FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Koechlin, E Corrado, G Pietrini, P Grafman, J AF Koechlin, E Corrado, G Pietrini, P Grafman, J TI Dissociating the role of the medial and lateral anterior prefrontal cortex in human planning SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE striatum; task switching; anticipation ID POSITRON-EMISSION-TOMOGRAPHY; SPATIAL WORKING-MEMORY; NEURONAL-ACTIVITY; FRONTAL-CORTEX; BASAL GANGLIA; LEARNED MOVEMENTS; PREMOTOR CORTEX; COGNITIVE TASKS; NEURAL SYSTEMS; LOBE LESIONS AB The anterior prefrontal cortex is known to subserve higher cognitive functions such as task management and planning. Less is known, however, about the functional specialization of this cortical region in humans. Using functional MRI, we report a double dissociation: the medial anterior prefrontal cortex, in association with the ventral striatum, was engaged preferentially when subjects executed tasks in sequences that were expected, whereas the polar prefrontal cortex, in association with the dorsolateral striatum, was involved preferentially when subjects performed tasks in sequences that were contingent on unpredictable events. These results parallel the functional segregation previously described between the medial and lateral premotor cortex underlying planned and contingent motor control and extend this division to the anterior prefrontal cortex, when task management and planning are required. Thus, our findings support the assumption that common frontal organizational principles underlie motor and higher executive functions in humans. C1 NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. Univ Paris 06, INSERM, U483, F-75005 Paris, France. RP Grafman, J (reprint author), NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. EM grafmanj@ninds.nih.gov RI Koechlin, Etienne/E-5061-2016; OI Grafman, Jordan H./0000-0001-8645-4457 NR 51 TC 197 Z9 199 U1 2 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 20 PY 2000 VL 97 IS 13 BP 7651 EP 7656 DI 10.1073/pnas.130177397 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 327UH UT WOS:000087811600128 PM 10852964 ER PT J AU Liu, ZW Donahue, RE Young, NS Brown, KE AF Liu, ZW Donahue, RE Young, NS Brown, KE TI Sequencing and characterization of A-2 plaque virus: A new member of the Picornaviridae family SO VIROLOGY LA English DT Article DE Picornavirus; A2 virus; enterovirus; hepatitis ID COMPLETE NUCLEOTIDE-SEQUENCE; ENCEPHALOMYOCARDITIS VIRUS; 3'-UNTRANSLATED REGION; APLASTIC-ANEMIA; POLIOVIRUS RNA; A VIRUS; HEPATITIS; GENOME; ENTEROVIRUSES; ORGANIZATION AB A-2 plaque virus (A2 virus) was originally isolated from the icteric-phase sera of US servicemen with Viral hepatitis in the 1960s, but apart from a preliminary characterization little is known about the agent. We have now successfully cloned and sequenced the complete viral genome. A2 viral RNA consists of 7312 nucleotides, excluding the 62 nucleotide poly(A) tract at the 3' end, with one large open reading frame. Although clearly a member of the Picornaviridae, there is low homology to the available sequences, suggesting it is only loosely related to the classic rhino/enterovirus genus. In addition, there was no reactivity with group specific monoclonal antibody blends against polioviruses, enteroviruses 70 and 71, coxsackievirus B, and echoviruses. Two tamarins were inoculated with A2 virus to study viral pathogenesis. Both animals that received A2 virus became transiently viremic 1 week after the infection, as determined by RT-PCR, and they developed an antibody response to A2 virus. However, no physical signs or biochemical abnormalities, including elevated liver transaminases, were observed. In addition, no liver samples from patients with fulminant hepatitis (n = 7) or controls (n = 7) were positive for A2 viral RNA nor was anti-A2 neutralizing antibody detected in sera from hepatitis patients (n = 14), healthy laboratory donors (n = 14), or US blood donors (n = 33); however, most sera contained antibodies reactive with A2 virus proteins. These results suggest that A2 virus is a new member of the Picornaviridae but that its pathogenicity in nonhuman primates and association with human disease still need to be determined, (C) 2000 Academic Press. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Brown, KE (reprint author), Bldg 10,Rm 7C218,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 45 TC 2 Z9 2 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JUN 20 PY 2000 VL 272 IS 1 BP 168 EP 176 DI 10.1006/viro.2000.0355 PG 9 WC Virology SC Virology GA 330EG UT WOS:000087949400017 PM 10873759 ER PT J AU Dittmer, U Hasenkrug, KJ AF Dittmer, U Hasenkrug, KJ TI Different immunological requirements for protection against acute versus persistent friend retrovirus infections SO VIROLOGY LA English DT Article ID CD4(+) T-CELLS; MURINE LEUKEMIA-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; NEUTRALIZING ANTIBODIES; MONOCLONAL-ANTIBODIES; HIV-1 INFECTION; INDUCED ERYTHROLEUKEMIA; CHORIOMENINGITIS VIRUS; LIVE; MICE AB The propensity of retroviruses to rapidly establish persistent infections poses a formidable problem in Vaccination strategies. In the current study, we use a live attenuated vaccine to study protection against acute and persistent Friend Virus infections in mice. Adoptive transfers of immune CD8(+) T cells combined with passive immunizations with virus-neutralizing antibodies increased protection against acute disease compared with either treatment alone, but there was no protection against the establishment of persistent infection. In addition, the protection against acute disease elicited by the combination treatment was dependent on endogenous CD4(+) T cells as no protection was achieved in CD4(+) T-cell-depleted mice. Quantitative studies showed that doubling the numbers of immune lymphocytes used in adoptive transfer experiments increased protection against acute disease depending on the type of lymphocyte subset used in the transfer. CD8(+) T cells were the most potent subset for the transfer of such protection. However, even high numbers of immune CD8(+) T cells gave no protection against the establishment of persistent infections. The data indicate that strengthening the numbers of specific immune cell subsets may have a beneficial effect on protection against acute disease, but protection from establishment of persistence requires complex immune responses involving multiple lymphocyte subsets. (C) 2000 Academic Press. C1 NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Hasenkrug, KJ (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 40 TC 19 Z9 19 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JUN 20 PY 2000 VL 272 IS 1 BP 177 EP 182 DI 10.1006/viro.2000.0356 PG 6 WC Virology SC Virology GA 330EG UT WOS:000087949400018 PM 10873760 ER PT J AU Skiadopoulos, MH Surman, SR Durbin, AP Collins, PL Murphy, BR AF Skiadopoulos, MH Surman, SR Durbin, AP Collins, PL Murphy, BR TI Long nucleotide insertions between the HN and L protein coding regions of human parainfluenza virus type 3 yield viruses with temperature-sensitive and attenuation phenotypes SO VIROLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; VESICULAR STOMATITIS VIRUSES; VACCINE CANDIDATE; FOREIGN GENE; HEMAGGLUTININ-NEURAMINIDASE; STABLE EXPRESSION; RHESUS-MONKEYS; RABIES VIRUS; RECOMBINANT; GLYCOPROTEINS AB Recombinant parainfluenza virus 3 (rPIV3) is being developed as a vector to express foreign genes as a bivalent or multivalent live attenuated virus vaccine. In the present study, we examined the effect of inserted foreign sequence on virus replication in vitro and in vivo, focusing on the parameter of insert length. In one type of construct, foreign sequence of increasing length was flanked by PIV3 transcription signals and inserted as an additional gene unit (GU insert) between the HN and L genes, so that one additional mRNA would be made. in a second type of construct, foreign sequence was inserted into the downstream NCR (NCR insert) of the HN gene, so that the number of encoded mRNAs remained unchanged. In each case, the foreign sequence was designed to lack any significant open reading frame, which permitted an evaluation of the effect of insert length on replication independent of an effect of an expressed protein. The GU or NCR insert sizes ranged from 168 nucleotides (nt) to 3918 nt. rPIV3s containing GU insertions of up to 3918 nt in length, the largest size tested, were viable and replicated efficiently at permissive temperatures in vitro, but a reduction in plaque size was seen at 39 degrees C and 40 degrees C. The rPIV3 with a 3918-nt GU insertion was restricted in replication in the upper (fivefold) and lower (25-fold) respiratory tracts of hamsters. Although a 1908-nt GU insertion did not significantly modify replication of wild-type PIV3 in vitro or in vivo, its introduction significantly augmented the level of temperature sensitivity (Ls) and attenuation (att) specified by three mutations in the L protein of a cold-passaged attenuated PIV3 vaccine virus. rPIV3s bearing a 3126- or 3894-nt NCR insertion exhibited in vitro and in vivo phenotypes like those of the rPIV3s bearing similar-sized GU insertions. These findings indicate that rPIV3s whose genome length has been increased by more than 3000 nt by either a GU or an NCR insertion exhibit an unexpected host-range phenotype, that is, efficient replication in vitro but restricted replication in hamsters, especially in the lower respiratory tract. Furthermore, these effects were greatly enhanced when the rPIV3 backbone contained other ts or att mutations. The implications of these findings for the use of single-stranded, negative-sense RNA viruses as Vectors for vaccines are discussed. (C) 2000 Academic Press. C1 NIAID, Resp Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Skiadopoulos, MH (reprint author), NIAID, Resp Viruses Sect, Infect Dis Lab, NIH, Bldg 7,Room 100,7 Ctr Dr,MSC 0720, Bethesda, MD 20892 USA. FU NIAID NIH HHS [AI-000030, AI-000087] NR 45 TC 27 Z9 27 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JUN 20 PY 2000 VL 272 IS 1 BP 225 EP 234 DI 10.1006/viro.2000.0372 PG 10 WC Virology SC Virology GA 330EG UT WOS:000087949400023 PM 10873765 ER PT J AU Wang, ZF Chen, L Bayly, SF Torrence, PF AF Wang, ZF Chen, L Bayly, SF Torrence, PF TI Convergent synthesis of ribonuclease L-active 2 ',5 '- oligoadenylate-peptide nucleic acids SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID ANTISENSE CHIMERAS; TARGETING RNA; MESSENGER-RNA; 2-5A; 2',5'-OLIGOADENYLATE-ANTISENSE; DEGRADATION; BINDING; CELLS; DNA AB 2-5A was conjugated to N-(2-aminoethyl)-glycyl PNA by periodate oxidization, followed by coupling with amino-derivatized PNA and final cyanoborohydride reduction, An adduct of 2-5A pentamer with tetrameric thymine PNA activated RNase L with the same potency as earlier versions of 2-5A-PNA or 2-5A-DNA. (C) 2000 Elsevier Science Ltd. All rights reserved. C1 No Arizona Univ, Dept Chem, Flagstaff, AZ 86011 USA. NIDDKD, Med Chem Lab, Sect Biomed Chem, Bethesda, MD 20892 USA. No Arizona Univ, Dept Chem, Flagstaff, AZ 86011 USA. RP Torrence, PF (reprint author), No Arizona Univ, Dept Chem, Box 5698, Flagstaff, AZ 86011 USA. NR 27 TC 4 Z9 4 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JUN 19 PY 2000 VL 10 IS 12 BP 1357 EP 1360 DI 10.1016/S0960-894X(00)00240-7 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 326NV UT WOS:000087742400012 PM 10890163 ER PT J AU Nacro, K Bienfait, B Lewin, NE Blumberg, PM Marquez, VE AF Nacro, K Bienfait, B Lewin, NE Blumberg, PM Marquez, VE TI Diacylglycerols with lipophilically equivalent branched acyl chains display high affinity for protein kinase C (PK-C). A direct measure of the effect of constraining the glycerol backbone in DAG lactones (vol 10, pg 653, 2000) SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Correction C1 NCI, Labs Med Chem, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Nacro, K (reprint author), NCI, Labs Med Chem, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JUN 19 PY 2000 VL 10 IS 12 BP 1401 EP 1401 DI 10.1016/S0960-894X(00)00225-0 PG 1 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 326NV UT WOS:000087742400023 ER PT J AU Blanco, JCG Contursi, C Salkowski, CA DeWitt, DL Ozato, K Vogel, SN AF Blanco, JCG Contursi, C Salkowski, CA DeWitt, DL Ozato, K Vogel, SN TI Interferon regulatory factor (IRF)-1 and IRF-2 regulate interferon gamma-dependent cyclooxygenase 2 expression SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE inflammation; prostaglandin; macrophage; cytokine; septic shock ID SEQUENCE-BINDING-PROTEIN; NITRIC-OXIDE SYNTHASE; PROSTAGLANDIN ENDOPEROXIDE SYNTHASE-2; TRANSCRIPTION FACTOR IRF-1; HUMAN COLON-CANCER; FACTOR-I IRF-1; FACTOR KAPPA-B; IFN-GAMMA; GENE-EXPRESSION; CEREBRAL-ISCHEMIA AB Cyclooxygenases (Cox) are rate-limiting enzymes that initiate the conversion of arachidonic acid to prostanoids. Cox-2 is the inducible isoform that is upregulated by proinflammatory agents, initiating many prostanoid-mediated pathological aspects of inflammation. In this study, we demonstrate that interferon (IFN)-gamma alone or in synergy with lipopolysaccharide (LPS) or interleukin 1 alpha induces Cox-2 expression in mouse peritoneal macrophages, which is paralleled by changes in Cox-2 protein levels and prostaglandin E-2 (PGE(2)) release. Induction of Cox-2 was abrogated in macrophages that lack IFN regulatory factor (IRF)-1, consistent with an attenuated hepatic mRNA response in IRF-1(-/-) mice injected with LPS. Conversely, the absence of IRF-2 in macrophages resulted in a significant increase in both basal and inducible Cox-2 gene and protein expression as well as IFN-gamma-stimulated PGE(2) release, identifying IRF-2 as negative regulator of this promoter. Two IFN stimulation response elements were identified in the mouse Cox-2 promoter that were highly conserved in the human Cox-2 gene. Both bind endogenous IRF-1 and IRF-2 and regulate transcription in an IRF-1/2-dependent manner. Our data demonstrate conclusively the importance of IFN-gamma as a direct activator and coactivator of the Cox-2 gene, and the central role of IRF-1/2 family members in this process. C1 Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. Michigan State Univ, Dept Biochem, E Lansing, MI 48824 USA. RP Vogel, SN (reprint author), Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. FU NIAID NIH HHS [AI-18797, R01 AI018797, R37 AI018797, R56 AI018797]; NIGMS NIH HHS [GM-40713, GM-57323] NR 80 TC 101 Z9 104 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUN 19 PY 2000 VL 191 IS 12 BP 2131 EP 2144 DI 10.1084/jem.191.12.2131 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 327VH UT WOS:000087814400011 PM 10859338 ER PT J AU Zhu, XX Greig, NH Holloway, HW Whittaker, NF Brossi, A Yu, QS AF Zhu, XX Greig, NH Holloway, HW Whittaker, NF Brossi, A Yu, QS TI A practical conversion of natural physostigmine into the potent butyrylcholinesterase inhibitor N-1,N-8-bisnorcymserine SO TETRAHEDRON LETTERS LA English DT Article DE butyrylcholinesterase; Alzheimer's disease therapeutic; physostigmine; anticholinesterase; N-1,N-8-bisnorcymserine ID ANTICHOLINESTERASE ACTIVITIES; ALZHEIMERS-DISEASE; ANTIPODAL ISOMERS; ANALOGS; PHENSERINE AB A rapid novel synthetic route to the potent reversible butyrylcholinesterase inhibitor (-)-N-1,N-8-bis-norcymserine (1) is reported from physostigmine (2) in a 20% total yield. Details on the formation of the imino-quinone 6 obtained in the oxidation of N-1-benzylnoresermethole (4) and its conversion into N-1-bis-noreseroline (7) are given. As expected, the product of this synthesis, (1), had identical biological activity to the same agent produced by total synthesis. (C) 2000 Elsevier Science Ltd. All rights reserved. C1 NIA, Intramural Res Program, Gerontol Res Ctr 4E02, Lab Neurosci,NIH, Baltimore, MD 21224 USA. NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Sch Pharm, Chapel Hill, NC 27599 USA. RP Greig, NH (reprint author), NIA, Intramural Res Program, Gerontol Res Ctr 4E02, Lab Neurosci,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 13 TC 12 Z9 13 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD JUN 19 PY 2000 VL 41 IS 25 BP 4861 EP 4864 DI 10.1016/S0040-4039(00)00740-1 PG 4 WC Chemistry, Organic SC Chemistry GA 327LA UT WOS:000087794300008 ER PT J AU Zoghlache, MD Burger, K Schuck, S Moller, HJ Rapoport, SI Allain, H Hampel, H AF Zoghlache, MD Burger, K Schuck, S Moller, HJ Rapoport, SI Allain, H Hampel, H TI Multiconceptual therapy in Alzheimer's disease SO PRESSE MEDICALE LA French DT Article ID DEMENTIA; EFFICACY; DRUGS AB Social and economical impact: Alzheimer's disease is a neurodegenerative dementia raising major public health concern in industrialized countries. The consequences are not only medical but also social and economical. Perspectives: it is thus important to establish diagnostic principles, therapeutic goals, and global strategies guiding the behavior of physicians, family and patients laced with this dreaded disease. Currently, only a few rare symptomatic treatments are available, but research in this field points to potentially effective preventive and etiopathogentic therapeutic protocols associating drugs, social support, and psychotherapy. (C) 2000, Masson, Paris. C1 Univ Munich, Fac Med, Lab Pharmacol Expt & Clin, F-35043 Rennes, France. NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. RP Allain, H (reprint author), Univ Munich, Fac Med, Lab Pharmacol Expt & Clin, 2 Ave Pr Leon Bernard, F-35043 Rennes, France. NR 29 TC 0 Z9 0 U1 1 U2 1 PU MASSON EDITEUR PI PARIS 06 PA 120 BLVD SAINT-GERMAIN, 75280 PARIS 06, FRANCE SN 0755-4982 J9 PRESSE MED JI Presse Med. PD JUN 17 PY 2000 VL 29 IS 21 BP 1197 EP 1201 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 331MU UT WOS:000088023500012 ER PT J AU Pinkerton, SD Holtgrave, DR DiFranceisco, W Semaan, S Coyle, SL Johnson-Masotti, AP AF Pinkerton, SD Holtgrave, DR DiFranceisco, W Semaan, S Coyle, SL Johnson-Masotti, AP TI Cost-threshold analyses of the National AIDS Demonstration Research HIV prevention interventions SO AIDS LA English DT Article DE cost-effectiveness; prevention; modeling; injection drug use; economic analysis; HIV ID RISK-REDUCTION; NEEDLE-EXCHANGE; DRUG-USERS; INFECTION; MODEL; TRANSMISSION; PREVALENCE AB Objective: The goal of the multisite National AIDS Demonstration Research (NADR) program was to reduce the sexual and drug injection-related HIV risks of out-of-treatment injection drug users and their sex partners. Previous analyses have established that the NADR interventions were effective at changing participants' risky behaviors. This study was to determine whether the NADR program also was cost-effective. Methods: Data from eight NADR study sites were included in the analysis. A mathematical model was used to translate reported sexual and injection-related behavior changes into an estimate of the number of infections prevented by the NADR interventions and then to calculate the corresponding savings in averted HIV/AIDS medical care costs and quality-adjusted years of life, assuming United Stares values for these parameters. Because cost data were not collected in the original NADR evaluation, the savings in averted medical care costs were compared with the cost of implementing a similar intervention program for injection drug users. Results: The eight NADR interventions prevented approximately 129 infections among 6629 participants and their partners. Overall, the NADR program would be cost saving (i.e. provide net economic savings) ii it cost less than US$2107 per person and would be cast-effective ii it cost less than US$10 264 per person. Both of these estimates are considerably larger than the US$273 per person cost of the comparison intervention. There was substantial cross-site variability. Conclusions: The results of this analysis strongly suggest that the NADR interventions were cost-saving overall and were; at the very least, cost-effective at all eight sites. In the United States and other developed counties, investments in HIV-prevention interventions such as these have the potential to save substantial economic resources by averting HIV-related medical care expenses among injection drug users. (C) 2000 Lippincott Williams & Wilkins. C1 Med Coll Wisconsin, Ctr AIDS Intervent Res, Dept Psychiat & Behav Med, Milwaukee, WI 53202 USA. Ctr Dis Control & Prevent, Natl Ctr HIV STD & TB Prevent, Atlanta, GA USA. Natl Inst Drug Abuse, Bethesda, MD USA. RP Pinkerton, SD (reprint author), Med Coll Wisconsin, Ctr AIDS Intervent Res, Dept Psychiat & Behav Med, 2071 N Summit Ave, Milwaukee, WI 53202 USA. FU PHS HHS [U62/CCU513481-01] NR 51 TC 24 Z9 24 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 JUN 16 PY 2000 VL 14 IS 9 BP 1257 EP 1268 DI 10.1097/00002030-200006160-00024 PG 12 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 326KY UT WOS:000087735700024 PM 10894291 ER PT J AU Baxter, JD Mayers, DL Wentworth, DN Neaton, JD Hoover, ML Winters, MA Mannheimer, SB Thompson, MA Abrams, DI Brizz, BJ Ioannidis, JPA Merigan, TC AF Baxter, JD Mayers, DL Wentworth, DN Neaton, JD Hoover, ML Winters, MA Mannheimer, SB Thompson, MA Abrams, DI Brizz, BJ Ioannidis, JPA Merigan, TC CA CPCRA 046 Study Team Terry Beirn Comm TI A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy SO AIDS LA English DT Article DE antiretroviral therapy; HIV drug resistance/resistance mutations; viral load ID IMMUNODEFICIENCY-VIRUS TYPE-1; SOCIETY USA PANEL; REVERSE-TRANSCRIPTASE; HIV-INFECTION; UPDATED RECOMMENDATIONS; ZIDOVUDINE; TRANSMISSION; MUTATION; INHIBITORS; CHILDREN AB Objective: To determine the short-term effects of using genotypic antiretroviral resistance testing (GART) with expert advice in the management of patients failing on a protease inhibitor and two nucleoside reverse transcriptase inhibitors. Design: Prospective randomized controlled trial. Setting: Multicenter community-based clinical trials network. Patients: One-hundred and fifty-three HIV-infected adults with a threefold or greater rise in plasma HIV-1 RNA on at least 16 weeks of combination antiretroviral therapy. Interventions: Randomization was either to a GART group, where genotype interpretation and suggested regimens were provided to clinicians, or to a no-CART group, where treatment choices were made without such input. Main outcomes measures: Plasma HIV-1 RNA levels and CD4 cell counts were measured at 4, 8, and 12 weeks following randomization. The primary endpoint was change in HIV-1 RNA levels from baseline to the average of the 4 and 8 week levels. Results: The average baseline CD4 cell count was 230 X 10(6) cells/l and the median HIV-1 RNA was 28 085 copies/ml. At entry, 82 patients were failing on regimens containing indinavir, 51 on nelfinavir, 11 on ritonavir, and nine on saquinavir. HIV-1 RNA, averaged at 4 and 8 weeks, decreased by 1.79 log(10) for the 78 CART patients and -0.61 log(10) for the 78 no-CART patients (treatment difference. -0.53 log, 95% confidence interval, -0.77 to -0.29; P=0.00001). Overall, the best virologic responses occurred in patients who received three or more drugs to which their HIV-1 appeared to be susceptible. Conclusion: In patients failing triple drug therapy, CART with expert advice was superior to no-CART as measured by short-term viral load responses. (C) 2000 Lippincott Williams & Wilkins. C1 Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Cooper Hosp, Camden, NJ 08103 USA. Henry Ford Hosp, Detroit, MI 48202 USA. Univ Minnesota, Minneapolis, MN USA. Coriell Inst, Camden, NJ USA. Stanford Univ, Ctr AIDS Res, Stanford, CA 94305 USA. Harlem Hosp, New York, NY USA. AIDS Res Consortium, Atlanta, GA USA. San Francisco Gen Hosp, San Francisco, CA 94110 USA. Social & Sci Syst Inc, Bethesda, MD USA. NIAID, Bethesda, MD 20892 USA. Univ Ioannina, Sch Med, GR-45110 Ioannina, Greece. RP Baxter, JD (reprint author), Div Infect Dis, Educ & Res Bldg,Room 272,401 Haddon Ave, Camden, NJ 08103 USA. RI Ioannidis, John/G-9836-2011 NR 30 TC 375 Z9 381 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUN 16 PY 2000 VL 14 IS 9 BP F83 EP F93 DI 10.1097/00002030-200006160-00001 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 326KY UT WOS:000087735700001 PM 10894268 ER PT J AU Hartt, JK Liang, T Sahagun-Ruiz, A Wang, JM Gao, JL Murphy, PM AF Hartt, JK Liang, T Sahagun-Ruiz, A Wang, JM Gao, JL Murphy, PM TI The HIV-1 cell entry inhibitor T-20 potently chemoattracts neutrophils by specifically activating the N-formylpeptide receptor SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE chemotaxis; inflammation; neutrophil; AIDS/HIV; G-protein-coupled receptor ID IMMUNODEFICIENCY-VIRUS TYPE-1; ENVELOPE GLYCOPROTEIN; HUMAN PHAGOCYTES; GENE-CLUSTER; GP41; PEPTIDE; FUSION; DOMAIN; EXPRESSION; MOUSE AB T-20, a synthetic peptide corresponding to the heptad repeat sequence of HIV-1 gp41, blocks HIV-1 entry by targeting gp41, and is currently in clinical trials as an anti-retroviral agent. We recently reported that in vitro T-20 also functions as a phagocyte chemoattractant and; a chemotactic agonist at the phagocyte N-formylpeptide receptor (FPR). Here we show that T-20 is also a potent chemotactic agonist in vitro at a related human phagocyte receptor FPRL1R. To test the relative importance of FPR and FPRL1R in primacy cells, we identified the corresponding mouse T-20 receptors, mFPR and FPR2, which are both expressed in neutrophils, and compared T-20 action on neutrophils from wild type and mFPR knockout mice. Surprisingly, although T-20 activates mFPR and FPR2 in transfected cells with equal potency and efficacy in both calcium flux and chemotaxis assays, neutrophils from mFPR knockout mice did not respond to T-20. These results provide genetic evidence that FPR is the major phagocyte T-20 receptor in vivo and point to the potential feasibility of studying T-20 effects on immunity in a mouse model. This may help define the cause of local inflammation after T-20 injection that has recently been reported in Phase I clinical trials. (C) 2000 Academic Press. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. NCI, Mol Immunoregulat Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Gao, JL (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Room 11N113, Bethesda, MD 20892 USA. NR 26 TC 27 Z9 28 U1 0 U2 0 PU ACADEMIC PRESS INC 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 JUN 16 PY 2000 VL 272 IS 3 BP 699 EP 704 DI 10.1006/bbrc.2000.2846 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 327HD UT WOS:000087787700014 PM 10860818 ER PT J AU Katz, BZ Zohar, M Teramoto, H Matsumoto, K Gutkind, JS Lin, DC Lin, S Yamada, KM AF Katz, BZ Zohar, M Teramoto, H Matsumoto, K Gutkind, JS Lin, DC Lin, S Yamada, KM TI Tensin can induce JNK and p38 activation SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID FOCAL ADHESION KINASE; GTP-BINDING PROTEINS; JUN NH2-TERMINAL KINASE; CELL-CYCLE PROGRESSION; SIGNAL-TRANSDUCTION; C-JUN; TYROSINE KINASES; RHO-GTPASES; PATHWAY; INTEGRINS AB Cells organize diverse types of specialized adhesion sites upon attachment to extracellular matrix (ECM) components. One of the physiological roles of such cell-ECM interactions is to initiate and regulate adhesion-mediated signal transduction responses. The association of cells with fibronectin fibrils has been shown to regulate the JNK and p38 signaling pathways. We tested whether tensin, a cytoskeletal component localized to both focal contacts and fibronectin-associated fibrillar adhesions, can induce these signaling pathways. We found that tensin overexpression resulted in activation of both the c-Jun amino-terminal kinase (JNK) and p38 pathways. Tensin-mediated JNK activation was independent of the activities of the small GTP binding proteins Rac and Cdc42, but did depend on SEK, a kinase involved in the JNK pathway. We suggest that tensin may directly activate the JNK and p38 pathways, acting downstream or independent of the activities of the small GTP binding proteins Rac and Cdc42. (C) 2000 Academic Press. C1 Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. Univ Calif Irvine, Dept Dev & Cell Biol, Irvine, CA 92697 USA. RP Katz, BZ (reprint author), Tel Aviv Med Ctr, Inst Hematol, 6 Weizman St, Tel Aviv, Israel. RI Gutkind, J. Silvio/A-1053-2009; OI Yamada, Kenneth/0000-0003-1512-6805 NR 31 TC 16 Z9 16 U1 0 U2 2 PU ACADEMIC PRESS INC 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 JUN 16 PY 2000 VL 272 IS 3 BP 717 EP 720 DI 10.1006/bbrc.2000.2853 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 327HD UT WOS:000087787700017 PM 10860821 ER PT J AU White, DM Walker, S Brenneman, DE Gozes, I AF White, DM Walker, S Brenneman, DE Gozes, I TI CREB contributes to the increased neurite outgrowth of sensory neurons induced by vasoactive intestinal polypeptide and activity-dependent neurotrophic factor SO BRAIN RESEARCH LA English DT Article DE vasoactive intestinal polypeptide; activity-dependent neurotrophic factor; Dorsal root ganglion cells; cAMP responsive binding protein; pain ID ELEMENT-BINDING PROTEIN; ROOT GANGLION-CELLS; NERVE GROWTH-FACTOR; CYCLIC-AMP; PERIPHERAL AXOTOMY; SCIATIC-NERVE; GENE-EXPRESSION; MESSENGER-RNAS; SPINAL-CORD; CROSS-TALK AB Our recent experiments suggest that vasoactive intestinal polypeptide (VIP) enhances neurite outgrowth of dissociated rat dorsal root ganglion cells, indirectly, via the release of a trophic factor from the spinal cord. In this study, we have examined the possible contribution of activity-dependent neurotrophic factor (ADNF) to the trophic actions of VIP. In addition, as we have shown that the factor mediating the trophic actions of VIP acts via protein kinase A we have also examined the contribution of CREB, which is a transcription factor activated by protein kinase A. As previously shown, supernatant taken from spinal cord incubated with VIP, significantly increased the percentage of sensory neurons with neurites. Antiserum against ADNF attenuated the trophic effect of the VIP-conditioned supernatant. Consistently, the ADNF agonist, ADNF(14) (0.001-0.1 fM), significantly enhanced the percentage of cells with neurite outgrowth. Furthermore, the trophic action of ADNF(14) was attenuated by a protein kinase A inhibitor, Rp-cAMPS, whereas the inactive isomer, Sp-cAMPS, had no effect. Preincubation of cells with 5 mu M CREB antisense oligonucleotides, attenuated the increase in neurite outgrowth induced by either the supernatant or ADNF(14). The sense oligonucleotide had no influence on the enhanced neurite outgrowth. We also found that both the supernatant and ADNF(14) induced an increase in the percentage of cells expressing phosphorylated CREB. The data suggests that VIP induces a release of neurotrophic factors, such as ADNF, which enhance neurite outgrowth. In addition, protein kinase A and CREB appear to contribute to the neurotrophic actions of VIP and ADNF. The mechanisms underlying the neurotrophic action of VIP, may have important implications for sprouting and/or synaptic reorganization of central terminals of sensory neurons, which may contribute to neuropathic pain that commonly occurs following peripheral nerve damage. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Univ Sydney, Royal N Shore Hosp, Dept Anaesthesia & Pain Management, St Leonards, NSW 2065, Australia. NICHD, Sect Dev & Mol Pharmacol, Dev Neurobiol Lab, Bethesda, MD USA. Tel Aviv Univ, Sackler Sch Med, Dept Clin Biochem, IL-69978 Tel Aviv, Israel. RP White, DM (reprint author), Univ Sydney, Royal N Shore Hosp, Dept Anaesthesia & Pain Management, St Leonards, NSW 2065, Australia. NR 43 TC 49 Z9 65 U1 0 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 JUN 16 PY 2000 VL 868 IS 1 BP 31 EP 38 DI 10.1016/S0006-8993(00)02259-9 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 327EK UT WOS:000087780500004 PM 10841885 ER PT J AU Chan, SL Mayne, M Holden, CP Geiger, JD Mattson, MP AF Chan, SL Mayne, M Holden, CP Geiger, JD Mattson, MP TI Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AMYLOID PRECURSOR PROTEIN; FAMILIAL ALZHEIMERS-DISEASE; INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; RAT-BRAIN; ENDOPLASMIC-RETICULUM; LINKED PRESENILIN-1; MUTANT PRESENILIN-1; CULTURED NEURONS; CA2+ RELEASE; BETA-PEPTIDE AB Many cases of early-onset inherited Alzheimer's disease (AD) are caused by mutations in the presenilin-1 (PSI) gene. PS1 mutations may perturb cellular Ca2+ homeostasis and thereby render neurons vulnerable to excitotoxicity and apoptosis. We now report that PC12 cells expressing PS1 mutations and primary hippocampal neurons from PS1 mutant knockin mice exhibit greatly increased levels of ryanodine receptors (RyR) and enhanced Ca2+ release following stimulation with caffeine. Double-labeling immunostaining and co-immunoprecipitation analyses indicate that PS1 and RyR are colocalized and interact physically, Caffeine treatment sensitizes neurons expressing mutant PS1 to apoptosis induced by amyloid beta-peptide, a neurotic peptide linked to the pathogenesis of AD. When taken together with recent evidence for alterations in RyR in brains of AD patients, our data suggest that PS1 mutations may promote neuronal degeneration in AD by increasing transcription and translation of RyR and altering functional properties of ryanodine-sensitive Ca2+ pools. C1 NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. Univ Kentucky, Sanders Brown Res Ctr Aging, Lexington, KY 40536 USA. Univ Manitoba, Fac Med, Dept Pharmacol & Therapeut, Winnipeg, MB R3E 0W3, Canada. RP Mattson, MP (reprint author), NIA, Neurosci Lab, NIH, GRC 4F01,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 FU NIA NIH HHS [P01AG10386] NR 37 TC 197 Z9 202 U1 2 U2 17 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 16 PY 2000 VL 275 IS 24 BP 18195 EP 18200 DI 10.1074/jbc.M000040200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 325CU UT WOS:000087659400040 PM 10764737 ER PT J AU Huang, Y Hutter, D Liu, YS Wang, XT Sheikh, MS Chan, AML Holbrook, NJ AF Huang, Y Hutter, D Liu, YS Wang, XT Sheikh, MS Chan, AML Holbrook, NJ TI Transforming growth factor-beta 1 suppresses serum deprivation-induced death of A549 cells through differential effects on c-Jun and JNK activities SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED PROTEIN-KINASE; SIGNAL-TRANSDUCTION PATHWAYS; TGF-BETA; CYCLE ARREST; MAP KINASES; RETINOBLASTOMA PROTEIN; OXIDATIVE STRESS; UV IRRADIATION; AP-1 FUNCTION; APOPTOSIS AB Transforming growth factor (TGF)-beta 1, a pleiotropic cytokine involved in regulating growth and differentiation, can exert both pro-apoptotic and anti-apoptotic effects depending on the cell type or circumstances. We observed that TGF-beta 1 blocked apoptosis resulting from serum withdrawal in A549 human lung carcinoma cells. This was associated with suppression of JNK activation that occurs concomitant with the onset of apoptosis in the absence of TGF-beta 1, suggesting that JNK plays an active role in the death process and that TGF-beta 1 exerts its protective influence by altering JNK activity. Overexpression of a dominant negative mutant form of SEK1, an upstream activator of JNK, likewise suppressed JNK activation and inhibited apoptosis. Investigation of early events following TGF-beta 1 treatment revealed an early induction and phosphorylation of c-Jun that was absent in cells subjected to serum withdrawal alone. That TGF-beta 1-induced expression of c-Jun is important for survival mas supported by the finding that overexpression of non-phosphosphorylatable dominant negative mutant c-Jun, c-Jun(S73A), attenuated the protective influence of TGF-beta 1. Our findings suggest that JNK activation is a late but essential event in serum deprivation-induced apoptosis in A549 cells. TGF-beta 1 prevents apoptosis, in part, through the early induction and phosphorylation of c-Jun, which in turn results in attenuated JNK activation. C1 NIA, Biol Chem Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. NCI, Gene Response Sect, Div Basic Sci, Bethesda, MD 20892 USA. Mt Sinai Sch Med, Derald H Ruttenberg Canc Ctr, New York, NY 10029 USA. RP Holbrook, NJ (reprint author), NIA, Biol Chem Lab, Gerontol Res Ctr, 5600 Nathan Shock Dr,Box 12, Baltimore, MD 21224 USA. RI Liu, Yusen/E-3527-2011 NR 76 TC 47 Z9 50 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 16 PY 2000 VL 275 IS 24 BP 18234 EP 18242 DI 10.1074/jbc.M909431199 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 325CU UT WOS:000087659400045 PM 10748131 ER PT J AU Dmitrieva, N Kultz, D Michea, L Ferraris, J Burg, M AF Dmitrieva, N Kultz, D Michea, L Ferraris, J Burg, M TI Protection of renal inner medullary epithelial cells from apoptosis by hypertonic stress-induced p53 activation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LASER-SCANNING CYTOMETRY; HYPEROSMOTIC STRESS; RESPONSE ELEMENT; GENE; PROMOTER; MOUSE; PHOSPHORYLATION; FIBROBLASTS; INDUCTION; SIGNALS AB Acute hypertonicity causes cell cycle delay and apoptosis in mouse renal inner medullary collecting duct cells (mIMCD3) and increases GADD45 expression. Be cause the tumor suppressor protein p53 may be involved in these effects, we have investigated the role of p53 in mIMCD3 response to hyperosmotic stress. Acute elevation of osmolality with NaCl addition from the control level of 320 mosmol/kg to 500-600 mosmol/kg greatly increased the levels of total and Ser(15)-phosphorylated p53 within 15 min. However, similar elevation of osmolality with urea did not increase p53 levels. Our studies indicate that induced p53 is transcriptionally active because NaCl addition to 500-600 mosmol/kg stimulated transcription of a luciferase reporter containing a p53 consensus element and appropriately altered mRNA levels of known transcriptional targets of p53, i.e. increased MDM-2 and decreased BCL-2 levels. Elevating NaCl further to 700-800 mosmol/kg rapidly killed most of the cells by apoptosis, At these higher NaCl concentrations, p53 levels were further increased although Ser(15) phosphorylation and transcriptional activity were significantly lower than levels at 500-600 mosmol/kg. At NaCl-induced 500 mosmol/kg, apoptosis was rare in the presence of control, nonspecific oligonucleotide but highly prevalent upon addition of p53 antisense oligonucleotide that substantially reduced p53 levels. We conclude that induction of active p53 in mIMCD3 cells by hypertonic stress contributes to cell survival. C1 NHLBI, NIH, Bethesda, MD 20892 USA. Univ Florida, Whitney Lab, St Augustine, FL 32086 USA. RP Dmitrieva, N (reprint author), NHLBI, NIH, Bldg 10,Rm 6N260, Bethesda, MD 20892 USA. RI Dmitrieva, Natalia/A-2924-2013 OI Dmitrieva, Natalia/0000-0001-8074-6950 NR 29 TC 86 Z9 86 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 16 PY 2000 VL 275 IS 24 BP 18243 EP 18247 DI 10.1074/jbc.M000522200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 325CU UT WOS:000087659400046 PM 10747924 ER PT J AU Caraco, C Aloj, L Chen, LY Chou, JY Eckelman, WC AF Caraco, C Aloj, L Chen, LY Chou, JY Eckelman, WC TI Cellular release of [F-18]2-fluoro-2-deoxyglucose as a function of the glucose-6-phosphatase enzyme system SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STORAGE-DISEASE TYPE-1A; RECOMBINANT ADENOVIRUSES IMPROVES; CEREBRAL GLUCOSE-UTILIZATION; METABOLIC-RATE; LIVER; GENE; ESTABLISHMENT; INACTIVATION; TRANSPORTER; PHOSPHATE AB [F-18]-2-Fluoro-2-deoxyglucose (FDG) is a glucose analog currently utilized for positron emission tomography imaging studies in humans. FDG taken up by the liver is rapidly released. This property is attributed to elevated glucose-6-phosphatase (Glc-6-Pase) activity. To characterize this issue we studied the relationship between Glc-6-Pase activity and FDG; release kinetics in a cell culture system. We overexpressed the Glc-6-Pase catalytic unit in a Glc-6-Pase deficient mouse hepatocyte (Ho-15) and in A431 tumor cell lines. Glc-6-Pase enzyme activity and FDG release rates were determined in cells transfected with the Glc-6-Pase gene (Ho-15-D3 and A431-AC3), in mock-transfected cells of both cell lines, and in wild-type mouse hepatocytes (WT10) as control. Although the highest level of Glc-6-Pase activity was measured in A431-AC3, Ho-15-D3 cells showed much faster FDG release rates. The faster FDG release correlated with the level of glucose 6-phosphate transporter (Glc-6-PT) mRNA, which was found to be expressed at higher levels in Ho-15 compared with A431 cells. Overexpression of Glc-6-PT in A431-AC3 produced a dramatic increase in FDG release compared with control cells. This study gives the first direct evidence that activity of the Glc-6-Pase complex can be quantified in vivo by measuring FDG release. Adequate levels of Glc-6-Pase catalytic unit and Glc-6-PT are required for this function. FDG-positron emission tomography may be utilized to evaluate functional status of the Glc-6-Pase complex. C1 NICHD, Positron Emiss Tomog Dept, Warren G Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NICHD, Dept Nucl Med, Ctr Clin, NIH, Bethesda, MD 20892 USA. NICHD, Dept Nucl Med, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Eckelman, WC (reprint author), NICHD, Positron Emiss Tomog Dept, Warren G Magnuson Clin Ctr, NIH, Bldg 10,Rm 1C495,10 Ctr Dr,MSC 1180, Bethesda, MD 20892 USA. NR 27 TC 31 Z9 31 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 16 PY 2000 VL 275 IS 24 BP 18489 EP 18494 DI 10.1074/jbc.M908096199 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 325CU UT WOS:000087659400079 PM 10764804 ER PT J AU Wolf, YI Grishin, NV Koonin, EV AF Wolf, YI Grishin, NV Koonin, EV TI Estimating the number of protein folds and families from complete genome data SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE protein structure classification; structural genomics; sampling; logarithmic distribution ID STRUCTURAL CLASSIFICATION; SEQUENCES; SUPERFAMILIES; SCOP; RECOGNITION AB Using the data on proteins encoded in complete genomes, combined with a rigorous theory of the sampling process, we estimate the total number of protein folds and families, as well as the number of folds and families in each genome. The total number of folds in globular, water-soluble proteins is estimated at about 1000, with structural information currently available for about one-third of that number. The sequenced genomes of unicellular organisms encode from approximately 25%, for the minimal genomes of the Mycoplasmas, to 70-80% for larger genomes, such as Escherichia coli and yeast, of the total number of folds, The number of protein families with significant sequence conservation was estimated to be between 4000 and 7000, with structures available for about 20% of these. (C) 2000 Academic Press. