARCINOGENICITY; ANEUPLOIDY C1 Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Huff, J (reprint author), Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. NR 14 TC 9 Z9 9 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 0273-2300 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD JUN PY 2003 VL 37 IS 3 BP 407 EP 408 DI 10.1016/S0273-2300(03)00009-6 PG 2 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA 684BT UT WOS:000183186100006 PM 12758220 ER PT J AU Dalakas, MC AF Dalakas, MC TI Neuroimmunotherapy - Preface SO SEMINARS IN NEUROLOGY LA English DT Editorial Material C1 NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), NINDS, Neuromuscular Dis Sect, NIH, Bldg 10,Room 4N248,10 Ctr Dr,MSC 1382, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0271-8235 J9 SEMIN NEUROL JI Semin. Neurol. PD JUN PY 2003 VL 23 IS 2 BP 117 EP 117 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 706KR UT WOS:000184453300002 ER PT J AU Hohlfeld, R Dalakas, MC AF Hohlfeld, R Dalakas, MC TI Basic principles of immunotherapy for neurologic diseases SO SEMINARS IN NEUROLOGY LA English DT Article DE immunomodulation; neuroimmunological diseases; immunosuppressive therapy ID PROGRESSIVE MULTIPLE-SCLEROSIS; STEM-CELL TRANSPLANTATION; INTERFERON BETA-1B; NEUTRALIZING ANTIBODIES; MYCOPHENOLATE-MOFETIL; MYASTHENIA-GRAVIS; CONTROLLED TRIAL; DOUBLE-BLIND; GLATIRAMER ACETATE; IMMUNE-SYSTEM AB Immunosuppressive drugs and immunomodulating procedures can improve the quality of life in patients with immune-related neurologic diseases and can even be lifesaving if properly used to avoid deleterious or irreversible adverse effects. For the successful use of these drugs or procedures, the treating physician must be familiar and comfortable with the drugs' mode of action, the accuracy of the diagnosis, the goals and expectations of therapy, and the risk-benefit ratio of the therapy. Improvement must be based on a beneficial change in activities of daily living and not solely on a change in the laboratory test values. C1 Univ Munich, Inst Clin Neuroimmunol, D-81377 Munich, Germany. NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Hohlfeld, R (reprint author), Univ Munich, Inst Clin Neuroimmunol, Marchioninistr 15, D-81377 Munich, Germany. NR 52 TC 14 Z9 14 U1 0 U2 0 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0271-8235 J9 SEMIN NEUROL JI Semin. Neurol. PD JUN PY 2003 VL 23 IS 2 BP 121 EP 131 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 706KR UT WOS:000184453300003 PM 12894378 ER PT J AU Blevins, G Martin, R AF Blevins, G Martin, R TI Future immunotherapies in multiple sclerosis SO SEMINARS IN NEUROLOGY LA English DT Article DE multiple sclerosis; immunotherapy; clinical trials; review ID MYELIN-BASIC-PROTEIN; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; ALTERED PEPTIDE LIGAND; T-CELL VACCINATION; SECONDARY PROGRESSIVE MS; PLACEBO-CONTROLLED TRIAL; CENTRAL-NERVOUS-SYSTEM; RANDOMIZED CONTROLLED TRIAL; II CLINICAL-TRIAL AB Immunotherapy of multiple sclerosis (MS) will continue to benefit from an increasing understanding of this disease. This knowledge results in newly defined targets for novel therapies. In this article the development of future immunotherapies will be discussed by classifying the approaches into three main types: (1) antigen-specific therapies; (2) agents with a defined target in pathogenic steps of the MS lesion; and (3) therapies with broad immunomodulatory activity. Success in developing new immunotherapies depends on understanding the underlying complexity and heterogeneity of the disease. The current practice of employing a single therapy across a heterogeneous group of MS patients is in part a likely reason for their modest efficacy. The mechanism of action of a single agent may target the appropriate defect in one individual but not others. The therapy of MS in the future will most likely use a combination of agents that are directed at the underlying disease state and stage in the individual patient. C1 NIH, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Martin, R (reprint author), NIH, Neuroimmunol Branch, NIH, Bldg 10,Room 5B16,10 Ctr Dr, Bethesda, MD 20892 USA. NR 72 TC 13 Z9 13 U1 0 U2 0 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0271-8235 J9 SEMIN NEUROL JI Semin. Neurol. PD JUN PY 2003 VL 23 IS 2 BP 147 EP 157 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 706KR UT WOS:000184453300005 PM 12894380 ER PT J AU Dalakas, MC AF Dalakas, MC TI Therapeutic approaches in patients with inflammatory myopathies SO SEMINARS IN NEUROLOGY LA English DT Article DE polymyositis; dermatomyositis; inclusion-body myositis ID INCLUSION-BODY MYOSITIS; INTRAVENOUS IMMUNOGLOBULIN; CONTROLLED TRIAL; DOUBLE-BLIND; POLYMYOSITIS; DERMATOMYOSITIS; LYMPHOCYTES; EXPRESSION; CELLS AB Among the group of inflammatory myopathies, dermatomyositis (DM) remains the most treatable subset responding, in the majority of the cases, to steroids, intravenous immunoglobulin (IVIg), or immunosuppressants. Inclusion-body myositis (IBM) remains the most difficult disease to treat; in uncontrolled studies immunosuppressants and steroids have not helped, and controlled trials with IVIg have been disappointing. Polymyositis (PM) is a very uncommon, although still overdiagnosed, disorder and its rarity poses difficulties in performing large-scale therapeutic studies; based on small series, however, PM seems to variably respond to immunotherapeutic interventions. The most consistent problem in the treatment of inflammatory myopathies remains the distinction of true PM from the difficult-to-treat cases of IBM, or from necrotizing myopathies and dystrophic processes where secondary endomysial inflammation may be prominent. The future in the management of PM, DM, and IBM seems promising because of the availability of new agents directed at T-cell activation molecules, cytokines, chemokines, and adhesion receptors. In IBM, the use of such immunomodulatory drugs may be combined with agents that block cytokine-enhancing amyloid or with agents that inhibit the formation and polymerization of amyloid fibrils. C1 NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), NINDS, Neuromuscular Dis Sect, NIH, Bldg 10,Room 4N248,10 Ctr Dr,MSC 1382, Bethesda, MD 20892 USA. NR 28 TC 28 Z9 29 U1 0 U2 0 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0271-8235 J9 SEMIN NEUROL JI Semin. Neurol. PD JUN PY 2003 VL 23 IS 2 BP 199 EP 206 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 706KR UT WOS:000184453300010 PM 12894385 ER PT J AU Kwak, LW AF Kwak, LW TI Translational development of active immunotherapy for hematologic malignancies SO SEMINARS IN ONCOLOGY LA English DT Review ID B-CELL LYMPHOMA; COLONY-STIMULATING FACTOR; IMMUNE-RESPONSES; DENDRITIC CELLS; VACCINATION C1 NIH, Ft Detrick, MD 21702 USA. RP Kwak, LW (reprint author), NIH, Bldg 567,Rm 205, Ft Detrick, MD 21702 USA. NR 9 TC 9 Z9 12 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 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD JUN PY 2003 VL 30 IS 3 SU 8 BP 17 EP 22 DI 10.1016/S0093-7754(03)00232-X PG 6 WC Oncology SC Oncology GA 705QY UT WOS:000184407200003 PM 12881808 ER PT J AU Carey, JC Klebanoff, MA AF Carey, JC Klebanoff, MA CA Natl Inst Child Hlth Human Dev Mat TI What have we learned about vaginal infections and preterm birth? SO SEMINARS IN PERINATOLOGY LA English DT Review ID PLACEBO-CONTROLLED TRIAL; BACTERIAL VAGINOSIS; PREGNANT-WOMEN; FETAL FIBRONECTIN; METRONIDAZOLE; CLINDAMYCIN; PREMATURITY; PREDICTION; DELIVERY; ERYTHROMYCIN C1 NICHD, DESPR, NIH, Bethesda, MD 20892 USA. Maricopa Integrated Hlth Syst & Med Profess, Phoenix, AZ USA. RP Klebanoff, MA (reprint author), NICHD, DESPR, NIH, 6100 Execut Blvd,Room 7B05,MSC 7510, Bethesda, MD 20892 USA. FU NIAID NIH HHS [AI38514]; NICHD NIH HHS [U10-HD 27917, U10-HD 27861, U10-HD 27915, U10-HD 27869, U10-HD 34210, U10-HD 21414, U10-HD 27860, U10-HD 34122, U10-HD 27883, U10-HD 34116, U10-HD 21410, U10-HD 27905, U10-HD 34208, U10-HD 34136, U10-HD 36801, U10-HD 27889] NR 27 TC 17 Z9 17 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 0146-0005 J9 SEMIN PERINATOL JI Semin. Perinatol. PD JUN PY 2003 VL 27 IS 3 BP 212 EP 216 DI 10.1016/S0146-0005(03)00020-X PG 5 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 698FQ UT WOS:000183987800005 PM 12889588 ER PT J AU Uwaifo, GI Fallon, EM Calis, KA Drinkard, B McDuffie, JR Yanovski, JA AF Uwaifo, GI Fallon, EM Calis, KA Drinkard, B McDuffie, JR Yanovski, JA TI Improvement in hypertrophic cardiomyopathy after significant weight loss: Case report SO SOUTHERN MEDICAL JOURNAL LA English DT Article DE cardiac hypertrophy; hypertrophic cardiomyopathy; byper-tension; obesity; weight loss ID LEFT-VENTRICULAR MASS; OBESITY CARDIOMYOPATHY; HYPERTENSION; HEART; PRESSURE; RISK; CARDIOPATHY; DYSFUNCTION AB A 17-year-old obese boy found to have familial apical hypertrophic cardiomyopathy on routine screening was enrolled in a weight loss program on the basis of the hypothesis that significant weight loss would improve his cardiac status. He was followed with serial dual-energy x-ray absorptiometry, electrocardiography, echocardiography, and blood pressure and pulse rate measurements. Within 1 year, he lost 49 kg, with a body mass index reduction from 43.6 to 28.1 kg/m(2) and associated reductions in systolic blood pressure, diastolic blood pressure, pulse pressure, mean heart rate, rate pressure product, and echocardiographic indices of left ventricular mass that resulted in a change from the initial geometric finding of eccentric left ventricular hypertrophy to a "normal" left ventricular mass with minimal asymmetric apical left ventricular thickening. Significant weight loss in an obese adolescent with presumed familial apical hypertrophic cardiomyopathy was associated with striking improvement in cardiac functional indices, which could have profound implications for long-term cardiovascular risk. C1 NICHHD, Dev Endocrinol Branch, Bethesda, MD 20892 USA. NICHHD, Dept Pharm, Bethesda, MD 20892 USA. NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. RP Uwaifo, GI (reprint author), MedStar Res Inst, Suite 50,650 Penn Ave SE, Washington, DC 20003 USA. EM uwaifog@mail.nih.gov RI Uwaifo, Gabriel/M-2361-2016 OI Uwaifo, Gabriel/0000-0002-6962-9304 NR 29 TC 4 Z9 4 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0038-4348 J9 SOUTH MED J JI South.Med.J. PD JUN PY 2003 VL 96 IS 6 BP 626 EP 631 DI 10.1097/01.SMJ.0000053254.23595.14 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 831CC UT WOS:000222169500025 PM 12938797 ER PT J AU Lattimore, SU Chalela, J Davis, L DeGraba, T Ezzeddine, M Haymore, J Nyquist, P Baird, AE Hallenbeck, J Warach, S AF Lattimore, SU Chalela, J Davis, L DeGraba, T Ezzeddine, M Haymore, J Nyquist, P Baird, AE Hallenbeck, J Warach, S TI Impact of establishing a primary stroke center at a community hospital on the use of thrombolytic therapy - The NINDS suburban hospital stroke center experience SO STROKE LA English DT Article DE emergency medical services; hospital planning; stroke units; stroke, acute; thrombolytic therapy ID ACUTE ISCHEMIC STROKE; TISSUE-PLASMINOGEN ACTIVATOR AB Background and Purpose-To increase the proportion of ischemic stroke patients treated with thrombolytic therapy, the establishment of primary stroke centers in community hospitals has been advocated. We evaluated the use of thrombolytic therapy before and after institution of a primary stroke center in a community hospital. Methods-The availability of an on-call stroke emergency response team was the only significant additional resource required for this hospital. All eligible patients were treated with intravenous tissue plasminogen activator (tPA). The number of patients with cerebrovascular disease, number and proportion of patients treated with tPA, times to treatment, and patient outcomes were recorded during the first 2 years of the stroke center. Results-During the 12 months before institution of the stroke center, 3 ischemic stroke patients (1.5%) were treated with tPA. During the 2-year period of around-the-clock coverage, 44 of 420 ischemic stroke patients (10.5%) were treated with intravenous tPA, a significant increase in tPA use (P<0.0001). Conclusions-Establishment of a primary stroke center at a community hospital resulted in a substantial increase in the proportion of patients receiving thrombolytic therapy for ischemic stroke. If this experience is generalized, the beneficial impact of primary stroke centers on stroke outcomes and costs to the healthcare system may be substantial. C1 NINDS, Stroke Branch, Bethesda, MD 20892 USA. Natl Naval Med Res Inst, Dept Neurol, Clin Stroke Res Unit, Bethesda, MD USA. Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Dept Neurosurg, Atlanta, GA USA. Washington Adventist Hosp, Ctr Neurosci Serv, Takoma Pk, MD USA. INOVA Fairfax Hosp, Stroke Program, Falls Church, VA USA. RP Warach, S (reprint author), NINDS, Stroke Branch, 10 Ctr Dr,MSC 1063,Bldg 10,Room B1D733, Bethesda, MD 20892 USA. EM Warachs@ninds.nih.gov NR 11 TC 59 Z9 59 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUN PY 2003 VL 34 IS 6 BP E55 EP E57 DI 10.1161/01.STR.0000073789.12120.F3 PG 3 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 686YJ UT WOS:000183348300062 PM 12750543 ER PT J AU DeMartino, RE Crosby, AE EchoHawk, M Litts, DA Pearson, J Reed, GA West, M AF DeMartino, RE Crosby, AE EchoHawk, M Litts, DA Pearson, J Reed, GA West, M TI A call to collaboration: The federal commitment to suicide prevention SO SUICIDE AND LIFE-THREATENING BEHAVIOR LA English DT Article AB The federal government, largely through the U.S. Department of Health and Human Services (HHS), sponsors an array of science-based suicide prevention initiatives. This article details the prevention-related agendas and collaborative efforts of five operating divisions within the Department of Health and Human Services: the Substance Abuse and Mental Health Services Administration, National Institutes of Health, Centers for Disease Control and Prevention, Indian Health Service, and Health Resources and Services Administration. The article highlights HHSs activities and their link to the National Strategy for Suicide Prevention, the plan which will guide the nation's suicide prevention efforts for the next decade. C1 US Dept Hlth & Human Serv, Subst Abuse & Mental Hlth Serv Adm, Washington, DC 20201 USA. US Dept Hlth & Human Serv, Ctr Dis Control & Prevent, Washington, DC 20201 USA. US Dept Hlth & Human Serv, Indian Hlth Serv, Washington, DC 20201 USA. US Dept Hlth & Human Serv, NIH, Washington, DC 20201 USA. Suicide Prevent Subst Abuse & Mental Hlth Serv Ad, Washington, DC 20201 USA. US Dept Hlth & Human Serv, Hlth Resources & Serv Adm, Washington, DC 20201 USA. RP DeMartino, RE (reprint author), US PHS, Subst Abuse & Mental Hlth Serv Adm, 5600 Fishers Lane,Room 17C-26, Rockville, MD 20857 USA. NR 8 TC 5 Z9 5 U1 0 U2 0 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0363-0234 J9 SUICIDE LIFE-THREAT JI Suicide Life-Threat. Behav. PD SUM PY 2003 VL 33 IS 2 BP 101 EP 110 DI 10.1521/suli.33.2.101.22772 PG 10 WC Psychiatry; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 700WZ UT WOS:000184135300001 PM 12882412 ER PT J AU Fujita, M Al-Tikriti, MS Tamagnan, G Zoghbi, SS Bozkurt, A Baldwin, RM InniS's, RB AF Fujita, M Al-Tikriti, MS Tamagnan, G Zoghbi, SS Bozkurt, A Baldwin, RM InniS's, RB TI Influence of acetylcholine levels on the binding of a SPECT nicotinic acetylcholine receptor ligand [I-123]5-I-A-85380 SO SYNAPSE LA English DT Article DE physostigmine; baboon; equilibrium; 3-[2(S)-2-azetidinylmethoxy]pyridine ID POSITRON-EMISSION-TOMOGRAPHY; IN-VIVO BINDING; ALZHEIMERS-DISEASE; WORKING-MEMORY; ION CHANNELS; BLOOD-FLOW; BRAIN; ANESTHETICS; NEUROTRANSMITTERS; 5-IODO-A-85380 AB Although in vitro theory indicates that ligand binding is sensitive to competition with neurotransmitters, only some imaging ligands have shown such competition in vivo. The purpose of this study was to determine whether increases in acetylcholine (ACh) levels induced by an acetylcholinesterase inhibitor, physostigmine, inhibit in vivo binding of [I-123]5-iodo-3-(2(S)-2-azetidinyl-methoxy) pyridine (5-I-A-85380), a single photon emission computed tomography ligand for the high-affinity type nicotinic ACh receptor (nAChR). Baboons were used for seven studies with a bolus plus constant infusion equilibrium paradigm. After achieving equilibrium at 5 h, physostigmine (0.02 (n=1), 0.067 (n=3), and 0.2 (n=3) mg/kg) was administered intravenously and data were acquired for up to 8 h. To confirm equilibrium conditions, [I-123]5-I-A-85380 plasma levels were measured in four studies, including all studies with 0.2 mg/kg physostigmine. Prior to physostigmine administration, thalamic activities were stable, with changes of 1.1%/h or less, except in one study with a gradual increase of 4.2%/h. Thalamic activities were decreased by 15% in one study with 0.067 mg/kg and 14-17% in all studies with 0.2 mg/kg physostigmine administration (P=0.009). In these studies with 0.2 mg/kg physostigmine administration, [I-123]5-I-A-85380 plasma levels showed a transient or a sustained increase after physostigmine administration that would have increased thalamic activities. These results suggest that elevated ACh levels induced by physostigmine can effectively compete in vivo with [I-123]5-I-A-85380 binding at nAChRs. However, decreased thalamic activities could have been caused by other mechanisms, including internalization of the receptor with an associated decreased affinity for radioligand. C1 Yale Univ, Dept Psychiat, West Haven, CT USA. VA Connecticut HCS, West Haven, CT USA. Yale Univ, Dept Diagnost Radiol, West Haven, CT USA. Yale Univ, Dept Pharmacol, West Haven, CT USA. RP Fujita, M (reprint author), NIMH, Mol Imaging Branch, Bldg 1,Room B3-06B,1 Ctr Dr,MSC-0135, Bethesda, MD 20892 USA. FU NIDA NIH HHS [P50 DA84733] NR 46 TC 20 Z9 20 U1 0 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD JUN 1 PY 2003 VL 48 IS 3 BP 116 EP 122 DI 10.1002/syn.10194 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 669YE UT WOS:000182378100002 PM 12645036 ER PT J AU Ashby, CR Paul, M Gardner, EL Heidbreder, CA Hagan, JJ AF Ashby, CR Paul, M Gardner, EL Heidbreder, CA Hagan, JJ TI Acute administration of the selective D-3 receptor antagonist SB-277011A blocks the acquisition and expression of the conditioned place preference response to heroin in male rats SO SYNAPSE LA English DT Article ID DOPAMINE; REWARD; SEEKING; COCAINE C1 St Johns Univ, Coll Pharm & Allied Hlth Profess, Dept Pharmaceut Sci, Jamaica, NY 11439 USA. Eon Labs, Laurelton, NY 11413 USA. NIDA, Intramural Res Program, NIH, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. GlaxoSmithKline Pharmaceut, Psychiat Ctr Excellence Drug Discovery, Dept Drug Dependence & Behav Neurochem, I-37135 Verona, Italy. RP Ashby, CR (reprint author), St Johns Univ, Coll Pharm & Allied Hlth Profess, PHS Dept, 8000 Utopia Pkwy, Jamaica, NY 11439 USA. NR 11 TC 75 Z9 78 U1 2 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD JUN 1 PY 2003 VL 48 IS 3 BP 154 EP 156 DI 10.1002/syn.10188 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 669YE UT WOS:000182378100007 PM 12645041 ER PT J AU Fontelo, P Ackerman, M Kim, G Locatis, C AF Fontelo, P Ackerman, M Kim, G Locatis, C TI The PDA as a portal to knowledge sources in a wireless setting SO TELEMEDICINE JOURNAL AND E-HEALTH LA English DT Article ID MEDLINE AB Two recent parallel developments, the widespread deployment of wireless networks and increased use of handheld devices like the personal digital assistant (PDA), have contributed to the development of mobile access to the Internet. Recent surveys show that approximately 25% or more of physicians use PDAs. Although used mainly for personal information management and static medical applications, PDAs have capabilities to connect to the Internet. We studied the use of handheld devices to access MEDLINE and other knowledge sources in a wireless setting. C1 Natl Lib Med, Off High Performance Comp & Commun, Bethesda, MD 20894 USA. Natl Lib Med, Cognit Sci Branch, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. RP Fontelo, P (reprint author), Natl Lib Med, Off High Performance Comp & Commun, B1N30,Bldg 38A, Bethesda, MD 20894 USA. NR 12 TC 17 Z9 18 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1530-5627 J9 TELEMED J E-HEALTH JI Telemed. J. e-Health PD SUM PY 2003 VL 9 IS 2 BP 141 EP 147 DI 10.1089/153056203766437480 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 694GQ UT WOS:000183766400003 PM 12855037 ER PT J AU Brock, DW AF Brock, DW TI Precommitment in bioethics: Some theoretical issues SO TEXAS LAW REVIEW LA English DT Article C1 Natl Inst Hlth, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Brock, DW (reprint author), Natl Inst Hlth, Dept Clin Bioeth, Bethesda, MD 20892 USA. NR 14 TC 7 Z9 7 U1 0 U2 0 PU TEXAS LAW REVIEW PUBL INC PI AUSTIN PA 727 E 26TH ST, AUSTIN, TX 78705 USA SN 0040-4411 J9 TEX LAW REV JI Tex. Law Rev. PD JUN PY 2003 VL 81 IS 7 BP 1805 EP 1821 PG 17 WC Law SC Government & Law GA 701WX UT WOS:000184192900004 PM 15478264 ER PT J AU Zajaczkowski, MB Cukierman, E Galbraith, CG Yamada, KM AF Zajaczkowski, MB Cukierman, E Galbraith, CG Yamada, KM TI Cell-matrix adhesions on poly(vinyl alcohol) hydrogels SO TISSUE ENGINEERING LA English DT Article ID EXTRACELLULAR-MATRIX; FOCAL ADHESIONS; FIBRONECTIN; INTEGRINS; MIGRATION; ALGINATE; DYNAMICS; CONTACT AB Cell-matrix adhesions regulate cell morphology, intracellular signaling, gene expression, and phenotype. Understanding how different methods of attaching matrix proteins to substrates affect the molecular arrangement of these adhesions offers the possibility of controlling cell function and architecture. The goal of this study was to visualize and quantify the cell-matrix adhesions formed by human fibroblasts on the matrix protein fibronectin covalently attached to poly(vinyl) alcohol (PVA) hydrogels. These adhesions were then compared with the cell adhesions formed in routine cell culture on fibronectin noncovalently coated onto glass coverslips or those formed on fibronectin covalently immobilized onto glass coverslips. Cell adhesions were characterized by immunofluorescence confocal microscopy utilizing paxillin as a marker for focal adhesions and alpha(5) integrin as a marker for fibrillar adhesions. As expected, distinct focal and fibrillar adhesions were observed in routine cell culture on coverslips coated noncovalently with fibronectin. Cells cultured on fibronectin covalently linked to PVA demonstrated diminished spatial separation of paxillin and a5 integrin, accompanied by a reduction in fibrillar adhesions and fibronectin fibrillogenesis. Cells on fibronectin covalently immobilized on glass displayed the strongest marker colocalization and the most complete loss of fibrillar adhesions and lack of fibrillogenesis. These results indicate that fibronectin-conjugated PVA promotes the formation of cell adhesion structures intermediate in composition between those formed on noncovalently attached and covalently immobilized fibronectin. Furthermore, they imply that bioactive polymers can selectively induce specific cell-matrix adhesions, a characteristic that may have consequences in various tissue-engineering applications. C1 NIDCR, CDBRB, NIH, Bethesda, MD 20892 USA. RP Yamada, KM (reprint author), NIDCR, CDBRB, NIH, Bldg 30,Room 421,30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. OI Yamada, Kenneth/0000-0003-1512-6805 NR 25 TC 29 Z9 29 U1 0 U2 17 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1076-3279 J9 TISSUE ENG JI Tissue Eng. PD JUN PY 2003 VL 9 IS 3 BP 525 EP 533 DI 10.1089/107632703322066705 PG 9 WC Cell & Tissue Engineering SC Cell Biology GA 692VP UT WOS:000183681200014 PM 12857420 ER PT J AU Henningfield, JE Moolchan, ET Zeller, M AF Henningfield, JE Moolchan, ET Zeller, M TI Regulatory strategies to reduce tobacco addiction in youth SO TOBACCO CONTROL LA English DT Article; Proceedings Paper CT Conference on Innovative Approaches to Youth Tobacco Control CY JUL 08-11, 2002 CL SANTA FE, NEW MEXICO SP Univ Michigan Tobacco Res Network ID NICOTINE DEPENDENCE; ADOLESCENT SMOKING; SMOKELESS TOBACCO; HARM REDUCTION; PUBLIC-HEALTH; PRODUCT REGULATION; SMOKERS; ISSUES; CHALLENGES; CIGARETTES AB Preventing tobacco addiction and achieving cessation in established users are the cornerstones of efforts to reduce tobacco use and disease. It has been increasingly recognised that reducing tobacco toxin exposure has theoretical potential to reduce disease in continuing tobacco users. This has been controversial because such approaches also carry the potential to undermine prevention and cessation. As complicated as harm reduction issues are for adults, they are still more complicated for youth. Harm reduction is not a singular approach, but rather a concept that encompasses an extremely diverse array of potential approaches. These carry equally diverse potential risks and benefits. The regulatory framework (for example, whether or not the Food and Drug Administration regulates the approach) is also predicted to be a major factor in determining the consequences of harm reduction approaches. This paper examines the various issues and potential approaches concerning the application of harm reduction to youth. We conclude that although some carry great risk, others may actually support broader tobacco control efforts to prevent tobacco use and foster cessation in youth and adults. C1 Johns Hopkins Univ, Sch Med, Pinney Associates, Bethesda, MD 20814 USA. Natl Inst Drug Abuse, Intramural Res Program, Bethesda, MD USA. RP Henningfield, JE (reprint author), Johns Hopkins Univ, Sch Med, Pinney Associates, 4800 Montgomery Lane,Suite 1000, Bethesda, MD 20814 USA. NR 120 TC 6 Z9 7 U1 0 U2 3 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0964-4563 J9 TOB CONTROL JI Tob. Control PD JUN PY 2003 VL 12 SU 1 BP I14 EP I24 DI 10.1136/tc.12.suppl_1.i14 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 683XU UT WOS:000183177000004 PM 12773782 ER PT J AU Cunningham, ML Bogdanffy, MS Zacharewski, TR Hines, RN AF Cunningham, ML Bogdanffy, MS Zacharewski, TR Hines, RN TI Workshop overview: Use of genomic data in risk assessment SO TOXICOLOGICAL SCIENCES LA English DT Article DE Human Genome Project; genomic research; high-throughput genomic technologies; risk assessment; regulatory guidelines ID GENE-EXPRESSION; CANCER; POLYMORPHISMS; TOXICOGENOMICS; TECHNOLOGIES; PREDICTION; TOXICOLOGY; GENOTYPES AB The completion of the Human Genome Project has provided the foundation to analyze the expression of all genes transcribed in a specific cell, as well as a reference against which to assess genetic variability and its impact on susceptibility. Recent advances in genomic technologies have set the stage for better understanding and predicting individual adaptive and toxicological responses after toxicant exposure. Thus, it is now possible to simultaneously assess expression levels for thousands of different genes using DNA microarrays, as well as assess posttranscriptional and posttranslational events using high throughput proteomics. Similarly, the risk of toxicant exposure-induced disease used to be estimated across populations with widely varying responses. However, new high-throughput genomic technologies have the potential to greatly improve the accuracy of risk assessment, allowing identification of sensitive subpopulations at risk and ultimately leading to personalized risk profiles based on genetic composition. Recognizing the importance these technologies will have on the practice of risk assessment and the development of regulatory guidelines, the Society of Toxicology sponsored a workshop to evaluate the current status of genomic research; the ethical, legal, and social issues associated with these approaches; and, in this context, how data derived from these technologies would impact risk assessment. This article summarizes the evaluation by experts in genomic research and risk assessment in the first workshop to provide a forum for interaction between these scientific disciplines. C1 NIEHS, Natl Ctr Toxicogenom, Res Triangle Pk, NC 27709 USA. NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. DuPont Co Inc, Haskell Lab, Newark, DE 19714 USA. Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. Med Coll Wisconsin, Dept Pediat, Birth Defects Res Ctr, Milwaukee, WI 53226 USA. RP Cunningham, ML (reprint author), NIEHS, Natl Ctr Toxicogenom, 111 Alexander Dr,Mail Drop B3-10, Res Triangle Pk, NC 27709 USA. OI Hines, Ronald/0000-0002-3094-4200 NR 23 TC 29 Z9 31 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JUN PY 2003 VL 73 IS 2 BP 209 EP 215 DI 10.1093/toxsci/kfg071 PG 7 WC Toxicology SC Toxicology GA 681MP UT WOS:000183040200002 PM 12700425 ER PT J AU Shimoda, R Achanzar, WE Qu, W Nagamine, T Takagi, H Mori, M Waalkes, MP AF Shimoda, R Achanzar, WE Qu, W Nagamine, T Takagi, H Mori, M Waalkes, MP TI Metallothionein is a potential negative regulator of apoptosis SO TOXICOLOGICAL SCIENCES LA English DT Article DE metallothionein; apoptosis; etoposide; cadmium; zinc ID DOWN-REGULATION; PROGNOSTIC-SIGNIFICANCE; SUPPRESSES APOPTOSIS; EPITHELIAL-CELLS; OXIDATIVE STRESS; GENE-EXPRESSION; HUMAN PROSTATE; ZINC PROTECTS; NITRIC-OXIDE; CADMIUM AB Apoptotic resistance can either be desirable or undesirable, depending on the conditions. In cancer chemotherapy, it is critical that tumor cells are selectively and effectively killed while leaving normal cells undamaged. Since acquisition of apoptotic resistance appears to be a common occurrence during malignant transformation, elucidating the mechanisms underlying apoptotic resistance is an area of intense study. Previous studies have revealed that metallothionein (MT) can protect cells from apoptosis induced by oxidative stress and metals. In the present study, we tested the hypothesis that the presence of MT may somehow modulate apoptosis. Our results revealed a strong linear negative correlation between basal MT levels and etoposide-induced apoptosis in the human tumor cell lines PLC/PRF/5, H460, and HepG2 (r = -0.991). In HepG2 cells, 24 h pretreatment with cadmium resulted in concentration-dependent increases in MT levels and marked decreases in etoposide-induced apoptosis. Zinc pretreatment also resulted in increased MT synthesis and decreased etoposide-induced apoptosis. More importantly, induced MT levels were negatively correlated with sensitivity to etoposide-induced apoptosis (r = -0.965). These suggest that MT may play a role m regulating apoptosis and that modulating MT expression may provide a strategy for altering cellular resistance to chemotherapeutic compounds. C1 NIEHS, Inorgan Carcinogenesis Sect, NCI, Res Triangle Pk, NC 27709 USA. Gunma Univ, Sch Med, Dept Internal Med 1, Maebashi, Gumma 3718511, Japan. Gunma Univ, Sch Med, Dept Hlth Sci, Maebashi, Gumma 3718511, Japan. RP Waalkes, MP (reprint author), NIEHS, Inorgan Carcinogenesis Sect, NCI, POB 12233,Mail Drop F0-09,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 46 TC 99 Z9 107 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JUN PY 2003 VL 73 IS 2 BP 294 EP 300 DI 10.1093/toxsci/kfg095 PG 7 WC Toxicology SC Toxicology GA 681MP UT WOS:000183040200010 PM 12700406 ER PT J AU Barlow, NJ Phillips, SL Wallace, DG Sar, M Gaido, KW Foster, PMD AF Barlow, NJ Phillips, SL Wallace, DG Sar, M Gaido, KW Foster, PMD TI Quantitative changes in gene expression in fetal rat testes following exposure to Di(n-butyl) phthalate SO TOXICOLOGICAL SCIENCES LA English DT Article DE di(n-butyl); phthalate; steroidogenesis; male reproductive development; gene expression; fetal testes; litter variability; c-kit ID STEM-CELL FACTOR; MALE REPRODUCTIVE DEVELOPMENT; C-KIT; LEYDIG-CELLS; VENTRAL PROSTATE; LATE-GESTATION; BLOOD-FLOW; RECEPTOR; HORMONE; MICE AB Di(n-butyl) phthalate (DBP) alters male reproductive development by decreasing testicular testosterone (T) production when fetuses are exposed on. gestation days (GD) 12-21. Previous studies have shown altered gene expression for enzymes in the T biosynthetic pathway following exposure to DBP. The objectives of this study were to develop a more detailed understanding of the effect of DBP on steroidogenesis, using a robust study design with increased numbers of dams and fetuses, compared with previous studies, and to explore messenger RNA (mRNA) expression for other critical genes involved in androgen biosynthesis and signaling. Additionally, immunohistochemical localization of protein expression for several key genes was performed to further confirm mRNA changes. Fetal Leydig cell lipid levels were also examined histochemically, using oil red O. Six to seven pregnant Crl:CD(SD)BR rats per group were gavaged with corn oil or DBP at 500 mg/kg/day on GD 12-19. Testicular RNA isolated from three randomly selected GD 19 fetuses per litter was used for real-time RT-PCR for the following genes: scavenger receptor class B-1 (SRB1), steroidogenic acute regulatory protein (StAR), P450 side-chain cleavage enzyme (P450scc), 3beta-hydroxysteroid dehydrogenase (3beta-HSD), P450c17, 17beta-hydroxysteroid dehydrogenase (17beta-HSD), androgen receptor (AR), luteinizing hormone receptor (LHR), follicle-stimulating hormone receptor (FSHR), stem cell factor tyrosine kinase receptor (c-kit), stem cell factor (SCF), proliferating cell nuclear antigen (PCNA), and testosterone-repressed prostate message-2 (TRPM-2). mRNA expression was downregulated for SRB1, StAR, P450scc, 3beta-HSD, P450c17, and c-kit following DBP exposure, and TRPM-2 was upregulated. 17beta-HSD, AR, LHR, FSHR, and PCNA were not significantly changed. Immunohistochemical staining for c-kit was seen in fetal Leydig cells, which has not been previously reported. Downregulation of most of the genes in the T biosynthetic pathway confirms and extends previous findings. Diminished Leydig cell lipid content and alteration of cholesterol transport genes also support altered cholesterol metabolism and transport as a potential mechanism for decreased T synthesis following exposure to DBP. C1 NIEHS, Res Triangle Pk, NC 27709 USA. CIIT Ctr Hlth Res, Res Triangle Pk, NC 27709 USA. RP Foster, PMD (reprint author), NIEHS, POB 12233 MD E1-06, Res Triangle Pk, NC 27709 USA. NR 54 TC 165 Z9 182 U1 3 U2 18 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JUN PY 2003 VL 73 IS 2 BP 431 EP 441 DI 10.1093/toxsci/kfg087 PG 11 WC Toxicology SC Toxicology GA 681MP UT WOS:000183040200022 PM 12700402 ER PT J AU Biswas, R Tabor, E Hsia, CC Wright, DJ Laycock, ME Fiebig, EW Peddada, L Smith, R Schreiber, GB Epstein, JS Nemo, GJ Busch, MP AF Biswas, R Tabor, E Hsia, CC Wright, DJ Laycock, ME Fiebig, EW Peddada, L Smith, R Schreiber, GB Epstein, JS Nemo, GJ Busch, MP TI Comparative sensitivity of HBVNATs and HBsAg assays for detection of acute HBV infection SO TRANSFUSION LA English DT Article ID HEPATITIS-B VIRUS; BLOOD-TRANSFUSION; VIRAL-INFECTIONS; NAT; PREVALENCE; DONORS; SAFETY; RISK AB BACKGROUND: A study was designed to estimate relative analytic sensitivity and window-period (WP) closure and to project incremental yield of newer HBsAg tests, pooled-sample NAT, and single-sample NAT, compared to currently licensed HBsAg tests. STUDY DESIGN AND METHODS: HBV DNA and HBsAg test results for 23 HBV seroconversion (SC) panels were first analyzed to construct a model of primary HBV viremia. One-hundred representative samples were then selected from 10 panels and coded with 28 analytical controls. All 128 samples were tested by seven HBsAg tests and by four pooled-sample and three single-sample NAT assay formats. Results were analyzed to obtain differential times to HBV detection and combined with HBV incidence rates to project comparative yields. RESULTS: HBV doubling time during the ramp-up phase was estimated at 2.56 days. HBsAg concentrations at cutoff for new tests ranged from 0.07 to 0.12 ng per mL, compared with 0.13 to 0.62 ng per mL for licensed tests. Estimated viral load at cutoff ranged from 102 to 267 IU per mL for new tests and from 363 to 1069 IU per mL for licensed tests. HBsAg tests detected 31 to 63 percent of early ramp-up phase samples in the 100-member seroconversion panel study, while pooled-sample NAT detected 55 to 71 percent and single-sample NAT, 82 to 99 percent. Compared with currently licensed HBsAg assays, newer HBsAg assays would reduce the WP by 2 to 9 days; pooled-sample NAT would reduce the WP by 9 to 11 days; and single-sample NAT would reduce the WP by 25 to 36 days. CONCLUSION: Newer HBsAg tests would be expected to detect an additional 15 to 21 infected units per 107 donations, compared to licensed HBsAg tests. Sensitivity, WP closure, and yield projections for newer HBsAg assays and pooled-sample NAT are comparable. Single-sample NAT would increase yield by 13 to 15 units per 107 donations over pooled-sample NAT and newer HBsAg assays and by 35 to 50 units per 107 donations over currently licensed HBsAg assays. C1 Univ Calif San Francisco, Blood Ctr Pacific, San Francisco, CA 94118 USA. US FDA, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. Westat Corp, Rockville, MD USA. San Francisco Gen Hosp, San Francisco, CA 94110 USA. Alpha Therapeut Corp, Los Angeles, CA USA. Natl Genet Inst, Los Angeles, CA USA. NHLBI, Bethesda, MD 20892 USA. Blood Syst Inc, Scottsdale, AZ USA. RP Busch, MP (reprint author), Univ Calif San Francisco, Blood Ctr Pacific, 270 Masonic Ave, San Francisco, CA 94118 USA. NR 26 TC 169 Z9 191 U1 0 U2 4 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD JUN PY 2003 VL 43 IS 6 BP 788 EP 798 DI 10.1046/j.1537-2995.2003.00424.x PG 11 WC Hematology SC Hematology GA 682YB UT WOS:000183119000017 PM 12757531 ER PT J AU Bronte, V Serafini, P Mazzoni, A Segal, DM Zanovello, P AF Bronte, V Serafini, P Mazzoni, A Segal, DM Zanovello, P TI L-arginine metabolism in myeloid cells controls T-lymphocyte functions SO TRENDS IN IMMUNOLOGY LA English DT Article ID NITRIC-OXIDE SYNTHASE; TUMOR-BEARING MICE; IN-VIVO; TRYPTOPHAN CATABOLISM; IMMUNE SUPPRESSION; DENDRITIC CELLS; NO SYNTHESIS; MACROPHAGES; ACTIVATION; ARGINASE AB Although current attention has focused on regulatory T lymphocytes as suppressors of autoimmune responses, powerful immunosuppression is also mediated by a subset of myeloid cells that enter the lymphoid organs and peripheral tissues during times of immune stress. If these myeloid suppressor cells (MSCs) receive signals from activated T lymphocytes in the lymphoid organs, they block T-cell proliferation. MSCs use two enzymes involved in arginine metabolism to control T-cell responses: inducible nitric oxide synthase (NOS2), which generates nitric oxide (NO) and arginase 1 (Arg1), which depletes the milieu of arginine. Th1 cytokines induce NOS2, whereas Th2 cytokines upregulate Arg1. Induction of either enzyme alone results in a reversible block in T-cell proliferation. When both enzymes are induced together, peroxynitrites, generated by NOS2 under conditions of limiting arginine, cause activated T lymphocytes to undergo apoptosis. Thus, NOS2 and Arg1 might act separately or synergistically in vivo to control specific types of T-cell responses, and selective antagonists of these enzymes might prove beneficial in fighting diseases in which T-cell responses are inappropriately suppressed. This Opinion is the second in a series on the regulation of the immune system by metabolic pathways. C1 Dept Oncol & Surg Sci, I-35128 Padua, Italy. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Bronte, V (reprint author), Dept Oncol & Surg Sci, Via Gattamelata 64, I-35128 Padua, Italy. RI Serafini, Paolo/C-8195-2012; Bronte, Vincenzo/K-7902-2016 OI Serafini, Paolo/0000-0002-3651-9176; Bronte, Vincenzo/0000-0002-3741-5141 NR 45 TC 261 Z9 270 U1 0 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD JUN PY 2003 VL 24 IS 6 BP 302 EP 306 DI 10.1016/S1471-4906(03)00132-7 PG 5 WC Immunology SC Immunology GA 695ZH UT WOS:000183859900008 PM 12810105 ER PT J AU Marincola, FM Wang, E Herlyn, M Seliger, B Ferrone, S AF Marincola, FM Wang, E Herlyn, M Seliger, B Ferrone, S TI Tumors as elusive targets of T-cell-based active immunotherapy SO TRENDS IN IMMUNOLOGY LA English DT Review ID DIFFERENTIATION ANTIGEN EXPRESSION; MELANOMA-ASSOCIATED ANTIGENS; PULSED DENDRITIC CELLS; METASTATIC MELANOMA; CLASS-I; IMMUNE-RESPONSE; INFILTRATING LYMPHOCYTES; PEPTIDE VACCINATION; PERIPHERAL-BLOOD; GENE-EXPRESSION AB The understanding of tumor-host interactions remains elusive despite significant progress in the identification of tumor antigens (TAs) recognized by autologous T cells. In particular, most human tumors do not regress and continue to grow in spite of spontaneous or immunization-induced immune responses demonstrated in circulating lymphocytes. Indeed, systemic immune responses might insufficiently address the complexity of tumor-host interactions because of factors, such as (1) the lack of productive T-cell receptor (TCR) engagement with epitope owing to qualitative and/or quantitative defects in the generation and maintenance of the immune response, (2) insufficient costimulation provided by the host, (3) the lack of localization of the immune response in target tissues and (4) the complexity of tumor-host interactions within the tumor microenvironment caused by temporal changes in tumor phenotypes and an array of immune mediators expressed in the tumor microenvironment. Here, we will review current knowledge of the different 'levels' of immune response that might be necessary for immunotherapy to be effective in the treatment of cancer. Furthermore, we will discuss the information still required in order to understand the mechanism(s) governing tumor rejection by the immune system in response to TA-specific immunization. C1 NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. Wistar Inst Anat & Biol, Dept Anat, Philadelphia, PA 19104 USA. Univ Mainz, Dept Internal Med, D-55101 Mainz, Germany. Roswell Pk Canc Inst, Dept Immunol, Buffalo, NY 14263 USA. RP Marincola, FM (reprint author), NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, 9000 Rockville Pike, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA67108, P01CA89480, P30CA16056] NR 67 TC 132 Z9 136 U1 1 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD JUN PY 2003 VL 24 IS 6 BP 335 EP 342 DI 10.1016/S1471-4906(03)00116-9 PG 8 WC Immunology SC Immunology GA 695ZH UT WOS:000183859900013 PM 12810110 ER PT J AU Yang, DS Miles, FA AF Yang, DS Miles, FA TI Short-latency ocular following in humans is dependent on absolute (rather than relative) binocular disparity SO VISION RESEARCH LA English DT Article DE optokinetic eye movements; binocular disparity; visual motion; motion segmentation ID TEMPORAL VISUAL AREA; HUMAN OPTOKINETIC NYSTAGMUS; CLASSICAL RECEPTIVE-FIELD; VERGENCE EYE-MOVEMENTS; RANDOM-DOT STEREOGRAMS; CORTICAL AREA; MACAQUE MONKEY; FUNCTIONAL-PROPERTIES; STEREOSCOPIC DEPTH; MOTION AB A previous study showed that the initial ocular following responses elicited by sudden motion of a large random-dot pattern were only modestly attenuated when that whole pattern was shifted out of the plane of fixation by altering its horizontal binocular disparity, but the same disparity applied to a restricted region of the dots had a much more powerful effect [Vision Research 41 (2001) 3371]. Thus, if the dots were partitioned into horizontal bands, for example, and alternate bands were moved in opposite directions to the left or right then ocular following was very weak, but if the (conditioning) dots moving in one direction were all shifted out of the plane of fixation (by applying horizontal disparity to them) then strong ocular following was now seen in the direction of motion of the (test) dots in the plane of fixation, i.e., moving images became much less effective when they were given binocular disparity. We sought to determine if the greater impact of disparity with the partitioned images was because there were additional relative disparity cues. We used a similar partitioned display and found that the dependence of ocular following on the absolute disparity of the conditioning stimulus had a Gaussian form with an x-offset that was close to zero disparity and, importantly, this offset was almost unaffected by changing the absolute disparity of the test stimulus. We conclude from this that it is the absolute-rather than the relative-disparity that is important, and that ocular following has a strong preference for moving images whose absolute disparities are close to zero. This is consistent with the idea that ocular following selectively stabilizes the retinal images of objects in and around the plane of fixation and works in harmony with disparity vergence, which uses absolute disparity to bring objects of interest into the plane of fixation [Archives of Ophthalmology 55 (1956) 848]. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. Columbus Childrens Hosp, Dept Ophthalmol, Columbus, OH 43205 USA. RP Miles, FA (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Room 2A50,49 Convent Dr, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 EY000153-24] NR 47 TC 18 Z9 18 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 J9 VISION RES JI Vision Res. PD JUN PY 2003 VL 43 IS 12 BP 1387 EP 1396 DI 10.1016/S0042-6989(03)00146-9 PG 10 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 683BR UT WOS:000183127300007 PM 12742108 ER PT J AU Chan, TJ Libutti, SK McCart, JA Chen, C Khan, A Skarulis, MK Weinstein, LS Doppman, JL Marx, SJ Alexander, HR AF Chan, TJ Libutti, SK McCart, JA Chen, C Khan, A Skarulis, MK Weinstein, LS Doppman, JL Marx, SJ Alexander, HR TI Persistent primary hyperparathyroidism caused by adenomas identified in pharyngeal or adjacent structures SO WORLD JOURNAL OF SURGERY LA English DT Article ID PARATHYROID ADENOMA; RECURRENT HYPERPARATHYROIDISM; PREOPERATIVE LOCALIZATION; REOPERATION; MANAGEMENT; ANATOMY; EXPLORATION; ETIOLOGY; STRATEGY; SURGERY AB Abnormalities in the normal migration of the parathyroid glands during embryological development of the head and neck may result in considerable variability in the location of parathyroid tissue. Ectopic parathyroid adenomas present diagnostic and technical challenges and are frequently the cause of persistent primary hyperparathyroidism (HPT) after unsuccessful initial parathyroid surgery. We report a series of eight patients with persistent primary HPT who had adenomas in rare and unusual locations associated with various pharyngeal structures. Four were located within the epineurium of the vagus nerve at or above the level of the carotid bifurcation, and four were located within the paranasopharyngeal space or oropharynx. Noninvasive and invasive preoperative imaging studies were crucial in localizing the neoplasms in these patients and permitted the use of a direct surgical approach, resulting in cure in all patients and a low complication rate. The location of parathyroid glands in high pharyngeal and cervical structures is a consequence of anomalous or arrested descent through developing pharyngeal structures and illustrates the remarkable spectrum of ectopic parathyroid adenomas that occur secondary to this phenomenon. C1 NCI, NIH, Bethesda, MD 20892 USA. Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. Kaiser Permanente, Kensington, MD 20895 USA. RP Alexander, HR (reprint author), NCI, NIH, 10 Ctr Dr,Bldg 10,Room 2B07, Bethesda, MD 20892 USA. OI Weinstein, Lee/0000-0002-1899-5152 NR 24 TC 14 Z9 14 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0364-2313 J9 WORLD J SURG JI World J.Surg. PD JUN PY 2003 VL 27 IS 6 BP 675 EP 679 DI 10.1007/s00268-003-6812-3 PG 5 WC Surgery SC Surgery GA 692VB UT WOS:000183680000009 PM 12734681 ER PT J AU Sobngwi, E Boudou, P Mauvais-Jarvis, F Leblanc, H Velho, G Vexiau, P Porcher, R Hadjadj, S Pratley, R Tataranni, PA Calvo, F Gautier, JF AF Sobngwi, E Boudou, P Mauvais-Jarvis, F Leblanc, H Velho, G Vexiau, P Porcher, R Hadjadj, S Pratley, R Tataranni, PA Calvo, F Gautier, JF TI Effect of a diabetic environment in utero on predisposition to type 2 diabetes SO LANCET LA English DT Article ID INSULIN SECRETORY DYSFUNCTION; IMPAIRED GLUCOSE-TOLERANCE; PIMA-INDIANS; LIFE-STYLE; MELLITUS; RESISTANCE; MOTHERS; PRECURSORS; NIDDM; RATS AB Background Type 2 diabetes is affected by genetics and environmental factors. We aimed to assess the effect of an in-utero diabetic environment independently of the genetic background for type 2 diabetes. Methods We measured insulin sensitivity and insulin secretion in response to oral and intravenous glucose in 15 non-diabetic adult offspring of mothers with type 1 diabetes (exposed participants) and 16 offspring of type 1 diabetic fathers (controls). No participants had type 1 diabetes-associated autoantibodies. We also measured pancreatic polypeptide, a marker of parasympathetic drive to the pancreas. Findings There was no difference between the groups with respect to percent body fat and insulin sensitivity. Five of the 15 exposed participants, but none of the controls had impaired glucose tolerance (p=0.02). Early insulin secretion after an oral glucose tolerance test was lower in exposed participants than in controls: 8.6 IU/mmol (SD 5.4) in exposed participants with impaired glucose tolerance, 14.2 IU/mmol (6.5) in those with normal glucose tolerance and 17.7 IU/mmol (10.9) in controls (p=0.04). Mean insulin secretion rate during glucose infusion study was 4.7 pmol/kg per min (3.6) in people with impaired glucose tolerance, 5.5 pmol/kg per min (4.5) in exposed participants with normal glucose tolerance and 7.5 pmol/kg per min (6.1) in controls (p<0.0001). The area under the curve of pancreatic polypeptide 120 min after oral glucose ingestion was 1007 (429) in people with impaired glucose tolerance, 2829 (1701) in those with normal glucose tolerance, and 3224 (1352) in controls (p=0.04). Interpretation Exposure to a diabetic environment in utero is associated with increased occurence of impaired glucose tolerance and a defective insulin secretory response in adult offspring, independent of genetic predisposition to type 2 diabetes. This insulin secretory defect could be related to low parasympathetic tone. Epidemiological studies are needed to confirm our observations before therapeutic strategies can be devised. C1 Univ Paris 07, St Louis Hosp, Assistance Pub Hop Paris,Sch Med, Dept Endocrinol & Diabet, Paris, France. Univ Paris 07, St Louis Hosp, Assistance Pub Hop Paris,Sch Med, Clin Invest Ctr,INSERM CIC9504, Paris, France. Univ Paris 07, St Louis Hosp, Assistance Pub Hop Paris,Sch Med, Dept Biostat & Med Informat, Paris, France. Hop St Vincent de Paul, INSERM, U561, F-75674 Paris, France. Ctr Hosp Reg & Univ Poitiers, Dept Endocrinol & Diabet, Poitiers, France. NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. RP Gautier, JF (reprint author), Hop St Louis, INSERM, Dept Endocrinol & Diabet, Ave Claude Vellefaux, F-75010 Paris, France. NR 23 TC 149 Z9 151 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 MAY 31 PY 2003 VL 361 IS 9372 BP 1861 EP 1865 DI 10.1016/S0140-6736(03)13505-2 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 684KL UT WOS:000183205800011 PM 12788573 ER PT J AU Blackstone, C Roberts, RG Seeburg, DP Sheng, M AF Blackstone, C Roberts, RG Seeburg, DP Sheng, M TI Interaction of the deafness-dystonia protein DDP/TIMM8a with the signal transduction adaptor molecule STAM1 SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE mitochondria; intermembrane space; dystonia; deafness; zinc; mitochondrial import; cytokine; JAK/STAT; endosome; apoptosis ID INTERMEMBRANE SPACE; PEPTIDE-1 DDP1; JANUS KINASES; TIM COMPLEXES; CELL-GROWTH; RAT-BRAIN; MITOCHONDRIA; IMPORT; PATHWAYS; FAMILY AB The Mohr-Tranebiaerg-Jensen deafness-dystonia-optic atrophy protein DDP/TIMM8a is translated on cytoplasmic ribosomes but targeted ultimately to the mitochondrial intermembrane space, where it is involved in mitochondrial protein import. STAM I is a cytoplasmic signal-transducing adaptor molecule implicated in cytokine signaling. We report here a direct interaction between DDP and STAM 1, identified by yeast two-hybrid screening and confirmed by co-immunoprecipitation, fusion protein "pull downs," and nuclear redistribution assays. DDP coordinates Zn2+, and Zn2+ was found to stimulate the DDP-STAM1 interaction in vitro. Endogenous STAM1 localizes predominantly to early endosomes, and we found no evidence that STAM1 is imported into mitochondria in vitro. Thus, the DDP-STAM1 interaction likely occurs in the cytoplasm or at the mitochondrial outer membrane. The DDP-STAM1 interaction requires a coiled-coil region in STAM1 that overlaps with the immunoreceptor tyrosine-based activation motif (ITAM), a region previously shown to be important for interaction with Jak2/3 and hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs). Thus, DDP binding may alter the interactions of STAM1 with several cytoplasmic proteins involved in cell signaling and endosomal trafficking. (C) 2003 Elsevier Science (USA). All rights reserved. C1 MIT, RIKEN, Picower Ctr Learning & Memory, Ctr Res Neurosci,Howard Hughes Med Inst, Cambridge, MA 02139 USA. NINDS, Cellular Neurol Unit, NIH, Bethesda, MD 20892 USA. Guys Hosp, Div Med & Mol Genet, GKT, Sch Med, London SE1 9RT, England. RP Sheng, M (reprint author), MIT, RIKEN, Picower Ctr Learning & Memory, Ctr Res Neurosci,Howard Hughes Med Inst, 77 Massachusetts Ave,Room E18-25, Cambridge, MA 02139 USA. EM msheng@mit.edu RI Roberts, Roland/C-3596-2009; OI Roberts, Roland/0000-0001-6636-1579 NR 31 TC 14 Z9 15 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 30 PY 2003 VL 305 IS 2 BP 345 EP 352 DI 10.1016/S0006-291X(03)00767-8 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 681RH UT WOS:000183048800022 PM 12745081 ER PT J AU Prag, G Misra, S Jones, EA Ghirlando, R Davies, BA Horazdovsky, BF Hurley, JH AF Prag, G Misra, S Jones, EA Ghirlando, R Davies, BA Horazdovsky, BF Hurley, JH TI Mechanism of ubiquitin recognition by the CUE domain of Vps9p SO CELL LA English DT Article ID PROTEIN-PROTEIN INTERACTIONS; DAMAGE-INDUCIBLE PROTEINS; UBA DOMAINS; DNA-DAMAGE; ENDOPLASMIC-RETICULUM; BINDS UBIQUITIN; HIV-1 VPR; SURFACE; MOTIF; DEGRADATION AB Coupling of ubiquitin conjugation to ER degradation (CUE) domains are similar to50 amino acid monoubiquitin binding motifs found in proteins of trafficking and ubiquitination pathways. The 2.3 Angstrom structure of the Vps9p-CUE domain is a dimeric domain-swapped variant of the ubiquitin binding UBA domain. The 1.7 Angstrom structure of the CUE:ubiquitin complex shows that one CUE dimer binds one ubiquitin molecule. The bound CUE dimer is kinked relative to the unbound CUE dimer and wraps around ubiquitin. The CUE monomer contains two ubiquitin binding surfaces on opposite faces of the molecule that cannot bind simultaneously to a single ubiquitin molecule. Dimerization of the CUE domain allows both surfaces to contact a single ubiquitin molecule, providing a mechanism for high-affinity binding to monoubiquitin. C1 NIDDKD, Mol Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Mayo Clin & Mayo Fdn, Mayo Clin Canc Ctr, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Dept Biochem & Mol Biol, Rochester, MN 55905 USA. RP Hurley, JH (reprint author), NIDDKD, Mol Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RI Ghirlando, Rodolfo/A-8880-2009; OI Misra, Saurav/0000-0002-1385-8554 FU NIGMS NIH HHS [GM55301] NR 57 TC 154 Z9 157 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD MAY 30 PY 2003 VL 113 IS 5 BP 609 EP 620 DI 10.1016/S0092-8674(03)00364-7 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 687VL UT WOS:000183397600011 PM 12787502 ER PT J AU Huang, LE Bunn, HF AF Huang, LE Bunn, HF TI Hypoxia-inducible factor and its biomedical relevance SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID ENDOTHELIAL GROWTH-FACTOR; TUMOR-SUPPRESSOR PROTEIN; UBIQUITIN-PROTEASOME PATHWAY; MICE PARTIALLY DEFICIENT; PAS DOMAIN PROTEIN; FACTOR 1-ALPHA; TRANSCRIPTION FACTOR; GENE-EXPRESSION; HIF-ALPHA; PROLYL HYDROXYLATION C1 NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Hematol, Boston, MA 02115 USA. RP Huang, LE (reprint author), NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. NR 79 TC 203 Z9 227 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 MAY 30 PY 2003 VL 278 IS 22 BP 19575 EP 19578 DI 10.1074/jbc.R200030200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 682EH UT WOS:000183078000001 PM 12639949 ER PT J AU Stevens, LA Bourgeois, C Bortell, R Moss, J AF Stevens, LA Bourgeois, C Bortell, R Moss, J TI Regulatory role of arginine 204 in the catalytic activity of rat alloantigens ART2a and ART2b SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NICOTINAMIDE ADENINE-DINUCLEOTIDE; AUTO-ADP-RIBOSYLATION; NAD GLYCOHYDROLASE; RT6; RIBOSYLTRANSFERASES; EXPRESSION; MONO(ADP-RIBOSYL)TRANSFERASES; AUTOMODIFICATION; ACTIVATION; IDENTIFY AB ART2a (RT6.1) and ART2b (RT6.2) are NAD glycohydrolases (NADases) that are linked to T lymphocytes by glycosylphosphatidylinositol anchors. Although both mature proteins possess three conserved regions ( I, II, III) that form the NAD-binding site and differ by only ten amino acids, only ART2b is auto-ADP-ribosylated and only ART2a is glycosylated. To investigate the structural basis for these differences, wild-type and mutant ART2a and ART2b were expressed in rat mammary adenocarcinoma (NMU) cells and released with phosphatidylinositol-specific phospholipase C. All mutants were immunoreactive NADases. Arginine 204 (Arg(204)), NH2-terminal to essential glutamate 209 in Region III, is found in ART2b, but not ART2a. Replacement of Arg(204) in ART2b with lysine, tyrosine, or glutamate abolished auto-ADP-ribosylation. Unlike wild-type ART2a, ART2a( Y204R) was auto-ADP-ribosylated. The tryptophan mutant ART2b( R204W) was auto-ADP-ribosylated and exhibited enhanced NADase activity. Incubation with NAD and auto-ADP-ribosylation decreased the NADase activities of wild-type ART2b and ART2b ( R204W), whereas activity of ART2b( R204K), which is not auto-modified, was unchanged by NAD. Facilitation of auto-ADP-ribosylation by tryptophan 204 suggests that the hydrophobic amino acid mimics an ADP-ribosylated arginine. Thus, Arg(204) in ART2b serves as a regulatory switch whose presence is required for additional auto-ADP-ribosylation and regulation of catalytic activity. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. Univ Massachusetts, Med Ctr, Diabet Div, Worcester, MA 01605 USA. RP Stevens, LA (reprint author), NHLBI, Pulm Crit Care Med Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 25 TC 7 Z9 7 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 MAY 30 PY 2003 VL 278 IS 22 BP 19591 EP 19596 DI 10.1074/jbc.M210364200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 682EH UT WOS:000183078000005 PM 12649291 ER PT J AU Marszal, E Danino, D Shrake, A AF Marszal, E Danino, D Shrake, A TI A novel mode of polymerization of alpha(1)-proteinase inhibitor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PLASMINOGEN-ACTIVATOR INHIBITOR-1; ALPHA-1-PROTEINASE INHIBITOR; CIRCULAR-DICHROISM; CRYSTAL-STRUCTURE; CONFORMATIONAL DISEASE; ALPHA-1-ANTITRYPSIN; ALPHA(1)-ANTITRYPSIN; SERPINS; LIVER; DEFICIENCY AB Patients homozygous for the Z mutant form of alpha(1)-proteinase inhibitor (alpha(1)-PI) have an increased risk for the development of liver disease because of the accumulation in hepatocytes of inclusion bodies containing linear polymers of mutant alpha(1)-PI. The most widely accepted model of polymerization proposes that a linear, head-to-tail polymer forms by sequential insertion of the reactive center loop (RCL) of one alpha(1)-PI monomer between the central strands of the A beta-sheet of an adjacent monomer. This model derives primarily from two observations: peptides that are homologous with the RCL insert into the A beta-sheet of alpha(1)-PI monomer and this insertion prevents alpha(1)-PI polymerization. Normal alpha(1)-PI monomer does not spontaneously polymerize; however, here we show that the disulfide-linked dimer of normal alpha(1)-PI spontaneously forms linear polymers in buffer. The monomers within this dimer are joined head-to-head. Thus, the arrangement of monomers in these polymers must be different from that predicted by the loop-A sheet model. Therefore, we propose a new model for alpha(1)-PI polymer. In addition, polymerization of disulfide-linked dimer is not inhibited by the presence of the peptide even though dimer appears to interact with the peptide. Thus, RCL insertion into A beta-sheets may not occur during polymerization of this dimer. C1 US FDA, Ctr Biol Evaluat & Res, Div Hematol, Off Blood Res & Review, Bethesda, MD 20892 USA. NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Shrake, A (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Hematol, Off Blood Res & Review, Bethesda, MD 20892 USA. RI Danino, Dganit/D-6832-2016 OI Danino, Dganit/0000-0002-9782-4940 NR 58 TC 9 Z9 11 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 MAY 30 PY 2003 VL 278 IS 22 BP 19611 EP 19618 DI 10.1074/jbc.M210720200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 682EH UT WOS:000183078000008 PM 12649292 ER PT J AU Chen, F Ma, L Dawson, PA Sinal, CJ Sehayek, E Gonzalez, FJ Breslow, J Ananthanarayanan, M Shneider, BL AF Chen, F Ma, L Dawson, PA Sinal, CJ Sehayek, E Gonzalez, FJ Breslow, J Ananthanarayanan, M Shneider, BL TI Liver receptor homologue-1 mediates species- and cell line-specific bile acid-dependent negative feedback regulation of the apical sodium-dependent bile acid transporter SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ORPHAN NUCLEAR RECEPTOR; BINDING-PROTEIN; SERUM-CHOLESTEROL; MESSENGER-RNA; RAT ILEUM; IDENTIFICATION; INHIBITION; RABBITS; GENE; HYPERCHOLESTEROLEMIA AB Intestinal reclamation of bile salts is mediated in large part by the apical sodium-dependent bile acid transporter (ASBT). The bile acid responsiveness of ASBT is controversial. Bile acid feeding in mice results in decreased expression of ASBT protein and mRNA. Mouse but not rat ASBT promoter activity was repressed in Caco-2, but not IEC-6, cells by chenodeoxycholic acid. A potential liver receptor homologue-1 (LRH-1) cis-acting element was identified in the bile acid-responsive region of the mouse but not rat promoter. The mouse, but not rat, promoter was activated by LRH-1, and this correlated with nuclear protein binding to the mouse but not rat LRH-1 element. The short heterodimer partner diminished the activity of the mouse promoter and could partially offset its activation by LRH-1. Interconversion of the potential LRH-1 cis-elements between the mouse and rat ASBT promoters was associated with an interconversion of LRH-1 and bile acid responsiveness. LRH-1 protein was found in Caco-2 cells and mouse ileum, but not IEC-6 cells or rat ileum. Bile acid response was mediated by the farnesoid X receptor, as shown by the fact that overexpression of a dominant-negative farnesoid X-receptor eliminated the bile acid mediated down-regulation of ASBT. In addition, ASBT expression in farnesoid X receptor null mice was unresponsive to bile acid feeding. In summary cell line- and species-specific negative feedback regulation of ASBT by bile acids is mediated by farnesoid X receptor via small heterodimer partner-dependent repression of LRH-1 activation of the ASBT promoter. C1 Mt Sinai Med Ctr, Mt Sinai Sch Med, New York, NY 10029 USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC 27157 USA. NIH, Bethesda, MD 20892 USA. Rockefeller Univ, New York, NY 10021 USA. RP Shneider, BL (reprint author), Mt Sinai Med Ctr, Mt Sinai Sch Med, Box 1656,1 Gustave L Levy Pl, New York, NY 10029 USA. RI Breslow, Jan/B-7544-2008 FU NIDDK NIH HHS [DK 02076, DK 20632, DK 54165, R01 DK047987] NR 40 TC 135 Z9 139 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 MAY 30 PY 2003 VL 278 IS 22 BP 19909 EP 19916 DI 10.1074/jbc.M207903200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 682EH UT WOS:000183078000045 PM 12456679 ER PT J AU Blackshear, PJ Lai, WS Kennington, EA Brewer, G Wilson, GM Guan, XJ Zhou, P AF Blackshear, PJ Lai, WS Kennington, EA Brewer, G Wilson, GM Guan, XJ Zhou, P TI Characteristics of the interaction of a synthetic human tristetraprolin tandem zinc finger peptide with AU-rich element-containing RNA substrates SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MESSENGER-RNA; DEFICIENCY SYNDROME; PROTEINS; ALPHA; BINDING; DESTABILIZATION; DEADENYLATION; ASSOCIATION; RESONANCES; UBIQUITIN AB Tristetraprolin (TTP) and its two known mammalian family members are tandem CCCH zinc finger proteins that can bind to AU-rich elements (AREs) in cellular mRNAs and destabilize those transcripts, apparently by initiating their deadenylation. Previous studies have shown that the similar to70-amino acid tandem zinc finger domain of TTP is required and sufficient for RNA binding, and that the integrity of both zinc fingers is also required. However, little is known about the kinetics or structure of the peptide-RNA interaction, in part because of difficulties in obtaining soluble recombinant protein or peptides. We characterized the binding of a synthetic 73-amino acid peptide from human TTP to the tumor necrosis factor (TNF) ARE by gel mobility shift analyses and fluorescence anisotropy experiments. Both types of studies yielded a peptide-RNA dissociation constant of similar to10 nM. Surprisingly, we found that the "footprint" from the TNF ARE required for peptide binding was only similar to9 bases and that two molecules of peptide could bind to probes containing as little as 19 bases. An identical recombinant peptide exhibited gel shift characteristics similar to those of the synthetic peptide. NMR analysis of the N-15-labeled recombinant peptide suggested that its first zinc finger was structured in solution but that the second was not. The titration of oligonucleotides representing 17, 13, and even 9 bases of the TNF ARE caused an essentially identical, dramatic shift of existing resonances, and the appearance of new resonances in the peptide spectra, so that all amino acids could be assigned. These data suggest that this TTP peptide-RNA complex is structured in solution and might be amenable to NMR structure determination. C1 NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. NIEHS, Off Clin Res, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Microbiol Mol Genet & Immunol, Piscataway, NJ 08854 USA. RP NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, A2-05,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM black009@niehs.nih.gov OI Zhou, Pei/0000-0002-7823-3416 FU NCI NIH HHS [R01-CA52443] NR 26 TC 80 Z9 81 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 MAY 30 PY 2003 VL 278 IS 22 BP 19947 EP 19955 DI 10.1074/jbc.M301290200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 682EH UT WOS:000183078000050 PM 12639954 ER PT J AU Geiszt, M Lekstrom, K Witta, J Leto, TL AF Geiszt, M Lekstrom, K Witta, J Leto, TL TI Proteins homologous to p47(phox) and p67(phox) support superoxide production by NAD(P)H oxidase 1 in colon epithelial cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHAGOCYTE NADPH OXIDASE; CHRONIC GRANULOMATOUS-DISEASE; RESPIRATORY BURST OXIDASE; FLAVOCYTOCHROME B(558); ACTIVATION DOMAIN; PHOSPHORYLATION; TRANSFORMATION; IDENTIFICATION; COMPONENTS; CLONING AB Superoxide production by phagocytes involves activation of a multi-component NADPH oxidase. Recently, several homologues of the catalytic component of the phagocyte oxidase, gp91(phox), were identified in various tissues. Here we describe two proteins, p41 and p51, with significant homology to two cytosolic components of the phagocytic oxidase, p47(phox) and p67(phox). Like p47(phox), p41 contains an amino-terminal Phox homology domain, two SH3 domains, and a conserved carboxyl-terminal, proline-rich motif. Similarly, p51 is homologous to p67(phox), containing four amino-terminal tetratricopeptide repeats, a conserved "activation domain" motif, a PB1 domain, and a carboxyl-terminal SH3 domain. The highest levels of p41 transcript are detected in the colon and in other gastrointestinal tissues that express Nox1, the predominant gp91(phox) homologue in these tissues. In contrast, the p51 transcript showed a more widespread expression pattern, suggesting that it may support other tissue-specific oxidases. Mouse colon in situ hybridization detected both transcripts in the epithelial cells of colon crypts. Heterologous co-expression of p41 and p51 significantly enhances the superoxide-generating activity of Nox1-expressing cells; thus, p41 and p51 appear to be novel regulators of Nox1. These proteins also support the activity of gp91(phox), albeit at much lower levels than the cytosolic phox counterparts. Our results suggest colon epithelial cells contain a multi-component NAD(P) H oxidase with a molecular architecture similar to the phagocytic oxidase. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Semmelweis Univ, Fac Med, Dept Physiol, H-1444 Budapest, Hungary. Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD 20814 USA. RP Leto, TL (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Rm 11N106, Bethesda, MD 20892 USA. NR 28 TC 209 Z9 218 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 MAY 30 PY 2003 VL 278 IS 22 BP 20006 EP 20012 DI 10.1074/jbc.M301289200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 682EH UT WOS:000183078000057 PM 12657628 ER PT J AU Lin, ZC Zhang, PW Zhu, XG Melgari, JM Huff, R Spieldoch, RL Uhl, GR AF Lin, ZC Zhang, PW Zhu, XG Melgari, JM Huff, R Spieldoch, RL Uhl, GR TI Phosphatidylinositol 3-kinase, protein kinase C, and MEK1/2 kinase regulation of dopamine transporters (DAT) require N-terminal DAT phosphoacceptor sites SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID COCAINE ANALOG RECOGNITION; FUNCTIONAL REGULATION; PHORBOL ESTERS; STRIATAL SYNAPTOSOMES; RAT STRIATUM; PHOSPHORYLATION; EXPRESSION; RECEPTORS; CLONING; CELLS AB The dopamine transporter (DAT) modulates dopamine neurotransmission and is a primary target for psychostimulant influences on locomotion and reward. Selective DAT expression by dopaminergic neurons has led to use of cocaine analog DAT radioligands to assess rates of progression of dopamine neuronal degeneration in Parkinson's disease. We have documented that DAT is a phosphoprotein that is regulated by phosphorylation through pathways that include protein kinase C cascades. We now extend this work using drugs selective for phosphatidylinositol 3-kinase (PI3K), protein kinase C, MEK1/2, p38 kinase, and Ca2+/calmodulin kinase II. We compare the drug effects on wild type DAT to the effects on 20 DAT mutants and a DAT deletion. PI3K and MEK1/2 modulators exert strong effects on DAT expression patterns and dopamine uptake V-max. PKC principally modulates V-max. Neither p38 nor Ca2+/calmodulin kinase II agents exert significant influences on wild type DAT. Several mutants and a DAT with an N-terminal deletion display alterations that interact with the effects of kinase modulators, especially S7A for PKC effects; T62A, S581A, and T612A for PI3K effects; and S12A and T595A mutants for MEK1/2 effects. P-32-Labeling studies confirm several of these effects of kinase pathway modulators on DAT phosphorylation. DAT expression and activities can be regulated by kinase cascades that require phosphoacceptor sites most concentrated in its N terminus. These results have a number of implications for DAT regulation and mandate caution in using DAT radioligand binding to infer changes in dopaminergic neuronal integrity after treatments that alter activities of these kinase pathways. C1 NIDA, Mol Neurobiol Branch, IRP, NIH, Baltimore, MD 21224 USA. RP Uhl, GR (reprint author), NIDA, Mol Neurobiol Branch, IRP, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 44 TC 44 Z9 45 U1 2 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 MAY 30 PY 2003 VL 278 IS 22 BP 20162 EP 20170 DI 10.1074/jbc.M209584200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 682EH UT WOS:000183078000075 PM 12660249 ER PT J AU Gonzalez-Sapienza, G Cachau, RE AF Gonzalez-Sapienza, G Cachau, RE TI Identification of critical residues of an immunodominant region of Echinococcus granulosus antigen B SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PEPTIDES; PHAGE; LIGANDS AB Immune evasion strategies often shape the immunogenicity of parasite components. We recently found that the N-terminal extension of the major subunit of Echinococcus granulosus antigen B (AgB), the causative agent of hydatid disease, concentrates the immunoreactive B cell epitopes of the native molecule. The nature of this immunodominance was analyzed using four monoclonal antibodies (mAbs) defining overlapping epitopes in this region of the AgB molecule. The minimal epitope requirements of these mAbs were determined using phage display peptide libraries. The consensus sequences isolated with the mAbs, and alanine replacement analysis with synthetic peptides mapped the relevant molecular contacts within a short stretch corresponding to residues 17-24 of the AgB major subunit. Substitution of two critical residues within this stretch produced a dramatic loss of antigenicity, as determined by using patient sera. The circular dichroism spectra of the antigen, together with the distribution of the contact residues, suggest that this region adopts an amphipathic alpha-helix structure that clusters the contact residues on its polar side. To provide further insight in the interpretation of the structure activity relationships for this immunoreactive region of E. granulosus AgB, we developed a model for the N-terminal extension of the AgB major subunit, which helps to rationalize our data. C1 Univ Republica, Fac Quim, Catedra Inmunol, Inst Higiene, Montevideo 11600, Uruguay. NCI, Adv Biomed Comp Ctr, NIH, Sci Applicat Int Corp, Frederick, MD 21702 USA. RP Gonzalez-Sapienza, G (reprint author), Univ Republica, Fac Quim, Catedra Inmunol, Inst Higiene, Av A Navarro 3051, Montevideo 11600, Uruguay. FU NCI NIH HHS [N01-CO-12400] NR 22 TC 30 Z9 36 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 MAY 30 PY 2003 VL 278 IS 22 BP 20179 EP 20184 DI 10.1074/jbc.M212724200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 682EH UT WOS:000183078000077 PM 12660242 ER PT J AU Wright, G Higgin, JJ Raines, RT Steenbergen, C Murphy, E AF Wright, G Higgin, JJ Raines, RT Steenbergen, C Murphy, E TI Activation of the prolyl hydroxylase oxygen-sensor results in induction of GLUT1, heme oxygenase-1, and nitric-oxide synthase proteins and confers protection from metabolic inhibition to cardiomyocytes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HYPOXIA-INDUCIBLE FACTOR; NECROSIS-FACTOR-ALPHA; CARDIAC MYOCYTES; HIF-ALPHA; FACTOR-I; EXPRESSION; GENE; 4-HYDROXYLASE; MECHANISM; COLLAGEN AB Recently an oxygen-sensing/transducing mechanism has been identified as a family of O-2-dependent prolyl hydroxylase domain-containing enzymes (PHD). In normoxia, PHD hydroxylates a specific proline residue that directs the degradation of constitutively synthesized hypoxia-inducible factor-1alpha. During hypoxia, the cessation of hydroxylation of this proline results in less degradation and thus increases hypoxia-inducible factor-1alpha protein levels. In this study we have examined the consequences of activating the PHD oxygen-sensing pathway in cultured neonatal myocytes using ethyl-3,4 dihydroxybenzoate and dimethyloxalylglycine, inhibitors that, similar to hypoxia, inhibit this family of O-2-dependent PHD enzymes. Increased glucose uptake and enhanced glycolytic metabolism are classical cellular responses to hypoxia. Ethyl-3,4 dihydroxybenzoate treatment of cardiomyocyte cultures for 24 h increased [H-3] deoxy-4-glucose uptake concurrent with an induction of GLUT1 protein. In addition, ethyl-3,4 dihydroxybenzoate, dimethyloxalylglycine, and hypoxia treatments were found to induce protein levels of nitricoxide synthase-2 and heme oxygenase-1, two important cardioregulatory proteins whose expression in response to hypoxic conditions is poorly understood. In conjunction with these changes in gene expression, activation of the PHD oxygen-sensing mechanism was found to preserve myocyte viability in the face of metabolic inhibition with cyanide and 2-deoxyglucose. These results point to a key role for the PHD pathway in the phenotypic changes that are observed in a hypoxic myocyte and may suggest a strategy to pharmacologically induce protection in heart. C1 NIEHS, Lab Signal Transduct, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. Duke Univ, Sch Med, Dept Pathol, Durham, NC 27710 USA. Univ Wisconsin, Dept Chem, Madison, WI 53706 USA. Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. RP Murphy, E (reprint author), NIEHS, Lab Signal Transduct, Dept Hlth & Human Serv, NIH, 111 Alexander Dr,Bldg 101,F207, Res Triangle Pk, NC 27709 USA. RI Raines, Ronald/A-5009-2013 OI Raines, Ronald/0000-0001-7164-1719 FU NHLBI NIH HHS [R01 HL039752, HL39752]; NIAMS NIH HHS [AR44276] NR 34 TC 48 Z9 49 U1 0 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 MAY 30 PY 2003 VL 278 IS 22 BP 20235 EP 20239 DI 10.1074/jbc.M301391200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 682EH UT WOS:000183078000085 PM 12649278 ER PT J AU Louis, JM Nesheiwat, I Chang, LC Clore, GM Bewley, CA AF Louis, JM Nesheiwat, I Chang, LC Clore, GM Bewley, CA TI Covalent trimers of the internal N-terminal trimeric coiled-coil of gp41 and antibodies directed against them are potent inhibitors of HIV envelope-mediated cell fusion SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; PEPTIDE INHIBITOR; NEUTRALIZING ANTIBODIES; ACTIVE CONFORMATION; ANTIVIRAL ACTIVITY; ATOMIC-STRUCTURE; SIV GP41; ENTRY; GLYCOPROTEIN; GP120 AB We have engineered two soluble, covalently linked, trimeric polypeptides, N35(CCG)-N13 and N34(CCG) comprising only the internal trimeric coiled-coil of the ectodomain of HIV-1 gp41. Both trimers inhibit human immunodeficiency virus, type 1 ( HIV-1) envelope (Env)mediated cell fusion at nanomolar concentrations by targeting the exposed C-terminal region of the gp41 ectodomain in the prehairpin intermediate state. The IC50 values for N35(CCG)-N13 and N34(CCG) are similar to15 and similar to95 nM, respectively, in a quantitative vaccinia virus-based reporter gene assay for HIV-1 Env-mediated cell fusion using Env from the T cell tropic strain LAV. Polyclonal antibodies were raised against N35(CCG)-N13 and a tightly binding fraction of anti-N35(CCG)-N13 inhibits T cell and macrophage tropic HIV-1 Env- mediated cell fusion with respective IC50 values of similar to0.5 and similar to1.5 mug/ml at 37 degreesC. The tightly binding anti-N35(CCG)-N13 antibody fraction targets the exposed internal trimeric coiled-coil in the prehairpin intermediate state of gp41 in a manner analogous to peptides derived from the C region of the gp41 ectodomain. The potency of the tightly binding anti-N35(CCG)-N13 antibody fraction in the fusion assay is comparable with that of the broadly neutralizing monoclonal antibody 2G12. These results indicate that N35(CCG)-N13 is a potential anti-HIV therapeutic agent and represents a suitable immunogen for the generation of neutralizing monoclonal antibodies targeted to the internal trimeric coiled-coil of gp41. The data on the tightly binding anti-N35(CCG)-N13 antibody fraction demonstrate that the internal trimeric coiled-coil of gp41 in the prehairpin intermediate state is accessible to antibodies and that access is not restricted by either antibody size or the presence of a kinetic barrier. C1 NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bewley, CA (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bldg 8,Rm 1A-02, Bethesda, MD 20892 USA. RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 NR 37 TC 88 Z9 91 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 MAY 30 PY 2003 VL 278 IS 22 BP 20278 EP 20285 DI 10.1074/jbc.M301627200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 682EH UT WOS:000183078000090 PM 12654905 ER PT J AU Furuta, T Takemura, H Liao, ZY Aune, GJ Redon, C Sedelnikova, OA Pilch, DR Rogakou, EP Celeste, A Chen, HT Nussenzweig, A Aladjem, MI Bonner, WM Pommier, Y AF Furuta, T Takemura, H Liao, ZY Aune, GJ Redon, C Sedelnikova, OA Pilch, DR Rogakou, EP Celeste, A Chen, HT Nussenzweig, A Aladjem, MI Bonner, WM Pommier, Y TI Phosphorylation of histone H2AX and activation of Mre11, Rad50, and Nbs1 in response to replication-dependent DNA double-strand breaks induced by mammalian DNA topoisomerase I cleavage complexes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL-CYCLE CHECKPOINTS; S-PHASE; PROTEIN-KINASE; 7-HYDROXYSTAUROSPORINE UCN-01; GENOMIC INSTABILITY; DAMAGE; REPAIR; CYTOTOXICITY; CAMPTOTHECIN; RADIATION AB DNA double-strand breaks originating from diverse causes in eukaryotic cells are accompanied by the formation of phosphorylated H2AX (gammaH2AX) foci. Here we show that gammaH2AX formation is also a cellular response to topoisomerase I cleavage complexes known to induce DNA double-strand breaks during replication. In HCT116 human carcinoma cells exposed to the topoisomerase I inhibitor camptothecin, the resulting gammaH2AX formation can be prevented with the phosphatidylinositol 3-OH kinase-related kinase inhibitor wortmannin; however, in contrast to ionizing radiation, only camptothecin-induced gammaH2AX formation can be prevented with the DNA replication inhibitor aphidicolin and enhanced with the checkpoint abrogator 7-hydroxystaurosporine. This gammaH2AX formation is suppressed in ATR ( ataxia telangiectasia and Rad3-related) deficient cells and markedly decreased in DNA-dependent protein kinase-deficient cells but is not abrogated in ataxia telangiectasia cells, indicating that ATR and DNA-dependent protein kinase are the kinases primarily involved in gammaH2AX formation at the sites of replication-mediated DNA double-strand breaks. Mre11- and Nbs1-deficient cells are still able to form gammaH2AX. However, H2AX-/- mouse embryonic fibroblasts exposed to camptothecin fail to form Mre11, Rad50, and Nbs1 foci and are hypersensitive to camptothecin. These results demonstrate a conserved gammaH2AX response for double-strand breaks induced by replication fork collision. gammaH2AX foci are required for recruiting repair and checkpoint protein complexes to the replication break sites. C1 NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Bldg 37,Rm 5068A, Bethesda, MD 20892 USA. RI Aune, Gregory/I-5895-2015; Aladjem, Mirit/G-2169-2010 OI Aune, Gregory/0000-0002-2750-6461; Aladjem, Mirit/0000-0002-1875-3110 NR 71 TC 311 Z9 326 U1 1 U2 13 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 MAY 30 PY 2003 VL 278 IS 22 BP 20303 EP 20312 DI 10.1074/jbc.M300198200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 682EH UT WOS:000183078000093 PM 12660252 ER PT J AU Lowry, DF Hoyt, DW Khazi, FA Bagu, J Lindsey, AG Wilson, DM AF Lowry, DF Hoyt, DW Khazi, FA Bagu, J Lindsey, AG Wilson, DM TI Investigation of the role of the histidine-aspartate pair in the human exonuclease III-like abasic endonuclease, Ape1 SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE Ape1; His-Asp pair; NMR; DNA repair; abasic ID HUMAN APURINIC/APYRIMIDINIC ENDONUCLEASE; NUCLEAR-MAGNETIC-RESONANCE; BARRIER HYDROGEN-BONDS; ACTIVE-SITE; DNA-REPAIR; MAJOR HUMAN; CRYSTAL-STRUCTURE; CATALYTIC-TRIAD; CHYMOTRYPSIN; RECOGNITION AB Hydrogen bonded histidine-aspartate (His-Asp) pairs are critical constituents in several key enzymatic reactions. To date, the role that these pairs play in catalysis is best understood in serine and trypsin-like proteases, where structural and biochemical NMR studies have revealed important pK(a) values and hydrogen bonding patterns within the catalytic pocket. However, the role of the His-Asp pair in metal-assisted catalysis is less clear. Here, we apply liquid-state NMR to investigate the role of a. critical histidine residue of apurinic endonuclease 1 (Ape1), a human DNA repair enzyme that cleaves adjacent to abasic sites in DNA using one or more divalent cations and an active-site His-Asp pair. The results of these studies suggest that the Ape1 His-Asp pair does not function as either a general base catalyst or a metal ligand. Rather, the pair likely stabilizes the pentavalent transition state necessary for phospho-transfer. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 Pacific NW Natl Lab, Environm Mol Sci Lab, Richland, WA 99352 USA. NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. RP Lowry, DF (reprint author), Pacific NW Natl Lab, Environm Mol Sci Lab, POB 999, Richland, WA 99352 USA. RI Hoyt, David/H-6295-2013 FU NCI NIH HHS [CA79056] NR 27 TC 22 Z9 24 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 MAY 30 PY 2003 VL 329 IS 2 BP 311 EP 322 DI 10.1016/S0022-2836(03)00382-6 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 684NT UT WOS:000183214000010 PM 12758078 ER PT J AU Gopich, IV Szabo, A AF Gopich, IV Szabo, A TI Single-macromolecule fluorescence resonance energy transfer and free-energy profiles SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID PROTEIN; DYNAMICS; SPECTROSCOPY AB What is the dynamical and structural information contained in single-molecule fluorescence resonance energy, transfer (FRET) experiments where the donor and acceptor photons emitted during a fixed time window T are counted? To answer this question, a theory is developed to obtain the probability distribution of the energy-transfer efficiency obtained from trajectories of duration T. The efficiency is an explicit function of the distance between a fluorescent donor and acceptor attached to the macromolecule; thus, the efficiency can formally be converted to a distance. The resulting distance probability distribution or, equivalently, the potential of mean force or free-energy profile, however, depends on the size of the observation time window T. Illustrative calculations are presented for a random coil polymer and for a protein that exhibits two-state folding kinetics. It is found that the apparent free-energy profiles look physically reasonable, even for long observation times during which significant fluctuations occur. Such, profiles are, however, deceptive unless the observation time is approximately an order of magnitude smaller than the relaxation time of the donor-acceptor distance. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Szabo, A (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. RI Szabo, Attila/H-3867-2012 NR 18 TC 69 Z9 70 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD MAY 29 PY 2003 VL 107 IS 21 BP 5058 EP 5063 DI 10.1021/jp027481o PG 6 WC Chemistry, Physical SC Chemistry GA 681ZT UT WOS:000183066000025 ER PT J AU Baptista, MJ O'Farrell, C Hardy, J Cookson, MR AF Baptista, MJ O'Farrell, C Hardy, J Cookson, MR TI Microarray analysis reveals induction of heat shock proteins mRNAs by the torsion dystonia protein, TorsinA SO NEUROSCIENCE LETTERS LA English DT Article DE dystonia; torsinA; dystonia gene; microarray analysis; quantitative reverse transcription-polymerase chain reaction; heat shock proteins ID MUTANT TORSINA; GENE; FORMS; CELLS AB An in-frame deletion (DeltaE302/303) in the TorsinA gene has been demonstrated to be responsible for primary torsion dystonia, showing dominant inheritance with reduced penetrance. The DeltaE302/303 torsinA mutation forms intracellular ER derived inclusions in a variety of cultured cells, which may suggest that the mutations might evoke ER stress. We used microarray analysis of human derived cell lines expressing the DeltaE302/303 torsinA mutation in order to reveal alterations in gene expression in the hope of identifying genetic modifying loci or novel markers for disease pathogenesis. We identified transcriptional changes in multiple members of the heat shock protein family of genes, confirmed by reverse transcription-polymerase chain reaction, which could be indicative of ER stress. However, both wild type and mutant torsinA were affected to a similar extent, suggesting that this is not related to either disease state or the formation of ER-derived inclusions. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved. C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Mayo Clin, Neurogenet Lab, Jacksonville, FL 32224 USA. RP Baptista, MJ (reprint author), NIA, Neurogenet Lab, NIH, 9000 Rockville Pike,Bldg 10,Room 6C103,MSC1589, Bethesda, MD 20892 USA. RI Hardy, John/C-2451-2009 NR 15 TC 7 Z9 7 U1 0 U2 0 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 MAY 29 PY 2003 VL 343 IS 1 BP 5 EP 8 DI 10.1016/S0304-3940(03)00302-1 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 683CE UT WOS:000183128900002 PM 12749984 ER PT J AU Mayo, DJ AF Mayo, DJ TI Readability of informed-consent forms SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NIMH, Bethesda, MD 20892 USA. RP Mayo, DJ (reprint author), NIMH, Bethesda, MD 20892 USA. NR 4 TC 3 Z9 3 U1 0 U2 0 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 MAY 29 PY 2003 VL 348 IS 22 BP 2262 EP 2263 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 683EK UT WOS:000183134700035 PM 12774823 ER PT J AU Proia, RL AF Proia, RL TI Glycosphingolipid functions: insights from engineered mouse models SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES LA English DT Article; Proceedings Paper CT Discussion Meeting of the Royal-Society CY MAR 13-14, 2002 CL ROYAL SOC, LONDON, ENGLAND HO ROYAL SOC DE gangliosides; glycosphingolipids; knockout mice ID MYELIN-ASSOCIATED GLYCOPROTEIN; ADHESION MOLECULE TAG-1; COMPLEX GANGLIOSIDES; LIPID RAFTS; MICE; SIGNAL; REGENERATION; INHIBITOR; DOMAINS; EXHIBIT AB Glycosphingolipids are remarkable for their structural complexity and their distinctive patterns that mark different tissues and stages of development. The physiological functions of glycosphingolipids are likely to be profound and are only beginning to emerge. Much of this new information is due to the study of mutant mice lacking specific sets of glycosphingolipids, the topic of this review. C1 NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Proia, RL (reprint author), NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RI Proia, Richard/A-7908-2012 NR 29 TC 56 Z9 57 U1 0 U2 0 PU ROYAL SOC LONDON PI LONDON PA 6 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T ROY SOC B JI Philos. Trans. R. Soc. Lond. Ser. B-Biol. Sci. PD MAY 29 PY 2003 VL 358 IS 1433 BP 879 EP 883 DI 10.1098/rstb.2003.1268 PG 5 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 687WY UT WOS:000183401000006 PM 12803921 ER PT J AU Brady, RO AF Brady, RO TI Enzyme replacement therapy: conception, chaos and culmination SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES LA English DT Article; Proceedings Paper CT Discussion Meeting of the Royal-Society CY MAR 13-14, 2002 CL ROYAL SOC, LONDON, ENGLAND HO ROYAL SOC DE lipid storage disorders; enzyme replacement; benefits to patients ID TYPE-1 GAUCHER-DISEASE; PURIFIED GLUCOCEREBROSIDASE; ALPHA-GALACTOSIDASE; FABRYS-DISEASE; DEFICIENCY; EFFICACY; INFUSION; STORAGE; TISSUE; TRIAL AB Soon after the enzymatic defects in Gaucher disease and in Niemann-Pick disease were discovered, enzyme replacement or enzyme supplementation was proposed as specific treatment for patients with these and related metabolic storage disorders. While relatively straightforward in concept, successful implementation of this approach required many years of intensive effort to bring it to fruition. Procedures were eventually developed to produce sufficient quantities of the requisite enzymes for clinical trials and to target therapeutic enzymes to lipid-storing cells. These achievements led to the development of effective enzyme replacement therapy for patients with Gaucher disease and for Fabry disease. These demonstrations provide strong incentive for the application of this strategy for the treatment of many human disorders of metabolism. C1 NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Brady, RO (reprint author), NINDS, Dev & Metab Neurol Branch, NIH, 9000 Rockville Pike,Bldg 10,Rm 3D04, Bethesda, MD 20892 USA. NR 45 TC 39 Z9 41 U1 1 U2 1 PU ROYAL SOC LONDON PI LONDON PA 6 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T ROY SOC B JI Philos. Trans. R. Soc. Lond. Ser. B-Biol. Sci. PD MAY 29 PY 2003 VL 358 IS 1433 BP 915 EP 919 DI 10.1098/rstb.2003.1269 PG 5 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 687WY UT WOS:000183401000010 PM 12803925 ER PT J AU Hong, IS Kim, YK Choi, WS Seo, DW Yoon, JW Han, JW Lee, HY Lee, HW AF Hong, IS Kim, YK Choi, WS Seo, DW Yoon, JW Han, JW Lee, HY Lee, HW TI Purification and characterization of nitric oxide synthase from Staphylococcus aureus SO FEMS MICROBIOLOGY LETTERS LA English DT Article DE nitric oxide synthase; purification; Staphylococcus aureus ID COMPLETE GENOME SEQUENCE; BACILLUS-SUBTILIS; DEINOCOCCUS-RADIODURANS; L-ARGININE; IDENTIFICATION; PROTEIN; CLONING AB We previously reported the presence of nitric oxide synthase (NOS) in Staphylococcus aureus ATCC6538P whose activity was induced by methanol. In the present study, the methanol-induced NOS was purified 900-fold from S. aureus by means of Mono Q ion exchange column, 2',5'-ADP-agarose affinity column, and Superdex 200HR gel permeation column chromatography. The purified bacterial NOS showed two protein bands with 67 and 64 kDa molecular mass on SDS-PAGE. However, the molecular mass of the NOS was 135 kDa on Superdex 200HR gel permeation column chromatography, indicating that the native enzyme exists as a heterodimer. This bacterial NOS had K-m value of 13.4 X 10(-6) M for L-arginine and V-max of 35.3 nmol min(-1) mg(-1) protein. In addition, reduced nicotinamide adenine dinucleotide phosphate, flavin adenine dinucleotide, flavin mononucleotide, tetrahydrobiopterin, calmodulin and Ca2+ were required as cofactors in the conversion Of L-arginine to L-citrulline, and NOS inhibitors selectively inhibited the activity of the purified NOS. (C) 2003 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved. C1 Sungkyunkwan Univ, Dept Pharm, Coll Pharm, Suwon 440746, South Korea. Konkuk Univ, Dept Immunol, Coll Med, Chungcheongbuk Do 380701, South Korea. NCI, Extracellular Matrix Pathol Sect, Pathol Lab, Div Clin Sci,NIH, Bethesda, MD 20892 USA. Konyang Univ, Dept Pharmacol, Coll Med, Nonsan 320711, South Korea. RP Lee, HW (reprint author), Sungkyunkwan Univ, Dept Pharm, Coll Pharm, Suwon 440746, South Korea. EM hylee@skku.ac.kr OI Seo, Dong-Wan/0000-0003-4971-834X NR 24 TC 21 Z9 24 U1 2 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1097 J9 FEMS MICROBIOL LETT JI FEMS Microbiol. Lett. PD MAY 28 PY 2003 VL 222 IS 2 BP 177 EP 182 DI 10.1016/S0378-1097(03)00254-4 PG 6 WC Microbiology SC Microbiology GA 685AR UT WOS:000183239100004 PM 12770704 ER PT J AU Jencks, SF Huff, ED Cuerdon, T AF Jencks, SF Huff, ED Cuerdon, T TI Measuring improvement in quality of care - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 Ctr Medicare & Med Serv, Off Clin Stand & Qual, Baltimore, MD USA. Ctr Medicare & Med Serv, Div Clin Stand & Qual Care, Boston, MA USA. NIMH, Hlth & Behav Sci Res Branch, Bethesda, MD 20892 USA. RP Jencks, SF (reprint author), Ctr Medicare & Med Serv, Off Clin Stand & Qual, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 1 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 MAY 28 PY 2003 VL 289 IS 20 BP 2647 EP 2647 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 682DG UT WOS:000183075600020 ER PT J AU Penzak, SR Acosta, EP Turner, M Tavel, JA Masur, H AF Penzak, SR Acosta, EP Turner, M Tavel, JA Masur, H TI Analysis of generic nevirapine products in developing countries SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NIH, Warren G Magnuson Clin Ctr, Dept Pharm, Bethesda, MD 20892 USA. Univ Alabama, Div Clin Pharmacol, Birmingham, AL 35294 USA. NIAID, Bethesda, MD 20892 USA. RP Penzak, SR (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Pharm, Bethesda, MD 20892 USA. NR 4 TC 19 Z9 19 U1 0 U2 0 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 MAY 28 PY 2003 VL 289 IS 20 BP 2648 EP 2649 DI 10.1001/jama.289.20.2648-c PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 682DG UT WOS:000183075600023 PM 12771111 ER PT J AU Wassertheil-Smoller, S Hendrix, SL Limacher, M Heiss, G Kooperberg, C Baird, A Kotchen, T Curb, JD Black, H Rossouw, JE Aragaki, A Safford, M Stein, E Laowattana, S Mysiw, WJ AF Wassertheil-Smoller, S Hendrix, SL Limacher, M Heiss, G Kooperberg, C Baird, A Kotchen, T Curb, JD Black, H Rossouw, JE Aragaki, A Safford, M Stein, E Laowattana, S Mysiw, WJ CA WHI Investigators TI Effect of estrogen plus progestin on stroke in postmenopausal women - The Women's Health Initiative: A randomized trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HORMONE REPLACEMENT THERAPY; C-REACTIVE PROTEIN; DENSITY LIPOPROTEIN CHOLESTEROL; CAROTID-ARTERY STENOSIS; ISCHEMIC STROKE; RISK-FACTORS; CARDIOVASCULAR-DISEASE; CEREBRAL INFARCTION; CIGARETTE-SMOKING; CLINICAL-TRIAL AB Context The Women's Health Initiative (WHI) trial of estrogen plus progestin was stopped early because of adverse effects, including an increased risk of stroke in the estrogen plus progestin group. Objective To assess the effect of estrogen plus progestin on ischemic and hemorrhagic stroke and in subgroups, and to determine whether the effect of estrogen plus progestin was modified by baseline levels of blood biomarkers. Design Multicenter double-blind, placebo-controlled, randomized clinical trial involving 16608 women aged 50 through 79 years with an average follow-up of 5.6 years. Baseline levels of blood-based markers of inflammation, thrombosis, and lipid levels were measured in the first 140 centrally confirmed stroke cases and 513 controls. Interventions Participants received 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate (n=8506) or placebo (n=8102). Main Outcome Measures Overall strokes and stroke subtype and severity were centrally adjudicated by stroke neurologists. Results One hundred fifty-one patients (1.8%) in the estrogen plus progestin and 107 (1.3%) in the placebo groups had strokes. Overall 79.8% of strokes were ischemic. For combined ischemic and hemorrhagic strokes, the intention-to-treat hazard ratio (HR) for estrogen plus progestin vs placebo was 1.31 (95% confidence interval [CI], 1.02-1.68); with adjustment for adherence, the HR was 1.50 (95% CI, 1.08-2.08). The HR for ischemic stroke was 1.44 (95% CI, 1.09-1.90) and for hemorrhagic stroke, 0.82 (95% CI, 0.43-1.56). Point estimates of the HRs indicate that excess risk of all stroke was apparent in all age groups, in all categories of baseline stroke risk, and in women with and without hypertension, prior history of cardiovascular disease, use of hormones, statins, or aspirin. Other risk factors for stroke, including smoking, blood pressure, diabetes, lower use of vitamin C supplements, blood-based biomarkers of inflammation, higher white blood cell count, and higher hematocrit levels did not modify the effect of estrogen plus progestin on stroke risk. Conclusions Estrogen plus progestin increases the risk of ischemic stroke in generally healthy postmenopausal women. Excess risk for all strokes attributed to estrogen plus progestin appeared to be present in all subgroups of women examined. C1 Albert Einstein Coll Med, Dept Epidemiol & Social Med, Bronx, NY 10461 USA. Wayne State Univ, WHI Clin Ctr, Detroit, MI USA. Univ Florida, WHI Clin Ctr, Gainesville, FL USA. Univ N Carolina, Sch Med & Publ Hlth, Durham, NC USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. NINDS, Stroke Neurosci Unit, Bethesda, MD 20892 USA. Med Coll Wisconsin, Milwaukee, WI 53226 USA. Womens Hlth Hawaii, Honolulu, HI USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. NHLBI, Bethesda, MD 20892 USA. Univ Med & Dent New Jersey, Newark, NJ 07103 USA. Med Res Labs, Highland Hts, KY USA. Georgetown Washington Univ, Washington, DC USA. Ohio State Univ, Columbus, OH 43210 USA. RP Wassertheil-Smoller, S (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Social Med, 1300 Morris Pk Ave,Room 1312 Belfer, Bronx, NY 10461 USA. RI Mysiw, Walter/E-3724-2011 NR 50 TC 619 Z9 633 U1 2 U2 10 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 MAY 28 PY 2003 VL 289 IS 20 BP 2673 EP 2684 DI 10.1001/jama.289.20.2673 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 682DG UT WOS:000183075600026 PM 12771114 ER PT J AU Eastham, JA Riedel, E Scardino, PT Shike, M Fleisher, M Schatzkin, A Lanza, E Latkany, L Begg, CB AF Eastham, JA Riedel, E Scardino, PT Shike, M Fleisher, M Schatzkin, A Lanza, E Latkany, L Begg, CB CA Poly Prevention Trial Study Grp TI Variation of serum prostate-specific antigen levels - An evaluation of year-to-year fluctuations SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID MULTICENTER CLINICAL-TRIAL; DIGITAL RECTAL EXAMINATION; HIGH-FIBER DIET; RADICAL PROSTATECTOMY; BIOLOGICAL VARIATION; CANCER MORTALITY; RANDOMIZED TRIAL; STAGE T1C; LOW-FAT; MEN AB Context Serum prostate-specific antigen (PSA) testing is frequently used in early detection programs for prostate cancer. While PSA testing has resulted in an increase in prostate cancer detection, its routine use has been questioned because of a lack of specificity. Objective To determine whether year-to-year fluctuations in PSA levels are due to natural variation and render a single PSA test result unreliable. Design, Setting, and Participants Retrospective analysis of an unscreened population of 972 men (median age, 62 years) participating in the Polyp Prevention Trial (1991-1998). Five consecutive blood samples were obtained during a 4-year period and were assessed for total and free PSA levels. Main Outcome Measure Abnormal PSA test result based on a PSA level higher than 4 ng/mL; a PSA level higher than 2.5 ng/mL; a PSA level above the age-specific cutoff; a PSA level in the range of 4 to 10 ng/mL and a free-to-total ratio of less than 0.25 ng/mL; or a PSA velocity higher than 0.75 ng/mL per year. Results Prostate biopsy would have been recommended in 207 participants (21%) with a PSA level higher than 4 ng/mL; in 358 (37%) with a level higher than 2.5 ng/mL; in 172 (18%) with a level above the age-specific cutoff; in 190 (20%) with a level between 4 and 10 ng/mL and a free-to-total ratio of less than 0.25 ng/mL; and in 145 (15%) with a velocity higher than 0.75 ng/mL per year. Among men with an abnormal PSA finding, a high proportion had a normal PSA finding at 1 or more subsequent visits during 4-year follow-up: 68 (44%) of 154 participants with a PSA level higher than 4 ng/mL; 116 (40%) of 291 had a level higher than 2.5 ng/mL; 64 (55%) of 117 had an elevated level above the age-specific cutoff; and 76 (53%) of 143 had a level between 4 and 10 ng/mL and a free-to-total ratio of less than 0.25 ng/mL. Conclusion An isolated elevation in PSA level should be confirmed several weeks later before proceeding with further testing, including prostate biopsy. C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Eastham, JA (reprint author), 353 E 68th St,Suite 527, New York, NY 10021 USA. FU NCI NIH HHS [N01-SC-05318] NR 34 TC 131 Z9 137 U1 0 U2 2 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 MAY 28 PY 2003 VL 289 IS 20 BP 2695 EP 2700 DI 10.1001/jama.289.20.2695 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 682DG UT WOS:000183075600028 PM 12771116 ER PT J AU Eldho, NV Feller, SE Tristram-Nagle, S Polozov, IV Gawrisch, K AF Eldho, NV Feller, SE Tristram-Nagle, S Polozov, IV Gawrisch, K TI Polyunsaturated docosahexaenoic vs docosapentaenoic acid - Differences in lipid matrix properties from the loss of one double bond SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID MOLECULAR-DYNAMICS SIMULATION; NUCLEAR-MAGNETIC-RESONANCE; BILAYER STRUCTURE DETERMINATION; LINOLENATE LINOLEATE BALANCE; VISUAL-ACUITY DEVELOPMENT; ACYL CHAIN UNSATURATION; NOESY CROSS-RELAXATION; X-RAY; FATTY-ACIDS; MODEL DIACYLGLYCEROLS AB Insufficient supply to the developing brain of docosahexaenoic acid (22:6n3, DHA), or its omega-3 fatty acid precursors, results in replacement of DHA with docosapentaenoic acid (22:5n6, DPA), an omega-6 fatty acid that is lacking a double bond near the chain's methyl end. We investigated membranes of 1-stearoyl(d(35))-2-docosahexaenoyl-sn-glycero-3-phosphocholine and 1-stearoyl(d35)-2-docosapentaenoylsn-glycero-3-phosphocholine by solid-state NMR, X-ray diffraction, and molecular dynamics simulations to determine if the loss of this double bond alters membrane physical properties. The low order parameters of polyunsaturated chains and the NMR relaxation data indicate that both DHA and DPA undergo rapid conformational transitions with correlation times of the order of nanoseconds at carbon atom C-2 and of picoseconds near the terminal methyl group. However, there are important differences between DHA- and DPA-containing lipids: the DHA chain with one additional double bond is more flexible at the methyl end and isomerizes with shorter correlation times. Furthermore, the stearic acid paired with the DHA in mixed-chain lipids has lower order, in particular in the middle of the chain near carbons C10-12, indicating differences in the packing of hydrocarbon chains. Such differences are also reflected in the electron density profiles of the bilayers and in the simulation results. The DHA chain has a higher density near the lipid-water interface, whereas the density of the stearic acid chain is higher in the bilayer center. The loss of a single double bond from DHA to DPA results in a more even distribution of chain densities along the bilayer normal. We propose that the function of integral membrane proteins such as rhodopsin is sensitive to such a redistribution. C1 NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. Wabash Coll, Dept Chem, Crawfordsville, IN 47933 USA. Carnegie Mellon Univ, Dept Phys, Pittsburgh, PA 15213 USA. RP Gawrisch, K (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. RI Tristram-Nagle, Prof. Stephanie/N-7811-2014 OI Tristram-Nagle, Prof. Stephanie/0000-0003-2271-7056 FU NIGMS NIH HHS [GM44976] NR 84 TC 143 Z9 147 U1 1 U2 19 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 MAY 28 PY 2003 VL 125 IS 21 BP 6409 EP 6421 DI 10.1021/ja029029o PG 13 WC Chemistry, Multidisciplinary SC Chemistry GA 681HY UT WOS:000183031800026 PM 12785780 ER PT J AU Shiflett, PR Taylor-McCabe, KJ Michaczyk, R Silks, LA Gupta, G AF Shiflett, PR Taylor-McCabe, KJ Michaczyk, R Silks, LA Gupta, G TI Structural studies on the hairpins at the 3 ' untranslated region of an anthrax toxin gene SO BIOCHEMISTRY LA English DT Article ID TRANSCRIPTION TERMINATION; ESCHERICHIA-COLI; HYDROGEN-EXCHANGE; HIGH-RESOLUTION; INTERNAL GT; NMR-SPECTRA; DNA; MISMATCHES; PREDICTION; SEQUENCE AB Three proteins, namely, protective antigen (PA), edema factor (EF), and lethal factor (LF), encoded by the pX01 plasmid of Bacillus anthracis play a major role in the pathogenesis of target host cells. PA combines with EF and LF to form bipartite PA-EF and PA-LF toxins and facilitates intracellular delivery of EF and LF both of which cause cytotoxicity to the host. Since the level of PA is crucial to pathogenesis by anthrax toxins, it is important to understand how the host environment regulates the expression of the PA (or pagA) gene by utilizing the 5' and 3' untranslated regions (UTR). The 5' UTR sequence determines the initiation of transcription, whereas the 3' UTR sequence determines the efficient termination and stability of the transcript. Although, the role of the 5'UTR sequence of pagA has been investigated, little is known about the role of the 3' UTR. Since hairpin formation at the 3'UTR of a gene is an established mechanism for efficient termination and stability of the transcript, we carried out structural studies, including gel electrophoresis, circular dichroism, and two-dimensional nuclear magnetic resonance spectroscopy, to determine whether the 3' UTR sequences of pagA also form hairpin structures. Our results unequivocally demonstrate that both the coding and the noncoding 3' UTR sequences form stable hairpin structures. It is quite likely that the hairpins at the 3'UTR may contribute to efficient termination and stability of the pagA transcript. C1 Los Alamos Natl Lab, McClintock Resource, Grp B1, Biosci Div, Los Alamos, NM 87545 USA. Los Alamos Natl Lab, NIH, Natl Stable Isotope Resource, Szilard Resource,Biosci Div,Grp B3, Los Alamos, NM 87545 USA. RP Gupta, G (reprint author), Los Alamos Natl Lab, McClintock Resource, Grp B1, Biosci Div, Mail Stop M888, Los Alamos, NM 87545 USA. OI Michalczyk, Ryszard/0000-0001-8839-6473 FU NCRR NIH HHS [RR02231] NR 43 TC 3 Z9 4 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 MAY 27 PY 2003 VL 42 IS 20 BP 6078 EP 6089 DI 10.1021/bi034128f PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 681EP UT WOS:000183024200012 PM 12755609 ER PT J AU Caputo, E Camarca, A Moharram, R Tornatore, P Thatcher, B Guardiola, J Martin, BM AF Caputo, E Camarca, A Moharram, R Tornatore, P Thatcher, B Guardiola, J Martin, BM TI Structural study of GCDFP-15/gp17 in disease versus physiological conditions using a proteomic approach SO BIOCHEMISTRY LA English DT Article ID HUMAN SEMINAL PLASMA; ACTIN-BINDING PROTEIN; PROLACTIN-INDUCIBLE PROTEIN; FLIGHT-MASS-SPECTROMETRY; CD4-BINDING GLYCOPROTEIN; BREAST-CANCER; CD4 BINDING; APOCRINE EPITHELIUM; TUMOR-ANTIGENS; MARKER PROTEIN AB Gross cystic disease fluid protein (GCDFP-15), also known as prolactin-inducible protein (PIP), is a specific breast tumor marker. GCDFP-15/PIP is also identified as gp17 and/or seminal actin-binding protein (SABP) from seminal vesicles and as extraparotid glycoprotein (EP-GP) from salivary glands. It is an aspartyl proteinase able to specifically cleave fibronectin (FN), suggesting a possible involvement in mammary tumor progression and fertilization. Other functions were attributed to this protein(s) on the basis of its ability to interact with an array of molecules such as CD4, actin, and fibrinogen. We investigated the structure of the protein(s) under disease versus physiological conditions by RP-HPLC chromatography, ProteinChip technology, and QStar MS/MS mass spectrometry. The proteins behaved differently when examined by RP-HPLC chromatography and surface-enhanced laser desorption ionization time-of-flight (SELDI-TOF) mass spectrometry, suggesting different conformations and/or tissue-specific posttranslational modifications of the proteins, although their primary structure was identical by MS/MS analysis. Both showed a single N-glycosylation site. A different N-linked glycosylation pattern was observed in pathological GCDFP-15/PIP as compared with physiological gp17/SABP protein by coupling enzymatic digestion and ProteinChip technology. Furthermore, taking advantage of ProteinChip technology, we analyzed the interaction of both proteins with CD4 and FN. We observed that the physiological form was mainly involved in the binding to CD4. Moreover, we defined the specific FN binding-domain of this protein. These data suggested that, depending on its conformational state, the protein could differently bind to its various binding molecules and change its function(s) in the microenviroments where it is expressed. C1 NIMH, Unit Mol Struct, LNT, NIH, Bethesda, MD 20892 USA. CNR, Int Inst Genet & Biophys, A Buzzati Traverso, I-80125 Naples, Italy. Prot Solut, Stratford, ON N5A 7P6, Canada. Ciphergen Biosyst, Fremont, CA USA. RP Caputo, E (reprint author), NIMH, Unit Mol Struct, LNT, NIH, 10 Ctr Dr,Bldg 10 3N309, Bethesda, MD 20892 USA. OI CAPUTO, EMILIA/0000-0002-6485-8802 NR 34 TC 19 Z9 20 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 27 PY 2003 VL 42 IS 20 BP 6169 EP 6178 DI 10.1021/bi034038a PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 681EP UT WOS:000183024200022 PM 12755619 ER PT J AU Ahmad, Z Balsamo, LM Sachs, BC Xu, B Gaillard, WD AF Ahmad, Z Balsamo, LM Sachs, BC Xu, B Gaillard, WD TI Auditory comprehension of language in young children - Neural networks identified with fMRI SO NEUROLOGY LA English DT Article ID TEMPORAL-LOBE ACTIVATION; FUNCTIONAL MRI; SENTENCE COMPREHENSION; BRAIN ACTIVATION; PREFRONTAL CORTEX; SEX-DIFFERENCES; WADA TEST; DOMINANCE; SPEECH; LOCALIZATION AB Objective: The organization of neuronal systems that process language in young children is poorly understood. The authors used fMRI to identify brain regions underlying auditory comprehension in healthy young children. Methods: Fifteen right-handed children (mean age 6.8 years) underwent fMRI at 1.5-T using blood oxygen level dependent echoplanar imaging. They listened to stories with a reverse speech control condition. Group data were analyzed with statistical parametric mapping. Individual subject data were analyzed with a region of interest approach based on t-maps. An asymmetry index (AI = [(L-R)/(L+R)]) was calculated for each region. Results: Group analysis showed significant activation in the left middle temporal gyrus (Brodmann area [BA] 21) and left superior temporal gyrus (BA 22) along the superior temporal sulcus extending back to the angular gyrus (BA 39). Individual maps showed lateralized activation in temporal regions (AI > 0.49 +/- 0.39). There was minimal activation in the frontal lobe. There were no significant correlations between age and regional AI. Conclusion: Networks for auditory language processing are regionally localized and lateralized by age 5. These data may provide a means to interpret language fMRI studies performed in preparation for brain surgery, and may be employed to investigate the effect of chronic disease states, such as epilepsy, on language organization during critical periods for plasticity. C1 George Washington Univ, Sch Med, Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. NINDS, Clin Epilepsy Sect, NIH, Bethesda, MD 20892 USA. RP Gaillard, WD (reprint author), George Washington Univ, Sch Med, Childrens Natl Med Ctr, Dept Neurol, 111 Michigan Ave NW, Washington, DC 20010 USA. FU NINDS NIH HHS [KO8 NS 1663] NR 59 TC 86 Z9 86 U1 6 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAY 27 PY 2003 VL 60 IS 10 BP 1598 EP 1605 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 682LD UT WOS:000183092400010 PM 12771248 ER PT J AU Lincoln, S Wiley, J Lynch, T Langston, JW Chen, R Lang, A Rogaeva, E Munhoz, RP Harris, J Marder, K Klein, C Bisceglio, G Hussey, J West, A Hulihan, M Hardy, J Farrer, M AF Lincoln, S Wiley, J Lynch, T Langston, JW Chen, R Lang, A Rogaeva, E Munhoz, RP Harris, J Marder, K Klein, C Bisceglio, G Hussey, J West, A Hulihan, M Hardy, J Farrer, M TI Parkin-proven disease - Common founders but divergent phenotypes SO NEUROLOGY LA English DT Article ID JUVENILE PARKINSONISM; MUTATIONS; GENE; FAMILY; ONSET; ASSOCIATION; EUROPE AB Objective: To compare and contrast clinical and genetic findings in six probands with parkinsonism with a parkin exon 3 438- to 477-bp deletion (Ex3Delta40) to search for evidence of a common founder. Method: Clinical review, parkin gene sequencing, dosage studies, and high-resolution genotype/haplotype analysis were performed. Results: All subjects had two or more signs consistent with a diagnosis of possible or probable PD with age at onset younger than 45 years (mean +/- SD 29.3 +/- 10.2 years, range 16 to 42 years). Affected individuals were either homozygotes, compound heterozygotes, or Ex3Delta40 carriers with one normal parkin allele. Haplotype analysis revealed both Ex3Delta40 and Ex7 924 C-->T (R275W) mutations originated from common founders, the former most probably of Irish descent. Although three cases had Ex7 924 C-->T (R275W) and Ex3Delta40 mutations, their clinical presentation and mode of inheritance were variable. Conclusion: Parkin mutations on common parkin haplotypes provide testable hypotheses of parkin function in genetically defined parkinsonism. C1 Mayo Clin Jacksonville, Dept Neurosci, Jacksonville, FL 32224 USA. Mayo Clin Jacksonville, Neurogenet Lab, Jacksonville, FL 32224 USA. Columbia Univ, Dept Neurol, New York, NY USA. Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Parkinsons Inst, Sunnyvale, CA USA. Univ Coll Dublin, Mater Misericordiae Hosp, Dept Neurol, Dublin 2, Ireland. Toronto Western Hosp, Div Neurol, Dept Med, Toronto, ON M5T 2S8, Canada. Univ Toronto, Ctr Res Neurodegenerat Dis, Toronto, ON, Canada. Med Univ Lubeck, Dept Neurol, D-23538 Lubeck, Germany. RP Farrer, M (reprint author), Mayo Clin Jacksonville, Dept Neurosci, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. RI Hardy, John/C-2451-2009; Chen, Robert/B-3899-2009; OI Chen, Robert/0000-0002-8371-8629; West, Andrew/0000-0002-3034-4061 FU NINDS NIH HHS [NS36630] NR 24 TC 16 Z9 17 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 MAY 27 PY 2003 VL 60 IS 10 BP 1605 EP 1610 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 682LD UT WOS:000183092400011 PM 12771249 ER PT J AU Blevins, G Macaulay, R Harder, S Fladeland, D Yamashita, T Yazaki, M Asl, KH Benson, MD Donat, J AF Blevins, G Macaulay, R Harder, S Fladeland, D Yamashita, T Yazaki, M Asl, KH Benson, MD Donat, J TI Oculoleptomeningeal amyloidosis in a large kindred with a new transthyretin variant Tyr69His SO NEUROLOGY LA English DT Article ID LIVER-TRANSPLANTATION; LEPTOMENINGEAL AMYLOIDOSIS; MUTANT TRANSTHYRETIN; POLYNEUROPATHY; PREALBUMIN; FAMILY; GENE; DNA AB Objective: To describe the clinical, radiologic, and pathologic findings of a kindred with oculoleptomeningeal amyloidosis and a newly associated transthyretin mutation. Background: Transthyretin (TTR) amyloidosis can present in the form of oculoleptomeningeal amyloidosis. Clinical features include dementia, seizures, stroke-like episodes, subarachnoid hemorrhage, ataxia, myelopathy, deafness, radiculopathy, and ocular amyloidosis. Eight TTR mutations associated with oculoleptomeningeal amyloidosis have been described. Methods: Fourteen individuals from a kindred with oculoleptomeningeal amyloidosis were examined clinically and radiologically. Analysis of the TTR gene was performed. Neuropathologic examination was obtained on the index patient. Results: Affected individuals had vitreous amyloid, radiculopathy, seizures, stroke-like episodes, encephalopathy, and dementia. Severely affected individuals died by the end of the fifth decade. Leptomeningeal enhancement on contrast MRI and elevated CSF protein were the defining features on investigations. Sequencing of exon 3 in the TTR gene found a base pair substitution at codon 69. This resulted in heterozygosity for normal tyrosine and variant histidine (ATTR Tyr69His) in affected family members. Domino liver transplantation was attempted as treatment for one family member. Conclusions: The ATTR Tyr69His mutation is associated with oculoleptomeningeal amyloidosis. Expression of the genotype is variable. This has implications for treatment of affected individuals and counseling of family members. Efficacy of liver transplantation in patients with oculoleptomeningeal amyloidosis remains unknown. The authors advocate the investigation of liver transplantation in patients with severe symptoms due to oculoleptomeningeal amyloidosis. C1 NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. QE II Hlth Sci Ctr, Dept Pathol, Halifax, NS, Canada. Dalhousie Univ, Halifax, NS, Canada. Univ Saskatchewan, Royal Univ Hosp, Dept Med Imaging, Saskatoon, SK S7N 0W8, Canada. Univ Saskatchewan, Royal Univ Hosp, Div Neurol, Saskatoon, SK S7N 0W8, Canada. Indiana Univ, Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46204 USA. Richard L Roudebush Vet Affairs Med Ctr, Indianapolis, IN 46202 USA. RP Donat, J (reprint author), Univ Saskatchewan, Royal Univ Hosp, Div Neurol, 103 Hosp Dr, Saskatoon, SK S7N 0W8, Canada. NR 22 TC 44 Z9 48 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAY 27 PY 2003 VL 60 IS 10 BP 1625 EP 1630 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 682LD UT WOS:000183092400015 PM 12771253 ER PT J AU Shill, HA Alaedini, A Latov, N Hallett, M AF Shill, HA Alaedini, A Latov, N Hallett, M TI Anti-ganglioside antibodies in idiopathic and hereditary cerebellar degeneration SO NEUROLOGY LA English DT Article ID CELIAC-DISEASE; GLUTEN SENSITIVITY; DIAGNOSIS; SPECTRUM; ATAXIA AB Cerebellar degeneration has been associated with gluten sensitivity and celiac disease. Patients with celiac disease may have neuropathy and antibodies to gangliosides. The authors investigated the presence of antiganglioside antibodies in 22 patients with hereditary and nonhereditary ataxia and found 64% reactive in a novel agglutination test. C1 NINDS, Human Motor Control Sect, Neurol Branch, NIH, Bethesda, MD 20892 USA. Cornell Univ, Dept Neurol & Neurosci, New York, NY USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, Neurol Branch, NIH, Bldg 10,Room 5N226,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. NR 10 TC 15 Z9 15 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAY 27 PY 2003 VL 60 IS 10 BP 1672 EP 1673 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 682LD UT WOS:000183092400024 PM 12771262 ER PT J AU Williams, JG Pappu, K Campbell, SL AF Williams, JG Pappu, K Campbell, SL TI Structural and biochemical studies of p21(Ras) S-nitrosylation and nitric oxide-mediated guanine nucleotide exchange SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE guanosine triphosphatase; redox; cancer; reactive oxygen species; reactive nitrogen species ID GTP-BINDING PROTEINS; REDOX STRESS; RAS PROTEIN; ACTIVATION; RECRUITMENT; SENSITIVITY; SYNTHASES; EFFECTORS; KINASE; TARGET AB Ras is a guanine nucleotide-binding protein that cycles between inactive GDP-bound and active GTP-bound states to regulate a diverse array of cellular processes, including cell growth, apoptosis, and differentiation. The guanine nucleotide-bound state of Ras is tightly maintained by regulatory factors to promote regulated growth control. A class of regulatory molecules that lead to Ras activation are guanine nucleotide exchange factors (GEFs). Ras GEFs bind to Ras and facilitate GDP release, followed by GTP incorporation and Ras activation. Nitric oxide (NO) has also been shown to promote guanine nucleotide exchange (GNE) on Ras and increase cellular Ras-GTP levels, but the process by which NO-mediated GNE occurs is not clear. We initiated NMR structural and biochemical studies to elucidate how nitrosylation of Ras might lead to enhanced GNE. Surprisingly, our studies show that stable S-nitrosylation of Ras at Cys-118, does not affect the structure of Ras, its association with the Ras-binding domain of Raf (a downstream effector of Ras), or GNE rates relative to non-nitrosylated Ras. We have found, however, that the actual chemical process of nitrosylation, rather than the end-product of Ras S-nitrosylation, accounts for the enhanced GNE that we have observed and that has been previously observed by others. C1 Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. RP Campbell, SL (reprint author), NIEHS, Struct Biol Lab, 111 Alexander Dr,Mail Drop F0-04, Res Triangle Pk, NC 27709 USA. EM campbesl@med.unc.edu NR 34 TC 56 Z9 61 U1 2 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 27 PY 2003 VL 100 IS 11 BP 6376 EP 6381 DI 10.1073/pnas.1037299100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 684DT UT WOS:000183190700018 PM 12740440 ER PT J AU Shu, S Liu, X Korn, ED AF Shu, S Liu, X Korn, ED TI Dictylostelium and Acanthamoeba myosin II assembly domains go to the cleavage furrow of Dictyostelium myosin II-null cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HEAVY-CHAIN GENE; MOTOR DOMAIN; TAIL; LOCALIZATION; PHOSPHORYLATION; CYTOKINESIS; EXPRESSION; DISCOIDEUM; SEQUENCES; INVIVO AB How myosin II localizes to the cleavage furrow of dividing cells is largely unknown. We show here that a 283-residue protein, assembly domain (AD)1, corresponding to the AD in the tail of Dictyostelium, myosin II assembles into bundles of long tubules when expressed in myosin II-null cells and localizes to the cleavage furrow of dividing cells. AD1 mutants that do not polymerize in vitro do not go to the cleavage furrow in vivo. An assembly-competent polypeptide corresponding to the C-terminal 256 residues of Acanthamoeba myosin II also goes to the cleavage furrow of Dictyostelium myosin II-null cells. When overexpressed in wild-type cells, AD1 colocalizes with endogenous myosin II (possibly as a copolymer) in interphase, motile, and dividing cells and under caps of Con A receptors but has no effect on myosin II-dependent functions. These results suggest that neither a specific sequence, other than that required for polymerization, nor interaction with other proteins is required for localization of myosin II to the cleavage furrow. C1 NHLBI, Cell Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Korn, ED (reprint author), NHLBI, Cell Biol Lab, Natl Inst Hlth, Bldg 50,Room 2517,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Korn, Edward/F-9929-2012 NR 25 TC 15 Z9 15 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 27 PY 2003 VL 100 IS 11 BP 6499 EP 6504 DI 10.1073/pnas.0732155100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 684DT UT WOS:000183190700039 PM 12748387 ER PT J AU Welch, JS Ricote, M Akiyama, TE Gonzalez, FJ Glass, CK AF Welch, JS Ricote, M Akiyama, TE Gonzalez, FJ Glass, CK TI PPAR gamma and PPAR delta negatively regulate specific subsets of lipopolysaccharide and IFN-gamma target genes in macrophages SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ACTIVATED RECEPTOR-GAMMA; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; RETINOID-X-RECEPTOR; E-KNOCKOUT MICE; 15-DEOXY-DELTA(12,14)-PROSTAGLANDIN J(2); INFLAMMATORY CYTOKINES; CHOLESTEROL EFFLUX; OXIDIZED LDL; PROLIFERATOR; EXPRESSION AB Natural and synthetic agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma) regulate adipocyte differentiation, glucose homeostasis, and inflammatory responses. Although effects on adipogenesis and glucose metabolism are genetically linked to PPARgamma, the PPARgamma dependence of antiinflammatory responses of these substances is less clear. Here, we have used a combination of mRNA expression profiling and conditional disruption of the PPARgamma gene, in mice to characterize programs of transcriptional activation and repression by PPARgamma agonists in elicited peritoneal macrophages. Natural and synthetic PPARgamma agonists, including the thiazolidinedione rosiglitazone (Ro), modestly induced the expression of a surprisingly small number of genes, several of which were also induced by a specific PPARdelta agonist. The majority of these genes encode proteins involved in lipid homeostasis. In contrast, Ro inhibited induction of broad subsets of lipopolysaccharide and IFN-gamma target genes in a gene-specific and PPARgamma-dependent manner. At high concentrations, Ro inhibited induction of lipopolysaccharide target genes in PPARgamma-deficient macrophages, at least in part by activating PPARdelta. These studies establish overlapping transactivation and transrepression functions of PPARgamma and PPARdelta in macrophages and suggest that a major transcriptional role of PPARgamma is negative regulation of specific subsets of genes that are activated by T helper 1 cytokines and pathogenic molecules that signal through pattern recognition receptors. These findings support a physiological role of PPARgamma in regulating both native and acquired immune responses. C1 Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Glass, CK (reprint author), Univ Calif San Diego, Dept Cellular & Mol Med, 9500 Gilman Dr, La Jolla, CA 92093 USA. RI Ricote, Mercedes/L-4615-2014 OI Ricote, Mercedes/0000-0002-8090-8902 FU NIEHS NIH HHS [P42 ES010337, ES10337] NR 42 TC 292 Z9 301 U1 1 U2 7 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 MAY 27 PY 2003 VL 100 IS 11 BP 6712 EP 6717 DI 10.1073/pnas.1031789100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 684DT UT WOS:000183190700076 PM 12740443 ER PT J AU Murata, K Lechmann, M Qiao, M Gunji, T Alter, HJ Liang, TJ AF Murata, K Lechmann, M Qiao, M Gunji, T Alter, HJ Liang, TJ TI Immunization with hepatitis C virus-like particles protects mice from recombinant hepatitis C virus-vaccinia infection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID T-LYMPHOCYTE RESPONSE; IMMUNE-RESPONSE; VIRAL CLEARANCE; STRUCTURAL PROTEINS; PLUS RIBAVIRIN; CELL RESPONSE; INSECT CELLS; INDUCTION; CHIMPANZEES; EPITOPES AB We have recently demonstrated that immunization with hepatitis C virus-like particles (HCV-LPs) generated in insect cells can elicit both humoral and cellular immune responses in BALB/c mice. Here, we evaluate the immunogenicity of HCV-LPs in HLA2.1 transgenic (AAD) mice in comparison to DNA immunization. HCV-LP immunization elicited a significantly stronger humoral immune response than DNA immunization. HCV-LP-immunized mice also developed stronger HCV-specific cellular immune responses than DNA-immunized mice as determined by using quantitative enzyme-linked immunospot (ELISpot) assay and intracellular cytokine staining. In BALB/c mice, immunization with HCV-LPs resulted in a >5 log(10) reduction in vaccinia titer when challenged with a recombinant vaccinia expressing the HCV structural proteins (vvHCV.S), as compared to 1 log(10) decrease in DNA immunization. In HLA2.1 transgenic mice, a 1-2 log(10) reduction resulted from HCV-LP immunization, whereas no reduction was seen from DNA immunization. Adoptive transfer of lymphocytes from HCV-LP-immunized mice to naive mice provided protection against vvHCV.S challenge, and this transferred immunity can be abrogated by either CD4 or CD8 depletion. Our results suggest that HCV-LPs can induce humoral and cellular immune responses that are protective in a surrogate HCV challenge model and that a strong cellular immunity provided by both CD4 and CD8 effector lymphocytes may be important for protection from HCV infection. C1 NIDDKD, Liver Dis Sect, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. RP Liang, TJ (reprint author), NIDDKD, Liver Dis Sect, Bethesda, MD 20892 USA. NR 34 TC 106 Z9 112 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 27 PY 2003 VL 100 IS 11 BP 6753 EP 6758 DI 10.1073/pnas.1131929100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 684DT UT WOS:000183190700083 PM 12748380 ER PT J AU Carabeo, RA Mead, DJ Hackstadt, T AF Carabeo, RA Mead, DJ Hackstadt, T TI Golgi-dependent transport of cholesterol to the Chlamydia trachomatis inclusion SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; HAMSTER OVARY CELLS; TOXOPLASMA-GONDII; PLASMA-MEMBRANE; ENDOPLASMIC-RETICULUM; HOST-CELL; PARASITOPHOROUS VACUOLES; INTRACELLULAR-TRANSPORT; TRAFFICKING PATHWAYS; INFECTED CELLS AB Cholesterol, a lipid not normally found in prokaryotes, was identified in purified Chlamydia trachomatis elementary bodies and in the chlamydial parasitophorous vacuole (inclusion) membrane of infected HeLa cells. Chlamydiae obtained eukaryotic host cell cholesterol both from de novo synthesis or low-density lipoprotein. Acquisition of either de novo-synthesized cholesterol or low-density lipoprotein-derived cholesterol was microtubule-dependent and brefeldin A-sensitive, indicating a requirement for the Golgi apparatus. Transport also required chlamydial protein synthesis, indicative of a pathogen-directed process. The cholesterol trafficking pathway appears to coincide with a previously characterized delivery of sphingomyelin to the inclusion in that similar pharmacological treatments inhibited transport of both sphingomyelin and cholesterol. These results support the hypothesis that sphingomyelin and cholesterol may be cotransported via a Golgi-dependent pathway and that the chlamydial inclusion receives cholesterol preferentially from a brefeldin A-sensitive pathway of cholesterol trafficking from the Golgi apparatus to the plasma membrane. C1 NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. RP Hackstadt, T (reprint author), NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. NR 52 TC 157 Z9 161 U1 1 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 27 PY 2003 VL 100 IS 11 BP 6771 EP 6776 DI 10.1073/pnas.1131289100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 684DT UT WOS:000183190700086 PM 12743366 ER PT J AU Hu, Y Fortini, ME AF Hu, Y Fortini, ME TI Different cofactor activities in gamma-secretase assembly: evidence for a nicastrin-Aph-1 subcomplex SO JOURNAL OF CELL BIOLOGY LA English DT Article DE presenilin; Pen-2; Notch; Drosophila; amyloid ID ALZHEIMERS-DISEASE; BETA-APP; NOTCH; PRESENILIN; DROSOPHILA; CLEAVAGE; PROTEIN; APH-1; ACCUMULATION; MUTANTS AB The gamma-secretase complex is required for intramembrane cleavage of several integral membrane proteins, including the Notch receptor, where it generates an active signaling fragment. Four putative gamma-secretase components have been identified-presenilin (Psn), nicastrin (Nct), Aph-1, and Pen-2. Here, we use a stepwise coexpression approach to investigate the role of each new component in gamma-secretase assembly and activation. Coexpression of all four proteins leads to high level accumulation of mature Psn and increased proteolysis of Notch. Aph-1 and Nct may form a subcomplex that stabilizes the Psn holoprotein at an early step in gamma-secretase assembly. Subcomplex levels of Aph-1 are down-regulated by stepwise addition of Psn, suggesting that Aph-1 might not enter the mature complex. In contrast, Pen-2 accumulates proportionally with Psn, and is associated with Psn endoproteolysis during gamma-secretase assembly. These results demonstrate that Aph-1 and Pen-2 are essential cofactors for Psn, but that they play different roles in gamma-secretase assembly and activation. C1 NCI, Frederick, MD 21702 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. RP Fortini, ME (reprint author), NCI, Bldg 560,Rm 22-12, Frederick, MD 21702 USA. FU NIA NIH HHS [R01 AG014583, R01 AG14583] NR 24 TC 122 Z9 125 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 MAY 26 PY 2003 VL 161 IS 4 BP 685 EP 690 DI 10.1083/jcb.200304014 PG 6 WC Cell Biology SC Cell Biology GA 685WJ UT WOS:000183286700004 PM 12771124 ER PT J AU Tomita, S Chen, L Kawasaki, Y Petralia, RS Wenthold, RJ Nicoll, RA Bredt, DS AF Tomita, S Chen, L Kawasaki, Y Petralia, RS Wenthold, RJ Nicoll, RA Bredt, DS TI Functional studies and distribution define a family of transmembrane AMPA receptor regulatory proteins SO JOURNAL OF CELL BIOLOGY LA English DT Article DE synapse; glutamate receptor; plasticity; stargazin; trafficking ID CHANNEL GAMMA-SUBUNIT; POSTSYNAPTICALLY SILENT SYNAPSES; DOMAIN-CONTAINING PROTEIN; LONG-TERM DEPRESSION; CALCIUM-CHANNEL; ENDOPLASMIC-RETICULUM; CA2+ CHANNEL; MOUSE STARGAZER; MUTANT MOUSE; GENE FAMILY AB Functional expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in cerebellar granule cells requires stargazin, a member of a large family of four-pass transmembrane proteins. Here, we define a family of transmembrane AMPA receptor regulatory proteins (TARPs), which comprise stargazin, gamma-3, gamma-4, and gamma-8, but not related proteins, that mediate surface expression of AMPA receptors. TARPs exhibit discrete and complementary patterns of expression in both neurons and glia in the developing and mature central nervous system. In brain regions that express multiple isoforms, such as cerebral cortex, TARP-AMPA receptor complexes are strictly segregated, suggesting distinct roles for TARP isoforms. TARPs interact with AMPA receptors at the postsynaptic density, and surface expression of mature AMPA receptors requires a TARP. These studies indicate a general role for TARPs in controlling synaptic AMPA receptors throughout the central nervous system. C1 Univ Calif San Francisco, Sch Med, Dept Physiol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Med, Dept Mol & Cellular Pharmacol, San Francisco, CA 94143 USA. NIDOCD, Neurochem Lab, NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Mol & Cellular Pharmacol, San Francisco, CA 94143 USA. RP Bredt, DS (reprint author), Univ Calif San Francisco, Sch Med, Dept Physiol, 513 Parnassus Ave, San Francisco, CA 94143 USA. NR 58 TC 274 Z9 286 U1 1 U2 17 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 MAY 26 PY 2003 VL 161 IS 4 BP 805 EP 816 DI 10.1083/jcb.200212116 PG 12 WC Cell Biology SC Cell Biology GA 685WJ UT WOS:000183286700016 PM 12771129 ER PT J AU Tozser, J Shulenin, S Kadas, J Boross, M Bagossi, M Copeland, TD Nair, BC Sarngadharan, MG Oroszlan, S AF Tozser, J Shulenin, S Kadas, J Boross, M Bagossi, M Copeland, TD Nair, BC Sarngadharan, MG Oroszlan, S TI Human immunodeficiency virus type 1 capsid protein is a substrate of the retroviral proteinase while integrase is resistant toward proteolysis SO VIROLOGY LA English DT Article DE HIV-1 capsid protein; integrase; HIV-1 proteinase; oligopeptide substrates; enzyme kinetics ID HIV-1 PROTEASE; VIRAL PROTEASE; NUCLEOCAPSID PROTEIN; CRYSTAL-STRUCTURE; CYCLOPHILIN-A; IN-VITRO; INHIBITORS; REPLICATION; VIRIONS; ANALOG AB The capsid protein of human immunodeficiency virus type 1 was observed to undergo proteolytic cleavage in vitro when viral lysate was incubated in the presence of dithiothreitol at acidic pH. Purified HIV-1 capsid protein was also found to be a substrate of the viral proteinase in a pH-dependent manner; acidic pH (<7) was necessary for cleavage, and decreasing the pH toward 4 increased the degree of processing. Based on N-terminal sequencing of the cleavage products, the capsid protein was found to be cleaved at two sites, between residues 77 and 78 as well as between residues 189 and 190. Oligopeptides representing these cleavage sites were also cleaved at the expected peptide bonds. The presence of cyclophilin A decreased the degree of capsid protein processing. Unlike the capsid protein, integrase was found to be resistant toward proteolysis in good agreement with its presence in the preintegration complex. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Univ Debrecen, Fac Med, Dept Biochem & Mol Biol, H-4012 Debrecen, Hungary. NCI, Frederick, MD 21701 USA. RP Tozser, J (reprint author), Univ Debrecen, Fac Med, Dept Biochem & Mol Biol, H-4012 Debrecen, Hungary. EM tozser@indi.biochem.dote.hu RI Tozser, Jozsef/A-7840-2008; OI Tozser, Jozsef/0000-0003-0274-0056; Tozser, Jozsef/0000-0001-5076-8729 NR 50 TC 11 Z9 11 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 0042-6822 J9 VIROLOGY JI Virology PD MAY 25 PY 2003 VL 310 IS 1 BP 16 EP 23 DI 10.1016/S0042-6822(03)00074-6 PG 8 WC Virology SC Virology GA 685XY UT WOS:000183290700003 PM 12788626 ER PT J AU Sato, Y Yoshioka, K Suzuki, C Awashima, S Hosaka, Y Yewdell, J Kuroda, K AF Sato, Y Yoshioka, K Suzuki, C Awashima, S Hosaka, Y Yewdell, J Kuroda, K TI Localization of influenza virus proteins to nuclear dot 10 structures in influenza virus-infected cells SO VIROLOGY LA English DT Article ID GREEN FLUORESCENT PROTEIN; PROMYELOCYTIC LEUKEMIA PROTEIN; PML GROWTH-SUPPRESSOR; MEMBRANE M1 PROTEIN; A VIRUS; MATRIX PROTEIN; NS1 PROTEIN; INTRACELLULAR-LOCALIZATION; VIRAL RIBONUCLEOPROTEINS; TRANSCRIPTION-INHIBITION AB We studied influenza virus M1 protein by generating HeLa and MDCK cell lines that express M1 genetically fused to green fluorescent protein (GFP). GFP-M1 was incorporated into virions produced by influenza virus infected MDCK cells expressing the fusion protein indicating that the fusion protein is at least partially functional. Following infection of either HeLa or MDCK cells with influenza A virus (but not influenza B virus), GFP-M1 redistributes from its cytosolic/nuclear location and accumulates in nuclear dots. Immunofluorescence revealed that the nuclear dots represent nuclear dot 10 (ND10) structures. The colocalization of authentic M1, as well as NS1 and NS2 protein, with ND10 was confirmed by immunofluorescence following in situ isolation of ND10. These findings demonstrate a previously unappreciated involvement of influenza virus with ND10, a structure involved in cellular responses to immune cytokines as well as the replication of a rapidly increasing list of viruses. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Nihon Univ, Sch Med, Dept Immunol & Microbiol, Itabashi Ku, Tokyo 1738610, Japan. Osaka Univ Pharmaceut Sci, Dept Virol & Immunol, Takatsuki, Osaka 5691094, Japan. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Kuroda, K (reprint author), Nihon Univ, Sch Med, Dept Immunol & Microbiol, Itabashi Ku, Tokyo 1738610, Japan. RI yewdell, jyewdell@nih.gov/A-1702-2012 NR 77 TC 21 Z9 22 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 0042-6822 J9 VIROLOGY JI Virology PD MAY 25 PY 2003 VL 310 IS 1 BP 29 EP 40 DI 10.1016/S0042-6822(03)00104-1 PG 12 WC Virology SC Virology GA 685XY UT WOS:000183290700005 PM 12788628 ER PT J AU Musgrove, P AF Musgrove, P TI Judging health systems: reflections on WHO's methods SO LANCET LA English DT Editorial Material C1 NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Musgrove, P (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. NR 16 TC 19 Z9 21 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 MAY 24 PY 2003 VL 361 IS 9371 BP 1817 EP 1820 DI 10.1016/S0140-6736(03)13408-3 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 682CY UT WOS:000183074800025 PM 12781555 ER PT J AU Matsumi, S Kosalaraksa, P Tsang, H Kavlick, MF Harada, S Mitsuya, H AF Matsumi, S Kosalaraksa, P Tsang, H Kavlick, MF Harada, S Mitsuya, H TI Pathways for the emergence of multi-dideoxynucleoside-resistant HIV-1 variants SO AIDS LA English DT Article DE multi-dideoxynucleoside resistance; reverse transcriptase; viral fitness; anti-HIV agents ID IMMUNODEFICIENCY-VIRUS TYPE-1; REVERSE-TRANSCRIPTASE RESISTANT; HIGH-LEVEL RESISTANCE; POL GENE-MUTATIONS; DRUG-RESISTANCE; ANTIRETROVIRAL THERAPY; VIROLOGICAL FAILURE; PROTEASE INHIBITOR; ZIDOVUDINE; GLUTAMINE-151 AB Objective: To investigate the mechanism by which the Q151 M mutation in reverse transcriptase (RT) that confers multi-dideoxynucleoside resistance on HIV-1 and that requires a two base change (CAG-->ATG) develops, and to understand the reason for the relatively lengthy period of time required for its emergence under therapy with multiple nucleoside RT inhibitors (NRTI). Design and methods: Propagation assays and competitive HIV-1 replication assays were used to evaluate the fitness of various infectious clones, including two putative intermediates (HIV-1(Q151K(AAG>) and HIV-(1Q151L(CTG))) for HIV-1(Q151M(ATG)), in terms of sensitivity to zidovudine and didanosine. Steady-state kinetic constants of recombinant RT were also determined. Results: HIV-1(Q151L) replicated relatively poorly while HIV-(1Q151K) failed to replicate. When HIV-(1Q151L) was propagated further, it took three pathways in continuing to replicate: (i) HIV-(1Q151L) changed to HIV-1(Q151M) in eight of 16 experiments; (ii) HIV-1(Q151L) reverted to wild-type HIV-1 (HIV-1(WT)) in four of 16 experiments; and (iii) HIV-1(Q151L) acquired an additional mutation M2301 in four of 16 experiments improving HIV-1 fitness. The relative order of replicative fitness without drugs was: HIV-1(Q151M) > HIV-1(WT) > HIV-(1Q151L/M2301) > HIV-1 M2301 >> HIV-(1Q151L) >>> HIV-(1Q151K), HIV-(1Q151K/M2301). HIV-(1Q151M) was less susceptible to drugs, while HIV-(1Q151L/M2301) was as sensitive as HIV-1WT. Enzymatic assays corroborated that HIV-1(Q151L) is more replication-competent than HIV-1(WT) and HIV-1(Q151K) in the presence of drugs. Conclusion: HIV-1(Q151M) probably develops through a poorly replicating HIV-1(Q151L); however, it is also possible that it occurs through two concurrent base changes. The present data should explain the mechanism by which HIV-1(Q151M) emerges after longterm chemotherapy with NRTI. (C) 2003 Lippincott Williams Wilkins. C1 NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. Kumamoto Univ, Sch Med, Dept Internal Med 2, Kumamoto 860, Japan. Kumamoto Univ, Sch Med, Div Infect Dis, Kumamoto 860, Japan. RP Mitsuya, H (reprint author), NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, Ctr Canc Res,NIH, Bldg 10,Room 5A11,MSC1868,10 Ctr Dr, Bethesda, MD 20892 USA. RI Tsang, Hsinyi/C-9547-2011 NR 37 TC 22 Z9 23 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAY 23 PY 2003 VL 17 IS 8 BP 1127 EP 1137 DI 10.1097/01.aids.0000060387.18106.a7 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 687ZT UT WOS:000183408000003 PM 12819513 ER PT J AU Diaz, M Douek, DC Valdez, H Hill, BJ Petersond, D Sanne, I Piliero, PJ Koup, RA Green, SB Schnittman, S Lederman, MM AF Diaz, M Douek, DC Valdez, H Hill, BJ Petersond, D Sanne, I Piliero, PJ Koup, RA Green, SB Schnittman, S Lederman, MM TI T cells containing T Cell receptor excision circles are inversely related to HIV replication and are selectively and rapidly released into circulation with antiretroviral treatment SO AIDS LA English DT Article DE immune reconstitution; antiretroviral therapy; naive T cells; thymus; T cell receptor excision circles; HIV ID RECENT THYMIC EMIGRANTS; LYMPHOID-TISSUES; THERAPY; INDIVIDUALS; DISEASE; BLOOD AB Objective: To examine baseline predictors of T-cell receptor rearrangement excision circle (TREC) levels and their changes during treatment with combined antiretroviral therapy. Methods: Peripheral blood and lymph node lymphocytes were examined for the presence of TREC by real-time polymerase chain reaction and circulating lymphocyte phenotypes were examined by flow cytometry. Correlates for CD4 and CD8 cell TREC levels at baseline were identified among CD4 and CD8 immunophenotypes, viral load and patient demographics; the significance of TREC changes after initiation of antiretroviral therapy was assessed. Results: Circulating TREC levels correlated inversely with age, with HIV RNA levels, with activation markers on circulating T cells and with naive CD4 but not CD8 cell frequencies. With initiation of antiretroviral therapy, TREC and naive T cell frequencies increased in peripheral blood during the first 2 weeks of treatment and these changes correlated negatively with TREC frequencies in lymph node aspirates, particularly among CD8 T cells. Conclusions: These findings suggest that recent thymic emigrants are sequestered in lymphoid tissue during uncontrolled HIV replication and are selectively released into circulation rapidly after initiation of antiretroviral therapies. (C) 2003 Lippincott Williams Wilkins. C1 Case Western Reserve Univ, Univ Hosp Cleveland, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. Case Western Reserve Univ, Univ Hosp Cleveland, AIDS Res Ctr, Cleveland, OH 44106 USA. NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Univ Witwatersrand, Johannesburg, South Africa. Albany Med Coll, Albany, NY 12208 USA. Univ Arizona, Arizona Canc Ctr, Tucson, AZ USA. Bristol Myers Squibb Co, Wallingford, CT 06492 USA. RP Lederman, MM (reprint author), Case Western Reserve Univ, Univ Hosp Cleveland, Dept Epidemiol & Biostat, 2061 Cornell Rd, Cleveland, OH 44106 USA. FU NIAID NIH HHS [AI38858, AI36219] NR 11 TC 30 Z9 32 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAY 23 PY 2003 VL 17 IS 8 BP 1145 EP 1149 DI 10.1097/01.aids.0000060364.78202.10 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 687ZT UT WOS:000183408000005 PM 12819515 ER PT J AU Polis, MA Suzman, DL Yoder, CP Shen, JA Mican, JM Dewar, RL Metcalf, JA Falloon, J Davey, RT Kovacs, JA Feinberg, MB Masur, H Piscitelli, SC AF Polis, MA Suzman, DL Yoder, CP Shen, JA Mican, JM Dewar, RL Metcalf, JA Falloon, J Davey, RT Kovacs, JA Feinberg, MB Masur, H Piscitelli, SC TI Suppression of cerebrospinal fluid HIV burden in antiretroviral naive patients on a potent four-drug antiretroviral regimen SO AIDS LA English DT Article DE AIDS; cerebrospinal fluid; HIV; antiretroviral therapy; viral load; protease inhibitors ID IMMUNODEFICIENCY-VIRUS INFECTION; CENTRAL-NERVOUS-SYSTEM; HIV-1-INFECTED PATIENTS; VIRAL LOAD; POPULATION PHARMACOKINETICS; RNA LEVELS; PLASMA; INDINAVIR; THERAPY; TYPE-1 AB Objective: To determine the longitudinal response of HIV in the cerebrospinal fluid (CSF) to highly active antiretroviral therapy (HAART) and to investigate the levels of indinavir penetrating into the CSF. Design: Open study of HIV-infected subjects naive to therapy with protease inhibitors. Setting: Tertiary care referral center. Subjects: Twenty-five participants were begun on indinavir, nevirapine, zidovudine, and lamivudine. Interventions: Lumbar punctures were performed prior to therapy and 2 and 6 months after beginning therapy. Plasma and CSF were assayed for routine cell counts, chemistries, HIV load and indinavir levels. Results: Twenty-two subjects had CSF HIV RNA level data available at all three time points, three others at baseline and 2 months. At month 2 of therapy, nine of 25 (36%) subjects had CSF HIV RNA levels > 50 HIV RNA copies/ml. By 6 months, all 22 subjects had CSF HIV RNA levels < 50 HIV RNA copies/ml. CSF white blood cell counts fell from a baseline mean of 5.3 x 10(6)/l to 1.9 x 10(6)/l (P = 0.013) at 6 months. Plasma indinavir levels declined rapidly while CSF levels remained stable throughout the 8-h dosing interval. The median CSF indinavir level was 71 ng/ml, approximating the upper limit of the 95% inhibitory concentration for indinavir against HIV-1. Conclusions: CSF HIV RNA levels cannot be expected to fall below 50 HIV RNA copies/ml even after 2 months of therapy on HAART. Prolonged therapy may be required to suppress HIV levels within the central nervous system. (C) 2003 Lippincott Williams Wilkins. C1 NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. US Dept Hlth & Human Serv, Ctr Clin, NIH, Bethesda, MD USA. SAIC, Frederick Canc Res Ctr, Frederick, MD USA. Emory Univ, Sch Med, Atlanta, GA USA. RP Polis, MA (reprint author), NIAID, Immunoregulat Lab, Bldg 10,Room 11C103,10 Ctr Dr, Bethesda, MD 20892 USA. OI Polis, Michael/0000-0002-9151-2268 NR 31 TC 28 Z9 29 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAY 23 PY 2003 VL 17 IS 8 BP 1167 EP 1172 DI 10.1097/01.aids.0000060391.18106.95 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 687ZT UT WOS:000183408000008 PM 12819518 ER PT J AU Lederman, MA Douek, DC AF Lederman, MA Douek, DC TI Sometimes help may not be enough SO AIDS LA English DT Editorial Material ID T-CELL RESPONSES; ACUTE HIV-1 INFECTION; ANTIRETROVIRAL THERAPY; SKEWED MATURATION; IN-VIVO; CD8(+); CD4(+); LYMPHOCYTES; IMMUNODEFICIENCY; NONPROGRESSORS C1 Case Western Reserve Univ, Univ Hosp Cleveland, Ctr AIDS Res, Cleveland, OH 44106 USA. NIAID, Vaccine Res Ctr, Bethesda, MD USA. RP Lederman, MA (reprint author), Case Western Reserve Univ, Univ Hosp Cleveland, Ctr AIDS Res, Cleveland, OH 44106 USA. NR 26 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAY 23 PY 2003 VL 17 IS 8 BP 1249 EP 1251 DI 10.1097/01.aids.0000060366.78202.82 PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 687ZT UT WOS:000183408000018 PM 12819528 ER PT J AU Pace, A Garcia-Marin, LJ Tapia, JA Bragado, MJ Jensen, RT AF Pace, A Garcia-Marin, LJ Tapia, JA Bragado, MJ Jensen, RT TI Phosphospecific site tyrosine phosphorylation of p125(FAK) and proline-rich kinase 2 is differentially regulated by cholecystokinin receptor type A activation in pancreatic acini SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FOCAL ADHESION KINASE; SWISS 3T3 CELLS; GROWTH-FACTOR; ACTIN CYTOSKELETON; LOOP PHOSPHORYLATION; EPITHELIAL-CELLS; RAT HIPPOCAMPUS; TERMINAL DOMAIN; MAPK ACTIVATION; DIFFERENT MODES AB The focal adhesion kinases, p125(FAK) and proline-rich kinase 2 (PYK2), are involved in numerous processes as adhesion, cytoskeletal changes, and growth. These kinases have 45% homology and share three tyrosine phosphorylation (TyrP) sites. Little information exists on the ability of stimulants to cause TyrP of each kinase site and the cellular mechanism involved. We explored the ability of the neurotransmitter/hormone, CCK, to stimulate TyrP at each site. In rat pancreatic acini, CCK stimulated TyrP at each site in both kinases. TyrP was rapid except for pY397FAK. The magnitude of TyrP differed with the different FAK and PYK2 sites. The CCK dose-response curve for TyrP for sites in each kinase was similar. CCK-JMV, an agonist of the high affinity receptor state and antagonist of the low affinity receptor state, was less efficacious than CCK at each FAK/PYK2 site and inhibited CCK maximal stimulation. Thapsigargin decreased CCK-stimulated TyrP of pY402PYK2 and pY925FAK but not the other sites. GF109203X reduced TyrP of only the PYK2 sites, pY402 and pY580. GF109203X with thapsigargin decreased TyrP of pY402PYK2 and the three FAK sites more than either inhibitor alone. Basal TyrP of pY397FAK was greater than other sites. These results demonstrate that CCK stimulates tyrosine phosphorylation of each of the three homologous phosphorylation sites in FAK and PYK2. However, CCK-stimulated TyrP at these sites differs in kinetics, magnitude, and participation of the high/low affinity receptor states and by protein kinase C and [Ca2+](i). These results show that phosphorylation of these different sites is differentially regulated and involves different intracellular mechanisms in the same cell. C1 NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. Univ Extremadura, Dept Fisiol, Caceres 10071, Spain. Univ Extremadura, Dept Bioquim Biol Mol & Genet, Caceres 10071, Spain. RP Jensen, RT (reprint author), NIDDK, Digest Dis Branch, NIH, Bldg 10,Rm 9C-103,10 Ctr Dr,MSC 1804, Bethesda, MD 20892 USA. RI Garcia-Marin, Luis /L-4680-2014; Tapia, Jose/C-5181-2008; Bragado, Maria/L-6988-2014 OI Garcia-Marin, Luis /0000-0002-1795-7381; Tapia, Jose/0000-0002-3614-6867; Bragado, Maria/0000-0001-7770-0775 NR 75 TC 17 Z9 17 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 MAY 23 PY 2003 VL 278 IS 21 BP 19008 EP 19016 DI 10.1074/jbc.M300832200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 679PY UT WOS:000182932200038 PM 12651850 ER PT J AU Shah, BH Farshori, MP Jambusaria, A Catt, KJ AF Shah, BH Farshori, MP Jambusaria, A Catt, KJ TI Roles of Src and epidermal growth factor receptor transactivation in transient and sustained ERK1/2 responses to gonadotropin-releasing hormone receptor activation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; PROLONGED NUCLEAR RETENTION; SIGNAL-REGULATED KINASE-1/2; SMOOTH-MUSCLE CELLS; ANGIOTENSIN-II; EGF RECEPTOR; TYROSINE KINASES; PC12 CELLS; INTERNALIZATION KINETICS; BETA-ARRESTIN AB The duration as well as the magnitude of mitogen-activated protein kinase activation has been proposed to regulate gene expression and other specific intracellular responses in individual cell types. Activation of ERK1/2 by the hypothalamic neuropeptide gonadotropin-releasing hormone (GnRH) is relatively sustained in alphaT3-1 pituitary gonadotropes and HEK293 cells but is transient in immortalized GT1-7 neurons. Each of these cell types expresses the epidermal growth factor receptor (EGFR) and responds to EGF stimulation with significant but transient ERK1/2 phosphorylation. However, GnRH-induced ERK1/2 phosphorylation caused by EGFR transactivation was confined to GT1-7 cells and was attenuated by EGFR kinase inhibition. Neither EGF nor GnRH receptor activation caused translocation of phospho-ERK1/2 into the nucleus in GT1-7 cells. In contrast, agonist stimulation of GnRH receptors expressed in HEK293 cells caused sustained phosphorylation and nuclear translocation of ERK1/2 by a protein kinase C-dependent but EGFR-independent pathway. GnRH-induced activation of ERK1/2 was attenuated by the selective Src kinase inhibitor PP2 and the negative regulatory C-terminal Src kinase in GT1-7 cells but not in HEK293 cells. In GT1-7 cells, GnRH stimulated phosphorylation and nuclear translocation of the ERK1/2-dependent protein, p90(RSK-1) (RSK-1). These results indicate that the duration of ERK1/2 activation depends on the signaling pathways utilized by GnRH in specific target cells. Whereas activation of the G(q)/protein kinase C pathway in HEK293 cells causes sustained phosphorylation and translocation of ERK1/2 to the nucleus, transactivation of the EGFR by GnRH in GT1-7 cells elicits transient ERK1/2 signals without nuclear accumulation. These findings suggest that transactivation of the tightly regulated EGFR can account for the transient ERK1/2 responses that are elicited by stimulation of certain G protein-coupled receptors. C1 NICHD, ERRB, NIH, Bethesda, MD 20892 USA. RP Catt, KJ (reprint author), NICHD, ERRB, NIH, Bldg 49,Rm 6A36, Bethesda, MD 20892 USA. NR 49 TC 67 Z9 68 U1 1 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 MAY 23 PY 2003 VL 278 IS 21 BP 19118 EP 19126 DI 10.1074/jbc.M212932200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 679PY UT WOS:000182932200053 PM 12642580 ER PT J AU Yahiro, K Wada, A Nakayama, M Kimura, T Ogushi, K Niidome, T Aoyagi, H Yoshino, K Yonezawa, K Moss, J Hirayama, T AF Yahiro, K Wada, A Nakayama, M Kimura, T Ogushi, K Niidome, T Aoyagi, H Yoshino, K Yonezawa, K Moss, J Hirayama, T TI Protein-tyrosine phosphatase alpha, RPTP alpha, is a Helicobacter pylori VacA receptor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID VACUOLATING CYTOTOXIN; GASTRIC CELLS; TOXIN; BINDING; BETA; SENSITIVITY; INDUCTION; INFECTION; CLONING; DISEASE AB Helicobacter pylori vacuolating cytotoxin, VacA, induces vacuolation, mitochondrial damage, cytochrome c release, and apoptosis of gastric epithelial cells. To detect gastric proteins that serve as VacA receptors, we used VacA co-immunoprecipitation techniques following biotinylation of the cell surface and identified p250, a receptor-like protein-tyrosine phosphatase beta (RPTPbeta) as a VacA-binding protein (Yahiro, K., Niidome, T., Kimura, M., Hatakeyama, T., Aoyagi, H., Kurazono, H., Imagawa, K., Wada, A., Moss, J., and Hirayama, T. (1999) J. Biol. Chem. 274, 36693-36699). VacA causes vacuolation of G401 cells, a human kidney tumor cell line, although they do not express RPTPbeta. By co-immunoprecipitation with VacA, we identified p140 as a potential receptor in those cells. p140 purified by chromatography on a peanut agglutinin affinity matrix contained internal amino acid sequences of RGEENTDYVNASFIDGYRQK and AEGILDVFQTVK, which are identical to those in RPTPalpha. The peptide mass fingerprinting of p140 by time of flight-MS analysis also supported this identification. Treatment of G401 cells with RPTPalpha-morpholino antisense oligonucleotide before exposure to toxin inhibited vacuolation. These data suggest that RPTPbeta acts as a receptor for VacA in G401 cells. Thus, two receptor tyrosine phosphatases, RPTPalpha and RPTPbeta, serve as VacA receptors. C1 Nagasaki Univ, Inst Trop Med, Dept Bacteriol, Nagasaki 8528523, Japan. Japan Sci & Technol Corp, PRESTO, Saitama, Japan. Nagasaki Univ, Fac Engn, Dept Appl Chem, Nagasaki 8528521, Japan. Kobe Univ, Biosignal Res Ctr, Kobe, Hyogo 6578501, Japan. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Hirayama, T (reprint author), Nagasaki Univ, Inst Trop Med, Dept Bacteriol, Nagasaki 8528523, Japan. RI Niidome, Takuro/F-1508-2010 OI Niidome, Takuro/0000-0002-8070-8708 NR 32 TC 72 Z9 77 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 MAY 23 PY 2003 VL 278 IS 21 BP 19183 EP 19189 DI 10.1074/jbc.M300117200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 679PY UT WOS:000182932200062 PM 12626515 ER PT J AU Ghorbel, MT Sharman, G Leroux, M Barrett, T Donovan, DM Becker, KG Murphy, D AF Ghorbel, MT Sharman, G Leroux, M Barrett, T Donovan, DM Becker, KG Murphy, D TI Microarray analysis reveals interleukin-6 as a novel secretory product of the hypothalamo-neurohypophyseal system SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PITUITARY-ADRENAL AXIS; GENE-EXPRESSION; MESSENGER-RNA; HYPOTHALAMONEUROHYPOPHYSEAL SYSTEM; RAT-BRAIN; CDNA MICROARRAYS; DNA ARRAYS; IN-VITRO; VASOPRESSIN; NEURONS AB Physiological activation of the hypothalamo-neurohypophyseal system (HNS) by dehydration results is a massive release of vasopressin (VP) from the posterior pituitary. This is accompanied by a functional remodeling of the HNS. In this study we used cDNA arrays in an attempt to identify genes that exhibit differential expression in the hypothalamus following dehydration. Our study revealed nine candidate genes, including interleukin-6 (IL-6) as a putative novel secretory product of HNS worthy of further analysis. In situ hybridization and immunocytochemistry confirmed that IL-6 is robustly expressed in the supraoptic (SON) and the paraventricular (PVN) nuclei of the hypothalamus. By double-staining immunofluorescence we showed that IL-6 is largely co-localized with VP in the SON and PVN. In situ hybridization, immunocytochemistry, and Western blotting all revealed IL-6 up-regulation in the SON and PVN following dehydration, thus validating the array data. The same dehydration stimulus resulted in an increase in IL-6 immunoreactivity in the axons of the internal zone of the median eminence and a marked reduction in IL-6-like material in the posterior pituitary gland. We thus suggest that IL-6 takes the same secretory pathway as VP and is secreted from the posterior pituitary following a physiological stimulus. C1 Univ Bristol, Bristol Royal Infirm, Univ Res Ctr Neuroendocrinol, Bristol BS2 8HW, Avon, England. NIA, DNA Array Unit, NIH, Baltimore, MD 21224 USA. USDA, Biotechnol & Germplasm Lab, Beltsville, MD 20705 USA. RP Ghorbel, MT (reprint author), Univ Bristol, Sch Med Sci, Dept Anat, MRC Ctr Synapt Plast, Univ Walk, Bristol BS8 1TD, Avon, England. RI Murphy, David/C-3967-2012; OI Murphy, David/0000-0003-2946-0353; Becker, Kevin/0000-0002-6794-6656 NR 40 TC 45 Z9 45 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 MAY 23 PY 2003 VL 278 IS 21 BP 19280 EP 19285 DI 10.1074/jbc.M209902200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 679PY UT WOS:000182932200073 PM 12639960 ER PT J AU Hiol, A Davey, PC Osterhout, JL Waheed, AA Fischer, ER Chen, CK Milligan, G Druey, KM Jones, TLZ AF Hiol, A Davey, PC Osterhout, JL Waheed, AA Fischer, ER Chen, CK Milligan, G Druey, KM Jones, TLZ TI Palmitoylation regulates regulators of G-protein signaling (RGS) 16 function - I. Mutation of amino-terminal cysteine residues on RGS16 prevents its targeting to lipid rafts and palmitoylation of an internal cysteine residue SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PLASMA-MEMBRANE LOCALIZATION; FUSION PROTEINS; ALPHA-SUBUNITS; BINDING; RECEPTOR; DOMAIN; G-ALPHA(13); ASSOCIATION; TRANSDUCIN; MODULATION AB Regulators of G-protein signaling (RGS) proteins down-regulate signaling by heterotrimeric G-proteins by accelerating GTP hydrolysis on the Galpha subunits. Palmitoylation, the reversible addition of palmitate to cysteine residues, occurs on several RGS proteins and is critical for their activity. For RGS16, mutation of Cys-2 and Cys-12 blocks its incorporation of [H-3]palmitate and ability to turn-off G(i) and G(q) signaling and significantly inhibited its GTPase activating protein activity toward a Galpha subunit fused to the 5-hydroxytryptamine receptor 1A, but did not reduce its plasma membrane localization based on cell fractionation studies and immunoelectron microscopy. Palmitoylation can target proteins, including many signaling proteins, to membrane microdomains, called lipid rafts. A subpopulation of endogenous RGS16 in rat liver membranes and overexpressed RGS16 in COS cells, but not the nonpalmitoylated cysteine mutant of RGS16, localized to lipid rafts. However, disruption of lipid rafts by treatment with methyl-beta-cyclodextrin did not decrease the GTPase activating protein activity of RGS16. The lipid raft fractions were enriched in protein acyltransferase activity, and RGS16 incorporated [H-3] palmitate into a peptide fragment containing Cys-98, a highly conserved cysteine within the RGS box. These results suggest that the amino-terminal palmitoylation of an RGS protein promotes its lipid raft targeting that allows palmitoylation of a poorly accessible cysteine residue that we show in the accompanying article (Osterhout, J. L., Waheed, A. A., Hiol, A., Ward, R. J., Davey, P. C., Nini, L., Wang, J., Milligan, G., Jones, T. L. Z., and Druey, K. M. (2003) J. Biol. Chem. 278, 19309 19316) was critical for RGS16 and RGS4 GAP activity. C1 NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. NIAID, Microscopy Branch, NIH, Hamilton, MT 59840 USA. Univ Utah, Dept Ophthalmol, Salt Lake City, UT 84112 USA. Univ Glasgow, Inst Biomed & Life Sci, Div Biochem & Mol Biol, Mol Pharmacol Grp, Glasgow G12 8QQ, Lanark, Scotland. RP Jones, TLZ (reprint author), NIDDK, Metab Dis Branch, NIH, Bldg 10,Rm 9C101, Bethesda, MD 20892 USA. RI Milligan, Graeme/F-9426-2011 OI Milligan, Graeme/0000-0002-6946-3519 NR 49 TC 51 Z9 52 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 MAY 23 PY 2003 VL 278 IS 21 BP 19301 EP 19308 DI 10.1074/jbc.M210123200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 679PY UT WOS:000182932200076 PM 12642593 ER PT J AU Osterhout, JL Waheed, AA Hiol, A Ward, RJ Davey, PC Nini, L Wang, J Milligan, G Jones, TLZ Druey, KM AF Osterhout, JL Waheed, AA Hiol, A Ward, RJ Davey, PC Nini, L Wang, J Milligan, G Jones, TLZ Druey, KM TI Palmitoylation regulates regulator of G-protein signaling (RGS) 16 function - II. Palmitoylation of a cysteine residue in the RGS box is critical for RGS16 GTPase accelerating activity and regulation of G(i)-coupled signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RECEPTOR-CONSTITUTIVE ACTIVITY; PLASMA-MEMBRANE LOCALIZATION; TYROSINE PHOSPHORYLATION; ACTIVATING PROTEINS; ALPHA-SUBUNITS; GAP ACTIVITY; BINDING; KINASE; GAIP; INTERACTS AB Palmitoylation is a reversible post-translational modification used by cells to regulate protein activity. The regulator of G-protein signaling (RGS) proteins RGS4 and RGS16 share conserved cysteine (Cys) residues that undergo palmitoylation. In the accompanying article (Hiol, A., Davey, P. C., Osterhout, J. L., Waheed, A. A., Fischer, E. R., Chen, C. K., Milligan, G., Druey, K. M., and Jones, T. L. Z. (2003) J. Biol. Chem. 278, 19301-19308), we determined that mutation of NH2-terminal cysteine residues in RGS16 (Cys-2 and Cys-12) reduced GTPase accelerating (GAP) activity toward a 5-hydroxytryptamine (5-HT1A)/Galpha(o1) receptor fusion protein in cell membranes. NH2-terminal acylation also permitted palmitoylation of a cysteine residue in the RGS box of RGS16 (Cys-98). Here we investigated the role of internal palmitoylation in RGS16 localization and GAP activity. Mutation of RGS16 Cys-98 or RGS4 Cys-95 to alanine reduced GAP activity on the 5-HT1A/Galpha(o1) fusion protein and regulation of adenylyl cyclase inhibition. The C98A mutation had no effect on RGS16 localization or GAP activity toward purified G-protein alpha subunits. Enzymatic palmitoylation of RGS16 resulted in internal palmitoylation on residue Cys-98. Palmitoylated RGS16 or RGS4 WT but not C98A or C95A preincubated with membranes expressing 5-HT1a/Galpha(o1) displayed increased GAP activity over time. These results suggest that palmitoylation of a Cys residue in the RGS box is critical for RGS16 and RGS4 GAP activity and their ability to regulate G(i)-coupled signaling in mammalian cells. C1 NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. Univ Glasgow, Inst Biomed & Life Sci, Div Biochem & Mol Biol, Mol Pharmacol Grp, Glasgow G12 8QQ, Lanark, Scotland. RP Jones, TLZ (reprint author), NIDDK, Metab Dis Branch, NIH, Bldg 10,Rm 9C101, Bethesda, MD 20892 USA. RI Milligan, Graeme/F-9426-2011 OI Milligan, Graeme/0000-0002-6946-3519 NR 43 TC 31 Z9 32 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 MAY 23 PY 2003 VL 278 IS 21 BP 19309 EP 19316 DI 10.1074/jbc.M210124200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 679PY UT WOS:000182932200077 PM 12642592 ER PT J AU Glick, E Chau, JS Vigna, KL McCulloch, SD Adman, ET Kunkel, TA Loeb, LA AF Glick, E Chau, JS Vigna, KL McCulloch, SD Adman, ET Kunkel, TA Loeb, LA TI Amino acid substitutions at conserved tyrosine 52 alter fidelity and bypass efficiency of human DNA polymerase eta SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID XERODERMA-PIGMENTOSUM VARIANT; ESCHERICHIA-COLI DINB; THYMINE DIMER BYPASS; CRYSTAL-STRUCTURE; LESION-BYPASS; ERROR-PRONE; REPLICATION; MUTATIONS; PROTEIN; MECHANISM AB DNA polymerase eta (Poleta) is a member of a new class of DNA polymerases that is able to copy DNA containing damaged nucleotides. These polymerases are highly error-prone during copying of unaltered DNA templates. We analyzed the relationship between bypass efficiency and fidelity of DNA synthesis by introducing substitutions for Tyr-52, a highly conserved amino acid, within the human DNA polymerase eta (hPoleta) finger domain. Most substitutions for Tyr-52 caused reduction in bypass of UV-associated damage, measured by the ability to rescue the viability of UV-sensitive yeast cells at a high UV dose. For most mutants, the reduction in bypass ability paralleled the reduction in polymerization activity. Interestingly, the hPoleta Y52E mutant exhibited a greater reduction in bypass efficiency than polymerization activity. The reduction in bypass efficiency was accompanied by an up to 11-fold increase in the incorporation of complementary nucleotides relative to non-complementary nucleotides. The fidelity of DNA synthesis, measured by copying a gapped M13 DNA template in vitro, was also enhanced as much as 15-fold; the enhancement resulted from a decrease in transitions, which were relatively frequent, and a large decrease in transversions. Our demonstration that an amino acid substitution within the active site enhances the fidelity of DNA synthesis by hPoleta, one of the most inaccurate of DNA polymerases, supports the hypothesis that even error-prone DNA polymerases function in base selection. C1 Univ Washington, Dept Pathol, Joseph Gottstein Mem Canc Res Lab, Seattle, WA 98195 USA. Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA. NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Loeb, LA (reprint author), Univ Washington, Dept Pathol, Joseph Gottstein Mem Canc Res Lab, Seattle, WA 98195 USA. FU NIA NIH HHS [AG01751]; NIEHS NIH HHS [ES11045, P30ES07033] NR 43 TC 12 Z9 13 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 23 PY 2003 VL 278 IS 21 BP 19341 EP 19346 DI 10.1074/jbc.M300686200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 679PY UT WOS:000182932200081 PM 12644469 ER PT J AU Jensen, A Calvayrac, G Karahalil, B Bohr, VA Stevnsner, T AF Jensen, A Calvayrac, G Karahalil, B Bohr, VA Stevnsner, T TI Mammalian 8-oxoguanine DNA glycosylase 1 incises 8-oxoadenine opposite cytosine in nuclei and mitochondria, while a different glycosylase incises 8-oxoadenine opposite guanine in nuclei SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BASE EXCISION-REPAIR; OXIDATIVE DAMAGE; LIVER-MITOCHONDRIA; REACTION-MECHANISM; HUMAN HOMOLOG; HUMAN-CELLS; RAT-LIVER; ENDONUCLEASE; PROTEIN; LESIONS AB Cells are continuously exposed to oxidative species, which cause several types of oxidative DNA lesions. Repair of some of these lesions has been well characterized but little is known about the repair of many DNA lesions. The oxidized adenine base, 7,8-dihydro-8-oxoadenine (8-oxoA), is a relatively common DNA lesion, which is believed to be mutagenic in mammalian cells. This study investigates repair of 8-oxoA in nuclear and mitochondrial mammalian extracts. In nuclei, 8-oxoA: C and 8-oxoA: G base pairs are recognized and cleaved; in contrast, only 8-oxoA: C base pairs are cleaved in mitochondria. High stability of the DNA helix increased the efficiency of incision of 8-oxoA, and the efficiency decreased at DNA bends and condensed regions of the helix. Using liver extracts from mice knocked out for 8-oxoguanine DNA glycosylase 1 (OGG1), we demonstrated that OGG1 is the only glycosylase that incises 8-oxoA, when base-paired with cytosine in mitochondria and nuclei, but a different enzyme incises 8-oxoA when base-paired with guanine in the nucleus. Consistent with this result, a covalent DNA-protein complex was trapped using purified human OGG1 or human nuclear or mitochondrial extracts with a DNA substrate containing an 8-oxoA: C base pair. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Aarhus Univ, Dept Mol Biol, Danish Ctr Mol Gerontol, DK-8000 Aarhus C, Denmark. Gazi Univ, Fac Pharm, Dept Toxicol, TR-06330 Ankara, Turkey. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, Box 1,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 50 TC 35 Z9 37 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 MAY 23 PY 2003 VL 278 IS 21 BP 19541 EP 19548 DI 10.1074/jbc.M301504200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 679PY UT WOS:000182932200105 PM 12644468 ER PT J AU Lim, SE Ponamarev, MV Longley, MJ Copeland, WC AF Lim, SE Ponamarev, MV Longley, MJ Copeland, WC TI Structural determinants in human DNA polymerase gamma account for mitochondrial toxicity from nucleoside analogs SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE DNA polymerase; mitochondria; replication; antiviral nucleoside analogs; AIDS ID HUMAN-IMMUNODEFICIENCY-VIRUS; I KLENOW FRAGMENT; TYPE-1 REVERSE-TRANSCRIPTASE; PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA; ANTI-HIV DEOXYNUCLEOTIDES; P55 ACCESSORY SUBUNIT; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; KINETIC CHARACTERIZATION; ANGSTROM RESOLUTION AB Although antiviral nucleoside analog therapy successfully delays progression of HIV infection to AIDS, these drugs cause unwelcome side-effects by inducing mitochondrial toxicity. We and others have demonstrated that the mitochondrial polymerase, DNA polymerase gamma (pol gamma), participates in mitochondrial toxicity by incorporating these chain-terminating antiviral nucleotide analogs into DNA. Here, we explore the role of three highly conserved amino acid residues in the active site of human pol gamma that modulate selection of nucleotide analogs as substrates for incorporation. Sequence alignments, crystal structures and mutagenesis studies of family A DNA polymerases led us to change Tyr951 and Tyr955 in polymerase motif B to Phe and Ala, and Glu895 in polymerase motif A was changed to Ala. The mutant polymerases were tested for their ability to incorporate natural nucleotides and the five antiviral nucleoside analogs currently approved for antiviral therapy: AZT, ddC, D4T, 3TC and carbovir. Steady-state kinetic analysis of the pol gamma derivatives with the normal and antiviral nucleotides demonstrated that Tyr951 is largely responsible for the ability of pol gamma to incorporate dideoxynucleotides and D4T-MP. Mutation of Tyr951 to Phe renders the enzyme resistant to dideoxynucleotides and D4T-TP without compromising the activity of the polymerase. Alteration of Glu895 and Tyr955 to Ala had the largest effect on overall polymerase activity with normal nucleotides, producing dramatic increases in K-m(dNTP) and large decreases in k(cat). Mutation of Tyr955 in pol gamma causes the degenerative disease progressive external ophthalmoplegia in humans, and we show that this residue partially accounts for the ability of pol gamma to incorporate D4T-MP and carbovir. Alteration of Glu895 to Ala slightly increased discrimination against dideoxynucleotides and D4T-TP. The mechanisms by which pol gamma selects certain nucleotide analogs are discussed. Published by Elsevier Science Ltd. C1 NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Copeland, WC (reprint author), NIEHS, Mol Genet Lab, POB 12233, Res Triangle Pk, NC 27709 USA. NR 65 TC 64 Z9 65 U1 0 U2 5 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAY 23 PY 2003 VL 329 IS 1 BP 45 EP 57 DI 10.1016/S0022-2836(03)00405-4 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 682AF UT WOS:000183067000005 PM 12742017 ER PT J AU McDonald, D Wu, L Bohks, SM KewalRamani, VN Unutmaz, D Hope, TJ AF McDonald, D Wu, L Bohks, SM KewalRamani, VN Unutmaz, D Hope, TJ TI Recruitment of HIV and its receptors to dendritic cell-T cell junctions SO SCIENCE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; DC-SIGN; IMMUNOLOGICAL SYNAPSE; ANTIGEN; TRANS; ACTIVATION; INFECTION; SUBSETS AB Monocyte-derived dendritic cells (MDDCs) can efficiently bind and transfer HIV infectivity without themselves becoming infected. Using live-cell microscopy, we found that HIV was recruited to sites of cell contact in MDDCs. Analysis of conjugates between MDDCs and T cells revealed that, in the absence of antigen-specific signaling, the HIV receptors CD4, CCR5, and CXCR4 on the T cell were recruited to the interface while the MDDCs concentrated HIV to the same region. We propose that contact between dendritic cells and T cells facilitates transmission of HIV by locally concentrating virus, receptor, and coreceptor during the formation of an infectious synapse. C1 Univ Illinois, Dept Microbiol & Immunol, Chicago, IL 60612 USA. NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. Vanderbilt Univ, Dept Microbiol & Immunol, Nashville, TN 37232 USA. RP Hope, TJ (reprint author), Univ Illinois, Dept Microbiol & Immunol, Chicago, IL 60612 USA. RI Wu, Li/E-4330-2011 OI Wu, Li/0000-0002-5468-2487 FU NIAID NIH HHS [R01-AI47770, R01 AI052051, R01-AI49131, R01-AI52051] NR 19 TC 468 Z9 482 U1 4 U2 17 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 MAY 23 PY 2003 VL 300 IS 5623 BP 1295 EP 1297 DI 10.1126/science.1084238 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 681NN UT WOS:000183042400050 PM 12730499 ER PT J AU Kim, JM Wu, H Green, G Winkler, CA Kopp, JB Miner, JH Unanue, ER Shaw, AS AF Kim, JM Wu, H Green, G Winkler, CA Kopp, JB Miner, JH Unanue, ER Shaw, AS TI CD2-associated protein haploinsufficiency is linked to glomerular disease susceptibility SO SCIENCE LA English DT Article ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; NEPHROTIC SYNDROME; IMMUNOTACTOID GLOMERULOPATHY; DOWN-REGULATION; COMPLEX; MEMBRANE; CELLS AB Loss of CD2-associated protein (CD2AP), a component of the filtration complex in the kidney, causes death in mice at 6 weeks of age. Mice with CD2AP haploin-sufficiency developed glomerular changes at 9 months of age and had increased susceptibility to glomerular injury by nephrotoxic antibodies or immune complexes. Electron microscopic analysis of podocytes revealed defects in the formation of multivesicular bodies, suggesting an impairment of the intracellular degradation pathway. Two human patients with focal segmental glomerulosclerosis had a mutation predicted to ablate expression of one CD2AP allele, implicating CD2AP as a determinant of human susceptibility to glomerular disease. C1 Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Internal Med, Div Renal, St Louis, MO 63110 USA. NCI, Mol Epidemiol Sect, Lab Genom Divers, NIH, Frederick, MD 21702 USA. NIDDKD, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. RP Shaw, AS (reprint author), Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. OI Kopp, Jeffrey/0000-0001-9052-186X NR 23 TC 292 Z9 336 U1 0 U2 6 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 MAY 23 PY 2003 VL 300 IS 5623 BP 1298 EP 1300 DI 10.1126/science.1081068 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 681NN UT WOS:000183042400051 PM 12764198 ER PT J AU Brun, M Sabbagh, D Kim, S Dougherty, ER AF Brun, M Sabbagh, D Kim, S Dougherty, ER TI Corrected small-sample estimation of the Bayes error SO BIOINFORMATICS LA English DT Article ID GENE AB Motivation: A major problem of pattern classification is estimation of the Bayes error when only small samples are available. One way to estimate the Bayes error is to design a classifier based on some classification rule applied to sample data, estimate the error of the designed classifier, and then use this estimate as an estimate of the Bayes error. Relative to the Bayes error, the expected error of the designed classifier is biased high, and this bias can be severe with small samples. Results: This paper provides a correction for the bias by subtracting a term derived from the representation of the estimation error. It does so for Boolean classifiers, these being defined on binary features. Although the general theory applies to any Boolean classifier, a model is introduced to reduce the number of parameters. A key point is that the expected correction is conservative. Properties of the corrected estimate are studied via simulation. The correction applies to binary predictors because they are mathematically identical to Boolean classifiers. In this context the correction is adapted to the coefficient of determination, which has been used to measure nonlinear multivariate relations between genes and design genetic regulatory networks. An application using gene-expression data from a microarray experiment is provided on the website http://gspsnap.tamu.edu/smallsample/ (user:'smallsample', password:'smallsample)'). C1 Texas A&M Univ, Dept Elect Engn, College Stn, TX 77840 USA. NHGRI, Canc Genet Branch, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. RP Dougherty, ER (reprint author), Texas A&M Univ, Dept Elect Engn, College Stn, TX 77840 USA. NR 6 TC 4 Z9 5 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD MAY 22 PY 2003 VL 19 IS 8 BP 944 EP 951 DI 10.1093/bioinformatics/btg144 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 682MG UT WOS:000183095300006 PM 12761056 ER PT J AU Yang, HH Hu, Y Edmonson, M Buetow, K Lee, MP AF Yang, HH Hu, Y Edmonson, M Buetow, K Lee, MP TI Computation method to identify differential allelic gene expression and novel imprinted genes SO BIOINFORMATICS LA English DT Article ID CANCER; RELAXATION AB Motivation: Genomic imprinting plays an important role in both normal development and diseases. Abnormal imprinting is strongly associated with several human diseases including cancers. Most of the imprinted genes were discovered in the neighborhood of the known imprinted genes. This approach is difficult to extend to analyze the whole genome. We have decided to take a computational approach to systematically search the whole genome for the presence of mono-allelic expressed genes and imprinted genes in human genome. Results: A computational method was developed to identify novel imprinted or mono-allelic genes. Individuals represented in human cDNA libraries were genotyped using Bayesian statistics, and differential expression of polymorphic alleles was identified. A significant reduction in the number of libraries that expressed both alleles, measured by Z-statistics, is a strong indicator for an imprinted or a mono-allelic gene. C1 NCI, Lab Populat Genet, Gaithersburg, MD 20877 USA. RP Lee, MP (reprint author), NCI, Lab Populat Genet, Gaithersburg, MD 20877 USA. NR 11 TC 15 Z9 15 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD MAY 22 PY 2003 VL 19 IS 8 BP 952 EP 955 DI 10.1093/bioinformatics/btg127 PG 4 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 682MG UT WOS:000183095300007 PM 12761057 ER PT J AU Tanaka, N Hora, K Makishima, H Kamijo, Y Kiyosawa, K Gonzalez, FJ Aoyama, T AF Tanaka, N Hora, K Makishima, H Kamijo, Y Kiyosawa, K Gonzalez, FJ Aoyama, T TI In vivo stabilization of nuclear retinoid X receptor alpha in the presence of peroxisome proliferator-activated receptor alpha SO FEBS LETTERS LA English DT Article DE retinoid X receptor alpha; peroxisome proliferator-activated receptor alpha; heterodimer; stabilization ID THYROID-HORMONE RECEPTOR; PPAR-ALPHA; DIFFERENTIAL EXPRESSION; TARGETED DISRUPTION; TISSUE DISTRIBUTION; ACID RECEPTOR; RAT-LIVER; RXR; PROTEIN; MICE AB Retinoid X receptor a (RXRalpha) can reveal diverse functions through forming a heterodimer with peroxisome proliferator-activated receptor alpha (PPARalpha). However, the mechanism of regulation of the cellular RXRalpha level is unclear. Thus' quantitative change of RXRalpha was investigated in mouse liver. Nuclear RXRalpha level was constitutively lower in PPARalpha-null mice than in wild-type mice. The level was also increased by clofibrate treatment in wild-type mice without a concomitant increase of RXRalpha mRNA, but not in PPARalpha-null mice. Pulse chase experiments demonstrated that the presence of PPARalpha and its activation by ligands significantly affected the stability of nuclear RXRalpha. These findings suggest a novel regulatory mechanism of nuclear RXRalpha in vivo. (C) 2003 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies. C1 Shinshu Univ, Sch Med, Res Ctr Aging & Adaptat, Dept Aging Biochem, Matsumoto, Nagano 3908621, Japan. Shinshu Univ, Sch Med, Dept Internal Med 2, Matsumoto, Nagano 3908621, Japan. NCI, Lab Metab, Bethesda, MD 20892 USA. RP Aoyama, T (reprint author), Shinshu Univ, Sch Med, Res Ctr Aging & Adaptat, Dept Aging Biochem, 3-1-1 Asahi, Matsumoto, Nagano 3908621, Japan. NR 34 TC 12 Z9 12 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD MAY 22 PY 2003 VL 543 IS 1-3 BP 120 EP 124 DI 10.1016/S0014-5793(03)00423-X PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 682ZD UT WOS:000183121500024 PM 12753917 ER PT J AU DePamphilis, ML AF DePamphilis, ML TI The 'ORC cycle': a novel pathway for regulating eukaryotic DNA replication SO GENE LA English DT Review DE origin recognition complexes; replication origins; Orc1; cell division cycle; ubiquitination; nuclear structure ID ORIGIN RECOGNITION COMPLEX; XENOPUS EGG EXTRACTS; MINICHROMOSOME MAINTENANCE PROTEINS; EARLY G1 PHASE; CELL-CYCLE; SCHIZOSACCHAROMYCES-POMBE; SACCHAROMYCES-CEREVISIAE; MAMMALIAN NUCLEI; BUDDING YEAST; S-PHASE AB The function of the 'origin recognition complex' (ORC) in eukaryotic cells is to select genomic sites where pre-replication complexes (pre-RCs) can be assembled. Subsequent activation of these pre-RCs results in bi-directional DNA replication that originates at or close to the ORC DNA binding sites. Recent results have revealed that one or more of the six ORC subunits is modified during the G1 to S-phase transition in such a way that ORC activity is inhibited until mitosis is complete and a nuclear membrane is assembled. In yeast, Cdk1/Clb phosphorylates ORC. In frog eggs, pre-RC assembly destabilizes ORC/chromatin sites, and ORC is eventually hyperphosphorylated and released. In mammals, the affinity of Orc1 for chromatin is selectively reduced during S-phase and restored during early G1-phase. Unbound Orc1 is ubiquitinated during S-phase and in some cases degraded. Thus, most, perhaps all, eukaryotes exhibit some manifestation of an 'ORC cycle' that restricts the ability of ORC to initiate pre-RC assembly to the early G1-phase of the cell cycle, making the 'ORC cycle' the premier step in determining when replication begins. (C) 2003 Published by Elsevier Science B.V. C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP DePamphilis, ML (reprint author), NICHHD, NIH, Bldg 6-416,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 118 TC 88 Z9 89 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD MAY 22 PY 2003 VL 310 BP 1 EP 15 DI 10.1016/S0378-1119(03)00546-8 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 692UD UT WOS:000183677900001 PM 12801628 ER PT J AU Huang, XL Pawliczak, R Yao, XL Madara, P Alsaaty, S Shelhamer, JH Cowan, MJ AF Huang, XL Pawliczak, R Yao, XL Madara, P Alsaaty, S Shelhamer, JH Cowan, MJ TI Characterization of the human p11 promoter sequence SO GENE LA English DT Article DE S100 protein; annexin; transcriptional regulation; calpactin; Sp-1; AP-2; transcription start point; rapid amplification of cDNA ends; electrophoretic mobility shift assay; reporter gene ID ANNEXIN-II TETRAMER; CYTOSOLIC PHOSPHOLIPASE A(2); HUMAN EPITHELIAL-CELLS; TRANSCRIPTIONAL REGULATION; PLASMINOGEN ACTIVATION; GENE-EXPRESSION; SYNTHASE GENE; BOVINE BRAIN; PROTEIN; SP1 AB p11 is expressed in many different cell types, and serves a variety of regulatory functions. In order to better understand the transcriptional control of this protein, the 5' promoter region of the human p11 gene was cloned and sequenced. After confirming the transcription start point (TSP) using 5' rapid amplification of cDNA ends analysis, the 5' promoter was analysed. The sequence lacks a TATA box, but contains a variety of putative regulatory elements. There are two GAS sites, two AP-1 sites, two overlapping Sp-1 sites, and a gamma-IRE site clustered between -1080 and -1450. There is another cluster of putative regulatory sites between the TSP and -550 which contains two Sp-1 sites, two AP-2 sites, one GAS site, one NF-kappaB site, an incomplete CAAT box (8/9) and an overlapping Sp-1/AP-2 site at -17 to -26. Reporter gene constructs containing 4225 and 1498 bases 5' of the TSP demonstrated excellent unidirectional transcriptional activity in both constructs. Reporter genes containing serial 5' deletions were compared to the -1498 construct. The reporter gene which contained base pairs (bp) -36 to +89 had almost no activity. The reporter gene containing -188 to +89 had 50% of the -1498 construct, indicating that this sequence contains at least the minimal promoter. The Sp-1/AP-2 site near the transcription start site was studied by electrophoretic mobility shift and reporter gene assays. Addition of HeLa cell nuclear extract to labeled double-stranded (ds) oligonucleotide containing this sequence resulted in a gel shift which was inhibited by excess unlabeled ds oligonucleotide and by a consensus cold Sp-1 ds oligonucleotide, indicating specific Sp-1 binding. Excess AP-2 or NF-kappaB ds oligonucleotide had no effect on nuclear protein binding to the sequence. Mutation of the p11 wild-type Sp-1/AP-2 sequence eliminated both nuclear protein binding and the sequences ability to compete with native sequence for nuclear binding protein. A -1048 to +89 reporter construct containing a mutated Sp-1/AP-2 site resulted in a 40% decrease in transcriptional activity. Therefore, the 5' flanking sequence of the p11 gene exhibits promoter activity which may be localized to a variety of controlling regions, of which the proximal Sp-1/AP-2 site appears to be important for basal activity via its Sp-1 binding ability. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Univ Maryland, Div Pulm & Crit Care Med, Baltimore, MD 21201 USA. NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. Med Univ Lodz, Dept Allergy & Clin Immunol, PL-92213 Lodz, Poland. RP Cowan, MJ (reprint author), Univ Maryland, Div Pulm & Crit Care Med, 10 S Pine St,MSTF 800, Baltimore, MD 21201 USA. RI Pawliczak, Rafal/S-9649-2016; OI Pawliczak, Rafal/0000-0001-6784-453X NR 35 TC 12 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD MAY 22 PY 2003 VL 310 BP 133 EP 142 DI 10.1016/S0378-1119(03)00529-8 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 692UD UT WOS:000183677900013 PM 12801640 ER PT J AU Kutty, G Huang, SN Kovacs, JA AF Kutty, G Huang, SN Kovacs, JA TI Characterization of thioredoxin reductase genes (trr1) from Pneumocystis carinii and Pneumocystis jiroveci SO GENE LA English DT Article DE thioredoxin reductase; multicopy gene; PCP; kexin ID MAJOR SURFACE GLYCOPROTEIN; MOLECULAR CHARACTERIZATION; DIHYDROPTEROATE SYNTHASE; SACCHAROMYCES-CEREVISIAE; DIHYDROFOLATE-REDUCTASE; SERINE ENDOPROTEASE; IDENTIFICATION; EXPRESSION; ANTIBODIES; DIVERGENCE AB We have characterized the thioredoxin reductase (trr1) genes from Pneumocystis carinii and Pneumocystis jiroveci, and have demonstrated that multiple copies of an similar to500 base pair fragment of the trr1 gene are present in P. carinii, but not in P. jiroveci. Thioredoxin reductases encoded by the full-length genes have predicted molecular weights of similar to35,000 and show high homology to yeast Trr1. An NADPH-binding domain with a putative redox active site CAVC as well as an flavin-adenine dinucleotide-binding domain are highly conserved in both proteins, which were 85% identical. The multicopy trr1 gene fragments in P. carinii are not transcribed or expressed. Duplication of the gene fragment likely occurred in conjunction with duplication of the kexin homologue, protease-1, which is located immediately upstream of the trr1 gene. Thioredoxin reductase, an enzyme implicated in the growth, survival and pathogenicity of certain microbes, could be a potential target for therapeutic intervention in Pneumocystis infection. (C) 2003 Elsevier Science B.V. All rights reserved. C1 NIH, Dept Crit Care Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Kovacs, JA (reprint author), NIH, Dept Crit Care Med, Warren G Magnuson Clin Ctr, Bldg 10,Room 7D43,MSC 1662, Bethesda, MD 20892 USA. NR 31 TC 5 Z9 7 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD MAY 22 PY 2003 VL 310 BP 175 EP 183 DI 10.1016/S0378-1119(03)00549-3 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 692UD UT WOS:000183677900018 PM 12801645 ER PT J AU Aleman, C Zanuy, D Casanovas, J AF Aleman, C Zanuy, D Casanovas, J TI A quantum mechanical study on the electrostratic interactions of poly(L-lysine)center dot alkyl sulfate complexes SO JOURNAL OF PHYSICAL CHEMISTRY A LA English DT Article ID OPPOSITELY CHARGED SURFACTANTS; SOLID-STATE; STOICHIOMETRIC COMPLEXES; SYNTHETIC POLYPEPTIDES; SIDE-CHAIN; AB-INITIO; POLYELECTROLYTE; CONTINUUM; PROTEINS; ENERGIES AB We report a quantum mechanical study on the electrostatic interactions found in poly(L-lysine)(.)alkyl sulfate complexes, which are materials with interesting technological properties able to adopt self-assembled supramolecular structures. For this purpose, 19 reduced complexes were considered in the gas phase, chloroforrn solution, and aqueous solution. Calculations in the gas phase were carried out up to the MP2/6-311++G(d,p) level, while the influence of the bulk solvent was investigated at the HF/6-311++G(d,p) level using the polarizable continuum model. The electrostatic interaction characteristics of poly(L-lysine)(.)alkyl sulfate complexes have been compared with those of alkyltrimethylammonium(.)poly(alpha,L-glutamate) complexes, a related family of materials previously investigated. C1 Univ Politecn Catalunya, Dept Engn Quim ETS, Engn Ind Barcelona, E-08028 Barcelona, Spain. NCI, Lab Expt & Computat Biol, Frederick, MD 21702 USA. Univ Lleida, Dept Quim, Escola Univ Politecn, Lleida 25001, Spain. RP Aleman, C (reprint author), Univ Politecn Catalunya, Dept Engn Quim ETS, Engn Ind Barcelona, Diagonal 647, E-08028 Barcelona, Spain. RI Casanovas, Jordi/B-5435-2013; Zanuy, David/G-3930-2014 OI Casanovas, Jordi/0000-0002-4914-9194; Zanuy, David/0000-0001-7704-2178 NR 29 TC 7 Z9 8 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1089-5639 J9 J PHYS CHEM A JI J. Phys. Chem. A PD MAY 22 PY 2003 VL 107 IS 20 BP 4151 EP 4156 DI 10.1021/jp027467b PG 6 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 679QN UT WOS:000182933600020 ER PT J AU Senior, C AF Senior, C TI Beauty in the brain of the beholder SO NEURON LA English DT Review ID REWARD AB Facial beauty is an honest signal of the genotypic and phenotypic quality of the bearer. Beautiful people are thus regarded as high-value mates who maximize reproductive success by producing viable offspring. Here, the functional neuroanatomy of facial beauty is reviewed and placed into the context of the distributed model for human face perception. A proposed extension of the distributed model is provided, which takes into account the neuroanatomy of beautiful face perception. C1 NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Senior, C (reprint author), NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. NR 19 TC 59 Z9 64 U1 9 U2 21 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD MAY 22 PY 2003 VL 38 IS 4 BP 525 EP 528 DI 10.1016/S0896-6273(03)00293-9 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 682QV UT WOS:000183104000004 PM 12765605 ER PT J AU Fishman, A Martinez, F Naumheim, K Piantadosi, S Wise, R Ries, A Weinmann, G Wood, DE AF Fishman, A Martinez, F Naumheim, K Piantadosi, S Wise, R Ries, A Weinmann, G Wood, DE CA Natl Emphysema Treatment Trial Res TI A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; HEALTH-STATUS; REHABILITATION; QUESTIONNAIRE; TERM AB BACKGROUND: Lung-volume-reduction surgery has been proposed as a palliative treatment for severe emphysema. Effects on mortality, the magnitude and durability of benefits, and criteria for the selection of patients have not been established. METHODS: A total of 1218 patients with severe emphysema underwent pulmonary rehabilitation and were randomly assigned to undergo lung-volume-reduction surgery or to receive continued medical treatment. RESULTS: Overall mortality was 0.11 death per person-year in both treatment groups (risk ratio for death in the surgery group, 1.01; P=0.90). After 24 months, exercise capacity had improved by more than 10 W in 15 percent of the patients in the surgery group, as compared with 3 percent of patients in the medical-therapy group (P<0.001). With the exclusion of a subgroup of 140 patients at high risk for death from surgery according to an interim analysis, overall mortality in the surgery group was 0.09 death per person-year, as compared with 0.10 death per person-year in the medical-therapy group (risk ratio, 0.89; P=0.31); exercise capacity after 24 months had improved by more than 10 W in 16 percent of patients in the surgery group, as compared with 3 percent of patients in the medical-therapy group (P<0.001). Among patients with predominantly upper-lobe emphysema and low exercise capacity, mortality was lower in the surgery group than in the medical-therapy group (risk ratio for death, 0.47; P=0.005). Among patients with non-upper-lobe emphysema and high exercise capacity, mortality was higher in the surgery group than in the medical-therapy group (risk ratio, 2.06; P=0.02). CONCLUSIONS: Overall, lung-volume-reduction surgery increases the chance of improved exercise capacity but does not confer a survival advantage over medical therapy. It does yield a survival advantage for patients with both predominantly upper-lobe emphysema and low base-line exercise capacity. Patients previously reported to be at high risk and those with non-upper-lobe emphysema and high base-line exercise capacity are poor candidates for lung-volume-reduction surgery, because of increased mortality and negligible functional gain. C1 NETT Coordinating Ctr, Baltimore, MD 21205 USA. Univ Penn, Philadelphia, PA 19104 USA. Univ Michigan, Ann Arbor, MI 48109 USA. St Louis Univ, St Louis, MO 63103 USA. Johns Hopkins Univ, Baltimore, MD USA. Univ Calif San Diego, La Jolla, CA 92093 USA. NHLBI, Bethesda, MD 20892 USA. Univ Washington, Seattle, WA 98195 USA. RP Piantadosi, S (reprint author), NETT Coordinating Ctr, 615 N Wolfe St,Rm 5010, Baltimore, MD 21205 USA. OI Wise, Robert/0000-0002-8353-2349 FU NHLBI NIH HHS [N01HR76105, N01HR76101, N01HR76102, N01HR76103, N01HR76104, N01HR76106, N01HR76107, N01HR76108, N01HR76109, N01HR76110, N01HR76111, N01HR76112, N01HR76113, N01HR76114, N01HR76115, N01HR76116, N01HR76118, N01HR76119] NR 27 TC 865 Z9 903 U1 1 U2 30 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 MAY 22 PY 2003 VL 348 IS 21 BP 2059 EP 2073 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA 680YU UT WOS:000183008300003 PM 12759479 ER PT J AU Bridge, TP Fudala, PJ Herbert, S Leiderman, DB AF Bridge, TP Fudala, PJ Herbert, S Leiderman, DB TI Safety and health policy considerations related to the use of buprenorphine/naloxone as an office-based treatment for opiate dependence SO DRUG AND ALCOHOL DEPENDENCE LA English DT Review DE buprenorphine; naloxone; office-based treatment; opiate dependence; pharmacotherapy; safety ID DRUG-ABUSE TREATMENT; OPIOID DEPENDENCE; PRIMARY-CARE; METHADONE-MAINTENANCE; CYTOCHROME-P450 3A4; NARCOTIC ADDICTION; HEROIN DEPENDENCE; CRIMINAL ACTIVITY; RANDOMIZED TRIAL; N-DEALKYLATION AB dOpiate dependence remains a fundamental challenge confronting health delivery systems and is often characterized as a social and moral issue. The impact of this disorder on healthcare policy is changing with the increased incidence. of HIV, hepatitis C, and tuberculosis infections in opiate-dependent patients. These medical illnesses have substantial effect on escalating healthcare costs, and, therefore, also affect healthcare policy priorities, which are responsive to these costs. Pharmacological treatments for opiate dependence have had limited success; often the consequence of limited access to care. Hence, there is a need to develop new pharmacotherapies for opiate dependence that extend the range of clinical options, including new first-line treatment approaches. This paper will focus on the safety and health policy considerations related to the use of buprenorphine and buprenorphine/naloxone based on data derived from clinical trials and post-marketing surveillance that provide evidence for the use of the medications as first-line treatments in an office-based environment. The evaluation of this evidence formed the basis by the National Institute on Drug Abuse to support and pursue the evaluation and registration of buprenorphine/naloxone and burprenorphine in a public/private sector cooperative effort to become an office-based, first-line treatment for opiate dependence. (C) 2003 Published by Elsevier Science Ireland Ltd. C1 Natl Inst Drug Abuse, Div Treatment Res & Dev, Bethesda, MD 20892 USA. Univ Penn, Sch Med, VA Med Ctr, Philadelphia, PA 19104 USA. RP Bridge, TP (reprint author), 1846 Aquetong Rd, New Hope, PA 18938 USA. FU NIDA NIH HHS [3YO1-DA-30011-04] NR 61 TC 30 Z9 31 U1 2 U2 5 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD MAY 21 PY 2003 VL 70 SU 1 BP S79 EP S85 DI 10.1016/S0376-8716(03)00061-9 PG 7 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 687XJ UT WOS:000183402000008 PM 12738352 ER PT J AU Chiang, CN Hawks, RL AF Chiang, CN Hawks, RL TI Pharmacokinetics of the combination tablet of buprenorphine and naloxone SO DRUG AND ALCOHOL DEPENDENCE LA English DT Review DE buprenorphine; naloxone; pharmacokinetics; metabolism; opiate ID SUBLINGUAL BUPRENORPHINE; CLINICAL-PHARMACOLOGY; CYTOCHROME-P450 3A4; GAS-CHROMATOGRAPHY; DEPENDENT PATIENTS; OPIOID DEPENDENCE; N-DEALKYLATION; HUMAN PLASMA; LIQUID; NORBUPRENORPHINE AB The sublingual combination tablet formulation of buprenorphine and naloxone at a fixed dose ratio of 4:1 has been shown to be as effective as the tablet formulation containing only buprenorphine in treating opiate addiction. The addition of naloxone does not affect the efficacy of buprenorphine for two reasons: (1) naloxone is poorly absorbed sublingually relative to buprenorphine and (2) the half-life for buprenorphine is much longer than for naloxone (32 vs. I h for naloxone). The sublingual absorption of buprenorphine is rapid and the peak plasma concentration occurs I h after dosing. The plasma levels for naloxone are much lower and decline much more rapidly than those for buprenorphine. Increasing dose results in increasing plasma levels of buprenorphine, although this increase is not directly dose-proportional. There is a large inter-subject variability in plasma buprenorphine levels. Due to the large individual variability in opiate dependence level and the large variability in the pharmacokinetics (PK) of buprenorphine, the effective dose or effective plasma concentration is also quite variable. Doses must be titrated to a clinically effective level for individual patients. Published by Elsevier Science Ireland Ltd. C1 Natl Inst Drug Abuse, Div Treatment Res & Dev, Bethesda, MD 20892 USA. RP Chiang, CN (reprint author), Natl Inst Drug Abuse, Div Treatment Res & Dev, 6001 Execut Blvd,Room 4123, Bethesda, MD 20892 USA. NR 48 TC 80 Z9 80 U1 2 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD MAY 21 PY 2003 VL 70 SU 1 BP S39 EP S47 DI 10.1016/S0376-=8716(03)00058-9 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 687XJ UT WOS:000183402000005 PM 12738349 ER PT J AU Leshner, AI AF Leshner, AI TI Accessing opiate dependence treatment medications: buprenorphine products in an office-based setting SO DRUG AND ALCOHOL DEPENDENCE LA English DT Editorial Material C1 Natl Inst Drug Abuse, Bethesda, MD 20892 USA. RP Leshner, AI (reprint author), Amer Assoc Advancement Sci, 1200 New York Ave, Washington, DC 20005 USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD MAY 21 PY 2003 VL 70 SU 1 BP S103 EP S104 DI 10.1016/S0376-8716(03)00063-2 PG 2 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 687XJ UT WOS:000183402000010 PM 12738354 ER PT J AU Simonsen, L Blackwelder, WC Reichert, TA Miller, MA AF Simonsen, L Blackwelder, WC Reichert, TA Miller, MA TI Estimating deaths due to influenza and respiratory syncytial virus SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID MORTALITY; IMPACT C1 NIAID, NIH, Bethesda, MD 20892 USA. NIH, Fogarty Int Ctr, Bethesda, MD USA. RP Simonsen, L (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. OI Simonsen, Lone/0000-0003-1535-8526 FU PHS HHS [A1-15448] NR 5 TC 19 Z9 19 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 MAY 21 PY 2003 VL 289 IS 19 BP 2499 EP 2500 DI 10.1001/jama.289.19.2499-b PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 680KL UT WOS:000182976500012 PM 12759317 ER PT J AU Chobanian, AV Bakris, GL Black, HR Cushman, WC Green, LA Izzo, JL Jones, DW Materson, BJ Oparil, S Wright, JT Roccella, EJ AF Chobanian, AV Bakris, GL Black, HR Cushman, WC Green, LA Izzo, JL Jones, DW Materson, BJ Oparil, S Wright, JT Roccella, EJ CA Natl High Blood Pressure Educ Prog TI The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure - The JNC 7 Report SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID LEFT-VENTRICULAR DYSFUNCTION; CHRONIC HEART-FAILURE; END-POINT REDUCTION; PRACTICE GUIDELINES COMMITTEE; RANDOMIZED CONTROLLED TRIALS; ASSOCIATION TASK-FORCE; MYOCARDIAL-INFARCTION; CARDIOVASCULAR MORBIDITY; LOSARTAN INTERVENTION; SYSTOLIC HYPERTENSION AB "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure" provides a new guideline for hypertension prevention and management. The following are the key messages: (1) In persons older than 50 years, systolic blood pressure (BP) of more than 140 mm Hg is a much more important cardiovascular disease (CVD) risk factor than diastolic BP; (2) The risk of CVD, beginning at 115/75 mm Hg, doubles with each increment of 20/10 mm Hg; individuals who are normotensive at 55 years of age have a 90% lifetime risk for developing hypertension; (3) Individuals with a systolic BP of 120 to 139 mm Hg or a diastolic BP of 80 to 89 mm Hg should be considered as prehypertensive and require health-promoting lifestyle modifications to prevent CVD; (4) Thiazide-type diuretics should be used in drug treatment for most patients with uncomplicated hypertension, either alone or combined with drugs from other classes. Certain high-risk conditions are compelling indications for the initial use of other antihypertensive drug classes (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, calcium channel blockers); (5) Most patients with hypertension will require 2 or more antihypertensive medications to achieve goal BP (<140/90 mm Hgr or <130/80 mm Hg for patients with diabetes or chronic kidney disease); (6) If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy with 2 agents, 1 of which usually should be a thiazide-type diuretic; and (7) The most effective therapy prescribed by the most careful clinician will control hypertension only if patients are motivated. Motivation improves when patients have positive experiences with and trust in the clinician. Empathy builds trust and is a patent motivator. Finally, in presenting these guidelines, the committee recognizes that the responsible physician's judgment remains paramount. C1 NHLBI, Natl High Blood Pressure Educ Program, NIH, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. Rush Presbyterian St Lukes Med Ctr, Dept Prevent Med, Chicago, IL 60612 USA. Univ Tennessee, Ctr Hlth Sci, Vet Affairs Med Ctr, Dept Prevent Med, Memphis, TN 38163 USA. Univ Tennessee, Ctr Hlth Sci, Vet Affairs Med Ctr, Dept Med, Memphis, TN 38163 USA. Univ Michigan, Dept Family Med, Ann Arbor, MI 48109 USA. SUNY Buffalo, Sch Med, Dept Med & Pharmacol, Buffalo, NY 14260 USA. Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. Univ Mississippi, Med Ctr, Ctr Excellence Cardiovasc Renal Res, Jackson, MS 39216 USA. Univ Miami, Sch Med, Dept Med, Miami, FL USA. Univ Alabama, Dept Physiol & Med Biophys, Div Cardiovasc Dis, Birmingham, AL USA. Univ Hosp Cleveland, Dept Med, Cleveland, OH 44106 USA. Louis Stokes Cleveland Vet Affairs Med Ctr, Dept Med, Cleveland, OH USA. RP Roccella, EJ (reprint author), NHLBI, Natl High Blood Pressure Educ Program, NIH, 31 Ctr Dr,MSC 2480, Bethesda, MD 20892 USA. NR 81 TC 9730 Z9 10509 U1 206 U2 968 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 MAY 21 PY 2003 VL 289 IS 19 BP 2560 EP 2572 DI 10.1001/jama.289.19.2560 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 680KL UT WOS:000182976500025 PM 12748199 ER PT J AU Kamangar, F Limburg, P Taylor, P Dawsey, S AF Kamangar, F Limburg, P Taylor, P Dawsey, S TI Re: Helicobacter pylori and interleukin 1 genotyping: An opportunity to identify high-risk individuals for gastric carcinoma SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID CANCER; CAGA; INFECTION C1 NCI, Canc Prevent Studies Branch, Canc Res Ctr, Bethesda, MD 20892 USA. Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Kamangar, F (reprint author), NCI, Canc Prevent Studies Branch, Canc Res Ctr, 6116 Execut Blvd,Rm 705, Bethesda, MD 20892 USA. NR 7 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 MAY 21 PY 2003 VL 95 IS 10 BP 760 EP 760 PG 1 WC Oncology SC Oncology GA 681MT UT WOS:000183040500017 PM 12759399 ER PT J AU Dagdug, L Weiss, GH Gandjbakhche, AH AF Dagdug, L Weiss, GH Gandjbakhche, AH TI Effects of anisotropic optical properties on photon migration in structured tissues SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID SCALING RELATIONSHIPS; LIGHT-PROPAGATION; RANDOM-WALKS AB It is often adequate to model photon migration in human tissue in terms of isotropic diffusion or random walk models. A nearly universal assumption in earlier analyses is that anisotropic tissue optical properties are satisfactorily modelled by using a transport-corrected scattering coefficient which then allows one to use isotropic diffusion-like models. In the present paper we introduce a formalism, based on the continuous-time random walk, which explicitly allows the diffusion coefficients to differ along the three axes. The corrections necessitated by this form of anisotropy are analysed in the case of continuous-wave and time-resolved measurements and for both reflectance and transmission modes. An alternate model can be developed in terms of a continuous-time random walk in which the times between successive jumps differ along the three axes, but is not included here. C1 Ctr Informat Technol, Math & Stat Comp Lab, Bethesda, MD 20892 USA. NIH, Lab Integrat & Med Biophys, Inst Child Hlth & Human Dev, Bethesda, MD 20892 USA. RP Dagdug, L (reprint author), Ctr Informat Technol, Math & Stat Comp Lab, Bethesda, MD 20892 USA. NR 11 TC 41 Z9 41 U1 0 U2 1 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD MAY 21 PY 2003 VL 48 IS 10 BP 1361 EP 1370 AR PII S0031-9155(03)58944-8 DI 10.1088/0031-9155/48/10/309 PG 10 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 693AF UT WOS:000183691900009 PM 12812452 ER PT J AU Hart, RG Halperin, JL Pearce, LA Anderson, DC Kronmal, RA McBride, R Nasco, E Sherman, DG Talbert, RL Marler, JR AF Hart, RG Halperin, JL Pearce, LA Anderson, DC Kronmal, RA McBride, R Nasco, E Sherman, DG Talbert, RL Marler, JR CA Stroke Prevention Atrial Fibrillat TI Lessons from the Stroke Prevention in Atrial Fibrillation trials SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID RISK-FACTORS; CAROTID STENOSIS; ASPIRIN THERAPY; ISCHEMIC STROKE; AORTIC PLAQUE; SPAF-III; THROMBOEMBOLISM; PREVALENCE; WARFARIN; ANTICOAGULATION AB Atrial fibrillation predisposes to left atrial thrombus formation and carries a sixfold increased risk for stroke. Antithrombotic therapies are the mainstay for stroke prevention. The National Institute of Neurological Disorders and Stroke-sponsored Stroke Prevention in Atrial Fibrillation (SPAF) studies assessed the value of warfarin, aspirin, and their combination for preventing stroke in six multicenter trials involving 3950 participants. This review presents the major results and implications, which offer unique perspectives on antithrombotic therapies for stroke prevention in atrial fibrillation. Warfarin and aspirin reduce stroke. Anticoagulation substantially benefits high-risk patients with atrial fibrillation, while many younger patients with atrial fibrillation have a low stroke rate when given aspirin. Pathogenetic and transesophageal echocardiographic correlations shed light on mechanisms by which antithrombotic agents prevent stroke. Warfarin inhibits formation of atrial appendage thrombi and markedly reduces cardioembolic strokes, while aspirin primarily prevents smaller, noncardioembolic strokes. The SPAF III stroke risk stratification scheme has been validated for identifying patients with high versus moderate versus low risk for stroke. Women with atrial fibrillation benefit from anticoagulation significantly more than men do. Many elderly patients with recurrent paroxysmal atrial fibrillation have high rates of stroke. Antithrombotic prophylaxis should be individualized on the basis of the estimated risk for stroke during aspirin therapy and the risk for bleeding during anticoagulation. Overall, nearly one third of patients with atrial fibrillation are low risk and should be treated with aspirin, and about one third are high risk and should receive warfarin if it can be given safely. For patients at moderate risk for stroke, patient preferences and access to reliable anticoagulation monitoring are particularly relevant. C1 Univ Texas, Hlth Sci Ctr, Dept Med Neurol, San Antonio, TX 78229 USA. Mt Sinai Sch Med, Zena & Michael A Weiner Cardiovasc Inst, New York, NY USA. Univ Minnesota, Sch Med, Hennepin Cty Med Ctr, Minneapolis, MN 55455 USA. Univ Washington, Seattle, WA 98195 USA. Axio Res Corp, Seattle, WA USA. Univ Texas, Sch Pharm, Austin, TX 78712 USA. NINDS, Bethesda, MD 20892 USA. RP Hart, RG (reprint author), Univ Texas, Hlth Sci Ctr, Dept Med Neurol, 7703 Floyd Curl Dr,MC 7883, San Antonio, TX 78229 USA. FU NINDS NIH HHS [R01 NS 24-224] NR 47 TC 149 Z9 154 U1 0 U2 4 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD MAY 20 PY 2003 VL 138 IS 10 BP 831 EP 838 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 679KH UT WOS:000182920700007 PM 12755555 ER PT J AU Trinh, LB Phue, JN Shiloach, J AF Trinh, LB Phue, JN Shiloach, J TI Effect of methanol feeding strategies on production and yield of recombinant mouse endostatin from Pichia pastoris SO BIOTECHNOLOGY AND BIOENGINEERING LA English DT Article DE Pichia pastoris; growth strategies; methanol; endostatin ID FED-BATCH FERMENTATION; INTEGRATED DEVELOPMENT; BOTULINUM NEUROTOXIN; METHYLOTROPHIC YEAST; PROTEIN EXPRESSION; B PRODUCTION; GROWTH; ANGIOGENESIS; OPTIMIZATION; FRAGMENT AB Pichia pastoris, a methylotrophic yeast, is an efficient producer of recombinant proteins in which the heterologous gene is under the control of the methanol-induced AOX1 promoter. Hence, the accepted production procedure has two phases: In the first phase, the yeast utilizes glycerol and biomass is accumulated; in the second phase, the yeast utilizes methanol which is used both as an inducer for the expression of the recombinant protein and as a carbon source. Since the yeast is sensitive to methanol concentration, the methanol is supplied gradually to the growing culture. Three methanol addition strategies were evaluated for the purpose of optimizing recombinant endostatin production. Two strategies were based on the yeast metabolism; one responding to the methanol consumption using a methanol sensor, and the other responding to the oxygen consumption. In these two strategies, the methanol supply is unlimited. The third strategy was based on a predetermined exponential feeding rate, controling the growth rate at 0.02 h(-1), in this strategy the methanol supply is limited. Throughout the induction phase glycerol, in addition to methanol, was continuously added at a rate of 1 g L h(-1). Total endostatin production was similar in all three strategies, (400 mg was obtained from 3 L initial volume), but the amount of methanol added and the biomass produced were lower in the predetermined rate method. This caused the specific production of endostatin per biomass and per methanol to be 2 times higher in the predetermined rate than in the other two methods, making the growth control strategy not only more efficient but also more convenient for downstream processing. (C) 2003 Wiley Periodicals, Inc. C1 NIDDK, Biotechnol Unit, NIH, Bethesda, MD 20892 USA. RP Shiloach, J (reprint author), NIDDK, Biotechnol Unit, NIH, Bldg 6,Rm B1-33, Bethesda, MD 20892 USA. NR 31 TC 46 Z9 63 U1 2 U2 12 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0006-3592 J9 BIOTECHNOL BIOENG JI Biotechnol. Bioeng. PD MAY 20 PY 2003 VL 82 IS 4 BP 438 EP 444 DI 10.1002/bit.10587 PG 7 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 666MM UT WOS:000182181100008 PM 12632400 ER PT J AU Hernandez-Rodriguez, J Segarra, M Vilardell, C Sanchez, M Garcia-Martinez, A Esteban, MJ Grau, JM Urbano-Marquez, A Colomer, D Kleinman, HK Cid, MC AF Hernandez-Rodriguez, J Segarra, M Vilardell, C Sanchez, M Garcia-Martinez, A Esteban, MJ Grau, JM Urbano-Marquez, A Colomer, D Kleinman, HK Cid, MC TI Elevated production of interleukin-6 is associated with a lower incidence of disease-related ischemic events in patients with giant-cell arteritis - Angiogenic activity of interleukin-6 as a potential protective mechanism SO CIRCULATION LA English DT Article DE angiogenesis; interleukins; ischemia; inflammation ID BLOOD MONONUCLEAR-CELLS; HUMAN ENDOTHELIAL-CELLS; POLYMYALGIA-RHEUMATICA; INFLAMMATORY RESPONSE; LEUKOCYTE RECRUITMENT; TEMPORAL ARTERITIS; SOLUBLE RECEPTOR; IL-6; CYTOKINE; COMPLICATIONS AB Background-Patients with giant-cell arteritis (GCA) who develop a strong acute-phase response are at low risk of disease-related ischemic events. Methods and Results-To assess the potential protective role of proinflammatory cytokines in the development of ischemic events in GCA, we measured tissue expression (66 individuals) and/or circulating levels (80 individuals) of interleukin (IL)-1beta, tumor necrosis factor-alpha (TNF-alpha), and IL-6 in patients with biopsy-proven GCA. Tissue expression was determined by quantitative real-time polymerase chain reaction and immunohistochemistry. Circulating cytokines were determined by enzyme-linked immunoassay. We found that patients with disease-related ischemic events had lower IL-6 mRNA levels (5.9+/-2.1 versus 27.6+/-7.8 relative units, P=0.013), lower IL-6 immunohistochemical expression scores (1.5+/-0.9 versus 2.7+/-1, P=0.001), and lower circulating levels of IL-6 (13.6+/-2.1 versus 24+/-2.4 pg/mL, P=0.002) than patients without ischemic complications. No significant differences were found for either IL-1beta or TNF-alpha. We subsequently investigated direct effects of IL-6 on vessel wall components. We found that IL-6 stimulates endothelial cell proliferation and differentiation into capillary-like structures and induces full angiogenic activity in both ex vivo (aortic ring) and in vivo (chick chorioallantoic membrane) assays. Conclusions-GCA patients with ischemic complications have lower tissue expression and circulating levels of IL-6 than patients with no ischemic events. IL-6 has relevant direct effects on vascular wall components that might be protective: IL-6 activates a functional program related to angiogenesis that may compensate for ischemia in patients with GCA. C1 Univ Barcelona, Hosp Clin, Vasculitis Res Unit, Dept Internal Med,IDIBAPS, E-08036 Barcelona, Spain. Univ Barcelona, Hosp Clin, Vasculitis Res Unit, Dept Pathol,IDIBAPS, E-08036 Barcelona, Spain. Univ Barcelona, Hosp Clin, Vasculitis Res Unit, Dept Hematopathol,IDIBAPS, E-08036 Barcelona, Spain. Natl Inst Dent & Craniofacial Res, Craniofacial Dev & Regenerat Branch, NIH, Bethesda, MD USA. RP Cid, MC (reprint author), Univ Barcelona, Hosp Clin, Vasculitis Res Unit, Dept Internal Med,IDIBAPS, Villarroel 170, E-08036 Barcelona, Spain. EM mccid@clinic.ub.es OI Cid Xutgla, Maria Cinta/0000-0002-4730-0938; COLOMER, DOLORS/0000-0001-7486-8484 NR 35 TC 99 Z9 104 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 MAY 20 PY 2003 VL 107 IS 19 BP 2428 EP 2434 DI 10.1161/01.CIR.0000066907.83923.32 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 681AU UT WOS:000183014500009 PM 12742994 ER PT J AU Kim, MP Becker, LC Yanek, LR Moy, TF Chung, HS Becker, DM Wahl, LM AF Kim, MP Becker, LC Yanek, LR Moy, TF Chung, HS Becker, DM Wahl, LM TI Monocyte chemoattractant protein-1 A (-2518) G polymorphism is associated with occult ischemia in a high-risk asymptomatic population SO CIRCULATION LA English DT Meeting Abstract CT Asia Pacific Scientific Forum on New Discoveries in Cardiovascular Disease and Stroke CY JUN 08-10, 2003 CL HONOLULU, HAWAII SP World Heart Federat, Asian Pacific Soc Cardiol, Hong Kong Coll Cardiol, Japanese Circulat Soc, Chinese Soc Cardiol, Korean Soc Circulat, Japan Heart Fdn, Natl Heart, Lung, & Blood Inst C1 Johns Hopkins Med Inst, Baltimore, MD 21205 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 20 PY 2003 VL 107 IS 19 MA P148 BP E171 EP E171 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 681AU UT WOS:000183014500229 ER PT J AU Beauchesne, PD Bertrand, S Branche, R Linke, SP Revel, R Dore, JF Pedeux, RM AF Beauchesne, PD Bertrand, S Branche, R Linke, SP Revel, R Dore, JF Pedeux, RM TI Human malignant glioma cell lines are sensitive to low radiation doses SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE radiotherapy; glioma; ultrafractionation; low-dose hypersensitivity; xenograft ID ACCELERATED RADIOTHERAPY CHART; HUMAN TUMOR-CELLS; PHASE-III TRIAL; GLIOBLASTOMA-MULTIFORME; HYPERFRACTIONATED RADIOTHERAPY; INCREASED RADIORESISTANCE; NUDE-MICE; P53 GENE; IN-VITRO; MELANOMA AB Malignant gliomas display aggressive local behavior and are not cured by existing therapy. Some cell lines that are considered radioresistant respond to low radiation doses (<1 Gy) with increased cell killing (low-dose hypersensitivity). In our study, 4 of 5 human glioma cell lines exhibited significant X-ray sensitivity at doses below 1 Gy. The surviving fractions (SFs) obtained at 0.7 and/or 0.8 Gy were comparable to those at 1.5 Gy. Low-dose hypersensitivity was evident when irradiation was combined with etoposide treatment. Repeated irradiation with low doses was markedly more effective than irradiation with single, biologically equivalent doses in decreasing SFs, inhibiting xenograft tumor growth in mice. All experiments were conducted with an accelerator used in clinics, establishing that low-dose hypersensitivity was present following megavoltage X-irradiation. Thus, repeated low-dose irradiation (ultrafractionation) could greatly improve the effectiveness of radiotherapy of gliomas and could allow safe treatment of patients with cumulative doses greater than 60 Gy. (C) 2003 Wiley-Liss, Inc. C1 Ctr Hosp Univ St Etienne, Serv Neurochirurg, St Etienne, France. Ctr Leon Berard, INSERM, U453, F-69373 Lyon, France. NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Pedeux, RM (reprint author), NCI, Human Carcinogenesis Lab, NIH, 37 Convent Dr,Bldg 37,Room 2C26, Bethesda, MD 20892 USA. NR 52 TC 30 Z9 32 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAY 20 PY 2003 VL 105 IS 1 BP 33 EP 40 DI 10.1002/ijc.11033 PG 8 WC Oncology SC Oncology GA 666EC UT WOS:000182163000006 PM 12672027 ER PT J AU Jemal, A Travis, WD Tarone, RE Travis, L Devesa, SS AF Jemal, A Travis, WD Tarone, RE Travis, L Devesa, SS TI Lung cancer rates convergence in young men and women in the United States: Analysis by birth cohort and histologic type SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE lung cancer; adenocarcinoma; squamous cell carcinoma; SEER; birth cohort ID SMOKING-RELATED RISK; CIGARETTE-SMOKING; SEX-DIFFERENCES; SMOKERS; MORTALITY; CARCINOMA; GENDER; TRENDS; CESSATION AB Age-specific rates of lung cancer have been consistently higher for men than for women in the United States, due primarily to different patterns of cigarette smoking. Gender differences in cigarette smoking have diminished in recent birth cohorts, however, especially among whites. We used U.S. population-based incidence and mortality data and examined trends in age-specific rates of lung cancer by birth cohort according to gender, ethnic group, and histology to evaluate the generational changes in U.S. lung cancer risk for men vs. women. All tests of statistical significance are 2-sided (95% confidence interval [CI]). Lung cancer mortality rates have converged between men and women born after 1960, especially in whites. The male-to-female (M:F) mortality rate ratio for ages 35-39 years decreased from 3.0 (95% CI = 2.7-3.4) around the 1915 birth cohort to 1.1 (95% CI = 1.0-1.1) around the 1960 birth cohort among whites and from 4.0 (95% CI = 3.2-5.0) around the 1925 birth cohort to 1.5 (95% CI = 1.3-1.7) around the 1960 birth cohort among blacks. Similarly, incidence rates for white men and women converged rapidly for adenocarcinoma, small cell carcinoma, and large cell carcinoma, but less so for squamous cell carcinoma. These findings reflect the smoking patterns among white and black men and women: cigarette smoking prevalence at age 24 was essentially equal among white men and women born after 1960 but continued to be higher in black men than women. The convergence of lung cancer death rates among men and women born after 1960s supports the idea that males and females maybe equally susceptible to develop lung cancer from a given amount of cigarette smoking, rather than the hypothesis that women are more susceptible. (C) 2003 Wiley-Liss, Inc. C1 Amer Canc Soc, Atlanta, GA 30329 USA. Armed Forces Inst Pathol, Dept Pulm & Mediastinal Pathol, Washington, DC 20306 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Jemal, A (reprint author), Amer Canc Soc, 1599 Clifton Rd NE, Atlanta, GA 30329 USA. NR 38 TC 70 Z9 71 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAY 20 PY 2003 VL 105 IS 1 BP 101 EP 107 DI 10.1002/ijc.11020 PG 7 WC Oncology SC Oncology GA 666EC UT WOS:000182163000017 PM 12672038 ER PT J AU Backer, MV Gaynutdinov, TI Gorshkova, II Crouch, RJ Hu, T Aloise, R Arab, M Przekop, K Backer, JA AF Backer, MV Gaynutdinov, TI Gorshkova, II Crouch, RJ Hu, T Aloise, R Arab, M Przekop, K Backer, JA TI Humanized docking system for assembly of targeting drug delivery complexes SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE targeted delivery; assembled targeting complexes; vascular endothelial growth factor; human RNase; gene therapy ID ENDOTHELIAL GROWTH-FACTOR; VEGF FUSION PROTEINS; RECEPTORS; EXPRESSION; CELLS; RNASE; MODEL AB Targeted drug delivery requires loading' drugs onto targeting proteins. Traditional technologies for loading drugs rely on I chemical conjugation of drugs or drug carriers to targeting proteins. An alternative approach might rely on assembly of targeting complexes using a docking system that includes two components: a 'docking' tag fused to a targeting protein, and a 'payload' module containing an adapter protein for non-covalent binding to the docking tag. We describe here a fully humanized adapter/docking tag system based on non-covalent interaction between two fragments of human pancreatic RNase I. A 15 amino acid long N-terminal fragment of RNase I designed to serve as a docking tag, was fused to the N-terminus of human vascular endothelial growth factor that served as a targeting protein. An 18-125 and an 18-127 amino acid long fragments of RNase I were engineered, expressed and refolded into active conformations to serve as adapter proteins. Interactions between the targeting and adapter proteins were characterized using enzymatic analysis and surface plasmon resonance. Targeting DNA delivery complexes were assembled, characterized by dynamic light scattering, and found to be very effective in receptor-mediated DNA delivery. (C) 2003 Elsevier Science B.V. All rights reserved. C1 SibTech Inc, Newington, CT 06111 USA. NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Backer, MV (reprint author), SibTech Inc, 705 N Mt Rd, Newington, CT 06111 USA. FU NHLBI NIH HHS [2R44 HL6143-02] NR 25 TC 16 Z9 16 U1 2 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 J9 J CONTROL RELEASE JI J. Control. Release PD MAY 20 PY 2003 VL 89 IS 3 BP 499 EP 511 DI 10.1016/S0168-3659(03)00150-0 PG 13 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 682JH UT WOS:000183088000013 PM 12737851 ER PT J AU Mollaaghababa, R Pavan, WJ AF Mollaaghababa, R Pavan, WJ TI The importance of having your SOX on: role of SOX10 in the development of neural crest-derived melanocytes and glia SO ONCOGENE LA English DT Article DE SOX10; neural crest; glia; melanocytes; differentiation; transcription factor ID TRANSCRIPTION FACTOR SOX10; CENTRAL-NERVOUS-SYSTEM; SRY-RELATED GENE; WAARDENBURG-SYNDROME; HIRSCHSPRUNG-DISEASE; DOMINANT MEGACOLON; MOUSE DEVELOPMENT; STEM-CELLS; EXPRESSION; FAMILY AB SOX10(+) is a member of the high-mobility group-domain SOX family of transcription factors, which are ubiquitously found in the animal kingdom. Disruption of neural crest development in the Dominant megacolon (Dom) mice is associated with a Sox10 mutation. Mutations in human Sox10(+) gene have also been linked with the occurrence of neurocristopathies in the Waardenburg-Shah syndrome type IV (WS-IV), for which the Sox10(Dom) mice serve as a murine model. The neural crest disorders in the Sox10(Dom) mice and WS-IV patients consist of hypopigmentation, cochlear neurosensory deafness, and enteric aganglionosis. Consistent with these observations, a critical role for SOX10 in the proper differentiation of neural crest-derived melanocytes and glia has been demonstrated. Emerging data also show an important role for SOX10 in promoting the survival of neural crest precursor cells prior to lineage commitment. Several genes whose regulation is dependent on SOX10 function have been identified in the peripheral nervous system and in melanocytes, helping to begin the identification of the multiple pathways that appear to be modulated by SOX10 activity. In this review, we will discuss the biological relevance of these target genes to neural crest development and the properties of Sox10 as a transcription factor. C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Pavan, WJ (reprint author), NHGRI, NIH, 49 Convent Dr, Bethesda, MD 20892 USA. NR 87 TC 103 Z9 108 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 19 PY 2003 VL 22 IS 20 BP 3024 EP 3034 DI 10.1038/sj.onc.1206442 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 682MV UT WOS:000183096600002 PM 12789277 ER PT J AU Tucker, MA Goldstein, AM AF Tucker, MA Goldstein, AM TI Melanoma etiology: where are we? SO ONCOGENE LA English DT Review DE melanoma; epidemiology; nevi; genetic epidemiology ID CUTANEOUS MALIGNANT-MELANOMA; GERMAN-DERMATOLOGICAL-SOCIETY; DYSPLASTIC NEVUS SYNDROME; SUN-PROTECTION BEHAVIORS; MULTICENTER CASE-CONTROL; CDK4 GERMLINE MUTATIONS; DANISH CASE-CONTROL; MELANOCYTIC NEVI; PRONE FAMILIES; RISK-FACTORS AB Melanoma incidence rates are rising rapidly, particularly in older men. Older men are also more likely to have thick melanomas, which confer high mortality and morbidity. The reasons for the rate of increase are not known; increasing sun and UV exposure, however, is the major hypothesized explanation. In the past several years, two major susceptibility genes for melanoma, CDKN2A and CDK4, have been identified, but the two genes together account for a minority of familial melanoma. Other high-risk susceptibility genes are being sought actively. Genetic epidemiologic studies suggest that penetrance of each of the two identified genes is altered by other factors, either genetic or environmental. Epidemiologic studies have also identified other major host factors important in the development of melanoma. In European, North American, and Australian populations, the presence of clinically identified dysplastic nevi confers greatly increased risk of melanoma. A new measure of sun exposure, based on individual residential history, confers substantially increased risk of melanoma. Recent surveys of sun behavior in the US reveal extensive sunburning and use of tanning beds in adolescents and adults. Sun protective behaviors are not as prevalent as in Australia, where population rates of melanoma are stabilizing. C1 NCI, DCEG, Genet Epidemiol Branch, Bethesda, MD 20892 USA. RP Tucker, MA (reprint author), NCI, DCEG, Genet Epidemiol Branch, Execut Plaza S 7122,6120 Execut Blvd, Bethesda, MD 20892 USA. RI Tucker, Margaret/B-4297-2015 NR 122 TC 157 Z9 162 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 19 PY 2003 VL 22 IS 20 BP 3042 EP 3052 DI 10.1038/sj.onc.1206444 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 682MV UT WOS:000183096600004 PM 12789279 ER PT J AU Carr, KM Bittner, M Trent, JM AF Carr, KM Bittner, M Trent, JM TI Gene-expression profiling in human cutaneous melanoma SO ONCOGENE LA English DT Article DE gene expression profiling; melanoma ID B-CELL LYMPHOMA; MALIGNANT-MELANOMA; HUMAN CANCER; MICROARRAY; PATTERNS; CLASSIFICATION; INTERLEUKIN-2; PREDICTION; RESPONSES; SURVIVAL AB Genomic technology presents new and exciting opportunities to study complex human diseases. Several types of genomic analysis are helping to elucidate the biology of important human cancers. One of these, gene expression profiling, provides a more comprehensive view of the consequences of the genetic changes in cancer cells than was previously available. In addition to detailing the expression patterns of thousands of genes simultaneously, this exploding field of research has begun to build a new 'molecular taxonomy' of cancer and to identify novel disease genes for many human cancers, including cutaneous melanoma. Whether this new information will lead to improved treatments and prolonged survival for cancer patients remains to be determined. Here, we review the use of complementary DNA microarray technology to study gene expression patterns in cutaneous melanoma and highlight recent advances concerning the identification of novel melanoma disease-related genes. The fundamentals of microarray technology and analysis have been extensively discussed, and readers are referred to several recent reviews in this area. C1 Translat Genom Res Inst, Phoenix, AZ USA. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Trent, JM (reprint author), TGen, 400 N 5th St,Suite 1600, Phoenix, AZ 85004 USA. NR 30 TC 77 Z9 80 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 19 PY 2003 VL 22 IS 20 BP 3076 EP 3080 DI 10.1038/sj.onc.1206448 PG 5 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 682MV UT WOS:000183096600008 PM 12789283 ER PT J AU Jhappan, C Noonan, FP Merlino, G AF Jhappan, C Noonan, FP Merlino, G TI Ultraviolet radiation and cutaneous malignant melanoma SO ONCOGENE LA English DT Review DE cell cycle arrest; DNA damage response; DNA repair; melanoma; transgenic mice; UV radiation ID NORMAL HUMAN MELANOCYTES; COMPARATIVE GENOMIC HYBRIDIZATION; MELANOCORTIN-1 RECEPTOR VARIANTS; CYCLOBUTANE PYRIMIDINE DIMERS; INDUCED SIGNAL-TRANSDUCTION; HUMAN-SKIN FIBROBLASTS; FACTOR SCATTER FACTOR; CELL-CYCLE ARREST; STIMULATING HORMONE; DNA-REPAIR AB Recent years have seen a steady rise in the incidence of cutaneous malignant melanoma worldwide. Although it is now appreciated that the key to understanding the process by which melanocytes are transformed into malignant melanoma lies in the interplay between genetic factors and the ultraviolet (UV) spectrum of sunlight, the nature of this relation has remained obscure. Recently, prospects for elucidating the molecular mechanisms underlying such gene-environment interactions have brightened considerably through the development of UV-responsive experimental animal models of melanoma. Genetically engineered mice and human skin xenografts constitute novel platforms upon which to build studies designed to elucidate the pathogenesis of UV-induced melanomagenesis. The future refinement of these in vivo models should provide a wealth of information on the cellular and genetic targets of UV, the pathways responsible for the repair of UV-induced DNA damage, and the molecular interactions between melanocytes and other skin cells in response to UV. It is anticipated that exploitation of these model systems will contribute significantly toward the development of effective approaches to the prevention and treatment of melanoma. C1 NCI, Mol Biol Lab, Mol Genet Sect, Bethesda, MD 20892 USA. George Washington Univ, Sch Med, Sch Publ Hlth & Hlth Serv, Dept Environm & Occupat Hlth,Lab Photobil & Photo, Washington, DC 20037 USA. RP Merlino, G (reprint author), NCI, Mol Biol Lab, Mol Genet Sect, Bethesda, MD 20892 USA. NR 196 TC 107 Z9 111 U1 0 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 19 PY 2003 VL 22 IS 20 BP 3099 EP 3112 DI 10.1038/sj.onc.1206450 PG 14 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 682MV UT WOS:000183096600012 PM 12789287 ER PT J AU Jacobsson, LTH Jacobsson, ME Askling, J Knowler, WC AF Jacobsson, LTH Jacobsson, ME Askling, J Knowler, WC TI Perinatal characteristics and risk of rheumatoid arthritis SO BRITISH MEDICAL JOURNAL LA English DT Article C1 Malmo Univ Hosp, Dept Rheumatol, S-20502 Malmo, Sweden. Karolinska Hosp & Inst, Clin Epidemiol Unit, S-17176 Stockholm, Sweden. NIDDK, Diabet & Arthrit Epidemiol Sect, Phoenix, AZ 85014 USA. RP Jacobsson, LTH (reprint author), Malmo Univ Hosp, Dept Rheumatol, S-20502 Malmo, Sweden. NR 5 TC 44 Z9 45 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD MAY 17 PY 2003 VL 326 IS 7398 BP 1068 EP 1069 DI 10.1136/bmj.326.7398.1068 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 681ZD UT WOS:000183064700017 PM 12750209 ER PT J AU Myers, GJ Davidson, PW Cox, C Shamlaye, CF Palumbo, D Cernichiari, E Sloane-Reeves, J Wilding, GE Kost, J Huang, LS Clarkson, TW AF Myers, GJ Davidson, PW Cox, C Shamlaye, CF Palumbo, D Cernichiari, E Sloane-Reeves, J Wilding, GE Kost, J Huang, LS Clarkson, TW TI Prenatal methylmercury exposure from ocean fish consumption in the Seychelles child development study SO LANCET LA English DT Article ID IN-UTERO EXPOSURE; MATERNAL HAIR; OUTCOMES; MERCURY; DIET; AGE AB Introduction Exposure to methylmercury (MeHg) before birth can adversely affect children's neurodevelopment. The most common form of prenatal exposure is maternal fish consumption, but whether such exposure harms the fetus is unknown. We aimed to identify adverse neurodevelopmental effects in a fish-consuming population. Methods We investigated 779 mother-infant pairs residing in the Republic of Seychelles. Mothers reported consuming fish on average 12 meals per week. Fish in Seychelles contain much the same concentrations of MeHg as commercial ocean fish elsewhere. Prenatal MeHg exposure was determined from maternal hair growing during pregnancy. We assessed neurocognitive, language, memory, motor, perceptual-motor, and behavioural functions in children at age 9 years. The association between prenatal MeHg exposure and the primary endpoints was investigated with multiple linear regression with adjustment for covariates that affect child development. Findings Mean prenatal MeHg exposure was 6.9 parts per million (SD 4.5ppm). Only two endpoints were associated with prenatal MeHg exposure. Increased exposure was associated with decreased performance in the grooved pegboard using the non-dominant hand in males and improved scores in the hyperactivity index of the Conner's teacher rating scale. Covariates affecting child development were appropriately associated with endpoints. Interpretation These data do not support the hypothesis that there is a neurodevelopmental risk from prenatal MeHg exposure resulting solely from ocean fish consumption. C1 Univ Rochester, Med Ctr, Sch Med & Dent, Dept Biostat & Computat Biol, Rochester, NY 14620 USA. Univ Rochester, Sch Med & Dent, Dept Environm Med, Rochester, NY 14620 USA. NICHD, Dept Neurol, NIH, US Dept HHS, Bethesda, MD USA. NICHD, Dept Pediat, NIH, US Dept HHS, Bethesda, MD USA. NICHD, Dept Epidemiol Stat & Prevent, NIH, US Dept HHS, Bethesda, MD USA. Minist Hlth, Victoria, Seychelles. RP Myers, GJ (reprint author), Univ Rochester, Med Ctr, Sch Med & Dent, Dept Biostat & Computat Biol, 601 Elmwood Ave,Box 631, Rochester, NY 14620 USA. RI Myers , Gary /I-4901-2013 OI Myers , Gary /0000-0003-4317-015X FU NIEHS NIH HHS [T32 ES-007, ES-01247, R01-ES10219]; PHS HHS [R01-08442] NR 30 TC 316 Z9 326 U1 4 U2 31 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD MAY 17 PY 2003 VL 361 IS 9370 BP 1686 EP 1692 DI 10.1016/S0140-6736(03)13371-5 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 679KB UT WOS:000182919700009 PM 12767734 ER PT J AU Bhatnagar, RK Arora, N Sachidanand, S Shahabuddin, M Keister, D Chauhan, VS AF Bhatnagar, RK Arora, N Sachidanand, S Shahabuddin, M Keister, D Chauhan, VS TI Synthetic propeptide inhibits mosquito midgut chitinase and blocks sporogonic development of malaria parasite SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE chitinase; malaria parasite; propeptide ID PLASMODIUM-FALCIPARUM CHITINASE; PERITROPHIC MEMBRANE; MONOCLONAL-ANTIBODY; MANDUCA-SEXTA; TRANSMISSION; GALLINACEUM; PENETRATION; PROTEASE; PFCHT1 AB Incessant transmission of the parasite by mosquitoes makes most attempts to control malaria fail. Blocking of parasite transmission by mosquitoes therefore is a rational strategy to combat the disease. Upon ingestion of blood meal mosquitoes secrete chitinase into the midgut. This mosquito chitinase is a zymogen which is activated by the removal of a propeptide from the N-terminal. Since the midgut peritrophic matrix acts as a physical barrier, the activated chitinase is likely to contribute to the further development of the malaria parasite in the mosquito. Earlier it has been shown that inhibiting chitinase activity in the mosquito midgut blocked sporogonic development of the malaria parasite. Since synthetic propeptides of several zymogens have been found to be potent inhibitors of their respective enzymes, we tested propeptide of mosquito midgut chitinase as an inhibitor and found that the propeptide almost completely inhibited the recombinant or purified native Anopheles gambiae chitinase. We also examined the effect of the inhibitory peptide on malaria parasite development. The result showed that the synthetic propeptide blocked the development of human malaria parasite Plasmodium falciparum in the African malaria vector An. gambiae and avian malaria parasite Plasmodium gallinaceum in Aedes aegypti mosquitoes. This study implies that the expression of inhibitory mosquito midgut chitinase propeptide in response to blood meal may alter the mosquito's vectorial capacity. This may lead to developing novel strategies for controlling the spread of malaria. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Int Ctr Genet Engn & Biotechnol, New Delhi 110067, India. Mt Sinai Sch Med, Dept Physiol & Biophys, New York, NY 10029 USA. NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Bhatnagar, RK (reprint author), Int Ctr Genet Engn & Biotechnol, Aruna Asaf Ali Marg,POB 10504, New Delhi 110067, India. NR 25 TC 16 Z9 17 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 16 PY 2003 VL 304 IS 4 BP 783 EP 787 DI 10.1016/S0006-291X(03)00682-X PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 679GH UT WOS:000182912000032 PM 12727225 ER PT J AU Aravind, L Anantharaman, V AF Aravind, L Anantharaman, V TI HutC/FarR-like bacterial transcription factors of the GntR family contain a small molecule-binding domain of the chorismate lyase fold SO FEMS MICROBIOLOGY LETTERS LA English DT Article DE transcription regulator; fold prediction; chorismate lyase; GntR; helix-turn-helix domain; sequence profile analysis; ligand binding; active site ID FUNCTIONALLY DIVERSE SUPERFAMILY; ESCHERICHIA-COLI; PSI-BLAST; DATABASE SEARCHES; CRYSTAL-STRUCTURE; PREDICTION; SEQUENCE; PROTEINS; IDENTIFICATION; REPRESSOR AB Numerous bacterial transcription factors contain a DNA-binding helix-turn-helix domain and a signaling domain, linked together in a single polypeptide. Typically, this signaling domain is a small-molecule-binding domain that undergoes a conformational change upon recognizing a specific ligand. The HutC/FarR-like transcription factors of the GntR family are one of the largest groups of transcription factors in the proteomes of most free-living bacteria. Using sensitive sequence profile analysis we show that the HutC/FarR-like transcription factors contain a conserved ligand-binding domain, which possesses the same fold as chorismate lyase (Escherichia coli UbiC gene product). This relationship suggests that the C-terminal domain of the HutC/FarR-like transcription factors binds small molecules in a cleft similar to the substrate-binding site of the chorismate lyases. The sequence diversity within the predicted binding cleft of the HutC/ FarR ligand-binding domains is consistent with the ability of these transcription factors to respond to diverse small molecules, such as histidine (HutC), fatty acids (FarR), sugars (TreR) and alkylphosphonate (PhnF). UbiC-like chorismate lyases function in the ubiquinone biosynthesis pathway, and have characteristic charged, catalytic residues. Genome comparisons reveal that chorismate lyase orthologs are found in several bacteria, chloroplasts of eukaryotic algae and euryarchaea. In contrast, the GntR transcription regulators lack the conserved catalytic residues of the chorismate lyases, and have so far been detected only in bacteria. An ancestral, generic small-molecule-binding domain appears to have given rise to the enzymatic and non-catalytic ligand-binding versions of the same fold under the influence of different selective pressures. (C) 2003 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved. C1 Natl Lib Med, NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), Natl Lib Med, NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. OI Anantharaman, Vivek/0000-0001-8395-0009 NR 33 TC 32 Z9 35 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1097 J9 FEMS MICROBIOL LETT JI FEMS Microbiol. Lett. PD MAY 16 PY 2003 VL 222 IS 1 BP 17 EP 23 DI 10.1016/S0378-1097(03)00242-8 PG 7 WC Microbiology SC Microbiology GA 682WR UT WOS:000183115800003 PM 12757941 ER PT J AU Kitada, H Miyata, M Nakamura, T Tozawa, A Honma, W Shimada, M Nagata, K Sinal, CJ Guo, GL Gonzalez, FJ Yamazoe, Y AF Kitada, H Miyata, M Nakamura, T Tozawa, A Honma, W Shimada, M Nagata, K Sinal, CJ Guo, GL Gonzalez, FJ Yamazoe, Y TI Protective role of hydroxysteroid sulfotransferase in lithocholic acid-induced liver toxicity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SALT EXPORT PUMP; FARNESOID-X-RECEPTOR; BILE-ACID; NUCLEAR RECEPTOR; LIQUID-CHROMATOGRAPHY; MOLECULAR-CLONING; GENE-EXPRESSION; PROTEIN-3 MRP3; MOUSE-LIVER; RAT AB Supplement of 1% lithocholic acid (LCA) in the diet for 5-9 days resulted in elevated levels of the marker for liver damage aspartate aminotransferase and alkaline phosphatase activities in both farnesoid X receptor (FXR)-null and wild-type female mice. The levels were clearly higher in wild-type mice than in FXR-null mice, despite the diminished expression of a bile salt export pump in the latter. Consistent with liver toxicity marker activities, serum and liver levels of bile acids, particularly LCA and taurolithocholic acid, were clearly higher in wild-type mice than in FXR-null mice after 1% LCA supplement. Marked increases in hepatic sulfating activity for LCA (5.5-fold) and hydroxysteroid sulfotransferase (St) 2a (5.8-fold) were detected in liver of FXR-null mice. A 7.4-fold higher 3alpha-sulfated bile acid concentration was observed in bile of FXR-null mice fed an LCA diet compared with that of wild-type mice. Liver St2a content was inversely correlated with levels of alkaline phosphatase. In contrast, microsomal LCA 6beta-hydroxylation was not increased and was in fact lower in FXR-null mice compared in wild-type mice. Clear decreases in mRNA encoding sodium taurocholate cotransporting polypeptide, organic anion transporting polypeptide 1, and liver-specific organic anion transporter-1 function in bile acid import were detected in LCA-fed mice. These transporter levels are higher in FXR-null mice than wild-type mice after 1% LCA supplement. No obvious changes were detected in the Mrp2, Mrp3, and Mrp4 mRNAs. These results indicate hydroxysteroid sulfotransferase-mediated LCA sulfation as a major pathway for protection against LCA-induced liver damage. Furthermore, Northern blot analysis using FXR-null, pregnane X receptor-null, and FXR-pregnane X receptor double-null mice suggests a repressive role of these nuclear receptors on basal St2a expression. C1 Tohoku Univ, Grad Sch Pharmaceut Sci, Div Drug Metab & Mol Toxicol, Aoba Ku, Sendai, Miyagi 9808578, Japan. NCI, Metab Lab, NIH, Bethesda, MD 20892 USA. RP Miyata, M (reprint author), Tohoku Univ, Grad Sch Pharmaceut Sci, Div Drug Metab & Mol Toxicol, Aoba Ku, Sendai, Miyagi 9808578, Japan. NR 47 TC 105 Z9 108 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 MAY 16 PY 2003 VL 278 IS 20 BP 17838 EP 17844 DI 10.1074/jbc.M210634200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 677YX UT WOS:000182838300032 PM 12637555 ER PT J AU Williams, RC Rees, ML Jacobs, MF Pragai, Z Thwaite, JE Baillie, LWJ Emmerson, PT Harwood, CR AF Williams, RC Rees, ML Jacobs, MF Pragai, Z Thwaite, JE Baillie, LWJ Emmerson, PT Harwood, CR TI Production of Bacillus anthracis protective antigen is dependent on the extracellular chaperone, PrsA SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN SECRETION; SIGNAL PEPTIDASES; ALPHA-AMYLASE; SUBTILIS; EXPRESSION; GENE; BINDING; CLONING; PATHWAY; GROWTH AB Protective antigen (PA) is a component of the Bacillus anthracis lethal and edema toxins and the basis of the current anthrax vaccine. In its heptameric form, PA targets host cells and internalizes the enzymatically active components of the toxins, namely lethal and edema factors. PA and other toxin components are secreted from B. anthracis using the Sec-dependent secretion pathway. This requires them to be translocated across the cytoplasmic membrane in an unfolded state and then to be folded into their native configurations on the trans side of the membrane, prior to their release from the environment of the cell wall. In this study we show that recombinant PA (rPA) requires the extracellular chaperone PrsA for efficient folding when produced in the heterologous host, B. subtilis; increasing the concentration of PrsA leads to an increase in rPA production. To determine the likelihood of PrsA being required for PA production in its native host, we have analyzed the B. anthracis genome sequence for the presence of genes encoding homologues of B. subtilis PrsA. We identified three putative B. anthracis PrsA proteins (PrsAA, PrsAB, and PrsAC) that are able to complement the activity of B. subtilis PrsA with respect to cell viability and rPA secretion, as well as that of AmyQ, a protein previously shown to be PrsA-dependent. C1 Univ Newcastle Upon Tyne, Sch Med, Sch Cell & Mol Biosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. NIDCR, Oral Infect & Immunol Branch, NIH, Bethesda, MD 20892 USA. Def Sci & Technol Lab, Salisbury SP4 OJQ, Wilts, England. RP Harwood, CR (reprint author), Univ Newcastle Upon Tyne, Sch Med, Sch Cell & Mol Biosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. RI Pragai, Zoltan/E-1228-2015; OI Pragai, Zoltan/0000-0002-8397-4286; Baillie, Les/0000-0002-8186-223X; Harwood, Colin/0000-0002-3624-0001 NR 32 TC 37 Z9 45 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 MAY 16 PY 2003 VL 278 IS 20 BP 18056 EP 18062 DI 10.1074/jbc.M301244200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 677YX UT WOS:000182838300061 PM 12606539 ER PT J AU Pankov, R Cukierman, E Clark, K Matsumoto, K Hahn, C Poulin, B Yamada, KM AF Pankov, R Cukierman, E Clark, K Matsumoto, K Hahn, C Poulin, B Yamada, KM TI Specific beta(1) integrin site selectively regulates Akt/protein kinase B signaling via local activation of protein phosphatase 2A SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FOCAL ADHESION KINASE; INTESTINAL EPITHELIAL-CELLS; BETA-1 CYTOPLASMIC DOMAIN; PHOSPHATIDYLINOSITOL 3-KINASE; TYROSINE PHOSPHORYLATION; MONOCLONAL-ANTIBODY; FIBRONECTIN RECEPTOR; EXTRACELLULAR-MATRIX; PLASMA-MEMBRANE; STIMULATED AKT AB Integrin transmembrane receptors generate multiple signals, but how they mediate specific signaling is not clear. Here we test the hypothesis that particular sequences along the beta(1) integrin cytoplasmic domain may exist that are intimately related to specific integrin-mediated signaling pathways. Using systematic alanine mutagenesis of amino acids conserved between different beta integrin cytoplasmic domains, we identified the tryptophan residue at position 775 of human beta(1) integrin as specific and necessary for integrin-mediated protein kinase B/Akt survival signaling. Stable expression of a beta(1) integrin mutated at this amino acid in GD25 beta(1)-null cells resulted in reduction of Akt phosphorylation at both Ser(473) and Thr(308) activation sites. As a consequence, the cells were substantially more sensitive to serum starvation-induced apoptosis when compared with cells expressing wild type beta(1) integrin. This inactivation of Akt resulted from increased dephosphorylation by a localized active population of protein phosphatase 2A. Both Akt and protein phosphatase 2A were present in beta(1) integrin-organized cytoplasmic complexes, but the activity of this phosphatase was 2.5 times higher in the complexes organized by the mutant integrin. The mutation of Trp(775) specifically affected Akt signaling, without effects on other integrin-activated pathways including phosphoinositide 3-kinase, MAPK, JNK, and p38 nor did it influence activation of the integrin-responsive kinases focal adhesion kinase and Src. The identification of Trp(775) as a specific site for integrin-mediated Akt signaling supports the concept of specificity of signaling along the integrin cytoplasmic domain. C1 NIDCR, CDBRB, NIH, Bethesda, MD 20892 USA. NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. RP Pankov, R (reprint author), NIDCR, CDBRB, NIH, Bldg 30,Rm 421,30 Convent Dr MSC 4370, Bethesda, MD 20892 USA. RI Pankov, Roumen/B-3284-2014 OI Pankov, Roumen/0000-0002-3157-3659 NR 91 TC 72 Z9 73 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 MAY 16 PY 2003 VL 278 IS 20 BP 18671 EP 18681 DI 10.1074/jbc.M300879200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 677YX UT WOS:000182838300140 PM 12637511 ER PT J AU Janetka, JW Furness, MS Zhang, XY Coop, A Folk, JE Mattson, MV Jacobson, AE Rice, KC AF Janetka, JW Furness, MS Zhang, XY Coop, A Folk, JE Mattson, MV Jacobson, AE Rice, KC TI Enantioconvergent synthesis of (-)-(2R,5S)-1-allyl-2,5-dimethylpiperazine, an intermediate to delta-opioid receptor ligands SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID MEDIATED PHENOMENA; (+)-4-<(ALPHA-R)-ALPHA-((2S,5R)-4-ALLYL-2,5-DIMETHYL-1-PIPERAZINYL)-3-ME THOXYBE.; RHESUS-MONKEYS; AGONIST SNC80; L-SELECTRIDE; PROBES; ANTAGONISTS; REAGENT AB A convenient, high-yield enantioconvergent synthesis of (-)-1-allyl-(2S,5R)-dimethylpiperazine from trans-2,5-dimethylpiperazine has been developed. This compound is an important intermediate in the synthesis of delta-opioid receptor ligands. The process allows for the laboratory preparation of 100 g quantities of this enantiomerically pure diamine without chromatography. The key steps in the sequence were an efficient optical resolution using relatively inexpensive resolving agents, followed by interconversion of the unwanted (+)-enantiomer into the desired (-)-enantiomer. C1 NIDDKD, Med Chem Lab, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Rice, KC (reprint author), NIDDKD, Med Chem Lab, Dept Hlth & Human Serv, NIH, Bldg 8,Room B1-23, Bethesda, MD 20892 USA. EM kr21f@nih.gov RI Janetka, James/A-8216-2011 OI Janetka, James/0000-0002-9888-5411 NR 20 TC 8 Z9 8 U1 0 U2 0 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 MAY 16 PY 2003 VL 68 IS 10 BP 3976 EP 3980 DI 10.1021/jo0300385 PG 5 WC Chemistry, Organic SC Chemistry GA 677UA UT WOS:000182825000031 PM 12737580 ER PT J AU Chen, HL Subbarao, K Swayne, D Chen, Q Lu, XH Katz, J Cox, N Matsuoka, Y AF Chen, HL Subbarao, K Swayne, D Chen, Q Lu, XH Katz, J Cox, N Matsuoka, Y TI Generation and evaluation of a high-growth reassortant H9N2 influenza A virus as a pandemic vaccine candidate SO VACCINE LA English DT Article DE influenza virus; H9N2 subtype; pandemic influenza vaccine ID AVIAN INFLUENZA; H5N1 VIRUSES; A VIRUSES; TRANSMISSION; INFECTION; IMMUNITY; HUMANS AB H9N2 subtype avian influenza viruses (AIVs) are widely distributed in avian species and were isolated from humans in Hong Kong and Guangdong province, China in 1999 raising concern of their potential for pandemic spread. We generated a high-growth reassortant virus (G9/PR8) that contains the hemagglutinin (HA) and neuraminidase (NA) genes from the H9N2 avian influenza virus A/chicken/Hong Kong/G9/97 (G9) and six internal genes from A/Puerto Rico/8/34 (PR8) by genetic reassortment, for evaluation as a potential vaccine candidate in humans. Pathogenicity studies showed that the G9/PR8 reassortant was not highly pathogenic for mice or chickens. Two doses of a formalin-inactivated G9/PR8 virus vaccine induced hemagglutination inhibiting antibodies and conferred complete protection against challenge with G9 and the antigenically distinct H9N2 A/Hong Kong/1073/99 (G1-like) virus in a mouse model. These results indicate that the high growth G9/PR8 reassortant has properties that are desirable in a vaccine seed virus and is suitable for evaluation in humans for use in the event of an H9 pandemic. (C) 2002 Published by Elsevier Science Ltd. C1 Ctr Dis Control & Prevent, Influenza Branch, Atlanta, GA 30333 USA. USDA, ARS, SE Poultry Res Lab, Athens, GA USA. RP Subbarao, K (reprint author), NIAID, LID, NIH, Bldg 50,Rm 6132,50 South Dr, Bethesda, MD 20892 USA. NR 18 TC 44 Z9 51 U1 1 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD MAY 16 PY 2003 VL 21 IS 17-18 BP 1974 EP 1979 DI 10.1016/S0264-410X(02)00809-5 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 682PF UT WOS:000183100200024 PM 12706686 ER PT J AU Gu, XX Rudy, SE Chu, CY McCullagh, L Kim, HN Chen, J Li, JP Robbins, JB Van Waes, C Battey, JE AF Gu, XX Rudy, SE Chu, CY McCullagh, L Kim, HN Chen, J Li, JP Robbins, JB Van Waes, C Battey, JE TI Phase I of a lipooligosaccaride-based conjugate vaccine against nontypeable Haemophilus influenzae SO VACCINE LA English DT Article DE nontypeable Haemophilus influenzae (NTHi); conjugate vaccine; lipooligosaccharide; phase I; otitis media ID NONTYPABLE HEMOPHILUS-INFLUENZAE; ACUTE OTITIS-MEDIA; IMMUNE-RESPONSE; DETOXIFIED LIPOOLIGOSACCHARIDE; STRUCTURAL HETEROGENEITY; BACTERICIDAL ANTIBODY; MONOCLONAL-ANTIBODIES; CHRONIC-BRONCHITIS; CHINCHILLA MODEL; POLYSACCHARIDE AB Nontypeable Haemophilus influenzae (NTHi) accounts for about one-third of purulent otitis media (OM) in children and is a common cause of pulmonary infection in adults with decreased resistance. Based upon sero-epidemiological data in humans and immunochemical data in laboratory animals, a lipooligosaccharide (LOS)-tetanus toxoid (TT) conjugate was prepared and evaluated for its safety and immunogenicity in a Phase I study of 40 healthy adults. The conjugate was injected intramuscularly into all volunteers: 28 of them received a second injection 14 weeks later. Local and systemic reactions were monitored and sera, taken before and 2, 6, 14, 16, and 38 weeks after injection, were assayed for IgG, IgA, and IgM antibodies to the LOS by ELISA and for bactericidal activity. The results indicate that there were no significant local or systemic reactions after either injection. All volunteers had pre-existing IgG anti-LOS. The geometric mean (GM) level rose from 14 to 40 at 2 weeks, remained at 35 at 6 weeks (40 or 35 versus 14, P < 0.01) and dropped to 27 at 14 weeks after the first injection. There was also a rise 2 weeks after the second injection (27 versus 37, P < 0.05). A total of 52.5% of subjects showed serum-conversion (greater than four-fold increase) after one and two injections. At 38 weeks, the GM IgG anti-LOS was still higher than before initial injection (20 versus 14, P < 0.05). A similar pattern of reactivity was observed for IgA and IgM anti-LOS. Similar to that observed in mice, but not in rabbits, the conjugate-induced antibodies did not yield significant bactericidal activity in vitro. The LOS-TT conjugate is well tolerant in adults and a Phase II evaluation of the conjugate in children is planned. Published by Elsevier Science Ltd. C1 Natl Inst Deafness & Other Commun Disorders, Rockville, MD 20850 USA. Natl Inst Child Hlth & Human Dev, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Gu, XX (reprint author), Natl Inst Deafness & Other Commun Disorders, 5 Res Court, Rockville, MD 20850 USA. NR 48 TC 23 Z9 23 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD MAY 16 PY 2003 VL 21 IS 17-18 BP 2107 EP 2114 DI 10.1016/S0264-410X(02)00768-5 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 682PF UT WOS:000183100200039 PM 12706701 ER PT J AU Lee, LH Frasch, CE Falk, LA Klein, DL Deal, CD AF Lee, LH Frasch, CE Falk, LA Klein, DL Deal, CD TI Correlates of immunity for pneumococcal conjugate vaccines SO VACCINE LA English DT Article DE correlate; pneumococcal; conjugate vaccine ID STREPTOCOCCUS-PNEUMONIAE; CAPSULAR POLYSACCHARIDE; ANTIBODY AVIDITY; IGG ANTIBODY; INFANTS; EFFICACY; CHILDREN; IMMUNOGENICITY; IMMUNIZATION; VACCINATION AB The purpose of the NIAID/FDA joint workshop, "correlates of immunity for pneumococcal conjugate vaccines (PCVs)," was to discuss the present understanding of protective immunity against invasive pneumococcal disease and identify in vitro measures that may represent immunologic correlates in future clinical trials. Animal and clinical data support functional antibody as the basis for protection, but IgG antibody concentration has conventionally been the principle immunologic parameter for non-inferiority comparisons. No consensus for a pre-defined threshold antibody level was reached. Affinity maturation may contribute to protection, but its role has not been established. Opsonophagocytic activity, avidity and immunologic memory are important secondary measures to characterise functional antibody and long-term protective responses. Immunologic memory may also be useful for evaluation of new vaccine serotypes. More definitive qualitative and quantitative immunogenicity criteria for use by National Control Authorities still need to be established. Published by Elsevier Science Ltd. C1 US FDA, Ctr Biol Evaluat & Res, Div Vaccines & Related Prod Applicat, Rockville, MD 20852 USA. US FDA, Ctr Biol Evaluat & Res, Div Bacterial Prod, Rockville, MD 20852 USA. NIAID, Div Microbiol & Infect Dis, Bethesda, MD 20817 USA. RP Lee, LH (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Vaccines & Related Prod Applicat, HFM-475,1401 Rockville Pike, Rockville, MD 20852 USA. NR 32 TC 39 Z9 41 U1 1 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD MAY 16 PY 2003 VL 21 IS 17-18 BP 2190 EP 2196 DI 10.1016/S0264-410X(03)00025-2 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 682PF UT WOS:000183100200048 PM 12706710 ER PT J AU Huang, WY Winn, DM Brown, LM Gridley, G Bravo-Otero, E Diehl, SR Fraumeni, JF Hayes, RB AF Huang, WY Winn, DM Brown, LM Gridley, G Bravo-Otero, E Diehl, SR Fraumeni, JF Hayes, RB TI Alcohol concentration and risk of oral cancer in Puerto Rico SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE alcohol drinking; alcoholic beverages; Hispanic Americans; mouth neoplasms; pharynx ID PHARYNGEAL CANCER; CAVITY; DRINKING; MUCOSA; CONSUMPTION; BEVERAGE; TRACT; ACETALDEHYDE; SMOKING; TOBACCO AB Alcohol consumption is a major risk factor for cancers of the mouth and pharynx (oral cancer), but the differential risks by beverage type are unclear. In this 1992-1995 study, the authors examined oral cancer risk in Puerto Rico, comparing alcohol intake among 286 male cases aged 21-79 years and 417 population-based male controls, frequency matched by age. Heavy consumers of liquor (greater than or equal to43 drinks per week) had strongly increased risks of oral cancer (odds ratio = 6.4, 95% confidence interval: 2.4, 16.8); beer/wine showed only modest effects. Among liquor drinkers, risks were consistently greater for those who drank straight (undiluted) liquor than for those who usually drank mixed (diluted) liquor (odds ratio = 4.0, 95% confidence interval: 2.4, 6.7). Risks associated with combined exposure to tobacco were also more pronounced when subjects drank liquor straight. The elevated risks associated with drinking homemade rum were similar to those for other types of liquor. These results suggest that alcohol concentration is a risk factor for oral cancer independent of the total quantity of alcohol consumed. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Univ Puerto Rico, Sch Dent, San Juan, PR 00936 USA. Univ Med & Dent New Jersey, New Jersey Dent Sch, Newark, NJ 07103 USA. RP Huang, WY (reprint author), NCI, Div Canc Epidemiol & Genet, EPS 8109, Bethesda, MD 20892 USA. NR 25 TC 26 Z9 27 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAY 15 PY 2003 VL 157 IS 10 BP 881 EP 887 DI 10.1093/aje/kwg055 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 680CE UT WOS:000182958100004 PM 12746240 ER PT J AU Engels, EA Frisch, M Biggar, RJ Goedert, JJ AF Engels, EA Frisch, M Biggar, RJ Goedert, JJ TI Re: "Estimation of risk of cancers before occurrence of acquired immunodeficiency syndrome in persons infected with human immunodeficiency virus" SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. Statens Serum Inst, Danish Epidemiol Sci Ctr, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. RP Engels, EA (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. RI Frisch, Morten/E-9206-2016 OI Frisch, Morten/0000-0002-3864-8860 NR 4 TC 5 Z9 5 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAY 15 PY 2003 VL 157 IS 10 BP 955 EP 955 DI 10.1093/aje/kwg084 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 680CE UT WOS:000182958100013 PM 12746250 ER PT J AU Plantinga, L Natowicz, MR Kass, NE Hull, SC Gostin, LO Faden, RR AF Plantinga, L Natowicz, MR Kass, NE Hull, SC Gostin, LO Faden, RR TI Disclosure, confidentiality, and families: Experiences and attitudes of those with genetic versus nongenetic medical conditions SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Article DE confidentiality; disclosure; family members; hereditary disease; cross-sectional survey ID ANTIDISCRIMINATION LEGISLATION; INFORMATION; PRIVACY AB Despite policy attention to medical privacy and patient confidentiality, little empirical work exists documenting and comparing experiences of persons with genetic versus nongenetic medical conditions concerning persons' disclosure to others as well as their views about appropriate confidentiality to and within families. The goal of this cross-sectional interview study with nearly 600 participants was to document and compare the experiences, attitudes, and beliefs of persons with strictly genetic conditions to those of persons with or at risk for other serious medical conditions in terms of the degree to which they have disclosed to others that they have the condition and their views about how others ought to maintain the confidentiality of that information. While almost all participants reported that family members knew about their condition, results suggest participants want to control that disclosure themselves and do not want doctors to disclose information to family members without their knowledge. Similarly, participants do not think family members should be able to get information about them without their knowledge but feel overwhelmingly that it is a person's responsibility to disclose information about hereditary conditions to other family members. Ambivalence about confidentiality was evident: while most participants did not mind doctors sharing information with other doctors when it was for their benefit, the majority also felt that doctors should be punished for releasing information without their permission. The views and experiences reported here generally did not differ by whether participants had genetic versus nongenetic conditions, suggesting that the extensive policy focus on genetic information may be unwarranted. (C) 2003 Wiley-Liss, Inc. C1 Johns Hopkins Univ, Phoebe R Berman Bioeth Inst, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. Cleveland Clin Fdn, Neurometab Clin, Cleveland, OH 44195 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. NHGRI, Bioeth Res Sect, NIH, Washington, DC USA. Georgetown Univ, Washington, DC USA. Johns Hopkins Univ, Ctr Law & Publ Hlth, Baltimore, MD USA. RP Kass, NE (reprint author), Johns Hopkins Univ, Phoebe R Berman Bioeth Inst, 624 N Broadway,Hampton House,Room 348, Baltimore, MD 21205 USA. FU Intramural NIH HHS [Z99 HG999999] NR 9 TC 35 Z9 35 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET C JI Am. J. Med. Genet. C PD MAY 15 PY 2003 VL 119C IS 1 BP 51 EP 59 DI 10.1002/ajmg.c.10006 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 674QP UT WOS:000182647700008 PM 12704638 ER PT J AU James, CA Holtzman, NA Hadley, DW AF James, CA Holtzman, NA Hadley, DW TI Perceptions of reproductive risk and carrier testing among adolescent sisters of males with chronic granulomatous disease SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Article DE carrier testing; chronic granulomatous disease; genetic counseling; minors; family dynamics; adolescents; siblings ID SEVERE COMBINED IMMUNODEFICIENCY; FRAGILE-X-SYNDROME; CYSTIC-FIBROSIS; ATAXIA-TELANGIECTASIA; LINKED DISEASES; CHILDREN; ATTITUDES; SATISFACTION; CHILDHOOD; OPINIONS AB Although recent research has investigated the attitudes of parents, professionals, and adult siblings toward carrier testing of minors, no studies have focused on the experiences of minor siblings of individuals with X-linked and autosomal recessive conditions. To explore adolescent sisters' perceptions of their reproductive risks, attitudes toward carrier testing, and resources for information and support, we interviewed 14 parents and 9 sisters (ages 12-15) of males with chronic granulomatous disease (CGD), a primary immunodeficiency disorder inherited in both an X-linked recessive and autosomal recessive fashion. Our semistructured telephone interviews were audiotaped, transcribed, and subjected to template analysis (a common qualitative methodology). Girls were all aware that CGD is an inherited condition and each had made an assessment of her reproductive risk. All girls considered their parents to be their best source of information and support, but girls had trouble initiating discussions for fear of upsetting their parents. All girls and parents considered eventual carrier testing vital for reproductive decision-making and relationship-building. However, girls favored carrier testing at a later age and expressed more concerns about psychological risks associated with testing than did their parents. When faced with the hypothetical situation of being offered carrier testing "tomorrow," half of the parents and untested daughters disagreed on the desirability of the test, with parents more likely to favor testing. Including adolescent sisters in family-based genetic counseling that provides an opportunity for age-appropriate discussion of inheritance and the timing, risks, and benefits of carrier testing would be beneficial to them. Published 2003 Wiley-Liss, Inc.