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. Russian Acad Sci, Inst Cytol & Genet, Novosibirsk 630090, Russia. RP Grishin, NV (reprint author), Univ Texas, SW Med Ctr, Dept Biochem, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. NR 43 TC 129 Z9 132 U1 0 U2 1 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUN 16 PY 2000 VL 299 IS 4 BP 897 EP 905 DI 10.1006/jmbi.2000.3786 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 325MV UT WOS:000087680400007 PM 10843846 ER PT J AU Horti, AG Chefer, SI Mukhin, AG Koren, AO Gundisch, D Links, JM Kurian, V Dannals, RF London, ED AF Horti, AG Chefer, SI Mukhin, AG Koren, AO Gundisch, D Links, JM Kurian, V Dannals, RF London, ED TI 6-[F-18]fluoro-A-85380, a novel radioligand for in vivo imaging of central nicotinic acetylcholine receptors SO LIFE SCIENCES LA English DT Article DE nicotinic acetylcholine receptor; positron emission tomography (nAChRs); 6-[F-18]fluoro-3-(2(S)-azetidinyl-methoxy)pyridine (6-[F-18]fluoro-A-85380, 6-[F-18]FA) ID IN-VIVO; EPIBATIDINE; BRAIN; RADIOTRACER; AFFINITY; BINDING; ANALOG; PET AB A novel positron emission tomography (PET) radiotracer, 6-[F-18]fluoro-3-(2(S)-azetidinyl-methoxy)pyridine (6-[F-18]fluoro-A-85380, 6-[F-18]FA) was synthesized by a no-carrier-added fluorination, In 6-[F-18]FA bound to nicotinic acetylcholine receptors (nAChRs), with very high affinity (K-d 28 PM). In PET studies, 6-[F-18]FA specifically labeled central nAChRs in the brain of the Rhesus monkey and demonstrated highest levels of accumulation of radioactivity in brain regions enriched with the a,Pz subtype of nAChR, 6-[F-18]FA exhibited a target-to-non-target ratio (estimated as radioactivity in the thalamus to that in the cerebellum) of binding in primate brain similar to that previously determined for a labeled analog of epibatidine, [F-18]FPH. In contrast to [F-18]FPH, the novel tracer is expected to exhibit substantially less toxicity. Thus, the novel radioligand, 6-[18F]FA, appears to be a suitable candidate for imaging nAChRs in human brain. Published by Elsevier Science Inc. C1 NIDA, Brain Imaging Ctr, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Johns Hopkins Med Inst, Div Nucl Med, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Div Radiat Hlth Sci, Baltimore, MD 21205 USA. RP London, ED (reprint author), NIDA, Brain Imaging Ctr, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 23 TC 2 Z9 2 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD JUN 16 PY 2000 VL 67 IS 4 BP PL463 EP PL469 PG 7 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 326QP UT WOS:000087746500012 ER PT J AU Haffner, SM D'Agostino, R Saad, MF O'Leary, DH Savage, PJ Rewers, M Selby, J Bergman, RN Mykkanen, L AF Haffner, SM D'Agostino, R Saad, MF O'Leary, DH Savage, PJ Rewers, M Selby, J Bergman, RN Mykkanen, L TI Carotid artery atherosclerosis in type-2 diabetic and nondiabetic subjects with and without symptomatic coronary artery disease (the insulin resistance atherosclerosis study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID AVERAGE CHOLESTEROL LEVELS; MYOCARDIAL-INFARCTION; WALL THICKNESS; HEART-DISEASE; CARDIOVASCULAR-DISEASE; GLUCOSE; WOMEN; RISK; MEN; SENSITIVITY AB Type-2 diabetes mellitus is associated with a 2- to 4-fold increase in the risk of clinical coronary artery disease (CAD), It has been suggested that diabetic subjects without clinical CAD should be treated as aggressively for cardiovascular risk factors as subjects with CAD. This would be warranted if diabetic subjects without clinical CAD would have accelerated CAD similar to that of nondiabetic subjects with symptomatic CAD. To assess this suggestion, we compared the intima-media wall thickness in the common carotid artery (CCA) and internal carotid artery (ICA) in 43 diabetic subjects with clinical CAD, 446 diabetic subjects without clinical CAD, 47 nondiabetic subjects with clinical CAD, and 975 nondiabetic subjects without clinical CAD (all aged 40 to 70 years) in the Insulin Resistance Atherosclerosis Study. All data were adjusted for age, gender, ethnicity, and clinical results. Both diabetes and CAD were associated with increased atherosclerosis in the CCA. Likewise, diabetes wets significantly associated with increased atherosclerosis in the ICA; however, CAD was not associated with ICA intima-media wall thickness. As expected, diabetic subjects with CAD had the greatest intima-media wall thickness, whereas nondiabetic subjects without CAD had the least atherosclerosis. Subjects with diabetes but without CAD had slightly greater intima-media wall thickness than nondiabetic subjects with CAD, although these differences were not statistically significant. Thus, diabetic subjects even without CAD had extensive atherosclerosis in the carotid artery. These results support the suggestion that diabetic subjects should be treated as aggressively for cardiovascular risk factor management as subjects with pre-existing CAD. (C) 2000 by Excerpta Medica, Inc. C1 Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78229 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27103 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. Tufts Univ, Sch Med, Dept Radiol, Boston, MA USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ Colorado, Sch Med, Dept Prevent Med & Biometr, Denver, CO 80202 USA. Kaiser Permanente, Div Res, Oakland, CA USA. Univ So Calif, Dept Physiol & Biophys, Los Angeles, CA USA. RP Haffner, SM (reprint author), Univ Texas, Hlth Sci Ctr, Dept Med, 7703 Floyd Curl Dr,Mail Code 7873, San Antonio, TX 78229 USA. RI Dagostino Jr, Ralph/C-4060-2017 OI Dagostino Jr, Ralph/0000-0002-3550-8395 FU NHLBI NIH HHS [HL47887, HL47889, HL47890] NR 29 TC 60 Z9 63 U1 0 U2 1 PU EXCERPTA MEDICA INC PI NEW YORK PA 245 WEST 17TH STREET, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUN 15 PY 2000 VL 85 IS 12 BP 1395 EP 1400 DI 10.1016/S0002-9149(00)00784-0 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 322KB UT WOS:000087507800001 PM 10856382 ER PT J AU Unger, EF Goncalves, L Epstein, SE Chew, EY Trapnell, CB Cannon, RO Quyyumi, AA Stine, A Loscalzo, F Stiber, JA AF Unger, EF Goncalves, L Epstein, SE Chew, EY Trapnell, CB Cannon, RO Quyyumi, AA Stine, A Loscalzo, F Stiber, JA TI Effects at a single intracoronary injection of basic fibroblast growth factor in stable angina pectoris SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY-ARTERY DISEASE; COLLATERAL DEVELOPMENT; MYOCARDIAL-ISCHEMIA; GENE-THERAPY; ANGIOGENESIS; HEART AB We sought to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of basic fibroblast growth factor (bFGF), administered as a single intracoronary injection, to subjects with stable angina pectoris secondary to coronary artery disease. bFGF, on angiogenic growth factor, has been shown to enhance collateral development in animal models of progressive coronary occlusion. To our knowledge, this study represents the initial introduction of parenteral bFGF into humans. This was a phase 1, randomized, dose-escalation trial of bFGF in 25 subjects with coronary artery disease and stable angina. Subjects were randomized 2:1 to a single dose of bFGF or placebo, injected into the left main coronary artery. bFGF doses ranged from 3 to 100 mu g/kg, increasing in half-log increments. bFGF was generally well tolerated at doses of 3 to 30 mu g/kg. Plasma clearance was 20 +/- 2 ml/kg/min, with an elimination half-life of 85 +/- 11 minutes. bFGF caused acute hypotension (approximate to 10%) that did not appear to be dose-related through the dose range studied. Of the 9 subjects who received 30 to 100 mu g/kg bFGF, 2 had sustained hypotension, mild to moderate in severity, lasting 1 to 3 days, and 3 subjects developed bradycardia hours to days after bFGF administration. bFGF dilated epicardial coronary arteries (7.4 +/- 2.5% mean diameter increase, p < 0.02). Transient mild thrombocytopenia and proteinuria were observed in some subjects in the 30-mu g/kg cohort. No subject had signs suggesting systemic angiogenesis. Thus, intracoronary bFGF, at doses of 3 to 30 mu g/kg, was generally well tolerated in subjects with stable angina. (C) 2000 by Excerpta Medico, Inc. C1 US FDA, Ctr Biol Evaluat & Res, Pharmacol Toxicol Branch, Div Clin Trial Design & Anal, Rockville, MD 20852 USA. NEI, NHLBI, Cardiol Branch, NIH, Bethesda, MD USA. RP Unger, EF (reprint author), US FDA, Ctr Biol Evaluat & Res, Pharmacol Toxicol Branch, Div Clin Trial Design & Anal, 1401 Rockville Pike,HFM-576, Rockville, MD 20852 USA. OI Goncalves, Lino/0000-0001-9255-3064 NR 15 TC 93 Z9 99 U1 0 U2 4 PU EXCERPTA MEDICA INC PI NEW YORK PA 245 WEST 17TH STREET, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUN 15 PY 2000 VL 85 IS 12 BP 1414 EP 1419 DI 10.1016/S0002-9149(00)00787-6 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 322KB UT WOS:000087507800004 PM 10856385 ER PT J AU Blum, A Hathaway, L Mincemoyer, R Schenke, WH Csako, G Waclawiw, MA Panza, JA Connon, RO AF Blum, A Hathaway, L Mincemoyer, R Schenke, WH Csako, G Waclawiw, MA Panza, JA Connon, RO TI Hormonal, lipoprotein, and vascular effects of the selective estrogen receptor modulator Raloxifene in hypercholesterolemic men SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY HEART-DISEASE; CONJUGATED ESTROGENS; TESTOSTERONE; WOMEN; CONSTRICTION; CHOLESTEROL; PREVENTION; TAMOXIFEN; THERAPY; MALES AB To determine whether a compound with estrogenic properties is of atherogenic lipoprotein and vascular benefit to men at risk for atherosclerosis, 24 hypercholesterolemic men took raloxifene 60 mg or placebo daily for 1 month in a double-blind study, with cross over to the alternate treatment after 1 month without therapy. Raloxifene caused no significant reduction in levels of atherogenic lipoproteins, did not improve brachial artery flow-mediated dilation, and did not reduce levels of soluble cell adhesion molecules associated with atherosclerosis. C1 NHLBI, Cardiol Branch, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. RP Connon, RO (reprint author), NIH, Ctr Clin, Dept Clin Pathol, Bldg 10,Room 7B15,10 Ctr Dr MSC-1650, Bethesda, MD USA. NR 20 TC 11 Z9 12 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 245 WEST 17TH STREET, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUN 15 PY 2000 VL 85 IS 12 BP 1491 EP + DI 10.1016/S0002-9149(00)00802-X PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 322KB UT WOS:000087507800019 PM 10856400 ER PT J AU Evans, JL Roby, CA Burstein, AH AF Evans, JL Roby, CA Burstein, AH TI Recovery of fosphenytoin injection after simulated nasogastric administration SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Letter C1 Univ Maryland, Sch Pharm, Dept Pharm Practice & Sci, Baltimore, MD 21201 USA. NIH, Clin Pharmacokinet Res Lab, Clin Ctr Pharm Dept, Bethesda, MD 20892 USA. RP Evans, JL (reprint author), Univ Maryland, Sch Pharm, Dept Pharm Practice & Sci, 20 N Pine St, Baltimore, MD 21201 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD JUN 15 PY 2000 VL 57 IS 12 BP 1180 EP 1180 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 327GN UT WOS:000087786100024 PM 10911522 ER PT J AU Shafer, DE Inman, JK Lees, A AF Shafer, DE Inman, JK Lees, A TI Reaction of tris(2-carboxyethyl)phosphine (TCEP) with maleimide and alpha-haloacyl groups: Anomalous elution of TCEP by gel filtration SO ANALYTICAL BIOCHEMISTRY LA English DT Article ID DITHIOTHREITOL; PEPTIDES C1 Vir Syst Inc, Rockville, MD 20850 USA. Biosynexus Inc, Rockville, MD 20850 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Lees, A (reprint author), Vir Syst Inc, 9610 Med Ctr Dr, Rockville, MD 20850 USA. NR 10 TC 57 Z9 57 U1 1 U2 28 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD JUN 15 PY 2000 VL 282 IS 1 BP 161 EP 164 DI 10.1006/abio.2000.4609 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 327DE UT WOS:000087777300026 PM 10860517 ER PT J AU Nomizu, M Kuratomi, Y Ponce, ML Song, SY Miyoshi, K Otaka, A Powell, SK Hoffman, MP Kleinman, HK Yamada, Y AF Nomizu, M Kuratomi, Y Ponce, ML Song, SY Miyoshi, K Otaka, A Powell, SK Hoffman, MP Kleinman, HK Yamada, Y TI Cell adhesive sequences in mouse laminin beta 1 chain SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE laminin beta 1; active sites; cell adhesion; synthetic peptides ID EXPERIMENTAL METASTASIS FORMATION; TERMINAL GLOBULAR DOMAIN; SYNTHETIC PEPTIDES; TUMOR-GROWTH; S-LAMININ; BINDING SEQUENCES; ACID SEQUENCE; ALPHA-1 CHAIN; IDENTIFICATION; ANGIOGENESIS AB Laminin-1, a major component of the basement membrane, consists of three different chains, alpha 1, beta 1, and gamma 1. We sought to identify cell adhesive sequences from the mouse laminin beta 1 chain by testing HT-1080 fibrosarcoma and B16-F10 melanoma cells for binding to 187 overlapping; synthetic peptides which covered the entire chain. Fourteen peptides showed cell adhesive activities with either peptide-conjugated Sepharose beads or peptide-coated plates or both, Additional cells, including neuronal, endothelial, and salivary gland cells, showed biological responses in a cell type-specific manner. B-7, B-133, and B-160 showed the most potent cell attachment. Cell binding on three peptides (B-34, B-133, and B-160) was inhibited by EDTA. Cell adhesion to 11 of the 12 active peptides was inhibited to varying degrees by heparin. Of the 17 active peptides identified in the laminin beta 1 chain in this and other studies, 8 are clustered on the amino terminal globular domain, suggesting a possible important role in cell binding for this domain that may be multifunctional. These data demonstrate that the laminin beta 1 chain has multiple active sites for cell adhesion, some of which are cell-type specific. (C) 2000 Academic Press. C1 Natl Inst Dent & Cranofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. Kyoto Univ, Fac Pharmaceut Sci, Sakyo Ku, Kyoto 606, Japan. RP Nomizu, M (reprint author), Hokkaido Univ, Grad Sch Environm Earth Sci, Kita Ku, Kita 10 Nishi 5, Sapporo, Hokkaido 0600810, Japan. NR 54 TC 58 Z9 58 U1 0 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JUN 15 PY 2000 VL 378 IS 2 BP 311 EP 320 DI 10.1006/abbi.2000.1828 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 327DG UT WOS:000087777500013 PM 10860548 ER PT J AU Zhang, XL Chen, LP Hardwick, JP AF Zhang, XL Chen, LP Hardwick, JP TI Promoter activity and regulation of the CYP4F2 leukotriene B-4 omega-hydroxylase gene by peroxisomal proliferators and retinoic acid in HepG2 cells SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE CYP4F2 gene promoter; regulation; retinoic acid; peroxisomal proliferators ID ACTIVATED RECEPTOR-ALPHA; INFLAMMATORY BOWEL-DISEASE; POLYMORPHONUCLEAR LEUKOCYTES; CDNA CLONING; MOLECULAR-CLONING; PRIMARY CULTURES; KUPFFER CELLS; PPAR-ALPHA; RAT-BRAIN; KAPPA-B AB The human liver CYP4F2 gene (Accession No. AF221943) encodes a leukotriene B-4 omega-hydroxylase that metabolizes leukotriene B-4 (LTB4) to a less potent proinflammatory eicosanoid, 20-OH-LTB4. We sequenced a 6.7-kb genomic fragment of the human CYP4F2 gene that has the first five exons and 500 bp of the 5'-flanking region. The major transcription start site was found to be 49 bp upstream of the 3' end of exon 1 and the ATG translation initiation codon was located in exon 2, Besides the TATA box at -39 bp and basal transcription factor binding sites, the promoter region and 412-bp intron 1 have several putative binding sites for nuclear factors that may mediate the inflammatory response and lipid homeostasis. We found two DR1 elements in the 5' promoter, a DR2 element in intron 1, and RXR/RAR binding sites in both intron 1 and the 5' promoter. DNase I footprinting revealed three protected sequences. with the region containing two CAATT boxes at -71 and -111 bp important in CYP4F2 gene expression. Luciferase reporter assays showed that the 500-bp upstream sequence has strong promoter activity. Transient transfection experiments identified two sites in the 5' promoter and intron 1 that cooperate in gene transcription while exon 1 and a GC-rich region flanking exon 1 inhibit transcription. trans-Retinoic acid and 9-cis-retinoic acid stimulate promoter activity 3- and 6-fold, respectively, while cotransfection with RXR alpha or RAR/RXR alpha further enhanced activity. Peroxisome proliferators inhibit CYP4F2 gene promoter activity and cotransfection with PPAR alpha or PPAR alpha/RXR alpha can slightly attenuate this inhibition. Both saturated fatty acids and 12-hydroxydodecanoic acid (12-OH-C-12) can stimulate CYP4F2 gene promoter activity. Therefore, the CYP4F2 gene is repressed by peroxisomal proliferators and induced by retinoic acid, with RAR/RXR alpha mediating the induction while PPAR alpha/RXR functions neither in the repression nor in the induction by peroxisomal proliferators or retinoic acid. (C) 2000 Academic Press. C1 NE Ohio Univ, Coll Med, Dept Biochem & Mol Pathol, Rootstown, OH 44272 USA. NIDDKD, Lab Mol Recognit, NIH, Bethesda, MD 20892 USA. RP Hardwick, JP (reprint author), NE Ohio Univ, Coll Med, Dept Biochem & Mol Pathol, Rootstown, OH 44272 USA. FU NIDDK NIH HHS [DK42671] NR 71 TC 26 Z9 28 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JUN 15 PY 2000 VL 378 IS 2 BP 364 EP 376 DI 10.1006/abbi.2000.1836 PG 13 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 327DG UT WOS:000087777500019 PM 10860554 ER PT J AU Bussey, TJ Duck, J Muir, JL Aggleton, JP AF Bussey, TJ Duck, J Muir, JL Aggleton, JP TI Distinct patterns of behavioural impairments resulting from fornix transection or neurotoxic lesions of the perirhinal and postrhinal cortices in the rat SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE episodic memory; spatial memory; object recognition; visual discrimination; temporal lobe ID CORTEX LESIONS; HIPPOCAMPAL-LESIONS; OBJECT RECOGNITION; VISUAL-DISCRIMINATION; POSTERIOR CINGULATE; PREFRONTAL CORTEX; SPATIAL MEMORY; RHESUS-MONKEYS; TEMPORAL-LOBE; PLACE MEMORY AB The present study provides evidence that lesions of the fornix (FNX) and of the perirhinal/postrhinal cortex (PPRH), which both disconnect the hippocampus from other brain regions, can lead to distinct patterns of behavioural impairments on tests of spatial memory and spontaneous object recognition. For example, whereas FNX lesions impaired allocentric spatial delayed alternation in a T-maze but generally spared a test of spontaneous object recognition, PPRH lesions produced the opposite pattern of results. Indeed, on the T-maze task PPRH animals significantly outperformed controls when the retention delay was increased to 60 s. In addition, some evidence was found that contributions from both the fornix and perirhinal/postrhinal cortex may be required when object and spatial information must be integrated. In an object-in-place test, for example, PPRH animals failed according to two measures, and FNX animals failed according to one measure, to discriminate objects that had remained in fixed locations from those that had exchanged locations with other objects. Neither lesion, however, affected performance of a visuospatial conditional task, a Pavlovian autoshaping task, or a one-pair pattern discrimination task. It is suggested that the perirhinal/postrhinal cortex, rather than being specialised for a particular type of associative learning, is important for processing complex visual stimuli. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Cardiff Univ, Sch Psychol, Cardiff CF10 3YG, S Glam, Wales. RP Bussey, TJ (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 49 Room 1B80, Bethesda, MD 20892 USA. RI Bussey, Timothy/M-2758-2016; OI Bussey, Timothy/0000-0001-7518-4041; Aggleton, John/0000-0002-5573-1308 NR 45 TC 169 Z9 169 U1 1 U2 11 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 JUN 15 PY 2000 VL 111 IS 1-2 BP 187 EP 202 DI 10.1016/S0166-4328(00)00155-8 PG 16 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 324QA UT WOS:000087631800018 PM 10840144 ER PT J AU McElroy, SL Suppes, T Keck, PE Frye, MA Denicoff, KD Altshuler, LL Brown, ES Nolen, WA Kupka, RW Rochussen, J Leverich, GS Post, RM AF McElroy, SL Suppes, T Keck, PE Frye, MA Denicoff, KD Altshuler, LL Brown, ES Nolen, WA Kupka, RW Rochussen, J Leverich, GS Post, RM TI Open-label adjunctive topiramate in the treatment of bipolar disorders SO BIOLOGICAL PSYCHIATRY LA English DT Article DE topiramate; bipolar disorders; mania; cycling; weight ID REFRACTORY PARTIAL EPILEPSY; PLACEBO-CONTROLLED TRIAL; DOSE-RANGING TRIAL; DOUBLE-BLIND; CALCIUM INFLUX; DAILY DOSAGES; LITHIUM; MONOTHERAPY; SEIZURES; CORTEX AB Background: To preliminarily explore the spectrum of effectiveness and tolerability of the new antiepileptic drug topiramate in bipolar disorder, we evaluated the response of 56 bipolar outpatients in the Stanley Foundation Bipolar Outcome Network (SFBN) who had been treated with adjunctive topiramate in an open-label, naturalistic fashion. Methods: In this case series, response to topiramate was assessed every 2 weeks for the first 3 months according to standard ratings in the SFBN, and monthly thereafter while patients remained on topiramate. Patients' weights, body mass indices (BMIs), and side effects were also assessed. Results: Of the 54 patients who completed at least 2 weeks of open-label, add-on topiramate treatment, 30 had manic, mixed, or cycling symptoms, 11 had depressed symptoms, and 13 were relatively euthymic at the time topiramate was begun. Patients who had been initially treated for manic symptoms displayed significant reductions in standard ratings scores after 4 weeks, after 10 weeks, and at the last evaluation. Those patients who were initially depressed or treated while euthymic showed no significant changes. Patients as a group displayed significant decreases in weight and BMI from topiramate initiation to week 4, to week 10, and to the last evaluation. The most common adverse side effects were neurologic and gastrointestinal. Conclusion: These preliminary open observations of adjunctive topiramate treatment suggest that it may have antimanic or anticycling effects in some patients with bipolar disorder, and may be associated in some patients with bipolar disorder, and may be associated with appetite suppression and weight loss that is often viewed as beneficial by the patient and clinician. Controlled studies of topiramate's acute and long-term efficacy and side-effects in bipolar disorder appear warranted. (C) 2000 Society of Biological Psychiatry. C1 Univ Cincinnati, Coll Med, Biol Psychiat Program ML559, Stanley Fdn Bipolar Outcome Network, Cincinnati, OH 45267 USA. Univ Texas, SW Med Ctr, Dallas, TX 75230 USA. Univ Calif Los Angeles, Inst Neuropsychiat, Los Angeles, CA 90024 USA. W Los Angeles VA Med Ctr, Los Angeles, CA 90024 USA. NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. Univ Utrecht, Med Ctr, Utrecht, Netherlands. HC Rumke Grp, Utrecht, Netherlands. Stanley Fdn, Data Coordinating Ctr, Bethesda, MD USA. RP McElroy, SL (reprint author), Univ Cincinnati, Coll Med, Biol Psychiat Program ML559, Stanley Fdn Bipolar Outcome Network, 231 Bethesda Ave, Cincinnati, OH 45267 USA. RI Nolen, Willem/E-9006-2014 NR 36 TC 165 Z9 173 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 15 PY 2000 VL 47 IS 12 BP 1025 EP 1033 DI 10.1016/S0006-3223(99)00316-9 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 324CK UT WOS:000087604100002 PM 10862801 ER PT J AU Wang, LH Kirken, RA Yang, XY Erwin, RA DaSilva, L Yu, CR Farrar, WL AF Wang, LH Kirken, RA Yang, XY Erwin, RA DaSilva, L Yu, CR Farrar, WL TI Selective disruption of interleukin 4 autocrine-regulated loop by a tyrosine kinase inhibitor restricts activity of T-helper 2 cells SO BLOOD LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; SIGNAL-TRANSDUCTION; TRANSCRIPTION FACTOR; TH1/TH2 BALANCE; GENE-EXPRESSION; CLONE D10.G4.1; TH2 RESPONSES; IL-4; SUBSETS; STAT6 AB Interleukin (IL) 4 is a potent immunomodulatory cytokine secreted by T-helper 2 (Th2) cells and Th2 mast cells that promotes the commitment of cells. However, unregulated production and release of IL-4 can exacerbate allergic reactions and increase susceptibility to infectious organisms and viruses. Here, we present evidence that AG-490, a Janus tyrosine kinase (JAK) 2-JAK3 inhibitor, effectively blocked IL-4 gene expression and secretion in the Th2 cell line D10 that was not occurring after anti-CDS antibody stimulation, whereas AG-490 had no inhibitory effect on production of other Th2 cytokines or cytokines synthesized by the corresponding Th1 cell line clone 29, AG-490 potently inhibited IL-4-mediated proliferation of both D10 and the IL-4-dependent cell line CT.4S. Moreover, AG-490 markedly inhibited IL-4 activation of JAK3 and blocked the downstream activation of signal transducer and activator of transcription 6, as judged by tyrosine phosphorylation, DNA binding, and transcription assays. In contrast, AG-490 did not affect tumor necrosis factor alpha activation of NF-kappa B at similar concentrations of drug. These data suggest that tyrosine kinase inhibitors that inhibit JAK3 may have previously unrecognized and selective clinical potential as immunotherapeutic drugs to treat Th2-mediated diseases driven by IL-4, (C) 2000 by The American Society of Hematology. C1 NCI, Frederick Canc Res & Dev Ctr, Expt Immunol Lab, Frederick, MD 21702 USA. SAIC Frederick, Cytokine Mol Mechanisms Sect, Mol Immunoregulat Lab, Div Basic Sci, Frederick, MD USA. SAIC Frederick, Intramural Res Support Program, Frederick, MD USA. Univ Texas, Dept Integrat Biol & Pharmacol, Houston, TX USA. RP Farrar, WL (reprint author), NCI, Frederick Canc Res & Dev Ctr, Expt Immunol Lab, POB B,Bldg 560,Room 31-68, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 43 TC 14 Z9 14 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 15 PY 2000 VL 95 IS 12 BP 3816 EP 3822 PG 7 WC Hematology SC Hematology GA 325ME UT WOS:000087678700025 PM 10845915 ER PT J AU Raziuddin, A Bennett, M Winkler-Pickett, R Ortaldo, JR Longo, DL Murphy, WJ AF Raziuddin, A Bennett, M Winkler-Pickett, R Ortaldo, JR Longo, DL Murphy, WJ TI Synergistic effects of in vivo depletion of Ly-49A and Ly-49G2 natural killer cell subsets in the rejection of H2(b) bone marrow cell allografts SO BLOOD LA English DT Article ID NK CELLS; MULTIGENE FAMILY; RECEPTOR; MOLECULES; MICE; RECOGNITION; EXPRESSION; CLONING; LIGAND AB Subsets of murine natural killer (NK) cells exist that express the Ly-49 family of molecules that recognize different major histocompatibility complex (MHC) determinants. Bone marrow transplantation studies were performed to examine the in vivo functions of 2 of these subsets. Subsets of Ly-49A and Ly-49G2 NK share specificity for the same MHC class 1 ligand, Dd, binding of which results in an inhibitory signal to the NK cell but allows them to lyse H2(b) targets in vitro. We therefore examined the ability of these subsets to reject H2(b) bone marrow cell allografts in lethally irradiated mice. Surprisingly, depletion of Ly-49A(+) NK cells in BALB/c or B10.D2 mice (both H2(d)) had no effect on the rejection of H2b BMC, However, Ly-49A depletion did partially abrogate the ability of B10.BR (H2(k)) mice to reject H2b allografts, Although depletion of either Ly-49A(+) or Ly-49G2(+) NK cells alone had no effect on the ability of B10.D2 mice to reject H2b BMC, depletion of both subsets dramatically and synergistically abrogated rejection. Studies with various B10 congenic mice and their Fl hybrids indicate that this synergy between Ly49A and Ly4G2 depletion occurs in every instance. Thus, Ly-49A(+) NK cells appear to play a role in the rejection H2(b) bone marrow allografts, but, in most strains of mice studied, Ly-49G2(+) NK cells must also be eliminated. The putative roles of these NK cell subsets in clinical transplantation remains to be elucidated. (C) 2000 by The American Society of Hematology. C1 SAIC Frederick, Intramural Res Support Program, Frederick, MD USA. NCI, Frederick Canc Res & Dev Ctr, Expt Immunol Lab, Frederick, MD USA. Univ Texas, SW Med Ctr, Dallas, TX USA. NIA, Baltimore, MD 21224 USA. RP Murphy, WJ (reprint author), SAIC Frederick, Intramural Res Support Program, Bldg 567,Room 210, Frederick, MD USA. FU NCI NIH HHS [N01-CO-56000] NR 31 TC 15 Z9 15 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 JUN 15 PY 2000 VL 95 IS 12 BP 3840 EP 3844 PG 5 WC Hematology SC Hematology GA 325ME UT WOS:000087678700028 PM 10845918 ER PT J AU Apasov, S Chen, JF Smith, P Sitkovsky, M AF Apasov, S Chen, JF Smith, P Sitkovsky, M TI A(2A) receptor dependent and A(2A) receptor independent effects of extracellular adenosine on murine thymocytes in conditions of adenosine deaminase deficiency SO BLOOD LA English DT Article ID T-CELL DEVELOPMENT; COMBINED IMMUNODEFICIENCY; PURINERGIC RECEPTOR; DNA FRAGMENTATION; FLOW-CYTOMETRY; APOPTOSIS; INHIBITION; ATP; DIFFERENTIATION; MECHANISMS AB Adenosine deaminase (ADA) deficiency causes severe combined immunodeficiency (SCID) and is accompanied by T-cell depletion and accumulation of both intracellular and extracellular adenosine (extAdo) and deoxyadenosine, To better understand the causes of T-cell depletion in vivo and to discriminate between extracellular and intracellular effects of exogenously added adenosine in vitro, we investigated mechanisms of 2 different effects of adenosine on murine thymocytes. These effects of adenosine include direct induction of apoptosis in about 6% to 15% thymocytes and inhibition of T-cell receptor (TCR) induced activation of the majority of thymocytes with inhibited ADA, APA adenosine receptors, but not A(2B), All Or A(3) receptors, are shown to be mostly responsible for extAdo-triggered signaling (cyclic adenosine monophosphate [cAMP] accumulation) in murine thymocytes and this prompted studies of the effects of extAdo on thymocytes from A(2A)R gene-deficient mice. It is found that direct apoptotic effects of extAdo on CD4(+)CD8(+) double positive (DP) thymocytes are completely accounted for by signaling through A(2A)R, with no contribution of intracellular lymphotoxicity or of compensating A(2B)Rs because only A(2A)R +/+ but not A(2A)R -/- thymocytes were susceptible to apoptotic effects of extAdo, Studies of the effects of cAMP-raising agents support observations of extAdo/A(2A)R/cAMP-triggered apoptosis in Up thymocytes. Unexpectedly, the extAdo strongly inhibited TCR-triggered activation of both A(2A)R +/+ and A(2A)R -/- thymocytes in the presence of ADA inhibitors. This was confirmed with thymocytes from ADA gene-deficient mice, suggesting the existence of A(2A)R-independent effects of extAdo on thymocytes, The presented data raises questions about the identity and functional role of A(2A)R-expressing thyme cytes in T-cell differentiation and of the role of TCR-antagonizing effects of extAdo in conditions of ADA SCID. (C) 2000 by The American Society of Hematology. C1 NIAID, Immunol Lab, Biochem & Immunopharmacol Sect, NIH, Bethesda, MD 20982 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Mol Neurobiol Lab, Charlestown, MA USA. RP Sitkovsky, M (reprint author), NIAID, Immunol Lab, Biochem & Immunopharmacol Sect, NIH, Bldg 10, Bethesda, MD 20982 USA. NR 41 TC 41 Z9 42 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 15 PY 2000 VL 95 IS 12 BP 3859 EP 3867 PG 9 WC Hematology SC Hematology GA 325ME UT WOS:000087678700031 PM 10845921 ER PT J AU Takemoto, S Trovato, R Cereseto, A Nicot, C Kislyakova, T Casareto, L Waldmann, T Torelli, G Franchini, G AF Takemoto, S Trovato, R Cereseto, A Nicot, C Kislyakova, T Casareto, L Waldmann, T Torelli, G Franchini, G TI p53 stabilization and functional impairment in the absence of genetic mutation or the alteration of the p14(ARF)-MDM2 loop in ex vivo and cultured adult T-cell leukemia/lymphoma cells SO BLOOD LA English DT Article ID VIRUS TYPE-I; LEUKEMIA-LYMPHOMA VIRUS; CYCLE ARREST; TAX PROTEIN; HTLV-I; MDM2; EXPRESSION; P16(INK4A); TRANSFORMATION; LYMPHOCYTES AB Human T-cell lymphotropic virus type I (HTLV-I) transforms T cells in vitro, and the viral transactivator Tax functionally impairs the tumor suppressor p53 protein, which is also stabilized in HTLV-I-infected T cells. Thus, the functional impairment of p53 is essential to maintain the viral-induced proliferation of CD4+ mature T cells. However, in the CD4+ leukemic cells of patients with adult T-cell leukemia/lymphoma (ATLL), the viral transactivator does not appear to be expressed, and p53 mutations have been found only in a fraction of patients. We sought to investigate whether p53 function is impaired, in ex vivo samples from patients with ATLL, in the absence of genetic mutations. Here we demonstrate that the p53 protein is stabilized also in ex vivo ATLL samples (10 of 10 studied) and that at least in 2 patients p53 stabilization was not associated with genetic mutation. Furthermore, the assessment of p53 function after ionizing radiation of ATLL cells indicated an abnormal induction of the p53-responsive genes GADD45 and p21(WAF1) in 7 of 7 patients. In 2 of 2 patients, p53 regulation of cell-cycle progression appeared to be impaired as well. Because p53 is part of a regulatory loop that also involves MDM2 and p14(ARF), the status of the latter proteins was also assessed in cultured or fresh ATLL cells. The p97 MDM2 protein was not detected by Western blot analysis in established HTLV-I-infected T-cell lines or ex vivo ATLL cell lysates, However, the MDM2 protein could be easily detected after treatment of cells with the specific proteasome inhibitor lactacystin, suggesting a normal regulation of the p53-MDM2 regulating loop. Similarly, p14(ARF) did not appear to be aberrantly expressed in ex vivo ATLL cells nor in any of the established HTLV-l-infected T-cell lines studied. Thus, p53 stabilization in HTLV-I infection occurs in the absence of genetic mutation and alteration of the physiologic degradation pathway of p53, (C) 2000 by The American Society of Hematology. C1 NCI, Div Basic Sci, Basic Res Lab 41 0804, NIH, Bethesda, MD 20892 USA. NCI, Div Clin Sci, Metab Branch, NIH, Bethesda, MD 20892 USA. Univ Modena, Ctr Ematol Sperimentale, I-41100 Modena, Italy. RP Franchini, G (reprint author), NCI, Div Basic Sci, Basic Res Lab 41 0804, NIH, Bethesda, MD 20892 USA. NR 37 TC 51 Z9 51 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 JUN 15 PY 2000 VL 95 IS 12 BP 3939 EP 3944 PG 6 WC Hematology SC Hematology GA 325ME UT WOS:000087678700041 PM 10845931 ER PT J AU Beilmann, M Vande Woude, GF Dienes, HP Schirmacher, P AF Beilmann, M Vande Woude, GF Dienes, HP Schirmacher, P TI Hepatocyte growth factor-stimulated invasiveness of monocytes SO BLOOD LA English DT Article ID FACTOR-SCATTER FACTOR; HEMATOPOIETIC PROGENITOR CELLS; ACUTE LIVER-INJURY; FACTOR-RECEPTOR; MET PROTOONCOGENE; HEPATOPOIETIN-A; C-MET; CHEMOTACTIC PROTEIN-1; PARTIAL-HEPATECTOMY; EPITHELIAL-CELLS AB Hepatocyte growth factor (HGF) is a pluripotent cytokine with mitogenic, motogenic, and morphogenic activity for mainly epithelial and endothelial target cells, We previously demonstrated that the specific HGF receptor, MET, is induced in stimulated peripheral blood monocytes, In this study, we analyzed the functional consequences of MET activation in primary cultures of peripheral blood monocytes from healthy donors. After stimulation of MET-expressing monocytes with recombinant HGF, the gene-expression profile of peripheral blood mononuclear cells and monocytes was significantly modulated, especially with regard to genes involved in cell movement. After stimulation of primary cultured monocytes with HGF, invasion assays showed a significantly increased matrigel invasion rate that was completely abolished by neutralizing antibodies to HGF. The HGF-activated invasiveness and the altered gene-expression profile suggest a proinflammatory role for HGF stimulation of monocytes and support the hypothesis that the HGF/MET signaling system plays an important part in the activation of the nonspecific cellular inflammatory response, (C) 2000 by The American Society of Hematology. C1 Univ Cologne, Inst Pathol, D-50931 Cologne, Germany. NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Frederick, MD USA. RP Schirmacher, P (reprint author), Univ Cologne, Inst Pathol, Joseph Steizmann Str 9, D-50931 Cologne, Germany. NR 51 TC 56 Z9 59 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 JUN 15 PY 2000 VL 95 IS 12 BP 3964 EP 3969 PG 6 WC Hematology SC Hematology GA 325ME UT WOS:000087678700045 PM 10845935 ER PT J AU Champlin, RE Passweg, JR Zhang, MJ Rowlings, PA Pelz, CJ Atkinson, KA Barrett, AJ Cahn, JY Drobyski, WR Gale, RP Goldman, JM Gratwohl, A Gordon-Smith, EC Henslee-Downey, PJ Herzig, RH Klein, JP Marmont, AM O'Reilly, RJ Ringden, O Slavin, S Sobocinski, KA Speck, B Weiner, RS Horowitz, MM AF Champlin, RE Passweg, JR Zhang, MJ Rowlings, PA Pelz, CJ Atkinson, KA Barrett, AJ Cahn, JY Drobyski, WR Gale, RP Goldman, JM Gratwohl, A Gordon-Smith, EC Henslee-Downey, PJ Herzig, RH Klein, JP Marmont, AM O'Reilly, RJ Ringden, O Slavin, S Sobocinski, KA Speck, B Weiner, RS Horowitz, MM TI T-cell depletion of bone marrow transplants for leukemia from donors other than HLA-identical siblings: advantage of T-cell antibodies with narrow specificities SO BLOOD LA English DT Article ID VERSUS-HOST DISEASE; CHRONIC MYELOGENOUS LEUKEMIA; CHRONIC MYELOID-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; BLOOD PROGENITOR CELLS; PREVENT ACUTE GRAFT; MONOCLONAL-ANTIBODIES; UNRELATED DONORS; RISK-FACTORS; ALLOGENEIC TRANSPLANTATION AB T-cell depletion of donor marrow decreases graft-versus-host disease resulting from transplants from unrelated and human leukocyte antigen (HLA)-mis-matched related donors. However, there are diverse strategies for T-cell-depleted transplantation, and it is uncertain whether any improve leukemia-free survival (LFS), To compare strategies for T-cell-depleted alternative donor transplants and to compare T-cell depleted with non-T-cell-depleted transplants, we studied 870 patients with leukemia who received T-cell-depleted transplants from unrelated or HLA-mismatched related donors from 1982 to 1994, Outcomes were compared with those of 998 non-T-cell-depleted transplants. We compared LFS using different strategies for T-cell-depleted transplantation considering T-cell depletion technique, intensity of pretransplant conditioning, and posttransplant immune suppression using proportional hazards regression to adjust for other prognostic variables. Five categories of T-cell depletion techniques were considered: narrow-specificity antibodies, broad-specificity antibodies, Campath antibodies, elutriation, and lectins, Strategies resulting in similar LFS were pooled to compare T-cell-depleted with non-T-cell-depleted transplants. Recipients of transplants T-cell depleted by narrow-specificity antibodies had lower treatment failure risk (higher LFS) than recipients of transplants T-cell depleted by other techniques. Compared with nonT-cell-depleted transplants (5-year probability +/- 95% confidence interval [CI] of LFS, 31% +/- 4%), 5-year LFS was 29% +/- 5% (P = NS) after transplants T-cell depleted by narrow-specificity antibodies and 16% +/- 4% (P < .0001) after transplants T cell depleted by other techniques. After alternative donor transplantation, T-cell depletion of donor marrow by narrow-specificity antibodies resulted in LFS rates that were higher than those for transplants T-cell depleted using other techniques but similar to those for non-T-cell-depleted transplants. (C) 2000 by The American Society of Hematology. C1 Med Coll Wisconsin, Int Bone Marrow Transplant Registry, Milwaukee, WI 53226 USA. Med Coll Wisconsin, Hlth Policy Inst, Milwaukee, WI 53226 USA. Med Coll Wisconsin, Div Hematol Oncol, Milwaukee, WI 53226 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Coulter Cellular Therapies, Medford, MA USA. NHLBI, Bethesda, MD 20892 USA. Hop Jean Minjoz, F-25030 Besancon, France. Ctr Adv Studies Leukemia, Santa Monica, CA USA. St George Hosp, Sch Med, London, England. Royal Postgrad Med Sch, London, England. Univ S Carolina, Columbia, SC 29208 USA. Univ Louisville, Louisville, KY 40292 USA. Osped San Martino Genova, Genoa, Italy. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Huddinge Univ Hosp, S-14186 Huddinge, Sweden. Hadassah Univ Hosp, IL-91120 Jerusalem, Israel. Tulane Univ, Med Ctr, New Orleans, LA 70118 USA. RP Horowitz, MM (reprint author), Med Coll Wisconsin, Int Bone Marrow Transplant Registry, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. FU NCI NIH HHS [P01-CA40053, U24-CA76518] NR 57 TC 104 Z9 110 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 JUN 15 PY 2000 VL 95 IS 12 BP 3996 EP 4003 PG 8 WC Hematology SC Hematology GA 325ME UT WOS:000087678700050 PM 10845940 ER PT J AU Narimatsu, S Kobayashi, N Masubuchi, Y Horie, T Kakegawa, T Kobayashi, H Hardwick, JP Gonzalez, FJ Shimada, N Ohmori, S Kitada, M Asaoka, K Kataoka, H Yamamoto, S Satoh, T AF Narimatsu, S Kobayashi, N Masubuchi, Y Horie, T Kakegawa, T Kobayashi, H Hardwick, JP Gonzalez, FJ Shimada, N Ohmori, S Kitada, M Asaoka, K Kataoka, H Yamamoto, S Satoh, T TI Species difference in enantioselectivity for the oxidation of propranolol by cytochrome P450 2D enzymes SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE CYP2D6; human liver microsomes; monkey liver microsomes; propranolol; enantioselectivity; heterologous expression system ID HUMAN LIVER-MICROSOMES; BUNITROLOL 4-HYDROXYLATION; RHESUS-MONKEY; RAT-LIVER; IN-VITRO; SUBSTRATE METABOLISM; NONHUMAN-PRIMATES; CYNOMOLGUS MONKEY; PHASE-I; CYP2D6 AB We examined and compared enantioselectivity in the oxidation of propranolol (PL) by liver microsomes from humans and Japanese monkeys (Macaca fuscata). PL was oxidized at the naphthalene ring to 4-hydroxypropranolol, 5-hydroxypropranolol and side chain N-desisopropylpropranolol by human liver microsomes with enantioselectivity of [R(+)> S(-)] in PL oxidation rates at substrate concentrations of 10 mu M and 1 mM. In contrast, reversed enantioselectivity [R(+)< S(-)] in PL 5-hydroxylation and N-desalkylation rates at the same substrate concentrations was observed in monkey liver microsomes, although the selectivity was the same for PL 4-hydroxylation between the two species. All oxidation reactions of the PL enantiomers in human liver microsomes showed biphasic kinetics, i.e. the reactions could be expressed as the summation of a low-K-m phase and a high-K-m phase. Inhibition studies using antibodies and characterization of CYP2D6 enzymes expressed in insect cells or human lymphoblastoid cells indicated that the enantioselectivity of PL oxidation, especially the ring 4- and 5-hydroxylations reflected the properties of CYP2D6 in human liver microsomes. In monkey liver microsomes, all of the oxidation reactions of S( -)-PL showed biphasic kinetics, whereas ring 4- and 5-hydroxylations were monophasic and side chain N-desisopropylation was biphasic for R(+)-PL. Similarly, from the results of inhibition studies using antibodies and inhibitors of cytochrome P450 (P450), it appears that the reversed selectivity [R(+)3.0.CO;2-5 PG 6 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 330QG UT WOS:000087972300007 PM 10861694 ER PT J AU Riker, AI Kammula, US Panelli, MC Wang, E Ohnmacht, GA Steinberg, SM Rosenberg, SA Marincola, FM AF Riker, AI Kammula, US Panelli, MC Wang, E Ohnmacht, GA Steinberg, SM Rosenberg, SA Marincola, FM TI Threshold levels of gene expression of the melanoma antigen gp100 correlate with tumor cell recognition by cytotoxic T lymphocytes SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID METASTATIC MELANOMA; HETEROGENEOUS EXPRESSION; IN-VIVO; LINES; IMMUNOTHERAPY; TYROSINASE; LESIONS; MART-1; PEPTIDE; MAGE-1 AB The level of expression of melanoma antigens (MA) may modulate the host immunologic response. Thus, the accurate measurement of MA expression may allow proper patient selection for antigen-specific therapies and yield important information for the evaluation of clinical results. in this study, we measured the absolute levels of MA messenger ribonucleic acid (mRNA) in tumor cell lines utilizing realtime quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). mRNA levers of MART-1, gp100, tyrosinase, TRP-1 and TRP-2, melanoma differentiation antigens and MAGE-1, MAGE-3 and ESO-1 cancer testis (CT) antigens were compared in 24 early-passage (<5 passages in culture) and 12 archival melanoma cell lines. MA mRNA expression was extremely variable among cell lines, occasionally reaching levels comparable to ribosomal RNA (rRNA). gp100 and MART-I mRNA levels correlated with protein expression measurement obtained by FAGS analysis. More significantly, a threshold of gp 100 mRNA expression required for T-cell stimulation and target-cell killing was identified. This threshold level corresponded to approximately 500 mRNA copies per 10(8) copies of rRNA. Our results suggest that the measurements of MA mRNA levels may yield useful information relevant to the interpretation of clinical outcome during antigen-specific treatments. Published 2000 Wiley-Liss, Inc. C1 NCI, Surg Branch, Div Clin Sci, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Rockville, MD USA. RP Marincola, FM (reprint author), NCI, Surg Branch, Div Clin Sci, Bldg 10,Room 2B56,10 Ctr Dr,MSC 1184, Bethesda, MD 20892 USA. RI Riker, Adam/A-6065-2011 NR 22 TC 52 Z9 53 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 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUN 15 PY 2000 VL 86 IS 6 BP 818 EP 826 DI 10.1002/(SICI)1097-0215(20000615)86:6<818::AID-IJC10>3.0.CO;2-W PG 9 WC Oncology SC Oncology GA 319EB UT WOS:000087327600010 PM 10842196 ER PT J AU Hornung, F Scala, G Lenardo, MJ AF Hornung, F Scala, G Lenardo, MJ TI TNF-alpha-induced secretion of C-C chemokines modulates C-C chemokine receptor 5 expression on peripheral blood lymphocytes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; VIRUS TYPE-1 INFECTION; RHEUMATOID-ARTHRITIS; T-LYMPHOCYTES; HIV-1 INFECTION; HUMAN-MONOCYTES; ALVEOLAR MACROPHAGES; INDUCED APOPTOSIS; CCR5 EXPRESSION AB Peripheral blood lymphocytes express CCR5, a chemokine receptor for immune cell migration and calcium signaling that serves as an important coreceptor for the HIV. After in vitro stimulation, CCR5 expression is dramatically increased on mature T lymphocytes, especially on the CD45RO(+) memory subset. In this study, we report that TNF-alpha delays the surface expression of CCR5 on PBLs after activation and diminishes CCR5 irrespective of its initial level, Functional loss of CCR5 is reflected in a decreased capability of the treated cells to migrate and signal calcium after MIP-1 beta stimulation. The effect is mediated via the p80 type IT TNF receptor (TNFR2), which induces NF-KB among other factors, leading to an enhanced secretion of the chemokines macrophage-inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta, and RANTES. Expression of these chemokines directly down-regulates CCR5, These findings reveal a new regulatory mechanism utilized by activated peripheral T cells to modulate their chemotaxis and potentially other functions mediated by CCR5, including the infection of T lymphocytes by macrophage-tropic HIV strains. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Lenardo, MJ (reprint author), NIAID, Immunol Lab, NIH, 10 Ctr Dr,MSC 1892,Bldg 10,Room 11N311, Bethesda, MD 20892 USA. RI SCALA, GIUSEPPE/A-3280-2009 NR 71 TC 47 Z9 47 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 15 PY 2000 VL 164 IS 12 BP 6180 EP 6187 PG 8 WC Immunology SC Immunology GA 322KJ UT WOS:000087508500013 PM 10843668 ER PT J AU Junn, E Han, SH Im, JY Yang, Y Cho, EW Um, HD Kim, DK Lee, KW Han, PL Rhee, SG Choi, I AF Junn, E Han, SH Im, JY Yang, Y Cho, EW Um, HD Kim, DK Lee, KW Han, PL Rhee, SG Choi, I TI Vitamin D-3 up-regulated protein 1 mediates oxidative stress via suppressing the thioredoxin function SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LEUKEMIA-DERIVED FACTOR; DNA-BINDING ACTIVITY; HYDROGEN-PEROXIDE; REDOX REGULATION; FACTOR ADF; DIRECT ASSOCIATION; CELL-DEATH; EXPRESSION; MECHANISM; APOPTOSIS AB As a result of identifying the regulatory proteins of thioredoxin (TRX), a murine homologue for human vitamin D-3 up-regulated protein 1 (VDUP1) was identified from a yeast two-hybrid screen. Cotransfection into 293 cells and precipitation assays confirmed that mouse VDUP1 (mVDUP1) bound to TRX, but it failed to bind to a Cys(32) and Cys(35) mutant TRX, suggesting the redox-active site Is critical for binding. mVDUP1 was ubiquitously expressed in various tissues and located in the cytoplasm, Biochemical analysis showed that mVDUP1 inhibited the insulin-reducing activity of TRX, When cells were treated with various stress stimuli such as H2O2 and heat shock, mVDUP1 was significantly induced. TRX is known to interact with other proteins such as proliferation-associated gene and apoptosis signal-regulating kinase 1, Coexpression of mVDUP1 interfered with the interaction between TRX and proliferation-associated gene or TRX and ASK-I, suggesting its roles in cell proliferation and oxidative stress, To investigate the roles of mVDUP1 in oxidative stress, mVDUP1 was overexpressed in NIH 3T3 cells. When cells were exposed to stress, cell proliferation was declined with elevated apoptotic cell death compared with control cells, In addition, c-Jun N-terminal kinase activation and IL-6 expression were elevated. Taken together, these results demonstrate that mVDUP1 functions as an oxidative stress mediator by inhibiting TRX activity. C1 Korea Res Inst Biosci & Biotechnol, Immunol Lab, Taejon 305333, South Korea. Yonsei Univ, Coll Med, Cell Biol Lab, Yonsei Med Res Ctr, Seoul, South Korea. NHLBI, Lab Cell Signalling, NIH, Bethesda, MD 20892 USA. RP Choi, I (reprint author), Korea Res Inst Biosci & Biotechnol, Immunol Lab, Taejon 305333, South Korea. OI Han, Pyung-Lim/0000-0002-1735-6746 NR 50 TC 292 Z9 308 U1 1 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2000 VL 164 IS 12 BP 6287 EP 6295 PG 9 WC Immunology SC Immunology GA 322KJ UT WOS:000087508500027 PM 10843682 ER PT J AU Khan, AR Baker, BM Ghosh, P Biddison, WE Wiley, DC AF Khan, AR Baker, BM Ghosh, P Biddison, WE Wiley, DC TI The structure and stability of an HLA-A*0201/octameric tax peptide complex with an empty conserved peptide-N-terminal binding site SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MHC CLASS-I; T-CELL-RECEPTOR; ANTIGENIC PEPTIDE; VIRAL PEPTIDES; HISTOCOMPATIBILITY ANTIGENS; 3-DIMENSIONAL STRUCTURE; ANGSTROM RESOLUTION; CRYSTAL-STRUCTURES; HTLV-1 TAX; MOLECULE AB The crystal structure of the human class I MHC molecule HLA-A2 complexed with of an octameric peptide, Tax8 (LFGYPVYV), from human T cell lymphotrophic virus-1 (HTLV-1) has been determined. This structure is compared with a newly refined, higher resolution (1.8 Angstrom) structure of HLA-A2 complexed with the nonameric Tax9 peptide (LLFGYPVYV) with one more N-terminal residue, Despite the absence of a peptide residue (P1) bound in the conserved N-terminal peptide-binding pocket of the Tax8/HLA-A2 complex, the structures of the two complexes are essentially identical. Water molecules in the Tax8 complex replace the terminal amino group of the Tax9 peptide and mediate a network of hydrogen bonds among the secondary structural elements at that end of the peptide-binding groove. Thermal denaturation measurements indicate that the Tax8 complex is much less stable, Delta T-m = 16 degrees C, than the Tax9 complex, but both can sensitize target cells for lysis by some Tax-specific CTL from HTLV-1 infected individuals. The absence of a Pi peptide residue is thus not enough to prevent formation of a "closed conformation" of the peptide-binding site, TCR affinity measurements and cytotoxic T cell assays indicate that the Tax8/HLA-A2 complex does not functionally cross-react with the A6-TCR-bearing T cell clone specific for Tax9/HLA-A2 complexes. C1 Harvard Univ, Howard Hughes Med Inst, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA. NINDS, Mol Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Wiley, DC (reprint author), Harvard Univ, Howard Hughes Med Inst, Dept Mol & Cellular Biol, 7 Divin Ave, Cambridge, MA 02138 USA. RI Baker, Brian/B-4584-2009 OI Baker, Brian/0000-0002-0864-0964 NR 53 TC 116 Z9 118 U1 0 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2000 VL 164 IS 12 BP 6398 EP 6405 PG 8 WC Immunology SC Immunology GA 322KJ UT WOS:000087508500040 PM 10843695 ER PT J AU Hoffmann, KF Cheever, AW Wynn, TA AF Hoffmann, KF Cheever, AW Wynn, TA TI IL-10 and the dangers of immune polarization: Excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; MANSONI-INFECTED MICE; GRANULOMA-FORMATION; TNF-ALPHA; HEPATIC-FIBROSIS; INTERFERON-GAMMA; NITRIC-OXIDE; IFN-GAMMA; HELMINTH INFECTION; TOXOPLASMA-GONDII AB To dissect the controversial roles of type 1 and type 2 cytokines to the pathogenesis of schistosomiasis, we generated IL-10m-4 and IL-10/IL-12-deficient mice that develop highly polarized type 1 and type 2 cytokine responses, respectively. Interestingly, the Th1-polarized IL-10/IL-4-deficient mice rapidly lost weight at the onset of egg-laying and displayed 100% mortality by wk 9 postinfection. This acute mortality was linked to overexpression of the proinflammatory mediators IFN-gamma, TNF-alpha, and inducible NO and the formation of nonfibrotic granulomas. Elevated serum aspartate transaminase levels confirmed that mortality was in part attributable to acute hepatotoxicity, In contrast, the Th2-polarized IL-10/IL-12-deficient mice developed a progressive wasting disease that correlated with increased hepatic fibrosis, formation of large eosinophil-rich granulomas, a l0-fold increase in IL-4 and IL-13, and significant mortality during the chronic stages of infection. Surprisingly, IL-10-deficient mice displayed pathological Features that were characteristic of both extremes, while wild-type mice developed relatively successful long term chronic infections. These data demonstrate that IL-10 significantly suppresses type 1 and type 2 cytokine development in IL-4- and IL-12-deficient mice, respectively, thereby impeding the development of severe egg-induced pathology in the single cytokine-deficient animals. Together, these findings reveal the central regulatory role of IL-10 in the pathogenesis of schistosomiasis and illustrate that excessive type 1 and type 2 cytokine responses trigger distinct, but equally detrimental, forms of pathology following infection. C1 NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Biomed Res Inst, Rockville, MD 20852 USA. RP Wynn, TA (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike,Bldg 4,Room 126, Bethesda, MD 20892 USA. RI Wynn, Thomas/C-2797-2011 NR 50 TC 281 Z9 291 U1 2 U2 12 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 15 PY 2000 VL 164 IS 12 BP 6406 EP 6416 PG 11 WC Immunology SC Immunology GA 322KJ UT WOS:000087508500041 PM 10843696 ER PT J AU Bosio, CM Gardner, D Elkins, KL AF Bosio, CM Gardner, D Elkins, KL TI Infection of B cell-deficient mice with CDC 1551, a clinical isolate of Mycobacterium tuberculosis: Delay in dissemination and development of lung pathology SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PULMONARY TUBERCULOSIS; AVIUM COMPLEX; IFN-GAMMA; T-CELLS; INTERFERON; VIRULENT; GENE; VACCINATION; CHEMOKINES; MECHANISM AB Long-term survival of mice infected with Mycobacterium tuberculosis is dependent upon IFN-gamma and T cells, but events in early phases of the immune response are not well, understood, In this study, we describe a role for B cells during early immune responses to infection with a clinical isolate of M. tuberculosis (CDC 1551), Following a low-dose infection with M. tuberculosis CDC 1551, similar numbers of bacteria were detected in the lungs of both B cell knockout (IgH 6(-), BKO) and C57BL/6J (wild-type) mice. However, despite comparable bacterial loads in the lungs, less severe pulmonary granuloma formation and delayed dissemination of bacteria from lungs to peripheral organs were observed in BKO mice. BKO mice reconstituted with naive B cells, but not those given M, tuberculosis-specific Abs, before infection developed pulmonary granulomas and dissemination patterns similar to wildtype animals. Further analysis of lung cell populations revealed greater numbers of lymphocytes, especially CD8(+) T cells, macrophages, and neutrophils in wild-type and reconstituted mice than in BKO mice. Thus, less severe lesion formation and delayed dissemination of bacteria found in BKO mice were dependent on B cells, not Abs, and were associated with altered cellular infiltrate to the lungs. These observations demonstrate an important, previously unappreciated, role for B cells during early immune responses to M. tuberculosis infections. C1 US FDA, Lab Mycobacteria, Div Bacterial Prod, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. NIH, Vet Resource Branch, Comparat Pathol Sect, Rockville, MD 20852 USA. RP Elkins, KL (reprint author), US FDA, Lab Mycobacteria, Div Bacterial Prod, Ctr Biol Evaluat & Res, 1401 Rockville Pike,HFM431, Rockville, MD 20852 USA. RI Bosio, Catharine/D-7456-2015 NR 30 TC 92 Z9 98 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 JUN 15 PY 2000 VL 164 IS 12 BP 6417 EP 6425 PG 9 WC Immunology SC Immunology GA 322KJ UT WOS:000087508500042 PM 10843697 ER PT J AU Wang, ZQ Yang, DL Mohanakrishnan, AK Fanwick, PE Nampoothiri, P Hamel, E Cushman, M AF Wang, ZQ Yang, DL Mohanakrishnan, AK Fanwick, PE Nampoothiri, P Hamel, E Cushman, M TI Synthesis of B-ring homologated estradiol analogues that modulate tubulin polymerization and microtubule stability SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ENDOGENOUS ESTROGEN METABOLITE; LUNG-CANCER CELLS; MAMMALIAN METABOLITE; 17-BETA-ESTRADIOL METABOLITES; INHIBITS ANGIOGENESIS; ENLARGEMENT REACTION; ENDOTHELIAL-CELLS; 2-METHOXYESTRADIOL; APOPTOSIS; COLCHICINE AB 2-Methoxyestradiol is a cytotoxic human metabolite of estradiol with the ability to bind to the colchicine site of tubulin and inhibit its polymerization, and its 2-ethoxy analogue is even more potent. On the basis of a hypothetical relationship between the structures of colchicine and 2-methoxyestradiol, a B-ring-expanded 2-ethoxyestradiol analogue was synthesized in which the B-ring of the steroid is replaced by the B-ring of colchicine. The synthesis relied on the B-ring expansion of available B-keto estradiol derivatives as opposed to a total synthesis of the homologated steroid framework. The relative configurations of the acetamido substituents in both epimers of the final product were determined by NQESY NMR and confirmed by X-ray crystallography. The epimer having the 6 alpha-acetamido substituent was more active as an inhibitor of tubulin polymerization, and it was also more cytotoxic than the 6 beta-epimer. These results are consistent with the proposed structural resemblance of 2-methoxyestradiol and colchicine. Several of the synthetic intermediates proved to be potent inhibitors of tubulin polymerization. On the other hand, a 3,17 beta-diacetylated, B-ring-expanded analogue of 2-ethoxyestradiol having a ketone at C-6 resembled paclitaxel (Taxol) in its ability to enhance tubulin polymerization and stabilize microtubules. The corresponding 3-acetate and the 17 beta-acetate were both synthesized, and it was determined that the 17 beta-acetate, but not the 3-acetate, conferred on the steroid derivative its paclitaxel-like activity. C1 Purdue Univ, Sch Pharm & Pharmacal Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Canc Res & De, Frederick, MD 21702 USA. RP Cushman, M (reprint author), Purdue Univ, Sch Pharm & Pharmacal Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. RI Fanwick, Phillip/A-8625-2009 FU NCI NIH HHS [N01-CM67260] NR 40 TC 53 Z9 54 U1 1 U2 5 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 JUN 15 PY 2000 VL 43 IS 12 BP 2419 EP 2429 DI 10.1021/jm0001119 PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 325QZ UT WOS:000087689000016 PM 10882369 ER PT J AU Ma, JX Lugo, B Shah, S Godfrey, EW Daniels, MP AF Ma, JX Lugo, B Shah, S Godfrey, EW Daniels, MP TI Synaptic localization and axonal targeting of agrin secreted by ventral spinal cord neurone in culture SO JOURNAL OF NEUROBIOLOGY LA English DT Article DE agrin; neuromuscular junction; motor neuron; axon; secretion ID ACETYLCHOLINE-RECEPTOR CLUSTERS; HEPARAN-SULFATE PROTEOGLYCAN; CELL-ADHESION MOLECULE; NERVE-MUSCLE SYNAPTOGENESIS; EMBRYONIC RAT MOTONEURONS; NEUROMUSCULAR-JUNCTION; EXTRACELLULAR-MATRIX; HIPPOCAMPAL-NEURONS; BASAL LAMINA; ALPHA-DYSTROGLYCAN AB Agrin secreted by motor neurons is a critical signal for postsynaptic differentiation at the developing neuromuscular junction. We used cultures of chick ventral spinal cord neurons with rat myotubes and immunofluorescence with species-specific antibodies to determine the distribution of agrin secreted by neurons and compare it to the distribution of agrin secreted by myotubes. Ln addition, we determined the distribution of agrin secreted by isolated chick ventral spinal cord neurons and rat motor neurons grown on a substrate that binds agrin. In cocultures, neuronal agrin was concentrated along axons at sites of axon-induced acetylcholine receptor (AChR) aggregation and was found at every such synaptic site, consistent with its role in synaptogenesis. Smaller amounts of agrin were found on dendrites and cell bodies and rarely were associated with AChR aggregation. Muscle agrin, recognized by an antibody against rat agrin, was found at nonsynaptic sites of AChR aggregation but was not detected at synaptic sites, in contrast to neuronal agrin, in cultures of isolated chick neurons or rat motor neurons, agrin was deposited relatively uniformly around axons and dendrites during the first 2-3 days in culture. In older cultures, agrin immunoreactivity was markedly more intense around axons than dendrites, indicating that motor neurons possess an intrinsic, developmentally regulated program to target agrin secretion to axons. (C) 2000 John Wiley & Sons, Inc.*. C1 NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. Med Coll Wisconsin, Dept Anat & Cell Biol, Milwaukee, WI 53226 USA. RP Daniels, MP (reprint author), NHLBI, Lab Biochem Genet, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 53 TC 4 Z9 5 U1 0 U2 0 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0022-3034 J9 J NEUROBIOL JI J. Neurobiol. PD JUN 15 PY 2000 VL 43 IS 4 BP 338 EP 351 DI 10.1002/1097-4695(20000615)43:4<338::AID-NEU3>3.0.CO;2-G PG 14 WC Neurosciences SC Neurosciences & Neurology GA 326CE UT WOS:000087713700003 PM 10861560 ER PT J AU Walker, ML Burgess, SA Sellers, JR Wang, F Hammer, JA Trinick, J Knight, PJ AF Walker, ML Burgess, SA Sellers, JR Wang, F Hammer, JA Trinick, J Knight, PJ TI Two-headed binding of a processive myosin to F-actin SO NATURE LA English DT Article ID MOTOR PROTEIN; RESOLUTION; FILAMENTS; MOLECULES; MOVEMENT; ATP AB Myosins are motor proteins in cells. They move along actin by changing shape after making stereospecific interactions with the actin subunits(1). As these are arranged helically, a succession of steps will follow a helical path. However, if the myosin heads are long enough to span the actin helical repeat (similar to 36 nm), linear motion is possible. Muscle myosin (myosin II) heads are about 16 nm long(2), which is insufficient to span the repeat(3). Myosin V, however, has heads of about 31 nm that could span 36 nm (refs 4, 5) and thus allow single two-headed molecules to transport cargo by walking straight 5. Here we use electron microscopy to show that while working, myosin V spans the helical repeat. The heads are mostly 13 actin subunits apart, with values of 11 or 15 also found. Typically the structure is polar and one head is curved, the other straighter. Single particle processing reveals the polarity of the underlying actin filament, showing that the curved head is the leading one. The shape of the leading head may correspond to the beginning of the working stroke of the motor. We also observe molecules attached by one head in this conformation. C1 Univ Leeds, Sch Biomed Sci, Astbury Ctr Struct Mol Biol, Leeds LS2 9JT, W Yorkshire, England. NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Knight, PJ (reprint author), Univ Leeds, Sch Biomed Sci, Astbury Ctr Struct Mol Biol, Leeds LS2 9JT, W Yorkshire, England. NR 27 TC 238 Z9 241 U1 4 U2 21 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 15 PY 2000 VL 405 IS 6788 BP 804 EP + PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 324KJ UT WOS:000087620600054 PM 10866203 ER PT J AU Sobol, RW Prasad, R Evenski, A Baker, A Yang, XP Horton, JK Wilson, SH AF Sobol, RW Prasad, R Evenski, A Baker, A Yang, XP Horton, JK Wilson, SH TI The lyase activity of the DNA repair protein beta-polymerase protects from DNA-damage-induced cytotoxicity SO NATURE LA English DT Article ID BASE-EXCISION-REPAIR; 5'-TERMINAL DEOXYRIBOSE-PHOSPHATE; DEOXYRIBOPHOSPHODIESTERASE DRPASE ACTIVITY; ESCHERICHIA-COLI; SITE; CELLS; IDENTIFICATION; RESIDUES; CONTAINS; RELEASE AB Small DNA lesions such as oxidized or alkylated bases are repaired by the base excision repair (BER) pathway(1). BER includes removal of the damaged base by a lesion-specific DNA glycosylase, strand scission by apurinic/apyrimidinic endonuclease, DNA resynthesis and ligation(2). BER may be further subdivided into DNA beta-polymerase (beta-pol)-dependent single-nucleotide repair and beta-pol-dependent or -independent long patch repair subpathways(3-6). Two important enzymatic steps in mammalian single-nucleotide BER are contributed by beta-pol: DNA resynthesis of the repair patch and lyase removal of 5'-deoxyribose phosphate (dRP)(2). Fibroblasts from beta-pol null mice are hypersensitive to monofunctional DNA-methylating agents, resulting in increases in chromosomal damage, apoptosis and necrotic cell death(3,7). Here we show that only the dRP lyase activity of beta-pol is required to reverse methylating agent hypersensitivity in beta-pol null cells. These results indicate that removal of the dRP group is a pivotal step in BER in vivo. Persistence of the dRP moiety in DNA results in the hypersensitivity phenotype of beta-pol null cells and may signal downstream events such as apoptosis and necrotic cell death. C1 NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 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 27 TC 228 Z9 235 U1 1 U2 7 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 15 PY 2000 VL 405 IS 6788 BP 807 EP 810 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 324KJ UT WOS:000087620600055 PM 10866204 ER PT J AU Chen, SL Le, SY Newton, DL Maizel, JV Rybak, SM AF Chen, SL Le, SY Newton, DL Maizel, JV Rybak, SM TI A gender-specific mRNA encoding a cytotoxic ribonuclease contains a 3 ' UTR of unusual length and structure SO NUCLEIC ACIDS RESEARCH LA English DT Article ID BICOID MESSENGER-RNA; PANCREATIC RIBONUCLEASE; SECONDARY STRUCTURES; TISSUE DISTRIBUTION; MOLECULAR-CLONING; CANCER-THERAPY; TUMOR-CELLS; GENE FAMILY; SEQUENCE; EXPRESSION AB A cDNA (2855 nt) encoding a putative cytotoxic ribonuclease (rapLR1) related to the antitumor protein onconase was cloned from a library derived from the liver of gravid female amphibian Rana pipiens. The cDNA was mainly comprised (83%) of 3' untranslated region (UTR). Secondary structure analysis predicted two unusual folding regions (UFRs) in the RNA 3' UTR. Two of these regions (711-1442 and 1877-2130 nt) contained remarkable, stalk-like, stem-loop structures greater than 38 and 12 standard deviations more stable than by chance, respectively, Secondary structure modeling demonstrated similar structures in the 3' UTRs of other species at low frequencies (0.01-0.3%). The size of the rapLR1 cDNA corresponded to the major hybridizing RNA cross-reactive with a genomic clone encoding onconase (3.6 kb). The transcript was found only in liver mRNA from female frogs. In contrast, immunoreactive onconase protein was detected only in oocytes. Deletion of the 3' UTR facilitated the in vitro translation of the rapLR1 cDNA. Taken together these results suggest that these unusual UFRs may affect mRNA metabolism and/or translation. C1 NCI, Lab Expt & Computat Biol, Div Basic Sci, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, Lab Biochem Physiol, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, Intramural Res Support Program, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Maizel, JV (reprint author), NCI, Lab Expt & Computat Biol, Div Basic Sci, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 50 TC 22 Z9 22 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUN 15 PY 2000 VL 28 IS 12 BP 2375 EP 2382 DI 10.1093/nar/28.12.2375 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 325XD UT WOS:000087701000014 PM 10871370 ER PT J AU Brosh, RM Karow, JK White, EJ Shaw, ND Hickson, ID Bohr, VA AF Brosh, RM Karow, JK White, EJ Shaw, ND Hickson, ID Bohr, VA TI Potent inhibition of Warner and Bloom helicases by DNA miner groove binding drugs SO NUCLEIC ACIDS RESEARCH LA English DT Article ID WERNER-SYNDROME PROTEIN; SYNDROME GENE-PRODUCT; SINGLE-STRANDED-DNA; ESCHERICHIA-COLI; MINOR-GROOVE; ANTICANCER AGENTS; ATPASE ACTIVITIES; MAJOR ADDUCT; REPLICATION; SPECIFICITY AB Maintenance of genomic integrity is vital to ail organisms, A number of human genetic disorders, including Werner Syndrome, Bloom Syndrome and Rothmund-Thomson Syndrome, exhibit genomic instability with some phenotypic characteristics of premature aging and cancer predisposition. Presumably the aberrant cellular and clinical phenotypes in these disorders arise from defects in important DNA metabolic pathways such as replication, recombination or repair. These syndromes are ail characterized by defects in a member of the RecQ family of DNA helicases. To obtain a better understanding of how these enzymes function in DNA metabolic pathways that directly influence chromosomal integrity, we have examined the effects of non-covalent DNA modifications on the catalytic activities of purified Werner (WRN) and Bloom (BLM) DNA helicases, A panel of DNA-binding ligands displaying unique properties for interacting with double helical DNA was tested for their effects on the unwinding activity of WRN and BLM helicases on a partial duplex DNA substrate. The levels of inhibition by a number of these compounds were distinct from previously reported values for viral, prokaryotic and eukaryotic helicases. The results demonstrate that BLM and WRN proteins exhibit similar sensitivity profiles to these DNA-binding ligands and are most potently inhibited by the structurally related minor groove binders distamycin A and netropsin (K-i less than or equal to 1 mu M). The distinct inhibition of WRN and BLM helicases by the minor groove binders suggest that these helicases unwind double-stranded DNA by a related mechanism. C1 NIA, Genet Mol Lab, GRC, NIH, Baltimore, MD 21224 USA. Univ Oxford, John Radcliffe Hosp, Inst Mol Med, Imperial Canc Res Fund Labs, Oxford OX3 9DS, England. RP Bohr, VA (reprint author), NIA, Genet Mol Lab, GRC, NIH, Box 1,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 59 TC 47 Z9 49 U1 2 U2 6 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 JUN 15 PY 2000 VL 28 IS 12 BP 2420 EP 2430 DI 10.1093/nar/28.12.2420 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 325XD UT WOS:000087701000020 PM 10871376 ER PT J AU Nakaigawa, N Weirich, G Schmidt, L Zbar, B AF Nakaigawa, N Weirich, G Schmidt, L Zbar, B TI Tumorigenesis mediated by MET mutant M1268T is inhibited by dominant-negative Src SO ONCOGENE LA English DT Article DE MET; c-Src; papillary renal cancer ID FACTOR SCATTER FACTOR; PAPILLARY RENAL CARCINOMAS; TYROSINE KINASE RECEPTOR; ROUS-SARCOMA VIRUS; C-SRC; PROTOONCOGENE PRODUCT; ACTIVATING MUTATIONS; CELL CARCINOMA; RON RECEPTOR; GROWTH AB We recently described germline and somatic mutations in the MET gene associated with papillary renal carcinoma type 1, MET mutation M1268T was Located in a codon highly conserved