(dagger) C1 Johns Hopkins Univ, Johns Hopkins Med Inst, Div Cardiol, Baltimore, MD USA. NHGRI, Genet Counseling Res Unit, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP James, CA (reprint author), Johns Hopkins Univ Hosp, Carnegie 592,600 Wolfe St, Baltimore, MD 21287 USA. NR 38 TC 15 Z9 15 U1 1 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET C JI Am. J. Med. Genet. C PD MAY 15 PY 2003 VL 119C IS 1 BP 60 EP 69 DI 10.1002/ajmg.c.10007 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 674QP UT WOS:000182647700009 PM 12704639 ER PT J AU Devan, BD Stouffer, EM Petri, HL McDonald, RJ Olds, JL AF Devan, BD Stouffer, EM Petri, HL McDonald, RJ Olds, JL TI Partial reinforcement across trials impairs escape performance but spares place learning in the water maze SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE spatial learning; place navigation; water maze procedures; aversive motivation; competitive contingencies; alternative place/cue responses; thigraotaxis; learning versus performance; interactive memory systems; rats ID ON-DEMAND PLATFORM; DORSAL STRIATUM; SPATIAL LOCALIZATION; CAUTIONARY NOTE; MEMORY-SYSTEMS; HIPPOCAMPUS; INFORMATION; NAVIGATION; RAT; DISSOCIATION AB We studied the effects of partial reinforcement on escape performance and place learning in the water maze. Rats given 50% reinforcement across trials (i.e. the escape platform was present only on odd trials) were compared to controls given 100% reinforcement (platform present on all trials). Control groups either received 8 or 4 trials per day, which was equal to either the total number of trials (100%-8) or reinforced escapes (100%-4) of the 50% group. Analysis of escape performance (latency) revealed that the 50% group was impaired relative to the 100%-8 group, but not the 100%-4 group, during the first 5 days of acquisition. The 50% group was impaired relative to both control groups on days 6-10 of overtraining. However, analyses of within-trial behavior (target annulus preference and thigmotaxis) on nonreinforced trials suggest that the 50% group did learn the location of the hidden platform (place information), in addition to a wall-based thigmotactic response. By dividing the 60 s nonreinforced trials into three 20-s time bins, we were able to detect a significant preference for the target annulus early in the trial (bin I of trial 40 and bins 1-2 of trial 80). Further, there was a significant increase in time spent in the periphery of the pool, near the wall, in the last time bin of trial 40. Because the platform was in the middle zone, this behavior competed with a place response. We conclude that across-trial partial reinforcement procedures may promote response competition and mask evidence of place learning in addition to weakening escape performance late in training. (C) 2002 Elsevier Science B.V. All rights reserved. C1 George Mason Univ, Krasnow Inst Adv Study, Fairfax, VA 22030 USA. NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. Towson Univ, Lab Comparat Neuropsychol, Dept Psychol, Towson, MD 21252 USA. Univ Toronto, Dept Psychol, Neurosci Program, Toronto, ON M5S 1A1, Canada. RP Devan, BD (reprint author), NeuroLog Inc, Behav Pharmacol, 15010 Broschart Rd,Suite 200, Rockville, MD 20850 USA. RI Olds, James/D-2867-2011 NR 27 TC 13 Z9 13 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD MAY 15 PY 2003 VL 141 IS 2 BP 91 EP 104 AR PII S0166-4328(02)00294-2 DI 10.1016/S0166-4328(02)00294-2 PG 14 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 682NU UT WOS:000183099000001 PM 12742245 ER PT J AU Lipska, BK Luu, S Halim, ND Weinberger, DR AF Lipska, BK Luu, S Halim, ND Weinberger, DR TI Behavioral effects of neonatal and adult excitotoxic lesions of the mediodorsal thalamus in the adult rat SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE amphetamine; locomotion; ventral hippocampus; prefrontal cortex; development; stress; ibotenic acid ID MEDIAL PREFRONTAL CORTEX; SPATIAL WORKING-MEMORY; VENTRAL HIPPOCAMPUS; NUCLEUS-ACCUMBENS; PRELIMBIC CORTEX; PYRAMIDAL CELLS; AXON TERMINALS; SCHIZOPHRENIA; NEURONS; DAMAGE AB We examined in the rat, the effects of neonatal (postnatal Day 7) and adult excitotoxic lesions of the mediodorsal thalamus (MDT), a brain area innervating the prefrontal cortex and implicated as a site of neuropathology in schizophrenia. Previous studies showed that rats with neonatal excitotoxic damage of the ventral hippocampus (VH), used as an animal model of this disorder, display in young adulthood a variety of abnormalities reminiscent of schizophrenia, including hyperactivity to stressful stimuli and amphetamine. It has been speculated that behavioral abnormalities of the neonatally VH lesioned animals are mediated through MDT projections to the prefrontal cortex. We tested if rats with ibotenic acid (1.5 mug per hemisphere in neonates, 2 mug in adults) lesions of MDT exhibited motor hyperactivity in the same experimental conditions (i.e. in response to novelty, saline injections and amphetamine administration) as rats with the VH lesions. We found that, in contrast to rats with VH lesions, neonatally lesioned MDT rats showed reduced vertical activity in response to amphetamine and no changes in locomotor activity to novelty, saline or amphetamine injections 7 weeks postlesion. Adult lesioned MDT rats exhibited no changes in motor activity as compared to controls at 7 weeks postlesion. These results indicate that neonatal or adult excitotoxic lesions of MDT do not produce behavioral changes analogous to those seen after neonatal VH lesions and do not appear to reproduce animal model-like features of schizophrenia. (C) 2003 Elsevier Science B.V. All rights reserved. C1 NIMH, Intramural Res Program, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Lipska, BK (reprint author), NIMH, Intramural Res Program, Clin Brain Disorders Branch, NIH, 10 Ctr Dr,Bldg 10,Rm 4N306, Bethesda, MD 20892 USA. NR 48 TC 7 Z9 7 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD MAY 15 PY 2003 VL 141 IS 2 BP 105 EP 111 DI 10.1016/S0166-4328(03)00027-5 PG 7 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 682NU UT WOS:000183099000002 PM 12742246 ER PT J AU Tozser, J Bagossi, N Zahuczky, G Specht, SI Majerova, E Copeland, TD AF Tozser, J Bagossi, N Zahuczky, G Specht, SI Majerova, E Copeland, TD TI Effect of caspase cleavage-site phosphorylation on proteolysis SO BIOCHEMICAL JOURNAL LA English DT Article DE caspase-3; caspase-7; caspase-8; cleavage site; oligopeptide; substrate specificity ID PROTEIN-KINASE; IN-VIVO; ALZHEIMERS-DISEASE; GROWTH ARREST; APOPTOSIS; SUBSTRATE; PROTEASES; PRESENILIN-1; ACTIVATION; FAMILY AB Caspases are important mediators of apoptotic cell death. Several cellular protein substrates of caspases contain potential phosphorylation site(s) at the cleavage-site region, and some of these sites have been verified to be phosphorylated. Since phosphorylation may affect substantially the substrate susceptibility towards proteolysis, phosphorylated, non-phosphorylated and substituted oligopeptides representing such cleavage sites were studied as substrates of apoptotic caspases 3, 7 and 8. Peptides containing phosphorylated serine residues at P4 and P1' positions were found to be substantially less susceptible towards proteolysis as compared with the serine-containing analogues, while phosphoserine at P3 did not have a substantial effect. PI serine as well as P1-phosphorylated, serine-containing analogues of an oligopeptide representing the poly(ADP-ribose) polymerase cleavage site of caspase-3 were not hydrolysed by any of these enzymes, whereas the P I aspartate-containing peptides were efficiently hydrolysed. These findings were interpreted with the aid of molecular modelling. Our results suggest that cleavage-site phosphorylation in certain positions could be disadvantageous or detrimental with respect to cleavability by caspases. Cleavage-site phosphorylation may therefore provide a regulatory mechanism to protect substrates from caspase-mediated degradation. C1 Univ Debrecen, Fac Med, Dept Biochem & Mol Biol, H-4012 Debrecen, Hungary. NCI, Basic Res Lab, Canc Res Ctr, Frederick, MD 21701 USA. SAIC Frederick, Frederick, MD 21701 USA. RP Tozser, J (reprint author), Univ Debrecen, Fac Med, Dept Biochem & Mol Biol, H-4012 Debrecen, Hungary. EM tozscr@indi.biochem.dote.hu RI Tozser, Jozsef/A-7840-2008; OI Tozser, Jozsef/0000-0003-0274-0056; Tozser, Jozsef/0000-0001-5076-8729 NR 42 TC 37 Z9 37 U1 0 U2 1 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0264-6021 EI 1470-8728 J9 BIOCHEM J JI Biochem. J. PD MAY 15 PY 2003 VL 372 BP 137 EP 143 DI 10.1042/BJ20021901 PN 1 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 682BQ UT WOS:000183070800014 PM 12589706 ER PT J AU Gao, ZG Blaustein, JB Gross, AS Melman, N Jacobson, KA AF Gao, ZG Blaustein, JB Gross, AS Melman, N Jacobson, KA TI N-6-substituted adenosine derivatives: selectivity, efficacy, and species differences at A(3) adenosine receptors SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE purines; nucleosides; GPCR; cyclic AMP; receptor binding; structure-activity relationships ID A(3)-ADENOSINE RECEPTOR; PARTIAL AGONISTS; BINDING; PHARMACOLOGY; ANTAGONISTS; RADIOLIGAND; ACTIVATION; ANALOGS; LIGANDS; A(1) AB The activation of the human A(3) adenosine receptor (AR) by a wide range of N-6-substituted adenosine derivatives was studied in intact CHO cells stably expressing this receptor. Selectivity of binding at rat and human ARs was also determined. Among N-6-alkyl substitutions. small e-alkyl groups were associated with selectivity for human A(3)ARs vs. rat A(3)ARs, and multiple points of branching were associated with decreased hA(3)AR efficacy. N-6-Cycloalkyl-substituted adenosines were full (less than or equal to5 carbons) or partial (greater than or equal to6 carbons) hA(3)AR agonists. N-6-(endo-Norbornyl)adenosine 13 was the most selective for both rat and human A(1)ARs. Numerous N-6-arylmethyl analogues. including substituted benzyl, tended to be more potent in binding to A I and A3 vs. A(2A)ARs (with variable degrees of partial to full A(3)AR agonisms). A chloro substituent decreased the efficacy depending on its position on the benzyl ring. The A3AR affinity and efficacy of N-6-arylethyl adenosines depended highly on stereochemistry, steric bulk, and ring constraints. Stereoselectivity of binding was demonstrated for N-6-(R-1-phenylethyl)adenosine vs. N-6-(S-1-phenylethyl)adenosine, as well as for the N6-(1-phenyl-2-pentyl)adenosine, at the rat, but not human A(3)AR. Interestingly, DPMA, a potent agonist for the A(2A)AR (K-i = 4 nM), was demonstrated to be a moderately potent antagonist for the human A(3)AR (K-i = 106 nM). N-6-[(1S,2R)-2-Phenyl-1-cyclopropyl]adenosine 48 was 1100-fold more potent in binding to human (K-i = 0.63 nM) than rat A(3)ARs. Dual acting A(1)/A(3) agonists (N-6-3-chlorobenzyl-29, N-6-(S-1-phenylethyl)-39, and 2-chloro-N-6'-(R-phenylisopropyl)adenosine 53) might be useful for cardioprotection. (C) 2003 Elsevier Science 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, Room B1A-19,Bldg 8A, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031117-20] NR 26 TC 92 Z9 94 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD MAY 15 PY 2003 VL 65 IS 10 BP 1675 EP 1684 DI 10.1016/S0006-2952(03)00153-9 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 684NL UT WOS:000183213400011 PM 12754103 ER PT J AU Bremner, JD Vythilingam, M Vermetten, E Southwick, SM McGlashan, T Staib, LH Soufer, R Charney, DS AF Bremner, JD Vythilingam, M Vermetten, E Southwick, SM McGlashan, T Staib, LH Soufer, R Charney, DS TI Neural correlates of declarative memory for emotionally valenced words in women with posttraumatic stress disorder related to early childhood sexual abuse SO BIOLOGICAL PSYCHIATRY LA English DT Article DE positron emission tomography; memory; posttraumatic stress disorder; stress; hippocampus; frontal cortex ID POSITRON-EMISSION-TOMOGRAPHY; MEDIAL PREFRONTAL CORTEX; TRAUMA-RELATED STIMULI; SCRIPT-DRIVEN IMAGERY; CEREBRAL BLOOD-FLOW; SHORT-TERM-MEMORY; HIPPOCAMPAL VOLUME; CINGULATE CORTEX; ADULT SURVIVORS; RAPE VICTIMS AB Background: Animal studies have shown that early stressors result in lasting changes in structure and function of brain areas involved in memory, including hippocampus and frontal cortex. Patients with childhood abuse-related posttraumatic stress disorder (PTSD) have alterations in both declarative and nondeclarative memory function, and imaging studies in PTSD have demonstrated changes in function during stimulation of trauma-specific memories in hippocampus, medial prefrontal cortex, and cingulate. The purpose of this study was to assess neural correlates of emotionally valenced declarative memory in women with early childhood sexual abuse and PTSD. Methods: Women with early childhood sexual abuse-related PTSD (n = 10) and women without abuse or PTSD (n = H) underwent positron emission tomographic (PET) measurement of cerebral blood flow during a control condition and during retrieval of neutral (e.g., "metal-iron") and emotionally valenced (e.g., "rape-mutilate") word pairs. Results: During retrieval of emotionally valenced word pairs, PTSD patients showed greater decreases in blood flow in an extensive area, which included orbitofrontal cortex, anterior cingulate, and medial prefrontal cortex (Brodmann's areas 25, 32, 9), left hippocampus, and fusiform gyrus/inferior temporal gyrus, with increased activation in posterior cingulate, left inferior parietal cortex, left middle frontal gyrus, and visual association and motor cortex. There were no differences in patterns of brain activation during retrieval of neutral word pairs between patients and control subjects. Conclusions: These findings are consistent with dysfunction of specific brain areas involved in memory and emotion in PTSD. Regions implicated in this study of emotionally valenced declarative memory are similar to those from prior imaging studies in PTSD using trauma-specific stimuli for symptom provocation, adding further supportive evidence for a dysfunctional network of brain areas involved in memory, including hippocampus, medial prefrontal cortex, and cingulate, in PTSD. (C) 2003 Society of Biological Psychiatry. C1 Emory Univ, Sch Med, Emory Ctr Positron Emiss Tomog, Dept Psychiat & Behav Sci, Atlanta, GA USA. Emory Univ, Sch Med, Emory Ctr Positron Emiss Tomog, Dept Radiol, Atlanta, GA USA. Atlanta Dept Vet Affairs Med Ctr, Decatur, GA USA. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. Yale Univ, Sch Med, Dept Radiol, New Haven, CT 06510 USA. Yale Univ, Sch Med, Dept Med Cardiol, New Haven, CT 06510 USA. RP Bremner, JD (reprint author), Emory Univ Hosp, PET Ctr, Room E154,1256 Briarcliff Rd,West Campus, Atlanta, GA 30306 USA. RI Bremner, James/B-1632-2013; OI Vermetten, Eric/0000-0003-0579-4404; Staib, Lawrence/0000-0002-9516-5136 FU NHLBI NIH HHS [HL059619-02]; NIMH NIH HHS [1R01MH56120-02] NR 55 TC 138 Z9 147 U1 3 U2 20 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 15 PY 2003 VL 53 IS 10 BP 879 EP 889 DI 10.1016/S0006-3223(02)01891-7 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 676BZ UT WOS:000182733200005 PM 12742675 ER PT J AU Bertolino, A Frye, M Callicott, JH Mattay, VS Rakow, R Shelton-Repella, J Post, R Weinberger, DR AF Bertolino, A Frye, M Callicott, JH Mattay, VS Rakow, R Shelton-Repella, J Post, R Weinberger, DR TI Neuronal pathology in the hippocampal area of patients with bipolar disorder: A study with proton magnetic resonance spectroscopic imaging SO BIOLOGICAL PSYCHIATRY LA English DT Article DE magnetic resonance spectroscopy; N-acetyl-aspartate; hippocampus; bipolar disorder ID N-ACETYL-ASPARTATE; CEREBRAL BLOOD-FLOW; MOOD DISORDERS; CORTICAL GRAY; HUMAN BRAIN; SCHIZOPHRENIA; DEPRESSION; ACETYLASPARTATE; INCREASES; VOLUME AB Background: The brain regions involved in the pathophysiology of bipolar disorder have not been definitively determined. Previous studies have suggested possible involvement of the hippocampus and of prefrontal regions. Proton magnetic resonance spectroscopic imaging (H-1-MRSI) allows measurement of N-acetylaspartate (NAA, marker of neuronal integrity), choline-containing compounds (CHO), and creatine+phosphocreatine (CRE) in multiple brain regions. The objective of this study was to assess possible NAA reductions in hippocampus and prefrontal regions in patients with bipolar disorder. Methods: We studied 17 patients with bipolar disorder and 17 age- and gender-matched healthy subjects on a 1.5-T nuclear magnetic resonance (NMR) machine. With H-1-MRSI we measured ratios of areas under the metabolite peaks of the proton spectra (i.e., NAA/CRE, NAA/CHO, CHO/CRE) for multiple cortical and subcortical regions. Results: Patients showed significant reductions of NAA/CRE bilaterally in the hippocampus. There were no significant changes in CHO/CRE or in NAA ratios in any other area sampled. Conclusions: This study shows that patients with bipolar disorder have a regional reduction of NAA relative signals, suggesting neuronal damage or malfunction of the hippocampus. As suggested by other studies, neuronal pathology in the hippocampus may be involved in the pathophysiology of bipolar disorder and in susceptibility to psychosis. (C) 2003 Society of Biological Psychiatry. C1 NIMH, Clin Brain Disorders Branch, Intramural Res Programs, NIH, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, Biol Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP Weinberger, DR (reprint author), NIMH, Clin Brain Disorders Branch, Intramural Res Programs, NIH, Bethesda, MD 20892 USA. RI Bertolino, Alessandro/O-6352-2016 OI Bertolino, Alessandro/0000-0002-1251-1380 NR 50 TC 113 Z9 125 U1 4 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 15 PY 2003 VL 53 IS 10 BP 906 EP 913 DI 10.1016/S0006-3223(02)01911-X PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 676BZ UT WOS:000182733200008 PM 12742678 ER PT J AU Komatsu, M Mammolenti, M Jones, M Jurecic, R Sayers, TJ Levy, RB AF Komatsu, M Mammolenti, M Jones, M Jurecic, R Sayers, TJ Levy, RB TI Antigen-primed CD8(+) T cells can mediate resistance, preventing allogeneic marrow engraftment in the simultaneous absence of perforin-, CD95L-, TNFR1- and TRAIL-dependent killing SO BLOOD LA English DT Article ID HEMATOPOIETIC STEM-CELLS; TUMOR-NECROSIS-FACTOR; NATURAL-KILLER-CELLS; APOPTOSIS-INDUCING LIGAND; BONE-MARROW; GRAFT-REJECTION; PROGENITOR CELLS; IRRADIATED MICE; LONG-TERM; EFFECTOR MECHANISMS AB Engraftment failure following allogeneic bone marrow (BM) transplantation is of clinical concern particularly involving T-cell-depleted inoculum and transplantations for aplastic anemia. Immune resistance by lymphoid and natural killer (NK) populations with "barrier" function is well established. Major histocompatibility complex (MHC)-identical marrow allo-grafts were examined to investigate effector pathways in non-NK-mediated resistance. Barrier function was examined in cytotoxic normal and deficient B6 (H-2(b)) recipients primed to donor minor histocompatibility antigen (MIHA) prior to BM transplantation. Host resistance was sensitively evaluated by colony-forming unit (CFU) assays to directly assess for donor progenitor cell (PC) and peripheral chlmerism. B6 host CD8(+) T cells but not CD4(+) or NK1.1(+) cells effected rejection of primitive (CFU-HPP [high-proliferative potential]) and lineage-committed (CFU-IL3/GM [interieukin 3/granulocyte macro-phage]) allogeneic donor progenitors. To address complementation by the cytotoxic pathways existing in singly deficient (perforin or FasL) recipients, cytotoxically double (perforin plus FasL) deficient (cdd) recipients were used. Resistance in B6-cdd recipients was comparable to that of wild-type B6 recipients and was also dependent on CD8(+) T cells. A "triple" cytotoxic deficient model, involving transplantation of TNFR1(-/-) (tumor necrosis factor receptor 1) progenitor grafts did not diminish the ability of B6-cdd recipients to reject allografts. Finally, injection of anti-TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) monoclonal antibody (mAb) in B6-cdd recipients also failed to inhibit rejection of TNFR1(-/-) marrow grafts. In total, these studies demonstrate that CD8(+) host T cells can effectively resist MHC-matched MiHA-mismatched donor PCs via alternative effector pathway(s) independent of perforin-, FasL-, TNIFR-1-,and TRAIL-dependent cytotoxicity. Therefore, inhibition of these effector pathways in sensitized recipients is unlikely to result in stem cell engraftment following PC allografts. (C) 2003 by The American Society of Hematology. C1 Univ Miami, Sch Med, Dept Microbiol & Immunol, Miami, FL 33101 USA. Burnham Inst, La Jolla, CA 92037 USA. NCI, Basic Res Program, SAIC Frederick, Frederick, MD USA. RP Levy, RB (reprint author), Univ Miami, Sch Med, Dept Microbiol & Immunol, POB 016960 R-138, Miami, FL 33101 USA. RI Sayers, Thomas/G-4859-2015 FU NCRR NIH HHS [1R01 RR11576]; NHLBI NIH HHS [5R01 HL52461]; PHS HHS [N01-C0-12400] NR 63 TC 26 Z9 26 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 15 PY 2003 VL 101 IS 10 BP 3991 EP 3999 DI 10.1182/blood-2002-09-2859 PG 9 WC Hematology SC Hematology GA 677EB UT WOS:000182793000042 PM 12521999 ER PT J AU Chen, VW Ruiz, B Killeen, JL Cote, TR Wu, XC Correa, CN AF Chen, VW Ruiz, B Killeen, JL Cote, TR Wu, XC Correa, CN TI Pathology and classification of ovarian tumors SO CANCER LA English DT Article ID CHROMOSOME 17Q; DIFFERENTIATION; CARCINOMAS; CANCER; ORIGIN; CELL AB Supported in part by the Centers for Disease Control and Prevention under cooperative agreement U75/CCU515998 to the North American Association of Central Cancer Registries. The authors appreciate the in-kind support from all the contributors to this supplement. The authors are also grateful for the contributions of David Roney and Andrew Lake of Information Management Services (IMS), Inc. for the computer support required for the preparation of analytic files and to the National Cancer Institute for providing support for these computer services. Address for reprints: Holly L. Howe, Ph.D., North American Association of Central Cancer Registries, 2121 White Oaks Dr., Springfield, IL 62704; Fax: (217) 698-0188; E-mail: hhowe@naaccr.org. Received March 18, 2002; revision received September 25, 2002; accepted January 15, 2003. *This article is a US Government work and, as such, is in the public domain of the United States of America. C1 Louisiana State Univ, Ctr Hlth Sci, Louisiana Tumor Registry, New Orleans, LA USA. Kapiolani Med Ctr Women & Children, Honolulu, HI USA. NCI, Bethesda, MD 20892 USA. RP Chen, VW (reprint author), Amer Assoc Cent Canc Registries, 2121 White Oaks Dr, Springfield, IL 62704 USA. FU ODCDC CDC HHS [U75/CCU515998] NR 32 TC 132 Z9 139 U1 1 U2 10 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD MAY 15 PY 2003 VL 97 IS 10 SU S BP 2631 EP + DI 10.1002/cncr.11345 PG 13 WC Oncology SC Oncology GA 675VG UT WOS:000182716500002 PM 12733128 ER PT J AU Roffers, SD Wu, XC Johnson, CH Correa, CN AF Roffers, SD Wu, XC Johnson, CH Correa, CN TI Incidence of extraovarian primary cancers in the United States, 1992-1997 SO CANCER LA English DT Article ID PRIMARY PERITONEAL CARCINOMA; SEROUS CARCINOMA; ENDOMETRIAL CARCINOMA; PAPILLARY CARCINOMA; PROGNOSTIC FACTORS; FALLOPIAN-TUBE; OVARIAN; ADENOCARCINOMA; WOMEN AB Supported in part by the Centers for Disease Control and Prevention under cooperative agreement U75/CCU515998 to the North American Association of Central Cancer Registries. The authors appreciate the in-kind support from all the contributors to this supplement. The authors are also grateful for the contributions of David Roney and Andrew Lake of Information Management Services (IMS), Inc., for the computer support required for the preparation of analytic files and to the National Cancer Institute for providing support for these computer services. Address for reprints: Holly L. Howe, Ph.D., 2121 W. White Oaks Drive, Springfield, IL 62704-6495; Fax: (217) 698-0800; E-mail: hhowe@naaccr.org Received March 18, 2002; revision received September 25, 2002; accepted January 15, 2003. *This article is a US Government work and, as such, is in the public domain of the United States of America. C1 Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. Louisiana State Univ, Louisiana Tumor Registry, Hlth Sci Ctr, New Orleans, LA USA. NCI, Bethesda, MD 20892 USA. RP Roffers, SD (reprint author), 2121 W White Oakds Dr, Springfield, IL 62704 USA. FU ODCDC CDC HHS [U75/CCU515998] NR 24 TC 8 Z9 8 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD MAY 15 PY 2003 VL 97 IS 10 SU S BP 2643 EP + DI 10.1002/cncr. PG 6 WC Oncology SC Oncology GA 675VG UT WOS:000182716500003 PM 12733129 ER PT J AU Goodman, MT Howe, HL Tung, KH Hotes, J Miller, BA Coughlin, SS Chen, VW AF Goodman, MT Howe, HL Tung, KH Hotes, J Miller, BA Coughlin, SS Chen, VW TI Incidence of ovarian cancer by race and ethnicity in the United States, 1992-1997 SO CANCER LA English DT Article ID COLLABORATIVE ANALYSIS; RISK-FACTORS; WOMEN; HYSTERECTOMY; CARCINOMA; TUMORS AB Supported in part by the Centers for Disease Control and Prevention under cooperative agreement U75/CCU515998 and contract N01-PC-25005 from the National Cancer Institute. The authors appreciate the in-kind support from all the contributors to this supplement and also are grateful for the contributions of David Roney and Andrew Lake of Information Management Services (IMS), Inc. for the computer support required for the preparation of analytic files and to the National Cancer Institute for providing support for these computer services. Address for correspondence: Holly L. Howe, Ph.D., North American Association of Central Cancer Registries, 2121 W. White Oaks Drive, Springfield, IL 62704-6495; Fax: (217) 698-0188; E-mail: hhowe@naaccr.org Received March 18, 2002; revision received September 25, 2002; accepted January 15, 2003. *This article is a US Government work and, as such, is in the public domain in the United States of America. C1 N Amer Assoc Cent Canc Registries, Springfield, IL 62704 USA. Univ Hawaii, Canc Res Ctr, Honolulu, HI 96822 USA. NCI, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Div Canc Prevent & Control, Atlanta, GA USA. Louisiana State Univ, Hlth Sci Ctr, Louisiana Tumor Registry, New Orleans, LA 70112 USA. RP Howe, HL (reprint author), N Amer Assoc Cent Canc Registries, 2121 W White Oaks Dr, Springfield, IL 62704 USA. FU NCI NIH HHS [N01-PC-25005]; ODCDC CDC HHS [U75/CCU515998] NR 25 TC 41 Z9 41 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD MAY 15 PY 2003 VL 97 IS 10 SU S BP 2676 EP + DI 10.1002/cncr.11349 PG 11 WC Oncology SC Oncology GA 675VG UT WOS:000182716500006 PM 12733132 ER PT J AU Wu, GJ Nomoto, S Hoque, MO Dracheva, T Osada, M Lee, CCR Dong, SM Guo, ZM Benoit, N Cohen, Y Rechthand, P Califano, J Moon, CS Ratovitski, E Jen, J Sidransky, D Trink, B AF Wu, GJ Nomoto, S Hoque, MO Dracheva, T Osada, M Lee, CCR Dong, SM Guo, ZM Benoit, N Cohen, Y Rechthand, P Califano, J Moon, CS Ratovitski, E Jen, J Sidransky, D Trink, B TI Delta Np63 alpha and TAp63 alpha regulate transcription of genes with distinct biological functions in cancer and development SO CANCER RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMA; P53 TARGET GENES; WILD-TYPE P53; EXPRESSION; CLONING; PROTEIN; P63; TRANSACTIVATION; FOS; IDENTIFICATION AB The p63 gene shows remarkable structural similarity to the p53 and p73 genes. Because of two promoters, the p63 gene generates two types of protein isoforms, TAp63 and DeltaNp63. Each type yields three isotypes (alpha, beta, gamma) because of differential splicing of the p63 COOH terminus. The purpose of this study was to determine whether there is a functional link between the distinct p63 isotypes in their transcriptional regulation of downstream targets and their role in various cellular functions. TAp63alpha and DeltaNp63alpha adenovirus expression vectors were introduced into Saos2 cells for 4 and 24 h, and then gene profiling was performed using a DNA microarray chip analysis. Seventy-four genes (>2-fold change in expression) were identified that overlapped between two independent studies. Thirty-five genes were selected for direct expression testing of which 27 were confirmed by reverse transcription-PCR or Northern blot analysis. A survey of these genes shows that p63 can regulate a wide range of downstream gene targets with various cellular functions, including cell cycle control, stress, and signal transduction. Our study thus revealed p63 transcriptional regulation of many genes in cancer and development while often demonstrating opposing regulatory functions for TAp63alpha and DeltaNp63alpha. C1 Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Div Head & Neck Canc Res, Baltimore, MD 21205 USA. NCI, Lab Populat Genet, Rockville, MD USA. Johns Hopkins Univ, Sch Med, Dept Dermatol, Baltimore, MD 21205 USA. RP Sidransky, D (reprint author), Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Div Head & Neck Canc Res, 818 Ross Res Bldg,710 Rutland Ave, Baltimore, MD 21205 USA. RI Lee, Chyi-Chia/I-1938-2013 OI Lee, Chyi-Chia/0000-0002-5306-7781 FU NCI NIH HHS [CA-58184-01]; NIAID NIH HHS [R01-AI47224-01]; NIDCR NIH HHS [R01-DE 012588-0] NR 49 TC 181 Z9 189 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 2003 VL 63 IS 10 BP 2351 EP 2357 PG 7 WC Oncology SC Oncology GA 680MH UT WOS:000182981600002 PM 12750249 ER PT J AU Shiseki, M Nagashima, M Pedeux, RM Kitahama-Shiseki, M Miura, K Okamura, S Onogi, H Higashimoto, Y Appella, E Yokota, J Harris, CC AF Shiseki, M Nagashima, M Pedeux, RM Kitahama-Shiseki, M Miura, K Okamura, S Onogi, H Higashimoto, Y Appella, E Yokota, J Harris, CC TI p29ING4 and p28ING5 bind to p53 and p300, and enhance p53 activity SO CANCER RESEARCH LA English DT Article ID CANDIDATE TUMOR-SUPPRESSOR; C-TERMINAL DOMAIN; DNA-DAMAGE; TRANSCRIPTIONAL REGULATION; HISTONE ACETYLATION; CELL-GROWTH; IN-VIVO; P33(ING1); COMPLEX; GENE AB We identified and characterized two new ING family genes, p29ING4 and p28ING5, coding for two proteins of 249 and 240 amino acids, respectively. Both p29ING4 and p28ING5 proteins have a plant homeodomain ringer motif also found in other ING proteins, and which is common in proteins involved in chromatin remodeling. p29ING4 or p28ING5 overexpression resulted in a diminished colony-forming efficiency, a decreased cell population in S phase, and the induction of apoptosis in a p53-dependent manner. Both p291NG4 and p28ING5 activate the p21/waf1 promoter, and induce p21/WAF1 expression. p29ING4 and p28ING5 enhance p53 acetylation at Lys-382 residues, and physically interact with p300, a member of histone acetyl transferase complexes, and p53 in vivo. These results indicate that p29ING4 and p28ING5 may be significant modulators of p53 function. C1 NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Natl Canc Ctr, Res Inst, Div Biol, Tokyo 104, Japan. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, 37 Convent Dr,Bldg 37,Room 2C05, Bethesda, MD 20892 USA. OI Miura, Koh/0000-0001-7303-9430 NR 43 TC 166 Z9 204 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 2003 VL 63 IS 10 BP 2373 EP 2378 PG 6 WC Oncology SC Oncology GA 680MH UT WOS:000182981600007 PM 12750254 ER PT J AU Linke, SP Sengupta, S Khabie, N Jeffries, BA Buchhop, S Miska, S Henning, W Pedeux, R Wang, XW Hofseth, LJ Yang, Q Garfield, SH Sturzbecher, HW Harris, CC AF Linke, SP Sengupta, S Khabie, N Jeffries, BA Buchhop, S Miska, S Henning, W Pedeux, R Wang, XW Hofseth, LJ Yang, Q Garfield, SH Sturzbecher, HW Harris, CC TI p53 interacts with hRAD51 and hRAD54, and directly modulates homologous recombination SO CANCER RESEARCH LA English DT Review ID WILD-TYPE P53; HUMAN RAD51 PROTEIN; C-TERMINAL DOMAIN; NORMAL HUMAN FIBROBLASTS; STRANDED-DNA ENDS; CELL-CYCLE ARREST; MUTANT P53; P53-MEDIATED APOPTOSIS; GENE AMPLIFICATION; MAMMALIAN-CELLS AB p53 inhibits tumorigenesis through a variety of functions, including mediation of cell cycle arrest, premature senescence, and apoptosis. p53 also can associate with several DNA helicases and proteins involved in homologous recombination. In this study, we show that p53, hRAD51, and hRAD54 coimmunoprecipitated and colocalized with each other at endogenous levels in normal cells. Colocalization was observed with the phosphoserine-15 form of p53 at presumed DNA processing sites after the induction of DNA breaks. hRAD54 bound directly to the p53 COOH terminus in vitro without a nucleic acid intermediate. We then investigated the functional consequences of these protein interactions. A host cell reactivation assay revealed that the elevation in recombination observed after p53 inactivation is dependent on the hRAD51 pathway and that p53-dependent antirecombinogenic activity can be attributed to p53 binding to hRAD51 directly. These data support the hypothesis that p53 helps maintain genetic stability through transcription-independent modulation of homologous recombination factors. C1 NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. Med Univ Lubeck, Inst Human Genet, D-23538 Lubeck, Germany. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, NIH, 37 Convent Dr,Bldg 37,Room 2C05, Bethesda, MD 20892 USA. RI Wang, Xin/B-6162-2009; OI Sengupta, Sagar/0000-0002-6365-1770 NR 103 TC 106 Z9 107 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 2003 VL 63 IS 10 BP 2596 EP 2605 PG 10 WC Oncology SC Oncology GA 680MH UT WOS:000182981600038 PM 12750285 ER PT J AU Barnes, GL Javed, A Waller, SM Kamal, MH Hebert, KE Hassan, MQ Bellahcene, A van Wijnen, AJ Young, MF Lian, JB Stein, GS Gerstenfeld, LC AF Barnes, GL Javed, A Waller, SM Kamal, MH Hebert, KE Hassan, MQ Bellahcene, A van Wijnen, AJ Young, MF Lian, JB Stein, GS Gerstenfeld, LC TI Osteoblast-related transcription factors Runx2 (Cbfa1/AML3) and MSX2 mediate the expression of bone sialoprotein in human metastatic breast cancer cells SO CANCER RESEARCH LA English DT Article ID HORMONE-RELATED PROTEIN; HUMAN PROSTATE-CANCER; MATRIX PROTEINS; IN-VIVO; GENE; DIFFERENTIATION; OSTEOPONTIN; MICE; MYC; LYMPHOMAGENESIS AB Human breast cancers are known to preferentially metastasize to skeletal sites, however, the mechanisms that mediate the skeletal preference (orthotropism) of specific types of cancers remains poorly understood. There is a significant clinical correlation between the expression of bone sialoprotein (BSP) and skeletal metastasis of breast cancers. Our laboratory, as well as others, have proposed the concept that skeletal selective metastasis and associated disease may be attributable to a mimicry of skeletal cellular phenotypes by metastasizing cancer cells. We hypothesize that breast cancer cell expression of phenotypic properties of skeletal cell types, including BSP as one component of that phenotype, is the result of ectopic expression or activity of one or more central transcriptional regulators of bone cell gene expression. To test this hypothesis, we examined the molecular mechanisms that regulate bsp expression in human breast cancer cell lines with previously characterized metastatic potentials. Our results demonstrate that the majority of the distal bsp promoter sequences act to repress BSP expression in cancer cells and that most of the promoter activity resides in the proximal -110 by of the bsp promoter. In this region, we identified a putative Runx binding element providing a basis for a mechanism for skeletal gene activation. Our results demonstrate that Runx2 is ectopically expressed in breast cancer cells and that one isoform of Runx2 can activate bsp expression in these cells. In addition, we observe that bsp expression is additionally regulated by the homeodomain factor Msx2, another regulator of osteoblast-associated genes. Thus, this is the first report of osteoblast-related transcription factors being expressed in human breast cancer cells and provides a component of a mechanism that may explain the osteoblastic phenotype of human breast cancer cells that preferentially metastasize to bone. C1 Boston Univ, Med Ctr, Dept Orthopaed Surg, Boston, MA 02118 USA. Univ Massachusetts, Sch Med, Dept Cell Biol, Worcester, MA 01655 USA. Univ Massachusetts, Sch Med, Ctr Canc, Worcester, MA 01655 USA. Univ Liege, Metastasis Res Lab, B-4000 Liege, Belgium. NIDR, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. RP Barnes, GL (reprint author), Boston Univ, Med Ctr, Dept Orthopaed Surg, 715 Albany St,R-205, Boston, MA 02118 USA. RI Kamal, Mohammad/B-2747-2016; OI Kamal, Mohammad/0000-0002-2833-4550; /0000-0002-0477-1211; Javed, Amjad/0000-0002-0847-8266 FU NCI NIH HHS [CA82834]; NIAMS NIH HHS [R01 AR049069]; NICHD NIH HHS [HD22400] NR 46 TC 132 Z9 137 U1 3 U2 11 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 2003 VL 63 IS 10 BP 2631 EP 2637 PG 7 WC Oncology SC Oncology GA 680MH UT WOS:000182981600043 PM 12750290 ER PT J AU Roden, MM Nelson, LD Knudsen, TA Jarosinski, PF Starling, JM Shiflett, SE Calis, K DeChristoforo, R Donowitz, GR Buell, D Walsh, TJ AF Roden, MM Nelson, LD Knudsen, TA Jarosinski, PF Starling, JM Shiflett, SE Calis, K DeChristoforo, R Donowitz, GR Buell, D Walsh, TJ TI Triad of acute infusion-related reactions associated with liposomal amphotericin B: Analysis of clinical and epidemiological characteristics SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID PERSISTENT FEVER; TOXICITY; NEUTROPENIA; THERAPY; SAFETY AB We investigated the clinical characteristics and treatment of patients with a distinctive triad of acute infusion-related reactions (AIRRs) to liposomal amphotericin B (L-AMB) via single-center and multicenter analyses. AIRRs occurred alone or in combination within 1 of 3 symptom complexes: (1) chest pain, dyspnea, and hypoxia; (2) severe abdomen, flank, or leg pain; and (3) flushing and urticaria. The frequency of AIRRs in the single-center analysis increased over time. Most AIRRs (86%) occurred within the first 5 min of infusion. All patients experienced rapid resolution of symptoms after intravenous diphenhydramine was administered. The multicenter analysis demonstrated a mean overall frequency of 20% (range, 0%-100%) of AIRRs among 64 centers. A triad of severe AIRRs to L-AMB may occur in some centers; most of these reactions may be effectively managed by diphenhydramine administration and interruption of L-AMB infusion. C1 NCI, Pediat Oncol Branch, Immunocompromised Host Sect, Bethesda, MD 20892 USA. NIH, Dept Pharm, Ctr Clin, Bethesda, MD 20892 USA. Univ Virginia, Charlottesville, VA USA. Fujisawa Healthcare, Deerfield, IL USA. RP Walsh, TJ (reprint author), NCI, Pediat Oncol Branch, Immunocompromised Host Sect, Bldg 10,Rm 13N240,10 Ctr Dr, Bethesda, MD 20892 USA. NR 19 TC 31 Z9 36 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 15 PY 2003 VL 36 IS 10 BP 1213 EP 1220 DI 10.1086/374553 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 678MZ UT WOS:000182872200002 PM 12746764 ER PT J AU Lo, SC Wang, RYH Grandinetti, T Zou, NX Haley, CLD Hayes, MM Wear, DJ Shih, JWK AF Lo, SC Wang, RYH Grandinetti, T Zou, NX Haley, CLD Hayes, MM Wear, DJ Shih, JWK TI Mycoplasma hominis lipid-associated membrane protein antigens for effective detection of M-hominis - Specific antibodies in humans SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID INFECTION; PENETRANS; HIV AB Lipid-associated membrane proteins (LAMPs) from 14 Mycoplasma hominis isolates or strains share similar protein and antigenicity profiles. Of 31 human immunodeficiency virus-infected patients from whose samples M. hominis was cultured, 28 tested strongly positive for serum antibodies to M. hominis LAMPs. The remaining 3 serum samples showed low antibody titer to LAMPs from all of the 14 M. hominis isolates or strains, which was likely the result of the compromised immune systems of the patients. Thus, M. hominis LAMPs as a whole are homogenous in antigenicity within the species, despite having many different serotypes. Serological study involving 564 healthy blood donors and 211 patients attending sexually transmitted disease clinics by LAMPs showed that general populations were widely exposed to M. hominis. Women were infected with M. hominis at a younger age than were men. The prevalence of infection increased markedly among sexually active persons. C1 Armed Forces Inst Pathol, Dept Infect & Parasit Dis Pathol, Washington, DC 20306 USA. Amer Registry Pathol, Washington, DC USA. Amer Red Cross, Natl Capital Chapter, Washington, DC 20006 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Lo, SC (reprint author), Armed Forces Inst Pathol, Dept Infect & Parasit Dis Pathol, Bldg 54,Rm 4091,6825 16th St NW, Washington, DC 20306 USA. NR 22 TC 5 Z9 7 U1 1 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 15 PY 2003 VL 36 IS 10 BP 1246 EP 1253 DI 10.1086/374851 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 678MZ UT WOS:000182872200007 PM 12746769 ER PT J AU Keiser, PB Nash, TE AF Keiser, PB Nash, TE TI Prolonged perilesional edema after treatment of Parenchymal neurocysticercosis: Methotrexate as a corticosteroid-sparing agent SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID HIGH-DOSE PRAZIQUANTEL; GLIOSIS AB Treatment of neurocysticercosis with larvicidal agents is commonly complicated by seizures and transient neurologic deficits as a result of the host immune response to dying cysts. We report a case in which treatment with high-dose praziquantel resulted in prolonged perilesional edema requiring use of corticosteroids and corticosteroid-sparing agents for >1 year, suggesting a role for methotrexate in the management of this condition. C1 NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Nash, TE (reprint author), NIH, Parasit Dis Lab, 9000 Rockville Pike,Bldg 4,Rm B1-01, Bethesda, MD 20892 USA. NR 11 TC 5 Z9 5 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 15 PY 2003 VL 36 IS 10 BP E122 EP E126 DI 10.1086/374667 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 678MZ UT WOS:000182872200030 PM 12746791 ER PT J AU Kriederman, BM Myloyde, TL Witte, MH Dagenais, SL Witte, CL Rennels, M Bernas, MJ Lynch, MT Erickson, RP Caulder, MS Miura, N Jackson, D Brooks, BP Glover, TW AF Kriederman, BM Myloyde, TL Witte, MH Dagenais, SL Witte, CL Rennels, M Bernas, MJ Lynch, MT Erickson, RP Caulder, MS Miura, N Jackson, D Brooks, BP Glover, TW TI FOXC2 haploinsufficient mice are a model for human autosomal dominant lymphedema-distichiasis syndrome SO HUMAN MOLECULAR GENETICS LA English DT Article ID TRANSCRIPTION FACTOR; HEREDITARY LYMPHEDEMA; MUTANT MICE; GENE; MUTATIONS; MFH1; LYMPHANGIOGENESIS; EXPRESSION; PHENOTYPE; INSULIN AB Lymphedema-distichiasis (LD) (OMIM 153400) is a rare autosomal-dominant condition characterized by pubertal onset of lower limb lymphedema and an aberrant second row of eyelashes arising from the meibomian glands. In some patients cardiac, skeletal and other defects coexist. We previously identified inactivating, nonsense and frameshift mutations in the forkhead transcription factor FOXC2 in affected members of LD families. To further delineate the relationship of FOXC2 deficiency to the clinical (and lymphangiodysplastic) phenotype in this syndrome, we performed dynamic lymphatic imaging and immunohistochemical examination of lymphatic tissues in mice heterozygous (+/-) for a targeted disruption of Foxc2. Adult heterozygote mice characteristically exhibited a generalized lymphatic vessel and lymph node hyperplasia and rarely exhibited hindlimb swelling. Retrograde lymph flow through apparently incompetent interlymphangion valves into the mesenteric nodes, intestinal wall and liver was also observed. In addition, Foxc2 +/- mice uniformly displayed distichiasis. We conclude that Foxc2 haploinsufficient mice mimic closely the distinctive lymphatic and ocular phenotype of LD patients. Furthermore, the craniofacial, cardiovascular and skeletal abnormalities sometimes associated with LD have previously been shown to be fully penetrant in homozygous Foxc2 null mice. This Foxc2 mutant mouse thus provides an ideal model for exploring molecular mechanisms and physiologic events in mesenchymal differentiation associated with. lymphatic growth and development and the clinical abnormalities seen in human LD syndrome. C1 Univ Arizona, Coll Med, Dept Surg, Lymphol Labs, Tucson, AZ 85724 USA. Univ Arizona, Dept Pathol, Tucson, AZ 85724 USA. Univ Arizona, Dept Pediat, Tucson, AZ 85724 USA. Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. Hamamatsu Univ Sch Med, Dept Biochem, Hamamatsu, Shizuoka, Japan. Univ Oxford, Dept Pathol, Oxford, England. NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. RP Kriederman, BM (reprint author), Univ Arizona, Coll Med, Dept Surg, Lymphol Labs, 1501 N Campbell Ave,Room 4406,POB 245063, Tucson, AZ 85724 USA. EM lymph@u.arizona.edu FU NCRR NIH HHS [R25RR15670]; NHLBI NIH HHS [HL71206] NR 31 TC 116 Z9 122 U1 0 U2 5 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 MAY 15 PY 2003 VL 12 IS 10 BP 1179 EP 1185 DI 10.1093/hmg/ddg123 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 679YU UT WOS:000182950200011 PM 12719382 ER PT J AU Zhang, CX Baffi, J Cousins, SW Csaky, KG AF Zhang, CX Baffi, J Cousins, SW Csaky, KG TI Oxidant-induced cell death in retinal pigment epithelium cells mediated through the release of apoptosis-inducing factor SO JOURNAL OF CELL SCIENCE LA English DT Article DE apoptosis; RPE cells; apoptosis-inducing factor; caspase; cell-free ID MACULAR DEGENERATION; CYTOCHROME-C; ROCK-I; MITOCHONDRIAL; NECROSIS; INVOLVEMENT; ACTIVATION; MEMBRANE; ZINC; RPE AB In the present study, the pathways involved in oxidant-induced cell death of a primary cell of the retina, ARPE-19, were investigated and compared with a leukemic cell, U937 cells. Both ARPE-19 and U937 cells exhibited similar viability when exposed to menadione. At lethal doses, both cell lines demonstrated extensive membrane blebbing. However, although U937 cells exhibited caspase-3, -9 PARP cleavage and 200 bp laddering, no such cleavage or laddering was noted in ARPE-19 cells. Furthermore, addition of exogenous cytochrome c and ATP to a cell-free system again resulted in cleavage of caspase-3 and -9 in extracts of U937 but not ARPE cells. Further studies in ARPE-19 cells undergoing menadione-induced cell death demonstrated mitochondrial membrane depolarization, release of cytochrome c, nuclear translocation of apoptosis-inducing factor and subsequent 50 kilo-base pair laddering, and nuclear shrinkage. All of these findings were abrogated by the pretreatment of ARPE-19 cells with hepatocyte growth factor/scatter factor. These findings demonstrate the complex nature of cell death in primary cells of the retina and highlight the role of caspase-independent signals, growth factors and intracellular survival factors in programmed cell death pathways. C1 NEI, Bethesda, MD 20892 USA. Univ Miami, Dept Ophthalmol, Miami, FL 33152 USA. RP Csaky, KG (reprint author), NEI, Bldg 10,Room 10N119,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 45 TC 30 Z9 31 U1 0 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD MAY 15 PY 2003 VL 116 IS 10 BP 1915 EP 1923 DI 10.1242/jcs.00390 PG 9 WC Cell Biology SC Cell Biology GA 682NT UT WOS:000183098900007 PM 12668724 ER PT J AU Coorssen, JR Blank, PS Albertorio, F Bezrukov, L Kolosova, I Chen, XF Backlund, PS Zimmerberg, J AF Coorssen, JR Blank, PS Albertorio, F Bezrukov, L Kolosova, I Chen, XF Backlund, PS Zimmerberg, J TI Regulated secretion: SNARE density, vesicle fusion and calcium dependence SO JOURNAL OF CELL SCIENCE LA English DT Article DE secretory vesicles; exocytosis; membrane fusion; sea urchins; quantitative immunoblotting ID ADRENAL CHROMAFFIN CELLS; BOTULINUM TOXIN-A; MEMBRANE-FUSION; TRANSMITTER RELEASE; PHOSPHOLIPID-VESICLES; SYNTAXIN 1A; NEUROTRANSMITTER RELEASE; CLOSTRIDIAL NEUROTOXINS; NEURONAL-SYNAPTOBREVIN; SYNAPTIC TRANSMISSION AB SNAREs such as VAMP, SNAP-25 and syntaxin are essential for intracellular trafficking, but what are their exact molecular roles and how are their interactions with other proteins manifest? Capitalizing on the differential sensitivity of SNAREs to exogenous proteases, we quantified the selective removal of identified SNAREs from native secretory vesicles without loss of fusion competence. Using previously established fusion assays and a high sensitivity immunoblotting protocol, we analyzed the relationship between these SNARE proteins and Ca2+- triggered membrane fusion. Neither the extent of fusion nor the number of intermembrane fusion complexes per vesicle were correlated with the measured density of identified egg cortical vesicle (CV) SNAREs. Without syntaxin, CVs remained fusion competent. Surprisingly, for one (but not another) protease the Ca2+ dependence of fusion was correlated with CV SNARE density, suggesting a native protein complex that associates with SNAREs, the architecture of which ensures high Ca2+ sensitivity. As SNAREs may function during CV docking in vivo, and as further proteolysis after SNARE removal eventually ablates fusion, we hypothesize that the triggered steps of regulated fusion (Ca2+ sensitivity and the catalysis and execution of fusion) require additional proteins that function downstream of SNAREs. C1 NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. NICHHD, Unit Biol Computat, NIH, Bethesda, MD 20892 USA. Univ Calgary, Fac Med, Neurosci Res Grp, Dept Physiol & Biophys, Calgary, AB T2N 4N1, Canada. RP Coorssen, JR (reprint author), NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. NR 73 TC 36 Z9 37 U1 1 U2 3 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 MAY 15 PY 2003 VL 116 IS 10 BP 2087 EP 2097 DI 10.1242/jcs.00374 PG 11 WC Cell Biology SC Cell Biology GA 682NT UT WOS:000183098900022 PM 12692190 ER PT J AU McTiernan, A Rajan, KB Tworoger, SS Irwin, M Bernstein, L Baumgartner, R Gilliland, F Stanczyk, FZ Yasui, Y Ballard-Barbash, R AF McTiernan, A Rajan, KB Tworoger, SS Irwin, M Bernstein, L Baumgartner, R Gilliland, F Stanczyk, FZ Yasui, Y Ballard-Barbash, R TI Adiposity and sex hormones in postmenopausal breast cancer survivors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BODY-MASS; MENOPAUSAL STATUS; BINDING GLOBULIN; WOMEN; ESTROGEN; OBESITY AB Purpose: Overweight and obese women with breast cancer have poorer survival compared with thinner women. One possible reason is that breast cancer survivors with higher degrees of adiposity have higher concentrations of tumor-promoting hormones. This study examined the association between adiposity and concentrations of estrogens, androgens, and sex hormone-binding globulin (SHBG) in a population-based sample of postmenopausal women with breast cancer. Methods: We studied the associations between body mass index (BMI), body fat mass, and percent body fat, measured by dual-energy x-ray absorptiometry scan, waist circumference, and waist-to-hip circumference ratio, with concentrations of estrone, estradiol, testosterone, SHBG, dehydroepiandrosterone sulfate, free estradiol, and free testosterone in 505 postmenopausal women in western Washington and New Mexico with incident stage 0 to IIIA breast cancer. Blood and adiposity measurements were performed between 4 and 12 months after diagnosis. Results: Obese women (BMI greater than or equal to 30) had 35% higher concentrations of estrone and 130% higher concentrations of estradiol compared with lighter-weight women (BMI < 22.0; P = .005 and .002, respectively). Similar associations were observed for body fat mass, percent body fat, and waist circumference. Testosterone concentrations also increased with increasing levels of adiposity (P = .0001). Concentrations of free estradiol and free testosterone were two to three times greater in overweight and obese women compared with lighter-weight women (P = .0001). Conclusion: These data provide information about potential hormonal explanations for the association between adiposity and breast cancer prognosis. These sex hormones may be useful biomarkers for weight loss intervention studies in women with breast cancer. (C) 2003 by American Society of Clinical Oncology. C1 Fred Hutchinson Canc Res Ctr, Canc Prevent Res Program, Seattle, WA 98109 USA. Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. Yale Univ, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. Univ So Calif, Los Angeles, CA USA. Univ New Mexico, Albuquerque, NM 87131 USA. NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP McTiernan, A (reprint author), Fred Hutchinson Canc Res Ctr, Canc Prevent Res Program, MP-900,1100 Fairview Ave N, Seattle, WA 98109 USA. RI Perez , Claudio Alejandro/F-8310-2010; Yasui, Yutaka/E-2564-2015; OI Perez , Claudio Alejandro/0000-0001-9688-184X; Yasui, Yutaka/0000-0002-7717-8638; Tworoger, Shelley/0000-0002-6986-7046; Rajan, Kumar/0000-0003-1268-4617 FU NCI NIH HHS [N01 PC067010, N01 CN005228, N01 PC035138-22, N01-CN-05228, N01-CN-75036-20, T32 CA009661, T32 CA09661]; NCRR NIH HHS [M01 RR000037, M01-RR-00037] NR 26 TC 168 Z9 170 U1 0 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 15 PY 2003 VL 21 IS 10 BP 1961 EP 1966 DI 10.1200/JCO.2003.07.057 PG 6 WC Oncology SC Oncology GA 679CL UT WOS:000182903400010 PM 12743149 ER PT J AU Noben-Trauth, N Lira, R Nagase, H Paul, WE Sacks, DL AF Noben-Trauth, N Lira, R Nagase, H Paul, WE Sacks, DL TI The relative contribution of IL-4 receptor signaling and IL-10 to susceptibility to Leishmania major SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD4(+) T-CELLS; BALB/C MICE; KALA-AZAR; VISCERAL LEISHMANIASIS; MURINE LEISHMANIASIS; INTERFERON-GAMMA; IN-VIVO; INTERLEUKIN-10; EXPRESSION; RESPONSES AB The roles of IL-10 and IL-4 receptor signaling were evaluated in a murine model of Leishmania major infection. In previous studies the L major substrain LV39 caused progressive, nonhealing lesions in BALB/c mice deficient for IL-4R alpha-chain (IL-4Ralpha), while substrain IR173 was highly controlled. To explore whether IL-10 is responsible for inducing susceptibility to LV39, wild-type and IL-4Ralpha(-/-) mice were treated with anti-IL-10R mAb, and in a genetic approach, the IL-4Ralpha(-/-) mice were crossed with BALB/c IL-10(-/-) mice. In contrast to the lack of resistance conferred by 1L-4Ralpha gene deletion, partial resistance to LV39 was conferred by IL-10 gene deletion or treatment of BALB/c mice with anti-IL-10R mAb. Lesion sizes and LV39 parasite numbers were further and dramatically reduced in both anti-IL-10R-treated IL-4Ralpha(-/-) mice and IL-4Ralpha x IL-10 double knockouts. Anti-IL-10R mAb treatment further suppressed parasite growth in IL-4Ralpha(-/-) mice infected with L. major IR173. Production of IFN-gamma was only increased relative to wild-type or littermate controls in IL-4Ralpha(-/-) mice with complementary defects in IL-10. Comparisons of WN-gamma-treated infected macrophages in vitro indicated that LV39 required 25- to 500-fold greater concentrations of IFN-gamma than IR173-infected macrophages to achieve a similar efficiency of parasite killing. These studies suggest that regardless of parasite substrain, IL-10 is as important as IL-4/IL-13 in promoting susceptibility to L. major and even more so for those substrains that are relatively resistant to IFN-gamma mediated killing. C1 George Washington Univ, Med Ctr, Dept Immunol, Washington, DC 20037 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Noben-Trauth, N (reprint author), George Washington Univ, Med Ctr, Dept Immunol, Ross Hall,Room 407,2300 Eye St NW, Washington, DC 20037 USA. FU NIAID NIH HHS [AI01721] NR 32 TC 93 Z9 98 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 MAY 15 PY 2003 VL 170 IS 10 BP 5152 EP 5158 PG 7 WC Immunology SC Immunology GA 676NJ UT WOS:000182758200034 PM 12734362 ER PT J AU Equils, O Schito, ML Karahashi, H Madak, Z Yarali, A Michelsen, KS Sher, A Arditi, M AF Equils, O Schito, ML Karahashi, H Madak, Z Yarali, A Michelsen, KS Sher, A Arditi, M TI Toll-like receptor 2 (TLR2) and TLR9 signaling results in HIV-long terminal repeat trans-activation and HIV replication in HIV-1 transgenic mouse spleen cells: Implications of simultaneous activation of TLRs on HIV replication SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; DERMAL ENDOTHELIAL-CELLS; A-ASSOCIATED PROTEINS; GENE-EXPRESSION; BACTERIAL-DNA; FACTOR-ALPHA; CUTTING EDGE; STAPHYLOCOCCUS-AUREUS AB Opportunistic infections are common in HIV-infected patients; they activate HIV replication and contribute to disease progression. In the present study we examined the role of Toll-like receptor 2 (TLR2) and TLR9 in HIV-long terminal repeat (HIV-LTR) trans-activation and assessed whether TLR4 synergized with TLR2 or TLR9 to induce HIV replication. Soluble Mycobacterium tuberculosis factor (STF) and phenol-soluble modulin from Staphylococcus epidermidis induced HIV-LTR trans-activation in human microvessel endothelial cells cotransfected with TLR2 cDNA. Stimulation of ex vivo spleen cells from HIV-1 transgenic mice with TLR4, TLR2, and TLR9 ligands (LPS, STF, and CpG DNA, respectively) induced p24 Ag production in a dose-dependent manner. Costimulation of HIV-1 transgenic mice spleen cells with LPS and STF or CpG DNA induced TNF-alpha and IFN-gamma production in a synergistic manner and p24 production in an additive fashion. In the THP-1 human monocytic cell line stably expressing the HIV-LTR-luciferase construct, LPS and STF also induced HIV-LTR trans-activation in an additive manner. This is the first time that TLR2 and TLR9 and costimulation of TLRs have been shown to induce HIV replication. Together these results underscore the importance of TLRs in bacterial Ag- and CpG DNA-induced HIV-LTR trans-activation and HIV replication. These observations may be important in understanding the role of the innate immune system and the molecular mechanisms involved in the increased HIV replication and HIV disease progression associated with multiple opportunistic infections. C1 Univ Calif Los Angeles, Sch Med, Cedars Sinai Med Ctr,Burns & Allen Res Inst, Div Pediat Infect Dis,Steven Spielberg Pediat Res, Los Angeles, CA 90048 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Equils, O (reprint author), Cedars Sinai Med Ctr, Dept Pediat, 8700 Beverly Blvd,Room 4220, Los Angeles, CA 90048 USA. FU NHLBI NIH HHS [HL-66436-02]; NIAID NIH HHS [AI40275, KO8AI51216]; NICHD NIH HHS [P30HD34610] NR 57 TC 80 Z9 86 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2003 VL 170 IS 10 BP 5159 EP 5164 PG 6 WC Immunology SC Immunology GA 676NJ UT WOS:000182758200035 PM 12734363 ER PT J AU Parkhurst, MR DePan, C Riley, JP Rosenberg, SA Shu, SY AF Parkhurst, MR DePan, C Riley, JP Rosenberg, SA Shu, SY TI Hybrids of dendritic cells and tumor cells generated by electrofusion simultaneously present immunodominant epitopes from multiple human tumor-associated antigens in the context of MHC class I and class II molecules SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; INDUCE ANTITUMOR IMMUNITY; MELANOMA ANTIGEN; CANCER-IMMUNOTHERAPY; CARCINOMA-CELLS; METASTATIC MELANOMA; BONE-MARROW; ADOPTIVE TRANSFER; PHASE-I; PEPTIDE AB Hybrid cells generated by fusing dendritic cells with tumor cells (DC-TC) are currently being evaluated as cancer vaccines in preclinical models and human immunization trials. In this study, we evaluated the production of human DC-TC hybrids using an electrofusion protocol previously defined for murine cells. Human DCs were electrically fused with allogeneic melanoma cells (888mel) and were subsequently analyzed for coexpression of unique DC and TC markers using FACS and fluorescence microscopy. Dually fluorescent cells were clearly observed using both techniques after staining with Abs against distinct surface molecules suggesting that true cell fusion had occurred. We also evaluated the ability of human DC-TC hybrids to present tumor-associated epitopes in the context of both MHC class I and class H molecules. Allogeneic DCs expressing HLA-A*0201, HLA-DRbeta1*0401, and HLA-DRbeta1*0701 were fused with 888mel cells that do not express any of these MHC molecules, but do express multiple melanoma-associated Ags. DC-888mel hybrids efficiently presented HLA-A*0201-restricted epitopes from the melanoma Ags MART-1, gp100, tyrosinase, and tyrosinase-related protein 2 as evaluated by specific cytokine secretion from six distinct CTL lines. In contrast, DCs could not cross-present MHC class I-restricted epitopes after exogenously loading with gp100 protein. DC-888mel hybrids also presented HLA-DRbeta1*0401- and HLA-DRbeta1*0701-restricted peptides from gp100 to CD4(+) T cell populations. Therefore, fusions of DCs and tumor cells express both MHC class I- and class H-restricted tumor-associated epitopes and may be useful for the induction of tumor-reactive CD8(+) and CD4(+) T cells in vitro and in human vaccination trials. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. Cleveland Clin Fdn, Surg Res Ctr, Cleveland, OH 44195 USA. RP Parkhurst, MR (reprint author), NCI, Surg Branch, NIH, Bldg 10,Room 2B42,9000 Rockville Pike, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 SC003811-33]; NCI NIH HHS [P01 CA012582, P01 CA12582] NR 64 TC 79 Z9 89 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2003 VL 170 IS 10 BP 5317 EP 5325 PG 9 WC Immunology SC Immunology GA 676NJ UT WOS:000182758200054 PM 12734382 ER PT J AU Wong, S Young, NS Brown, KE AF Wong, S Young, NS Brown, KE TI Prevalence of parvovirus B19 in liver tissue: No association with fulminant hepatitis or hepatitis-associated aplastic anemia SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 9th Parvovirus Workshop CY AUG 28-31, 2002 CL BOLOGNA, ITALY ID POLYMERASE-CHAIN-REACTION; ACUTE VIRAL-HEPATITIS; SPORADIC NON-A; NON-B; G-VIRUS; BONE-MARROW; INFECTION; FAILURE; DNA; IDENTIFICATION AB Parvovirus B19 has been proposed as the etiological agent of fulminant hepatitis (FH) or hepatitis-associated aplastic anemia (HAA). We studied the prevalence of parvovirus B19 in liver-tissue samples from patients with FH and HAA and from control subjects. In the first study, parvovirus B19 DNA was detected by nested polymerase chain reaction (PCR) in 4 of 15 livers from patients with FH and in 3 of 22 livers from patients with nonviral hepatic disease. In a second confirmatory study, livers were tested for parvovirus B19 and its variant erythroviruses, V9 and A6. Tissues were also tested by reverse-transcriptase PCR for the presence of parvovirus B19 transcripts as a marker of viral replication. There was no significant difference in the prevalence of parvovirus B19 DNA in livers from patients with FH or HAA, compared with liver-tissue samples from patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection; parvovirus B19 transcripts were not detected. There was a significant increase (P <.1) in the prevalence of variant erythrovirus sequences in livers of patients with HBV or HCV hepatitis, the reason for which is currently unknown. C1 NHLBI, Virus Discovery Grp, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Brown, KE (reprint author), NHLBI, Virus Discovery Grp, Hematol Branch, NIH, Bldg 10,Rm 7C218,9000 Rockville Pike, Bethesda, MD 20892 USA. FU NIDDK NIH HHS [N01-DK-9-2310] NR 33 TC 60 Z9 66 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2003 VL 187 IS 10 BP 1581 EP 1586 DI 10.1086/374781 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 673HA UT WOS:000182573600009 PM 12721938 ER PT J AU Pessoa, L Kastner, S Ungerleider, LG AF Pessoa, L Kastner, S Ungerleider, LG TI Neuroimaging studies of attention: From modulation of sensory processing to top-down control SO JOURNAL OF NEUROSCIENCE LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; HUMAN EXTRASTRIATE CORTEX; VISUAL CORTICAL AREAS; EMOTIONAL FACIAL EXPRESSIONS; LATERAL INTRAPARIETAL AREA; POSTERIOR PARIETAL CORTEX; SELECTIVE ATTENTION; SPATIAL ATTENTION; VISUOSPATIAL ATTENTION; NEURAL MECHANISMS C1 NIMH, Lab Brain & Cognit, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Princeton Univ, Dept Psychol, Ctr Study Brain Mind & Behav, Princeton, NJ 08544 USA. RP Pessoa, L (reprint author), NIMH, Lab Brain & Cognit, NIH, Dept Hlth & Human Serv, 49 Convent Dr,Bldg 49,Room 1B80, Bethesda, MD 20892 USA. EM pessoa@ln.nimh.nih.gov NR 97 TC 258 Z9 263 U1 5 U2 29 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 MAY 15 PY 2003 VL 23 IS 10 BP 3990 EP 3998 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 681AT UT WOS:000183014300005 PM 12764083 ER PT J AU Gilligan, JJ Lampe, FW Nguyen, VQ Vieira, NE Yergey, AL AF Gilligan, JJ Lampe, FW Nguyen, VQ Vieira, NE Yergey, AL TI Hydration of alkylammonium ions in the gas phase SO JOURNAL OF PHYSICAL CHEMISTRY A LA English DT Article ID PROTONATED AMINES; HYDROGEN-BOND; CLUSTERS; EQUILIBRIA; DIAMINES; WATER; ELECTROSPRAY; ASSOCIATION; COMPLEXES; SOLVATION AB Electrospray ionization-high-pressure mass spectrometry was used to determine the enthalpy, entropy, and Gibbs free energy for the equilibrium gas-phase ion-molecule association reactions of CmH2m+1NH3+ (m = 1-8), (CH3)(2)NH2+, and (CH3)(3)NH+ with one to three water ligands. A subset of these ions has been studied previously, and the thermochemical properties determined in this investigation compare favorably with the previously published results, providing validation of our experimental technique and method. In addition, the present measurements show that the addition of a water ligand to the monohydrated alkylammonium ion results in an increased stabilization in its structure and binding. 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, Bethesda, MD 20892 USA. NR 26 TC 11 Z9 11 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1089-5639 J9 J PHYS CHEM A JI J. Phys. Chem. A PD MAY 15 PY 2003 VL 107 IS 19 BP 3687 EP 3691 DI 10.1021/jp022517y PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 678YH UT WOS:000182893900014 ER PT J AU Mohrenweiser, HW Wilson, DM Jones, IM AF Mohrenweiser, HW Wilson, DM Jones, IM TI Challenges and complexities in estimating both the functional impact and the disease risk associated with the extensive genetic variation in human DNA repair genes SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Review DE challenges and complexities; disease risk; human DNA repair genes ID BASE-EXCISION-REPAIR; SINGLE-NUCLEOTIDE POLYMORPHISMS; PURIFIED HUMAN PROTEINS; DOUBLE-STRAND BREAKS; IONIZING-RADIATION SENSITIVITY; ACID SUBSTITUTION VARIANTS; 41 CANDIDATE GENES; MISMATCH REPAIR; MAMMALIAN-CELLS; CANCER RISK AB Individual risk and the population incidence of disease result from the interaction of genetic susceptibility and exposure. DNA repair is an example of a cellular process where genetic variation in families with extreme predisposition is documented to be associated with high disease likelihood, including syndromes of premature aging and cancer. Although the identification and characterization of new genes or variants in cancer families continues to be important, the focus of this paper is the current status of efforts to define the impact of polymorphic amino acid substitutions in DNA repair genes on individual and population cancer risk. There is increasing evidence that mild reductions in DNA repair capacity, assumed to be the consequence of common genetic variation, affect cancer predisposition. The extensive variation being found in the coding regions of DNA repair genes and the large number of genes in each of the major repair pathways results in complex genotypes with potential to impact cancer risk in the general population. The implications of this complexity for molecular epidemiology studies, as well as concepts that may make these challenges more manageable, are discussed. The concepts include both experimental and computational approaches that could be employed to develop predictors of disease susceptibility based on DNA repair genotype, focusing initially on studies to assess functional impact on individual proteins and pathways and then on molecular epidemiology studies to assess exposure-dependent health risk. In closing, we raise some of the non-technical challenges to the utilization of the full richness of the genetic variation to reduce disease occurrence and ultimately improve health care. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, Livermore, CA 94551 USA. NIA, Lab Mol Gerontol, GRC, NIH, Baltimore, MD 21224 USA. RP Mohrenweiser, HW (reprint author), Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, L-448,7000 East Ave, Livermore, CA 94551 USA. EM mohrenweiser1@llnl.gov FU NCI NIH HHS [1 U-1 CA83180-03] NR 149 TC 155 Z9 160 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD MAY 15 PY 2003 VL 526 IS 1-2 BP 93 EP 125 DI 10.1016/S0027-5107(03)00049-6 PG 33 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 676HX UT WOS:000182746200011 PM 12714187 ER PT J AU Paul, WE Germain, RN AF Paul, WE Germain, RN TI Charles A. Janeway Jr (1943-2003) - Obituary SO NATURE LA English DT Biographical-Item C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Paul, WE (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 1 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 0028-0836 J9 NATURE JI Nature PD MAY 15 PY 2003 VL 423 IS 6937 BP 237 EP 237 DI 10.1038/423237a PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 678EX UT WOS:000182853100030 PM 12748629 ER PT J AU Eriksson, M Brown, WT Gordon, LB Glynn, MW Singer, J Scott, L Erdos, MR Robbins, CM Moses, TY Berglund, P Dutra, A Pak, E Durkin, S Csoka, AB Boehnke, M Glover, TW Collins, FS AF Eriksson, M Brown, WT Gordon, LB Glynn, MW Singer, J Scott, L Erdos, MR Robbins, CM Moses, TY Berglund, P Dutra, A Pak, E Durkin, S Csoka, AB Boehnke, M Glover, TW Collins, FS TI Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome SO NATURE LA English DT Article ID PRELAMIN-A; NUCLEAR-ENVELOPE; UNIPARENTAL DISOMY; HUMAN-DISEASE; CHROMOSOME-1; HOMOZYGOSITY; PROTEINS; PATIENT; MICE; LMNA AB Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by features reminiscent of marked premature ageing(1,2). Here, we present evidence of mutations in lamin A (LMNA) as the cause of this disorder. The HGPS gene was initially localized to chromosome 1q by observing two cases of uniparental isodisomy of 1q - the inheritance of both copies of this material from one parent - and one case with a 6-megabase paternal interstitial deletion. Sequencing of LMNA, located in this interval and previously implicated in several other heritable disorders(3,4), revealed that 18 out of 20 classical cases of HGPS harboured an identical de novo ( that is, newly arisen and not inherited) single-base substitution, G608G( GGC > GGT), within exon 11. One additional case was identified with a different substitution within the same codon. Both of these mutations result in activation of a cryptic splice site within exon 11, resulting in production of a protein product that deletes 50 amino acids near the carboxy terminus. Immunofluorescence of HGPS fibroblasts with antibodies directed against lamin A revealed that many cells show visible abnormalities of the nuclear membrane. The discovery of the molecular basis of this disease may shed light on the general phenomenon of human ageing. C1 NHGRI, NIH, Bethesda, MD 20892 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. New York State Inst Basic Res Dev Disabil, Dept Human Genet, Staten Isl, NY 10314 USA. Tufts Univ, Sch Med, Dept Anat & Cellular Biol, Boston, MA 02111 USA. Rhode Isl Hosp, Dept Pediat, Providence, RI 02903 USA. Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. Brown Univ, Dept Biochem Mol Biol & Cell Biol, Providence, RI 02912 USA. RP Collins, FS (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. FU NIGMS NIH HHS [T32 GM007544] NR 28 TC 950 Z9 986 U1 22 U2 129 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAY 15 PY 2003 VL 423 IS 6937 BP 293 EP 298 DI 10.1038/nature01629 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 678EX UT WOS:000182853100044 PM 12714972 ER PT J AU Mounkes, LC Kozlov, S Hernandez, L Sullivan, T Stewart, CL AF Mounkes, LC Kozlov, S Hernandez, L Sullivan, T Stewart, CL TI A progeroid syndrome in mice is caused by defects in A-type lamins SO NATURE LA English DT Article ID DREIFUSS MUSCULAR-DYSTROPHY; NUCLEAR-ENVELOPE; GENE; EXPRESSION; MUTATIONS; DISEASE; CELLS AB Numerous studies of the underlying causes of ageing have been attempted by examining diseases associated with premature ageing, such as Werner's syndrome and Hutchinson - Gilford progeria syndrome (HGPS). HGPS is a rare genetic disorder resulting in phenotypes suggestive of accelerated ageing, including shortened stature, craniofacial disproportion, very thin skin, alopecia and osteoporosis, with death in the early teens predominantly due to atherosclerosis(1). However, recent reports suggest that developmental abnormalities may also be important in HGPS(1,2). Here we describe the derivation of mice carrying an autosomal recessive mutation in the lamin A gene (Lmna) encoding A-type lamins, major components of the nuclear lamina(3). Homozygous mice display defects consistent with HGPS, including a marked reduction in growth rate and death by 4 weeks of age. Pathologies in bone, muscle and skin are also consistent with progeria. The Lmna mutation resulted in nuclear morphology defects and decreased lifespan of homozygous fibroblasts, suggesting premature cell death. Here we present a mouse model for progeria that may elucidate mechanisms of ageing and development in certain tissue types, especially those developing from the mesenchymal cell lineage. C1 NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. RP Stewart, CL (reprint author), NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. NR 26 TC 210 Z9 218 U1 1 U2 22 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAY 15 PY 2003 VL 423 IS 6937 BP 298 EP 301 DI 10.1038/nature01631 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 678EX UT WOS:000182853100045 PM 12748643 ER PT J AU Scheel, JR Garrett, LJ Allen, DM Carter, TA Randolph-Moore, L Gambello, MJ Gage, FH Wynshaw-Boris, A Barlow, C AF Scheel, JR Garrett, LJ Allen, DM Carter, TA Randolph-Moore, L Gambello, MJ Gage, FH Wynshaw-Boris, A Barlow, C TI An inbred 129SvEv GFPCre transgenic mouse that deletes loxP-flanked genes in all tissues SO NUCLEIC ACIDS RESEARCH LA English DT Article ID TRANSIENT EXPRESSION; FERTILIZED-EGGS; CRE RECOMBINASE; MICE AB A common method for generating mice with subtle genetic manipulations uses homologous recombination (HR) in embryonic stem (ES) cells to replace a wild-type gene with a slightly modified one. Generally, a drug resistance gene is inserted with the modified gene to select correctly targeted clones. Often, however, the presence of this drug resistance gene interferes with the normal locus and creates a null or hypomorphic allele. Flanking of the selectable marker by loxP sites followed by Cre-mediated deletion after drug selection can overcome this problem. The simplest method used to remove a loxP-flanked selectable marker is to breed an animal carrying a loxP-flanked drug resistance gene to an animal that expresses Cre recombinase in the germline. To date only outbred transgenic mice are available for this purpose. This can be problematic for phenotypic analysis in many organ systems, including the brain, and for the analysis of behavior. While attempting to make 129S6/SvEvTac inbred background (isogenic to our ES cells) mice that express Cre under the control of several tissue-specific promoters, we serendipitously generated a line that excises loxP-flanked drug resistance genes in all tissues, including the germline. This reagent allows deletion of loxP-flanked sequences while maintaining the mutation on an inbred background. C1 Salk Inst Biol Studies, Genet Lab, La Jolla, CA 92037 USA. NIH, Genet & Mol Biol Lab, Bethesda, MD 20892 USA. Univ Calif San Diego, Program Biomed Sci, La Jolla, CA 92093 USA. RP Barlow, C (reprint author), Salk Inst Biol Studies, Genet Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. FU NINDS NIH HHS [F31 NS010860, F31 NS10860-01] NR 11 TC 14 Z9 14 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAY 15 PY 2003 VL 31 IS 10 AR e57 DI 10.1093/nar/gkg057 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 676GR UT WOS:000182743400029 PM 12736323 ER PT J AU Senchenko, V Liu, J Braga, E Mazurenko, N Loginov, W Seryogin, Y Bazov, I Protopopov, A Kisseljov, FL Kashuba, V Lerman, MI Klein, G Zabarovsky, ER AF Senchenko, V Liu, J Braga, E Mazurenko, N Loginov, W Seryogin, Y Bazov, I Protopopov, A Kisseljov, FL Kashuba, V Lerman, MI Klein, G Zabarovsky, ER TI Deletion mapping using quantitative real-time PCR identifies two distinct 3p21.3 regions affected in most cervical carcinomas SO ONCOGENE LA English DT Article DE quantitative real-time PCR; human chromosome 3p; tumor suppressor genes; NotI linking clone; loss of heterozygosity; cervical carcinoma ID TUMOR-SUPPRESSOR GENE; HUMAN-CHROMOSOME 3P21.3; LUNG-CANCER; 3P DELETIONS; SHORT ARM; INTRAEPITHELIAL NEOPLASIA; EPIGENETIC INACTIVATION; ALLELIC LOSS; HETEROZYGOSITY; FREQUENT AB We report chromosome 3p deletion mapping of 32 cervical carcinoma (CC) biopsies using 26 microsatellite markers located in frequently deleted 3p regions to detect loss of heterozygosity and homozygous loss. In addition, two STS markers (NLJ-003 and NL3-001) located in the 3p21.3 telomeric (3p21.3T) and 3p21.3 centromeric (3p21.3C) regions, respectively, were used for quantitative real-time PCR as TaqMan probes. We show that quantitative real-time PCR is reliable and sensitive and allows discriminating between 0, 1 and 2 marker copies per human genome. For the first time, frequent (five of 32 cases, i.e. 15.6%) homozygous deletions were demonstrated in CCs in both 3p21.3T and 3p21.3C regions. The smallest region homozygously deleted in 3p21.3C was located between D3S1568 (CACNA2D2 gene) and D3S4604 (SEMA3F gene) and contains 17 genes previously defined as lung cancer candidate Tumor suppressor genes (TSG(s)). The smallest region homozygously deleted in 3p21.3T was flanked by D3S1298 and NL1-024 (D3S4285), excluding DLEC1 and MYD88 as candidate TSGs involved in cervical carcinogenesis. Overall, this region contains five potential candidates, namely GOLGA4, APRG1, ITGA9, HYA22 and VILL, which need to be analysed. The data showed that aberrations of either NLJ-003 or NL3-001 were detected in 29 cases (90.6%) and most likely have a synergistic effect (P<0.01). The study also demonstrated that aberrations in 3p21.3 were complex and in addition to deletions, may involve gene amplification as well. The results strongly suggest that 3p21.3T and 3p21.3C regions harbor genes involved in the origin and/or development of CCs and imply that those genes might be multiple TSG(s). C1 Karolinska Inst, Ctr Genom & Bioinformat, Ctr Microbiol & Tumor Biol, S-17177 Stockholm, Sweden. Russian Acad Sci, Ctr Bioengn, Moscow 117312, Russia. Russian State Genet Ctr, Moscow 113545, Russia. Russian Acad Med Sci, Blokhin Canc Res Ctr, Moscow 115478, Russia. NCI, Canc Causing Genes Sect, Immunobiol Lab, Ctr Canc Res, Frederick, MD 21702 USA. Russian Acad Sci, VA Engelhardt Mol Biol Inst, Moscow 119991, Russia. RP Zabarovsky, ER (reprint author), Karolinska Inst, Ctr Genom & Bioinformat, Ctr Microbiol & Tumor Biol, S-17177 Stockholm, Sweden. RI Zabarovsky, Eugene/A-6645-2010; Senchenko, Vera/C-8992-2014; Braga, Eleonora/P-5574-2016 OI Senchenko, Vera/0000-0002-3119-515X; FU PHS HHS [N01-C0-56000] NR 52 TC 47 Z9 54 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 15 PY 2003 VL 22 IS 19 BP 2984 EP 2992 DI 10.1038/sj.onc.1206429 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 677TY UT WOS:000182824800014 PM 12771950 ER PT J AU Kim, HS Jacobson, KA AF Kim, HS Jacobson, KA TI Synthesis of a novel conformationally locked carbocyclic nucleoside ring system SO ORGANIC LETTERS LA English DT Article ID ORGANIC-SYNTHESIS; CLOSING METATHESIS; NUCLEIC-ACID; SUGAR RING; NUCLEOTIDES; ADENOSINE; P2Y(1) AB [GRAPHICS] A fast and efficient synthetic route to novel Northern locked carbocyclic nucleosides (as precursors of carbocyclic locked nucleic acids or cLNAs) is described. The target nucleoside with a oxabicyclo[2.2.1]heptane ring system was prepared from a simple starting material, diethyl malonate. Ring closure by intramolecular O-alkylation provided the target ring system as the major isomer over the [3.2.0] oxetane system. The adenine moiety was introduced through a reactive triflate after inversion of the stereochemistry of the corresponding alcohol by oxidation and reduction. C1 NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Wonkwang Univ, Coll Pharm, Iksan 570749, Chonbuk, South Korea. Wonkwang Univ, Med Resources Res Ctr, Iksan 570749, Chonbuk, South Korea. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031116-20, Z01 DK031117-20] NR 19 TC 28 Z9 28 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 J9 ORG LETT JI Org. Lett. PD MAY 15 PY 2003 VL 5 IS 10 BP 1665 EP 1668 DI 10.1021/ol034326z PG 4 WC Chemistry, Organic SC Chemistry GA 677TU UT WOS:000182824300018 PM 12735747 ER PT J AU Woodson, K Hayes, R Wideroff, L Villaruz, L Tangrea, J AF Woodson, K Hayes, R Wideroff, L Villaruz, L Tangrea, J TI Hypermethylation of GSTP1, CD44, and E-cadherin genes in prostate cancer among US Blacks and Whites SO PROSTATE LA English DT Article DE hypermethylation; GSTP1; CD44; E-cadherin; real-time methylation-sensitive PCR; prostate cancer ID ISLAND METHYLATION CHANGES; RADICAL PROSTATECTOMY; DNA HYPERMETHYLATION; RACIAL-DIFFERENCES; AFRICAN-AMERICAN; SUPPRESSOR GENE; UNITED-STATES; EXPRESSION; PATTERNS; PROGRESSION AB BACKGROUND. In the US, the incidence and mortality of prostate cancer is about twofold higher among US Blacks compared to Whites, suggesting racial differences in prostate tumor occurrence and aggressiveness. The reason for these racial differences is unknown. Epigenetic events such as promoter-region gene hypermethylation may be influenced by environmental exposures and have been implicated in prostate carcinogenesis (by the silencing of tumor suppressors and other regulatory genes). METHODS. Using real-time methylation-sensitive PCR, we assessed differences in DNA hypermethylation of GSTP1, CD44, and E-cadherin (three genes thought to be important in the progression of prostate cancer) in archival tumor tissue of black (n = 47) and white men (n = 64). RESULTS. We found a high prevalence of GSTP1 hypermethylation overall (84%) but no differences by race (89 and 83% in black vs. white men, respectively), tumor stage, or grade. Although CD44 hypermethylation was less prevalent overall (found in 32% of tumors), we observed a 1.7-fold higher frequency among black men (43 vs. 25% in black vs. white men, P = 0.05) and a correlation with tumor grade (CD44 was hypermethylated in 10, 42, and 52% of well, moderate, and poorly differentiated tumors, respectively, P = 0.003) but not disease stage. The E-cadherin gene was not hypermethylated in any of the tumors. In summary, of the three genes examined, only CD44 hypermethylation differed by race and correlated with tumor grade, independent of race. CONCLUSIONS. These preliminary findings suggest that differences in gene promoter hypermethylation may potentially underlie racial differences in prostate cancer pathogenesis and should be explored in larger studies. (C) 2003 Wiley-Liss, Inc. C1 NCI, Canc Res Ctr, Canc Prevent Studies Branch, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, Appl Res Branch, Bethesda, MD 20892 USA. NCI, Div Epidemiol & Genet, Bethesda, MD 20892 USA. RP Woodson, K (reprint author), NCI, Canc Res Ctr, Canc Prevent Studies Branch, 6116 Execut Blvd,MSC 8314, Bethesda, MD 20892 USA. RI Hernandez, Jessica/G-6527-2011 NR 34 TC 73 Z9 74 U1 0 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0270-4137 J9 PROSTATE JI Prostate PD MAY 15 PY 2003 VL 55 IS 3 BP 199 EP 205 DI 10.1002/pros.10236 PG 7 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 675DE UT WOS:000182677100006 PM 12692786 ER PT J AU Aeschbach, D Sher, L Postolache, TT Matthews, JR Jackson, MA Wehr, TA AF Aeschbach, D Sher, L Postolache, TT Matthews, JR Jackson, MA Wehr, TA TI Dissimilar circadian regulation of thyrotropin and free thyroid hormone between short sleepers and long sleepers SO SLEEP LA English DT Meeting Abstract CT 17th Annual Meeting of the Associated-Professional-Sleep-Societies CY JUN 03-08, 2003 CL CHICAGO, ILLINOIS SP Assoc Prof Sleep Soc C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. Columbia Univ, New York, NY USA. NIMH, Bethesda, MD 20892 USA. Univ Texas, Med Branch, Galveston, TX 77550 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 MAY 15 PY 2003 VL 26 BP A110 EP A110 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 677ZY UT WOS:000182841100272 ER PT J AU Gottlieb, DJ DeStefano, AL Foley, DJ Redline, S Givelber, RJ Young, TB AF Gottlieb, DJ DeStefano, AL Foley, DJ Redline, S Givelber, RJ Young, TB TI Apolipoprotein E e4 allele is associated with sleep-disordered breathing: The sleep heart health study SO SLEEP LA English DT Meeting Abstract CT 17th Annual Meeting of the Associated-Professional-Sleep-Societies CY JUN 03-08, 2003 CL CHICAGO, ILLINOIS SP Assoc Prof Sleep Soc C1 Boston Univ, Sch Med, Boston, MA 02215 USA. Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. NIA, Bethesda, MD 20892 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Univ Wisconsin, Madison, WI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 MAY 15 PY 2003 VL 26 BP A414 EP A415 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 677ZY UT WOS:000182841101045 ER PT J AU Goutagny, R Fort, P Salvert, D Boissard, R Gomeza, J Wess, J Luppi, PH AF Goutagny, R Fort, P Salvert, D Boissard, R Gomeza, J Wess, J Luppi, PH TI Sleep-waking cycle and EEG rhythmic activities in mice lacking M2, M3, M4 or M2/M4 muscarinic receptors SO SLEEP LA English DT Meeting Abstract CT 17th Annual Meeting of the Associated-Professional-Sleep-Societies CY JUN 03-08, 2003 CL CHICAGO, ILLINOIS SP Assoc Prof Sleep Soc C1 CNRS, FRE 2469, Lyon, France. NIDDK, NIH, Bethesda, MD USA. RI Luppi, Pierre-Herve/C-4333-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 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 MAY 15 PY 2003 VL 26 BP A67 EP A67 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 677ZY UT WOS:000182841100165 ER PT J AU Sanchez-Alavez, M Huitron-Resendiz, S Ball, S Zhukov, VI Wills, D Berg, G Chesebro, B Henriksen, SJ Oldstone, MB Criado, JR AF Sanchez-Alavez, M Huitron-Resendiz, S Ball, S Zhukov, VI Wills, D Berg, G Chesebro, B Henriksen, SJ Oldstone, MB Criado, JR TI Sleep rebound response in mice devoid of prion gene after total sleep deprivation SO SLEEP LA English DT Meeting Abstract CT 17th Annual Meeting of the Associated-Professional-Sleep-Societies CY JUN 03-08, 2003 CL CHICAGO, ILLINOIS SP Assoc Prof Sleep Soc C1 Scripps Res Inst, Dept Neuropharmacol, La Jolla, CA USA. NIH, Rocky Mt Labs, Hamilton, MT USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 MAY 15 PY 2003 VL 26 BP A203 EP A203 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 677ZY UT WOS:000182841100506 ER PT J AU Vgontzas, AN Zoumakis, M Bixler, EO Chrousos, GP Lin, HM AF Vgontzas, AN Zoumakis, M Bixler, EO Chrousos, GP Lin, HM TI Continuous positive airway pressure does not reverse hypercortisolism, hypercytokinemia, or insulin resistance associated with sleep apnea SO SLEEP LA English DT Meeting Abstract CT 17th Annual Meeting of the Associated-Professional-Sleep-Societies CY JUN 03-08, 2003 CL CHICAGO, ILLINOIS SP Assoc Prof Sleep Soc C1 Penn State Univ, Coll Med, Dept Psychiat, Sleep Res & Treatment Ctr, Hershey, PA USA. NIH, Pediat & Reprod Endocrinol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 MAY 15 PY 2003 VL 26 BP A229 EP A229 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 677ZY UT WOS:000182841100572 ER PT J AU Borkowf, CB Albert, PS Abnet, CC AF Borkowf, CB Albert, PS Abnet, CC TI Using lowess to remove systematic trends over time in predictor variables prior to logistic regression with quantile categories SO STATISTICS IN MEDICINE LA English DT Article DE cancer; laboratory measurement drift; lowess; measurement error; quantile-category; trend removal ID MARGINAL DISTRIBUTIONS; EMPIRICAL QUANTILES; BIOMARKERS; CHINA AB In case-control studies one may employ logistic regression to model the relationship between binary responses and continuous predictor variables that have been categorized by the empirical quartiles of the controls. Sometimes, however, systematic trends over time (or drifts) contaminate the laboratory measurements of predictor variables. In this paper we consider the use of locally weighted robust regression (lowess) to estimate and remove these systematic trends when the trends for the cases and controls have a common shape. One can then use the lowess adjusted data in the desired logistic regression model. We illustrate these methods with a case-control study that was designed to assess the risk of oesophageal cancer as a function of the quartile categories of sphinganine levels in the blood serum. Upon examination of the data, it was discovered that the sphinganine laboratory measurements were contaminated by a systematic trend, the magnitude of which depended only on the day of analysis. This trend needed to be removed before performing further analyses of the data. In addition, we present simulations to examine the use of lowess methods to estimate and remove various shapes of trends from contaminated predictor data before constructing logistic regression models with quartile categories. We found that using the trend-contaminated data tends to give attenuated parameter estimates and hence lower significance and power levels than using the uncontaminated data. Conversely, using appropriate lowess methods to adjust the data tends to give nearly unbiased parameter estimates, near nominal significance levels, and improved power. Published in 2003 by John Wiley Sons, Ltd. C1 NCI, Canc Res Ctr, Canc Prevent Studies Branch, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diagn, Biometr Res Branch, Bethesda, MD 20892 USA. RP Borkowf, CB (reprint author), Ctr Dis Control & Prevent, Natl Ctr Infect Dis, Div Viral & Rickettsial Dis, Influenza Branch,Epidemiol Sect, Mail Stop A32,1600 Clifton Rd NE, Atlanta, GA 30333 USA. RI Abnet, Christian/C-4111-2015 OI Abnet, Christian/0000-0002-3008-7843 NR 10 TC 29 Z9 29 U1 1 U2 7 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD MAY 15 PY 2003 VL 22 IS 9 BP 1477 EP 1493 DI 10.1002/sim.1507 PG 17 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 674UQ UT WOS:000182655100011 PM 12704611 ER PT J AU Lunney, JR Lynn, J Foley, DJ Lipson, S Guralnik, JM AF Lunney, JR Lynn, J Foley, DJ Lipson, S Guralnik, JM TI Patterns of functional decline at the end of life SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID OLDER PERSONS; DISABILITY; SERVICES; HOSPICE; DISEASE; HEALTH; ADULTS; HEART AB Context Clinicians have observed various patterns of functional decline at the end of life, but few empirical data have tested these patterns in large populations. Objective To determine if functional decline differs among 4 types of illness trajectories: sudden death, cancer death, death from organ failure, and frailty. Design, Setting, and Participants Cohort analysis of data from 4 US regions in the prospective, longitudinal Established Populations for Epidemiologic Studies of the Elderly (EPESE) study. Of the 14456 participants aged 65 years or older who provided interviews at baseline (1981-1987), 4871 died during the first 6 years of follow-up; 4190 (86%) of these provided interviews within 1 year before dying. These decedents were evenly distributed in 12 cohorts based on the number of months between the final interview and death. Main Outcome Measures Self-or proxy-reported physical function (performance of 7 activities of daily living [ADLs]) within 1 year prior to death; predicted ADL dependency prior to death. Results Mean function declined across the 12 cohorts, simulating individual decline in the final year of life. Sudden death decedents were highly functional even in the last month before death (mean [95% confidence interval {CI}] numbers of ADL dependencies: 0.69 [0.19-1.19] at 12 months before death vs 1.22 [0.59-1.85] at the final month of life, P=.20); cancer decedents were highly functional early in their final year but markedly more disabled 3-months prior to death (0.77 [0.30-1.24] vs 4.09 [3.37-4.81], P<.001); organ failure decedents experienced a fluctuating. pattern of decline, with substantially poorer function during the last 3 months before death (2.10 [1.49-2.70] vs 3.66 [2.94-4.38], P<.001); and frail decedents were relatively more disabled in the final year and especially dependent during the last month (2.92 [2.24-3.60] vs 5.84 [5.33-6.35], P<.001). After controlling for age, sex, race, education, marital status, interval between final interview and death, and other demographic differences, frail decedents were more than 8 times more likely than sudden death decedents to be ADL dependent (OR, 8.32 [95% CI, 6.46-10.73); cancer decedents, one and a half times more likely (OR, 1.57 [95% CI, 1.25-1.96]); and organ failure decedents, 3 times more likely (OR, 3.00 [95% CI, 2.39-3.77]). Conclusions Trajectories of functional decline at the end of life are quite variable. Differentiating among expected trajectories and related needs would help shape tailored strategies and better programs of care prior to death. C1 NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. Washington Home Ctr Palliat Care Studies, Washington, DC USA. Hebrew Home Greater Washington, Rockville, MD USA. RP Lunney, JR (reprint author), NIA, Lab Epidemiol Demog & Biometry, NIH, Gateway Bldg,Suite 3C-309, Bethesda, MD 20892 USA. FU NINR NIH HHS [K22-NR07967] NR 23 TC 485 Z9 487 U1 1 U2 39 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 MAY 14 PY 2003 VL 289 IS 18 BP 2387 EP 2392 DI 10.1001/jama.289.18.2387 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 677WF UT WOS:000182831200028 PM 12746362 ER PT J AU Sobol, RW Foley, JF Nyska, A Davidson, MG Wilson, SH AF Sobol, RW Foley, JF Nyska, A Davidson, MG Wilson, SH TI Regulated over-expression of DNA polymerase beta mediates early onset cataract in mice SO DNA REPAIR LA English DT Article DE DNA polymerase beta; base excision repair; cataract; transgenic ID BASE-EXCISION-REPAIR; LENS EPITHELIAL-CELLS; OXIDATIVE STRESS; GENE-EXPRESSION; STRAND BREAKS; DAMAGE; APOPTOSIS; OVEREXPRESSION; CYTOTOXICITY; INSTABILITY AB Base excision repair (BER) is a tightly coordinated mechanism for repair of DNA base damage (via alkylation and oxidation) and base loss. From E. coli to yeast to human cells, subtle alterations in expression of BER proteins lead to mutagenic or genome instability phenotypes. DNA polymerase beta (beta-pol), the major BER polymerase, has been found to be over-expressed in human tumor tissues and more recently it has been shown that over-expression of beta-pol results in a mutator and genome instability phenotype. These previous reports imply that beta-pol over-expression is deleterious and suggests that such an imbalance may cause an overall functional deficiency in the BER pathway. In the present study, we have developed a bicistronic tetracycline-responsive transgenic system to over-express beta-pol in mice. We find that over-expression of beta-pol in the lens epithelium results in the early onset of severe cortical cataract, with cataractogenesis beginning within 4 days after birth. In utero and post-natal suppression of transgenic Flag-beta-pol expression by doxycycline administration completely prevents cataract formation through adulthood, yet cataract is subsequently observed following removal of doxycycline and re-expression of the transgene. Cataract development accompanies increased expression of cyclooxygenase-2 in the lenticular fibers of the lens, implicating oxidative stress in the development of this cataractous phenotype. Although the mechanism for the transgene mediated cataractogenesis is not clear at this time, it is nevertheless intriguing that increased expression of beta-pol leads to such a phenotype. These results suggest that either a beta-pol expression imbalance negatively affects overall fidelity and/or BER capacity or that beta-pol has a role in lens epithelial cell differentiation. Published by Elsevier Science B.V. C1 NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. N Carolina State Univ, Coll Vet Med, Dept Clin Sci, Raleigh, NC 27606 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. RI Sobol, Robert/E-4125-2013 OI Sobol, Robert/0000-0001-7385-3563 NR 45 TC 23 Z9 24 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD MAY 13 PY 2003 VL 2 IS 5 BP 609 EP 622 DI 10.1016/S1568-7864(03)00026-0 PG 14 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 676VE UT WOS:000182772600012 PM 12713817 ER PT J AU Diaz, M Storb, U AF Diaz, M Storb, U TI A novel cytidine dearninase AIDS in the delivery of error-prone polymerases to immunoglobulin genes SO DNA REPAIR LA English DT Article DE immunoglobulin genes; somatic hypermutation; activation induced deanimase; class switch recombination; translesion DNA synthesis ID B MESSENGER-RNA; SOMATIC HYPERMUTATION; DEAMINASE AID; CELL-LINE; MOLECULAR-CLONING; CONVERSION; MUTATION; MICE; ZETA; PROTEIN AB Immunoglobulin genes undergo somatic hypermutation in activated B lymphocytes. The mutations are targeted to the variable region of the gene, apparently by co-transcriptional deposition of a mutation complex. The novel activation induced deaminase (AID) gene is required for this process and recent work indicates that it is the cytidine deaminase activity of the AID protein rather than an associated RNA editing function that is required [Curr. Biol. 12 (2002) 1748; Nature 419 (2002) I: Nature 418 (2002) 99]. The authors review the implications of this work and argue that deamination of deoxy-cytidine to deoxy-uracil seems to initiate several pathways in which error-prone polymerases are postulated to create mutations. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Univ Chicago, Dept Mol Genet & Cell Biol, Chicago, IL 60637 USA. NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Storb, U (reprint author), Univ Chicago, Dept Mol Genet & Cell Biol, 920 E 58Th St, Chicago, IL 60637 USA. NR 30 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD MAY 13 PY 2003 VL 2 IS 5 BP 623 EP 627 DI 10.1016/S1568-7864(02)00240-9 PG 5 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 676VE UT WOS:000182772600013 PM 12713818 ER PT J AU Friedberg, EC Hanaoka, F Tanaka, K Wilson, SH Yasui, A AF Friedberg, EC Hanaoka, F Tanaka, K Wilson, SH Yasui, A TI Report on the First US-Japan DNA Repair Meeting Sendai, Japan, October 27-31, 2002 SO DNA REPAIR LA English DT Editorial Material C1 Univ Texas, SW Med Ctr, Dept Pathol, Lab Mol Pathol, Dallas, TX 75390 USA. Osaka Univ, Grad Sch Frontier Biosci, Suita, Osaka 5650871, Japan. Osaka Univ, Grad Sch Frontier Biosci, Human Cell Biol Grp, Labs Organismal Biosyst, Suita, Osaka 5650871, Japan. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. Tohoku Univ, Dept Mol Genet, Inst Dev Aging & Canc, Aoba Ku, Sendai, Miyagi 9808575, Japan. RP Friedberg, EC (reprint author), Univ Texas, SW Med Ctr, Dept Pathol, Lab Mol Pathol, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. OI /0000-0001-7243-8261 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 1568-7864 J9 DNA REPAIR JI DNA Repair PD MAY 13 PY 2003 VL 2 IS 5 BP 639 EP 652 DI 10.1016/S1568-7864(03)00038-7 PG 14 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 676VE UT WOS:000182772600015 PM 12713820 ER PT J AU Pearl, PL Gibson, KM Acosta, MT Vezina, LG Theodore, WH Rogawski, MA Novotny, EJ Gropman, A Conry, JA Berry, GT Tuchman, M AF Pearl, PL Gibson, KM Acosta, MT Vezina, LG Theodore, WH Rogawski, MA Novotny, EJ Gropman, A Conry, JA Berry, GT Tuchman, M TI Clinical spectrum of succinic semialdehyde dehydrogenase deficiency SO NEUROLOGY LA English DT Review ID GAMMA-HYDROXYBUTYRIC ACID; 4-HYDROXYBUTYRIC ACIDURIA; VIGABATRIN THERAPY; GABA-METABOLISM; MICE DEFICIENT; PHENOTYPE; SEIZURES; BRAIN; MRI AB Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder affecting CNS gamma-aminobutyric acid (GABA) degradation. SSADH, in conjunction with GABA transaminase, converts GABA to succinate. In the absence of SSADH, GABA is converted to 4-OH-butyrate. The presence of 4-OH-butyrate, a highly volatile compound, may be undetected on routine organic acid analysis. Urine organic acid testing was modified at the authors' institution in 1999 to screen for the excretion of 4-OH-butyrate by selective ion monitoring gas chromatography-mass spectrometry in addition to total ion chromatography. Since then, five patients with 4-hydroxybutyric aciduria have been identified. The authors add the clinical, neuroimaging, and EEG findings from a new cohort of patients to 51 patients reported in the literature with clinical details. Ages ranged from 1 to 21 years at diagnosis. Clinical findings include mild-moderate mental retardation, disproportionate language dysfunction, hypotonia, hyporeflexia, autistic behaviors, seizures, and hallucinations. Brain MRI performed in five patients at the authors' institution revealed symmetric increased T2 signal in the globus pallidi. SSADH deficiency is an under-recognized, potentially manageable neurometabolic disorder. Urine organic acid analysis should include a sensitive method for the detection of 4-hydroxybutyrate and should be obtained from patients with mental retardation or neuropsychiatric disturbance of unknown etiology. C1 George Washington Univ, Childrens Natl Med Ctr, Sch Hlth Sci, Dept Neurol, Washington, DC 20010 USA. George Washington Univ, Childrens Natl Med Ctr, Sch Hlth Sci, Dept Metab, Washington, DC 20010 USA. George Washington Univ, Childrens Natl Med Ctr, Sch Hlth Sci, Dept Radiol, Washington, DC 20010 USA. Oregon Hlth Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Dept Pediat, Portland, OR 97201 USA. NINDS, Epilepsy Res Branch, NIH, Bethesda, MD 20892 USA. Yale Univ, Sch Med, New Haven, CT USA. RP Pearl, PL (reprint author), George Washington Univ, Childrens Natl Med Ctr, Sch Hlth Sci, Dept Neurol, 111 Michigan Ave NW, Washington, DC 20010 USA. RI Rogawski, Michael/B-6353-2009; OI Rogawski, Michael/0000-0002-3296-8193; Berry, Gerard/0000-0001-5299-3313 FU NINDS NIH HHS [NS-40270] NR 26 TC 98 Z9 103 U1 0 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 MAY 13 PY 2003 VL 60 IS 9 BP 1413 EP 1417 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 676LT UT WOS:000182754100005 PM 12743223 ER PT J AU Johnson, CD Balagurunathan, Y Lu, KP Tadesse, M Falahatpisheh, MH Carroll, RJ Dougherty, ER Afshari, CA Ramos, KS AF Johnson, CD Balagurunathan, Y Lu, KP Tadesse, M Falahatpisheh, MH Carroll, RJ Dougherty, ER Afshari, CA Ramos, KS TI Genomic profiles and predictive biological networks in oxidant-induced atherogenesis SO PHYSIOLOGICAL GENOMICS LA English DT Article DE analysis of variance; atherosclerosis; bioinformatics; cDNA microarray; polycyclic aromatic hydrocarbons; vascular smooth muscle cells ID SMOOTH-MUSCLE CELLS; C-HA-RAS; GENE-EXPRESSION; ATHEROSCLEROTIC PLAQUE; BINDING-PROTEIN; BENZOPYRENE; APOPTOSIS; BENZO(A)PYRENE; METABOLISM; MICE AB Atherogenic stimuli trigger complex responses in vascular smooth muscle cells (VSMCs) that culminate in activation/repression of overlapping signal transduction cascades involving oxidative stress. In the case of benzo[a] pyrene (BaP), a polycyclic aromatic hydrocarbon present in tobacco smoke, the atherogenic response involves interference with redox homeostasis by oxidative intermediates of BaP metabolism. The present studies were conducted to define genomic profiles and predictive gene biological networks associated with the atherogenic response of murine (aortic) VSMCs to BaP. A combined oxidant-antioxidant treatment regimen was used to identify redox-sensitive targets during the early course of the atherogenic response. Gene expression profiles were defined using cDNA microarrays coupled to analysis of variance and several clustering methodologies. A predictor algorithm was then applied to gain insight into critical gene-gene interactions during atherogenesis. Supervised and nonsupervised analyses identified clones highly regulated by BaP, unaffected by antioxidant, and neutralized by combined chemical treatments. Lymphocyte antigen-6 complex, histocompatibility class I component factors, secreted phosphoprotein, and several interferon-inducible proteins were identified as novel redox-regulated targets of BaP. Predictor analysis confirmed these relationships and identified immune-related genes as critical molecular targets of BaP. Redox-dependent patterns of gene deregulation indicate that oxidative stress plays a prominent role during the early stages of BaP-induced atherogenesis. C1 Texas A&M Univ, Ctr Environm & Rural Hlth, College Stn, TX 77843 USA. Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Ramos, KS (reprint author), Univ Louisville, Hlth Sci Ctr, Dept Biochem & Mol Biol, Louisville, KY 40292 USA. OI Johnson, Charles/0000-0003-3892-7082 FU NCI NIH HHS [CA90301]; NIEHS NIH HHS [ES-04849, ES-07273, ES-09106] NR 46 TC 24 Z9 24 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD MAY 13 PY 2003 VL 13 IS 3 BP 263 EP 275 DI 10.1152/physiolgenomics.00006.2003 PG 13 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 678EW UT WOS:000182853000009 PM 12657712 ER PT J AU Veech, RL AF Veech, RL TI A humble hexose monophosphate pathway metabolite regulates short- and long-term control of lipogenesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID ELEMENT-BINDING PROTEIN; PYRUVATE-KINASE GENE; TRANSCRIPTION FACTOR; GLUCOSE-UTILIZATION; DEPHOSPHORYLATION; MECHANISM; LIVER; PHOSPHORYLATION; AMP C1 NIAAA, Metab & Mol Biol Lab, Dept Hlth & Human Serv, NIH, Rockville, MD 20852 USA. RP Veech, RL (reprint author), NIAAA, Metab & Mol Biol Lab, Dept Hlth & Human Serv, NIH, 12501 Washington Ave, Rockville, MD 20852 USA. NR 16 TC 25 Z9 25 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 13 PY 2003 VL 100 IS 10 BP 5578 EP 5580 DI 10.1073/pnas.1132039100 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 679UB UT WOS:000182939400003 PM 12721358 ER PT J AU Moore, RE Kim, YW Philpott, CC AF Moore, RE Kim, YW Philpott, CC TI The mechanism of ferrichrome transport through Arn1p and its metabolism in Saccharomyces cerevisiae SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MAJOR FACILITATOR SUPERFAMILY; MICROBIAL IRON TRANSPORT; SIDEROPHORE-IRON; YEAST; IDENTIFICATION; GENE; ENCODES; ACQUISITION; LIPOCALIN; PERMEASE AB Siderophores are low molecular weight compounds, synthesized and secreted by microorganisms, that specifically bind ferric iron with exceptionally high affinity. Microbes capture these compounds and take up the bound iron through specific, high-affinity systems. Saccharomyces cerevisiae can take up iron bound to siderophores through the transporters of the ARN family; however, the mechanism by which the siderophore-bound iron enters the cell via these transporters is not known. Here we describe how ferrichrome, a siderophore of the hydroxamate class, is taken up by Arn1p. Arn1p exhibits two surface binding sites for ferrichrome, one that is similar in affinity to the kappa(T) for uptake and one of a much higher affinity that is specific for the metallated form of ferrichrome. Ferrichrome may gain access to the higher-affinity site through endocytosis. Tracer studies using C-14-labeled ferrichrome bound to either iron(III) or aluminum(III), a nonreducible ligand for ferrichrome, indicate that ferrichrome enters the cell as the intact metallosiderophore and accumulates in the cytosol. Both ferrichrome chelates were relatively stable within the cell, and metal-free ferrichrome did not accumulate, indicating a role for ferrichrome in intracellular iron storage. Iron stored as ferrichrome was readily mobilized to meet the metabolic needs of the cell. C1 NIDDKD, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. Univ Wisconsin, Dept Chem, Oshkosh, WI 54901 USA. RP NIDDKD, Liver Dis Sect, NIH, DHHS Bldg 10,Room 9B-16,10 Ctr Dr,MSC 1800, Bethesda, MD 20892 USA. EM carolinep@intra.niddk.nih.gov NR 39 TC 24 Z9 28 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 MAY 13 PY 2003 VL 100 IS 10 BP 5664 EP 5669 DI 10.1073/pnas.1030323100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 679UB UT WOS:000182939400021 PM 12721368 ER PT J AU Webster, JI Tonelli, LH Moayeri, M Simons, SS Leppla, SH Sternberg, EM AF Webster, JI Tonelli, LH Moayeri, M Simons, SS Leppla, SH Sternberg, EM TI Anthrax lethal factor represses glucocorticoid and progesterone receptor activity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PROTEIN-KINASE KINASE; TOXIN-INDUCED CYTOTOXICITY; BACILLUS-ANTHRACIS; PROTECTIVE ANTIGEN; PROTEOLYTIC INACTIVATION; C-JUN; MACROPHAGES; CELLS; SUSCEPTIBILITY; CONSEQUENCES AB We report here that a bacterial toxin, anthrax lethal toxin (LeTx), at very low concentrations represses glucocorticoid receptor (GR) transactivation in a transient transfection system and the activity of an endogenous GR-regulated gene in both a cellular system and an animal model. This repression is noncompetitive and does not affect ligand binding or DNA binding, suggesting that anthrax lethal toxin (LeTx) probably exerts its effects through a cofactor(s) involved in the interaction between GR and the basal transcription machinery. LeTx-nuclear receptor repression is selective, repressing GR, progesterone receptor B (PR-B), and estrogen receptor a (ERalpha), but not the mineralocorticoid receptor (MR) or ERbeta. GR repression was also caused by selected p38 mitogen-activated protein (MAP) kinase inhibitors, suggesting that the LeTx action may result in part from its known inactivation of MAP kinases. Simultaneous loss of GR and other nuclear receptor activities could render an animal more susceptible to lethal or toxic effects of anthrax infection by removing the normally protective anti-inflammatory effects of these hormones, similar to the increased mortality seen in animals exposed to both GR antagonists and infectious agents or bacterial products. These finding have implications for development of new treatments and prevention of the toxic effects of anthrax. C1 NIMH, Sect Neuroendocrine Immunol & Behav, NIH, Bethesda, MD 20892 USA. NIAID, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIDDKD, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Sternberg, EM (reprint author), NIMH, Sect Neuroendocrine Immunol & Behav, NIH, Bldg 36,Room 1A23,36 Convent Dr,MSC 4020, Bethesda, MD 20892 USA. NR 53 TC 47 Z9 49 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 13 PY 2003 VL 100 IS 10 BP 5706 EP 5711 DI 10.1073/pnas.1036973100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 679UB UT WOS:000182939400028 PM 12724519 ER PT J AU Armstrong, N Mayer, M Gouaux, E AF Armstrong, N Mayer, M Gouaux, E TI Tuning activation of the AMPA-sensitive GluR2 ion channel by genetic adjustment of agonist-induced conformational changes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LIGAND-BINDING CORE; GLUTAMATE-RECEPTOR DESENSITIZATION; NUCLEOTIDE-GATED CHANNELS; MOLECULAR MECHANISM; KAINATE; DOMAIN; CYCLOTHIAZIDE; MODULATION; CONSTRUCT AB The (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazole) propionic acid (AMPA) receptor discriminates between agonists in terms of binding and channel gating; AMPA is a high-affinity full agonist, whereas kainate is a low-affinity partial agonist. Although there is extensive literature on the functional characterization of partial agonist activity in ion channels, structure-based mechanisms are scarce. Here we investigate the role of Leu-650, a binding cleft residue conserved among AMPA receptors, in maintaining agonist specificity and regulating agonist binding and channel gating by using physiological, x-ray crystallographic, and biochemical techniques. Changing Leu-650 to Thr yields a receptor that responds more potently and efficaciously to kainate and less potently and efficaciously to AMPA relative to the WT receptor. Crystal structures of the Leu-650 to Thr mutant reveal an increase in domain closure in the kainate-bound state and a partially closed and a fully closed conformation in the AMPA-bound form. Our results indicate that agonists can induce a range of conformations in the GluR2 ligand-binding core and that domain closure is directly correlated to channel activation. The partially closed, AMPA-bound conformation of the L650T mutant likely captures the structure of an agonist-bound, inactive state of the receptor. Together with previously solved structures, we have determined a mechanism of agonist binding and subsequent conformational rearrangements. C1 Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. Columbia Univ, Howard Hughes Med Inst, New York, NY 10032 USA. NICHHD, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. RP Gouaux, E (reprint author), Columbia Univ, Dept Biochem & Mol Biophys, 630 W 168th St, New York, NY 10032 USA. RI Mayer, Mark/H-5500-2013 NR 32 TC 115 Z9 118 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 MAY 13 PY 2003 VL 100 IS 10 BP 5736 EP 5741 DI 10.1073/pnas.1037393100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 679UB UT WOS:000182939400033 PM 12730367 ER PT J AU Ma, BY Elkayam, T Wolfson, H Nussinov, R AF Ma, BY Elkayam, T Wolfson, H Nussinov, R TI Protein-protein interactions: Structurally conserved residues distinguish between binding sites and exposed protein surfaces SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE protein-protein interfaces; hot spots; molecular recognition; binding site prediction; residue conservation ID MULTIPLE STRUCTURE ALIGNMENT; HOT-SPOTS; SHAPE COMPLEMENTARITY; MOLECULAR RECOGNITION; DUAL RECOGNITION; INTERFACES; COMMON; SPECIFICITY; SEQUENCE; ENERGY AB Polar residue hot spots have been observed at protein-protein binding sites. Here we show that hot spots occur predominantly at the interfaces of macromolecular complexes, distinguishing binding sites from the remainder of the surface. Consequently, hot spots can be used to define binding epitopes. We further show a correspondence between energy hot spots and structurally conserved residues. The number of structurally conserved residues, particularly of high ranking energy hot spots, increases with the binding site contact size. This finding may suggest that effectively dispersing hot spots within a large contact area, rather than compactly clustering them, may be a strategy to sustain essential key interactions while still allowing certain protein flexibility at the interface. Thus, most conserved polar residues at the binding interfaces confer rigidity to minimize the entropic cost on binding, whereas surrounding residues form a flexible cushion. Furthermore, our finding that similar residue hot spots occur across different protein families suggests that affinity and specificity are not necessarily coupled: higher affinity does not directly imply greater specificity. Conservation of Trp on the protein surface indicates a highly likely binding site. To a lesser extent, conservation of Phe and Met also imply a binding site. For all three residues, there is a significant conservation in binding sites, whereas there is no conservation on the exposed surface. A hybrid strategy, mapping sequence alignment onto a single structure illustrates the possibility of binding site identification around these three residues. C1 NCI, Basic Res Program, SAIC Frederick Inc, Lab Expt & Computat Biol, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Sch Med, Sackley Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Sch Comp Sci, Fac Exact Sci, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Basic Res Program, SAIC Frederick Inc, Lab Expt & Computat Biol, Frederick, MD 21702 USA. RI Wolfson, Haim/A-1837-2011; Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU NCI NIH HHS [N01-CO-12400, N01CO12400] NR 50 TC 365 Z9 375 U1 4 U2 33 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 MAY 13 PY 2003 VL 100 IS 10 BP 5772 EP 5777 DI 10.1073/pnas.1030237100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 679UB UT WOS:000182939400039 PM 12730379 ER PT J AU Miura, M Gronthos, S Zhao, MR Lu, B Fisher, LW Robey, PG Shi, ST AF Miura, M Gronthos, S Zhao, MR Lu, B Fisher, LW Robey, PG Shi, ST TI SHED: Stem cells from human exfoliated deciduous teeth SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE odontoblast; bone regeneration; neural differentiation; adipocyte; dental pulp stem cell ID MARROW STROMAL CELLS; HUMAN DENTAL-PULP; BONE-MARROW; IN-VIVO; NEURAL CREST; BRAIN; NEURONS; FUSION; BLOOD; MOUSE AB To isolate high-quality human postnatal stem cells from accessible resources is an important goal for stem-cell research. In this study we found that exfoliated human deciduous tooth contains multipotent stem cells [stem cells from human exfoliated deciduous teeth (SHED)]. SHED were identified to be a population of highly proliferative, clonogenic cells capable of differentiating into a variety of cell types including neural cells, adipocytes, and odontoblasts. After in vivo transplantation, SHED were found to be able to induce bone formation, generate dentin, and survive in mouse brain along with expression of neural markers. Here we show that a naturally exfoliated human organ contains a population of stem cells that are completely different from previously identified stem cells. SHED are not only derived from a very accessible tissue resource but are also capable of providing enough cells for potential clinical application. Thus, exfoliated teeth may be an unexpected unique resource for stem-cell therapies including autologous stem-cell transplantation and tissue engineering. C1 Natl Inst Dental & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. Inst Med & Vet Sci, Div Haematol, Mesenchymal Stem Cell Grp, Adelaide, SA 5000, Australia. NICHHD, Sect Neural Dev & Plast, NIH, Bethesda, MD 20892 USA. RP Shi, ST (reprint author), Natl Inst Dental & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bldg 30,Room 228,Convent Dr,MSC-4320, Bethesda, MD 20892 USA. RI Lu, Bai/A-4018-2012; Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 28 TC 1036 Z9 1120 U1 11 U2 108 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 MAY 13 PY 2003 VL 100 IS 10 BP 5807 EP 5812 DI 10.1073/pnas.0937635100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 679UB UT WOS:000182939400045 PM 12716973 ER PT J AU Gorelik, J Shevchuk, AI Frolenkov, GI Diakonov, IA Lab, MJ Kros, CJ Richardson, GP Vodyanoy, I Edwards, CRW Klenerman, D Korchev, YE AF Gorelik, J Shevchuk, AI Frolenkov, GI Diakonov, IA Lab, MJ Kros, CJ Richardson, GP Vodyanoy, I Edwards, CRW Klenerman, D Korchev, YE TI Dynamic assembly of surface structures in living cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SCANNING ION-CONDUCTANCE; BRUSH-BORDER; ORGANOTYPIC CULTURES; MOUSE COCHLEA; ACTIN; MORPHOLOGY; MICROSCOPY; BUNDLES; LOCALIZATION; CYTOSKELETON AB Although the dynamics of cell membranes and associated structures is vital for cell function, little is known due to lack of suitable methods. We found, using scanning ion conductance microscopy, that microvilli, membrane projections supported by internal actin bundles, undergo a life cycle: fast height-dependent growth, relatively short steady state, and slow height-independent retraction. The microvilli can aggregate into relatively stable structures where the steady state is extended. We suggest that the intrinsic dynamics of microvilli, combined with their ability to make stable structures, allows them to act as elementary "building blocks" for the assembly of specialized structures on the cell surface. C1 Univ London Imperial Coll Sci Technol & Med, Div Med, London W12 0NN, England. Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. Univ Sussex, Sch Biol Sci, Brighton BN1 9QG, E Sussex, England. Off Naval Res, Arlington, VA 22217 USA. Univ Newcastle Upon Tyne, Dept Physiol Sci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. RP Korchev, YE (reprint author), Univ London Imperial Coll Sci Technol & Med, Div Med, Hammersmith Hosp Campus,Du Cane Rd, London W12 0NN, England. RI Korchev, Yuri/D-2498-2009; OI Klenerman, David/0000-0001-7116-6954; Korchev, Yuri/0000-0002-4872-8696; Frolenkov, Gregory/0000-0002-9810-5024 NR 28 TC 84 Z9 88 U1 2 U2 19 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 MAY 13 PY 2003 VL 100 IS 10 BP 5819 EP 5822 DI 10.1073/pnas.1030502100 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 679UB UT WOS:000182939400047 PM 12721367 ER PT J AU Fitzpatrick, LA Buzas, E Gagne, TJ Nagy, A Horvath, C Ferencz, V Mester, A Kari, B Ruan, M Falus, A Barsony, J AF Fitzpatrick, LA Buzas, E Gagne, TJ Nagy, A Horvath, C Ferencz, V Mester, A Kari, B Ruan, M Falus, A Barsony, J TI Targeted deletion of histidine decarboxylase gene in mice increases bone formation and protects against ovariectomy-induced bone loss SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID OSTEOCLAST DIFFERENTIATION; MAST-CELLS; PARATHYROID-HORMONE; TISSUE-CULTURE; DEFICIENT MICE; KAPPA-B; HISTAMINE; RESORPTION; RECEPTOR; OSTEOPOROSIS AB Targeted disruption of the histidine decarboxylase gene (HDC-/-), the only histamine-synthesizing enzyme, led to a histamine-deficient mice characterized by undetectable tissue histamine levels, impaired gastric acid secretion, impaired passive cutaneous anaphylaxis, and decreased mast cell degranulation. We used this model to study the role of histamine in bone physiology. Compared with WT mice, HDC-/- mice receiving a histamine-free diet had increased bone mineral density, increased cortical bone thickness, higher rate of bone formation, and a marked decrease in osteoclasts. After ovariectomy, cortical and trabecular bone loss was reduced by 50% in HDC-/- mice compared with WT. Histamine deficiency protected the skeleton from osteoporosis directly, by inhibiting osteoclastogenesis, and indirectly, by increasing calcitriol synthesis. Quantitative RT-PCR showed elevated 25-hydroxyvitamin D-1alpha-hydroxylase and markedly decreased 25-hydroxyvitamin D-24-hydroxylase mRNA levels. Serum parameters confirming this indirect effect included elevated calcitriol, phosphorus, alkaline phosphatase, and receptor activator of NF-kappaB ligand concentrations, and suppressed parathyroid hormone concentrations in HDC-/- mice compared with WT mice. After ovariectomy, histamine-deficient mice were protected from bone loss by the combination of increased bone formation and reduced bone resorption. C1 NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. Mayo Clin & Mayo Fdn, Div Endocrinol Metab Diabet & Nutr, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Div Internal Med, Rochester, MN 55905 USA. Mt Sinai Hosp, Samuel Lunenfeld Inst, Toronto, ON M5G 1X5, Canada. Semmelweis Univ, Fac Med, Dept Genet, H-1085 Budapest 7, Hungary. Semmelweis Univ, Fac Med, Dept Cell Biol, H-1085 Budapest 7, Hungary. Semmelweis Univ, Fac Med, Dept Immunobiol, H-1085 Budapest 7, Hungary. RP Barsony, J (reprint author), NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RI Nagy, Andras/G-6465-2013; OI Buzas, Edit/0000-0002-3744-206X NR 42 TC 47 Z9 47 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 MAY 13 PY 2003 VL 100 IS 10 BP 6027 EP 6032 DI 10.1073/pnas.0934373100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 679UB UT WOS:000182939400083 PM 12716972 ER PT J AU Moir, S Ogwaro, KM Malaspina, A Vasquez, J Donoghue, ET Hallahan, CW Liu, SY Ehler, LA Planta, MA Kottilil, S Chun, TW Fauci, AS AF Moir, S Ogwaro, KM Malaspina, A Vasquez, J Donoghue, ET Hallahan, CW Liu, SY Ehler, LA Planta, MA Kottilil, S Chun, TW Fauci, AS TI Perturbations in B cell responsiveness to CD4(+) T cell help in HIV-infected individuals SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IMMUNODEFICIENCY-VIRUS INFECTION; CD40 LIGAND EXPRESSION; ANTIRETROVIRAL THERAPY; INTERLEUKIN-2 RECEPTOR; IFN-GAMMA; ANTIBODY-RESPONSES; CD40-CD40 LIGAND; IN-VIVO; ACTIVATION; ANTIGEN AB HIV infection induces a wide array of B cell dysfunctions. We have characterized the effect of plasma viremia on the responsiveness of B cells to CD4(+) T cell help in HIV-infected patients. In HIV-negative donors, B cell proliferation correlated with CD154 expression on activated CD4(+) T cells and with the availability of IL-2, whereas in HIV-infected virennic patients, reduced B cell proliferation was observed despite normal CD154 expression on activated CD4(+) T cells. Reduced triggering of B cells by activated CD4(+) T cells was clearly observed in HIV-infected viremic patients compared with aviremic patients with comparable CD4(+) T cell counts, and a dramatic improvement in B cell function was observed in patients whose plasma viremia was controlled by effective antiretroviral therapy. The degree of B cell dysfunction in viremic patients correlated strongly with the inability of B cells to express CD25 in response to activated CD4(+) T cells, resulting in an inability to mount a normal proliferative response to IL-2. Similar defects in responsiveness to IL-2 were observed in the B cells of HIV-infected viremic patients in the context of 8 cell receptor stimulation. These data provide new insight into the mechanisms associated with ineffective humoral responses in HIV disease. C1 Natl Inst Allergy & Infect Dis, Immunoregulat Lab, Dept Hlth, NIH, Bethesda, MD 20892 USA. Natl Inst Allergy & Infect Dis, Immunoregulat Lab, Human Serv, NIH, Bethesda, MD 20892 USA. RP Moir, S (reprint author), Natl Inst Allergy & Infect Dis, Immunoregulat Lab, Dept Hlth, NIH, Bldg 10,Rm 6A02, Bethesda, MD 20892 USA. NR 43 TC 67 Z9 71 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 MAY 13 PY 2003 VL 100 IS 10 BP 6057 EP 6062 DI 10.1073/pnas.0730819100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 679UB UT WOS:000182939400088 PM 12730375 ER PT J AU Brown, P Meyer, R Cardone, F Pocchiari, M AF Brown, P Meyer, R Cardone, F Pocchiari, M TI Ultra-high-pressure inactivation of prion infectivity in processed meat: A practical method to prevent human infection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE food processing; scrapie; bovine spongiform encephalopathy; new variant Creutzfeldt-Jakob disease; prion disease ID CREUTZFELDT-JAKOB-DISEASE; HYDROSTATIC-PRESSURE; PROTEIN; TECHNOLOGY; SCRAPIE; PLASMA; FOODS AB Bovine spongiform encephalopathy contamination of the human food chain most likely resulted from nervous system tissue in mechanically recovered meat used in the manufacture of processed meats. We spiked hot dogs with 263K hamster-adapted scrapie brain (10% wt/wt) to produce an infectivity level of approximate to 9 log(10) mean lethal doses (LD50) per g of paste homogenate. Aliquots were subjected to short pressure pulses of 690, 1,000, and 1,200 MPa at running temperatures of 121-137degreesC. Western blots of PrPres were found to be useful indicators of infectivity levels, which at all tested pressures were significantly reduced as compared with untreated controls: from approximate to 10(3) LD50 per g at 690 MPa to approximate to 10(6) LD50 per g at 1,200 MPa. The application of commercially practical conditions of temperature and pressure could ensure the safety of processed meats from bovine spongiform encephalopathy contamination, and could also be used to study phase transitions of the prion protein from its normal to misfolded state. C1 NIH, Bethesda, MD 20892 USA. Washington Farms, Tacoma, WA 98443 USA. Ist Super Sanita, I-00161 Rome, Italy. RP Brown, P (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. RI Cardone, Franco/D-1724-2009 OI Cardone, Franco/0000-0002-2376-0470 NR 21 TC 61 Z9 63 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 13 PY 2003 VL 100 IS 10 BP 6093 EP 6097 DI 10.1073/pnas.1031826100 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 679UB UT WOS:000182939400094 PM 12732724 ER PT J AU Hikida, T Kitabatake, Y Pastan, I Nakanishi, S AF Hikida, T Kitabatake, Y Pastan, I Nakanishi, S TI Acetylcholine enhancement in the nucleus accumbens prevents addictive behaviors of cocaine and morphine SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID INTEGRATION; RATS; MICE; INTERNEURONS; WITHDRAWAL; EXPRESSION; ABLATION; SYSTEM; REWARD; BRAIN AB Drug addiction poses serious social, medical, and economic problems, but effective treatments for drug addiction are still limited. Cocaine and morphine elevate dopamine levels in the nucleus accumbens (NAc), and the overwhelming actions of dopamine are implicated in reinforcement and addiction of abusive drugs. In our previous studies, we reported the regulatory role of acetylcholine (ACh) in the NAc function by selectively ablating the NAc cholinergic neurons with use of immunotoxin-mediated cell targeting. These studies indicated that ACh and dopamine acted convergently but oppositely on the NAc circuit and that cholinergic cell ablation enhanced long-lasting behavioral changes of cocaine addiction. In this investigation, we showed that immunotoxin-mediated ablation of the NAc cholinergic neurons enhanced not only the sensitivity to morphine in conditioned place preference but also negative reinforcement of morphine withdrawal in conditioned place aversion. Remarkably, acetylcholinesterase (AChE) inhibitors that act on the brain AChE suppressed both cocaine- and morphine-induced conditioned place preference and blocked the induction and persistence of cocaine-evoked hyperlocomotion. Importantly, this inhibition was abolished by ablation of the NAc cholinergic neurons. These results demonstrate that centrally active AChE inhibitors prevent long-lasting behavioral abnormalities associated with cocaine and morphine addictions by potentiating the actions of ACh released from the NAc cholinergic neurons. Centrally active AChE inhibitors could thus be approached as novel and potential therapeutic agents for drug addiction. C1 Kyoto Univ, Fac Med, Dept Biol Sci, Kyoto 6068501, Japan. NCI, Mol Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Nakanishi, S (reprint author), Kyoto Univ, Fac Med, Dept Biol Sci, Kyoto 6068501, Japan. NR 26 TC 93 Z9 98 U1 2 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 13 PY 2003 VL 100 IS 10 BP 6169 EP 6173 DI 10.1073/pnas.0631749100 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 679UB UT WOS:000182939400107 PM 12721372 ER PT J AU Mattay, VS Goldberg, TE Fera, F Hariri, AR Tessitore, A Egan, MF Kolachana, B Callicott, JH Weinberger, DR AF Mattay, VS Goldberg, TE Fera, F Hariri, AR Tessitore, A Egan, MF Kolachana, B Callicott, JH Weinberger, DR TI Catechol O-methyltransferase val(158)-met genotype and individual variation in the brain response to amphetamine SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RAT PREFRONTAL CORTEX; PARKINSONS-DISEASE; WORKING-MEMORY; DOPAMINERGIC MODULATION; IN-VITRO; PERFORMANCE; COGNITION; COMT; METHYLPHENIDATE; SCHIZOPHRENIA AB Monamines subserve many critical roles in the brain, and monoaminergic drugs such as amphetamine have a long history in the treatment of neuropsychiatric disorders and also as a substance of abuse. The clinical effects of amphetamine are quite variable, from positive effects on mood and cognition in some individuals, to negative responses in others, perhaps related to individual variations in monaminergic function and monoamine system genes. We explored the effect of a functional polymorphism (val(158)-Met) in the catechol O-methyltransferase gene, which has been shown to modulate prefrontal dopamine animals and prefrontal cortical function in humans, on the modulatory actions of amphetamine on the prefrontal cortex. Amphetamine enhanced the efficiency of prefrontal cortex function assayed with functional MRI during a working memory task in subjects with the high enzyme activity val/val genotype, who presumably have relatively less prefrontal synaptic dopamine, at all levels of task difficulty. In contrast, in subjects with the low activity met/met genotype who tend to have superior baseline prefrontal function, the drug had no effect on cortical efficiency at low-to-moderate working memory load and caused deterioration at high working memory load. These data illustrate an application of functional neuroimaging in pharmacogenomics and extend basic evidence of an inverted-"U" functional-response curve to increasing dopamine signaling in the prefrontal cortex. Further, individuals with the met/met catechol O-methyltransferase genotype appear to beat increased risk for an adverse response to amphetamine. C1 NIMH, Clin Brain Disorders Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20982 USA. RP Weinberger, DR (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Dept Hlth & Human Serv, Bldg 10,Ctr Dr,Room 4S-235, Bethesda, MD 20982 USA. RI Hariri, Ahmad/D-5761-2011; Callicott, Joseph/C-9102-2009 OI Callicott, Joseph/0000-0003-1298-3334 NR 35 TC 641 Z9 652 U1 5 U2 43 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 MAY 13 PY 2003 VL 100 IS 10 BP 6186 EP 6191 DI 10.1073/pnas.0931309100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 679UB UT WOS:000182939400110 PM 12716966 ER PT J AU Choleris, E Gustafsson, JA Korach, KS Muglia, LJ Pfaff, DW Ogawa, S AF Choleris, E Gustafsson, JA Korach, KS Muglia, LJ Pfaff, DW Ogawa, S TI An estrogen-dependent four-gene micronet regulating social recognition: A study with oxytocin and estrogen receptor-alpha and -beta knockout mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ANIMAL-MODELS; ANXIETY; MOUSE; VASOPRESSIN; BEHAVIOR; EXPRESSION; RESPONSES; LACKING; SYSTEM; BRAIN AB Estrogens control many physiological and behavioral processes, some of which are connected to reproduction. These include sexual and other social behaviors. Here we implicate four gene products in a micronet required for mammalian social recognition, through which an individual learns to recognize other individuals. Female mice whose genes for the neuropeptide oxytocin (OT) or the estrogen receptor (ER)-beta or ER-alpha had been selectively "knocked out" were deficient specifically in social recognition and social anxiety. There was a remarkable parallelism among results from three separate gene knockouts. The data strongly suggest the involvement in social recognition of the four genes coding for ER-alpha, ER-beta, OT, and the OT receptor. We thus propose here a four-gene micronet,which links hypothalamic and limbic forebrain neurons in the estrogen control over the OT regulation of social recognition. In our model, estrogens act on the OT system at two levels: through ER-alpha, they regulate the production of OT in the hypothalamic paraventricular nucleus, and through ER-alpha, they drive the transcription of the OT receptor in the amygdala. The proper operation of a social recognition mechanism allows for the expression of appropriate social behaviors, aggressive or affiliative. C1 Washington Univ, Dept Pediat, Pain Ctr, St Louis, MO 63110 USA. NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. Karolinska Inst, Dept Med Nutr, S-14186 Huddinge, Sweden. Rockefeller Univ, Neurobiol & Behav Lab, New York, NY 10021 USA. RP Choleris, E (reprint author), Univ Guelph, Dept Psychol, MacKinnon Bldg,5th Floor, Guelph, ON N1G 2W1, Canada. OI Korach, Kenneth/0000-0002-7765-418X NR 41 TC 217 Z9 222 U1 1 U2 20 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 13 PY 2003 VL 100 IS 10 BP 6192 EP 6197 DI 10.1073/pnas.0631699100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 679UB UT WOS:000182939400111 PM 12730370 ER PT J AU Ren, M Senatorov, VV Chen, RW Chuang, DM AF Ren, M Senatorov, VV Chen, RW Chuang, DM TI Postinsult treatment with lithium reduces brain damage and facilitates neurological recovery in a rat ischemia/reperfusion model SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID FOCAL CEREBRAL-ISCHEMIA; SYNTHASE KINASE 3-BETA; HEAT-SHOCK RESPONSE; NF-KAPPA-B; PROTECTS NEURONS; CELL-DEATH; EXCITOTOXICITY; EXPRESSION; STROKE; NEUROPROTECTION AB Lithium has long been a primary drug used to treat bipolar mood disorder, even though the drug's therapeutic mechanisms remain obscure. Recent studies demonstrate that lithium has neuroprotective effects against glutamate-induced excitotoxicity in cultured neurons and in vivo. The present study was undertaken to examine whether postinsult treatment with lithium reduces brain damage induced by cerebral ischemia. We found that s.c. injection of lithium dose dependently (0.5-3 mEq/kg) reduced infarct volume in the rat model of middle cerebral artery occlusion/reperfusion. Infarct volume was reduced at a therapeutic dose of 1 mEq/kg even when administered up to 3 h after the onset of ischemia. Neurological deficits induced by ischemia were also reduced by daily administration of lithium over 1 week. Moreover, lithium treatment decreased the number of neurons showing DNA damage in the ischemic brain. These neuroprotective effects were associated with an up-regulation of cytoprotective heat shock protein 70 (HSP70) in the ischemic brain hemisphere as determined by immunohistochemistry and Western blotting analysis. Lithium-induced HSP70 up-regulation in the ischemic hemisphere was preceded by an increase in the DNA binding activity of heat shock factor 1, which regulates the transcription of HSP70. Physical variables and cerebral blood flow were unchanged by lithium treatment. Our results suggest that postinsult lithium treatment reduces both ischemia-induced brain damage and associated neurological deficits. Moreover, the heat shock response is likely to be involved in lithium's neuroprotective actions. Additionally, our studies indicate that lithium may have clinical utility for the treatment of patients with acute stroke. C1 NIMH, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Chuang, DM (reprint author), NIMH, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. NR 37 TC 147 Z9 161 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 13 PY 2003 VL 100 IS 10 BP 6210 EP 6215 DI 10.1073/pnas.0937423100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 679UB UT WOS:000182939400114 PM 12732732 ER PT J AU Anson, RM Guo, ZH de Cabo, R Iyun, T Rios, M Hagepanos, A Ingram, DK Lane, MA Mattson, MP AF Anson, RM Guo, ZH de Cabo, R Iyun, T Rios, M Hagepanos, A Ingram, DK Lane, MA Mattson, MP TI Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE caloric restriction; hippocampus; insulin; beta-hydroxybutyrate; ketosis ID BETA-HYDROXYBUTYRATE; KETOGENIC DIET; BODY-WEIGHT; LIFE-SPAN; PARKINSONS-DISEASE; FOOD RESTRICTION; BRAIN-DAMAGE; INSULIN; MICE; GROWTH AB Dietary restriction has been shown to have several health benefits including increased insulin sensitivity, stress resistance, reduced morbidity, and increased life span. The mechanism remains unknown, but the need for a long-term reduction in caloric intake to achieve these benefits has been assumed. We report that when C57BL/6 mice are maintained on an intermittent fasting (alternate-day fasting) dietary-restriction regimen their overall food intake is not decreased and their body weight is maintained. Nevertheless, intermittent fasting resulted in beneficial effects that met or exceeded those of caloric restriction including reduced serum glucose and insulin levels and increased resistance of neurons in the brain to excitotoxic stress. Intermittent fasting therefore has beneficial effects on glucose regulation and neuronal resistance to injury in these mice that are independent of caloric intake. C1 NIA, Neurosci Lab, Ctr Gerontol Res, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Ctr Gerontol Res, GRC 4F01,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI de Cabo, Rafael/E-7996-2010; Mattson, Mark/F-6038-2012; de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 NR 41 TC 256 Z9 263 U1 12 U2 70 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 MAY 13 PY 2003 VL 100 IS 10 BP 6216 EP 6220 DI 10.1073/pnas.1035720100 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 679UB UT WOS:000182939400115 PM 12724520 ER PT J AU Hussain, AI Shanmugam, V Bhullar, VB Beer, BE Vallet, D Gautier-Hion, A Wolfe, ND Karesh, WB Kilbourn, AM Tooze, Z Heneine, W Switzer, WM AF Hussain, AI Shanmugam, V Bhullar, VB Beer, BE Vallet, D Gautier-Hion, A Wolfe, ND Karesh, WB Kilbourn, AM Tooze, Z Heneine, W Switzer, WM TI Screening for simian foamy virus infection by using a combined antigen Western blot assay: evidence for a wide distribution among Old World primates and identification of four new divergent viruses SO VIROLOGY LA English DT Article DE simian foamy virus; diagnosis; western blot; PCR; phylogeny; divergent viruses; primate ID HEALTH; SERA AB Simian foamy viruses (SFVs) belong to a genetically and antigenically diverse class of retroviruses that naturally infect a wide range of nonhuman primates (NHPs) and can also be transmitted to humans occupationally exposed to NHPs. Current serologic detection of SFV infection requires separate Western blot (WB) testing by using two different SFV antigens [SFVAGM (African green monkey) and SFVCFZ (chimpanzee)). However, this method is labor intensive and validation is limited to only small numbers of NBPs. To facilitate serologic SFV testing, we developed a WB assay that combines antigens from both SFVAGM and SFVCPZ. The combined-antigen WB (CA-WB) assay was validated with 145 serum samples from 129 NWs (32 African and Asian species) and 16 humans, all with known SFV infection status determined by PCR. Concordant CA-WB results were obtained for all 145 PCR-positive or -negative primate and human specimens, giving the assay a 100% sensitivity and specificity. In addition. no reactivity was observed in sera from persons positive for human immunodeficiency virus or human T cell lymphotropic virus (HIV/HTLV) (n = 25) or HIV/HTLV-negative U.S. blood donors (n = 100). Using the CA-WB assay, we screened 360 sera from 43 Old World primate species and found an SFV prevalence of about 68% in both African and Asian primates. We also isolated SFV from the blood of four seropositive primates (Allenopithecus nigroviridis, Trachypithecus francoisi, Hylobates pilearus, and H. leucogenys) not previously known to be infected with SFV. Phylogenetic analysis of integrase sequences from these isolates confirmed that all four SFVs represent new, distinct, and highly divergent lineages. These results demonstrate the ability of the CA-WB assay to detect infection in a large number of NHP species, including previously uncharacterized infections with divergent SFVs. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Ctr Dis Control & Prevent, HIV & Retrovirol Branch, Div HIV STD & TB Lab Res, Atlanta, GA 30333 USA. NIAID, Mol Microbiol Lab, NIH, Rockville, MD 20852 USA. Univ Rennes 1, CNRS, UMR 6552, F-35380 Paimpont, France. Johns Hopkins Univ, Sch Publ Hlth, Ctr Immunizat Res, Baltimore, MD 21202 USA. Wildlife Conservat Soc, Wildlife Hlth Sci, Bronx, NY 10460 USA. Cercopan, Calabar, Cross River Sta, Nigeria. RP Switzer, WM (reprint author), Ctr Dis Control & Prevent, HIV & Retrovirol Branch, Div HIV STD & TB Lab Res, 1600 Clifton Rd,Mail Stop G-19, Atlanta, GA 30333 USA. FU FIC NIH HHS [KO1 TW00003-01] NR 28 TC 63 Z9 63 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAY 10 PY 2003 VL 309 IS 2 BP 248 EP 257 DI 10.1016/S0042-6822(03)00070-9 PG 10 WC Virology SC Virology GA 685BX UT WOS:000183241900008 PM 12758172 ER PT J AU Frank, S Robert, EG Youle, RJ AF Frank, S Robert, EG Youle, RJ TI Scission, spores, and apoptosis: a proposal for the evolutionary origin of mitochondria in cell death induction SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID DYNAMIN-RELATED GTPASE; STREPTOMYCES-COELICOLOR; CHLOROPLAST DIVISION; OUTER-MEMBRANE; PROTEIN FTSZ; FISSION; DNM1P; BAX; YEAST; MORPHOLOGY AB Mitochondria fragment prior to caspase activation during many pathways of apoptosis. Inhibition of the machinery that normally regulates mitochondrial morphology in healthy cells inhibits the fission that occurs during apoptosis and actually delays the process of cell death. Interestingly, there are certain parallels between mitochondrial fission and bacterial sporulation. As bacterial sporulation can be considered a stress response we suggest that a primordial stress response of endosymbiont mitochondrial progenitors may have been adopted for the stress response of early eukaryotes. Thus, the mitochondrial fission process may represent an early stress response of primitive mitochondria that could have integrated the stress signals and acted as an initial sensor for the eukaryotic response system. The fact that mitochondria fragment during apoptosis using the machinery descended from or that superceded the bacterial stress response of sporulation is consistent with this hypothesis. This hypothesis would explain why what is generally considered the "power house" of the cell came to integrate the cell death response and regulate apoptosis. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NINDS, Biochem Sect, SNB, NIH, Bethesda, MD 20892 USA. RP Youle, RJ (reprint author), NINDS, Biochem Sect, SNB, NIH, Bldg 10,Room 5D-37, Bethesda, MD 20892 USA. NR 43 TC 20 Z9 20 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 9 PY 2003 VL 304 IS 3 BP 481 EP 486 DI 10.1016/S0006-291X(03)00620-X PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 679GB UT WOS:000182911400007 PM 12729582 ER PT J AU Mattson, MP Liu, D AF Mattson, MP Liu, D TI Mitochondrial potassium channels and uncoupling proteins in synaptic plasticity and neuronal cell death SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Review DE apoptosis; axons; calcium; dendrites; glutamate; hippocampus; ischemia ID K-ATP CHANNELS; AMYLOID BETA-PEPTIDE; LONG-TERM POTENTIATION; PERMEABILITY TRANSITION PORE; BROWN ADIPOSE-TISSUE; PARKINSONS-DISEASE; HIPPOCAMPAL-NEURONS; NEURODEGENERATIVE DISORDERS; DIETARY RESTRICTION; DENDRITIC SPINES AB The function of the nervous system relies upon synaptic transmission, a process in which a neurotransmitter released from presynaptic terminals of one neuron (in response to membrane depolarization and calcium influx) activates post-synaptic receptors on dendrites of another neuron. Synapses are subjected to repeated bouts of oxidative and metabolic stress as the result of changing ion gradients and ATP usage. Mitochondria play central roles in meeting the demands of synapses for ATP and in regulating calcium homeostasis, and mitochondrial dysfunction can cause dysfunction and degeneration of synapses, and can trigger cell death. We have identified two types of mitochondrial proteins that serve the function of protecting synapses and neurons against dysfunction and death. Mitochondrial ATP-sensitive potassium (MitoKATP) channels modulate inner membrane potential and oxyradical production; mitochondrial potassium fluxes can affect cytochrome c release and caspase activation and may determine whether neurons live or die in experimental models of stroke and Alzheimer's disease. Uncoupling proteins (UCPs) are a family of mitochondrial membrane proteins that uncouple electron transport from ATP production by transporting protons across the inner membrane. Neurons express at least three UCPs including the widely expressed UCP-2 and the neuron-specific UCP-4 and UCP-5 (BMCP-1). We have found that UCP-4 protects neurons against apoptosis by a mechanism involving suppression of oxyradical production and stabilization of cellular calcium homeostasis. The expression of UCP-4 is itself regulated by changes in energy metabolism. In addition to their roles in neuronal cell survival and death, MitoKATP channels and UCPs may play roles in regulating neuronal differentiation during development and synaptic plasticity in the adult. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NIA, Gerontol Res Ctr, Neurosci Lab, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Gerontol Res Ctr, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 111 TC 97 Z9 100 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 9 PY 2003 VL 304 IS 3 BP 539 EP 549 DI 10.1016/S0006-291X(03)00627-2 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 679GB UT WOS:000182911400014 PM 12729589 ER PT J AU Katz, JL Libby, TA Kopajtic, T Husbands, SM Newman, AH AF Katz, JL Libby, TA Kopajtic, T Husbands, SM Newman, AH TI Behavioral effects of rimcazole analogues alone and in combination with cocaine SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE rimcazole; dopamine; GBR 12909 ID SIGMA-RECEPTOR LIGANDS; CONDITIONED PLACE PREFERENCE; RATS DISCRIMINATING COCAINE; DOPAMINE UPTAKE; GBR-12909; ATTENUATE; MICE; TRANSPORTERS; INVOLVEMENT; DEPENDENCE AB Several sigma receptor ligands have been reported to also have affinity for the dopamine transporter, among them rimcazole (9-[3-(cis-3,5-dimethyl-1-piperazinyl)propyl]carbazole dihydrochloride). However, rimcazole lacks behavioral effects like those of other dopamine uptake inhibitors, such as cocaine and GBR 12909 (1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride). Because of this profile, the interactions with cocaine of rimcazole and several of its novel analogues were assessed. The compounds studied were rimcazole, its N-methyl analogue, SH 1-73 (9-[3-(cis-3,5-dimethyl-4-methyl-1-piperazinyl)-propyl]carbazole hydrobromide), the dibrominated analogue, SH 1-76 (3,6-dibromo-9-[3-(cis-3,5-dimethyl-1-piperazinyl)-propyl] carbazole hydrochloride), and the N-propylphenyl analogues, SH 3-24 ([3 -(cis-3,5-dimethyl-4- [3-phenylpropyl]-1-piperazinyl)-propyl] diphenylamine hydrochloride) and SH 3-28 (9-[3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]carbazole hydrobromide). The former has a diphenyl-amine group in place of the carbazole moiety of rimcazole, giving the compound additional structural similarity to GBR 12909. The rimcazole analogues produced dose-related decreases in locomotor activity, and also decreased cocaine-stimulated activity in mice. In rats trained to discriminate 10 mg/kg cocaine (i.p.) from saline injections, cocaine and GBR 12909 each produced a dose-related increase in cocaine-appropriate responding. Cocaine also increased rates of responding. SH 3-28 decreased cocaine-appropriate responding at the cocaine training dose to about 58% (SH 3 -28) with two of five subjects selecting the cocaine response key. Neither rimcazole nor SH 3 -24 produced a significant attenuation of the discriminative effects of cocaine. Rimcazole and its analogs all attenuated the increases in rates of responding produced by cocaine. In contrast to effects obtained with rimcazole analogs, GBR 12909 potentiated the cocaine-induced increases in locomotor activity and operant behavior, as well as the discriminative-stimulus effects of cocaine. The present results indicate that analogues of rimcazole can attenuate the behavioral effects of cocaine, and though the mechanism for these effects is not presently clear, it is possible that this attenuation maybe mediated by actions of the rimcazole analogues at the dopamine transporter and/or sigma receptors. (C) 2003 Elsevier Science B.V. All rights reserved. C1 NIDA, Psychobiol Sect, Medicat Discovery Res Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. NIDA, Med Chem Sect, Medicat Discovery Res Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Katz, JL (reprint author), NIDA, Psychobiol Sect, Medicat Discovery Res Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Husbands, Stephen/D-5926-2011; OI Katz, Jonathan/0000-0002-1068-1159; Husbands, Stephen/0000-0002-9928-6322 NR 32 TC 26 Z9 27 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD MAY 9 PY 2003 VL 468 IS 2 BP 109 EP 119 DI 10.1016/S0014-2999(03)01638-8 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 680EZ UT WOS:000182964500005 PM 12742518 ER PT J AU Ikeyama, S Wang, XT Li, J Podlutsky, A Martindale, JL Kokkonen, G van Huizen, R Gorospe, M Holbrook, NJ AF Ikeyama, S Wang, XT Li, J Podlutsky, A Martindale, JL Kokkonen, G van Huizen, R Gorospe, M Holbrook, NJ TI Expression of the pro-apoptotic gene gadd153/chop is elevated in liver with aging and sensitizes cells to oxidant injury SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED PROTEIN-KINASE; EXTENDED LIFE-SPAN; OXIDATIVE STRESS; CAENORHABDITIS-ELEGANS; ENDOPLASMIC-RETICULUM; CALORIC RESTRICTION; SIGNAL-TRANSDUCTION; HYDROGEN-PEROXIDE; CELLULAR-RESPONSE; GROWTH AB Aging is generally accompanied by reduced tolerance to oxidative stress and altered responsiveness to proliferative signals. We have shown that hepatocytes derived from aged rats (24-26 months) exhibit greater sensitivity to H2O2 treatment and reduced proliferation following epidermal growth factor (EGF) treatment than cells of young adult rats (5-6 months). Here we examined the effects of aging and calorie restriction (CR) on expression of the oxidative stress-inducible and pro-apoptotic gene gadd153 (chop) in these hepatocytes, and we investigated its influence on sensitivity to oxidants. We show that aging was associated with elevated expression of gadd153, both basally and in response to H2O2 treatment. CR, which attenuates age-associated declines in stress tolerance, prevented the age-related increase in gadd153 expression. EGF treatment also resulted in gadd153 induction in old cells. This effect was absent in young cells and in old cells of CR rats. gadd153 induction by EGF was reactive oxygen species-dependent and correlated with heightened sensitivity to subsequent H2O2 treatment, suggesting that elevated Gadd153 contributes to the greater sensitivity of EGF-pretreated old cells to oxidative stress. Additional support for this hypothesis was provided by experiments with Rat1 fibroblasts in which conditional expression of Gadd153 conferred increased sensitivity to H2O2. We propose a model whereby the diminished ability of old hepatocytes to overcome an EGF-triggered reactive oxygen species load leads to induction of the proapoptotic gene gadd153, which, in turn, sensitizes the cells to oxidant injury. Our findings point to gadd153 expression levels as an important factor in liver aging. C1 Yale Univ, Sch Med, Sect Geriatr, New Haven, CT 06520 USA. NIA, Biol Cellulaire & Mol Lab, IRP, Baltimore, MD 21224 USA. RP Holbrook, NJ (reprint author), Yale Univ, Sch Med, Sect Geriatr, Dept Internal Med, POB 208025, New Haven, CT 06511 USA. FU NIA NIH HHS [T30AG21342]; PHS HHS [T30-3489] NR 50 TC 46 Z9 49 U1 1 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 MAY 9 PY 2003 VL 278 IS 19 BP 16726 EP 16731 DI 10.1074/jbc.M300677200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 677QG UT WOS:000182818600038 PM 12609979 ER PT J AU Cisneros, FJ Wilson, R Travlos, G Anderson, LM Branch, S AF Cisneros, FJ Wilson, R Travlos, G Anderson, LM Branch, S TI Susceptibility to postnatal growth retardation induced by 5-AZA-2 '-deoxycytidine in utero: Gender specificity and correlation with reduced insulin-like growth factor 1 SO LIFE SCIENCES LA English DT Article DE 5-AZA-2 '-deoxycytidine; in utero exposure; growth retardation; reproduction; gender dimorphism ID FACTOR-I; DNA METHYLATION; GENE-EXPRESSION; TRANSGENIC MICE; SEX STEROIDS; HORMONE; 5-AZACYTIDINE; MOUSE; RAT; REPRODUCTION AB The DNA demethylating agent 5-AZA-2'-deoxyxytidine (5-AZA-CdR) alters gene expression in mice exposed during developmental stages and causes malformations and growth suppression. The aim of this study was to determine if 5-AZA-CdR-induced growth retardation is associated with alterations in energy metabolism or in serum IGF-1 levels.' Mice were exposed in utero to 5-AZA-CdR at gestation day 10. At postnatal day 21, exposed pups were weaned and body weights recorded. At 3 months of age, reproductive capacity was studied. At 5 months old, after body weight was recorded mice were killed and :serum :was collected to determine serum glucose, corticosterone, and IGF-1 levels. The body weights of both treated males and females were reduced at weaning compared with controls, but by 5 months of age, only the male body weight was affected. Reproductive capacity of males and females was reduced with males being more affected. Levels of corticosterone and glucose were not altered. Serum IGF-1 levels were lower in males exposed in utero to 5-AZA-CdR when compared to controls, but not in females, and correlated significantly with body weights. Our data suggest that the decreased levels of IGF-1 associated with the treatment could be the cause of the observed growth retardation in the in utero-exposed mice. A gender dimorphic effect, where males are more affected, is evident. (C) 2003 Elsevier Science Inc. All rights reserved. C1 N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA. NIEHS, Res Triangle Pk, NC 27709 USA. NCI, Comparat Carcinogenesis Lab, Ft Detrick, MD 21702 USA. RP Branch, S (reprint author), N Carolina State Univ, Dept Environm & Mol Toxicol, 850 Main Campus Dr, Raleigh, NC 27695 USA. RI Matthews Branch, Stacy/E-6200-2017 OI Matthews Branch, Stacy/0000-0002-1048-6097 FU NIEHS NIH HHS [ES 08452] NR 24 TC 7 Z9 7 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD MAY 9 PY 2003 VL 72 IS 25 BP 2887 EP 2894 DI 10.1016/S0024-3205(03)00229-7 PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 671LX UT WOS:000182467200007 PM 12697271 ER PT J AU Zerhouni, E AF Zerhouni, E TI Embryonic stem cells - Stem cell programs SO SCIENCE LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Zerhouni, E (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 4 Z9 4 U1 0 U2 1 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 MAY 9 PY 2003 VL 300 IS 5621 BP 911 EP 912 DI 10.1126/science.1084819 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 675WD UT WOS:000182719800032 PM 12738840 ER PT J AU Priola, SA Chesebro, B Caughey, B AF Priola, SA Chesebro, B Caughey, B TI A view from the top - Prion diseases from 10,000 feet SO SCIENCE LA English DT Editorial Material C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. RP Priola, SA (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. NR 2 TC 20 Z9 20 U1 1 U2 6 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 MAY 9 PY 2003 VL 300 IS 5621 BP 917 EP + DI 10.1126/science.1085920 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 675WD UT WOS:000182719800035 PM 12738843 ER PT J AU Jeong, MR Hashimoto, R Senatorov, VV Fujimaki, K Ren, M Lee, MS Chuang, DM AF Jeong, MR Hashimoto, R Senatorov, VV Fujimaki, K Ren, M Lee, MS Chuang, DM TI Valproic acid, a mood stabilizer and anticonvulsant, protects rat cerebral cortical neurons from spontaneous cell death: a role of histone deacetylase inhibition SO FEBS LETTERS LA English DT Article DE valproate; neuroprotection; cerebral cortical neuron; historic deacetylase; bipolar mood disorder; lithium ID LIFE-SPAN; LITHIUM AB We studied the neuroprotective effects of valproic acid (VPA), a primary mood stabilizer and anticonvulsant, in cultured rat cerebral cortical neurons (CCNs). CCNs underwent spontaneous cell death when their age increased in culture. As shown by mitochondrial activity and calcein-AM assays, treatment of CCNs with VPA starting from day 9 in vitro markedly increased viability and prolonged the life span of the cultures. The neuroprotective action of VPA was time-dependent and occurred at therapeutic levels with a maximal effect at about 0.5 mM. LiCl (1 mM) also protected CCNs from aging-induced, spontaneous cell death but less effectively. VPA-induced neuroprotection in aging CCN cultures was associated with a robust increase in histone H3 acetylation levels and the protective effect was mimicked by treatment with a histone deacetylase inhibitor, trichostatin A, but not by VPA analogs which are inactive in blocking histone deacetylase. Our results suggest a role of histone deacetylase inhibition in mediating the neuroprotective action of VPA. (C) 2003 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies. C1 Natl Inst Mental Hlth, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. Korea Univ, Coll Med, Dept Psychiat, Seoul 136701, South Korea. RP Chuang, DM (reprint author), Natl Inst Mental Hlth, Mol Neurobiol Sect, NIH, Bldg 10,Rm 4C-206,10 Ctr Dr MSC 1363, Bethesda, MD 20892 USA. RI Hashimoto, Ryota/P-8572-2014 OI Hashimoto, Ryota/0000-0002-5941-4238 NR 19 TC 99 Z9 109 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD MAY 8 PY 2003 VL 542 IS 1-3 BP 74 EP 78 DI 10.1016/S0014-5793(03)00350-8 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 677FK UT WOS:000182796100015 PM 12729901 ER PT J AU Kickhoefer, VA Emre, N Stephen, AG Poderycki, MJ Rome, LH AF Kickhoefer, VA Emre, N Stephen, AG Poderycki, MJ Rome, LH TI Identification of conserved vault RNA expression elements and a non-expressed mouse vault RNA gene SO GENE LA English DT Article DE vault RNA; vertebrates; TATA box ID POLYMERASE-III; PARTICLES; TRANSCRIPTION; PROMOTER; BINDING; CONTAIN; RAT AB Vault RNA (vRNA) genes have been cloned from several vertebrates including rat, mouse, and humans. Their copy numbers vary, as does the length of the encoded RNA. We have determined that the mouse genome contains two vRNA genes; one is expressed the other is a pseudogene. In vitro transcription of the rat vRNA gene by RNA polymerase III has previously been shown to be dependent on a combination of both external and internal promoter sequence elements. By comparing the upstream regions of the vertebrate vRNA genes, a 25 bp conserved sequence and a TATA box can be identified. Furthermore, the unique arrangement of the internal promoter boxes (one A and two B boxes) is conserved in the expressed human vRNA genes even though a new RNA polymerase III termination sequence has evolved between the two B boxes. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Univ Calif Los Angeles, David Geffen Sch Med, Dept Biol Chem, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Frederick, MD 21702 USA. RP Kickhoefer, VA (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Biol Chem, 10833 Le Conte Ave,33-131 CHS Mail Code 173717, Los Angeles, CA 90095 USA. RI Rome, Leonard/E-8786-2016; OI Rome, Leonard/0000-0002-1236-2063; Kickhoefer, Valerie/0000-0002-0048-0580 NR 15 TC 18 Z9 18 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD MAY 8 PY 2003 VL 309 IS 2 BP 65 EP 70 DI 10.1016/S0378-1119(03)00507-9 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 686HD UT WOS:000183314600001 PM 12758122 ER PT J AU Galaviz-Hernandez, C Stagg, C de Ridder, G Tanaka, TS Ko, MSH Schlessinger, D Nagaraja, R AF Galaviz-Hernandez, C Stagg, C de Ridder, G Tanaka, TS Ko, MSH Schlessinger, D Nagaraja, R TI Plac8 and Plac9, novel placental-enriched genes identified through microarray analysis SO GENE LA English DT Article DE expression; trophoblast; spongiotrophoblast; transcription ID TRANSCRIPTION FACTOR; TROPHOBLAST CELLS; FINGER PROTEIN; MOUSE; EXPRESSION; CDNA; REVEALS; GENOME; HYBRIDIZATION; CHROMOSOME AB Microarray expression profiling of a collection of 15,000 mouse genes with placental and embryonic RNAs revealed candidates for placental-enriched genes, three of which we have confirmed and further characterized. One, Plac1, strongly expressed in all trophoblastderived cells in the placenta, has been described earlier (Genomics 68 (2000) 305). Here we report that of the other two, Plac8 expression is restricted to the spongiotrophoblast layer during development, whereas Plac9 is weakly expressed though highly enriched in placenta. For both, cDNAs with complete open reading frames were recovered and exon-intron structures inferred from comparisons of mouse cDNA and Genomic sequence. The predicted proteins (112 and 108 amino acids) both contain putative signal peptides, with a coiled-coil segment of mPLAC9 as the only other detected motif. Genomic sequence comparisons reveal that in addition to an apparent pseudogene on chromosome 1, Plac8 is expressed at mouse cytoband 5e3. It is tightly conserved in human in a syntenically equivalent ortholog at 4q21.23. Plac9 is present in a single copy on chromosome 14, with a syntenically equivalent human ortholog at 10q22.3. Putative promoter regions up to 10 kb 5' of the transcription units for Plac1, Plac8, and Plac9 contain sites for widely-expressed transcription factors which, by analogy to other instances, may be sufficient to explain placental enrichment. (C) 2003 Elsevier Science B.V. All rights reserved. C1 NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Nagaraja, R (reprint author), NIA, Genet Lab, NIH, Sutie 3000,333 Cassell Dr, Baltimore, MD 21224 USA. RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 NR 30 TC 47 Z9 47 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD MAY 8 PY 2003 VL 309 IS 2 BP 81 EP 89 DI 10.1016/S0378-1119(03)00508-0 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 686HD UT WOS:000183314600003 PM 12758124 ER PT J AU Chan, JCC Tycko, R AF Chan, JCC Tycko, R TI Recoupling of chemical shift anisotropies in solid-state NMR under high-speed magic-angle spinning and in uniformly C-13-labeled systems SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; SHIELDING TENSORS; ROTATING SOLIDS; POWDER PATTERNS; PULSE SEQUENCE; ROTARY RESONANCE; AMINO-ACIDS; PEPTIDES; ALANINE; SPECTROSCOPY AB We demonstrate the possibility of recoupling chemical shift anisotropy (CSA) interactions in solid-state nuclear magnetic resonance (NMR) under high-speed magic-angle spinning (MAS) while retaining a static CSA powder pattern line shape and simultaneously attenuating homonuclear dipole-dipole interactions. CSA recoupling is accomplished by a rotation-synchronized radio-frequency pulse sequence with symmetry properties that permit static CSA line shapes to be obtained. We suggest a specific recoupling sequence, which we call ROCSA, for which the scaling factors for CSA and homonuclear dipole-dipole interactions are 0.272 and approximately 0.05, respectively. This sequence is suitable for high-speed C-13 MAS NMR experiments on uniformly C-13-labeled organic compounds, including biopolymers. We demonstrate the ROCSA sequence experimentally by measuring the C-13 CSA patterns of the uniformly labeled, polycrystalline compounds L-alanine and N-acetyl-D,L-valine at MAS frequencies of 11 and 20 kHz. We also present experimental data for amyloid fibrils formed by a 15-residue fragment of the beta-amyloid peptide associated with Alzheimer's disease, in which four amino acid residues are uniformly labeled, demonstrating the applicability to biochemical systems of high molecular weight and significant complexity. Analysis of the CSA patterns in the amyloid fibril sample demonstrates the utility of ROCSA measurements as probes of peptide and protein conformation in noncrystalline solids. (C) 2003 American Institute of Physics. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RI Chan, Jerry/F-8075-2010 OI Chan, Jerry/0000-0002-5108-4166 NR 42 TC 76 Z9 77 U1 2 U2 43 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD MAY 8 PY 2003 VL 118 IS 18 BP 8378 EP 8389 DI 10.1063/1.1565109 PG 12 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 671FF UT WOS:000182454100033 ER PT J AU Smith, MBK Hose, BM Hawkins, A Lipchock, J Farnsworth, DW Rizzo, RC Tirado-Rives, J Arnold, E Zhang, W Hughes, SH Jorgensen, WL Michejda, CJ Smith, RH AF Smith, MBK Hose, BM Hawkins, A Lipchock, J Farnsworth, DW Rizzo, RC Tirado-Rives, J Arnold, E Zhang, W Hughes, SH Jorgensen, WL Michejda, CJ Smith, RH TI Molecular modeling calculations of HIV-1 reverse transcriptase nonnucleoside inhibitors: Correlation of binding energy with biological activity for novel 2-aryl-substituted benzimidazole analogues SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MONTE-CARLO SIMULATIONS; LINEAR-RESPONSE METHOD; PREDICTION; AFFINITIES; REPLICATION; HYDRATION; SOLVATION; PROTEIN; WATER; TIBO AB The energies and physical descriptors for the binding of 20 novel 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole analogues (BPBIs) to HIV-1 reverse transcriptase (RT) have been determined using Monte Carlo (MC) simulations. The crystallographic structure of the lead compound, 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methylbenzimidazole, was used as a starting point to model the inhibitors in both the bound and the unbound states. The energy terms and physical descriptors obtained from the calculations were correlated with their respective experimental EC50 values, resulting in an r(2) value of 0.70 and a root-mean-square deviation (rms) of 0.53 kcal/mol. The terms in the correlation include the change in total Coulombic energy and solvent-accessible surface area. Structural analysis of the data files from the BPBI calculations reveals that all of the analogues with good biological activity show the formation of a hydrogen bond between the ligand and the backbone nitrogen atom of lysine 103. By use of the structural results, two novel BPBI inhibitors have been designed and calculations have been carried out. The results show the formation of the desired hydrogen bonds, and the DeltaG(binding) values predict the compounds to be excellent RT inhibitors. Subsequent synthesis and biological activity testing of these analogues have shown the validity of the predictive calculations. If the BPBIs are modeled in a site constructed from the crystal coordinates of a member of another class of nonnucleoside inhibitors (the 4,5,6,7-tetrahydroimidazo[4,5, 1-jk] [1,4]benzodiazepine-2(1H)-thione. and -one (TIBO) compounds), the correlation with the same terms drops slightly, giving an r(2) value of 0.61 with an associated root-mean-square value of 0.53 kcal/mol. Conversely, if the TIBO compounds are modeled in a site constructed from the BPBI complex crystal coordinates, a correlation can be obtained using the drug-protein interaction energy and change in the total number of hydrogen bonds, giving an r(2) value of 0.63. These are the same descriptors that were used for the TIBO compounds modeled in their own sites, where the r(2) value was 0.72. These data suggest that it may be possible, in some cases, to design novel inhibitors utilizing structural data from related, but not identical, inhibitors. C1 NCI, Frederick, MD 21702 USA. McDaniel Coll, Dept Chem, Westminster, MD 21157 USA. Yale Univ, Dept Chem, New Haven, CT 06520 USA. Rutgers State Univ, CABM, Piscataway, NJ 08854 USA. Rutgers State Univ, Dept Chem, Piscataway, NJ 08854 USA. RP Smith, MBK (reprint author), NCI, Frederick, MD 21702 USA. RI Tirado-Rives, Julian/A-4992-2012 OI Tirado-Rives, Julian/0000-0001-7330-189X NR 29 TC 28 Z9 31 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 MAY 8 PY 2003 VL 46 IS 10 BP 1940 EP 1947 DI 10.1021/jm020271f PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 675RM UT WOS:000182709200017 ER PT J AU Bansal, D Miyake, K Vogel, SS Groh, S Chen, CC Williamson, R McNeil, PL Campbell, KP AF Bansal, D Miyake, K Vogel, SS Groh, S Chen, CC Williamson, R McNeil, PL Campbell, KP TI Defective membrane repair in dysferlin-deficient muscular dystrophy SO NATURE LA English DT Article ID SKELETAL-MUSCLE; MIYOSHI MYOPATHY; DISRUPTION; GENE; EXPRESSION; EXOCYTOSIS; COMPLEX; ACCUMULATION; MECHANISM; PROTEINS AB Muscular dystrophy includes a diverse group of inherited muscle diseases characterized by wasting and weakness of skeletal muscle(1). Mutations in dysferlin are linked to two clinically distinct muscle diseases, limb-girdle muscular dystrophy type 2B and Miyoshi myopathy, but the mechanism that leads to muscle degeneration is unknown(2,3). Dysferlin is a homologue of the Caenorhabditis elegans fer-1 gene, which mediates vesicle fusion to the plasma membrane in spermatids(4). Here we show that dysferlin-null mice maintain a functional dystrophin glycoprotein complex but nevertheless develop a progressive muscular dystrophy. In normal muscle, membrane patches enriched in dysferlin can be detected in response to sarcolemma injuries. In contrast, there are sub-sarcolemmal accumulations of vesicles in dysferlin-null muscle. Membrane repair assays with a two-photon laser-scanning microscope demonstrated that wildtype muscle fibres efficiently reseal their sarcolemma in the presence of Ca2+. Interestingly, dysferlin-deficient muscle fibres are defective in Ca2+-dependent sarcolemma resealing. Membrane repair is therefore an active process in skeletal muscle fibres, and dysferlin has an essential role in this process. Our findings show that disruption of the muscle membrane repair machinery is responsible for dysferlin-deficient muscle degeneration, and highlight the importance of this basic cellular mechanism of membrane resealing in human disease. C1 Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Physiol & Biophys, Howard Hughes Med Inst, Iowa City, IA 52242 USA. Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Neurol, Iowa City, IA 52242 USA. Med Coll Georgia, Dept Cellular Biol & Anat, Augusta, GA 30912 USA. NIAAA, Lab Mol Physiol, NIH, Rockville, MD 20852 USA. Univ Iowa, Coll Med, Dept Obstet & Gynecol, Iowa City, IA 52242 USA. RP Campbell, KP (reprint author), Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Physiol & Biophys, Howard Hughes Med Inst, Iowa City, IA 52242 USA. RI Vogel, Steven/A-3585-2012; Chen, Chien-Chang/D-2023-2015; OI Vogel, Steven/0000-0002-3005-2667 NR 27 TC 485 Z9 499 U1 4 U2 35 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAY 8 PY 2003 VL 423 IS 6936 BP 168 EP 172 DI 10.1038/nature01573 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 675MR UT WOS:000182699600046 PM 12736685 ER PT J AU Montcouquiol, M Rachel, RA Lanford, PJ Copeland, NG Jenkins, NA Kelley, MW AF Montcouquiol, M Rachel, RA Lanford, PJ Copeland, NG Jenkins, NA Kelley, MW TI Identification of Vangl2 and Scrb1 as planar polarity genes in mammals SO NATURE LA English DT Article ID NEURAL-TUBE DEFECTS; DROSOPHILA TISSUE POLARITY; LOOP-TAIL; CELL-DEVELOPMENT; INNER-EAR; MOUSE; STRABISMUS; MUTATION; MUTANT; LOCALIZATION AB In mammals, an example of planar cell polarity (PCP) is the uniform orientation of the hair cell stereociliary bundles within the cochlea. The PCP pathway of Drosophila(1-4) refers to a conserved signalling pathway that regulates the coordinated orientation of cells or structures within the plane of an epithelium. Here we show that a mutation in Vangl2, a mammalian homologue of the Drosophila PCP gene Strabismus/Van Gogh, results in significant disruptions in the polarization of stereociliary bundles in mouse cochlea as a result of defects in the direction of movement and/or anchoring of the kinocilium within each hair cell. Similar, but less severe, defects are observed in animals containing a mutation in the LAP protein family gene Scrb1 (homologous with Drosophila scribble). Polarization defects in animals heterozygous for Vangl2 and Scrb1 are comparable with Vangl2 homozygotes, demonstrating genetic interactions between these genes in the regulation of PCP in mammals. These results demonstrate a role for the PCP pathway in planar polarization in mammals, and identify Scrb1 as a PCP gene. C1 NIDCD, Sect Dev Neurosci, NIH, Rockville, MD 20850 USA. NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. Univ Maryland, College Pk, MD 20742 USA. RP Montcouquiol, M (reprint author), NIDCD, Sect Dev Neurosci, NIH, Rockville, MD 20850 USA. OI montcouquiol, mireille/0000-0001-8739-6519 NR 25 TC 424 Z9 433 U1 1 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAY 8 PY 2003 VL 423 IS 6936 BP 173 EP 177 DI 10.1038/nature01618 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 675MR UT WOS:000182699600047 PM 12724779 ER PT J AU Sarabi, A Chang, CF Wang, Y Tomac, AC Hoffer, BJ Morales, M AF Sarabi, A Chang, CF Wang, Y Tomac, AC Hoffer, BJ Morales, M TI Differential expression of the cell line-derived neurotrophic factor (GDNF) receptor GFR alpha 1 in heterozygous Gfr alpha 1 null-mutant mice after stroke SO NEUROSCIENCE LETTERS LA English DT Article DE neurotrophic factors; cell line-derived neurotrophic factor (GDNF); GDNF-receptor alpha-1; neuroprotection; ischemia ID FACTOR PROTECTS; RAT-BRAIN; CORTICAL INFARCTION; TOPICAL APPLICATION; IN-VIVO; C-RET; ISCHEMIA; NEURONS; INJURY; OCCLUSION AB Exogenous administration of glial cell line-derived neurotrophic factor (GDNF) reduces ischemia-induced cerebral infarction. Cerebral ischemia induces gene expression of GDNF, GDNF-receptor alpha-1 (GFRalpha-1) and c-Ret, suggesting that a GDNF signaling cascade mechanism may be involved in endogenous neuroprotection during ischemia. In the present study, we examined if this endogenous neuroprotective pathway was altered in Gfralpha-1 deficient mice. Since mice homozygous for the Gfralpha-1 deletion (-/-) die within 24 h of birth, stroke-induced changes in the levels of Gfralpha-1 mRNA were studied in Gfralpha-1 heterozygous (+/-) mice and their wild-type (+/+) littermates. The right middle cerebral artery was transiently ligated for 45 min in anesthetized mice. Animals were killed at 0, 6, 12 and 24 h after the onset of reperfusion and levels of Gfralpha-1 mRNA were measured by in situ hybridization histochemistry. Previously, we showed that Gfralpha-1 (+/-) mice are more vulnerable to focal cerebral ischemia. In the present study, we found that basal levels of GFRalpha-1 mRNA were at similar low levels in cortex and striatum in adult Gfralpha-1 (+/+) and Gfralpha-1 (+/-) mice and that ischemia/reperfusion induced upregulation of Gfralpha-1 mRNA in the lesioned and contralateral sides of cortex and striatum in both Gfralpha-1 (+/+) and GFRalpha-1 (+/-) mice. However, the ischemia/reperfusion induction of Gfralpha-1 mRNA was significantly higher in the cortex of wild type mice, as compared to Gfralpha-1 (+/-) mice. Moreover, the increased expression of Gfralpha-1 in striatum after reperfusion occurred earlier in the GFRalpha-1 (+/+) than in the Gfralpha-1 mice. These results indicate that after ischemia, there is a differential up-regulation of Gfralpha-1 expression in Gfralpha-1 (+/+) and Gfralpha-1 mice. Since GDNF has neuroprotective effects, the reduced up-regulation of Gfralpha-1 in Gfralpha-1 (+/-) mice at early time points after ischemia suggests that the responsiveness to GDNF and GDNF receptor mediated neuroprotection is attenuated in these genetically modified animals and may underlie their greater vulnerability. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved. C1 NIDA, IRP Dept, Cellular Neurophysiol Sect, NIH, Baltimore, MD 21224 USA. RP Hoffer, BJ (reprint author), NIDA, IRP Dept, Cellular Neurophysiol Sect, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 26 TC 13 Z9 13 U1 0 U2 0 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 MAY 8 PY 2003 VL 341 IS 3 BP 241 EP 245 DI 10.1016/S0304-3940(03)00195-2 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 669HW UT WOS:000182346700018 PM 12697293 ER PT J AU Kinoshita, I Leaner, V Katabami, M Manzano, RG Dent, P Sabichi, A Birrer, MJ AF Kinoshita, I Leaner, V Katabami, M Manzano, RG Dent, P Sabichi, A Birrer, MJ TI Identification of cJun-responsive genes in Rat-1a cells using multiple techniques: increased expression of stathmin is necessary for cJun-mediated anchorage-independent growth SO ONCOGENE LA English DT Article DE c-jun; transformation; microarray; AP-1 ID LEUKOCYTE INTEGRIN GENE; V-JUN; C-JUN; TRANSCRIPTION FACTOR; TISSUE INHIBITOR; CANCER-CELLS; PHOSPHOPROTEIN STATHMIN; SIGNAL TRANSDUCTION; GALECTIN-3 GENE; DOWN-REGULATION AB cJun is a major component of the transcription factor AP-1 and mediates a diverse set of biologic properties including proliferation, differentiation, and apoptosis. To identify cJun-responsive genes, we inducibly expressed cJun in Rat-1a cells and observed two distinct phenotypes: changes in cellular morphology with adherent growth and anchorage-independent growth. The biologic effects of cJun were entirely reversible demonstrating that they require the continued presence of cJun. To determine the genes, which mediate the biologic effects of cJun, we employed multiple methods including differential gene analysis, suppression subtractive hybridization, and cDNA microarrays. We identified 38 cJun-responsive genes including three uncharacterized genes under adherent and/or nonadherent conditions. Half of the known 36 genes were cytoskeleton- and adhesion-related genes, suggesting a major role of cJun in the regulation of the genes related to cell morphology. As proof of the principle that this approach could identify genes whose upregulation was necessary for nonadherent growth, we investigated one gene, stathmin whose upregulation by cJun was observed only under these conditions. Although overexpression of stathmin did not result in nonadherent growth, inhibition of stathmin protein expression by antisense oligonucleotides in cJun-induced Rat-1a cells prevented nonadherent growth. These results suggest that stathmin plays an essential role in anchorage-independent growth by cJun and may be a potential target for specific inhibitors for AP-1-dependent processes involved in carcinogenesis. C1 NCI, Cell & Canc Biol Dept, Ctr Canc Res, Rockville, MD 20850 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Radiat Oncol, Richmond, VA 23298 USA. RP Birrer, MJ (reprint author), NCI, Cell & Canc Biol Dept, Ctr Canc Res, Rockville, MD 20850 USA. NR 94 TC 30 Z9 33 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 8 PY 2003 VL 22 IS 18 BP 2710 EP 2722 DI 10.1038/sj.onc.1206371 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 673FJ UT WOS:000182569300002 PM 12743595 ER PT J AU Bianco, R Shin, I Ritter, CA Yakes, FM Basso, A Rosen, N Tsurutani, J Dennis, PA Mills, GB Arteaga, CL AF Bianco, R Shin, I Ritter, CA Yakes, FM Basso, A Rosen, N Tsurutani, J Dennis, PA Mills, GB Arteaga, CL TI Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors SO ONCOGENE LA English DT Article DE epidermal growth factor receptor; ZD1839; PTEN; tyrosine kinase inhibitors; Akt ID GROWTH-FACTOR RECEPTOR; BREAST-CANCER-CELLS; HUMAN GLIOBLASTOMA CELLS; ERBB SIGNALING NETWORK; PHOSPHATIDYLINOSITOL 3-KINASE; ZD1839 IRESSA; REGULATED KINASES; CELLULAR-SURVIVAL; CYCLE PROGRESSION; UP-REGULATION AB We have examined the possible mechanisms of resistance to the epidermal growth factor receptor (EGFR) inhibitors in tumor cells with variable levels of EGFR. ZD1839 (Iressa) is a small-molecular-weight, ATP-mimetic that specifically inhibits the EGFR tyrosine kinase. A431 cell growth was markedly inhibited by ZD1839 (IC(50)less than or equal to0.1 muM) whereas the MDA-468 cells were relatively resistant (IC50>2 muM). Low doses of ZD1839 delayed cell cycle progression and induced apoptosis in A431 cells but not in MDA-468 cells. In both cell tines, 0.1 muM ZD1839 eliminated EGFR phosphorylation. However, the basal activity of the phosphatidytinositol-3 kinase (PI3 K) target Akt was eliminated in A431 but not in MDA-468 cells, implying that their Akt activity is independent of EGFR signals. A431 cells express PTEN/MMAC1/TEP, a phosphatase that can dephosphorylate position D3 of phosphatidytinositol-3,4,5 trisphosphate, the site that recruits the plecstrin-homology domain of Akt to the cell membrane. On the contrary, MDA-468 cells lack the phosphatase and tensin homolog (PTEN), potentially setting Akt activity at a high threshold that is unresponsive to EGFR inhibition alone. Therefore, we reintroduced (PTEN) by retroviral infection in MDA-468 cells. In MDA-468/PTEN but not in vector controls, treatment with ZD1839 inhibited P-Akt levels, induced relocalization of the Forkbead factor FKHRL1 to the cell nucleus, and increased FKHRL1-dependent transcriptional activity. ZD1839 induced a greater degree of apoptosis and cell cycle delay in PTEN-reconstituted than in control cells. These data suggest that loss of PTEN, by permitting a high level of Akt activity independent of receptor tyrosine kinase inputs, can temporally dissociate the inhibition of the EGFR with that of Akt induced by EGFR inhibitors. Thus, in EGFR-expressing tumor cells with concomitant amplification(s) of PI3K-Akt signaling, combined blockade of the EGFR tyrosine kinase and Akt should be considered as a therapeutic approach. C1 Vanderbilt Univ, Sch Med, Dept Med, Div Oncol, Nashville, TN 37232 USA. Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Cell Biol & Genet, New York, NY 10021 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Mol Therapeut, Houston, TX 77030 USA. Vanderbilt Univ, Sch Med, Dept Canc Biol, Nashville, TN 37212 USA. Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. RP Arteaga, CL (reprint author), Vanderbilt Univ, Sch Med, Dept Med, Div Oncol, 2220 Pierce Ave,777 Preston Res Bldg, Nashville, TN 37232 USA. FU NCI NIH HHS [R01 CA80195, CA68485] NR 59 TC 336 Z9 357 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 8 PY 2003 VL 22 IS 18 BP 2812 EP 2822 DI 10.1038/sj.onc.1206388 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 673FJ UT WOS:000182569300012 PM 12743604 ER PT J AU Kovalchuk, AL Kim, JS Janz, S AF Kovalchuk, AL Kim, JS Janz, S TI E mu/S mu transposition into Myc is sometimes a precursor for T(12;15) translocation in mouse B cells SO ONCOGENE LA English DT Article DE genetic transposition; immunoglobulin heavy-chain locus; intronic heavy-chain enhancer; immunoglobulin switch region; chromosomal translocation ID CLASS-SWITCH RECOMBINATION; HEAVY-CHAIN GENE; VISIBLE CHROMOSOMAL TRANSLOCATIONS; C-MYC; MURINE PLASMACYTOMA; MULTIPLE-MYELOMA; ABERRANT REARRANGEMENT; IMMUNOGLOBULIN; REGION; ENHANCER AB Misguided immunoglobulin (Ig) class switch recombination (CSR) has been implicated in the origin of Myc-activating chromosomal translocations, T(12;15), in BALB/c mouse plasmacytomas (PCTs). CSR has also been involved in the progression of T(12;15); for example, the approximation of Myc to the 3'-Calpha enhancer. This study provides evidence for an additional mechanism by which aberrant CSR may facilitate T(12;15): transposition of Ig heavy-chain (IgH) sequences to Myc. Five IgH transposons containing the intronic heavy-chain enhancer, Emu, and a truncated switch mu region, Smu, were found in the first intron of Myc in lymph node cells of IL-6 transgenic BALB/c mice. In two cases Emu/Smu transposition primed Myc to get involved in apparent trans-chromosomal CSR to Cgamma1, presumably leading to T(12;15). Translocations preceded by Emu/Smu transposition can sometimes be distinguished from de novo translocations by molecular fingerprints in translocation breakpoint regions (Ig switch region [S] inversions and unusual gene orders in composite S regions). The presence of such fingerprints in some PCTs suggests that the tumors sometimes evolve from transposition-bearing precursors. We propose that Emu/Smu transposition to Myc may facilitate plasmacytomagenesis by sensitizing Myc to undergo T(12;15) translocation. T(12;15), in turn, juxtaposes Myc to the 3'-Calpha enhancer, which appears to be required for deregulating Myc in a manner that is conducive to PCT development. C1 NCI, Genet Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Janz, S (reprint author), NCI, Genet Lab, Ctr Canc Res, NIH, Bldg 37,Room 2B10, Bethesda, MD 20892 USA. NR 53 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 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 8 PY 2003 VL 22 IS 18 BP 2842 EP 2850 DI 10.1038/sj.onc.1206345 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 673FJ UT WOS:000182569300015 PM 12743607 ER PT J AU Colevas, AD Brown, JM Hahn, S Mitchell, J Camphausen, K Coleman, CN AF Colevas, AD Brown, JM Hahn, S Mitchell, J Camphausen, K Coleman, CN TI Development of investigational radiation modifiers SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID I CLINICAL-TRIALS; CONCURRENT CHEMOTHERAPY; CLONOGENIC SURVIVAL; INDUCED APOPTOSIS; PELVIC RADIATION; TUMOR-CELLS; CANCER; CARCINOMA; THERAPY; CISPLATIN C1 NCI, Invest Drug Branch, CTEP, Bethesda, MD 20892 USA. Stanford Univ, Stanford, CA 94305 USA. Univ Penn, Philadelphia, PA 19104 USA. RP Colevas, AD (reprint author), NCI, Invest Drug Branch, CTEP, 6130 Execut Blvd,EPN 7124, Bethesda, MD 20892 USA. OI Dicker, Adam/0000-0003-0733-3337 NR 29 TC 18 Z9 18 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 MAY 7 PY 2003 VL 95 IS 9 BP 646 EP 651 PG 6 WC Oncology SC Oncology GA 675BH UT WOS:000182672800007 PM 12734315 ER PT J AU Mariotto, A Feuer, EJ Abrams, J AF Mariotto, A Feuer, EJ Abrams, J TI Re: Trends in use of adjuvant multi-agent chemotherapy and tamoxifen for breast cancer in the United States: 1975-1999 - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 NCI, Canc Surveillance Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diagnosis, NIH, Bethesda, MD 20892 USA. RP Mariotto, A (reprint author), NCI, Canc Surveillance Res Program, Div Canc Control & Populat Sci, NIH, 6166 Execut Blvd,Suite 504,MSC 8317, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 7 PY 2003 VL 95 IS 9 BP 684 EP 685 PG 2 WC Oncology SC Oncology GA 675BH UT WOS:000182672800014 ER PT J AU Strickler, HD Goedert, JJ Devesa, SS Rosenberg, PS AF Strickler, HD Goedert, JJ Devesa, SS Rosenberg, PS TI Re: Trends in US pleural mesothelioma incidence rates following simian virus 40 contamination of early poliovirus vaccines - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 Albert Einstein Coll Med, Dept Epidemiol & Social Med, Bronx, NY 10461 USA. NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Strickler, HD (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Social Med, 1300 Morris Pk Ave,Belfer 1308, Bronx, NY 10461 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 7 PY 2003 VL 95 IS 9 BP 689 EP 689 PG 1 WC Oncology SC Oncology GA 675BH UT WOS:000182672800019 ER PT J AU Kumar, S Tsai, CJ Nussinov, R AF Kumar, S Tsai, CJ Nussinov, R TI Temperature range of thermodynamic stability for the native state of reversible two-state proteins SO BIOCHEMISTRY LA English DT Article ID HYDROPHOBIC FOLDING UNITS; CONFORMATIONAL STABILITY; COLD DENATURATION; GLUTAMATE-DEHYDROGENASE; LINEAR EXTRAPOLATION; THERMOTOGA-MARITIMA; THERMAL-STABILITY; DOMAIN SIZE; BINDING; THERMOSTABILITY AB The difference between the heat (T-G) and the cold (T-G') denaturation temperatures defines the temperature range (T-Range) over which the native state of a reversible two-state protein is thermodynamically stable. We have performed a correlation analysis for thermodynamic parameters in a selected data set of structurally nonhomologous single-domain reversible two-state proteins. We find that the temperature range is negatively correlated with the protein size and with the heat capacity change (DeltaC(p)) but is positively correlated with the maximal protein stability [DeltaG(T-S)]. The correlation between the temperature range and maximal protein stability becomes highly significant upon normalization of the maximal protein stability with protein size. The melting temperature (T-G) also shows a negative correlation with protein size. Consistently, T-G and T-G' show opposite correlations with DeltaC(p), indicating a dependence of the T-Range on the curvature of the protein stability curve. Substitution of proteins in our data set with their homologues and arbitrary addition or removal of a protein in the data set do not affect the outcome of our analysis. Simulations of the thermodynamic data further indicate that T-Range is more sensitive to variations in curvature than to the slope of the protein stability curve. The hydrophobic effect in single domains is the principal reason for these observations. Our results imply that larger proteins may be stable over narrower temperature ranges and that smaller proteins may have higher melting temperatures, suggesting why protein structures often differentiate into multiple substructures with different hydrophobic cores. Our results have interesting implications for protein thermostability. C1 NCI FCRF, Ft Detrick, MD 21702 USA. SAIC Frederick Inc, Basic Res Program, Ft Detrick, MD 21702 USA. Natl Canc Inst Frederick, Lab Expt & Computat Biol, Ft Detrick, MD 21702 USA. Tel Aviv Univ, Sackler Fac Med, Dept Human Genet Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI FCRF, Bldg 469,Rm 151, Ft Detrick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400] NR 54 TC 32 Z9 33 U1 1 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 MAY 6 PY 2003 VL 42 IS 17 BP 4864 EP 4873 DI 10.1021/bi027184+ PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 674DL UT WOS:000182621700012 PM 12718527 ER PT J AU Binz, AK Rodriguez, RC Biddison, WE Baker, BM AF Binz, AK Rodriguez, RC Biddison, WE Baker, BM TI Thermodynamic and kinetic analysis of a peptide-class I MHC interaction highlights the noncovalent nature and conformational dynamics of the class I heterotrimer SO BIOCHEMISTRY LA English DT Article ID LEUKOCYTE ANTIGEN (HLA)-A2; T-CELL RECEPTORS; CRYSTAL-STRUCTURES; VIRAL PEPTIDES; BINDING; COMPLEX; EMPTY; STABILITY; MOLECULES; TAX AB The class I major histocompatibility (MHC) molecule is a heterotrimer composed of a heavy chain, the small subunit beta(2)-microglobulin (beta(2)m), and a peptide. Fluorescence anisotropy has been used to assay the interaction of a labeled peptide with a recombinant, soluble form of the class I MHC HLA-A2. Consistent with earlier work, peptide binding is shown to be a two-step process limited by a conformational rearrangement in the heavy. chain/beta(2)m heterodimer. However, we identify two pathways for peptide dissociation from the heterotrimer: (1) initial peptide dissociation leaving a heavy chain/beta(2)m heterodimer and (2) initial dissociation Of beta(2)M, followed by peptide dissociation from the heavy chain. Eyring analyses of rate constants measured as a function of temperature permit for the first time a complete thermodynamic characterization of peptide binding. We find that in this case peptide binding is mostly entropically driven, likely reflecting the hydrophobic character of the peptide binding groove and the peptide anchor residues. Thermodynamic and kinetic analyses of peptide-MHC interactions as performed here may be of practical use in the engineering of peptides with desired binding properties and will aid in the interpretation of the effects of MHC and peptide substitutions on peptide binding and T cell reactivity. Finally, our data suggest a role for beta(2)M in dampening conformational dynamics in the heavy chain. Remaining conformational variability in the heavy chain once beta(2)m has bound may be a mechanism to promote promiscuity in peptide binding. C1 Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA. NINDS, Neuroimmunol Branch, Mol Immunol Sect, NIH, Bethesda, MD 20892 USA. RP Baker, BM (reprint author), Univ Notre Dame, Dept Chem & Biochem, 251 Nieuwland Sci Hall, Notre Dame, IN 46556 USA. RI Baker, Brian/B-4584-2009 OI Baker, Brian/0000-0002-0864-0964 FU NIGMS NIH HHS [1R01GM067079] NR 31 TC 29 Z9 30 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 6 PY 2003 VL 42 IS 17 BP 4954 EP 4961 DI 10.1021/bi034077m PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 674DL UT WOS:000182621700022 PM 12718537 ER PT J AU Fauci, AS AF Fauci, AS TI Anthony S. Fauci SO SCIENTIST LA English DT Editorial Material C1 NIAID, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU SCIENTIST INC PI PHILADELPHIA PA 3535 MARKET ST, SUITE 200, PHILADELPHIA, PA 19104-3385 USA SN 0890-3670 J9 SCIENTIST JI Scientist PD MAY 5 PY 2003 VL 17 IS 9 BP 11 EP 11 PG 1 WC Information Science & Library Science; Multidisciplinary Sciences SC Information Science & Library Science; Science & Technology - Other Topics GA 675CB UT WOS:000182674500005 ER PT J AU Gottesman, MM AF Gottesman, MM TI Pawing postdocs SO SCIENTIST LA English DT Letter C1 NIH, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SCIENTIST INC PI PHILADELPHIA PA 3535 MARKET ST, SUITE 200, PHILADELPHIA, PA 19104-3385 USA SN 0890-3670 J9 SCIENTIST JI Scientist PD MAY 5 PY 2003 VL 17 IS 9 BP 19 EP 19 PG 1 WC Information Science & Library Science; Multidisciplinary Sciences SC Information Science & Library Science; Science & Technology - Other Topics GA 675CB UT WOS:000182674500015 ER PT J AU Peters, U Sinha, R Chatterjee, N Subar, AF Ziegler, RG Kulldorff, M Bresalier, R Weissfeld, JL Flood, A Schatzkin, A Hayes, RB AF Peters, U Sinha, R Chatterjee, N Subar, AF Ziegler, RG Kulldorff, M Bresalier, R Weissfeld, JL Flood, A Schatzkin, A Hayes, RB CA Prostate Lung Colorectal Ovarian C TI Dietary fibre and colorectal adenoma in a colorectal cancer early detection programme SO LANCET LA English DT Article ID HIGH-FIBER DIET; RANDOMIZED TRIAL; RISK-FACTORS; LOW-FAT; POLYPS; RECURRENCE; MACRONUTRIENTS; CALCIUM; COLON AB Background Although dietary fibre has been reported to have no association with colorectal adenoma and cancer, in some studies this topic remains controversial. Methods We used a 137-item food frequency questionnaire to assess the relation of fibre intake and frequency of colorectal adenoma. The study was done within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, a randomised controlled trial designed to investigate methods for early detection of cancer. In our analysis, we compared fibre intake of 33 971 participants who were sigmoidoscopy-negative for polyps, with 3591 cases with at least one histologically verified adenoma in the distal large bowel (ie, descending colon, sigmoid colon, or rectum). Odds ratios were estimated by logistic regression analysis. Findings High intakes of dietary fibre were associated with a lower risk of colorectal adenoma, after adjustment for potential dietary and non-dietary risk factors. Participants in the highest quintile of dietary fibre intake had a 27% (95% Cl 14-38, P-trend=0.002) lower risk of adenoma than those in the lowest quintile. The inverse association was strongest for fibre from grains and cereals and from fruits. Risks were similar for advanced and non-advanced adenoma. Risk of rectal adenoma was not significantly associated with fibre intake. Interpretation Dietary fibre, particularly from grains, cereals, and fruits, was associated with decreased risk of distal colon adenoma. C1 NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, NIH,DHHS, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, NIH, DHHS, Bethesda, MD 20892 USA. Univ Connecticut, Sch Med, Farmington, CT USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Pittsburgh, Pittsburgh, PA USA. RP Peters, U (reprint author), NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, NIH,DHHS, 6129 Execut Blvd,EPS 3024, Bethesda, MD 20892 USA. RI Kulldorff, Martin/H-4282-2011; OI Kulldorff, Martin/0000-0002-5284-2993 NR 31 TC 174 Z9 196 U1 1 U2 36 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD MAY 3 PY 2003 VL 361 IS 9368 BP 1491 EP 1495 DI 10.1016/S0140-6736(03)13173-X PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 674WB UT WOS:000182658900006 PM 12737857 ER PT J AU Gomez-Roman, VR AF Gomez-Roman, VR TI HIV/AIDS prevention programs in developing countries are deficient without an appropriate scientific research infrastructure SO AIDS LA English DT Letter C1 NCI, Sect Immune Biol Retroviral Infect, Basic Res Lab, NIH, Bethesda, MD 20892 USA. RP Gomez-Roman, VR (reprint author), NCI, Sect Immune Biol Retroviral Infect, Basic Res Lab, NIH, Bethesda, MD 20892 USA. NR 6 TC 3 Z9 3 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAY 2 PY 2003 VL 17 IS 7 BP 1114 EP 1116 DI 10.1097/01.aids.0000060377.78202.7e PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 677XP UT WOS:000182834600034 PM 12700475 ER PT J AU Oh, JD Geller, AI Zhang, GR Chase, TN AF Oh, JD Geller, AI Zhang, GR Chase, TN TI Gene transfer of constitutively active protein kinase C into striatal neurons accelerates onset of levodopa-induced motor response alterations in parkinsonian rats SO BRAIN RESEARCH LA English DT Article DE chronic levodopa administration; 6-hydroxydopamine lesion; AMPA receptor; herpes simplex; vector type 1 vector; phosphorylation; basal ganglia ID LONG-TERM POTENTIATION; RECEPTOR GLUR1 SUBUNIT; FREE HSV-1 VECTORS; TYPE-1 PLASMID VECTORS; AMPA RECEPTOR; NMDA RECEPTOR; L-DOPA; POSTSYNAPTIC DENSITY; PHOSPHORYLATION SITES; GLUTAMATE RECEPTORS AB Alterations in motor response that complicate levodopa treatment of Parkinson's disease appear to involve sensitization of striatal ionotropic glutamate receptors. Since protein kinase C (PKC)-mediated phosphorylation regulates glutamatergic receptors of the alpha-amino-3-hydroxyl-5-methyl-4-isoxazole propionic acid (AMPA) subtype and has been linked to several forms of behavioral plasticity, activation of PKC signaling in striatal spiny neurons may also contribute to the motor plasticity changes associated with chronic levodopa therapy. To evaluate this possibility, we sought to augment PKC signaling by using Herpes Simplex Virus type 1 vectors (pHSvpkcDelta) to directly transfer the catalytic domain of the PKCbetaII gene into striatal neurons of parkinsonian rats. Microinjection of pHSVpkcDelta vectors lead to the persistent expression of PkcA (35% loss over 21 days) in medium spiny neurons together with an increase in serine 831 phosphorylation on AMPA receptor GluR1 subunits and hastened the appearance of the shortened response duration produced by chronic levodopa treatment (P<0.05). In pHSVpkcDelta-infected animals, intrastriatal injection of the PKC inhibitor NPC-15437 (1.0 mug) attenuated both the increased GluR1 phosphorylation (P<0.01) and the accelerated onset of the levodopa-induced response modifications (P<0.01). However, in rats that received levodopa treatment for 21 days without the gene transfer, intrastriatal NPC-15437 had no effect on the response shortening or on GluR1 S831 phosphorylation. The results suggest that an increase in PKC-mediated signaling, including, in part, phosphorylation of AMPA receptors, on striatal spiny neurons may be sufficient to promote the initial appearance, but not necessary the ultimate expression, of the levodopa-induced motor response changes occurring in a rodent model of the human motor complication syndrome. Published by Elsevier Science B.V. C1 Natl Inst Neurol Disorders & Stroke, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. Cent Michigan Univ, Dept Psychol, Mt Pleasant, MI 48859 USA. Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. RP Chase, TN (reprint author), Natl Inst Neurol Disorders & Stroke, Expt Therapeut Branch, NIH, Bldg 10,Room 5C103,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Geller, Alfred/C-6469-2012 FU NIA NIH HHS [R01 AG016777, R01 AG021193]; NINDS NIH HHS [R01 NS045855, R01 NS043107] NR 85 TC 13 Z9 14 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAY 2 PY 2003 VL 971 IS 1 BP 18 EP 30 DI 10.1016/S0006-8993(03)02348-5 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 673NJ UT WOS:000182586800003 PM 12691833 ER PT J AU Grabill, C Silva, AC Smith, SS Koretsky, AP Rouault, TA AF Grabill, C Silva, AC Smith, SS Koretsky, AP Rouault, TA TI MRI detection of ferritin iron overload and associated neuronal pathology in iron regulatory protein-2 knockout mice SO BRAIN RESEARCH LA English DT Article DE iron regulatory protein; ferritin; vacuolization; neurodegenerative disease; brain; magnetic resonance imaging ID CREUTZFELDT-JAKOB-DISEASE; HALLERVORDEN-SPATZ-SYNDROME; MULTIPLE SYSTEM ATROPHY; ALZHEIMERS-DISEASE; NEURODEGENERATIVE DISEASES; BRAIN IRON; SIGNAL; METABOLISM; T2; DEGENERATION AB Genetic ablation of iron regulatory protein 2 (IRP-2), a protein responsible for post-transcriptional regulation of expression of several iron metabolism proteins, predisposes IRP-2 -/- mice to develop adult onset neurodegenerative disease. Ferric iron reproducibly accumulates within axonal tracts and neuronal cell bodies in discrete regions of the brain, and areas of iron accumulation colocalize with areas of high ferritin expression. To better evaluate the onset and progression of neurodegeneration in IRP-2 -/- mice, we performed a high-resolution magnetic resonance imaging study comparing live, age-matched wild-type and IRP-2 -/- mice, using an 11.7-Tesla magnet and a custom-designed head coil. The mice were perfused after imaging, and iron stains and immunohistochemical studies were performed. We detected increases in the number of pixels with low T-2 values expected from accumulations of iron in IRP-2 -/- mice. Moreover, in several areas of the brain, including the substantia nigra and the superior colliculus, we detected areas with unusually high T-2 values that likely represented accumulation of water. On histopathological examination we discovered relatively small vacuoles in these brain regions of IRP-2 -/- mice. Our ability to gather T-2 data within regions of interest enabled us to define a bimodal T-2 intensity pattern that likely represents both ferritin iron accumulation and its associated pathological consequences within the brain. Our discoveries may have significant applications for the diagnosis and treatment of human diseases if such high-resolution techniques can be adapted for use in human subjects. (C) 2003 Elsevier Science B.V. All rights reserved. C1 NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NINDS, Lab Funct & Mol Imaging, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), NICHHD, Cell Biol & Metab Branch, Bldg 18T,Room 101 9000 Rockville Pike, Bethesda, MD 20892 USA. RI Silva, Afonso/A-7129-2009; Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU Intramural NIH HHS [Z01 NS003047-01] NR 38 TC 42 Z9 42 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAY 2 PY 2003 VL 971 IS 1 BP 95 EP 106 DI 10.1016/S0006-8993(03)02366-7 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 673NJ UT WOS:000182586800012 PM 12691842 ER PT J AU Poteser, M Wakabayashi, I Rosker, C Teubl, M Schindl, R Soldatov, NM Romanin, C Groschner, K AF Poteser, M Wakabayashi, I Rosker, C Teubl, M Schindl, R Soldatov, NM Romanin, C Groschner, K TI Crosstalk between voltage-independent Ca2+ channels and L-type Ca2+ channels in A7r5 vascular smooth muscle cells at elevated intracellular pH - Evidence for functional coupling between L-type Ca2+ channels and a 2-APB-sensitive cation channel SO CIRCULATION RESEARCH LA English DT Article DE intracellular pH; Ca2+ channels; nonselective cation channels; 2-APB; smooth muscle ID PORCINE CORONARY-ARTERY; ENTRY PATHWAYS; CALCIUM; ACTIVATION; RELEASE; STORE; RAT; INHIBITION; MECHANISM; CURRENTS AB This study was designed to investigate the role of voltage-independent and voltage-dependent Ca2+ channels in the Ca2+ signaling associated with intracellular alkalinization in A7r5 vascular smooth muscle cells. Extracellular administration of ammonium chloride (20 mmol/L) resulted in elevation of intracellular pH and activation of a sustained Ca2+ entry that was inhibited by 2-amino-ethoxydiphenyl borate (2-APB, 200 mumol/L) but not by verapamil (10 mumol/L). Alkalosis-induced Ca2+ entry was mediated by a voltage-independent cation conductance that allowed permeation of Ca2+(P-Ca/P(Na)approximate to6), and was associated with inhibition of L-type Ca2+ currents. Alkalosis-induced inhibition of L-type Ca2+ currents was dependent on the presence of extracellular Ca2+ and was prevented by expression of a dominant-negative mutant of calmodulin. In the absence of extracellular Ca2+, with Ba2+ or Na+ as charge carrier, intracellular alkalosis failed to inhibit but potentiated L-type Ca2+ channel currents. Inhibition of Ca2+ currents through voltage-independent cation channels by 2-APB prevented alkalosis-induced inhibition of L-type Ca2+ currents. Similarly, 2-APB prevented vasopressin-induced activation of nonselective cation channels and inhibition of L-type Ca2+ currents. We suggest the existence of a pH-controlled Ca-2+ entry pathway that governs the activity of smooth muscle L-type Ca2+ channels due to control of Ca2+/calmodulin-dependent negative feedback regulation. This Ca2+ entry pathway exhibits striking similarity with the pathway activated by stimulation of phospholipase-C-coupled receptors, and may involve a similar type of cation channel. We demonstrate for the first time the tight functional coupling between these voltage-independent Ca2+ channels and classical voltage-gated L-type Ca2+ channels. C1 Karl Franzens Univ Graz, Dept Pharmacol & Toxicol, A-8010 Graz, Austria. Yamagata Univ, Sch Med, Dept Hyg & Prevent Med, Yamagata 99023, Japan. Johannes Kepler Univ, Dept Biophys, A-4040 Linz, Austria. NIA, NIH, Baltimore, MD 21224 USA. RP Groschner, K (reprint author), Karl Franzens Univ Graz, Dept Pharmacol & Toxicol, A-8010 Graz, Austria. RI Groschner, Klaus/A-2550-2010; Schindl, Rainer/E-3959-2013; Romanin, Christoph/D-5399-2009 OI Schindl, Rainer/0000-0003-0896-8887; Romanin, Christoph/0000-0003-3756-4136 NR 30 TC 22 Z9 23 U1 0 U2 0 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 MAY 2 PY 2003 VL 92 IS 8 BP 888 EP 896 DI 10.1161/01.RES.0000069216.80612.66 PG 9 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 673KK UT WOS:000182580000011 PM 12663491 ER PT J AU van Huizen, R Martindale, JL Gorospe, M Holbrook, NJ AF van Huizen, R Martindale, JL Gorospe, M Holbrook, NJ TI P58(IPK), a novel endoplasmic reticulum stress-inducible protein and potential negative regulator of eIF2 alpha signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DOUBLE-STRANDED-RNA; EUKARYOTIC INITIATION FACTOR-2-ALPHA; TRANSLATIONAL CONTROL; TRANSCRIPTION FACTOR; MAMMALIAN-CELLS; MESSENGER-RNA; ER STRESS; CELLULAR INHIBITOR; GENE-EXPRESSION; KINASE PKR AB The unfolded protein response, which is activated in response to the loss of endoplasmic reticulum (ER) Ca2+ homeostasis and/or the accumulation of misfolded, unassembled, or aggregated proteins in the ER lumen, involves both transcriptional and translational regulation. In the current studies we sought to identify novel ER stress-induced genes by conducting microarray analysis on tunicamycin-treated cells. We identified P58(IPK). an inhibitor of the interferon-induced double-stranded RNA-activated protein kinase, as induced during ER stress. Additional studies suggested that p58(IPK) induction was mediated via ATF6 and that P58(IPK) played a role in down-regulating the activity of the pancreatic eIF2 kinase/eukaryotic initiation factor 2alpha (eIF2alpha)-like ER kinase/activation transcription factor (ATF) 4 pathway. Modulation of P58(IPK) levels altered the phosphorylation status of eIF2alpha, and thereby affected expression of its downstream targets, ATF4 and Gadd153. Overexpression of p58(IPK) inhibited eIF2alpha phosphorylation and reduced ATF4 and Gadd153 protein accumulation, whereas silencing of P58(IPK) expression enhanced pancreatic eIF2alpha-like ER kinase and eIF2alpha phosphorylation and increased ATF4 and Gadd153 accumulation. These findings implicate P58(IPK) as an important component of a negative feedback loop used by the cell to inhibit eIF2alpha signaling, and thus attenuate the unfolded protein response. C1 NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. Yale Univ, Sch Med, Dept Internal Med, Sect Geriatr, New Haven, CT 06520 USA. RP van Huizen, R (reprint author), NIA, Cellular & Mol Biol Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 45 TC 143 Z9 148 U1 1 U2 8 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 MAY 2 PY 2003 VL 278 IS 18 BP 15558 EP 15564 DI 10.1074/jbc.M212074200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 675EL UT WOS:000182680000014 PM 12601012 ER PT J AU Salim, S Sinnarajah, S Kehrl, JH Dessauer, CW AF Salim, S Sinnarajah, S Kehrl, JH Dessauer, CW TI Identification of RGS2 and type V adenylyl cyclase interaction sites SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN ALPHA-SUBUNITS; GTPASE-ACTIVATING PROTEINS; CYTOSOLIC DOMAINS; ESCHERICHIA-COLI; KINETIC-ANALYSIS; PHOSPHOLIPASE-C; FAMILY MEMBERS; EXPRESSION; REGULATOR; MECHANISM AB The production of cAMP is controlled on many levels, notably at the level of cAMP synthesis by the enzyme adenylyl cyclase. We have recently identified a new regulator of adenylyl cyclase activity, RGS2, which decreases cAMP accumulation when overexpressed in HEK293 cells and inhibits the in vitro activity of types III, V, and VI adenylyl cyclase. In addition, RGS2 blocking antibodies lead to elevated cAMF levels in olfactory neurons. Here we examine the nature of the interaction between RGS2 and type V adenylyl cyclase. In HEK293 cells expressing type V adenylyl cyclase, RGS2 inhibited Galpha(s)-Q227L- or beta(2)-adrenergic receptor-stimulated cAMP accumulation. Deletion of the N-terminal 19 amino acids of RGS2 abolished its ability to inhibit cAMP accumulation and to bind adenylyl cyclase. Further mutational analysis indicated that neither the C terminus, RGS GAP activity, nor the RGS box domain is required for inhibition of adenylyl cyclase. Alanine scanning of the N-terminal amino acids of RGS2 identified three residues responsible for the inhibitory function of RGS2. Furthermore, we show that RGS2 interacts directly with the C, but not the C-2 domain of type V adenylyl cyclase and that the inhibition by RGS2 is independent of inhibition by Galpha(i). These results provide clear evidence for functional effects of RGS2 on adenylyl cyclase activity that adds a new dimension to an intricate signaling network. C1 Univ Texas, Hlth Sci Ctr, Dept Integrat Biol & Pharmacol, Houston, TX 77030 USA. NIAID, Immunoregulat Lab, B Cell Mol Biol Sect, NIH, Bethesda, MD 20892 USA. RP Dessauer, CW (reprint author), Univ Texas, Hlth Sci Ctr, Dept Integrat Biol & Pharmacol, 6431 Fannin St, Houston, TX 77030 USA. OI Kehrl, John/0000-0002-6526-159X FU NIGMS NIH HHS [GM 60419, R01 GM060419, R01 GM060419-03] NR 42 TC 98 Z9 98 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 MAY 2 PY 2003 VL 278 IS 18 BP 15842 EP 15849 DI 10.1074/jbc.M210663200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 675EL UT WOS:000182680000050 PM 12604604 ER PT J AU Alani, E Lee, JY Schofield, MJ Kijas, AW Hsieh, P Yang, W AF Alani, E Lee, JY Schofield, MJ Kijas, AW Hsieh, P Yang, W TI Crystal structure and biochemical analysis of the MutS center dot ADP center dot Beryllium fluoride complex suggests a conserved mechanism for ATP interactions in mismatch repair SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL NUCLEAR ANTIGEN; DNA HELICASE-II; RECOGNITION COMPLEX; MOLECULAR SWITCH; YEAST MSH2-MSH6; STRAND BREAK; PROTEIN MUTS; HMUTS-ALPHA; ABC-ATPASE; BINDING AB During mismatch repair ATP binding and hydrolysis activities by the MutS family proteins are important for both mismatch recognition and for transducing mismatch recognition signals to downstream repair factors. Despite intensive. efforts, a MutS(.)ATP(.)DNA complex has eluded crystallographic analysis. Searching for ATP analogs that strongly bound to Thermus aquaticus (Taq) MutS, we found that ADP-beryllium fluoride (ABF), acted as a strong inhibitor of several MutS family ATPases. Furthermore, ABF promoted the formation of a ternary complex containing the Saccharomyces cerevisiae MSH2(.)MSH6 and MLH1(.)PMS1 proteins bound to mismatch DNA but did not promote dissociation of MSH2(.)MSH6 from mismatch DNA. Crystallographic analysis of the Taq MutS(.)DNA(.)ABF complex indicated that although this complex was very similar to that of MutS(.)DNA(.)ADP, both ADP(.)Mg(2+) moieties in the MutS(.)DNA(.)ADP structure were replaced by ABF. Furthermore, a disordered region near the ATP-binding pocket in the MutS B subunit became traceable, whereas the equivalent region in the A subunit that interacts with the mismatched nucleotide remained disordered. Finally, the DNA binding domains of MutS together with the mismatched DNA were shifted upon binding of ABF. We hypothesize that the presence of ABF is communicated between the two MutS subunits through the contact between the ordered loop and Domain III in addition to the intra-subunit helical lever arm that links the ATPase and DNA binding domains. C1 Cornell Univ, Dept Genet & Mol Biol, Ithaca, NY 14853 USA. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Genet Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Alani, E (reprint author), 459 Biotechnol Bldg, Ithaca, NY 14853 USA. RI Yang, Wei/D-4926-2011 OI Yang, Wei/0000-0002-3591-2195 FU NIGMS NIH HHS [GM 53085, R01 GM053085] NR 45 TC 39 Z9 39 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 MAY 2 PY 2003 VL 278 IS 18 BP 16088 EP 16094 DI 10.1074/jbc.M213193200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 675EL UT WOS:000182680000081 PM 12582174 ER PT J AU Derrien, A Zheng, B Osterhout, JL Ma, YC Milligan, G Farquhar, MG Druey, KM AF Derrien, A Zheng, B Osterhout, JL Ma, YC Milligan, G Farquhar, MG Druey, KM TI Src-mediated RGS16 tyrosine phosphorylation promotes RGS16 stability SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GROWTH-FACTOR RECEPTOR; C-SRC; FUNCTIONAL-CHARACTERIZATION; PROTEIN-KINASE; UP-REGULATION; EGF RECEPTOR; G-ALPHA; MODULATION; FAMILY; CELLS AB The amplitude of signaling evoked by stimulation of G protein-coupled receptors may be controlled in part by the GTPase accelerating activity of the regulator of G protein signaling (RGS) proteins. In turn, subcellular targeting, protein-protein interactions, or post-translational modifications such as phosphorylation may shape RGS activity and specificity. We found previously that RGS16 undergoes tyrosine phosphorylation on conserved tyrosine residues in the RGS box. Phosphorylation on Tyr(168) was mediated by the epidermal growth factor receptor (EGFR). We show here that endogenous RGS16 is phosphorylated after epidermal growth factor stimulation of MCF-7 cells. In addition, p60-Src or Lyn kinase phosphorylated recombinant RGS16 in vitro, and RGS16 underwent phosphorylation in the presence of constitutively active Src (Y529F) in EGFR- CHO-K1 cells. Blockade of endogenous Src activity by selective inhibitors attenuated RGS16 phosphorylation induced by pervanadate or receptor stimulation. Furthermore, the rate of RGS16 degradation was reduced in cells expressing active Src or treated with pervanadate or a G protein-coupled receptor ligand (CXCL12). Induction of RGS16 tyrosine phosphorylation was associated with increased RGS16 protein levels and enhanced GAP activity in cell membranes. These results suggest that Src mediates RGS16 tyrosine phosphorylation, which may promote RGS16 stability. C1 NIAID, Lab Allerg Dis, NIH, Rockville, MD 20852 USA. Univ Calif San Diego, Sch Med, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. Cornell Univ, Weill Med Coll, Dept Physiol, New York, NY 10021 USA. Univ Glasgow, Inst Biomed & Life Sci, Div Biochem & Mol Biol, Mol Pharmacol Grp, Glasgow G12 8QQ, Lanark, Scotland. RP Druey, KM (reprint author), NIAID, Lab Allerg Dis, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. RI Milligan, Graeme/F-9426-2011 OI Milligan, Graeme/0000-0002-6946-3519 NR 46 TC 31 Z9 32 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 MAY 2 PY 2003 VL 278 IS 18 BP 16107 EP 16116 DI 10.1074/jbc.M210371200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 675EL UT WOS:000182680000083 PM 12588871 ER PT J AU Trebak, M Bird, GSJ McKay, RRM Birnbaumer, L Putney, JW AF Trebak, M Bird, GSJ McKay, RRM Birnbaumer, L Putney, JW TI Signaling mechanism for receptor-activated canonical transient receptor potential 3 (TRPC3) channels SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CAPACITATIVE CALCIUM-ENTRY; INOSITOL TRISPHOSPHATE RECEPTOR; CA2+-PERMEABLE CATION CHANNEL; OPERATED HTRP3 CHANNELS; CA2+ CHANNELS; PHOSPHOLIPASE-C; FEEDBACK INHIBITION; CELLS; RELEASE; RAT AB Canonical transient receptor potential 3 (TRPC3) is a receptor-activated, calcium permeant, non-selective cation channel. TRPC3 has been shown to interact physically with the N-terminal domain of the inositol 1,4,5-trisphosphate receptor, consistent with a "conformational coupling" mechanism for its activation. Here we show that low concentrations of agonists that fail to produce levels of inositol 1,4,5-trisphosphate sufficient to induce Ca2+ release from intracellular stores substantially activate TRPC3. By several experimental approaches, we demonstrate that neither inositol 1,4,5-trisphosphate nor G proteins are required for TRPC3 activation. However, diacylglycerols were sufficient to activate TRPC3 in a protein kinase C-independent manner. Surface receptor agonists and exogenously applied diacylglycerols were not additive in activating TRPC3. In addition, inhibition of metabolism of diacylglycerol slowed the reversal of receptor-dependent TRPC3 activation. We conclude that receptor-mediated activation of phospholipase C in intact cells activates TRPC3 via diacylglycerol production, independently of G proteins, protein kinase C, or inositol 1,4,5-trisphosphate. C1 NIEHS, NIH, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. RP Trebak, M (reprint author), NIEHS, NIH, Lab Signal Transduct, POB 12233, Res Triangle Pk, NC 27709 USA. RI Trebak, Mohamed/E-7405-2014 NR 37 TC 106 Z9 108 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 MAY 2 PY 2003 VL 278 IS 18 BP 16244 EP 16252 DI 10.1074/jbc.M300544200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 675EL UT WOS:000182680000100 PM 12606542 ER PT J AU Sarafianos, SG Clark, AD Tuske, S Squire, CJ Das, K Sheng, DQ Ilankumaran, P Ramesha, AR Kroth, H Sayer, JM Jerina, DM Boyer, PL Hughes, SH Arnold, E AF Sarafianos, SG Clark, AD Tuske, S Squire, CJ Das, K Sheng, DQ Ilankumaran, P Ramesha, AR Kroth, H Sayer, JM Jerina, DM Boyer, PL Hughes, SH Arnold, E TI Trapping HIV-1 reverse transcriptase before and after translocation on DNA SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ANTIBODY FAB FRAGMENT; DOUBLE-STRANDED DNA; ANGSTROM RESOLUTION; SELECTIVE EXCISION; CRYSTAL-STRUCTURE; TEMPLATE-PRIMER; RESISTANCE; COMPLEX; DISULFIDES AB A disulfide cross-linking strategy was used to co-valently trap as a stable complex (complex N) a short-lived, kinetic intermediate in DNA polymerization. This intermediate corresponds to the product of polymerization prior to translocation. We also prepared the trapped complex that corresponds to the product of polymerization after translocation (complex P). The cross-linking method that we used is a variation of a technique developed by the Verdine and Harrison laboratories. It involves disulfide interchange between an engineered sulfhydryl group of the protein (Q258C mutation) and a disulfide-containing tether attached at the N-2 amino group of a modified dG in either the template or the primer strand of the nucleic acid. We report here a highly efficient synthesis of the precursor, bis(3-aminopropyl)disulfide dihydrochloride, used to introduce this substituent into the oligonucleotide. Efficient cross-linking takes place when the base pair containing the substituent is positioned seven registers from the dNTP-binding site (N site) and the N site is occupied. Complex N, but not complex P, is a substrate for the ATP-based excision reaction that unblocks nucleoside reverse transcriptase inhibitor (NRTI)-terminated primers and causes resistance to several NRTIs, confirming predictions that the excision reaction takes place only when the X-end of the primer is bound at the N site. These techniques can be used for biochemical and structural studies of the mechanism of DNA polymerization, translocation, and excision-based resistance of RT to NRTIs. They may also be useful in studying other DNA or RNA polymerases or other enzymes. C1 Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. Rutgers State Univ, Dept Chem & Chem Biol, Piscataway, NJ 08854 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. RP Arnold, E (reprint author), Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. OI Sarafianos, Stefan G/0000-0002-5840-154X FU NIAID NIH HHS [AI 27690]; NIGMS NIH HHS [GM 56609] NR 27 TC 54 Z9 56 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 MAY 2 PY 2003 VL 278 IS 18 BP 16280 EP 16288 DI 10.1074/jbc.M212911200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 675EL UT WOS:000182680000104 PM 12554739 ER PT J AU Mahadevan, J Nicholas, GM Bewley, CA AF Mahadevan, J Nicholas, GM Bewley, CA TI Solution conformations of mycothiol bimane, 1-D-GlcNAc-alpha-(1 -> 1)-D-myo-Ins and 1-D-GlcNAc-alpha-(1 -> 1)-L-myo-Ins SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID S-CONJUGATE AMIDASE; COUPLING-CONSTANTS; BROMOTYROSINE ALKALOIDS; INHIBITORS; NMR; IDENTIFICATION; REFINEMENT; THIOL AB Mycothiol is an abundant small molecular weight thiol found only in actinomycetes, which include mycobacteria. Mycothiol biosynthetic and detoxification enzymes are novel and unique to actinomycetes, thereby representing potential antimycobacterial targets. To better guide inhibitor design, we have determined by NMR the solution conformations of mycothiol bimane (MSmB) and the pseudodisaccharide 1-D-GlcNAc-alpha-(1 --> 1)-D-myo-Ins (D-GI), molecules that represent the natural substrates for the mycothiol-dependent detoxification enzyme mycothiol-S-conjugate amidase (MCA) and the mycothiol biosynthetic enzyme D-GlcNAc-alpha-(1 --> 1)-D-myo-Ins deacetylase (AcGI deacetylase), respectively. Comparison of the mean structure of MSmB and the energy-minimized structures of two competitive spiroisoxazoline-containing MCA inhibitors shows striking similarities between these molecules in the region of the scissile amide bond of MSmB and provides structural evidence that those inhibitors are substrate mimics. Owing to our earlier finding that AcGI deacetylase will not deacetylate the unnatural isomer 1-D-GlcNAc-alpha-(1 --> 1)-L-myo-Ins (L-GI), the solution conformation of L-GI was also determined. The interglycosidic bond angles for all three compounds are comparable. When considered together with the observation that a simplified cyclohexyl thioglycoside mycothiol analogue is a good substrate for MCA, it appears that the stereochemistry of the inositol ring is critical for deacetylase function, superseding the importance of the full complement of hydroxyl groups on the "nonreducing" ring. C1 NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Bewley, CA (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NR 32 TC 12 Z9 13 U1 1 U2 2 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 MAY 2 PY 2003 VL 68 IS 9 BP 3380 EP 3386 DI 10.1021/jo026872w PG 7 WC Chemistry, Organic SC Chemistry GA 672PB UT WOS:000182528600002 PM 12713335 ER PT J AU Hardy, J Singleton, A Gwinn-Hardy, K AF Hardy, J Singleton, A Gwinn-Hardy, K TI Ethnic differences and disease phenotypes SO SCIENCE LA English DT Letter ID SPINOCEREBELLAR ATAXIA TYPE-2; RESPONSIVE PARKINSONISM PHENOTYPE; EXPANSION; FAMILY C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. NINDS, NIH, Bethesda, MD 20892 USA. RP Hardy, J (reprint author), NIA, Neurogenet Lab, NIH, Bldg 10,Room 6C103,MSC1589, Bethesda, MD 20892 USA. RI Gwinn, Katrina/C-2508-2009; Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009 NR 14 TC 12 Z9 12 U1 0 U2 0 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 MAY 2 PY 2003 VL 300 IS 5620 BP 739 EP 740 DI 10.1126/science.300.5620.739 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 673KH UT WOS:000182579800021 PM 12730580 ER PT J AU Atlas, R Campbell, P Cozzarelli, N Curfman, G Fink, G Flanagin, A Fletcher, J George, B Hammes, G Heyman, D Inglesby, T Kaplan, S Kennedy, D Krug, J Levinson, R Marcus, E Metzger, H Morse, SS O'Brien, A Poste, G Renault, B Rich, R Rosengard, A Salzburg, S Scanlan, M Shenk, T Tabor, H Varmus, H Wimmer, E Yamamoto, K AF Atlas, R Campbell, P Cozzarelli, N Curfman, G Fink, G Flanagin, A Fletcher, J George, B Hammes, G Heyman, D Inglesby, T Kaplan, S Kennedy, D Krug, J Levinson, R Marcus, E Metzger, H Morse, SS O'Brien, A Poste, G Renault, B Rich, R Rosengard, A Salzburg, S Scanlan, M Shenk, T Tabor, H Varmus, H Wimmer, E Yamamoto, K CA Journal Editors Authors Grp TI Resolving academic freedom - Professional groups defend intellectual openness SO ACADEME-BULLETIN OF THE AAUP LA English DT Article C1 Amer Soc Microbiol, Buffalo, NY USA. NIAMSD, NIH, Bethesda, MD USA. Columbia Univ, New York, NY 10027 USA. Univ Penn, Philadelphia, PA 19104 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. SUNY Stony Brook, Stony Brook, NY 11794 USA. MIT, Cambridge, MA 02139 USA. RP Atlas, R (reprint author), Amer Soc Microbiol, Buffalo, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSN UNIV PROFESSORS PI WASHINGTON PA SUITE 500 1012 14TH ST, NW, WASHINGTON, DC 20005 USA SN 0190-2946 J9 ACADEME JI Academe-Bull. AAUP PD MAY-JUN PY 2003 VL 89 IS 3 BP 55 EP 58 PG 4 WC Education & Educational Research SC Education & Educational Research GA 678MF UT WOS:000182870400017 ER PT J AU Ramagopal, UA Dauter, M Dauter, Z AF Ramagopal, UA Dauter, M Dauter, Z TI SAD manganese in two crystal forms of glucose isomerase SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID D-XYLOSE ISOMERASE; ELECTRON-DENSITY MAPS; ANOMALOUS SCATTERING; ANGSTROM RESOLUTION; S-ATOMS; MACROMOLECULAR CRYSTALLOGRAPHY; PROTEIN; SULFUR; REFINEMENT; MECHANISM AB Glucose isomerase from Streptomyces rubiginosus was crystallized in two forms: I222, with one molecule of 44 kDa in the asymmetric unit, and P2(1)2(1)2, with two unique molecules. The I222 structure is known, but the P21212 form has not been solved before. X-ray diffraction data for the P21212 form were collected at a wavelength of 1.54 Angstrom and data for the I222 form were collected at three different wavelengths: 1.34, 1.07 and 0.98 Angstrom. The amount of anomalous signal from one Mn and eight S atoms in these data sets varies from 1.24% to as low as 0.56%. The dual-space direct-methods program SHELXD, run against the Bijvoet differences, gave a clear solution of all anomalous scatterers for all data sets. The Mn positions only were used for SAD phasing of all four data sets. The electron-density map after density modification, resulting from the phasing of a single-wavelength data set and based purely on the anomalous deltaf" contribution, was clearly interpretable; an almost complete model of the protein was built by wARP without human intervention in all four cases. As far as is known, this is the first time that an anomalous signal as low as 0.6% has successfully been used to determine the structure of a macromolecule. C1 SAIC Frederick Inc, Brookhaven Natl Lab, Upton, NY 11973 USA. NCI, Synchrotron Radiat Res Sect, Brookhaven Natl Lab, Upton, NY 11973 USA. RP Dauter, Z (reprint author), SAIC Frederick Inc, Brookhaven Natl Lab, Bldg 725A-X9, Upton, NY 11973 USA. NR 40 TC 27 Z9 28 U1 1 U2 3 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD MAY PY 2003 VL 59 BP 868 EP 875 DI 10.1107/S0907444903005663 PN 5 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 672WW UT WOS:000182546900011 PM 12777803 ER PT J AU Andrykovitch, M Routzahn, KM Li, M Gu, YJ Waugh, DS Ji, XH AF Andrykovitch, M Routzahn, KM Li, M Gu, YJ Waugh, DS Ji, XH TI Characterization of four orthologs of stringent starvation protein A SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID RNA-POLYMERASE; ESCHERICHIA-COLI; ANGSTROM RESOLUTION; EXPRESSION; GROWTH; SPECIFICITY; DATABASE; SSPA AB Orthologous proteins can be beneficial for X-ray crystallographic studies when a protein from an organism of choice fails to crystallize or the crystals are not suitable for structure determination. Their amino-acid sequences should be similar enough that they will share the same fold, but different enough so that they may crystallize under alternative conditions and diffract to higher resolution. This multi-species approach was employed to obtain diffraction-quality crystals of the RNA polymerase ( RNAP) associated stringent starvation protein A ( SspA). Although Escherichia coli SspA could be crystallized, the crystals failed to diffract well enough for structure determination. Therefore, SspA proteins from Yersinia pestis, Vibrio cholerae and Pseudomonas aeruginosa were cloned, expressed, purified and subjected to crystallization trials. The V. cholerae SspA protein failed to crystallize under any conditions tested and the P. aeruginosa SspA protein did not form crystals suitable for data collection. On the other hand, Y. pestis SspA crystallized readily and the crystals diffracted to 2.0 Angstrom. C1 NCI, Macromol Crystallog Lab, NIH, Frederick, MD 21702 USA. SAIC Frederick, Intramural Res Support Program, Ft Detrick, MD 21702 USA. RP Ji, XH (reprint author), NCI, Macromol Crystallog Lab, NIH, Frederick, MD 21702 USA. RI Gu, Yijun/B-6017-2012; Ji, Xinhua/C-9664-2012 OI Ji, Xinhua/0000-0001-6942-1514 NR 20 TC 1 Z9 1 U1 0 U2 0 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD MAY PY 2003 VL 59 BP 881 EP 886 DI 10.1107/S0907444903005699 PN 5 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 672WW UT WOS:000182546900013 PM 12777805 ER PT J AU Ross, GW O'Callaghan, JP Sharp, DS Petrovitch, H Miller, DB Abbott, RD Nelson, J Launer, LJ Foley, DJ Burchfiel, CM Hardman, J White, LR AF Ross, GW O'Callaghan, JP Sharp, DS Petrovitch, H Miller, DB Abbott, RD Nelson, J Launer, LJ Foley, DJ Burchfiel, CM Hardman, J White, LR TI Quantification of regional glial fibrillary acidic protein levels in Alzheimer's disease SO ACTA NEUROLOGICA SCANDINAVICA LA English DT Article DE gliosis; Alzheimer disease; dementia; glial fibrillary acidic protein ID MESSENGER-RNA; SENILE DEMENTIA; BRAIN; CRITERIA; GLIOSIS; INJURY; HAWAII; CERAD; ELISA; RAT AB Objectives - Our objectives were to quantify glial fibrillary acidic protein (GFAP) in brains of Alzheimer's disease (AD) cases, and non-AD controls to determine the regions with the most severe gliosis in AD. Material and methods - In a case-control design, we used an enzyme-linked immunosorbent assay (ELISA) to quantify GFAP in frozen brain from four areas of neocortex in 10 AD cases, 10 age-matched controls, and 10 younger controls from the Honolulu-Asia Aging Study autopsy archive. Results - Median age at death was 83.5 years for cases and age-matched controls, and 77 years for younger controls. For the AD cases compared with the age-matched controls, levels of GFAP in occipital (P =0.01), parietal (P =0.028), and temporal lobes (P =0.004) (but not frontal) were significantly higher in the cases. The median GFAP excess in AD cases compared with age matched controls was highest in the temporal lobe. Conclusions - Regional quantification of GFAP reveals that the glial response is most prominent in the temporal lobe in AD. C1 Dept Vet Affairs, Honolulu, HI USA. NIOSH, Morgantown, WV USA. Univ Hawaii, John A Burns Sch Med, Dept Med, Honolulu, HI 96822 USA. Univ Virginia, Sch Med, Dept Hlth Evaluat Sci, Div Biostat & Epidemiol, Charlottesville, VA 22908 USA. Pacific Hlth Res Inst, Honolulu, HI USA. NIA, NIH, Bethesda, MD 20892 USA. Kuakini Med Ctr Honolulu Asia Aging Study, Honolulu, HI USA. Univ Hawaii, John A Burns Sch Med, Dept Neuropathol, Honolulu, HI 96822 USA. RP Ross, GW (reprint author), Hlth Res Inst, Suite 307,846 S Hotel St, Honolulu, HI 96813 USA. RI Miller, Diane/O-2927-2013; O'Callaghan, James/O-2958-2013 FU NIA NIH HHS [N01-AG-4-2149] NR 30 TC 25 Z9 25 U1 0 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-6314 J9 ACTA NEUROL SCAND JI Acta Neurol. Scand. PD MAY PY 2003 VL 107 IS 5 BP 318 EP 323 DI 10.1034/j.1600-0404.2003.02098.x PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 671HF UT WOS:000182458700002 PM 12713522 ER PT J AU Hamilton, M Dahut, W Brawley, O Davis, P Wells-Jones, T Kohler, D Duray, P Liewehr, DJ Lakhani, N Steinberg, SM Figg, WD Reed, E AF Hamilton, M Dahut, W Brawley, O Davis, P Wells-Jones, T Kohler, D Duray, P Liewehr, DJ Lakhani, N Steinberg, SM Figg, WD Reed, E TI A phase I/II study of high-dose tamoxifen in combination with vinblastine in patients with androgen-independent prostate cancer SO ACTA ONCOLOGICA LA English DT Article ID GROWTH-FACTOR-BETA; PROTEIN-KINASE-C; HORMONAL-THERAPY; TGF-BETA; CELLS; INHIBITION; INDUCTION; EXPRESSION; CARCINOMA; TRIALS AB In this phase I/II clinical trial the antitumor activity of high-dose tamoxifen when administered in combination with vinblastine was assessed and the toxicity profile of this combination characterized. All 25 patients enrolled in this study were required to have androgen-independent prostate cancer and to maintain androgen ablation during treatment. Vinblastine was given by continuous infusion over 5 days. Doses were increased from 0.9 mg/m(2)/day to 1.5 mg/m(2)/day in successive cohorts of at least 3 patients, with no further escalation even in the absence of dose-limiting toxicity. Intra-patient dose escalation was permitted. Tamoxifen was administered at a dose of 200 mg/kg on day 1, then 120 mg/kg/day on day 2. Standard response criteria were utilized to assess antitumor activity and CTC toxicity criteria were used. Quality of life (QOL) pain assessments were evaluated at each visit to the clinic. Most patients tolerated the highest dose of vinblastine at 1.5 mg/m(2)/day by continuous infusion over 5 days with 200 mg/kg/day of tamoxifen on day 1 and day 2. One patient had a greater than 50% decline in prostate-specific antigen that lasted for 170 days. Two patients received dose reductions because of toxicity. The most common serious toxicities included neutropenia, and fatigue. Reversible neurosensory, neuromotor, neurocortical and neurocerebellar toxicities were reported. Six of the 25 patients enrolled in the study (24%) experienced reversible neurologic toxicity of at least grade III. No statistically significant differences between precycle assessment of QOL and subsequent cycles were observed. It is concluded that vinblastine at 1.5 mg/ m(2)/day continuous IV infusion combined with tamoxifen 200 mg/ kg/day on day 1 and day 2 is inactive, and not without toxicity in the treatment of advanced metastatic androgen-independent prostate cancer. C1 NCI, Med Branch, Ctr Canc Res, Mol Pharmacol Sect,NIH, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Med Branch, Ctr Canc Res, Mol Pharmacol Sect,NIH, 9000 Rockville Pike,Bldg 10,Room 5A01,MSC 1910, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 34 TC 9 Z9 9 U1 0 U2 4 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0284-186X J9 ACTA ONCOL JI Acta Oncol. PD MAY PY 2003 VL 42 IS 3 BP 195 EP 201 DI 10.1080/02841860310010718 PG 7 WC Oncology SC Oncology GA 682DH UT WOS:000183075700003 PM 12852695 ER PT J AU Avenevoli, S Merikangas, KR AF Avenevoli, S Merikangas, KR TI Familial influences on adolescent smoking SO ADDICTION LA English DT Review DE famly factors; family studies; genetic epidemiology; high risk studies; parental influence; peer influence; risk factor; sibling influence; smoking; tobacco use ID HIGH-SCHOOL-STUDENTS; CIGARETTE-SMOKING; PARENTAL SMOKING; TOBACCO USE; UNITED-STATES; RISK-FACTORS; DRUG-USE; ANTISMOKING SOCIALIZATION; PSYCHIATRIC-DISORDERS; GENETIC EPIDEMIOLOGY AB The family unit is the primary source of transmission of basic social, Cultural. genetic, and biological factors that may underlie individual differences in smoking. Existing information on the role of familial factors in tobacco use is characterized by two separate. but somewhat Overlapping, lines of research: genetic epidemiological studies and risk-factor research. The present paper summarizes and evaluates studies assessing the association between adolescent smoking and parent and sibling smoking behaviors. A review of 87 Studies reveals that methods are limited by a lack of standardized instruments. failure to measure important confounding and mediating I, actors. reliance on cross-sectional designs and the use of inconsistent definitions of tobacco-related behavior and assessment procedures. Moreover, there are no systematic family studies of the acquisition and continuation of smoking that have employed contemporary methodological standards for examining familial aggregation of tobacco behaviors among adolescents. Findings across studies show weak and inconsistent associations between parent and adolescent smoking; inconsistent. findings may be attributed to methodological issues or associated factors that may complicate the relation between parent and adolescent smoking. Sibling and peer smoking show greater associations with adolescent smoking. Suggestions for future research include contemporary family studies that delineate meaningful phenotypes of tobacco use and prospective work on the later stages of tobacco use and the timing of the influence and valence of parent and family factors. Integration of the risk factor approach within the family study design may enrich both approaches to elucidate familial influences on smoking. C1 NIMH, Mood & Anxiety Disorders Program, Intramural Res Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Avenevoli, S (reprint author), NIMH, Mood & Anxiety Disorders Program, Intramural Res Program, NIH,Dept Hlth & Human Serv, 15 K N Dr,MSC 2670, Bethesda, MD 20892 USA. NR 152 TC 190 Z9 192 U1 3 U2 28 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0965-2140 J9 ADDICTION JI Addiction PD MAY PY 2003 VL 98 SU 1 BP 1 EP 20 DI 10.1046/j.1360-0443.98.s1.2.x PG 20 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 681BZ UT WOS:000183018100002 PM 12752359 ER PT J AU Flay, B Clayton, RR AF Flay, B Clayton, RR TI Contexts and adolescent tobacco use trajectories SO ADDICTION LA English DT Editorial Material C1 Univ Illinois, Hlth Res & Policy Ctr, Chicago, IL 60607 USA. Univ Kentucky, NIDA, Ctr Prevent Res, Lexington, KY 40504 USA. RP Flay, B (reprint author), Univ Illinois, Hlth Res & Policy Ctr, 850 W Jackson Blvd,Suite 400, Chicago, IL 60607 USA. RI Flay, Brian/A-8517-2008 OI Flay, Brian/0000-0002-5209-2766 NR 0 TC 9 Z9 9 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0965-2140 J9 ADDICTION JI Addiction PD MAY PY 2003 VL 98 SU 1 BP III EP IV DI 10.1046/j.1360-0443.98.s1.1.x PG 2 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 681BZ UT WOS:000183018100001 ER PT J AU Ridenour, TA Cottler, LB Compton, WM Spitznagel, EL Cunningham-Williams, RM AF Ridenour, TA Cottler, LB Compton, WM Spitznagel, EL Cunningham-Williams, RM TI Is there a progression from abuse disorders to dependence disorders? SO ADDICTION LA English DT Article; Proceedings Paper CT 63rd Annual Meeting of the College-on-Problems-of-Drug-Dependence CY JUN, 2001 CL SCOTTSDALE, ARIZONA SP Coll Problems Drug Dependence DE alcohol; cannabis; cocaine; drug abuse; drug dependence; opiates; progression ID SUBSTANCE USE DISORDERS; ALCOHOL DEPENDENCE; DRUG-USE; RELIABILITY; INVOLVEMENT; BEHAVIOR; DRINKING; JAPANESE; PATTERNS; COCAINE AB Background Recent studies suggest that a progression occurs from alcohol abuse to alcohol dependence. Although DSM-IV criteria for all substance use-related diagnoses are based largely on the alcohol dependence syndrome, progression from abuse to dependence might not generalize to other substances. Aims This study tested whether a progression from DSM-IV abuse to dependence occurs related to the use of cannabis, cocaine and opiates. Design Retrospective data from the DSM-IV Substance Use Disorders Work Group (n = 1226) were reanalysed using McNemar's chi(2), configural frequency analyses and survival analyses. Participants were men and women who were primarily African-Americans or Caucasians. Settings Participants were recruited from community and clinical settings. The measure was the Composite International Diagnostic Interview-Substance Abuse Module. Findings For all substances, life-time dependence in the absence of life-time abuse was rare. Results were consistent with a progression occurring for alcohol and cannabis, but not for cocaine and opiates. Abuse and dependence occurred in the same year for 66% of the cocaine users who experienced both disorders (57% of users with any cocaine disorder) and 65% of the opiate users who experienced both disorders (46% of users with any opiate disorder). Because cocaine and opiate dependence in the absence of abuse were rare, it is possible that progressions in cocaine and opiate disorders occur more rapidly than cannabis and alcohol. Conclusions Research is needed to clarify the mechanisms that influence progressions of substance use disorders. Potential factors leading to between-drug variation in rate of progression of disorders are discussed. C1 Penn State Univ, Prevent Res Ctr, State Coll, PA 16801 USA. Washington Univ, Sch Med, St Louis, MO 63130 USA. NIDA, Div Epidemiol Serv & Prevent Res, Washington, DC USA. Washington Univ, Dept Psychiat, St Louis, MO USA. RP Ridenour, TA (reprint author), Penn State Univ, Prevent Res Ctr, 135 E Nittany Ave,Ste 402, State Coll, PA 16801 USA. RI Cunningham-Williams, Renee/C-2350-2013; OI Ridenour, Ty/0000-0002-9709-6808 FU NIAAA NIH HHS [AA12111]; NIDA NIH HHS [DA00430, DA00434, DA05585, DA12900]; NIMH NIH HHS [MH17104] NR 27 TC 28 Z9 28 U1 4 U2 5 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0965-2140 J9 ADDICTION JI Addiction PD MAY PY 2003 VL 98 IS 5 BP 635 EP 644 DI 10.1046/j.1360-0443.2003.00350.x PG 10 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 676MD UT WOS:000182755100014 PM 12751981 ER PT J AU Umhau, JC AF Umhau, JC TI Long-term abstinent alcoholics have a blunted blood glucose response to 2-deoxy-D-glucose - Reply SO ALCOHOL AND ALCOHOLISM LA English DT Letter C1 NIAAA, Clin Studies Lab, NIH, Bethesda, MD 20892 USA. RP Umhau, JC (reprint author), NIAAA, Clin Studies Lab, NIH, Bldg 10,Room 6S240,10 Ctr Dr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0735-0414 J9 ALCOHOL ALCOHOLISM JI Alcohol Alcohol. PD MAY-JUN PY 2003 VL 38 IS 3 BP 287 EP 287 DI 10.1093/alcalc/agg074 PG 1 WC Substance Abuse SC Substance Abuse GA 674KA UT WOS:000182634900017 ER PT J AU Barr, CS Newman, TK Becker, ML Champoux, M Lesch, KP Suomi, SJ Goldman, D Higley, JD AF Barr, CS Newman, TK Becker, ML Champoux, M Lesch, KP Suomi, SJ Goldman, D Higley, JD TI Serotonin transporter gene variation is associated with alcohol sensitivity in rhesus macaques exposed to early-life stress SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE nonhuman primate; serotonin transporter; environment; stress; alcohol sensitivity ID NONHUMAN PRIMATE MODEL; 5-HYDROXYINDOLEACETIC ACID CONCENTRATIONS; DIMINISHED SOCIAL COMPETENCE; ANXIETY-RELATED TRAITS; PSYCHOMOTOR PERFORMANCE; PROMOTER POLYMORPHISM; GENDER DIFFERENCES; EARLY EXPERIENCE; TOLERANCE; ETHANOL AB Background: Decreased sensitivity to alcohol has been demonstrated to be a predictor of alcoholism in humans, and variation in the gene-linked polymorphic region of the serotonin transporter (5-HTTLPR) is associated with the response to the motor-impairing effects of alcohol. In a nonhuman primate model of excessive alcohol intake, we have shown that decreased serotonin turnover is associated with both lower initial sensitivity to alcohol and higher prospective alcohol consumption using rhesus macaques. In addition, we have demonstrated that macaques separated from their mothers and reared in peer-only groups are more likely to consume alcohol as adults. Method: To examine the relationship between serotonin transporter genotype, early rearing experience, and initial sensitivity to alcohol, peer- and mother-reared, adolescent, alcohol-naive rhesus macaques (n=123) were rated for intoxication after intravenous administration of ethanol (2.2 g/kg and 2.0 g/kg for males and females, respectively) during two testing periods. Serotonin transporter (rh5-HTTLPR) genotype was determined using polymerase chain reaction followed by gel electrophoresis, and data were analyzed using ANOVA and the Mann-Whitney U test. Results: Our analyses demonstrate an effect of serotonin transporter gene variation on ethanol sensitivity, such that animals homozygous for the l allele exhibited decreased sensitivity to the ataxic and sedating effects of alcohol, This effect remained after correction for blood ethanol concentrations and birth cohort. When animals were segregated according to rearing condition, serotonin transporter gene variation predicted intoxication scores among peer-reared animals. Conclusions: As in some human reports, this study demonstrates a diminution in the response to alcohol in animals homozygous for the l rh5-HTTLPR allele. The phenotypic expression of this genotype in l/s animals, however. is environmentally dependent. C1 NIAAA, Clin Studies Lab, Primate Unit, NIH,Anim Ctr, Poolesville, MD 20837 USA. NICHHD, Comparat Ethol Lab, NIH, Poolesville, MD 20837 USA. NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. Univ Wurzburg, Clin & Mol Psychobiol Dept Psychiat & Psychothera, Wurzburg, Germany. RP Barr, CS (reprint author), NIAAA, Clin Studies Lab, Primate Unit, NIH,Anim Ctr, POB 529,Bldg 112, Poolesville, MD 20837 USA. RI Goldman, David/F-9772-2010; Lesch, Klaus-Peter/J-4906-2013 OI Goldman, David/0000-0002-1724-5405; Lesch, Klaus-Peter/0000-0001-8348-153X NR 37 TC 114 Z9 117 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2003 VL 27 IS 5 BP 812 EP 817 DI 10.1097/01.ALC.0000067976.62827.ED PG 6 WC Substance Abuse SC Substance Abuse GA 682GN UT WOS:000183083500010 PM 12766626 ER PT J AU Tamayo, C Richardson, MA AF Tamayo, C Richardson, MA TI Vitamin C as a cancer treatment: State of the science and recommendations for research SO ALTERNATIVE THERAPIES IN HEALTH AND MEDICINE LA English DT Review ID SYNERGISTIC ANTITUMOR-ACTIVITY; CELL LUNG-CANCER; BIOLOGICAL RESPONSE MODIFIERS; SK-N-SH; ASCORBIC-ACID; RADICAL INTENSITY; SODIUM ASCORBATE; IN-VITRO; COMPLEMENTARY/ALTERNATIVE MEDICINE; ANTIGEN PRESENTATION C1 InnoVis Commun, Encinitas, CA 92024 USA. NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. RP Tamayo, C (reprint author), InnoVis Commun, 169 Saxony Rd,Suite 104, Encinitas, CA 92024 USA. FU NCI NIH HHS [5 U24 CA66826-03] NR 178 TC 8 Z9 8 U1 0 U2 0 PU INNOVISION COMMUNICATIONS PI ALISO VIEJO PA 101 COLUMBIA, ALISO VIEJO, CA 92656 USA SN 1078-6791 J9 ALTERN THER HEALTH M JI Altern. Ther. Health Med. PD MAY-JUN PY 2003 VL 9 IS 3 BP 94 EP 102 PG 9 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA 678MN UT WOS:000182871100011 PM 12776480 ER PT J AU Crawford, CC Sparber, AG Jonas, WB AF Crawford, CC Sparber, AG Jonas, WB TI A systematic review of the quality of research on hands-on and distance healing: Clinical and laboratory studies SO ALTERNATIVE THERAPIES IN HEALTH AND MEDICINE LA English DT Article; Proceedings Paper CT 1st American Samueli Symposium CY JAN 10-12, 2003 CL NEWPORT BEACH, CALIFORNIA ID CORONARY-CARE UNIT; RANDOMIZED CONTROLLED TRIAL; INTERCESSORY PRAYER; THERAPEUTIC TOUCH; PAIN; POPULATION; ARTHRITIS; EFFICACY; OUTCOMES; REMOTE AB Purpose To systematically review the quality of published experimental clinical and laboratory research involving hands-on healing and distance healing between 1955 and 2001. Data Sources Studies were identified through comprehensive literature searches on spiritual healing in MEDLINE, PSYCH LIT EMBASE, CISCOM, and the Cochrane Library from their inceptions to December 2001. Study Selection We selected published randomized, controlled trials of spiritual healing (hands-on healing and distance healing) done in clinical and laboratory settings, all of which had been peer reviewed. Data Extraction Independent quality assessment of internal validity was conducted on all identfied studies using the comprehensive Likelihood of Validity Evaluation scale. Clinical and laboratory studies were analyzed separately and then subdivided into handson healing or distance healing interventions. Results A total of 45 laboratory and 45 clinical studies published between 1956 and 2001 met the inclusion criteria. Of the clinical studies, 31 (70.5%) reported positive outcomes as did 28 (62%) of the laboratory studies; 4 (9%) of the clinical studies reported negative outcomes as did 15 (33%) of the laboratory studies. The mean percent overall internal validity for clinical studies was 69% (65% for hands-on healing and 75% for distance healing) and for laboratory studies 82% (82% for hands-on healing and 81% for distance healing). Major methodological problems of these studies included adequacy of blinding, dropped data in laboratory studies, reliability of outcome measures, rare use of power estimations and confidence intervals, and lack of independent replication. Conclusions When laboratory studies were compared to clinical studies in the areas of hands-on healing and distance healing across the quality criteria for internal validity, distance healing studies scored better than hands-on healing studies, and laboratory studies fared better than clinical studies. Many studies of healing contained major problems that must he addressed in any future research. (Altern Ther Health Med. 2003;9(3 Suppl):96A-104A). C1 Samueli Inst Informat Biol, Alexandria, VA USA. Uniformed Serv Univ Hlth Sci, Dept Family Med, Bethesda, MD 20814 USA. NIH, Ctr Clin, Nursing & Patient Care Serv, Bethesda, MD 20892 USA. RP Crawford, CC (reprint author), Samueli Inst Informat Biol, Alexandria, VA USA. NR 77 TC 17 Z9 18 U1 0 U2 1 PU INNOVISION COMMUNICATIONS PI ALISO VIEJO PA 101 COLUMBIA, ALISO VIEJO, CA 92656 USA SN 1078-6791 J9 ALTERN THER HEALTH M JI Altern. Ther. Health Med. PD MAY-JUN PY 2003 VL 9 IS 3 SU S BP A96 EP A104 PG 9 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA 680RF UT WOS:000182990600009 PM 12776468 ER PT J AU Vasan, RS Larson, MG Levy, D Galderisi, M Wolf, PA Benjamin, EJ AF Vasan, RS Larson, MG Levy, D Galderisi, M Wolf, PA Benjamin, EJ TI Doppler transmitral flow indexes and risk of atrial fibrillation (The Framingham Heart Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID VENTRICULAR DIASTOLIC FUNCTION; FAILURE; VELOCITY; HEALTH; ADULTS; COHORT AB Atrial fibrillation (AF) is characterized by structural remodeling and atrial systolic failure. It is unclear if atrial filling abnormalities precede the onset of AF. We evaluated 942 Framingham Study subjects (587 women; mean age 75 years) who underwent Doppler echocardiographic evaluation at a routine examination and who did not hove a history of AF. We used multivariable Cox regression models (stratified by gender and prevalent cardiovascular disease) to examine the relations of Doppler transmitral flow indexes (ratio of the velocity-time time integrals of the early [E] and late [A] diastolic filling waves [VTI E/A], a correlate of atrial conduit function; E-wove deceleration time; the atrial filling fraction, an index of atrial systolic function; and peak A wave velocity) to the incidence of AF. At follow-up (mean 7 years), 85 subjects (41 women) developed AF. In models adjusting for established risk factors for AF (including left atrial size) at baseline, and for heart failure and myocardial infarction on follow-up, a 1 SD increment in VTI E/A was associated with a 28% increase in risk of AF (hazards ratio 1.28, 95% confidence interval 1.02 to 1.59). A 1 SD decrease in the atrial filling fraction was associated with a 28% higher risk of AF (hazards ratio, 1.28, 95% confidence interval 0.98 to 1.67). There was a U-shaped relation between peak A-wave velocity and risk of AF. Thus, in our elderly community-based sample, increased VTI E/A and a low atrial filling fraction were markers of increased risk of AF, suggesting that altered atrial filling may antedate AF. (C) 2003 by Excerpta Medica, Inc. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Univ Naples Federico II, Dept Med, Naples, Italy. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Cardiol, Boston, MA 02215 USA. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Clin Epidemiol, Boston, MA 02215 USA. NHLBI, Bethesda, MD 20892 USA. RP Vasan, RS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Galderisi, Maurizio/0000-0003-0311-9069; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [K24 HL 04334-01A1, N01-HC-25195]; NINDS NIH HHS [NS-17950] NR 28 TC 38 Z9 40 U1 0 U2 1 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 MAY 1 PY 2003 VL 91 IS 9 BP 1079 EP 1083 DI 10.1016/S0002-9149(03)00152-8 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 675NU UT WOS:000182702100008 PM 12714150 ER PT J AU Pinsky, PF Kramer, BS Reding, D Buys, S AF Pinsky, PF Kramer, BS Reding, D Buys, S TI Reported family history of cancer in the prostate, lung, colorectal, and ovarian cancer screening trial SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE ethnic groups; family characteristics; genetic predisposition to disease; neoplasms; questionnaires; sex factors ID BREAST-CANCER; ACCURACY AB The authors analyzed data from almost 150,000 subjects aged 55-74 years enrolled in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who completed a self-administered baseline questionnaire (1993-2001) that included items about family history of cancer. Male respondents reported significantly less family history of cancer than females. The relative underreporting by male respondents relative to females was greater for female family members (28% lower for sisters and 21% lower for mothers) than for male family members (13% lower for brothers and 9% lower for fathers). Black, Hispanic, and Asian respondents reported significantly less family history of cancer than Whites. Reported family history prevalences for parents decreased with respondents' age, while those for siblings increased with respondents' age. The four most commonly reported cancers in families were breast (11.8%), lung (10.1%), colorectal (9.4%), and prostate (7.3%) cancer. Expected prevalences in family members of history of cancer overall and history of specific types of cancer were calculated using incidence rates and life table data obtained from the Surveillance, Epidemiology, and End Results Program. Overall, the ratio of reported cancer rates to expected cancer rates in family members was approximately 0.7. Liver, bone, stomach, and brain cancer had greater-than-average reported:expected ratios, while lymphoma, bladder cancer, melanoma, and testicular cancer had lower-than-average ratios. C1 NCI, Div Canc Prevent, Bethesda, MD 20892 USA. NIH, Off Dis Prevent, Off Director, Bethesda, MD 20892 USA. Marshfield Clin Fdn Med Res & Educ, Marshfield, WI 54449 USA. Univ Utah, Sch Med, Dept Internal Med, Div Hematol Oncol, Salt Lake City, UT USA. RP Pinsky, PF (reprint author), NCI, Div Canc Prevent, 6130 Execut Blvd,EPN 3064, Bethesda, MD 20892 USA. NR 15 TC 45 Z9 45 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAY 1 PY 2003 VL 157 IS 9 BP 792 EP 799 DI 10.1093/aje/kwg043 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 674KE UT WOS:000182635300005 PM 12727673 ER PT J AU Alavanja, MCR Samanic, C Dosemeci, M Lubin, J Tarone, R Lynch, CF Knott, C Thomas, K Hoppin, JA Barker, J Coble, J Sandler, DP Blair, A AF Alavanja, MCR Samanic, C Dosemeci, M Lubin, J Tarone, R Lynch, CF Knott, C Thomas, K Hoppin, JA Barker, J Coble, J Sandler, DP Blair, A TI Use of agricultural pesticides and prostate cancer risk in the agricultural health study cohort SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE agrochemicals; fungicides, industrial; herbicides; insecticides; pesticides; prostatic neoplasms; risk ID UNITED-STATES; METHYL-BROMIDE; FAMILY HISTORY; MORTALITY; FARMERS; APPLICATORS; EXPOSURE; CANADA AB The authors examined the relation between 45 common agricultural pesticides and prostate cancer incidence in a prospective cohort study of 55,332 male pesticide applicators from Iowa and North Carolina with no prior history of prostate cancer. Data were collected by means of self-administered questionnaires completed at enrollment (1993-1997). Cancer incidence was determined through population-based cancer registries from enrollment through December 31, 1999. A prostate cancer standardized incidence ratio was computed for the cohort. Odds ratios were computed for individual pesticides and for pesticide use patterns identified by means of factor analysis. A prostate cancer standardized incidence ratio of 1.14 (95% confidence interval: 1.05, 1.24) was observed for the Agricultural Health Study cohort. Use of chlorinated pesticides among applicators over 50 years of age and methyl bromide use were significantly associated with prostate cancer risk. Several other pesticides showed a significantly increased risk of prostate cancer among study subjects with a family history of prostate cancer but not among those with no family history. Important family history-pesticide interactions were observed. C1 NCI, Div Canc Epidemiol & Genet, EPS, Bethesda, MD 20892 USA. Univ Iowa, Dept Epidemiol, Iowa City, IA USA. Battelle Ctr Publ Hlth Res & Evaluat, Durham, NC USA. US EPA, Res Triangle Pk, NC 27711 USA. NIEHS, Res Triangle Pk, NC 27709 USA. IMS Inc, Silver Spring, MD USA. RP Alavanja, MCR (reprint author), NCI, Div Canc Epidemiol & Genet, EPS, Room 8000, Bethesda, MD 20892 USA. OI Sandler, Dale/0000-0002-6776-0018 NR 39 TC 191 Z9 201 U1 2 U2 19 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAY 1 PY 2003 VL 157 IS 9 BP 800 EP 814 DI 10.1093/aje/kwg040 PG 15 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 674KE UT WOS:000182635300006 PM 12727674 ER PT J AU Olin, JT Reynolds, CF Light, E Cuthbert, BN AF Olin, JT Reynolds, CF Light, E Cuthbert, BN TI Career development and training in geriatric mental health - Report of an NIMH workshop SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article AB At a National Institute of Mental Health (NIMH)-sponsored meeting, the participants discussed means of increasing the pool of late-life mental-illness researchers. Approaches identified included encouraging retention of junior scientists through greater mentoring and support; creation of research postdoctoral programs by investigators and institutions that lack late-life emphasis; earlier commitment to late-life research with predoctoral training mechanisms; recruitment of ethnic and racial minority scholars into late-life research; and recruitment of newly established researchers through postdoctoral training mechanisms. Federal, public, and private mechanisms need to be better leveraged to grow late-life mental-illness research infrastructure and meet increasing demand and scientific opportunities. C1 NIMH, Bethesda, MD 20892 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. RP Olin, JT (reprint author), NIMH, 6001 Execut Blvd,Room 7160 MSC 9635, Bethesda, MD 20892 USA. FU NIMH NIH HHS [R25 MH 60473] NR 6 TC 2 Z9 2 U1 0 U2 0 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAY-JUN PY 2003 VL 11 IS 3 BP 275 EP 279 PG 5 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 673DQ UT WOS:000182565300004 PM 12724106 ER PT J AU Hattori, E Liu, CY Badner, JA Bonner, TI Christian, SL Maheshwari, M Detera-Wadleigh, SD Gibbs, RA Gershon, ES AF Hattori, E Liu, CY Badner, JA Bonner, TI Christian, SL Maheshwari, M Detera-Wadleigh, SD Gibbs, RA Gershon, ES TI Polymorphisms at the G72/G30 gene locus, on 13q33, are associated with bipolar disorder in two independent pedigree series SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article; Proceedings Paper CT 52nd Annual Meeting of the American-Society-of-Human-Genetics CY OCT 15-19, 2002 CL BALTIMORE, MARYLAND SP Amer Soc Human Genet, NICHHD, NCI, NIMH, Affymetrix Inc, Gentra Syst, NIDCD ID LINKAGE DISEQUILIBRIUM; SUSCEPTIBILITY LOCUS; INITIATIVE PEDIGREES; SCHIZOPHRENIA; HAPLOTYPE; GENOTYPE; DISEASE; ALLELES; ILLNESS; REGION AB Linkage evidence suggests that chromosome 13 (13q32-33) contains susceptibility genes for both bipolar disorder and schizophrenia. Recently, genes called "G72" and "G30" were identified, and polymorphisms of these overlapping genes were reported to be associated with schizophrenia. We studied two series of pedigrees with bipolar disorder: the Clinical Neurogenetics (CNG) pedigrees ( in which linkage to illness had been previously reported at 13q32-33), with 83 samples from 22 multiplex families, and the National Institute of Mental Health (NIMH) Genetics Initiative pedigrees, with 474 samples from 152 families. Sixteen single-nucleotide polymorphisms (SNPs) were genotyped at and around the G72/G30 locus, which covered a 157-kb region encompassing the entire complementary DNA sequences of G72 and G30. We performed transmission/disequilibrium testing (TDT) and haplotype analysis, since a linkage-disequilibrium block was present at this gene locus. In the CNG and NIMH data sets, the results of global TDT of the entire haplotype set were significant and consistent (P = .0004 and P = .008, respectively). In the CNG series, the associated genotypes divided the families into those with linkage and those without linkage ( partitioned by the linkage evidence). Analysis of the decay of haplotype sharing gave a location estimate that included G72/G30 in its 95% confidence interval. Although statistically significant association was not detected for individual SNPs in the NIMH data set, the same haplotype was consistently overtransmitted in both series. These data suggest that a susceptibility variant for bipolar illness exists in the vicinity of the G72/G30 genes. Taken together with the earlier report, this is the first demonstration of a novel gene(s), discovered through a positional approach, independently associated with both bipolar illness and schizophrenia. C1 Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. RIKEN, Lab Mol Psychiat, Brain Sci Inst, Wako, Saitama 35101, Japan. Cent S Univ, Natl Lab Med Genet China, Changsha, Hunan, Peoples R China. NIMH, Intramural Res Program, Bethesda, MD 20892 USA. Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. RP Hattori, E (reprint author), Univ Chicago, Dept Psychiat, 924 E 57th St,Room R022, Chicago, IL 60637 USA. RI Liu, Chunyu/G-7561-2012 OI Liu, Chunyu/0000-0002-5986-4415 FU NIMH NIH HHS [R01 MH065560, R01 MH65560-01, U01 MH46280, R01 MH059535, R01 MH59535]; PHS HHS [U01 H46282, U01 H46274] NR 33 TC 200 Z9 205 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAY PY 2003 VL 72 IS 5 BP 1131 EP 1140 DI 10.1086/374822 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 671PZ UT WOS:000182474400006 PM 12647258 ER PT J AU Antonellis, A Ellsworth, RE Sambuughin, N Puls, I Abel, A Lee-Lin, SQ Jordanova, A Kremensky, I Christodoulou, K Middleton, LT Sivakumar, K Ionasescu, V Funalot, B Vance, JM Goldfarb, LG Fischbeck, KH Green, ED AF Antonellis, A Ellsworth, RE Sambuughin, N Puls, I Abel, A Lee-Lin, SQ Jordanova, A Kremensky, I Christodoulou, K Middleton, LT Sivakumar, K Ionasescu, V Funalot, B Vance, JM Goldfarb, LG Fischbeck, KH Green, ED TI Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID CHROMOSOME 7P; CMT2D AB Charcot-Marie-Tooth disease type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V) are axonal peripheral neuropathies inherited in an autosomal dominant fashion. Our previous genetic and physical mapping efforts localized the responsible gene(s) to a well-defined region on human chromosome 7p. Here, we report the identification of four disease-associated missense mutations in the glycyl tRNA synthetase gene in families with CMT2D and dSMA-V. This is the first example of an aminoacyl tRNA synthetase being implicated in a human genetic disease, which makes genes that encode these enzymes relevant candidates for other inherited neuropathies and motor neuron diseases. C1 NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. NINDS, Clin Neurogenet Unit, NIH, Bethesda, MD 20892 USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Barrow Neurol Inst, Phoenix, AZ 85013 USA. George Washington Univ, Grad Program Genet, Washington, DC USA. Med Univ Sofia, Lab Mol Pathol, Sofia, Bulgaria. Cyprus Inst Neurol & Genet, Mol Genet Dept D, Nicosia, Cyprus. Univ Iowa, Dept Pediat, Div Med Genet, Iowa City, IA 52242 USA. Hop St Anne, INSERM, U573, F-75674 Paris, France. Hop St Anne, Dept Neurol, F-75674 Paris, France. Duke Univ, Ctr Human Genet, Inst Genome Sci & Policy, Durham, NC USA. RP Green, ED (reprint author), Bldg 50,Room 5222,50 South Dr,MSC 8002, Bethesda, MD 20892 USA. RI Jordanova, Albena/H-8323-2015 OI Jordanova, Albena/0000-0002-3833-3754 FU NINDS NIH HHS [P01 NS026630, NS 26630] NR 16 TC 278 Z9 291 U1 0 U2 5 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAY PY 2003 VL 72 IS 5 BP 1293 EP 1299 DI 10.1086/375039 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 671PZ UT WOS:000182474400022 PM 12690580 ER PT J AU Ahmed, ZM Morell, RJ Riazuddin, S Gropman, A Shaukat, S Ahmad, MM Mohiddin, SA Fananapazir, L Caruso, RC Husnain, T Khan, SN Riazuddin, S Griffith, AJ Friedman, TB Wilcox, ER AF Ahmed, ZM Morell, RJ Riazuddin, S Gropman, A Shaukat, S Ahmad, MM Mohiddin, SA Fananapazir, L Caruso, RC Husnain, T Khan, SN Riazuddin, S Griffith, AJ Friedman, TB Wilcox, ER TI Mutations of MYO6 are associated with recessive deafness, DFNB37 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID NONSYNDROMIC HEARING-LOSS; UNCONVENTIONAL MYOSIN-VI; SNELLS-WALTZER MICE; MEDIATED ENDOCYTOSIS; HUMAN HOMOLOG; HAIR-CELLS; GENE; ISOFORM AB Cosegregation of profound, congenital deafness with markers on chromosome 6q13 in three Pakistani families defines a new recessive deafness locus, DFNB37. Haplotype analyses reveal a 6-cM linkage region, flanked by markers D6S1282 and D6S1031, that includes the gene encoding unconventional myosin VI. In families with recessively inherited deafness, DFNB37, our sequence analyses of MYO6 reveal a frameshift mutation (36-37insT), a nonsense mutation (R1166X), and a missense mutation (E216V). These mutations, along with a previously published missense allele linked to autosomal dominant progressive hearing loss (DFNA22), provide an allelic spectrum that probes the relationship between myosin VI dysfunction and the resulting phenotype. C1 Natl Inst Deafness & Other Commun Disorders, Sect Human Genet, Genet Mol Lab, NIH, Rockville, MD 20850 USA. Natl Inst Deafness & Other Commun Disorders, Sect Gene Struct & Funct, Genet Mol Lab, NIH, Rockville, MD 20850 USA. Natl Inst Deafness & Other Commun Disorders, Hearing Sect, NIH, Rockville, MD 20850 USA. Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. NINDS, Neurogenet Branch, Washington, DC USA. Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. NHLBI, Clin Cardiol Sect, NIH, Bethesda, MD 20892 USA. NEI, Sect Ophthalm Mol Genet, NIH, Bethesda, MD 20892 USA. RP Friedman, TB (reprint author), Natl Inst Deafness & Other Commun Disorders, Sect Human Genet, Genet Mol Lab, NIH, 5 Res Court,2A-19, Rockville, MD 20850 USA. RI Nasim Khan, Shaheen/F-2135-2015; Husnain, Tayyab/G-3805-2015; OI Morell, Robert/0000-0003-1537-7356 FU NIDCD NIH HHS [T32 DC000035, Z01 DC000039, Z01 DC000064, ZO1 DC000039-06, ZO1 DC000064-02, ZO1 DC00035-06] NR 30 TC 101 Z9 106 U1 2 U2 5 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAY PY 2003 VL 72 IS 5 BP 1315 EP 1322 DI 10.1086/375122 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 671PZ UT WOS:000182474400025 PM 12687499 ER PT J AU Sharabi, Y Dendi, R Holmes, C Goldstein, DS AF Sharabi, Y Dendi, R Holmes, C Goldstein, DS TI Labile hypertension from baroreflex failure: A late sequela of neck irradiation SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Meeting Abstract CT 18th Annual Scientific Meeting of the American-Society-of-Hypertension CY MAY 14-17, 2003 CL NEW YORK, NEW YORK SP Amer Soc Hypertens DE baroreflex failure; labile hypertension; irradiation C1 NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. NR 0 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 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD MAY PY 2003 VL 16 IS 5 MA OR15 BP 7A EP 7A DI 10.1016/S0895-7061(03)00099-2 PN 2 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 677LK UT WOS:000182809000016 ER PT J AU Papademetriou, V Gordon, D Hartney, TJ Geraci, TS Piller, LB Ford, CE Reisin, E Summer, BM Wong, ND Narayan, P Nwachuku, C Haywood, JL AF Papademetriou, V Gordon, D Hartney, TJ Geraci, TS Piller, LB Ford, CE Reisin, E Summer, BM Wong, ND Narayan, P Nwachuku, C Haywood, JL TI Baseline characteristics of participants in the lipid lowering component of ALLHAT SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Meeting Abstract CT 18th Annual Scientific Meeting of the American-Society-of-Hypertension CY MAY 14-17, 2003 CL NEW YORK, NEW YORK SP Amer Soc Hypertens DE cholesterol; hypertension; lipids C1 VAMC, Washington, DC USA. NHLBI, NIH, Bethesda, MD 20892 USA. Univ Calif Irvine, Irvine, CA 92717 USA. NR 0 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 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD MAY PY 2003 VL 16 IS 5 MA OR28 BP 12A EP 12A DI 10.1016/S0895-7061(03)00112-2 PN 2 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 677LK UT WOS:000182809000029 ER PT J AU Svetkey, LP Ard, JD Erlinger, TP Aickin, M Vollmer, WM Stevens, V Elmer, P Cooper, L Harsha, D Appel, LJ AF Svetkey, LP Ard, JD Erlinger, TP Aickin, M Vollmer, WM Stevens, V Elmer, P Cooper, L Harsha, D Appel, LJ TI PREMIER trial: BP effects of lifestyle interventions in subgroups SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Meeting Abstract CT 18th Annual Scientific Meeting of the American-Society-of-Hypertension CY MAY 14-17, 2003 CL NEW YORK, NEW YORK SP Amer Soc Hypertens DE DASH diet; lifestyle modification; subgroups C1 Duke Univ, Med Ctr, Duke Hypertens Ctr, Durham, NC 27706 USA. Duke Univ, Med Ctr, Sarah Stedman Ctr Nutr Studies, Durham, NC 27706 USA. Johns Hopkins Univ, Welch Ctr, Baltimore, MD 21218 USA. Ctr Hlth Res, Portland, OR USA. NHLBI, NIH, Bethesda, MD 20892 USA. Pennington Biomed Res Ctr, Baton Rouge, LA USA. NR 0 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 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD MAY PY 2003 VL 16 IS 5 MA OR61 BP 28A EP 28A DI 10.1016/S0895-7061(03)00144-4 PN 2 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 677LK UT WOS:000182809000061 ER EF