among receptor tyrosine kinases, and homologous to the codon mutated in multiple endocrine neoplasia type 2B, and many cases of sporadic medullary carcinoma of the thyroid gland (Ret M918T), Ret M918T and MET M1268T have previously been shown to be highly active in mouse NIH3T3 transformation assays, and to change the substrate specificity of the kinase. We studied the mechanism of transformation mediated by MET M1268T by analysing a clone, F4, derived from NIH3T3 cells transformed by MET M1268T, In contrast to NIH3T3 cells, F4 cells grew in suspension in tissue culture, and rapidly formed tumors in nude mice. We found that c-Src was constitutively bound to MET proteins in F4 cells, and that Src kinase activity was elevated. Transfection of dominant negative Src constructs into F4 cells eliminated the ability of F4 cells to grow in suspension culture and retarded the growth of F4 cells in vivo. The ability of transfected dominant negative Src constructs to inhibit the growth of F4 cells correlated with the inhibition of phosphorylation of paxillin and focal adhesion kinase, Transfection of dominant negative Src constructs into F4 cells had no effect on Grb2 binding or PLC gamma phosphorylation, The results suggest that c-Src participates in the tumorigenic phenotype induced in NIH3T3 cells by MET M1268T by signaling through focal adhesion kinase and paxillin. C1 NCI, Frederick Canc Res & Dev Ctr, Immunobiol Lab, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. RP Zbar, B (reprint author), NCI, Frederick Canc Res & Dev Ctr, Immunobiol Lab, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 31 TC 24 Z9 24 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 15 PY 2000 VL 19 IS 26 BP 2996 EP 3002 DI 10.1038/sj.onc.1203628 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 323TQ UT WOS:000087581400006 PM 10871851 ER PT J AU Izmirlian, G Brock, D White, L AF Izmirlian, G Brock, D White, L TI Estimating incidence of dementia subtypes: assessing the impact of missed cases SO STATISTICS IN MEDICINE LA English DT Article; Proceedings Paper CT Conference on Statistical Methodology in Alzheimers Disease Research CY MAY 15-17, 1998 CL LEXINGTON, KENTUCKY ID MEAN SCORE METHOD; ALZHEIMERS-DISEASE; POPULATION; CERAD; AGE AB In many community-based studies on the incidence of dementia, a target population is screened and a subsample is clinically evaluated at baseline and follow-up. Incidence rates are affected by missed cases at both exams and this complicates the estimation of these rates. Recent work proposes a regression-based technique for;joint estimation of prevalence and incidence and suggests the use of surrogate information obtained on the entire cohort at both times to calculate the expected score equation contribution for individuals missing clinical exams at one or both times. This helps to quantify the impact of missed diagnosis upon the incidence estimates and their confidence intervals. We extend this work to the setting of subtypes of dementia for use in the Honolulu-Asia Aging Study on incidence of dementia. The technique is applied using two separate models for the effect of age on dementia incidence. Subsequently, shrinkage estimation methods are applied to provide more precise estimates of the rates. Published in 2000 by John Wiley & Sons, Ltd. C1 NIA, Epidemiol Demog & Biometry Program, NIH, Bethesda, MD 20892 USA. Kuakini Med Ctr, Honolulu Asia Aging Study, Honolulu, HI USA. RP Izmirlian, G (reprint author), NCI, Biometry Res Grp, Div Canc Prevent, Execut Plaza N Suite 344,6130 Execut Blvd,MSC 735, Bethesda, MD 20892 USA. NR 20 TC 4 Z9 4 U1 0 U2 0 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 JUN 15 PY 2000 VL 19 IS 11-12 BP 1577 EP 1591 DI 10.1002/(SICI)1097-0258(20000615/30)19:11/12<1577::AID-SIM447>3.3.CO;2-H PG 15 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 321WD UT WOS:000087476900018 PM 10844720 ER PT J AU Marin, C Jimenez, A Bonastre, M Chase, TN Tolosa, E AF Marin, C Jimenez, A Bonastre, M Chase, TN Tolosa, E TI Non-NMDA receptor-mediated mechanisms are involved in levodopa-induced motor response alterations in parkinsonian rats SO SYNAPSE LA English DT Article DE parkinsonism; levodopa; motor fluctuations; glutamate antagonists; rotation ID MONOAMINE-DEPLETED RATS; MPTP-TREATED MONKEYS; METHYL-D-ASPARTATE; PROTEIN-KINASE-A; L-DOPA; ANTAGONIST NBQX; TYROSINE PHOSPHORYLATION; INDUCED DYSKINESIAS; AMPA ANTAGONISTS; CAUDATE-NUCLEUS AB Chronic dopaminomimetic administration to parkinsonian animal models or Parkinson's disease patients leads to characteristic alteration in motor response. Previous studies suggested that the nonphysiologic stimulation of dopaminergic receptors on striatal medium spiny neurons enhances the synaptic efficacy of juxtaposed glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype. Resultant NMDA receptor sensitization due to differential changes in subunit phosphorylation appears to favor alterations in striatal output in ways that influence motor function. To detail the involvement of NMDA receptors further as well as to determine whether similar functional changes might develop in alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors, the effects of selective antagonist of AMPA receptors (6-nitro-7-sulfamoyl-benzo[f]-quinoxaline-2,3 (1H,4H)-dione sodium salt, NBQX, 10 mg/kg) on levodopa-induced response alterations in 6-hydroxydopamine (6-OHDA) lesioned rats were compared with drugs which act competitively (3-(+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonicacid, CPP, 6.25 mg/kg) or noncompetitively (dextromethorphan, 40 mg/kg) to block NMDA receptors, or a nonselective inhibitor of glutamatergic transmission (2-amino-6-trifluoromethoxy benzothiazole, riluzole, 5 mg/kg). We found that the shortened duration of the motor response to levodopa, which underlies human wearing-off fluctuations, was reversed to a similar degree by the acute coadministration of CPP, NBQX, or riluzole (n = 4-6) but dextromethorphan did not. These observations strengthen the possibility that a reduction in levodopa-associated changes in motor response by inhibitors of glutamatergic transmission acting generally or selectively at the glutamate binding-sites may relate to their ability to attenuate pathologic gain in striatal glutamatergic function. The capacity of NBQX to reverse these altered responses suggests that an enhanced synaptic efficacy of striatal AMPA receptors may also participate in the generation of these motor response changes in levodopa-treated parkinsonian rats. Synapse 36:267-274, 2000. (C) 2000 Wiley-Liss, Inc. C1 Hosp Clin Barcelona, Inst Invest Biomed Agusti Pi & Sunyer, Serv Neurol, Lab Neurol Expt, E-08036 Barcelona, Spain. NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Marin, C (reprint author), Hosp Clin Barcelona, Inst Invest Biomed Agusti Pi & Sunyer, Serv Neurol, Lab Neurol Expt, Villarroel 170, E-08036 Barcelona, Spain. NR 44 TC 49 Z9 51 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD JUN 15 PY 2000 VL 36 IS 4 BP 267 EP 274 DI 10.1002/(SICI)1098-2396(20000615)36:4<267::AID-SYN3>3.0.CO;2-Y PG 8 WC Neurosciences SC Neurosciences & Neurology GA 310PW UT WOS:000086837400003 PM 10819904 ER PT J AU Karrow, NA McCay, JA Brown, RD Musgrove, DL Pettit, DA Munson, AE Germolec, DR White, KL AF Karrow, NA McCay, JA Brown, RD Musgrove, DL Pettit, DA Munson, AE Germolec, DR White, KL TI Thalidomide stimulates splenic IgM antibody response and cytotoxic T lymphocyte activity and alters leukocyte subpopulation numbers in female B6C3F1 mice SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE thalidomide; immunomodulation; B6C3F1 mice ID HUMAN-IMMUNODEFICIENCY-VIRUS; CENTRAL IMMUNE-SYSTEM; TNF-ALPHA; CYTOKINE MODULATION; CELLS; PROLIFERATION; TUBERCULOSIS; EXPRESSION; MECHANISM; LEPROSY AB Thalidomide has been shown to have antiinflammatory and, more recently, immunomodulating properties, which are beneficial for the treatment of an ever-increasing list of immune related diseases. Although considerable knowledge regarding thalidomide's antiinflammatory properties has been acquired, relatively little is known about its immunomodulating properties in vivo. In this paper, a panel of immune assays was used to evaluate immunomodulation in female B6C3F1 mice treated intraperitoneally for 28 days with thalidomide (30, 100, or 150 mg/kg/day). Spleen antibody forming cell response was significantly enhanced by 37% in mice treated with 150 mg/kg/day, despite an 8% decrease in the percentage of Ig(+) B cells. A significant stimulatory trend was observed for the cytotoxic T cell response across thalidomide treatment groups. An evaluation of the spleen leukocyte subpopulations revealed a 23% increase in the absolute number of CD8+ T cells in the 150 mg/kg treatment group and a 9 and 11% decrease in the absolute number of NK cells in both the 100 and 150 mg/kg thalidomide treatment groups, respectively. These findings demonstrate that, in addition to modulating spleen leukocyte numbers, thalidomide also stimulates murine humoral and cellular immune responses in vivo. (C) 2000 Academic Press. C1 Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. NIEHS, Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP White, KL (reprint author), Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Med Coll Virginia Campus, Richmond, VA 23298 USA. NR 37 TC 20 Z9 22 U1 1 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUN 15 PY 2000 VL 165 IS 3 BP 237 EP 244 DI 10.1006/taap.2000.8939 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 329FZ UT WOS:000087897600007 PM 10873712 ER PT J AU Ojo, AO Meier-Kriesche, HU Hanson, JA Leichtman, AB Cibrik, D Magee, JC Wolfe, RA Agodoa, LY Kaplan, B AF Ojo, AO Meier-Kriesche, HU Hanson, JA Leichtman, AB Cibrik, D Magee, JC Wolfe, RA Agodoa, LY Kaplan, B TI Mycophenolate mofetil reduces late renal allograft loss independent of acute rejection SO TRANSPLANTATION LA English DT Article ID ACUTE CELLULAR REJECTION; PREVENT ACUTE REJECTION; RAT REMNANT KIDNEY; TRANSPLANTATION; NEPHROPATHY; DACLIZUMAB; BASILIXIMAB; RECIPIENTS; REDUCTION; FK-506 AB Background Mycophenolate Mofetil (MMF) has been shown to significantly decrease the number of acute rejection episodes in renal transplant recipients duping the 1st year. A beneficial effect of MMF on long term graft survival has been moire difficult to demonstrate. This beneficial effect has not been detected, despite the impact of acute rejection on the development of chronic allograft nephropathy and experimental evidence that MMF may have a salutary effect on chronic allograft; nephropathy independent of that of rejection. Methods. Data on 66,774 renal transplant recipients from the U.S. renal transplant scientific registry were analyzed. patients who received a solitary renal transplant between October 1, 1988 and June 30, 1997 were studied, The Cox proportional hazard regression was used to estimate relevant risk factors. Kaplan-Meier analysis was performed for censored graft survival. Results. MMF decreased the relative risk for development of chronic allograft failure (CAF) by 27% (risk ratio [RR] 0.73, P<0.001). This effect was independent of its outcome on acute rejection. Censored graft survival using MMF versus azathioprine was significantly improved by Kaplan-Meier analysis at 4 years (85.6% v, 81.9%). The effect of an acute rejection episode on the risk of developing CAF seems to be increasing over time (RR=1.9, 1988-91; RR=2.9, 1992-94; RR=3.7, 1995-97). Conclusion. MMF therapy decreases the risk of developing CAF, This improvement is only partly caused by the decrease in the incidence of acute rejection observed with MMF; but, is also caused by an effect independent of acute rejection. C1 Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Surg, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. NIDDKD, US Renal Data Syst, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. RP Kaplan, B (reprint author), Univ Michigan, Med Ctr, Dept Internal Med, Taubman Ctr 3914, Box 0364, Ann Arbor, MI 48109 USA. NR 26 TC 316 Z9 326 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JUN 15 PY 2000 VL 69 IS 11 BP 2405 EP 2409 DI 10.1097/00007890-200006150-00033 PG 5 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 325HD UT WOS:000087669400033 PM 10868649 ER PT J AU Brooks, MM Jones, RH Bach, RG Chaitman, BR Kern, MJ Orszulak, TA Follmann, D Sopko, G Blackstone, EH Califf, RM AF Brooks, MM Jones, RH Bach, RG Chaitman, BR Kern, MJ Orszulak, TA Follmann, D Sopko, G Blackstone, EH Califf, RM CA BARI Investigators TI Predictors of mortality and mortality from cardiac causes in the bypass angioplasty revascularization investigation (BARI) randomized trial and registry SO CIRCULATION LA English DT Article DE angioplasty; bypass; grafting; trials; mortality; diabetes mellitus ID CORONARY-ARTERY DISEASE; LONG-TERM SURVIVAL; MYOCARDIAL-INFARCTION; RACIAL-DIFFERENCES; SURGERY; MANAGEMENT; VARIABLES; OUTCOMES AB Background-The impact of percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG) on long-term mortality rates in the presence of various demographic, clinical, and angiographic factors is uncertain in the population of patients suitable for both procedures. Methods and Results-In the Bypass Angioplasty Revascularization Investigation (BARI) randomized trial and registry, 3610 patients who were eligible to receive PTCA and CABG were revascularized between 1989 and 1993. Multivariate Cox models were used to identify factors associated with 5-year mortality and cardiac mortality, with particular attention to factors that interact with treatment. Diabetic patients receiving insulin had higher mortality and cardiac mortality rates with PTCA compared with CABG (relative risk [RR] 1.78 and 2.63, respectively, P<0.001), and patients with ST elevation had higher cardiac mortality rates with CABG than with PTCA (RR 4.08, P<0.001). Factors most strongly associated with high overall mortality rates were insulin-treated diabetes, congestive heart failure, kidney failure, and older age. Black race was also associated with higher mortality rates (RR 1.49, P=0.19). Conclusions-A set of variables was identified that could be used to help select a revascularization procedure and to evaluate risk of long-term mortality in the population of patients considering revascularization. C1 Univ Pittsburgh, Epidemiol Data Ctr, Pittsburgh, PA 15261 USA. Duke Univ, Med Ctr, Durham, NC USA. St Louis Univ, Hlth Sci Ctr, St Louis, MO 63103 USA. Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. NHLBI, Bethesda, MD 20892 USA. Cleveland Clin, Cleveland, OH 44106 USA. RP Brooks, MM (reprint author), Univ Pittsburgh, Epidemiol Data Ctr, 127 Parran Hall, Pittsburgh, PA 15261 USA. OI Brooks, Maria/0000-0002-2030-7873 FU NHLBI NIH HHS [HL-38493, HL-38504, HL-38509] NR 18 TC 87 Z9 95 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 13 PY 2000 VL 101 IS 23 BP 2682 EP 2689 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 323NM UT WOS:000087571900015 PM 10851204 ER PT J AU Kawas, C Gray, S Brookmeyer, R Fozard, J Zonderman, A AF Kawas, C Gray, S Brookmeyer, R Fozard, J Zonderman, A TI Age-specific incidence rates of Alzheimer's disease - The Baltimore Longitudinal Study of Aging SO NEUROLOGY LA English DT Article DE AD; incidence; incidence rates; dementia ID VASCULAR DEMENTIA; RISK-FACTORS; POPULATION; PREVALENCE; COMMUNITY; EDUCATION; RELIABILITY; DIAGNOSIS; IMPACT; STATE AB Objective: To estimate age-specific incidence rates of AD in the Baltimore Longitudinal Study of Aging (BLSA). Background: The BLSA is a volunteer cohort of normal subjects followed longitudinally with biennial evaluations at the Gerontology Research Center of the National Institute on Aging. Methods: Subjects are 1236 participants (802 men, 434 women) in the BLSA with longitudinal follow-up between January 1985 and May 1998. The average length of follow-up was 7.5 years, with participants evaluated every 2 years by physical, neurologic, and neuropsychological examinations. Using Diagnostic and Statistical Manual of Mental Disorders, 3rd ed,, revised and National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria, the authors diagnosed dementia and AD. Results: The authors diagnosed 155 cases of dementia, of which 114 (74%) were AD. Incidence rates of AD increased with age from an estimated 0.08% per year (95% CI 0.00 to 0.43) in the 60 to 65 age group to an estimated 6.48% per year (95% CI 5.01 to 8.38) in the 85+ age group for men and women combined. The doubling time of incidence rates was estimated to be approximately 4.4 years and the median time of conversion from mild cognitive impairment to diagnosis of AD was estimated to be 4.4 years. There was a trend for women to have higher incidence rates than men and for fewer years of education to be associated with higher incidence rates; however, these effects mere not significant. Conclusion: Incidence rates for AD in the BLSA are consistent with published rates in other studies. The longitudinally followed subjects of the BLSA offer a unique opportunity to prospectively investigate the antecedents of AD. C1 Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Alzheimers Dis Res Ctr, Baltimore, MD USA. NIA, Baltimore Longitudinal Study Aging, Cognit Sect, NIH, Baltimore, MD USA. NIA, Clin Invest Lab, NIH, Baltimore, MD USA. NIA, Lab Personaol & Cognit, NIH, Baltimore, MD USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. RP Kawas, C (reprint author), Johns Hopkins Bayview Med Ctr, Ctr Asthma & Allergy, Dept Neurol, 5501 Hopkins Bayview Circle,Room 1B-82, Baltimore, MD 21224 USA. RI Fozard, James Leonard/B-3660-2009; OI Zonderman, Alan B/0000-0002-6523-4778 FU NCRR NIH HHS [M01 RR02719]; NIA NIH HHS [AG05146, AG08325] NR 38 TC 239 Z9 245 U1 3 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUN 13 PY 2000 VL 54 IS 11 BP 2072 EP 2077 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 322TZ UT WOS:000087526200009 PM 10851365 ER PT J AU Majtenyi, C Brown, P Cervenakova, L Goldfarb, LG Tateishi, J AF Majtenyi, C Brown, P Cervenakova, L Goldfarb, LG Tateishi, J TI A three-sister sibship of Gerstmann-Straussler-Scheinker disease with a CJD phenotype SO NEUROLOGY LA English DT Article DE Gerstmann-Straussler-Scheinker disease; Creutzfeldt-Jakob disease; phenotype ID CREUTZFELDT-JAKOB-DISEASE; PRION PROTEINS; MUTATION; FAMILY; HETEROGENEITY; PRNP AB Objective: To describe a rare phenotypic variant of P102L Gerstmann-Straussler-Scheinker disease (GSS). Background: Classic GSS is characterized by an early age at onset, prominent cerebellar signs with a slowly evolving dementia, and a neuropathology including multifocal PrP-positive plaques and variable but usually modest spongiform change. Methods: Clinical, neuropathologic, immunohistochemical, and molecular genetic analysis of three sisters in a Hungarian family was performed. Results: The clinical course of all three sisters was indistinguishable from sporadic Creutzfeldt-Jakob disease (CJD). Neuropathologic examination revealed spongiform changes, PrP (prion)-positive unicentric "kuru" or multicentric plaques, and abundant beta-A4-positive senile plaques. Molecular genetic analysis of the PRNP gene showed the heterozygous codon P102L mutation of classic GSS, with the methionine encoding allele of a heterozygous codon 129 coupled to the mutant 102 allele. Conclusion: The authors report the second recorded example of a sporadic CJD phenotype occurring in association with the P102L GSS genotype, and the first instance in which the phenotype was the rule rather than the exception, or was associated with prominent beta-A4 plaque formation. C1 Natl Inst Psychiat & Neurol, Dept Neuropathol, Budapest, Hungary. NINDS, Lab CNS Studies, Bethesda, MD USA. Kyushu Univ, Inst Neurol, Dept Neuropathol, Fukuoka, Japan. RP Brown, P (reprint author), NIH, Bldg 36,Rm 4A-05,36 Convent Dr,MSC 4122, Bethesda, MD 20892 USA. OI Brown, Peter/0000-0002-5201-3044 NR 17 TC 18 Z9 18 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 JUN 13 PY 2000 VL 54 IS 11 BP 2133 EP 2137 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 322TZ UT WOS:000087526200019 PM 10851377 ER PT J AU DeLisi, LE Craddock, NJ Detera-Wadleigh, S Foroud, T Gejman, P Kennedy, JL Lendon, C Macciardi, F McKeon, P Mynett-Johnson, L Nurnberger, JI Paterson, A Schwab, S Van Broeckhoven, C Wildenauer, D Crow, TJ AF DeLisi, LE Craddock, NJ Detera-Wadleigh, S Foroud, T Gejman, P Kennedy, JL Lendon, C Macciardi, F McKeon, P Mynett-Johnson, L Nurnberger, JI Paterson, A Schwab, S Van Broeckhoven, C Wildenauer, D Crow, TJ TI Update on chromosomal locations for psychiatric disorders: Report of the Interim Meeting of Chromosome Workshop Chairpersons from the VIIth World Congress of Psychiatric Genetics, Monterey, California, October 14-18, 1999 SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Review ID BIPOLAR AFFECTIVE-DISORDER; GENOME-WIDE SEARCH; SCHIZOPHRENIA SUSCEPTIBILITY GENES; TRANSMISSION RATIO DISTORTION; X-CHROMOSOME; LINKAGE DISEQUILIBRIUM; DARIERS-DISEASE; 72 FAMILIES; LOCUS; SCAN C1 SUNY Stony Brook, Hlth Sci Ctr, Dept Psychiat, Stony Brook, NY 11794 USA. Univ Birmingham, Dept Psychiat, Birmingham, W Midlands, England. NIMH, Dept Psychiat, NIH, Bethesda, MD 20892 USA. Indiana Univ, Sch Med, Dept Psychiat, Inst Psychiat Res, Indianapolis, IN 46202 USA. Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. Univ Toronto, CAMH, Clarke Div, Neurogenet Sect, Toronto, ON, Canada. St Patricks Hosp, Dublin, Ireland. Univ Dublin Trinity Coll, Dublin 2, Ireland. Univ Bonn, Dept Psychiat, D-5300 Bonn, Germany. Univ Antwerp, Mol Genet Lab, B-2020 Antwerp, Belgium. Univ Oxford, Warneford Hosp, Oxford, England. RP DeLisi, LE (reprint author), SUNY Stony Brook, Hlth Sci Ctr, Dept Psychiat, T-10, Stony Brook, NY 11794 USA. RI turton, miranda/F-4682-2011; crow, timothy/M-8327-2014; Paterson, Andrew/A-4088-2011; Macciardi, Fabio/N-3768-2014; OI crow, timothy/0000-0002-5482-6655; Paterson, Andrew/0000-0002-9169-118X; Macciardi, Fabio/0000-0003-0537-4266; Nurnberger, John/0000-0002-7674-1767 FU NIMH NIH HHS [R13MH60596] NR 134 TC 37 Z9 38 U1 4 U2 4 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 JI Am. J. Med. Genet. PD JUN 12 PY 2000 VL 96 IS 3 BP 434 EP 449 DI 10.1002/1096-8628(20000612)96:3<434::AID-AJMG40>3.0.CO;2-C PG 16 WC Genetics & Heredity SC Genetics & Heredity GA 320DP UT WOS:000087386700040 PM 10898931 ER PT J AU Paraskevis, D Magiorkinis, M Paparizos, V Pavlakis, GN Hatzakis, A AF Paraskevis, D Magiorkinis, M Paparizos, V Pavlakis, GN Hatzakis, A TI Molecular characterization of a recombinant HIV type 1 isolate (A/G/E/?): Unidentified regions may be derived from parental subtype E sequences SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; IDENTIFICATION; THAILAND; CLONES; GENOME AB Recombination is one of several factors contributing to the genetic diversity of HIV-1, which is divided into group M (itself comprising 11 subtypes, A-K) and two other groups named O and N, In the present study, the full-length genome of an HIV-1 isolate obtained from a Greek subject (GR17) infected in the Democratic Republic of the Congo (formerly Zaire) was analyzed to reveal a novel mosaic sequence composed of subtypes A, G, and E and regions of indeterminate classification, In particular, most of pol and tat/vpu, as well as the region encoding intracellular domain of gp41, did not cluster with any of the previously characterized HIV-1 subtypes, The clustering of the LTR of GR17 with subtype E was suggestive of a subtype E origin of the unclassified regions. However, the identification of distinct characteristics in the LTR, such as two functional NF-kappa B sites and a distinct TAR element, compared with those of circulating (A/E) recombinants, suggests that the partial subtype E sequences found in GR17 and the mosaic viruses (A/E) have not derived from each other, These results provide evidence that parental subtype E may have existed in the geographic area of Central Africa. C1 Univ Athens, Sch Med, Dept Hyg & Epidemiol, Natl Retrovirus Reference Ctr, GR-11527 Athens, Greece. Univ Athens, Andreas Syngros Hosp, Sch Med, Dept Dermatol Venereol, GR-16121 Athens, Greece. NCI, ABL Basic Res Program, FCRDC, Frederick, MD 21702 USA. RP Hatzakis, A (reprint author), Univ Athens, Sch Med, Dept Hyg & Epidemiol, Natl Retrovirus Reference Ctr, GR-11527 Athens, Greece. OI Paraskevis, Dimitrios/0000-0001-6167-7152 NR 29 TC 21 Z9 21 U1 1 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JUN 10 PY 2000 VL 16 IS 9 BP 845 EP 855 DI 10.1089/08892220050042783 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 327AV UT WOS:000087770800003 PM 10875610 ER PT J AU Peters, AA Coulthart, MB Oger, JJF Waters, DJ Crandall, KA Baumgartner, AA Ward, RH Dekaban, GA AF Peters, AA Coulthart, MB Oger, JJF Waters, DJ Crandall, KA Baumgartner, AA Ward, RH Dekaban, GA TI HTLV type I/II in British Columbia Amerindians: A seroprevalence study and sequence characterization of an HTLV type IIa isolate SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID VIRUS TYPE-I; T-CELL LEUKEMIA/LYMPHOMA; CLADOGRAM ESTIMATION; MAXIMUM-LIKELIHOOD; MITOCHONDRIAL-DNA; DRUG-USERS; INFECTION; DISEASE; POPULATION; NORTHWEST AB It has been established that the human T cell lymphotropic viruses type I and II (HTLV-I-and HTLV-II) are both present in some indigenous peoples of the Americas. While HTLV-I has been identified in coastal British Columbia Indians (BCIs), HTLV-II has not been previously reported in the BCIs or other Canadian Amerindians, The prevalence of HTLV-I and HTLV-II in these populations has not been extensively studied. In this article, we examine a group of BCIs from Vancouver Island who belong to the Nuu-Chah-Nnhh and are known to have an increased incidence of rheumatic disease. In 494 serum samples from this tribe, the levels of prevalence of HTLV-I and HTLV-II were 2.8 and 1.6%, respectively. No association could be made between arthropathy and HTLV-I infection. In addition, we characterized an HTLV-II isolate of a BCI from the coastal mainland of British Columbia and with a history of intravenous drug abuse. This case represents the first molecular characterization of a Canadian Amerindian HTLV-II isolate: a subtype IIa virus with phylogenetic affinity for intravenous drug user isolates and containing an extended form of the Tax protein. These results are consistent either with this strain having been sampled from a polymorphic ancestral pool of HTLV-U: that gave rise to the current epidemic spread of this virus by intravenous drug use and sexual transmission, or with its being "back-transmitted" Into the BC Amerindian population in association with intravenous drug use. C1 John P Robarts Res Inst, Gene Therapy & Mol Virol Grp, London, ON N6A 5K8, Canada. Univ Western Ontario, Dept Microbiol & Immunol, London, ON N6A 5C1, Canada. Canadian Sci Ctr Human & Anim Hlth, Bur Microbiol, Winnipeg, MB R3E 3R2, Canada. Univ British Columbia, Dept Med, Div Neurol, Vancouver, BC V6T 2B5, Canada. NCI, NIH, Frederick, MD 21701 USA. Brigham Young Univ, Dept Zool, Provo, UT 84602 USA. Univ Oxford, Inst Biol Anthropol, Oxford OX2 6Q5, England. RP Dekaban, GA (reprint author), John P Robarts Res Inst, Gene Therapy & Mol Virol Grp, 100 Perth Dr,Rm 2-12, London, ON N6A 5K8, Canada. RI Dekaban, Gregory/L-1987-2013; OI Dekaban, Gregory/0000-0002-3087-4660; Crandall, Keith/0000-0002-0836-3389 NR 43 TC 5 Z9 7 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JUN 10 PY 2000 VL 16 IS 9 BP 883 EP 892 DI 10.1089/08892220050042828 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 327AV UT WOS:000087770800007 PM 10875614 ER PT J AU McElrath, MJ Corey, L Montefiori, D Wolff, M Schwartz, D Keefer, M Belshe, R Graham, BS Matthews, T Wright, P Gorse, G Dolin, R Berman, P Francis, D Duliege, AM Bolognesi, D Stablein, D Ketter, N Fast, P AF McElrath, MJ Corey, L Montefiori, D Wolff, M Schwartz, D Keefer, M Belshe, R Graham, BS Matthews, T Wright, P Gorse, G Dolin, R Berman, P Francis, D Duliege, AM Bolognesi, D Stablein, D Ketter, N Fast, P CA AIDS Vaccine Evaluation Grp TI A phase II study of two HIV type 1 envelope vaccines, comparing their immunogenicity in populations at risk for acquiring HIV type 1 infection SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; NEUTRALIZING ANTIBODIES; PRIMARY ISOLATE; UNINFECTED RECIPIENTS; RECOMBINANT; GP120; CHIMPANZEES; RESPONSES; SAFETY; VACCINATION AB Several immunogens induce HIV-specific neutralization and in vitro lymphoproliferation in adults at low HIV-1 risk, but responses in persons at high HIV-1 risk are not known, We performed a multicenter. double-blinded, adjuvant-controlled trial with two gp120 vaccines in 296 HIV-1-uninfected volunteers, including 176 reporting higher HIV-1 risk activities. The immunogens were remarkably well tolerated, After three immunizations, 210 of 241 vaccinees (87%) developed neutralizing antibodies, which persisted in 59% after 2 years. The injection drug users receiving SF-2/gp120 had decreased antibody responses relative to the lower risk groups. Envelope-specific lymphoproliferation peaked after two immunizations, and 54% of vaccinees. mounted a DTH reaction to gp120 after 4 years. In summary, these immunogens have low adverse reactogenicity and induce durable antibody and T cell responses to the prototype strains, Unexpected differences in antibody responses among diverse HIV-1 risk strata lend support to the conduct of expanded phase II trials in populations other than low-risk volunteers. C1 Fred Hutchinson Canc Res Ctr, Program Infect Dis, Seattle, WA 98109 USA. Univ Washington, Sch Med, Seattle, WA 98109 USA. Duke Univ, Sch Med, Durham, NC 27710 USA. EMMES Corp, Potomac, MD 20854 USA. Johns Hopkins Univ, Sch Publ Hlth, Baltimore, MD 21205 USA. Univ Rochester, Rochester, NY 14642 USA. St Louis Univ, Sch Med, St Louis, MO 63110 USA. St Louis VA Med Ctr, St Louis, MO 63110 USA. Vanderbilt Univ, Sch Med, Nashville, TN 37232 USA. Genentech Inc, San Francisco, CA 94080 USA. Chiron Corp, Emeryville, CA 94608 USA. NIAID, Div AIDS Vaccine Res Branch, Bethesda, MD 20892 USA. RP McElrath, MJ (reprint author), Fred Hutchinson Canc Res Ctr, Program Infect Dis, POB 19024,1100 Fairview Ave N,D3-100, Seattle, WA 98109 USA. EM kd@u.washington.edu FU NIAID NIH HHS [N01-AI05065, N01-AI45210, N01-AI45206] NR 25 TC 48 Z9 49 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JUN 10 PY 2000 VL 16 IS 9 BP 907 EP 919 DI 10.1089/08892220050042846 PG 13 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 327AV UT WOS:000087770800009 PM 10875616 ER PT J AU Cao, F Ji, Y Huang, RX Zhao, TM Kindt, TJ AF Cao, F Ji, Y Huang, RX Zhao, TM Kindt, TJ TI Nucleotide sequence analyses of partial env(gp46) gene of human T-lymphotropic virus type I from inhabitants of Fujian Province in southeast China SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID TROPICAL SPASTIC PARAPARESIS; CELL LEUKEMIA-VIRUS; ANTIBODIES; ISOLATE; TAIWAN; ORIGIN AB Partial sequences from the env(gp46) gene of two human T-lymphotropic virus type I (HTLV-I) isolates (LIN and WEN) obtained from inhabitants of Fujian Province in southeast China were analyzed. A phylogenetic tree was constructed from these sequence data and those of other known HTLV-I isolates from all over the world. Comparisons of the LIN and WEN nucleotide sequences with other HTLV-I isolates showed diversity ranging from 0.73 to 7.00% for LIN and from 0.87 to 7.00% for WEN. Sequences of isolates LIN, WEN, MT-2,TSP1, and CH were most closely related, and the phylogenetic tree showed that all belong to the widespread subtype A of the cosmopolitan group. These preliminary data indicate that HTLV-I isolates from Fujian Province, China are closely related to HTLV-I strains from Japan and the Caribbean. C1 Chinese Acad Med Sci, Inst Blood Transfus, Chengdu 610081, Peoples R China. Peking Union Coll, Beijing 610081, Peoples R China. Xiamen Blood Ctr, Xiamen, Peoples R China. NIAID, Mol & Cellular Immunogenet Sect, NIH, Bethesda, MD 20892 USA. RP Cao, F (reprint author), Chinese Acad Med Sci, Inst Blood Transfus, POB 268, Chengdu 610081, Peoples R China. NR 17 TC 2 Z9 5 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JUN 10 PY 2000 VL 16 IS 9 BP 921 EP 923 DI 10.1089/08892220050042855 PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 327AV UT WOS:000087770800010 PM 10875617 ER PT J AU Murphy, EJ Schapiro, MB Rapoport, SI Shetty, HU AF Murphy, EJ Schapiro, MB Rapoport, SI Shetty, HU TI Phospholipid composition and levels are altered in down syndrome brain SO BRAIN RESEARCH LA English DT Article DE phospholipids; plasmalogens; Down Syndrome; brain; aging; cholesterol ID PERFORMANCE LIQUID-CHROMATOGRAPHY; DIHYDROXYACETONE PHOSPHATE ACYLTRANSFERASE; ALZHEIMERS-DISEASE BRAIN; ROOT GANGLION NEURONS; DOWNS-SYNDROME; MEMBRANE-LIPIDS; CHOLINE PLASMALOGENS; CEREBROSPINAL-FLUID; MAMMALIAN-TISSUES; ANIMAL-CELLS AB Phospholipid composition (mol %) and levels (nmol/mg protein) were determined in postmortem frontal cortical and cerebellar gray matter from older Down Syndrome (DS) patients (age range 38-68 years) and from control subjects. Neither DS nor control tissue exhibited any age-dependent alteration in phospholipid composition or levels. Total phospholipid content was significantly reduced approximately 20% in DS frontal cortex and cerebellum relative to these regions in control tissue. Individual phospholipid levels were also reduced in DS Frontal cortex and cerebellum, including a specific 37% decrease in phosphatidylinositol (PtdIns) and a nearly 35% decrease in ethanolamine plasmalogen. Because of the large decrease in phospholipid content in DS brain, the cholesterol/phospholipid ratio was calculated for each group. There was no significant difference in this ratio between groups, indicative of compensatory changes to keep the cholesterol/phospholipid ratio constant. Despite the large changes in DS brain phospholipid levels, significant changes in composition were limited to a 18% decrease in PtdIns mol % and a 22% increase in the mol % of sphingomyelin. These results suggest either a decrease in membrane phospholipids due to a loss of dendrites and dendritic spines, or a general defect in brain lipid metabolism in older DS subjects. The proportionally greater alterations in PtdIns and PlsEtn levels, indicate that the metabolism of these two phospholipids was affected to a greater extent than the other phospholipids. Further, because these changes are found in both the frontal cortical and cerebellar gray matter, they likely are related to the Down syndrome condition rather than to Alzheimer neuropathology. (C) 2000 Published by Elsevier Science B.V. All rights reserved. C1 NIA, Sect Brain Physiol & Metab, NIH, Bethesda, MD 20892 USA. RP Shetty, HU (reprint author), NIA, Sect Brain Physiol & Metab, NIH, Bldg 10,Room 6C103, Bethesda, MD 20892 USA. NR 67 TC 54 Z9 55 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 9 PY 2000 VL 867 IS 1-2 BP 9 EP 18 DI 10.1016/S0006-8993(00)02205-8 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 325JK UT WOS:000087672300002 PM 10837793 ER PT J AU Mendelman, A Zarchin, N Rifkind, J Mayevsky, A AF Mendelman, A Zarchin, N Rifkind, J Mayevsky, A TI Brain multiparametric responses to carbon monoxide exposure in the aging rat SO BRAIN RESEARCH LA English DT Article DE aging rat; mitochondrial redox state; extracellular K+; carbon monoxide effect; cerebral blood flow ID CEREBRAL BLOOD-FLOW; CORTICAL SPREADING DEPRESSION; HYPOXIA; CORTEX AB The multiparametric monitoring system was applied to study the effects of 2000 ppm carbon monoxide (CO) on brain functions in vivo in the aging rat. The vasodilatory (non hypoxic) effects of CO on CBF in normal adult rats, which were shown in concentrations of 1000-2000 ppm involved the effect of nitric oxide (NO). Energy metabolism was evaluated by optical monitoring of CBF and mitochondrial function by fluorometry of NADH. Ionic homeostasis was evaluated by monitoring the extracellular level of K+ and H+ and the DC steady potential. Seven aging rats (24 months) were exposed to 2000 ppm for 60 min and 120 min of recovery, while five control rats were exposed to air under the same conditions. A comparison between the CO group and the control group showed that the changes in CBF, NADH and light reflectance were not statistically significant while extracellular K+ was elevated and tissue pH became more acidic. Thus, the typical CO induced increase in CBF, was not recorded in the aging rats. We concluded that the brain vasodilatory response to CO was not active in the aging rat, while the ionic homeostasis responses were similar to those found in the adult rat. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Bar Ilan Univ, Fac Life Sci, IL-52900 Ramat Gan, Israel. NIA, NIH, Lab Cellular & Mil BIol GRC, Baltimore, MD 21224 USA. RP Mayevsky, A (reprint author), Bar Ilan Univ, Fac Life Sci, IL-52900 Ramat Gan, Israel. FU NIEHS NIH HHS [R29-ES-05211] NR 36 TC 9 Z9 10 U1 0 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 JUN 9 PY 2000 VL 867 IS 1-2 BP 217 EP 222 DI 10.1016/S0006-8993(00)02326-X PG 6 WC Neurosciences SC Neurosciences & Neurology GA 325JK UT WOS:000087672300025 PM 10837816 ER PT J AU Koonin, EV Aravind, L Kondrashov, AS AF Koonin, EV Aravind, L Kondrashov, AS TI The impact of comparative genomics on our understanding of evolution SO CELL LA English DT Review ID GENE; SEQUENCE; PROTEINS; HEDGEHOG C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. NR 20 TC 168 Z9 179 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JUN 9 PY 2000 VL 101 IS 6 BP 573 EP 576 DI 10.1016/S0092-8674(00)80867-3 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 322HQ UT WOS:000087504500002 PM 10892642 ER PT J AU Wassarman, KM Storz, G AF Wassarman, KM Storz, G TI 6S RNA regulates E-coli RNA polymerase activity SO CELL LA English DT Article ID ANTI-SIGMA FACTORS; ESCHERICHIA-COLI; OXIDATIVE STRESS; STATIONARY-PHASE; GENE; GROWTH; PROMOTER; PROTEIN; 6S-RNA AB The E. coli 6S RNA was discovered more than three decades ago, yet its function has remained elusive. Here, we demonstrate that 6S RNA associates with RNA polymerase in a highly specific and efficient manner. UV crosslinking experiments revealed that 6S RNA directly contacts the sigma(70) and beta/beta' subunits of RNA polymerase. 6S RNA accumulates as cells reach the stationary phase of growth and mediates growth phase-specific changes in RNA polymerase. Stable association between sigma(70) and core RNA polymerase in extracts is only observed in the presence of 6S RNA. We show 6S RNA represses expression from a sigma(70)-dependent promoter during stationary phase. Our results suggest that the interaction of 6S RNA with RNA polymerase modulates sigma(70)-holoenzyme activity. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Wassarman, KM (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. OI Storz, Gisela/0000-0001-6698-1241 NR 33 TC 260 Z9 267 U1 1 U2 15 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JUN 9 PY 2000 VL 101 IS 6 BP 613 EP 623 DI 10.1016/S0092-8674(00)80873-9 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 322HQ UT WOS:000087504500008 PM 10892648 ER PT J AU Melek, M Gellert, M AF Melek, M Gellert, M TI RAG1/2-mediated resolution of transposition intermediates: Two pathways and possible consequences SO CELL LA English DT Article ID DNA STRAND TRANSFER; V(D)J RECOMBINATION; RAG2 PROTEINS; IMMUNE-SYSTEM; 2 STEPS; C-MYC; GENES; MECHANISM; INTEGRATION; CLEAVAGE AB During B and T cell development, the RAG1/RAG2 protein complex cleaves DNA at conserved recombination signal sequences (RSS) to initiate V(D)J recombination. RAG1/2 has also been shown to catalyze transpositional strand transfer of RSS-containing substrates into target DNA to form branched DNA intermediates. We show that RAG1/2 can resolve these intermediates by two pathways. RAG1/2 catalyzes hairpin formation on target DNA adjacent to transposed RSS ends in a manner consistent with a model leading to chromosome translocations. Alternatively, disintegration removes transposed donor DNA from the intermediate. At high magnesium concentrations, such as are present in mammalian cells, disintegration is the favored pathway of resolution. This may explain in part why RAG1/2-mediated transposition does not occur at high frequency in cells. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gellert, M (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 36 TC 49 Z9 50 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JUN 9 PY 2000 VL 101 IS 6 BP 625 EP 633 DI 10.1016/S0092-8674(00)80874-0 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 322HQ UT WOS:000087504500009 PM 10892649 ER PT J AU Pedersen, LC Petrotchenko, EV Negishi, M AF Pedersen, LC Petrotchenko, EV Negishi, M TI Crystal structure of SULT2A3, human hydroxysteroid sulfotransferase SO FEBS LETTERS LA English DT Article DE hydroxysteroid sulfotransferase; dehydroepiandrosterone; crystal structure; sulfation ID ESTROGEN SULFOTRANSFERASE AB The crystal structure of SULT2A3 human hydroxy-steroid sulfotransferase has been solved at 2.4 Angstrom resolution in the presence of 3'-phosphoadenosine 5'-phosphate (PAP). The overall structure is similar to those of SULT1 enzymes such as estrogen sulfotransferase and the PAP binding site is conserved, however, significant differences exist in the positions of loops Pro14-Ser20, Glu79-Ile82 and Tyr234-Gln244 in the substrate binding pocket. Moreover, protein interaction in the crystal structure has revealed a possible dimer-directed conformational alteration that may regulate the SULT activity. (C) 2000 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved. C1 NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 19 TC 76 Z9 78 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUN 9 PY 2000 VL 475 IS 1 BP 61 EP 64 DI 10.1016/S0014-5793(00)01479-4 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 327PL UT WOS:000087801900014 PM 10854859 ER PT J AU Kimura, K Tsuji, T Takada, Y Miki, T Narumiya, S AF Kimura, K Tsuji, T Takada, Y Miki, T Narumiya, S TI Accumulation of GTP-bound RhoA during cytokinesis and a critical role of ECT2 in this accumulation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EXCHANGE FACTOR; CELL-ADHESION; PROTEIN-RHO; GTPASES; KINASE; CDC42; TARGET; CYCLE; G(1) AB We developed a new pull-down assay for GTP-Rho and examined its level during cell cycle. HeLa cells were arrested in the S phase by thymidine and were enriched in the prometaphase, metaphase, telophase, and G(1) phase by collecting at 0, 45, 90, and 180 min after the release from the nocodazole arrest, respectively. The level of GTP-Rho did not change significantly from the S phase to the prometaphase, but increased thereafter, peaking in the telophase, and returned to the original level in the G(1) phase. The GDP-GTP exchange activity for Rho measured in cell lysates in parallel increased also during the mitosis with a peak in the metaphase. Using this system, we examined a role of ECT2, an exchanger for Rho GTPases, suggested to be involved in cytokinesis (Tatsumoto, T., Xie, X., Blumenthal, R., Okamoto, I., and Miki., T. (1999) J. Cell. Biol, 147, 921-928). Expression of the dominant negative form of ECT2 completely suppressed both the rise of GTP-Rho in the telophase and the increased GDP-GTP exchange activity in the mitotic cell extracts. These results suggest a critical role of ECT2 in Rho activation during cytokinesis. C1 Kyoto Univ, Fac Med, Dept Pharmacol, Sakyo Ku, Kyoto 6068501, Japan. NCI, Mol Tumor Biol Sect, Basic Res Lab, NIH, Bethesda, MD 20892 USA. RP Narumiya, S (reprint author), Kyoto Univ, Fac Med, Dept Pharmacol, Sakyo Ku, Kyoto 6068501, Japan. NR 23 TC 122 Z9 128 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 9 PY 2000 VL 275 IS 23 BP 17233 EP 17236 DI 10.1074/jbc.C000212200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 321ZJ UT WOS:000087485000004 PM 10837491 ER PT J AU Goh, ELK Zhu, T Yakar, S LeRoith, D Lobie, PE AF Goh, ELK Zhu, T Yakar, S LeRoith, D Lobie, PE TI CrkII participation in the cellular effects of growth hormone and insulin-like growth factor-1 - Phosphatidylinositol-3 kinase dependent and independent effects SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FOCAL ADHESION KINASE; STIMULATES TYROSINE PHOSPHORYLATION; FACTOR-I IGF; RECEPTOR SUBSTRATE-1; V-CRK; C-CRK; ACTIN CYTOSKELETON; SIGNALING MOLECULE; ADAPTER PROTEIN; ACTIVATION AB We have examined the role of CrkII in the cellular response to both human growth hormone (hGH) and human insulin-like growth factor-1 (hIGF-1). We have demonstrated that overexpression of the adaptor molecule enhances both basal phosphatidylinositol 3-kinase (PI3-hinase) activity and also dramatically enhances the ability of both hormones to stimulate PI 3-kinase activity in the cell. Many of the effects of CrkII overexpression on hGH- and hIGF-1-stimulated cellular function can then be attributed to CrkII enhancement of PI 3-kinase stimulation by these hormones. Thus, CrkII-enhanced PI 3-kinase activity is used to enhance actin filament reorganization in response to both hGH and hIGF-1, to enhance stress activated protein kinase (SAPK) activity in response to hGH, and to diminish STAT5-mediated transcription in response to hGH. It is apparent, however, that CrkII also regulates cellular function independent of its ability to stimulate PI 3-kinase activity. This is evidenced by the ability of CrkII, in a PI 3-kinase-independent manner, to diminish the activation of p44/42 mitogen-activated protein kinase in response to both hGH and hIGF-1 and to inhibit the activation of SAPK by hIGF-1, Therefore, despite the common use of CrkII to activate PI 3-kinase, CrkII also allows hGH or hIGF-1 to selectively switch the activation of SAPK. Thus, common utilization of CrkII by hGH and hIGF-1 allows the execution of common cellular effects of these hormones, concomitant with the retention of hormonal specificity. C1 Inst Mol & Cell Biol, Singapore 117609, Singapore. NIDDK, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Lobie, PE (reprint author), Inst Mol & Cell Biol, 30 Med Dr, Singapore 117609, Singapore. RI ASTAR, IMCB/E-2320-2012; Goh, Eyleen/A-8006-2013 NR 42 TC 16 Z9 16 U1 1 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 9 PY 2000 VL 275 IS 23 BP 17683 EP 17692 DI 10.1074/jbc.M001972200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 321ZJ UT WOS:000087485000068 PM 10748058 ER PT J AU Fryer, CJ Kinyamu, HK Rogatsky, I Garabedian, MJ Archer, TK AF Fryer, CJ Kinyamu, HK Rogatsky, I Garabedian, MJ Archer, TK TI Selective activation of the glucocorticoid receptor by steroid antagonists in human breast cancer and osteosarcoma cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUMOR VIRUS PROMOTER; ADJUVANT TAMOXIFEN THERAPY; PROGESTERONE-RECEPTOR; IN-VIVO; CHROMATIN STRUCTURE; MMTV PROMOTER; TRANSCRIPTION FACTORS; ESTROGEN-RECEPTOR; MOLECULAR-BIOLOGY; DNA-BINDING AB Steroid hormones regulate the transcription of numerous genes via high affinity receptors that act in concert with chromatin remodeling complexes, coactivators and corepressors, We have compared the activities of a variety of glucocorticoid receptor (GR) antagonists in breast cancer and osteosarcoma cell lines engineered to stably maintain the mouse mammary tumor virus promoter. In both cell types, GR activation by dexamethasone occurs via the disruption of mouse mammary tumor virus chromatin structure and the recruitment of receptor coactivator proteins. However, when challenged with a variety of antagonists the GR displays differential ability to activate transcription within the two cell types. For the breast cancer cells, the antagonists fail to activate the promoter and do not promote the association of the GR with either remodeling or coactivator proteins. In contrast, in osteosarcoma cells, the antiglucocorticoids, RU486 and RU43044, exhibit partial agonist activity. The capacity of these antagonists to stimulate transcription in the osteosarcoma cells is reflected in the ability of the RU486-bound receptor to remodel chromatin and associate with chromatin-remodeling proteins. Similarly, the observation that the RU486-bound receptor does not fully activate transcription is consistent with its inability to recruit receptor coactivator proteins. C1 NIEHS, Chromatin & Gene Express Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Western Ontario, Dept Obstet & Gynaecol, London, ON N6A 4L6, Canada. Univ Western Ontario, Dept Biochem, London, ON N6A 4L6, Canada. NYU, Med Ctr, Dept Microbiol, New York, NY 10016 USA. NYU, Med Ctr, Kaplan Canc Ctr, New York, NY 10016 USA. RP Archer, TK (reprint author), NIEHS, Chromatin & Gene Express Sect, Reprod & Dev Toxicol Lab, NIH, 111 Alexander Dr,POB 12233,MD E4-06, Res Triangle Pk, NC 27709 USA. NR 49 TC 53 Z9 54 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 9 PY 2000 VL 275 IS 23 BP 17771 EP 17777 DI 10.1074/jbc.M908729199 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 321ZJ UT WOS:000087485000078 PM 10748103 ER PT J AU Yeagley, D Moll, J Vinson, CA Quinn, PG AF Yeagley, D Moll, J Vinson, CA Quinn, PG TI Characterization of elements mediating regulation of phosphoenolpyruvate carboxykinase gene transcription by protein kinase A and insulin - Identification of a distinct complex formed in cells that mediate insulin inhibition SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CCAAT/ENHANCER-BINDING-PROTEIN; DOMINANT-NEGATIVE INHIBITOR; DNA-BINDING; CAMP INDUCTION; PHOSPHATIDYLINOSITOL 3-KINASE; MULTIHORMONAL REGULATION; SIGNALING PATHWAYS; 3T3-L1 ADIPOCYTES; CATALYTIC SUBUNIT; LEUCINE ZIPPER AB The in vivo pattern of induction of phosphoenolpyruvate carboxykinase (PEPCK) gene transcription by cAMP and its inhibition by insulin is reproduced in H4IIe cells and is mediated by a bipartite cAMP/insulin response unit (C/IRU) consisting of a cAMP response element (-95/-87) and an upstream enhancer, AC (-271/-225), Studies in HepG2 cells showed that binding of AP-1 and CAAT/enhancer-binding protein (C/EBP) to AC is required for induction by cAMP, but insulin did not inhibit cAMP-induced PEPCK expression in HepG2 cells. Binding of H4IIe nuclear proteins to an AC element probe was inhibited by antibodies or a consensus site for C/EBP, but not AP-1, Transfection with dominant negative bZIP factors, which prevent endogenous factors from binding to DNA, showed that elimination of cAMP regulatory element-binding protein CREB or C/EBP activity blocked induction by protein kinase A (PRA), whereas elimination of AP-1 activity had no effect. In addition, promoters with multiple CREB sites, or a single CREB site and multiple C/EBP sites, mediated PKA induction, but this was inhibited to no greater extent than basal activity was by insulin. These results indicate that an AC factor other than C/EBP must mediate insulin inhibition. An A-site probe (-265/-247) or a probe across the middle of the AC element (-256/-237) competed for complexes formed by factors other than AP-1 or C/EBP, However, analysis of competitor oligonucleotides and antibodies for candidate factors failed to identify other factors. Scanning mutations throughout the AC element interfered with induction but allowed us to define five overlapping sites for regulatory factors in AC and to design probes binding just one or two factors, Comparison of the protein-DNA complexes formed on these smaller probes revealed that a specific complex present in rat liver and H4IIe cell nuclear extracts differed from those formed by HepG2 cell nuclear extracts. Our results suggest that multiple factors binding the AC element of the C/IRU interact with each other and CREB to regulate PEPCK induction by cAMP and inhibition by insulin and that the unique factor expressed in H4IIe cells is a candidate for involvement in insulin regulation of PKA-induced PEPCK gene transcription. C1 Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Quinn, PG (reprint author), Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, H166,500 Univ Dr, Hershey, PA 17033 USA. FU PHS HHS [R01 43871] NR 49 TC 16 Z9 16 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 9 PY 2000 VL 275 IS 23 BP 17814 EP 17820 DI 10.1074/jbc.M909842199 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 321ZJ UT WOS:000087485000084 PM 10748164 ER PT J AU Lai, WS Carballo, E Thorn, JM Kennington, EA Blackshear, PJ AF Lai, WS Carballo, E Thorn, JM Kennington, EA Blackshear, PJ TI Interactions of CCCH zinc finger proteins with mRNA - Binding of tristetraprolin-related zinc finger proteins to Au-rich elements and destabilization of mRNA SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID 3' SPLICE-SITE; ABNORMAL BRAIN-DEVELOPMENT; PRIMARY RESPONSE GENE; MESSENGER-RNA; TRANSCRIPTION FACTOR; NUCLEOTIDE-SEQUENCE; FACTOR U2AF(35); HUMAN HOMOLOG; TIS11 FAMILY; CELLS AB Macrophages derived from tristetraprolin (TTP)-deficient mice exhibited increased tumor necrosis factor alpha (TNF alpha) release as a consequence of increased stability of TNF alpha mRNA, TTP was then shown to destabilize TNF alpha mRNA after binding directly to the AU-rich region (ARE) of the 3'-untranslated region of the TNF alpha mRNA In mammals and in Xenopus, TTP is the prototype of a small family of three known zinc finger proteins containing two CCCH zinc fingers spaced 18 amino acids apart; a fourth more distantly related family member has been identified in Xenopus and fish. We show here that representatives of all four family members were able to bind to the TNF alpha ARE in a cell-free system and, in most cases, promote the breakdown of TNF alpha mRNA in intact cells. Because the primary sequences of these CCCH proteins are most closely related in their tandem zinc finger domains, we tested whether various fragments of TTP that contained both zinc fingers resembled the intact protein in these assays. We found that amino- and carboxyl-terminal truncated forms of TTP, as well as a 77 amino acid fragment that contained both zinc fingers, could bind to the TNF alpha ARE in cell-free cross-linking and gel shift assays. In addition, these truncated forms of TTP could also stimulate the apparent deadenylation and/or breakdown of TNF alpha mRNA in intact cells. Alignments of the tandem zinc finger domains from all four groups of homologous proteins have identified invariant residues as well as group-specific signature amino acids that presumably contribute to ARE binding and protein-specific activities, respectively. C1 NIEHS, Off Clin Res, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Signal Transduct, NIH, 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 NIEHS, Off Clin Res, NIH, A2-05,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM black009@niehs.nih.gov NR 37 TC 237 Z9 241 U1 1 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 9 PY 2000 VL 275 IS 23 BP 17827 EP 17837 DI 10.1074/jbc.M001696200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 321ZJ UT WOS:000087485000086 PM 10751406 ER PT J AU Holz, RW Hlubek, MD Sorensen, SD Fisher, SK Balla, T Ozaki, S Prestwich, GD Stuenkel, EL Bittner, MA AF Holz, RW Hlubek, MD Sorensen, SD Fisher, SK Balla, T Ozaki, S Prestwich, GD Stuenkel, EL Bittner, MA TI A pleckstrin homology domain specific for phosphatidylinositol 4,5-bisphosphate (PtdIns-4,5-P-2) and fused to green fluorescent protein identifies plasma membrane PtdIns-4,5-P-2 as being important in exocytosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ADRENAL CHROMAFFIN CELLS; PHOSPHOLIPASE-C; HIGH-AFFINITY; CA2+-ACTIVATED SECRETION; REGULATED EXOCYTOSIS; INOSITOL PHOSPHATES; SIGNALING MOLECULES; COMMON FOLD; ALPHA-SNAP; BINDING AB Kinetically distinct steps can be distinguished in the secretory response from neuroendocrine cells with slow ATP-dependent priming steps preceding the triggering of exocytosis by Ca2+, One of these priming steps involves the maintenance of phosphatidylinositol 4,5-bisphosphate (PtdIns-4,5-P-2) through lipid kinases and is responsible for at least 70% of the ATP-dependent secretion observed in digitonin-permeabilized chromaffin cells. PtdIns-4,5-P-2 is usually thought to reside on the plasma membrane. However, because phosphatidylinositol 4-kinase is an integral chromaffin granule membrane protein, PtdIns-4,5-P-2 important in exocytosis may reside on the chromaffin granule membrane. In the present study we have investigated the localization of PtdIns-1,5-P-2 that is involved in exocytosis by transiently expressing in chromaffin cells a pleckstrin homology (PH) domain that specifically binds PtdIns-4,5-P-2 and is fused to green fluorescent protein (GFP). The PH-GFP protein predominantly associated with the plasma membrane in chromaffin cells without any detectable association with chromaffin granules. Rhodamine-neomycin, which also binds to PtdIns-4,5-P-2, showed a similar subcellular localization. The transiently expressed PH-GFP inhibited exocytosis as measured by both biochemical and electrophysiological techniques. The results indicate that the inhibition was at a step after Ca2+ entry and suggest that plasma membrane PtdIns-4,5-P-2 is important for exocytosis, Expression of PH-GFP also reduced calcium currents, raising the possibility that PtdIns-4,5-P-2 in some manner alters calcium channel function in chromaffin cells. C1 Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Physiol, Ann Arbor, MI 48109 USA. Univ Michigan, Mental Hlth Res Inst, Ann Arbor, MI 48109 USA. NICHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. Univ Utah, Dept Med Chem, Salt Lake City, UT 84112 USA. RP Holz, RW (reprint author), Univ Michigan, Sch Med, Dept Pharmacol, 1301 MSRB 3, Ann Arbor, MI 48109 USA. OI Balla, Tamas/0000-0002-9077-3335 FU NIDDK NIH HHS [R01-DK50127]; NINDS NIH HHS [NS29632, R01-NS36227] NR 67 TC 136 Z9 140 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 9 PY 2000 VL 275 IS 23 BP 17878 EP 17885 DI 10.1074/jbc.M000925200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 321ZJ UT WOS:000087485000092 PM 10747966 ER PT J AU Malkov, VA Panyutin, IG Neumann, RD Zhurkin, VB Camerini-Otero, RD AF Malkov, VA Panyutin, IG Neumann, RD Zhurkin, VB Camerini-Otero, RD TI Radioprobing of a RecA-three-stranded DNA complex with iodine 125: Evidence for recognition of homology in the major groove of the target duplex SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE RecA; major groove; iodine 125; recognition of homology; three-stranded DNA ID ESCHERICHIA-COLI RECA; HUMAN RAD51 PROTEIN; CRYSTAL-STRUCTURE; GENETIC-RECOMBINATION; BRANCH MIGRATION; HELICAL REPEAT; MINOR-GROOVE; BINDING SITE; EXCHANGE; I-125 AB A fundamental problem in homologous recombination is how homology between DNAs is recognized. In all current models, a recombination protein loads onto a single strand of DNA and scans another duplex for homology. When homology is found, a synaptic complex is formed, leading to strand exchange and a heteroduplex. A novel technique based on strand cleavage by the Auger radiodecay of iodine 125, allows us to determine the distances between I-125 on the incoming strand and the target sugars of the duplex DNA strands in an Escherichia coli RecA protein-mediated synaptic complex. Analysis of these distances shows that the complex represents a post-strand exchange intermediate in which the heteroduplex is located in the center, while the outgoing strand forms a relatively wide helix intertwined with the heteroduplex and located in its minor groove. The structure implies that homology is recognized in the major groove of the duplex. (C) 2000 Academic Press. C1 NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. NCI, Ctr Clin, Dept Nucl Med, NIH, Bethesda, MD 20892 USA. NCI, Lab Expt & Computat Biol, NIH, Bethesda, MD 20892 USA. RP Camerini-Otero, RD (reprint author), NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. NR 50 TC 25 Z9 25 U1 0 U2 0 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUN 9 PY 2000 VL 299 IS 3 BP 629 EP 640 DI 10.1006/jmbi.2000.3770 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 322ZQ UT WOS:000087540100007 PM 10835273 ER PT J AU Sato, H Ogata, H De Luca, LM AF Sato, H Ogata, H De Luca, LM TI Annexin V inhibits the 12-O-tetradecanoylphorbol-13-acetate-induced activation of Ras/extracellular signal-regulated kinase (ERK) signaling pathway upstream of Shc in MCF-7 cells SO ONCOGENE LA English DT Article DE annexin V; MAPK; TPA; signal transduction; PKC ID BREAST-CANCER CELLS; PROTEIN-KINASE; CARCINOMA-CELLS; MAP KINASE; RAF-1 KINASE; C ACTIVITY; IN-VITRO; RAS; EXPRESSION; PHOSPHORYLATION AB Annexin V is a Ca2+-dependent phospholipid binding protein. Although it has been shown to inhibit protein kinase C (PKC) in cell-free systems, its role in the intact cell is unclear, A stable,MCF-7 human breast cancer cell overexpression system was established to investigate the function of annexin V, In these cells, 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced phosphorylation and kinase activity of ERK1/2 were suppressed. Morphological changes induced by TPA were reduced by annexin V overexpression as well as by the pan-PKC inhibitor, bisindolylmaleimide I, and by the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor, PD98059, TPA-induced MEK1/2 and Raf-l phosphorylation were reduced in these cells, The TP,S-enhanced active Ras, and its association with Raf-1, were reduced. TPA treatment of MCF-7 cells caused an increased association of She with Grb2, However, this increased association was prevented in the annexin V-overexpressors. p21(WAF/CIPI) is responsible for inhibition of cell cycle progression in MICF-7 cells. TPA induced the expression of p21(WAF/CIPI) to a greater extent in MCF-7 parent and control plasmid cells than in annexin V overexpressors, PD98059 inhibited this increase, suggesting that TPA upregulation of p21(WAF/CIPI) occurs via the MEK pathway, and that annexin V overexpression blunts it, This work shows that annexin V overexpression suppresses the TPA-induced Ras/ERK; signaling by inhibiting at/or upstream of She, possibly through the inhibition of PkCs. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. RP De Luca, LM (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. NR 56 TC 23 Z9 24 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 8 PY 2000 VL 19 IS 25 BP 2904 EP 2912 DI 10.1038/sj.onc.1203615 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 323BG UT WOS:000087544500004 PM 10871841 ER PT J AU Nagy, P Bisgaard, HC Schnur, J Thorgeirsson, SS AF Nagy, P Bisgaard, HC Schnur, J Thorgeirsson, SS TI Studies on hepatic gene expression in different liver regenerative models SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE liver; regeneration; c-myc; c-fos; c-jun; HGF; TGF-alpha; TGF-beta 1; 1L1 beta ID HEPATOCYTE GROWTH-FACTOR; NECROSIS-FACTOR RECEPTOR; FACTOR-ALPHA; RAT-LIVER; PARTIAL-HEPATECTOMY; MESSENGER-RNA; C-FOS; MICE; PROLIFERATION; INTERLEUKIN-1-BETA AB We have investigated the expression of several growth-related genes in the liver after partial hepatectomy in three experimental models: normal, Dexamethasone-pretreated, and hypophysectomized rats. Dexamethasone and hypophysectomy resulted in a delay in the peak of cell replication in 6 and 18 h, respectively, when compared to the normal animals. TGF alpha mRNA expression was shifted together with the DNA synthesis, but the expression of c-myc, c-fos, c-jun, HGF, TGF beta 1, IL1 beta did not delay, This result suggests that liver-derived TGF alpha but not the other factors are important in the timing of the proliferative response after partial hepatectomy. (C) 2000 Academic Press. C1 NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. Roskilde Univ, Inst Life Sci, Roskilde, Denmark. Semmelweis Univ, Inst Pathol & Expt Canc Res 1, H-1085 Budapest, Hungary. RP Nagy, P (reprint author), NCI, Expt Carcinogenesis Lab, NIH, MSC 4255,Bldg 37,Room 3C28, Bethesda, MD 20892 USA. EM peter_nagy@nih.gov NR 27 TC 10 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 7 PY 2000 VL 272 IS 2 BP 591 EP 595 DI 10.1006/bbrc.2000.2811 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 327HC UT WOS:000087787600048 PM 10833457 ER PT J AU Rabins, PV Black, BS Roca, R German, P McGuire, M Robbins, B Rye, R Brant, L AF Rabins, PV Black, BS Roca, R German, P McGuire, M Robbins, B Rye, R Brant, L TI Effectiveness of a nurse-based outreach program for identifying and treating psychiatric illness in the elderly SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID RANDOMIZED CONTROLLED TRIAL; MENTAL-HEALTH SERVICES; PRIMARY-CARE; HOME VISITATION; DEPRESSION; INTERVENTION; QUESTIONNAIRE; DISABILITY; RESIDENTS; POLICY AB Context Elderly persons with psychiatric disorders are less likely than younger adults to be diagnosed as having a mental disorder and receive needed mental health treatment. Lack of access to care is 1 possible cause of this disparity. Objective To determine whether a nurse-based mobile outreach program to seriously mentally ill elderly persons is more effective than usual care in diminishing levels of depression, psychiatric symptoms, and undesirable moves (eg, nursing home placement, eviction, board and care placement). Design Prospective randomized trial conducted between March 1993 and April 1996 to assess the effectiveness of the Psychogeriatric Assessment and Treatment in City Housing (PATCH) program. Setting Six urban public housing sites for elderly persons in Baltimore, Md. Participants A total of 945 (83 %) of 1195 residents in the 6 sites underwent screening for psychiatric illness, Among those screened, 342 screened positive and 603 screened negative. All screen-positive subjects aged 60 years and older (n=310) and a 10% random sample of screen-negative subjects aged 60 years and older (n=61) were selected for a structured psychiatric interview. Eleven subjects moved or died; 245 (82 %) of those who screened positive and 53 (88%) of those who screened negative were evaluated to determine who had a psychiatric disorder. Data were weighted to estimate the prevalence of psychiatric disorders at the 6 sites, Intervention Among the 6 sites, residents in 3 buildings were randomized to receive the PATCH model intervention, which included educating building staff to be case finders, performing assessment in residents' apartments, and providing care when indicated; and residents in the remaining 3 buildings were randomized to receive usual care (comparison group). Main Outcome Measures Number of undesirable moves and scores on the Montgomery-Asberg Depression Rating Scale (MADRS), a measure of depressive symptoms, and the Brief Psychiatric Rating Scale (BPRS), a measure of psychiatric symptoms and behavioral disorder, in intervention vs comparison sites, Results Based on weighted data, at 26 months of follow-up, psychiatric cases at the intervention sites had significantly lower (F-1=31.18; P<.001) MADRS scores (9.1 vs 15.2) and significantly lower (F-1=17.35; P<.001) BPRS scores (27.4 vs 33.9) than those at the nontreatment comparison sites. There was no significant difference between the groups in undesirable moves (relative risk, 0.97; 95% confidence interval, 0.44-2.17). Conclusions These results indicate that the PATCH intervention was more effective than usual care in reducing psychiatric symptoms in persons with psychiatric disorders and those with elevated levels of psychiatric symptoms. C1 Johns Hopkins Med Inst, Sheppard & Enoch Pratt Hosp, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Sheppard & Enoch Pratt Hosp, Sch Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Sheppard & Enoch Pratt Hosp, Sch Hyg & Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Sheppard & Enoch Pratt Hosp, Sch Hyg & Publ Hlth, Dept Mental Hyg, Baltimore, MD 21205 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Rabins, PV (reprint author), Johns Hopkins Hosp, Meyer 279,600 N Wolfe St, Baltimore, MD 21287 USA. NR 44 TC 44 Z9 44 U1 1 U2 7 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 JUN 7 PY 2000 VL 283 IS 21 BP 2802 EP 2809 DI 10.1001/jama.283.21.2802 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 320BQ UT WOS:000087381500034 PM 10838648 ER PT J AU Ali, IU AF Ali, IU TI Gatekeeper for endometrium: the PTEN tumor suppressor gene SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID MICROSATELLITE INSTABILITY; PHOSPHATASE-ACTIVITY; CANCER; CARCINOMA; MUTATIONS; PTEN/MMAC1; FREQUENT; HISTORY; COMMON C1 NCI, Div Canc Prevent, EPN, NIH, Bethesda, MD 20892 USA. RP Ali, IU (reprint author), NCI, Div Canc Prevent, EPN, NIH, Rm 201, Bethesda, MD 20892 USA. NR 25 TC 44 Z9 56 U1 0 U2 3 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUN 7 PY 2000 VL 92 IS 11 BP 861 EP 863 DI 10.1093/jnci/92.11.861 PG 3 WC Oncology SC Oncology GA 321TV UT WOS:000087471500002 PM 10841815 ER PT J AU Radmacher, MD Simon, R AF Radmacher, MD Simon, R TI Estimation of tamoxifen's efficacy for preventing the formation and growth of breast tumors - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 NCI, Div Canc Treatment & Diagnosis, Biometr Res Branch, Bethesda, MD 20892 USA. RP Radmacher, MD (reprint author), NIH, 7550 Wisconsin Ave,Rm 3C06,MS 9015, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUN 7 PY 2000 VL 92 IS 11 BP 943 EP 944 PG 2 WC Oncology SC Oncology GA 321TV UT WOS:000087471500021 ER PT J AU Minasov, G Teplova, M Stewart, GC Koonin, EV Anderson, WF Egli, M AF Minasov, G Teplova, M Stewart, GC Koonin, EV Anderson, WF Egli, M TI Functional implications from crystal structures of the conserved Bacillus subtilis protein Maf with and without dUTP SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TRANSFER-RNA SYNTHETASE; SACCHAROMYCES-CEREVISIAE; ISOMORPHOUS REPLACEMENT; THERMUS-THERMOPHILUS; ESCHERICHIA-COLI; GENOMICS; DATABASE; SITE; ION AB Three-dimensional structures of functionally uncharacterized proteins may furnish insight into their functions. The potential benefits of three-dimensional structural information regarding such proteins are particularly obvious when the corresponding genes are conserved during evolution, implying an important function, and no functional classification can be inferred from their sequences. The Bacillus subtilis Maf protein is representative of a family of proteins that has homologs in many of the completely sequenced genomes from archaea, prokaryotes, and eukaryotes, but whose function is unknown. As an aid in exploring function, we determined the crystal structure of this protein at a resolution of 1.85 Angstrom. The structure, in combination with multiple sequence alignment, reveals a putative active site. Phosphate ions present at this site and structural similarities between a portion of Maf and the anticodon-binding domains of several tRNA synthetases suggest that Maf may be a nucleic acid-binding protein. The crystal structure of a Maf-nucleoside triphosphate complex provides support for this hypothesis and hints at di- or oligonucleotides with either 5'- or 3'-terminal phosphate groups as ligands or substrates of Maf, A further clue comes from the observation that the structure of the Maf monomer bears similarity to that of the recently reported Methanococcus jannaschii Mj0226 protein. Just as for Maf, the structure of this predicted NTPase was determined as part of a structural genomics pilot project. The structural relation between Maf and Mj0226 was not apparent from sequence analysis approaches. These results emphasize the potential of structural genomics to reveal new unexpected connections between protein families previously considered unrelated. C1 Northwestern Univ, Sch Med, Dept Mol Pharmacol & Biol Chem, Chicago, IL 60611 USA. Northwestern Univ, Sch Med, Drug Discovery Program, Chicago, IL 60611 USA. Kansas State Univ, Coll Vet Med, Dept Diagnost Med Pathobiol, Manhattan, KS 66506 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Egli, M (reprint author), Northwestern Univ, Sch Med, Dept Mol Pharmacol & Biol Chem, Chicago, IL 60611 USA. OI Minasov, George/0000-0001-5460-3462 FU NIGMS NIH HHS [R01 GM055237, GM57049, GM55237] NR 39 TC 31 Z9 34 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 JUN 6 PY 2000 VL 97 IS 12 BP 6328 EP 6333 DI 10.1073/pnas.97.12.6328 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 322UA UT WOS:000087526300020 PM 10841541 ER PT J AU Xu, JM Liao, L Ning, C Yoshida-Komiya, H Deng, CX O'Malley, BW AF Xu, JM Liao, L Ning, C Yoshida-Komiya, H Deng, CX O'Malley, BW TI The steroid receptor coactivator SRC-3 (p/CIP/RAC3/AIB1/ACTR/TRAM-1) is required for normal growth, puberty, female reproductive function, and mammary gland development SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TRANSCRIPTIONAL COACTIVATOR; THYROID-HORMONE; HISTONE ACETYLTRANSFERASE; ESTROGEN-RECEPTOR; NUCLEAR RECEPTORS; GENE; ACTIVATION; PROTEIN; CANCER; TIF2 AB Steroid receptor coactivator-3 (SRC-3) is a coactivator of nuclear receptors in the SRC family as assayed in vitro. Here, we show that mouse SRC-3 is expressed in a tissue-specific fashion and distributed mainly in the oocytes. mammary glands, hippocampus. olfactory bulb, smooth muscle, hepatocytes, and vaginal epithelium. Genetic disruption of SRC-3 in mice results in a pleiotropic phenotype showing dwarfism. delayed puberty, reduced female reproductive function. and blunted mammary gland development. Hormonal analysis indicates that SRC-3 plays a role in both the growth hormone regulatory pathway and the production of estrogen. which may explain the observed phenotypes. These results suggest that the physiological role of SRC-3 is different from that of SRC-1 and prove the diversity among coactivator family members. C1 Baylor Coll Med, Dept Cellular & Mol Biol, Houston, TX 77030 USA. NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Xu, JM (reprint author), Baylor Coll Med, Dept Cellular & Mol Biol, 1 Baylor Plaza, Houston, TX 77030 USA. RI deng, chuxia/N-6713-2016 NR 37 TC 382 Z9 388 U1 1 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 6 PY 2000 VL 97 IS 12 BP 6379 EP 6384 DI 10.1073/pnas.120166297 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 322UA UT WOS:000087526300029 PM 10823921 ER PT J AU Paull, TT Gellert, M AF Paull, TT Gellert, M TI A mechanistic basis for Mre11-directed DNA joining at microhomologies SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DOUBLE-STRAND BREAKS; SACCHAROMYCES-CEREVISIAE; NONHOMOLOGOUS RECOMBINATION; ILLEGITIMATE RECOMBINATION; HOMOLOGOUS RECOMBINATION; MEIOTIC RECOMBINATION; ATAXIA-TELANGIECTASIA; JUNCTIONAL DIVERSITY; V(D)J RECOMBINATION; SEQUENCE HOMOLOGIES AB Repair of DNA double-strand breaks in vertebrate cells occurs mainly by an end-joining process that often generates junctions with sequence homologies of a few nucleotides. Mre11 is critical for this mode of repair in budding yeast and has been implicated in the microhomology-based joining. Here. we show that Mre11 exonuclease activity is sensitive to the presence of heterologous DNA. and to the structure and sequence of its ends. Addition of mismatched DNA ends stimulates degradation of DNA by Mre11. whereas cohesive ends strongly inhibit it. Furthermore, if a sequence identity is revealed during the course of degradation, it causes Mrell nuclease activity to pause, thus stabilizing the junction at a site of microhomology. A nuclease-deficient Mre11 mutant that still binds DNA can also stimulate degradation by wild-type Mrell. suggesting that Mre11-DNA complexes may interact to bridge DNA ends and facilitate DNA joining. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gellert, M (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 35 TC 140 Z9 141 U1 1 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 6 PY 2000 VL 97 IS 12 BP 6409 EP 6414 DI 10.1073/pnas.110144297 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 322UA UT WOS:000087526300034 PM 10823903 ER PT J AU Edskes, HK Wickner, RB AF Edskes, HK Wickner, RB TI A protein required for prion generation: [URE3] induction requires the Ras-regulated Mks1 protein SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES; YEAST SUP35 PROTEIN; DE-NOVO APPEARANCE; SACCHAROMYCES-CEREVISIAE; IN-VITRO; AMYLOID FORMATION; SHUTTLE VECTORS; PSI PRION; PROPAGATION; GENE AB Infectious proteins (prions) can arise de novo as well as by transmission from another individual. De novo prion generation is believed responsible for most cases of Creutzfeldt-Jakob disease and for initiating the mad cow disease epidemic. However, the cellular components needed for prion generation have not been identified in any system. The [URE3] prion of Saccharomyces cerevisiae is an infectious form of Ure2p. apparently a self-propagating amyloid. We now demonstrate a protein required for de novo prion generation. Mks1p negatively regulates Ure2p and is itself negatively regulated by the presence of ammonia and by the Ras-cAMP pathway. We find that in mks1 Delta strains, de novo generation of the [URE3] prion is blocked, although [URE3] introduced from another strain is expressed and propagates stably. Ras2(Val19) increases cAMP production and also blocks [URE3] generation. These results emphasize the distinction between prion generation and propagation. and they show that cellular regulatory mechanisms can critically affect prion generation. C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP NIDDKD, Lab Biochem & Genet, NIH, Bldg 8,Room 225,8 Ctr Dr,MSC 0830, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov NR 45 TC 38 Z9 38 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 JUN 6 PY 2000 VL 97 IS 12 BP 6625 EP 6629 DI 10.1073/pnas.120168697 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 322UA UT WOS:000087526300071 PM 10823922 ER PT J AU Petiniot, LK Weaver, Z Barlow, C Shen, RN Eckhaus, M Steinberg, SM Ried, T Wynshaw-Boris, A Hodes, RJ AF Petiniot, LK Weaver, Z Barlow, C Shen, RN Eckhaus, M Steinberg, SM Ried, T Wynshaw-Boris, A Hodes, RJ TI Recombinase-activating gene (RAG) 2-mediated V(D)J recombination is not essential for tumorigenesis in Atm-deficient mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ATAXIA-TELANGIECTASIA; TRANSGENIC MICE; LYMPHOMA; LYMPHOCYTES AB The majority of Atm-deficient mice die of malignant thymic lymphoma by 4-5 mo of age. Cytogenetic abnormalities in these tumors are consistently identified within the Tcr alpha/delta locus, suggesting that tumorigenesis is secondary to aberrant responses to double-stranded DNA breaks that occur during V(D)J recombination. Since V(D)J recombination is a recombinase-activating gene (RAG)-dependent process, we generated Rag2(-/-)Atm(-/-) mice to assess the requirement for RAG-dependent recombination in thymic lymphomagenesis, In contrast to expectation, the data presented here indicate that development of malignant thymic lymphoma in Atm(-/-) mice is not prevented by loss of RAG-2 and thus is not dependent on V(D)I recombination. Malignant thymic lymphomas in Rag2(-/-)Atm(-/-) mice occurred at a lower frequency and with a longer latency as compared with Atm(-/-) mice. Importantly, cytogenetic analysis of these tumors indicated that multiple chromosomal abnormalities occurred in each tumor, but that none of these involved the Tcr alpha/delta locus. Nonmalignant peripheral T cells from TCR-transgenic Rag2(-/-)Atm(-/-) mice also revealed a substantial increase in translocation frequency, suggesting that these translocations are early events in the process of tumorigenesis. These data are consistent with the hypothesis that the major mechanism of tumorigenesis in Atm(-/-) mice is via chromosomal translocations and other abnormalities that are secondary to aberrant responses to double-stranded DNA breaks. Furthermore, these data suggest that V(D)J recombination is a critical, but not essential, event during which Atm-deficient thymocytes are susceptible to developing chromosome aberrations that predispose to malignant transformation. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Dept Genet, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Off Director, Div Clin Sci,NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Genet Dis Res Branch, Bethesda, MD 20892 USA. Off Res Serv, Vet Resources Program, Bethesda, MD 20892 USA. NIA, NIH, Bethesda, MD 20892 USA. NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. RP Hodes, RJ (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Room 4B10,10 Ctr Dr,MSC 1360, Bethesda, MD 20892 USA. NR 23 TC 51 Z9 51 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 JUN 6 PY 2000 VL 97 IS 12 BP 6664 EP 6669 DI 10.1073/pnas.97.12.6664 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 322UA UT WOS:000087526300078 PM 10841564 ER PT J AU Belkaid, Y Valenzuela, JG Kamhawi, S Rowton, E Sacks, DL Ribeiro, JMC AF Belkaid, Y Valenzuela, JG Kamhawi, S Rowton, E Sacks, DL Ribeiro, JMC TI Delayed-type hypersensitivity to Phlebotomus papatasi sand fly bite: An adaptive response induced by the fly? SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LUTZOMYIA-LONGIPALPIS; SALIVA; ARTHROPODS; MACROPHAGES; INFECTION AB The saliva of bloodsucking arthropods contains a large array of pharmacologically active compounds that assist hematophagy, Arthropod saliva is also responsible for causing uncomfortable allergic responses in its vertebrate hosts. In this article, we investigate whether the sand fly Phlebotomus papatasi, known to produce a strong delayed-type hypersensitivity (DTH) in humans. could benefit from, and possibly adaptively induce, this response in their vertebrate hosts. In this study, we show that flies fed on humans to completion nearly twice as fast in DTH sites as compared with normal skin sites. DTH sites had significantly larger blood flow as measured by the laser Doppler method. Sand flies feeding at sites in mouse ears that had a DTH response also fed faster than at normal sites. We conclude that in the case of P, papatasi, and possibly other arthropods such as fleas and bed bugs, the strong saliva-induced DTH response may reflect an adaptation of the fly to manipulate host immunity for the insect's own advantage. C1 NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. Walter Reed Army Inst Res, Dept Entomol, Washington, DC 20307 USA. RP Ribeiro, JMC (reprint author), NIAID, Parasit Dis Lab, Bldg 4,Room 126,4 Ctr Dr,MSC-425, Bethesda, MD 20892 USA. RI Rowton, Edgar/A-4474-2012; Rowton, Edgar/A-1975-2011; OI Rowton, Edgar/0000-0002-1979-1485; Ribeiro, Jose/0000-0002-9107-0818 NR 21 TC 65 Z9 68 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 6 PY 2000 VL 97 IS 12 BP 6704 EP 6709 DI 10.1073/pnas.97.12.6704 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 322UA UT WOS:000087526300085 PM 10841567 ER PT J AU Thomas, JB Atkinson, RN Rothman, RB Burgess, JP Mascarella, SW Dersch, CM Xu, H Carroll, FI AF Thomas, JB Atkinson, RN Rothman, RB Burgess, JP Mascarella, SW Dersch, CM Xu, H Carroll, FI TI 4-[(8-alkyl-8-azabicyclo[3.2.1]octyl-3-yl)-3-arylanilino]-N,N-diethylben zamides: High affinity, selective ligands for the delta opioid receptor illustrate factors important to antagonist activity SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID AGONIST; BINDING; POTENT AB The tropane derived compounds, 4-[(8-alkyl-8-azabicyclo[3.2.1]octyl-3-yl)-3-arylanilino]-N,N-diethylbenzamides (5a-d), were synthesized and found to have high affinity and selectivity for the delta receptor. Compounds 5a-d are structurally similar to the full agonist (-)-RTI-5989-54 (3); yet, efficacy studies for compounds in this series (5a-d) reveal greatly diminished agonist activity as well as antagonism not found in piperidine-based compounds like 3. (C) 2000 Elsevier Science Ltd. All rights reserved. C1 Res Triangle Inst, Res Triangle Pk, NC 27709 USA. NIDA, Addict Res Sect, Clin Psychopharmacol Sect, Baltimore, MD 21224 USA. RP Carroll, FI (reprint author), Res Triangle Inst, POB 12194, Res Triangle Pk, NC 27709 USA. FU NIDA NIH HHS [DA09045] NR 12 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 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JUN 5 PY 2000 VL 10 IS 11 BP 1281 EP 1284 DI 10.1016/S0960-894X(00)00209-2 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 322WC UT WOS:000087531400034 PM 10866400 ER PT J AU Komoriya, A Packard, BZ Brown, MJ Wu, ML Henkart, PA AF Komoriya, A Packard, BZ Brown, MJ Wu, ML Henkart, PA TI Assessment of caspase activities in intact apoptotic thymocytes using cell-permeable fluorogenic caspase substrates SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE apoptosis; caspase; PhiPhiLux (TM); thymocyte; lymphocyte ID INTERLEUKIN-1-BETA CONVERTING-ENZYME; FAS-MEDIATED APOPTOSIS; CPP32-LIKE PROTEASES; IN-VIVO; ACTIVATION; DEATH; MICE; INHIBITION; RELEASE; FAMILY AB To detect caspase activities in intact apoptotic cells at the single cell, level, cell-permeable fluorogenic caspase substrates were synthesized incorporating the optimal peptide recognition motifs for caspases 1, 3/7, 6, 8, and 9. Caspase activities were then assessed at various times after in vitro treatment of mouse thymocytes with dexamethasone or anti-Fas antibody. Dexamethasone induced the following order of appearance of caspase activities as judged by now cytometry: LEHDase, WEHDase, VEIDase, IETDase, and DEVDase. Since the relative order of caspases 3 (DEVDase) and 6 (VEIDase) in the cascade has been controversial, this caspase activation order was reexamined using confocal microscopy. The VEIDase activity appeared before DEVDase in every apoptotic cell treated with dexamethasone. Tn contrast, anti-Fas stimulation altered this sequence: IETDase was the first measurable caspase activity and DEVDase preceded VEIDase. In an attempt to determine the intracellular target of the potent antiapoptotic agent carbobenzoxy-valyl-alanyl-aspartyl(beta-methyl ester)-fluoromethyl ketone (Z-VAD[OMe]-FMK), we examined its ability to inhibit previously activated intracellular caspases. However, no significant reductions of these activities were observed. These fluorogenic caspase substrates allow direct observation of the caspase cascade in intact apoptotic cells, showing that the order of downstream caspase activation is dependent on the apoptotic stimulus. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. OncoImmunin Inc, Gaithersburg, MD 20877 USA. RP Henkart, PA (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Rm 4B36, Bethesda, MD 20892 USA. NR 36 TC 131 Z9 133 U1 0 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUN 5 PY 2000 VL 191 IS 11 BP 1819 EP 1828 DI 10.1084/jem.191.11.1819 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 322UL UT WOS:000087527300002 PM 10839799 ER PT J AU Castellino, F Boucher, PE Eichelberg, K Mayhew, M Rothman, JE Houghton, AN Germain, RN AF Castellino, F Boucher, PE Eichelberg, K Mayhew, M Rothman, JE Houghton, AN Germain, RN TI Receptor-mediated uptake of antigen/heat shock protein complexes results in major histocompatibility complex class I antigen presentation via two distinct processing pathways SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE immunology; vaccines; macrophages; T cells; peptides ID MHC CLASS-I; EXOGENOUS ANTIGENS; PRESENTING CELLS; DENDRITIC CELLS; PEPTIDE-BINDING; B-CELLS; T-CELLS; MOLECULES; EXPRESSION; LYMPHOCYTES AB Heat shock proteins (HSPs) derived from tumors or virally infected cells carl stimulate antigen-specific CD8(+) T cell responses in vitro and in vivo. Although this antigenicity is known to arise from HSP-associated peptides presented to the immune system by major histocompatibility complex (MHC) class I molecules, the cell biology underlying this presentation process remains poorly understood. Here we show that HSP 70 binds to the surface of antigen presenting cells by a mechanism with the characteristics of a saturable receptor system. Alter this membrane interaction processing and MHC class I presentation of the HSP-associated antigen can occur via either a cytosolic (transporter associated with antigen processing [TAP] and proteasome-dependent) or an endosomal (TAP and proteasome-independent) route, with the preferred pathway determined by the sequence context of the optimal antigenic peptide within the HSP-associatsd material. These findings not only characterize two highly efficient, specific pathways leading to the conversion of HSP-associated antigens into ligands for CD8(+) T cells, they also imply the existence of a mechanism for receptor-facilitated transmembrane transport of HSP or HSP-associated ligands from the plasma membrane or lumen of endosomes into the cytosol. C1 NIAID, Lymphocyte Biol Sect, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Div Bacterial Prod, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Cellular Biochem & Biophys Program, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Program Immunol, New York, NY 10021 USA. RP Germain, RN (reprint author), NIAID, Lymphocyte Biol Sect, NIH, Bldg 10,Rm 11N311,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. NR 49 TC 305 Z9 330 U1 0 U2 6 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUN 5 PY 2000 VL 191 IS 11 BP 1957 EP 1964 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 322UL UT WOS:000087527300013 PM 10839810 ER PT J AU Riley, JL Schlienger, K Blair, PJ Carreno, B Craighead, N Kim, D Carroll, RG June, CH AF Riley, JL Schlienger, K Blair, PJ Carreno, B Craighead, N Kim, D Carroll, RG June, CH TI Modulation of susceptibility to HIV-1 infection by the cytotoxic T lymphocyte antigen 4 costimulatory molecule SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE HIV; costimulation; T cells; chemokine receptors; chemokines ID IMMUNODEFICIENCY-VIRUS TYPE-1; CELL ACTIVATION; CD28 COSTIMULATION; DENDRITIC CELLS; CTLA-4; EXPRESSION; STIMULATION; LIGATION; INDUCTION; RECEPTOR AB CD4 T cells activated in vitro by anti-CD3/28-coated beads are resistant to infection by CC chemokine receptor 5 (CCR5)-dependent HIV-1 isolates. In vivo, antigen-presenting cells (APCs) activate CD4 T cells in part by signaling through the T cell receptor and CD28, yet cells stimulated in this manner are susceptible to HIV-1 infection. We show that cytotoxic T lymphocyte antigen 4 (CTLA-4) engagement counteracts the CD28 antiviral effects, and that the ratio of CTLA-4 to CD28 engagement determines the susceptibility of HIV-1 infection. Furthermore, unopposed CTLA-4 signaling provided by CD28 blockade promotes vigorous HIV-1 replication, despite minimal T cell proliferation. Finally, CTLA-4 antibodies decrease the susceptibility of antigen-activated CD4 T cells to HIV, suggesting a potential approach to prevent or limit viral spread in HIV-1-infected individuals. C1 Univ Penn, Dept Mol & Cellular Engn, Philadelphia, PA 19104 USA. NIDDKD, Transplant & Autoimmun Branch, NIH, Bethesda, MD 20889 USA. Genet Inst, Cambridge, MA 02140 USA. Walter Reed Army Inst Res, Div Retrovirol, Rockville, MD 20850 USA. Henry M Jackson Fdn, Rockville, MD 20850 USA. RP June, CH (reprint author), Univ Penn, Dept Mol & Cellular Engn, BRB 2-3,Rm 554,421 Curie Blvd, Philadelphia, PA 19104 USA. OI Riley, James/0000-0002-1057-576X NR 57 TC 38 Z9 39 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUN 5 PY 2000 VL 191 IS 11 BP 1987 EP 1997 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 322UL UT WOS:000087527300016 PM 10839813 ER PT J AU Lynch, WP Portis, JL AF Lynch, WP Portis, JL TI Neural stem cells as tools for understanding retroviral neuropathogenesis SO VIROLOGY LA English DT Review ID CENTRAL-NERVOUS-SYSTEM; MURINE RETROVIRUS; TRANSGENIC MICE; SPONGIFORM NEURODEGENERATION; GENE DELIVERY; ENV GENE; MICROGLIA; VIRUS; PARTICIPATE; REPLICATION AB The discovery within the past decade that neural stem cells (NSCs) from the developing and adult mammalian brain can be propagated, cloned, and genetically manipulated ex vivo for ultimate transfer back into the CNS has opened the door to a novel means for modifying the CNS environment for experimental and therapeutic purposes. while a great deal of interest has been focused on the properties and promise of this new technology, especially in regard to cellular replacement and gene therapy, this minireview will focus on the recent use of NSCs to study the neuropathogenesis of the murine oncornaviruses. In brief, the use of this NSC-based approach has provided a means for selective reconstitution within the brain, of specific retroviral life cycle events, in order to consider their contribution to the induction of neurodegeneration. Furthermore, by virtue of their ability to disseminate virus within the brain, NSCs have provided a reliable means for assessing the true neurovirulence potential of murine oncornaviruses by directly circumventing a restriction to virus entry into the CNS. Importantly, these experiments have demonstrated that the neurovirulence of oncornaviruses requires late virus life cycle events occurring specifically within microglia, the resident macrophages of the brain. This initial application of NSC biology to the analysis of oncornavirus-CNS interactions may serve as an example for how other questions in viral neuropathogenesis might be addressed in the future, (C) 2000 Academic Press. C1 NE Ohio Univ, Coll Med, Dept Microbiol Immunol, Rootstown, OH 44272 USA. NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Lynch, WP (reprint author), NE Ohio Univ, Coll Med, Dept Microbiol Immunol, 4209 State Route 44,Box 95, Rootstown, OH 44272 USA. NR 20 TC 7 Z9 7 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JUN 5 PY 2000 VL 271 IS 2 BP 227 EP 233 DI 10.1006/viro.2000.0338 PG 7 WC Virology SC Virology GA 323KR UT WOS:000087565000003 PM 10860875 ER PT J AU Hallak, LK Collins, PL Knudson, W Peeples, ME AF Hallak, LK Collins, PL Knudson, W Peeples, ME TI Iduronic acid-containing glycosaminoglycans on target cells are required for efficient respiratory syncytial virus infection SO VIROLOGY LA English DT Article ID HEPARAN-SULFATE PROTEOGLYCANS; HERPES-SIMPLEX VIRUS; DERMATAN SULFATE; IN-VITRO; FLAVOBACTERIUM-HEPARINUM; CHONDROITIN SULFATE; ATTACHMENT PROTEIN; GENE-EXPRESSION; BINDING DOMAIN; GLYCOPROTEIN-G AB Respiratory syncytial virus (RSV) is an important human respiratory pathogen, particularly in infants. Glycosaminoglycans (GAGs) have been implicated in the initiation of RSV infection of cultured cells, but it is not clear what type of GAGs and GAG components are involved, whether the important GAGs are on the virus or the cell, or what the magnitude is of their contribution to infection. We constructed and rescued a recombinant green fluorescent protein (GFP)-expressing RSV (rgRSV) and used this virus to develop a sensitive system to assess and quantify infection by flow cytometry. Evaluation of a panel of mutant Chinese hamster ovary cell lines that are genetically deficient in various aspects of GAG synthesis showed that infection was reduced up to 80% depending on the type of GAG deficiency. Enzymatic removal of heparan sulfate and/or chondroitin sulfate from the surface of HEp-2 cells also reduced infection, and the removal of both reduced infection even further. Blocking experiments in which RSV was preincubated with various soluble GAGs revealed the relative blocking order of: heparin > heparan sulfate > chondroitin sulfate B. Iduronic acid is a component common to these GAGs, GAGs that do not contain iduronic acid, namely, chondroitin sulfate A and C and hyaluronic acid, did not inhibit infection. A role for iduronic acid-containing GAGs in RSV infection was confirmed by the ability of basic fibroblast growth factor to block infection, because basic fibroblast growth factor binds to GAGs containing iduronic acid. Pretreatment of cells with protamine sulfate, which binds and blocks GAGs, also reduced infection. In these examples, infection was reduced by pretreatment of the virus with soluble GAGs, pretreatment of the cells with GAG-binding molecules, pretreatment of the cells with GAG-destroying enzymes or in cells genetically deficient in GAGs. These results establish that the GAGs involved in RSV infection are present on the cell rather than on the virus particle. Thus, the presence of cell surface GAGs containing iduronic acid, like heparan sulfate and chondroitin sulfate B, is required for efficient RSV infection in cell culture. (C) 2000 Academic Press. C1 Rush Presbyterian St Lukes Med Ctr, Dept Immunol Microbiol, Chicago, IL 60612 USA. Rush Presbyterian St Lukes Med Ctr, Dept Biochem & Pathol, Chicago, IL 60612 USA. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Rush Presbyterian St Lukes Med Ctr, Dept Immunol Microbiol, 1653 W Congress Pkwy, Chicago, IL 60612 USA. EM mpeeples@rush.edu FU NIAID NIH HHS [AI25586] NR 80 TC 130 Z9 135 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 0042-6822 J9 VIROLOGY JI Virology PD JUN 5 PY 2000 VL 271 IS 2 BP 264 EP 275 DI 10.1006/viro.2000.0293 PG 12 WC Virology SC Virology GA 323KR UT WOS:000087565000009 PM 10860881 ER PT J AU Iwasaki, K Trus, BL Wingfield, PT Cheng, NQ Campusano, G Rao, VB Steven, AC AF Iwasaki, K Trus, BL Wingfield, PT Cheng, NQ Campusano, G Rao, VB Steven, AC TI Molecular architecture of bacteriophage T4 capsid: Vertex structure and bimodal binding of the stabilizing accessory protein, Soc SO VIROLOGY LA English DT Article DE cryo-electron microscopy; bacteriophage assembly; virus structure; phage display; quasi-equivalence; osmotic shock resistance ID CONFORMATIONAL-CHANGES; CIRCULAR-DICHROISM; FORM DETERMINATION; SURFACE LATTICE; HEAD; SYSTEM; INVITRO; DISPLAY; VIRUS; MODEL AB T4 encodes two dispensable proteins that bind to the outer surface of the mature capsid. Soc (9 kDa) stabilizes the capsid against extremes of alkaline pH and temperature, but Hoc (40 kDa) has no perceptible effect. Both proteins have been developed as display platforms. Their positions on the hexagonal surface lattice of gp23*, the major capsid protein, were previously defined by two-dimensional image averaging of negatively stained electron micrographs of elongated variant capsids. We have extended these observations by reconstructing cryo-electron micrographs of isometric capsids produced by a point mutant in gene 23, for both Hoc+.Soc+ and Hoc+.Soc- phages. The expected T = 13 lattice was observed, with a single Hoc molecule at the center of each gp23* hexamer. The vertices are occupied by pentamers of gp24*: despite limited sequence similarity with gp23*, the respective monomers are similar in size and shape, suggesting they may have the same fold. However, gp24* binds neither Hoc nor Soc; in situ, Soc is visualized as trimers at the trigonal points of the gp23* lattice and as monomers at the sites closest to the vertices. In solution, Soc is a folded protein (similar to 10% alpha-helix and 50-60% beta sheet) that is monomeric as determined by analytic ultracentrifugation. Thus its trimerization on the capsid surface is imposed by a template of three symmetry-related binding sites. The observed mode of Soc binding suggests that it stabilizes the capsid by a clamping mechanism and offers a possible explanation for the phenotype of osmotic shock resistance. (C) 2000 Academic Press. C1 NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. NIH, Computat Biosci & Engn Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. RP Steven, AC (reprint author), NIAMSD, Struct Biol Lab, NIH, Bldg 6,Rm B2-34,MSC 2717, Bethesda, MD 20892 USA. NR 57 TC 38 Z9 38 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JUN 5 PY 2000 VL 271 IS 2 BP 321 EP 333 DI 10.1006/viro.2000.0321 PG 13 WC Virology SC Virology GA 323KR UT WOS:000087565000014 PM 10860886 ER PT J AU Qu, Y Arckens, L Vandesande, F Vandenbussche, E AF Qu, Y Arckens, L Vandesande, F Vandenbussche, E TI Sampling extracellular aspartate, glutamate and gamma-aminobutyric acid in striate cortex of awake cat by in vivo microdialysis: surgical and methodological aspects SO BRAIN RESEARCH LA English DT Article DE in vivo microdialysis; visual cortex; awake cat; amino acid; HPLC-ED; surgical technique ID KITTEN VISUAL-CORTEX; ADULT CAT; REORGANIZATION; STIMULATION; SEROTONIN; BRAIN; NEUROTRANSMITTERS; NUCLEUS; PROTEIN; RELEASE AB A method which permits repeated microdialysis in the cortical layers of area 17 of the awake cat is described. Under visual control through a surgical microscope and using a stereotactic instrument, four probe guides are permanently implanted in area 17 of one hemisphere of the anesthetized animal and two fixation bars an mounted on the skull to allow fixation of the cat in a stereotactic frame. The implantation of four probe guides in the same hemisphere allows simultaneous sampling from different cortical regions serving different parts of the visual field. A removable transparent cover protects the probe guides. After recovery from surgery the awake cats are trained to adapt to a fixation of 5 h in a stereotaxic apparatus. Once adapted to that situation, the cats are ready for microdialysis experiments without anesthesia. The day of the experiment, the awake animal was fixed in the stereotactic frame and the probes inserted into the guides. To test the validity of the method, the basal efflux and the depolarization efflux, triggered by the addition of 65 mM K+ to the artificial cerebrospinal fluid, of the amino acids aspartate, glutamate and gamma-aminobutyric acid are measured by two HPLC-electrochemical detection methods. The exact localization of the probes and the reaction of the surrounding tissue is studied using immunocytochemistry for glutamate and glial fibrilary acidic protein. Our neurochemical and morphological results suggest the feasibility of multiple and repeated probe insertions for microdialysis experiments in the cerebral cortex of awake and behaving cat. This method provides a new tool to investigate the cortical plasticity. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Katholieke Univ Leuven, Inst Zool, Lab Neuroendocrinol & Immunol Biotechnol, B-3000 Louvain, Belgium. Katholieke Univ Leuven, Sch Med, Neuropsychol Lab, B-3000 Louvain, Belgium. RP Qu, Y (reprint author), NIA, Sect Brain Physiol & Metab, NIH, Bldg 10,Room 6C103, Bethesda, MD 20892 USA. RI Arckens, Lutgarde/C-3822-2016 NR 32 TC 9 Z9 9 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 2 PY 2000 VL 866 IS 1-2 BP 116 EP 127 DI 10.1016/S0006-8993(00)02256-3 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 320JX UT WOS:000087399000013 PM 10825487 ER PT J AU Schwartz, PJ Rosenthal, NE Kajimura, N Han, L Turner, EH Bender, C Wehr, TA AF Schwartz, PJ Rosenthal, NE Kajimura, N Han, L Turner, EH Bender, C Wehr, TA TI Ultradian oscillations in cranial thermoregulation and electroencephalographic slow-wave activity during sleep are abnormal in humans with annual winter depression SO BRAIN RESEARCH LA English DT Article DE seasonal affective disorder; body temperature; sleep; circadian rhythm; ultradian rhythm; EEG ID SEASONAL AFFECTIVE-DISORDER; EEG POWER-DENSITY; BLOOD-FLOW; BODY TEMPERATURES; LIGHT TREATMENT; REM-SLEEP; AMBIENT-TEMPERATURES; CIRCADIAN PACEMAKER; CORE TEMPERATURE; SYRIAN-HAMSTERS AB The level of core body, and presumably brain temperature during sleep varies with clinical state in patients with seasonal affective disorder (SAD), becoming elevated during winter depression and lowered during clinical remission induced by either light treatment or summer. During sleep, brain temperatures are in part determined by the level of brain cooling activity, which may be reflected by facial skin temperatures. In many animals, the level of brain cooling activity oscillates across the NREM-REM sleep cycle. Facial skin temperatures during sleep in patients with winter depression are abnormally low and uncorrelated with octal temperatures, although their relationship to EEG-defined sleep stages remains unknown. We therefore measured the sleep EEG, fore body and facial skin temperatures in 23 patients with winter depression and 23 healthy controls, and tested the hypothesis that ultradian oscillations in facial skin temperatures exist in humans and are abnormal in patients with winter depression. We found that facial skin temperatures oscillated significantly across the NREM-REM sleep cycle, and were again significantly lower and uncorrelated with rectal temperatures in patients with winter depression Mean slow-wave activity and NREM episode duration were significantly greater in patients with winter depression, whereas the intraepisodic dynamics of stow-wave activity were normal in patients with winter depression. These results suggest that brain cooling activity oscillates in an ultradian manner during sleep in humans and is reduced during winter depression, and provide additional support for the hypothesis that brain temperatures are elevated during winter depression. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Univ Cincinnati, Coll Med, Dept Psychiat, Cincinnati, OH USA. Vet Affairs Med Ctr, Cincinnati, OH 45267 USA. NIMH, Sect Biol Rhythms, Bethesda, MD 20892 USA. Natl Ctr Hosp Mental Nervous & Muscular Disorders, Tokyo, Japan. McGill Univ, Montreal, PQ, Canada. US FDA, Rockville, MD 20857 USA. RP Schwartz, PJ (reprint author), 3429 Cornell Pl, Cincinnati, OH 45220 USA. EM pjs4@ix.netcom.com RI Turner, Erick/A-4848-2008 OI Turner, Erick/0000-0002-3522-3357 NR 87 TC 15 Z9 16 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 2 PY 2000 VL 866 IS 1-2 BP 152 EP 167 DI 10.1016/S0006-8993(00)02271-X PG 16 WC Neurosciences SC Neurosciences & Neurology GA 320JX UT WOS:000087399000017 PM 10825491 ER PT J AU Jernigan, KM Blumenthal, R Puri, A AF Jernigan, KM Blumenthal, R Puri, A TI Varying effects of temperature, Ca2+ and cytochalasin on fusion activity mediated by human immunodeficiency virus type 1 and type 2 glycoproteins SO FEBS LETTERS LA English DT Article DE fusion activity of HIV-2 envelope glycoprotein ID ENVELOPE GLYCOPROTEIN; MEMBRANE-FUSION; CHEMOKINE RECEPTORS; SYNCYTIUM FORMATION; HIV CORECEPTORS; CELL TROPISM; PROTEIN; GP120; ENTRY; CD4 AB We examined fusion mediated by the human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) envelope glycoproteins under various experimental conditions. Incubation of HeLa cells expressing HIV-2(ROD) and HIV-2(SBL,ISY) envelope glycoproteins with HeLa-CD4 target cells resulted in fusion at temperatures greater than or equal to 25 degrees C whereas fusion with cells expressing HIV-1(Lai) occurred only at greater than or equal to 31 degrees C. HIV-2 envelope glycoprotein-mediated fusion proceeded in the absence of Ca2+ in the culture medium, whereas HIV-1 fusion required Ca2+ ions for fusion, In contrast to HIV-2 envelope glycoprotein fusion, incubations in the presence of the 0.5 mu M cytochalasin B completely inhibited HIV-1 envelope glycoprotein-mediated fusion. Our results suggest that in contrast to HIV-2, HIV-1 fusion is dependent on dynamic processes in the target membrane. (C) 2000 Federation of European Biochemical Societies. C1 NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, LECB,NIH, Frederick, MD 21702 USA. RP Puri, A (reprint author), NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, LECB,NIH, POB B,Bldg 469,Rm 211,Miller Dr, Frederick, MD 21702 USA. NR 27 TC 19 Z9 19 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUN 2 PY 2000 VL 474 IS 2-3 BP 246 EP 251 DI 10.1016/S0014-5793(00)01600-8 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 323DX UT WOS:000087550500025 PM 10838094 ER PT J AU Wang, GS Sondej, M Garrett, DS Peterkofsky, A Clore, GM AF Wang, GS Sondej, M Garrett, DS Peterkofsky, A Clore, GM TI A common interface on histidine-containing phosphocarrier protein for interaction with its partner proteins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SUGAR PHOSPHOTRANSFERASE SYSTEM; N-TERMINAL DOMAIN; ESCHERICHIA-COLI PHOSPHOENOLPYRUVATE; ENZYME-I; RESOLUTION STRUCTURE; BINDING-SITE; HPR; NMR; IDENTIFICATION; TRANSPORT AB The bacterial phosphoenolpyruvate:sugar phosphotransferase system accomplishes both the transport and phosphorylation of sugars as well as the regulation of some cellular processes. An important component of this system is the histidine-containing phosphocarrier protein, HPr, which accepts a phosphoryl group from enzyme I, transfers a phosphoryl group to IIA proteins, and is an allosteric regulator of glycogen phosphorylase. Because the nature of the surface on HPr that interacts with this multiplicity of proteins from Escherichia coli was previously undefined, we investigated these interactions by nuclear magnetic resonance spectroscopy. The chemical shift changes of the backbone and side-chain amide H-1 and N-15 nuclei of uniformly N-15-labeled HPr in the absence and presence of natural abundance glycogen phosphorylase, glucose-specific enzyme ZIA, or the N-terminal domain of enzyme I have been determined. Mapping these chemical shift perturbations onto the three-dimensional structure of HPr permitted us to identify the binding surface(s) of HPr for interaction with these proteins. Here we show that the mapped interfaces on HPr are remarkably similar, indicating that HPr employs a similar surface in binding to its partners. C1 NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Peterkofsky, A (reprint author), NHLBI, Lab Biochem Genet, NIH, Bldg 36,Room 4C-11, Bethesda, MD 20892 USA. RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 NR 21 TC 28 Z9 28 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 2 PY 2000 VL 275 IS 22 BP 16401 EP 16403 DI 10.1074/jbc.C000167200 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 320FY UT WOS:000087392200001 PM 10764730 ER PT J AU Matsuo, T Stauffer, JK Walker, RL Meltzer, P Thiele, CJ AF Matsuo, T Stauffer, JK Walker, RL Meltzer, P Thiele, CJ TI Structure and promoter analysis of the human unc-33-like phosphoprotein gene - E-box required for maximal expression in neuroblastoma and myoblasts SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CAENORHABDITIS-ELEGANS; AXONAL GUIDANCE; RETINOIC ACID; NERVOUS-SYSTEM; DIFFERENTIATION; IDENTIFICATION; OUTGROWTH; PROTEINS; HOMOLOG; FAMILY AB The human unc-33-like phosphoprotein (hUlip/ CRMP-4) is a member of a family of developmentally regulated genes that are highly expressed in the nervous system. Mutations in the C. elegans unc-33 gene lead to worms with abnormal movements. The hUlip gene encodes a 570-amino acid protein with 98% homology 60 its murine (Ulip) (Byk, T., Dobransky, T., Cifuentes-Diaz, C., and Sobel, A. (1996) J. Neurosci. 16, 688-701) and rat (CRMP-4) (Wang, L. H., and Strittmatter, S. M. (1996) J. Neurosci, 16, 6197-6207) counterparts (Gaetano, C., Matsuo, T., and Thiele, C. J. (1997) J.. Biol. Chem. 272, 12195-12201). The hUlip gene was isolated from a human genomic library. It contains 15 exons, including an exon defined by an anaplastic oligodendroglioma expressed sequence tag, and spans at least 61.7 kilobases. hUlip lacks sequences corresponding to the first six exons found in unc-33. unc-33 exons correspond to homologous hUlip exons as follows: VII to 1 and 2, VIII to 3-9, IX to 10-12, and X to 13 and 14. Using the hUlip clone 1 phage, fluorescence in situ hybridization analysis indicates that the hybridization signal localizes to human chromosome 5q32. Deletion analysis of 5'-flanking sequences delineated the sequences sufficient to express a reporter gene in both neuroblastoma cells and myoblasts. A consensus MyoD/myogenin binding site is located in a region of the downstream promoter that is nearly identical to its mouse homologue. Mutagenesis shows that this conserved MyoD/myogenin site is necessary for full promoter activity in both myoblasts and neuroblastoma cells. C1 NCI, Cell & Mol Biol Sect, Pediat Oncol Branch, Div Clin Sci,NIH, Bethesda, MD 20892 USA. NIH, Natl Human Genome Res Inst, Mol Genet Sect, Canc Genet Branch, Bethesda, MD 20892 USA. RP Thiele, CJ (reprint author), NCI, Cell & Mol Biol Sect, Pediat Oncol Branch, Div Clin Sci,NIH, Bldg 10-13N240, Bethesda, MD 20892 USA. NR 24 TC 18 Z9 18 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 2 PY 2000 VL 275 IS 22 BP 16560 EP 16568 DI 10.1074/jbc.M001312200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 320FY UT WOS:000087392200024 PM 10748015 ER PT J AU Jin, SQ Antinore, MJ Lung, FT Dong, X Zhao, HC Fan, FY Colchagie, AB Blanck, P Roller, PP Fornace, AJ Zhan, QM AF Jin, SQ Antinore, MJ Lung, FT Dong, X Zhao, HC Fan, FY Colchagie, AB Blanck, P Roller, PP Fornace, AJ Zhan, QM TI The GADD45 inhibition of Cdc2 kinase correlates with GADD45-mediated growth suppression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL-CYCLE CONTROL; P53-REGULATED PROTEIN GADD45; HUMAN CANCER-CELLS; IONIZING-RADIATION; DEPENDENT KINASES; DAMAGING AGENTS; MAMMALIAN G(1); HELA-CELLS; P53; CHECKPOINTS AB Cell cycle growth arrest is an important cellular response to genotoxic stress. Gadd45, a p58-regulated stress protein, plays an important role in the cell cycle G(2)-M checkpoint following exposure to certain types of RNA-damaging agents such as UV radiation and methylmethane sulfonate. Recent findings indicate that Gradd45 interacts with Cdc2 protein and inhibits Cdc2 kinase activity. In the present study, a series of Myc-tagged Gadd45 deletion mutants and a Gadd45 overlapping peptide library were used to define the Gadd45 domains that are involved in the interaction of Gadd45 with Cdc2. Both in vitro and in vivo studies indicate that the interaction of Gadd45 with Cdc2 involves a central region of the Gadd45 protein (amino acids 65-84). The Cdc2-binding domain of Gadd45 is also required for Gadd45 inhibition of Cdc2 kinase activity. Sequence analysis of the central Gadd45 region reveals no homology to inhibitory motifs of known cyclin-dependent kinase inhibitors, indicating that the Cdc2-binding and -inhibitory domains on Gadd45 are a novel motif. The peptide containing the Cdc2-binding domain (amino acids 65-84) disrupted the Cdc2-cyclin B1 protein complex, suggesting that dissociation of this complex results from a direct interaction between the Gadd45 and Cdc2 proteins. GADD45-induced cell cycle G(2)-M arrest was abolished when its Cdc2 binding motif was disrupted. Importantly, a short term survival assay demonstrated that GADD45-induced cell cycle G(2)-M arrest correlates with GADD45-mediated growth suppression. These findings indicate that the cell cycle G(2)-M growth arrest mediated by GADD45 is one of the major mechanisms by which GADD45 suppresses cell growth. C1 Univ Pittsburgh, Pittsburgh Canc Inst, Dept Radiat Oncol, Sch Med, Pittsburgh, PA 15213 USA. NCI, Med Chem Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NCI, Gene Response Sect, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Zhan, QM (reprint author), Univ Pittsburgh, Pittsburgh Canc Inst, Dept Radiat Oncol, Sch Med, Pittsburgh, PA 15213 USA. RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X FU NCI NIH HHS [CA83874] NR 51 TC 139 Z9 147 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 2 PY 2000 VL 275 IS 22 BP 16602 EP 16608 DI 10.1074/jbc.M000284200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 320FY UT WOS:000087392200030 PM 10747892 ER PT J AU Fedarko, NS Fohr, B Robey, PG Young, MF Fisher, LW AF Fedarko, NS Fohr, B Robey, PG Young, MF Fisher, LW TI Factor H binding to bone sialoprotein and osteopontin enables tumor cell evasion of complement-mediated attack SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN BREAST-CANCER; CLASS-I ANTIGEN; BTA STAT TEST; SECRETED PHOSPHOPROTEIN; IMMUNE EVASION; MESSENGER-RNA; SIALIC-ACID; ECHINOCOCCUS-GRANULOSUS; NEISSERIA-GONORRHOEAE; REGULATORY PROTEINS AB Metastatic cancer cells, like trophoblasts of the developing placenta, are invasive and must escape immune surveillance to survive. Complement has long been thought to play a significant role in the tumor surveillance mechanism. Bone sialoprotein (BSP) and osteopontin (OPN, ETA-1) are expressed by trophoblasts and are strongly up-regulated by many tumors. Indeed, BSP has been shown to be a positive indicator of the invasive potential of some tumors. In this report, we show that BSP and OPN form rapid and tight complexes with complement Factor H. Besides its key role in regulating complement-mediated cell lysis, Factor H also appears to play a role when "hijacked'' by invading organisms in enabling cellular evasion of complement, me have investigated whether BSP and OPN may play a similar role in tumor cell complement evasion by testing to see whether these glycoproteins could promote tumor cell survival. Recombinant OPN and BSP can protect murine erythroleukemia cells from attack by human complement as web as human MCF-7 breast cancer cells and U-266 myeloma cells from attack by guinea pig complement. The mechanism of this gain of function by tumor cell expression of BSP or OPN has been defined using specific peptides and antibodies to block BSP and OPN protective activity. The expression of BSP and OPN in tumor cells provides a selective advantage for survival via initial binding to alpha(V)beta(3) integrin (both) or CD44 (OPN) on the cell surface, followed by sequestration of Factor H to the cell surface and inhibition of complement-mediated cell lysis. C1 Johns Hopkins Univ, Dept Med, Div Geriatr, Baltimore, MD 21224 USA. NIDCR, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. RP Fedarko, NS (reprint author), Rm 5A-64 JHAAC,5501 Hopkins Bayview Circle, Baltimore, MD 21224 USA. RI Robey, Pamela/H-1429-2011 OI Fedarko, Neal/0000-0001-6055-6279; Robey, Pamela/0000-0002-5316-5576 NR 88 TC 139 Z9 148 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 2 PY 2000 VL 275 IS 22 BP 16666 EP 16672 DI 10.1074/jbc.M001123200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 320FY UT WOS:000087392200039 PM 10747989 ER PT J AU Wang, WH Wang, SB Yan, L Madara, P Cintron, AD Wesley, RA Danner, RL AF Wang, WH Wang, SB Yan, L Madara, P Cintron, AD Wesley, RA Danner, RL TI Superoxide production and reactive oxygen species signaling by endothelial nitric-oxide synthase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NECROSIS-FACTOR-ALPHA; U937 CELLS; EXPRESSION; TETRAHYDROBIOPTERIN; PEROXYNITRITE; GENERATION; ACTIVATION; DISMUTASE; ANION; DYSFUNCTION AB Reactive oxygen species can function as intracellular messengers, but linking these signaling events with specific enzymes has been difficult. Purified endothelial nitric-oxide synthase (eNOS) can generate superoxide (O-2(<(.)over bar>)) under special conditions but is only known to participate in cell signaling through NO. Here we show that eNOS regulates tumor necrosis factor alpha (TNF alpha) through a mechanism dependent on the production of O-2(<(.)over bar>) and completely independent of NO. Expression of eNOS in transfected U937 cells increased phorbol 12-myristate 13-acetate-induced TNF alpha promoter activity and TNF alpha production. N-omega-Methyl-L-arginine, an inhibitor of eNOS that blocks NO production but not its NADPH oxidase activity, did not prevent TNF alpha up-regulation. Likewise, Gln(361)eNOS, a competent NADPH oxidase that lacks NOS activity, retained the ability to increase TNF alpha. Similar to the effect of eNOS, a O-2(<(.)over bar>) donor dose-dependently increased TNF alpha production in differentiated U937 cells. In contrast, cotransfection of superoxide dismutase with eNOS prevented TNF alpha up-regulation, as did partial deletion of the eNOS NADPH binding site, a mutation associated with loss of O-2(<(.)over bar>) production. Thus, eNOS may straddle a bifurcating pathway that can lead to the formation of either NO or O-2(<(.)over bar>) interrelated but often opposing free radical messengers. This arrangement has possible implications for atherosclerosis and septic shock where endothelial dysfunction results from imbalances in NO and O-2(<(.)over bar>) production. C1 NIH, Dept Crit Care Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Danner, RL (reprint author), NIH, Dept Crit Care Med, Warren Grant Magnuson Clin Ctr, Bldg 10,Rm 7D43,10 Ctr Dr,MSC 1662, Bethesda, MD 20892 USA. NR 35 TC 63 Z9 67 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 2 PY 2000 VL 275 IS 22 BP 16899 EP 16903 DI 10.1074/jbc.M000301200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 320FY UT WOS:000087392200071 PM 10747895 ER PT J AU Kireeva, ML Komissarova, N Kashlev, M AF Kireeva, ML Komissarova, N Kashlev, M TI Overextended RNA : DNA hybrid as a negative regulator of RNA polymerase II processivity SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE RNA polymerase II; transcription elongation; RNA : DNA hybrid; stability ID ELONGATION COMPLEXES; TRANSCRIPTION ELONGATION; NASCENT RNA; TERNARY COMPLEXES; INITIATION; PROMOTER; PREINITIATION; TERMINATION; MECHANISM; TEMPLATE AB An eight nucleotide RNA:DNA hybrid at the 3' end of the transcript is required for the stability of the elongation complex (EC) of RNA polymerase II. A non-template DNA strand is not needed for the stability of the EC, which contains this minimal hybrid. Here, we apply a recently developed method for promoter-independent assembly of functional EC of RNA polymerase II from synthetic RNA and DNA oligonucleotides to study the minimal composition of the nucleic acid array required for stability of the complex with RNA longer than eight nucleotides. We found that upon RNA extension beyond 14-16 nt in the course of transcription, non-template DNA becomes essential for maintaining a stable EC. Our data suggest that the overextended RNA:DNA hybrid formed in the absence the non-template DNA acts as a negative regulator of EC stability. The dissociation of the EC correlates with the backsliding of the polymerase along the overextended hybrid. The dual role of the hybrid provides a mechanism for the control of a correct nucleic acid architecture in the EC and of RNA polymerase II processivity. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. RP Kashlev, M (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Bldg 539,Room 222, Frederick, MD 21702 USA. NR 35 TC 43 Z9 43 U1 0 U2 2 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUN 2 PY 2000 VL 299 IS 2 BP 325 EP 335 DI 10.1006/jmbi.2000.3755 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 321FY UT WOS:000087446500004 PM 10860741 ER PT J AU Kent, S Marshall, GR Wlodawer, A AF Kent, S Marshall, GR Wlodawer, A TI Determining the 3D structure of HIV-1 protease SO SCIENCE LA English DT Letter C1 Gryphon Sci, S San Francisco, CA 94080 USA. Washington Univ, Ctr Mol Design, Inst Biomed Comp, St Louis, MO 63110 USA. NCI, Frederick Canc Res Facil, Frederick, MD 21702 USA. RP Kent, S (reprint author), Gryphon Sci, 250 E Grand Ave, S San Francisco, CA 94080 USA. NR 3 TC 5 Z9 5 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 JUN 2 PY 2000 VL 288 IS 5471 BP 1590 EP 1590 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 320BZ UT WOS:000087382300018 PM 10858137 ER PT J AU Straus, SE AF Straus, SE TI Complementary and alternative medicine: Challenges and opportunities for American medicine SO ACADEMIC MEDICINE LA English DT Editorial Material C1 NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Straus, SE (reprint author), NIH, Natl Ctr Complementary & Alternat Med, Bldg 10, Bethesda, MD 20892 USA. NR 3 TC 14 Z9 16 U1 3 U2 3 PU HANLEY & BELFUS INC PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD JUN PY 2000 VL 75 IS 6 BP 572 EP 573 DI 10.1097/00001888-200006000-00005 PG 2 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 323RB UT WOS:000087577800005 PM 10875501 ER PT J AU Clarke, LP Croft, BY Menkens, A Torres-Anjel, MJ Hoffman, JM Sullivan, DC AF Clarke, LP Croft, BY Menkens, A Torres-Anjel, MJ Hoffman, JM Sullivan, DC TI National Cancer Institute initiative for development of novel imaging technologies SO ACADEMIC RADIOLOGY LA English DT Article C1 NCI, Div Canc Treatment & Diag, Biomed Imaging Program, Bethesda, MD 20892 USA. RP Sullivan, DC (reprint author), NCI, Div Canc Treatment & Diag, Biomed Imaging Program, EPN 800,6130 Execut Blvd,MSC 7400, Bethesda, MD 20892 USA. RI Croft, Barbara/D-1248-2013 OI Croft, Barbara/0000-0003-2544-150X NR 6 TC 4 Z9 4 U1 0 U2 0 PU ASSOC UNIV RADIOLOGISTS PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523-2251 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD JUN PY 2000 VL 7 IS 6 BP 481 EP 483 DI 10.1016/S1076-6332(00)80427-4 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 318LV UT WOS:000087286300013 PM 10845407 ER PT J AU Castillo, LC Gracia, F Roman, GC Levine, P Reeves, WC Kaplan, J AF Castillo, LC Gracia, F Roman, GC Levine, P Reeves, WC Kaplan, J TI Spinocerebellar syndrome in patients infected with human T-lymphotropic virus types I and II (HTLV-I/HTLV-II): report of 3 cases from Panama SO ACTA NEUROLOGICA SCANDINAVICA LA English DT Article DE human retroviruses; HTLV-I; HTLV-II; cerebellar disorders; tropical spastic paraparesis; magnetic resonance imaging; Panama ID TROPICAL SPASTIC PARAPARESIS; SPORADIC OLIVOPONTOCEREBELLAR ATROPHY; MULTIPLE-SCLEROSIS; HTLV-1-ASSOCIATED MYELOPATHY; DISEASE; SYSTEM; DNA AB Cerebellar symptoms at onset are unusual in HTLV-I/II-associated tropical spastic paraparesis (TSP). A prospective study of neurological disorders in Panama (1985-1990) revealed 13 patients with TSP and 3 with HTLV-I/II-associated spinocerebellar syndrome (HSCS) presenting at onset loss of balance, wide-based stance and gait, truncal instability, and mild leg ataxia (vermian cerebellar syndrome), with absent upper limb dysmetria but with postural tremor, downbeat nystagmus, and dysarthria. In 4-5 years, spinal cord manifestations of TSP developed, including spastic paraparesis, pyramidal signs, bladder and sphincter disturbances. Two patients were infected with HTLV-I and another one, a Guaymi Amerindian woman, with HTLV-II. Magnetic resonance imaging (MRI) demonstrated cerebellar atrophy involving predominantly the superior vermis. Mild axonal peripheral neuropathy in the lower limbs, dorsal column involvement and inflammatory myopathy were found by neurophysiology studies. There are 14 similar cases reported in Japan and Canada, but to our knowledge these are the first documented cases of HSCS in the tropics. A cerebellar syndrome constitutes another form of presentation of HTLV-I/II infection of the nervous system. C1 Gorgas Mem Lab, Div Epidemiol, Panama City, Panama. NINDS, Neuroepidemiol Branch, NIH, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, Dept Med, Div Neurol, San Antonio, TX 78284 USA. NCI, Viral Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Viral Exanthems & Herpesvirus Branch, Atlanta, GA USA. Ctr Dis Control & Prevent, Retrovirus Dis Branch, Div Viral & Rickettsial Dis, Ctr Infect Dis, Atlanta, GA USA. RP Roman, GC (reprint author), POB 460746, San Antonio, TX 78246 USA. NR 54 TC 17 Z9 17 U1 0 U2 1 PU MUNKSGAARD INT PUBL LTD 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 JUN PY 2000 VL 101 IS 6 BP 405 EP 412 DI 10.1034/j.1600-0404.2000.80180.x PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 319HP UT WOS:000087335700009 PM 10877159 ER PT J AU Fournier, JG Kopp, N Streichenberger, N Escaig-Haye, F Langeveld, J Brown, P AF Fournier, JG Kopp, N Streichenberger, N Escaig-Haye, F Langeveld, J Brown, P TI Electron microsocopy of brain amyloid plaques from a patient with new variant Creutzfeldt-Jakob disease SO ACTA NEUROPATHOLOGICA LA English DT Article DE biopsy; new variant Creutzfeldt-Jakob disease immunoelectron microscopy; amyloid plaques; dystrophic neurites ID AGENT; NEUROPATHOLOGY; SCRAPIE; STRAIN; CJD AB Cerebral cortex biopsy from a patient with new variant Creutzfeldt-Jakob disease (nvCJD) has been examined at the electron microscope level. Spongiform changes corresponded mostly to distended neurites scattered in the neuropil or surrounding amyloid plaques. These latter exhibited heterogeneous submicroscopic morphology including variable amount of loosely interwoven amyloid fibrils admired in a cellular-rich environment constituted essentially by abnormal neuronal processes. By immunoelectron microscopy, fibrils and some membrane structures reacted with anti-prion protein (PrP) antibodies. One striking aspect was the presence of many small dystrophic neurites without paired helical filaments. Moreover, amyloid fibrils showed unexpected intimate association with abnormal membranes, suggesting a relationship between PrP fibrillogenesis and membrane alteration. These ultrastructural findings provide an additional criterion to distinguish nvCJD- from sporadic CJD-type plaques and reinforce the hypothesis that nvCJD brain is infected by a distinctive strain of the transmissible agent encephalopathy. C1 Hop La Pitie Salpetriere, Inst Myol, INSERM, U523, F-75651 Paris 13, France. Hop Neurol, Neuropathol Lab, F-69394 Lyon, France. Inst Anim Sci & Hlth ID DLO, NL-8200 Lelystad, Netherlands. NINDS, Lab Cent Nervous Syst Studies, NIH, Bethesda, MD 20892 USA. RP Fournier, JG (reprint author), Hop La Pitie Salpetriere, Inst Myol, INSERM, U523, 47 Blvd Hop, F-75651 Paris 13, France. NR 12 TC 12 Z9 12 U1 0 U2 1 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0001-6322 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD JUN PY 2000 VL 99 IS 6 BP 637 EP 642 PG 6 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 320YW UT WOS:000087429000006 PM 10867797 ER PT J AU Sookkumnerd, T Hsu, JT Ito, Y AF Sookkumnerd, T Hsu, JT Ito, Y TI Gradient formation in membrane unit for differential precipitation of proteins SO AICHE JOURNAL LA English DT Article; Proceedings Paper CT AIChE 99 Meeting CY 1999 CL DALLAS, TEXAS SP AIChE ID AMMONIUM-SULFATE AB A new protein fractionation technique presented transfers ammonium sulfate to create a gradient of ammonium sulfate inside a membrane unit for differential precipitation of proteins called "centrifugal precipitation chromatography. "Because it does not require any solid support, it should provide a better alternative to the conventional chromatography with solid stationary phase. To understand the phenomena and achieve a better separation, a mathematical model explaining the ammonium sulfate gradient formation inside the stationary membrane unit is investigated. The model is extended with empirical correlation to the centrifugal membrane unit-a new approach for protein purification. The model agreed well with the experiments for both stationary and centrifugal units. Upon using the model to calculate the ammonium sulfate gradient formation in a membrane unit, this new technique can be useful in separating a mixture of proteins whose solubility in ammonium sulfate solution differs. To demonstrate the technique experimentally, mixtures of proteins are loaded into the column; the partial resolution between proteins is achieved with the step concentration switch of the inlet ammonium sulfate solution. C1 Lehigh Univ, Dept Chem Engn, Biopharmaceut Technol Inst, Bethlehem, PA 18015 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Hsu, JT (reprint author), Lehigh Univ, Dept Chem Engn, Biopharmaceut Technol Inst, Bethlehem, PA 18015 USA. NR 20 TC 6 Z9 6 U1 2 U2 4 PU AMER INST CHEMICAL ENGINEERS PI NEW YORK PA 3 PARK AVE, NEW YORK, NY 10016-5901 USA SN 0001-1541 J9 AICHE J JI AICHE J. PD JUN PY 2000 VL 46 IS 6 BP 1191 EP 1200 DI 10.1002/aic.690460611 PG 10 WC Engineering, Chemical SC Engineering GA 325GR UT WOS:000087668300010 ER PT J AU Vanakoski, J Mazzanti, C Naukkarinen, H Virkkunen, M Goldman, D AF Vanakoski, J Mazzanti, C Naukkarinen, H Virkkunen, M Goldman, D TI An abundant proneurotensin polymorphism, 479A > G, and a test of its association with alcohol dependence in a Finnish population SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE proneurotensin; dopamine; polymorphism; alcohol dependence ID CENTRAL-NERVOUS-SYSTEM; QUANTITATIVE TRAIT LOCI; NEUROMEDIN-N; NEUROTENSIN MEASURES; ETHANOL-CONSUMPTION; HUMAN-BRAIN; GENE; EXPRESSION; MECHANISMS; SEQUENCES AB Background: Neurotensin is a 13-amino acid neuropeptide that endogenously modulates dopamine release in the central nervous system. In substance dependence, the mesolimbic dopamine system has been postulated to be a central structure that mediates rewarding and reinforcing effects. Neurotensin receptors in the neurons of the ventral tegmental area facilitate dopamine release, making the neurotensin gene an excellent candidate gene for alcohol dependence and for other behaviors that involve reinforcement. Methods: A total of 639 psychiatrically interviewed Finns were genotyped for proneurotensin 479A>G polymorphism. We used the polymorphism as a marker to study the association between proneurotensin gene and alcohol dependence by comparing 229 unrelated Finnish healthy controls to 134 unrelated alcohol-dependent (DSM-III-R criteria) subjects who were also criminal offenders. In addition, 276 relatives of the alcohol-dependent and control subjects were genotyped. Results: The frequencies of the genotypes in the whole sample (n = 639) were 0.84 for 479A/A, 0.16 for 479A/G, and 0.003 for 479G/G. The frequency of the rarer 4796 allele was 0.07 and 0.06 in controls and alcohol-dependent subjects, respectively, and this difference was not statistically significant (chi(2) = 0.264, df = 1,p = 0.61, controls vs. alcohol-dependent subjects). Conclusions: The results of the comparison between psychiatrically interviewed controls and alcoholics from a relatively well defined population indicate that the proneurotensin 479A>G polymorphism is not strongly associated with alcohol dependence. The results do not rule out a role for this gene in the pathogenesis of alcoholism or in differential vulnerability. C1 NIAAA, NIH, DICBR, LNG, Rockville, MD 20852 USA. Univ Helsinki, Dept Pharmacol & Toxicol, FIN-00170 Helsinki, Finland. Univ Helsinki, Dept Psychiat, FIN-00170 Helsinki, Finland. RP Vanakoski, J (reprint author), NIAAA, NIH, DICBR, LNG, 12420 Parklawn Dr,Pk 5 Bldg,Room 451,MSC 8110, Rockville, MD 20852 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 23 TC 4 Z9 4 U1 0 U2 0 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 JUN PY 2000 VL 24 IS 6 BP 762 EP 765 DI 10.1111/j.1530-0277.2000.tb02053.x PG 4 WC Substance Abuse SC Substance Abuse GA 326VE UT WOS:000087757000003 PM 10888062 ER PT J AU Goldberg, AE Newlin, DB AF Goldberg, AE Newlin, DB TI Season of birth and substance abuse: Findings from a large national sample SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE season of birth; substance abuse; epidemiologic survey; alcoholism ID BIPOLAR DISORDER; SCHIZOPHRENIA; ALCOHOLISM; TYPOLOGY; RISK; DEPENDENCE; EXPOSURE; PLACE AB Background: Season of birth is a putative etiological factor for several psychiatric illnesses. An excess of late winter and early spring births has been demonstrated repeatedly for schizophrenia, which has usually been interpreted as the result of prenatal or infant exposure to seasonally mediated "harmful effects," such as infectious diseases. This study determined whether the seasonal birth rates of substance abusers differed from those of unaffected control groups. Methods: The 1992 National Longitudinal Alcohol Epidemiologic Survey, an interview-based study of 42,862 men and women, provided data to assess the association between quarter year of birth and lifetime diagnoses of substance abuse. Results: Logistic regression revealed decreases in winter births in men with histories of alcohol dependence. The significant interaction of sex with season of birth reflected an excess of fail births among male but not female alcoholics. In contrast, there was no evidence of seasonality of birth among alcohol abusers. Men and women with histories of illicit drug use had excesses of fall birth. Discussion: Birth rates of men with past or present alcohol dependence, and of men and women with histories of illicit drug use, implicated seasonal factors in the pathogenesis of substance abuse. The similar birth patterns of illicit drug users and male alcoholics suggest that they may share some common etiological factor, such as seasonal effects on environmental temperature, hormonal function, or susceptibility to viral infection during pregnancy or early infancy. C1 NIDA, IRP, Baltimore, MD 21224 USA. Univ Massachusetts, Amherst, MA 01003 USA. RP Newlin, DB (reprint author), NIDA, IRP, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 33 TC 9 Z9 9 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2000 VL 24 IS 6 BP 774 EP 780 PG 7 WC Substance Abuse SC Substance Abuse GA 326VE UT WOS:000087757000005 PM 10888064 ER PT J AU Menninger, JA Baron, AE Conigrave, KM Whitfield, JB Saunders, JB Helander, A Eriksson, CJP Grant, B Hoffman, PL Tabakoff, B AF Menninger, JA Baron, AE Conigrave, KM Whitfield, JB Saunders, JB Helander, A Eriksson, CJP Grant, B Hoffman, PL Tabakoff, B CA WHO ISBRA Collaborative Study Inve TI Platelet adenylyl cyclase activity as a trait marker of alcohol dependence SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE platelet; adenylyl cyclase; alcohol dependence; abstinence; markers ID CARBOHYDRATE-DEFICIENT TRANSFERRIN; MONOAMINE-OXIDASE ACTIVITY; FAMILY HISTORY; ABSTINENT ALCOHOLICS; USE DISORDER; ESTERASE-D; CONSUMPTION; LINKAGE; PROTEIN; LYMPHOCYTES AB Background: There is compelling evidence that genetic factors play a major role in the development of alcohol dependence. Platelet adenylyl cyclase (AC) activity has been proposed as a biochemical marker for differentiating alcohol-dependent and nondependent subjects, but the sensitivity and specificity of this marker have not been ascertained. The objective of this study was to determine the sensitivity and specificity of platelet AC activity in identifying alcohol-dependent subjects and to ascertain the effect of medical/psychiatric variables, drinking and smoking history, and age and body weight on AC activity. Methods: The cross-sectional study was conducted from 1995 to 1998. Participants were 210 Australian White men who were community volunteers and alcohol treatment inpatients in Sydney, Australia. There were 41 nondrinkers, 140 drinkers, and 29 men who were entering alcohol treatment. The main outcome measure was platelet AC activity. Classification variables were plasma ethanol, gamma-glutamyltransferase, aspartate aminotransferase, serum carbohydrate-deficient transferrin (CDT), and urinary 5-hydroxytryptophol-hydroxyindoleacetic acid (5-HTOL/5-HIAA) levels, and World Health Organization/International Society for Biomedical Research on Alcoholism Interview Schedule variables, which included alcohol use and dependence criteria. Results: Among subjects who reported abstinence for at least 4 days, both cesium fluoride (CsF)- and forskolin-stimulated platelet AC activities were significantly lower in those with a lifetime history of alcohol dependence compared with those with no such history (p < 0.005 and p < 0.05, respectively). The sensitivity and specificity of CsF-stimulated AC activity to discriminate individuals with a lifetime history of alcohol dependence were 75% and 79%, respectively. Similar values for sensitivity and specificity for CsF-stimulated AC activity were calculated when discriminating current alcohol dependence in the subjects in our sample. Irrespective of the history of alcohol dependence, persons who had consumed alcohol recently (within the last 3-4 days) showed significantly higher mean basal, CsF-stimulated, and forskolin-stimulated AC activity (p < 0.001), as did those who had elevated 5-HTOL/5-HIAA ratios or CDT levels, indicative of recent (heavy) drinking The "normalization" of platelet AC activity to baseline levels after an individual stops drinking may be related to the generation of new platelets during the abstinence period. Conduct disorder and antisocial personality disorder were not associated with low AC activity, but low forskolin-stimulated AC activity was associated with major depression. Conclusions: We found that CsF- and forskolin-stimulated platelet AC activity discriminates between subjects with and without alcohol dependence in a population of subjects who had not consumed significant quantities of ethanol recently. Recent alcohol consumption is a confounding variable that can alter the measured levels of AC activity. Forskolin-stimulated platelet AC activity also may be influenced by a history of major depression. C1 Univ Colorado, Hlth Sci Ctr, Dept Pharmacol, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Dept Psychiat, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Dept Prevent Med & Biometr, Denver, CO 80262 USA. Univ Sydney, Sydney, NSW 2006, Australia. Royal Prince Alfred Hosp, Dept Drug & Alcohol, Sydney, NSW, Australia. Royal Prince Alfred Hosp, Dept Biochem, Sydney, NSW, Australia. Royal Prince Alfred Hosp, Dept Psychol Med, Sydney, NSW, Australia. Natl Publ Hlth Inst, Dept Mental Hlth & Alcohol Res, Helsinki, Finland. NIAAA, Div Biometry & Epidemiol, Rockville, MD 20852 USA. Karolinska Inst, Alcohol & Drug Dependence Unit, Dept Clin Neurosci, Stockholm, Sweden. RP Tabakoff, B (reprint author), Univ Colorado, Hlth Sci Ctr, Dept Pharmacol, 4200 E 9th Ave,Campus Bos C-236, Denver, CO 80262 USA. OI Conigrave, Katherine/0000-0002-6428-1441 NR 51 TC 24 Z9 25 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2000 VL 24 IS 6 BP 810 EP 821 DI 10.1111/j.1530-0277.2000.tb02060.x PG 12 WC Substance Abuse SC Substance Abuse GA 326VE UT WOS:000087757000010 PM 10888069 ER PT J AU Yanovski, JA Diament, AL Sovik, KN Nguyen, TT Li, HZ Sebring, NG Warden, CH AF Yanovski, JA Diament, AL Sovik, KN Nguyen, TT Li, HZ Sebring, NG Warden, CH TI Associations between uncoupling protein 2, body composition, and resting energy expenditure in lean and obese African American, white, and Asian children SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE body mass index; weight; obesity; polymorphism; genetics; childhood ID BROWN ADIPOSE-TISSUE; MESSENGER-RNA EXPRESSION; AUTOSOMAL GENOMIC SCAN; JUVENILE-ONSET OBESITY; LOW-CALORIE DIET; METABOLIC-RATE; PIMA-INDIANS; DNA POLYMORPHISM; WEIGHT-GAIN; MASS INDEX AB Background: Little is known about genes that affect childhood body weight. Objective: The objective of this study was to examine the association between alleles of the mitochondrial uncoupling protein 2 (UCP2) gene and obesity because UCP2 may influence energy expenditure. Design: We related UCP2 genotype to body composition and resting energy expenditure in 105 children aged 6-10 y. Overweight children and nonoverweight children of overweight parents were genotyped for a 45-base pair deletion/insertion (del/ins) in 3'-untranslated region of exon 8 and for an exon 4 C to T transition. Results: Eighty-nine children were genotyped for the exon 8 allele: 50 children had del/del, 33 had del/ins, and 6 had ins/ins. Mean (+/-SD) body mass index (BMI; in kg/m(2)) was greater for children with del/ins (24.1 +/- 5.9) than for children with del/del (20.4 +/- 4.8; P < 0.001), BMI of ins/ins children (23.7 +/- 7.8) was not significantly different from that of del/ins children. A greater BMI in del/ins children was independent of race and sex. Body composition was also different according to UCP2 genotype. All body circumferences and skinfold thicknesses examined were significantly greater in del/ins than in del/del children. Body fat mass as determined by dual-energy X-ray absorptiometry was also greater in del/ins than in del/del children (P < 0.005). For 104 children genotyped at exon 4, no significant differences in BMI or body composition were found among the 3 exon 4 genotypes, Neither resting energy expenditure nor respiratory quotient were different according to UCP2 exon 4 or exon 8 genotype, Conclusions: The exon 8 ins/del polymorphism of UCP2 appears to be associated with childhood-onset obesity, The UCP2/UCP3 genetic locus may play a role in childhood body weight. C1 NIH, Warren Grant Magnuson Clin Ctr, Div Nutr Res Coordinat, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Nutr, Bethesda, MD 20892 USA. NICHHD, Dev Endocrinol Branch, Unit Growth & Obes, Bethesda, MD 20892 USA. Univ Calif Davis, Rowe Program Genet, Davis, CA 95616 USA. Univ Calif Davis, Dept Pediat, Davis, CA 95616 USA. RP Yanovski, JA (reprint author), NIH, Warren Grant Magnuson Clin Ctr, Div Nutr Res Coordinat, 10 Ctr Dr MSC 1862,Bldg 10,Room 10N262, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 HD000641-12, Z99 HD999999]; NHLBI NIH HHS [HL35773]; NICHD NIH HHS [Z01 HD000641, HD00641]; NIDDK NIH HHS [DK52581, R01 DK052581] NR 50 TC 63 Z9 70 U1 1 U2 3 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUN PY 2000 VL 71 IS 6 BP 1405 EP 1412 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 320XN UT WOS:000087426300007 PM 10837279 ER PT J AU Thompson, FE Kipnis, V Subar, AF Krebs-Smith, SM Kahle, LL Midthune, D Potischman, N Schatzkin, A AF Thompson, FE Kipnis, V Subar, AF Krebs-Smith, SM Kahle, LL Midthune, D Potischman, N Schatzkin, A TI Evaluation of 2 brief instruments and a food-frequency questionnaire to estimate daily number of servings of fruit and vegetables SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT 3rd International Conference on Diet Assessment Methods CY MAY, 1998 CL ARNHEM, NETHERLANDS DE diet; epidemiologic methods; surveillance; validation study; data collection; questionnaires; screener; food-frequency; questionnaire; epidemiology; nutrition; nutritional epidemiology; NIH-AARP Diet and Health Study ID CANCER PREVENTION; DIETARY-INTAKE; ENERGY-INTAKE; CONSUMPTION; HEALTH; ADULTS AB Background: Measurement of fruit and vegetable intake is important in the surveillance of populations and in epidemiologic studies that examine the relations between diet and disease. Some situations require the use of brief dietary assessment tools. Objective: Our objective was to evaluate the performance of 2 brief dietary assessment instruments, a 7-item standard screener and a new 16-item screener, and a complete food-frequency questionnaire (FFQ) in measuring total fruit and vegetable consumption. Design: About 800 men and women from the National Institutes of Health-AARP Diet and Health Study completed an FFQ, 1 of the 2 screeners, and two 24-h dietary recalls. Fruit and vegetable intakes as measured by each screener and the FFQ were compared with estimated true usual intake by using a measurement-error model. Results: Median daily servings of fruit and vegetables were underestimated by both screeners. The estimated agreement between true intake and the screener was higher for the new screener than for the standard screener and was higher for women than for men. The estimated agreement between true intake and the FFQ was higher than that for both screeners. Attenuation coefficients for the FFQ and screeners were comparable. Conclusions: For estimating median intakes of fruit and vegetables and the prevalence of recommended intakes being met, the use of screeners without appropriate adjustment is suboptimal. For estimating relative risks in the relations between fruit and vegetable intake and disease, screeners and this FFQ are similar in performance. C1 NCI, Div Canc Control & Populat Sci, Appl Res Program, Risk Factor Surveillance & Methodol Branch, Bethesda, MD 20892 USA. Informat Management Serv Inc, Silver Spring, MD USA. RP Thompson, FE (reprint author), NCI, Div Canc Control & Populat Sci, Appl Res Program, Risk Factor Surveillance & Methodol Branch, EPN 4016,6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. NR 29 TC 124 Z9 125 U1 4 U2 16 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUN PY 2000 VL 71 IS 6 BP 1503 EP 1510 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 320XN UT WOS:000087426300019 PM 10837291 ER PT J AU Dwyer, J Roberfroid, MB Crowell, JA Green, GM Meydani, M Craig, L Marriott, BM Milner, JA Hathcock, JN Bistrian, BR AF Dwyer, J Roberfroid, MB Crowell, JA Green, GM Meydani, M Craig, L Marriott, BM Milner, JA Hathcock, JN Bistrian, BR TI Physiologically active food components: Their role in optimizing health and aging - Discussion 1 SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Editorial Material ID PERICONCEPTIONAL VITAMIN SUPPLEMENTATION; NEURAL-TUBE DEFECTS; ALPHA-TOCOPHEROL; PREVENTION C1 Tufts Univ, Sch Med, New England Med Ctr Hosp, Boston, MA 02111 USA. Tufts Univ, Sch Nutr, New England Med Ctr Hosp, Boston, MA 02111 USA. Univ Catholique Louvain, Dept Pharmaceut Sci, B-1200 Brussels, Belgium. NCI, Chemoprevent Branch, Rockville, MD USA. Univ Texas, Hlth Sci Ctr, Dept Physiol, San Antonio, TX 78284 USA. Tufts Univ, USDA, Human Nutr Res Ctr Aging, Vasc Biol Program, Boston, MA 02111 USA. Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Pittsburgh, PA USA. No Arizona Univ, Dept Biol Sci, Flagstaff, AZ 86011 USA. Penn State Univ, Dept Nutr, University Pk, PA 16802 USA. Council Responsible Nutr, Washington, DC USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA USA. RP Dwyer, J (reprint author), Tufts Univ, Sch Med, New England Med Ctr Hosp, Boston, MA 02111 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUN PY 2000 VL 71 IS 6 SU S BP 1674S EP 1675S PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 321NW UT WOS:000087462400006 ER PT J AU Hecker, AL Beck, MA Bistrian, BR Milner, JA Hathcock, JN Field, CJ Crowell, JA AF Hecker, AL Beck, MA Bistrian, BR Milner, JA Hathcock, JN Field, CJ Crowell, JA TI Physiologically active food components: Their role in optimizing health and aging - Discussion 2 SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Editorial Material C1 Univ N Carolina, Chapel Hill, NC 27514 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA USA. Penn State Univ, Dept Nutr, University Pk, PA 16802 USA. Council Responsible Nutr, Nutr & Regulatory Sci, Washington, DC USA. Univ Alberta, Dept Agr Food & Nutr Sci, Edmonton, AB, Canada. NCI, Chemoprevent Branch, Rockville, MD USA. RP Hecker, AL (reprint author), Univ N Carolina, Chapel Hill, NC 27514 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUN PY 2000 VL 71 IS 6 SU S BP 1680S EP 1681S PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 321NW UT WOS:000087462400008 ER PT J AU Roberfroid, MB Arab, L Meydani, M Dwyer, J Green, GM Crowell Milner, JA Weisburger, JH AF Roberfroid, MB Arab, L Meydani, M Dwyer, J Green, GM Crowell Milner, JA Weisburger, JH TI Physiologically active food components: Their role in optimizing health and aging - Discussion 3 SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Editorial Material ID ADIPOSE-TISSUE; PLASMA; SERUM C1 Univ Catholique Louvain, Dept Pharmaceut Sci, B-1200 Brussels, Belgium. Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. Tufts Univ, USDA, Human Nutr Res Ctr Aging, Vasc Biol Program, Boston, MA 02111 USA. Tufts Univ, Sch Med, New England Med Ctr Hosp, Boston, MA 02111 USA. Tufts Univ, Sch Nutr, New England Med Ctr Hosp, Boston, MA 02111 USA. Univ Texas, Hlth Sci Ctr, Dept Physiol, San Antonio, TX 78284 USA. NCI, Chemoprevent Branch, Rockville, MD USA. Penn State Univ, Dept Nutr, University Pk, PA 16802 USA. Amer Hlth Fdn, Valhalla, NY 10595 USA. RP Roberfroid, MB (reprint author), Univ Catholique Louvain, Dept Pharmaceut Sci, B-1200 Brussels, Belgium. NR 7 TC 2 Z9 3 U1 0 U2 0 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUN PY 2000 VL 71 IS 6 SU S BP 1696S EP 1697S PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 321NW UT WOS:000087462400012 ER PT J AU Arab, L Mukhtar, H Watson, RR Milner, JA Weisburger, JH Meydani, M Beck, MA Crowell Green, GM Dwyer, J AF Arab, L Mukhtar, H Watson, RR Milner, JA Weisburger, JH Meydani, M Beck, MA Crowell Green, GM Dwyer, J TI Physiologically active food components: Their role in optimizing health and aging - Discussion 4 SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Editorial Material C1 Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC 27514 USA. Case Western Reserve Univ, Dept Dermatol, Cleveland, OH 44106 USA. Univ Arizona, Arizona Prevent Ctr, Tucson, AZ USA. Penn State Univ, Dept Nutr, University Pk, PA 16802 USA. Amer Hlth Fdn, Valhalla, NY 10595 USA. Tufts Univ, USDA, Human Nutr Res Ctr Aging, Vasc Biol Program, Boston, MA 02111 USA. NCI, Chemoprevent Branch, Rockville, MD USA. Univ Texas, Hlth Sci Ctr, Dept Physiol, San Antonio, TX 78284 USA. Tufts Univ, Sch Med, New England Med Ctr Hosp, Boston, MA 02111 USA. Tufts Univ, Sch Nutr, New England Med Ctr Hosp, Boston, MA 02111 USA. RP Arab, L (reprint author), Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC 27514 USA. NR 2 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUN PY 2000 VL 71 IS 6 SU S BP 1703S EP 1704S PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 321NW UT WOS:000087462400014 ER PT J AU Watson, RR Lamartiniere, CA Weisburger, JH Milner, JA Dwyer, J Crowell Hecker, AL AF Watson, RR Lamartiniere, CA Weisburger, JH Milner, JA Dwyer, J Crowell Hecker, AL TI Physiologically active food components: Their role in optimizing health and aging - Discussion 5 SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Editorial Material C1 Univ Arizona, Arizona Prevent Ctr, Tucson, AZ 85721 USA. Univ Alabama, Ctr Comprehens Canc, Grad Training Program Toxicol, Birmingham, AL 35294 USA. Amer Hlth Fdn, Valhalla, NY 10595 USA. Penn State Univ, Dept Nutr, University Pk, PA 16802 USA. Tufts Univ, New England Med Ctr Hosp, Sch Med, Boston, MA 02111 USA. Tufts Univ, New England Med Ctr Hosp, Sch Nutr, Boston, MA 02111 USA. NCI, Chemoprevent Branch, Rockville, MD USA. RP Watson, RR (reprint author), Univ Arizona, Arizona Prevent Ctr, Tucson, AZ 85721 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUN PY 2000 VL 71 IS 6 SU S BP 1708S EP 1709S PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 321NW UT WOS:000087462400016 ER PT J AU Zheng, TZ Holford, TR Mayne, ST Owens, PH Zhang, B Boyle, P Carter, D Ward, B Zhang, YW Zahm, SH AF Zheng, TZ Holford, TR Mayne, ST Owens, PH Zhang, B Boyle, P Carter, D Ward, B Zhang, YW Zahm, SH TI Exposure to electromagnetic fields from use of electric blankets and other in-home electrical appliances and breast cancer risk SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE breast neoplasms; case-control studies; electromagnetic fields ID FREQUENCY MAGNETIC-FIELDS; POWER; HYPOTHESIS; MELATONIN; LEUKEMIA; WOMEN AB Exposure to electromagnetic fields (EMFs) from use of electric blankets and other in-home electrical appliances has been hypothesized to increase breast cancer risk. To test the hypothesis, the authors analyzed data from a case-control study of female breast cancer conducted in Connecticut in 1994-1997, A total of 608 incident breast cancer patients and 609 age frequency-matched controls, 31-85 years old, were interviewed by trained study interviewers using a standardized, structured questionnaire to obtain information on lifetime use of various in-home electrical appliances. A total of 40% of the cases and 43% of the controls reported regular use of electric blankets in their lifetime, which gave an adjusted odds ratio of 0.9 (95% confidence interval (CI): 0.7, 1.1). For those who reported using electric blankets continuously throughout the night, the adjusted odds ratio was 0.9 (95% CI: 0.7, 1.2) when compared with never users. The risk did not vary according to age at first use, duration of use, or menopausal and estrogen receptor status. The authors also did not find an association between use of other major in-home electrical appliances and breast cancer risk. In conclusion, exposure to EMFs from in-home electrical appliance use was not found to increase breast cancer risk in this study. C1 Yale Univ, Sch Med, New Haven, CT USA. Yale Canc Ctr, New Haven, CT USA. McGill Univ, Montreal, PQ, Canada. European Inst Oncol, Milan, Italy. NCI, Bethesda, MD 20892 USA. RP Zheng, TZ (reprint author), 129 Church St,Suite 700, New Haven, CT 06510 USA. RI Boyle, Peter/A-4380-2014; Zahm, Shelia/B-5025-2015 OI Boyle, Peter/0000-0001-6251-0610; FU NCI NIH HHS [CA-62986] NR 39 TC 29 Z9 32 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 JUN 1 PY 2000 VL 151 IS 11 BP 1103 EP 1111 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 320EZ UT WOS:000087390000010 PM 10873135 ER PT J AU Biggar, RJ AF Biggar, RJ TI Re: "Sex ratios, family size, and birth order" - Reply SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter C1 NCI, Viral Epidemiol Branch, Bethesda, MD 20852 USA. RP Biggar, RJ (reprint author), NCI, Viral Epidemiol Branch, Bethesda, MD 20852 USA. NR 2 TC 0 Z9 0 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 JUN 1 PY 2000 VL 151 IS 11 BP 1134 EP 1134 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 320EZ UT WOS:000087390000015 ER PT J AU Bai, Y Goldstein, A Khoury, MJ Flanders, WD AF Bai, Y Goldstein, A Khoury, MJ Flanders, WD TI A new approach to apply family history in case-control studies. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Genet Epidemiol Branch, DCEG, NIH, Rockville, MD 20852 USA. NR 0 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 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2000 VL 151 IS 11 SU S MA 178 BP S45 EP S45 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 321MZ UT WOS:000087460400180 ER PT J AU Bai, Y Goldstein, A Khoury, MJ Flanders, WD AF Bai, Y Goldstein, A Khoury, MJ Flanders, WD TI An interesting issue in genetic epidemiology: Family history definition and its effect on the measure of environmental factors when it is treated as a confounder. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Genet Epidemiol Branch, DCEG, NIH, Rockville, MD 20852 USA. NR 0 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 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2000 VL 151 IS 11 SU S MA 177 BP S45 EP S45 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 321MZ UT WOS:000087460400178 ER PT J AU Baris, D Garrity, TJ Telles, JL Heineman, EF Olshan, A Zahm, SH AF Baris, D Garrity, TJ Telles, JL Heineman, EF Olshan, A Zahm, SH TI A cohort mortality study of Philadelphia firefighters. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. RI Zahm, Shelia/B-5025-2015 NR 0 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 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2000 VL 151 IS 11 SU S MA 335 BP S84 EP S84 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 321MZ UT WOS:000087460400334 ER PT J AU Bromley, CM Goldstein, AM Elder, DE Holly, EA Guerry, D Hartge, P Lassam, N Hogg, D Halpern, A Sagebiel, RW Tucker, MA AF Bromley, CM Goldstein, AM Elder, DE Holly, EA Guerry, D Hartge, P Lassam, N Hogg, D Halpern, A Sagebiel, RW Tucker, MA TI Heterogeneity of risk for melanoma with pancreatic cancer and digestive cancers. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. RI Tucker, Margaret/B-4297-2015 NR 0 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 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2000 VL 151 IS 11 SU S MA 99 BP S25 EP S25 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 321MZ UT WOS:000087460400099 ER PT J AU Chen, HL Tucker, KL Heineman, EF Graubard, BI Potischman, NA Russell, BM McComb, R Weisenburger, DD Ward, MH AF Chen, HL Tucker, KL Heineman, EF Graubard, BI Potischman, NA Russell, BM McComb, R Weisenburger, DD Ward, MH TI Diet and adult glioma. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. RI Tucker, Katherine/A-4545-2010 NR 0 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 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2000 VL 151 IS 11 SU S MA 239 BP S60 EP S60 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 321MZ UT WOS:000087460400238 ER PT J AU Chow, WH Gridley, G Fraumeni, JF Jarvholm, B AF Chow, WH Gridley, G Fraumeni, JF Jarvholm, B TI Obesity, hypertension, and kidney cancer risks in a large cohort study. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2000 VL 151 IS 11 SU S MA 301 BP S76 EP S76 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 321MZ UT WOS:000087460400301 ER PT J AU Colbert, LH Pietinen, P Virtamo, J Taylor, PR Albanes, D AF Colbert, LH Pietinen, P Virtamo, J Taylor, PR Albanes, D TI Physical activity and colorectal cancer risk in a cohort of Finnish men. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. RI Albanes, Demetrius/B-9749-2015 NR 0 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 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2000 VL 151 IS 11 SU S MA 80 BP S20 EP S20 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 321MZ UT WOS:000087460400081 ER PT J AU Flood, A Velie, EM Lacey, JV Schairer, C Schatzkin, A AF Flood, A Velie, EM Lacey, JV Schairer, C Schatzkin, A TI The association of dietary fruits and vegetables with colorectal cancer risk in a prospective cohort of women: The breast cancer detection demonstration project follow-up study. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 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 JUN 1 PY 2000 VL 151 IS 11 SU S MA 312 BP S78 EP S78 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 321MZ UT WOS:000087460400312 ER PT J AU Gray, K Longnecker, M Klebanoff, M Brock, J Zhou, H Needham, L AF Gray, K Longnecker, M Klebanoff, M Brock, J Zhou, H Needham, L TI In utero exposure to background levels of polychlorinated biphenyls and cognitive functioning among school-aged children. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 1 Z9 1 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 JUN 1 PY 2000 VL 151 IS 11 SU S MA 93 BP S24 EP S24 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 321MZ UT WOS:000087460400094 ER PT J AU Gridley, G Moradi, T Dosemeci, M Adami, HO Bath, H Nyren, O Zahm, SH AF Gridley, G Moradi, T Dosemeci, M Adami, HO Bath, H Nyren, O Zahm, SH TI Healthy worker effect among employed Swedish men and women: Cancer incidence and mortality SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RI Zahm, Shelia/B-5025-2015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2000 VL 151 IS 11 SU S MA 329 BP S83 EP S83 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 321MZ UT WOS:000087460400329 ER PT J AU Groves, FD Gridley, G Wacholder, S Shu, XO Robison, LL Neglia, JP Linet, MS AF Groves, FD Gridley, G Wacholder, S Shu, XO Robison, LL Neglia, JP Linet, MS TI Infant vaccinations and risk of childhood acute lymphoblastic leukemia in the United States. SO AMERICAN JOURNAL OF EPIDEMIOLOGY 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 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 JUN 1 PY 2000 VL 151 IS 11 SU S MA 113 BP S29 EP S29 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 321MZ UT WOS:000087460400114 ER PT J AU Hoffman, HJ Ko, CW MacTurk, RH Sklare, DA Chiu, MS Cosgrove, CM AF Hoffman, HJ Ko, CW MacTurk, RH Sklare, DA Chiu, MS Cosgrove, CM TI Aging and chronic problems with balance and dizziness based on the 1994/1995 disability supplement(DS). SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NIDCD, NIH, Bethesda, MD 20892 USA. NR 0 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 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2000 VL 151 IS 11 SU S MA 346 BP S87 EP S87 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 321MZ UT WOS:000087460400347 ER PT J AU Hoppin, JA Sandler, DP Alavanja, M AF Hoppin, JA Sandler, DP Alavanja, M TI Predictors of wheeze among farmers in the Agricultural Health Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 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 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2000 VL 151 IS 11 SU S MA 87 BP S22 EP S22 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 321MZ UT WOS:000087460400087 ER PT J AU Marcus, P Rothman, N Caporaso, N AF Marcus, P Rothman, N Caporaso, N TI CYP2D6 (debrisoquine metabolism) and lung cancer histology SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 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 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2000 VL 151 IS 11 SU S MA 100 BP S25 EP S25 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 321MZ UT WOS:000087460400101 ER PT J AU Parks, CG Cooper, GS Nylander-French, LA Savitz, DA AF Parks, CG Cooper, GS Nylander-French, LA Savitz, DA TI A population-based study of occupational exposure to crystalline silica and systemic lupus erythematosus. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 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 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2000 VL 151 IS 11 SU S MA 328 BP S82 EP S82 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 321MZ UT WOS:000087460400328 ER PT J AU Rooks, RN Simonsick, E Newman, A Kritchevsky, S Rubin, S Schulz, R Harris, T AF Rooks, RN Simonsick, E Newman, A Kritchevsky, S Rubin, S Schulz, R Harris, T TI Race, SES, and psychological correlates of objective cardiovascular measures in the health, aging, and body composition study. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NIA, Bethesda, MD 20892 USA. RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 NR 0 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 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2000 VL 151 IS 11 SU S MA 213 BP S54 EP S54 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 321MZ UT WOS:000087460400213 ER PT J AU Rowland, AS Stallone, L Bohlig, EM Sandler, DP AF Rowland, AS Stallone, L Bohlig, EM Sandler, DP TI Prevalence of stimulant medication treatment for attention-deficit/hyperactivity disorder (ADHD) among elementary school children SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 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 JUN 1 PY 2000 VL 151 IS 11 SU S MA 282 BP S71 EP S71 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 321MZ UT WOS:000087460400283 ER PT J AU Samanic, C Chow, WH Gridley, G Fraumeni, JF AF Samanic, C Chow, WH Gridley, G Fraumeni, JF TI Obesity and gastrointestinal cancer risk among white and black US veterans. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 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 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2000 VL 151 IS 11 SU S MA 79 BP S20 EP S20 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 321MZ UT WOS:000087460400079 ER PT J AU Stolzenberg-Solomon, RZ Limburg, PJ Blaser, MJ Perez-Perez, G Taylor, PR Virtamo, J Albanes, D AF Stolzenberg-Solomon, RZ Limburg, PJ Blaser, MJ Perez-Perez, G Taylor, PR Virtamo, J Albanes, D TI Helicobacter pylori seropositivity and exocrine pancreatic cancer: A nested case-control study in male smokers. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. RI Albanes, Demetrius/B-9749-2015 NR 0 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 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2000 VL 151 IS 11 SU S MA 307 BP S77 EP S77 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 321MZ UT WOS:000087460400306 ER PT J AU Weed, DL AF Weed, DL TI Epidemiology, beneficence, and the precautionary principle. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 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 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2000 VL 151 IS 11 SU S MA 359 BP S90 EP S90 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 321MZ UT WOS:000087460400358 ER PT J AU Wilcox, AJ AF Wilcox, AJ TI Perspectives on the study of early human pregnancy. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. NR 0 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 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2000 VL 151 IS 11 SU S MA 194 BP S49 EP S49 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 321MZ UT WOS:000087460400195 ER PT J AU Schechter, AN AF Schechter, AN TI Titus H.J. Huisman, MD, Ph.D. - Obituary SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Biographical-Item C1 NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. RP Schechter, AN (reprint author), NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD JUN PY 2000 VL 64 IS 2 BP 85 EP 86 DI 10.1002/(SICI)1096-8652(200006)64:2<85::AID-AJH1>3.0.CO;2-K PG 2 WC Hematology SC Hematology GA 315PW UT WOS:000087123000001 ER PT J AU Stone, DL Ginns, EI Krasnewich, D Sidransky, E AF Stone, DL Ginns, EI Krasnewich, D Sidransky, E TI Life-threatening splenic hemorrhage in two patients with Gaucher disease SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article DE glucocerebrosidase; Gaucher disease; splenectomy; splenic hemorrhage AB Massive splenomegaly is a frequent finding in patients with Gaucher disease, the most common of the sphingolipidoses. Even so, the risk for splenic rupture and intracapsular hemorrhage has not been emphasized due to the rarity of this occurrence and the fibrotic, rubbery consistency of splenic tissue In these patients. We report two adult patients with type 1 Gaucher disease who suffered life-threatening splenic bleeds that were not acutely diagnosed. Both patients ultimately required emergent splenectomies. Factors complicating the diagnosis of splenic hemorrhage in patients with Gaucher disease are discussed. Am. J, Hematol, 64:140-142 2000, Published 2000 Wiley-Liss, Inc.dagger. C1 NIMH, Clin Neurosci Branch, NIH, Bethesda, MD 20892 USA. RP Sidransky, E (reprint author), NIMH, Clin Neurosci Branch, NIH, Bldg 49,Room B1EE16,49 Convent Dr,MSC4405, Bethesda, MD 20892 USA. NR 4 TC 4 Z9 4 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 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD JUN PY 2000 VL 64 IS 2 BP 140 EP 142 DI 10.1002/(SICI)1096-8652(200006)64:2<140::AID-AJH14>3.3.CO;2-K PG 3 WC Hematology SC Hematology GA 315PW UT WOS:000087123000014 PM 10814997 ER PT J AU Koprivica, V Stone, DL Park, JK Callahan, M Frisch, A Cohen, IJ Tayebi, N Sidransky, E AF Koprivica, V Stone, DL Park, JK Callahan, M Frisch, A Cohen, IJ Tayebi, N Sidransky, E TI Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID ACID BETA-GLUCOSIDASE; NON-JEWISH PATIENTS; GLUCOCEREBROSIDASE GENE; GENOTYPE/PHENOTYPE CORRELATIONS; PHENOTYPIC VARIATION; MUTATION PROFILE; IDENTIFICATION; EXPRESSION; PSEUDOGENE; DEFICIENCY AB Gaucher disease results from the inherited deficiency of the enzyme glucocerebrosidase (EC 3.2.1.45). Although >100 mutations in the gene for human glucocerebrosidase have been described, most genotype-phenotype studies have focused upon screening for a few common mutations. In this study, we used several approaches-including direct sequencing, Southern blotting, long-template PCR, restriction digestions, and the amplification refraction mutation system (ARMS)-to genotype 128 patients with type 1 Gaucher disease (64 of Ashkenazi Jewish ancestry and 64 of non-Jewish extraction) and 24 patients with type 3 Gaucher disease. More than 97% of the mutant alleles were identified. Fourteen novel mutations (A90T, N117D, T134I, Y135X, R170C, W184R, A190T, Y304X, A341T, D399Y, c.153-154insTACAGC, c.203-204insC, c.222-224delTAC, and c.1122-1123insTG) and many rare mutations were detected. Recombinant alleles were found in 19% of the patients. Although 93% of the mutant alleles in our Ashkenazi Jewish type 1 patients were N370S, c.84-85insG, IVS2+1G-->A or L444P, these four mutations accounted for only 49% of mutant alleles in the non-Jewish type 1 patients. Genotype-phenotype correlations were attempted, Homozygosity or heterozygosity for N370S resulted in type 1 Gaucher disease, whereas homozygosity for L444P was associated with type 3. Genotype L444P/recombinant allele resulted in type 2 Gaucher disease, and homozygosity for a recombinant allele was associated with perinatal lethal disease. The phenotypic consequences of other mutations, particularly R463C, were more inconsistent. Our results demonstrate a high rate of mutation detection, a large number of novel and rare mutations, and an accurate assessment of the prevalence of recombinant alleles, Although some genotype-phenotype correlations do exist, other genetic and environmental factors must also contribute to the phenotypes encountered, and we caution against relying solely upon genotype for prognostic or therapeutic judgements. C1 NIMH, Clin Neurosci Branch, NIH, Bethesda, MD 20892 USA. Tel Aviv Univ, Rabin Med Ctr, Felsenstein Med Res Ctr, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Schneiders Childrens Med Ctr Israel, Rabin Med Ctr, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. RP Sidransky, E (reprint author), NIMH, Clin Neurosci Branch, NIH, Bldg 49,Room B1EE16,49 Convent Dr,MSC4405, Bethesda, MD 20892 USA. RI Cohen, Ian/H-3358-2013 NR 52 TC 161 Z9 171 U1 1 U2 6 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUN PY 2000 VL 66 IS 6 BP 1777 EP 1786 DI 10.1086/302925 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 337QU UT WOS:000088373800006 PM 10796875 ER PT J AU Rose, KM Tyroler, HA Nardo, CJ Arnett, DK Light, KC Rosamond, W Sharrett, AR Szklo, M AF Rose, KM Tyroler, HA Nardo, CJ Arnett, DK Light, KC Rosamond, W Sharrett, AR Szklo, M TI Orthostatic hypotension and the incidence of coronary heart disease: The atherosclerosis risk in communities study SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE orthostatic hypotension; CHD; middle-aged ID SYSTOLIC BLOOD-PRESSURE; POSTURAL HYPOTENSION; PREVALENCE; EXPERIENCE; HYPERTENSION; INFARCTION AB We examined the association between orthostatic hypotension (OH) at baseline examination (1987-1989) and the incidence of coronary heart disease (CHD) over an average of 6 years, among 12,433 black and white middle-aged men and women participating in the Atherosclerosis Risk in Communities (ARIC) study. OH was defined as a SEP decrease greater than or equal to 20 mm Hg or a DBP decrease greater than or equal to 10 mm Hg after changing from supine to standing. CHD events included definite or probable myocardial infarctions (MI), silent MI, and fatal CHD. Five percent of participants had OH. Prevalence increased with advancing age and was more common among those with cardiovascular disease (CVD)-related comorbidities and risk factors. Those with OH had an increased risk of CHD (hazard ratio [HR] = 3.49, 95% confidence interval [CI] = 2.58, 4.73). This association was attenuated after controlling for age, ethnicity, gender, comorbid conditions, and CVD risk factors (HR = 1.85, 95% CI = 1.31, 2.63). Am J Hypertens 2000;13:571-578 (C) 2000 American Journal of Hypertension, Ltd. C1 Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27514 USA. Immune Response Corp, Carlsbad, CA USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. Univ N Carolina, Sch Med, Dept Psychiat, Chapel Hill, NC USA. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Rose, KM (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, 137 E Franklin St,Nat Bank Plaza,Suite 306, Chapel Hill, NC 27514 USA. FU NHLBI NIH HHS [N01-HC-55015, N01-HC-55016, N01-HC-55019] NR 36 TC 122 Z9 131 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD JUN PY 2000 VL 13 IS 6 BP 571 EP 578 DI 10.1016/S0895-7061(99)00257-5 PN 1 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 329XF UT WOS:000087933200001 PM 10912737 ER PT J AU Province, MA Arnett, DK Hunt, SC Leiendecker-Foster, C Eckfeldt, JH Oberman, A Ellison, RC Heiss, G Mockrin, SC Williams, RR AF Province, MA Arnett, DK Hunt, SC Leiendecker-Foster, C Eckfeldt, JH Oberman, A Ellison, RC Heiss, G Mockrin, SC Williams, RR CA HyperGEN Grp TI Association between the alpha-adducin gene and hypertension in the hyperGEN study SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE hypertension; genetic epidemiology; association; regression trees ID BLOOD-PRESSURE; SALT SENSITIVITY; POINT MUTATIONS; PHENOTYPES; POPULATION; KIDNEY; LOCUS; RATS AB This report from the HyperGEN Study, one of four networks participating in the NHLBI-sponsored Family blood Pressure Program, presents the results of an association study based on 822 white and 572 black subjects (cases and controls) participating in the HyperGEN Network from five geographically diverse field centers. All cases met the Joint National Committee on Detection and Treatment of High Blood Pressure (JNC VI) criteria for hypertension (Stage I or higher). Each subject was clinically examined for risk factors for hypertension as well as genotyped for the point mutation Gly460Trp at the alpha-adducin locus on chromosome 4p. In the white group, the prevalence of genotypes with one or more Trp alleles was 26% in normotensives, versus 33% in hypertensives randomly selected from the population, and 39% among the multiply affected hypertensive sibships. Overall, in whites, the Trp allele significantly increased the odds of hypertension (P = .0056), with an odds ratio (OR) of 1.73 (95% confidence interval [CI] = 1.17, 2.54). The alpha-adducin gene remained a significant independent predictor of hypertension in a multivariate logistic model even after correcting for other risk factors for hypertension, including gender, age, body mass index (BMI), smoking, LDL cholesterol, triglycerides, urine sodium (Na), and urine potassium (K), (OR = 1.55, 95% CI = 1.03, 2.34). Through the use of regression trees, several geneby-environment interactions were implicated, suggesting that alpha-adducin appears to be a particularly important risk factor (OR = 4.2) for older (age > 60.5 years), less lean (BMI < 25.8 kg/m(2)) subjects with moderately high triglycerides (between 145.5 and 218.5 mg/dL). In the black group, the relationship was less clear. Overall, it was protective against hypertension. The prevalence of genotypes with one or more Trp alleles was 24% among normotensive versus 11% in hypertensive black subjects randomly selected from the population, and 13% among multiply affected hypertensive sibships, resulting in an OR of 0.48 (P = .0231; 95% CI = 0.25, 0.90). However, the Trp genotype was no longer a significant independent predictor of hypertension risk in the multivariate logistic model (OR = 0.79; 95% CI = 0.37, 1.67), suggesting that it may be operating through one or more of these other factors. Thus, we conclude that the cr-adducin gene is a significant, independent risk factor for hypertension in whites, but not in blacks, and may play a particularly important role for subjects with certain constellations of other risk factors. Am J Hypertens 2000;13:710-718 (C) 2000 American Journal of Hypertension, Ltd. C1 Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. Univ Utah, Sch Med, Cardiovasc Genet Res Clin, Salt Lake City, UT USA. Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. Univ Alabama, Div Prevent Med, Birmingham, AL USA. Boston Univ, Sch Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. NHLBI, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. RP Province, MA (reprint author), Washington Univ, Sch Med, Div Biostat, Box 8067,660 S Euclid, St Louis, MO 63110 USA. FU NHLBI NIH HHS [U10 HL54472, U10 HL54496, U10 HL54473] NR 27 TC 49 Z9 51 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD JUN PY 2000 VL 13 IS 6 BP 710 EP 718 DI 10.1016/S0895-7061(99)00282-4 PN 1 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 329XF UT WOS:000087933200022 PM 10912758 ER PT J AU Kamel, F Boyes, WK Gladen, BC Rowland, AS Alavanja, MCR Blair, A Sandler, DP AF Kamel, F Boyes, WK Gladen, BC Rowland, AS Alavanja, MCR Blair, A Sandler, DP TI Retinal degeneration in licensed pesticide applicators SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE retinal degeneration; fungicides; insecticides; organochlorines; carbamates; organophosphates; application methods ID AGRICULTURAL HEALTH; CARBON-DISULFIDE; VISUAL-SYSTEM; ORGANOPHOSPHATES; EXPOSURE; TOXICITY; WORKERS; COHORT; RATS AB Background Retinal degeneration is the lending cause of visual impairment in older adults, but little is known about its relationship to neurotoxic exposures. Methods The Agricultural Health Study is a cohort study of licensed pesticide applicators from Iowa and North Carolina. We used cross-sectional data from self administered questionnaires given at enrollment in 1994-1996 to compare pesticide use in 154 applicators who reported retinal degeneration and 17,804 controls. Results Retinal degeneration was associated with fungicide use (odds ratio = 1.8, 95% confidence interval = 1.3-2.6). This relationship was seen in subgroups defined by state, demographic characteristics, or medical history, as well as in the entire group. Risk increased with cumulative days of fungicide use (P for trend = 0.011) and was greater when application methods involving greater personal exposure were used. Retinal degeneration was also related to use of organochlorine or carbamate insecticides, but these associations were less consistent. Since nearly all applicators used organophosphate insecticides and herbicides, these exposures could not be effectively evaluated Conclusions These results suggest that exposure to some fungicides and insecticides may increase risk of retinal degeneration. Published 2000 Wiley-Liss, Inc. C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. US EPA, Washington, DC 20460 USA. NCI, Bethesda, MD 20892 USA. RP Kamel, F (reprint author), NIEHS, Epidemiol Branch, POB 12233,MD A3-05, Res Triangle Pk, NC 27709 USA. OI Kamel, Freya/0000-0001-5052-6615; Sandler, Dale/0000-0002-6776-0018 NR 20 TC 22 Z9 23 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 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD JUN PY 2000 VL 37 IS 6 BP 618 EP 628 DI 10.1002/(SICI)1097-0274(200006)37:6<618::AID-AJIM6>3.0.CO;2-E PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 310EA UT WOS:000086812500006 PM 10797505 ER PT J AU Tanawattanacharoen, S Falk, RJ Jennette, JC Kopp, JB AF Tanawattanacharoen, S Falk, RJ Jennette, JC Kopp, JB TI Parvovirus B19 DNA in kidney tissue of patients with focal segmental glomerulosclerosis SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE glomerulosclerosis; parvovirus B19; polymerase chain reaction (PCR); in situ hybridization ID INFECTION; ARTHRITIS; DISEASE; VIRUS AB Focal segmental glomerulosclerosis (FSGS) represents a clinicopathological syndrome with diverse causes. We examined the possibility that some cases of FSGS are associated with parvovirus B19 infection. We studied renal biopsy tissue from 40 patients, including those with idiopathic FSGS, collapsing FSGS, membranous nephropathy, and minimal change disease, as well as normal renal tissue removed at the time of nephrectomy from 4 patients. DNA was extracted from frozen blocks of kidney tissue and amplified using nested polymerase chain reaction. Parvovirus B19 DNA was amplified from 8 of 10 patients with idiopathic FSGS, 9 of 10 patients with collapsing FSGS, 6 of 10 patients with membranous nephropathy, 5 of 10 patients with minimal change disease, and 2 of 4 cancer nephrectomy samples. The prevalence of parvovirus B19 DNA was greater among patients with idiopathic FSGS and collapsing FSGS compared with patients with other diagnoses (P = 0,05), In situ hybridization studies using digoxigenin-labeled DNA probes failed to detect parvovirus B19 nucleic acid in any of the kidney tissue samples. These results suggest that parvovirus B19 DNA is commonly found in the kidneys of patients with a range of renal diagnoses, possibly representing latent DNA from past infection. The failure to localize parvovirus B19 nucleic acid within kidney argues against ongoing, high-level viral replication. Nevertheless, the increased prevalence of B19 DNA in patients with idiopathic FSGS and collapsing FSGS could indicate a pathogenic role for the virus in the cause of FSGS in certain patients. (C) 2000 by the National Kidney Foundation, Inc. C1 NIDDKD, Kidney Dis Sect, Bethesda, MD 20892 USA. Univ N Carolina, Dept Med, Chapel Hill, NC USA. Univ N Carolina, Dept Pathol, Chapel Hill, NC USA. RP Kopp, JB (reprint author), NIDDKD, Kidney Dis Sect, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. OI Kopp, Jeffrey/0000-0001-9052-186X NR 17 TC 72 Z9 79 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUN PY 2000 VL 35 IS 6 BP 1166 EP 1174 DI 10.1016/S0272-6386(00)70055-2 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 323HB UT WOS:000087559100021 PM 10845832 ER PT J AU Kimmel, PL AF Kimmel, PL TI Go to bed and get a good night's sleep: You need your rest! SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Editorial Material ID STAGE RENAL-DISEASE; HEMODIALYSIS-PATIENTS; APNEA SYNDROME; TRANSPLANTATION; DISORDERS; MORTALITY; KIDNEY C1 George Washington Univ, Med Ctr, Div Renal Dis & Hypertens, Washington, DC 20037 USA. NIDDKD, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD USA. RP Kimmel, PL (reprint author), George Washington Univ, Med Ctr, Div Renal Dis & Hypertens, Washington, DC 20037 USA. NR 14 TC 10 Z9 10 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 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUN PY 2000 VL 35 IS 6 BP 1221 EP 1223 DI 10.1016/S0272-6386(00)70062-X PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 323HB UT WOS:000087559100028 PM 10845839 ER PT J AU Maymon, E Romero, R Pacora, P Gervasi, MT Edwin, SS Gomez, R Seubert, DE AF Maymon, E Romero, R Pacora, P Gervasi, MT Edwin, SS Gomez, R Seubert, DE TI Matrilysin (matrix metalloproteinase 7) in parturition, premature rupture of membranes, and intrauterine infection SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 66th Annual Meeting of the Pacific-Coast-Obstetrical-and-Gynecological-Society CY OCT 20-24, 1999 CL CANCUN, MEXICO SP Pacific Coast Obstet & DE intra-amniotic infection; matrilysin; matrix metalloproteinase; preterm labor ID RAT UTERUS; PRETERM; MMP-7; IMPLANTATION; EXPRESSION; CYTOKINE; CLEAVAGE; ALPHA AB OBJECTIVE: Matrix metalloproteinases are enzymes capable of degrading extracellular matrix components. Matrilysin (matrix metalloproteinase 7), a novel member of this family, degrades fibronectin and proteoglycans. The objective of this study was to determine whether parturition (either term or preterm), premature rupture of the membranes, and microbial invasion of the amniotic cavity are associated with changes in the amniotic fluid concentration of matrilysin. STUDY DESIGN: A cross-sectional study was conducted with 275 women in the following categories: (1) second trimester, (2) term not in labor, (3) term in labor, (4) term with microbial invasion of the amniotic cavity, (5) preterm labor with intact membranes without microbial invasion of the amniotic cavity who delivered at term, (6) preterm labor without microbial invasion of the amniotic cavity who delivered preterm, (7) preterm labor with microbial invasion of the amniotic cavity, (8) preterm premature rupture of membranes with and without microbial invasion of the amniotic cavity, and (9) term premature rupture of membranes not in labor and without microbial invasion of the amniotic cavity. Matrilysin concentrations were measured with a sensitive specific immunoassay that was validated for amniotic fluid. RESULTS: Matrilysin was detectable in 97.4% (268/275) of the samples. The concentration of matrilysin increased with advancing gestational age (r = 0.8; P < .001). Parturition at term was not associated with a significant increase in amniotic fluid concentration of matrilysin. Preterm parturition in the absence of microbial invasion of the amniotic cavity was associated with a significant increase in amniotic fluid concentration of matrilysin (preterm labor with preterm delivery: median, 1.7 ng/mL; range, 0.45-21.6 mg/mL; vs preterm labor with term delivery: median, 1,2 ng/mL; range, 0.17-42.1 ng/mL; P < .05). Premature rupture of membranes without microbial invasion of the amniotic cavity (either term or preterm) was not associated with a significant change in the amniotic fluid matrilysin concentration. Intra-amniotic infection was associated with a significant increase in amniotic fluid matrilysin among both patients with preterm labor and patients with preterm premature rupture of membranes (preterm labor with microbial invasion of the amniotic cavity: median, 3.2 ng/mL; range, 0.16-21.9 ng/mL; vs preterm labor and delivery without microbial invasion of the amniotic cavity: median, 1.7 ng/mL; range, 0.45-21.6 ng/mL; vs preterm labor with term delivery: median, 1.2 ng/mL; range, 0.17-42.1 ng/mL; P < .01 for each comparison; and preterm premature rupture of membranes without microbial invasion of the amniotic cavity: median, 1.7 ng/mL; range, 0.29-13.9 ng/mL; vs preterm premature rupture of membranes with microbial invasion of the amniotic cavity: median, 3.6 ng/mL; range, 0.59-20.3 nl/mL; P < .01). CONCLUSION: Matrilysin is a physiologic constituent of amniotic fluid, and its concentration increases with advancing gestational age. Microbial invasion of the amniotic cavity in preterm gestations was associated with a significant increase in amniotic fluid concentration of matrilysin. Matrilysin therefore may play a role in the host defense mechanism. C1 Wayne State Univ, Hutzel Hosp, NICHHD, Perinatol Res Branch,Dept Obstet & Gynecol, Detroit, MI 48201 USA. NICHHD, Perinatol Res Branch, Bethesda, MD 20892 USA. RP Maymon, E (reprint author), Wayne State Univ, Hutzel Hosp, NICHHD, Perinatol Res Branch,Dept Obstet & Gynecol, 4707 St Antoine Blvd, Detroit, MI 48201 USA. NR 29 TC 43 Z9 45 U1 0 U2 1 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JUN PY 2000 VL 182 IS 6 BP 1545 EP 1551 DI 10.1067/mob.2000.107652 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 330XY UT WOS:000087987800095 PM 10871477 ER PT J AU Seubert, DE Maymon, E Pacora, P Gervasi, MT Berry, SM Torry, DS Romero, R AF Seubert, DE Maymon, E Pacora, P Gervasi, MT Berry, SM Torry, DS Romero, R TI A study of the relationship between placenta growth factor and gestational age, parturition, rupture of membranes, and intrauterine infection SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 66th Annual Meeting of the Pacific-Coast-Obstetrical-and-Gynecological-Society CY OCT 20-24, 1999 CL CANCUN, MEXICO SP Pacific Coast Obstet & DE placenta growth factor; angiogenesis; amniotic fluid; preterm labor; rupture of membranes; intra-amniotic infection ID VASCULAR ENDOTHELIUM; FLT-1 RECEPTOR; SERUM LEVELS; PREECLAMPSIA; ANGIOGENESIS; EXPRESSION; VEGF; LOCALIZATION; PREGNANCIES; KDR AB OBJECTIVE: Placenta growth factor is a potent angiogenic factor produced by the human placenta that has been implicated in the pathogenesis of preeclampsia and intrauterine growth restriction. Placenta growth factor belongs to the vascular endothelial growth factor family and is capable of inducing proliferation, migration, and activation of endothelial cells. The objective of this study was to determine the relationship between amniotic fluid concentration of placenta growth factor and gestational age, parturition (term and preterm), spontaneous rupture of the membranes, and intra-amniotic infection. STUDY DESIGN: Amniotic fluid samples obtained from 273 pregnant patients were assayed in the following clinical groups: midtrimester pregnancy, preterm labor who delivered at term, preterm labor without microbial invasion of the amniotic cavity who delivered preterm, preterm labor with microbial invasion of the amniotic cavity, term not in labor, term in labor, term with microbial invasion of the amniotic cavity, preterm premature rupture of membranes with and without microbial invasion of the amniotic cavity, and term with premature rupture of membranes without microbial invasion of the amniotic cavity. The placenta growth factor concentrations were determined by an immunoassay that is both sensitive and specific. RESULTS: Placenta growth factor was detectable in 96.3% (263/273) of samples. Amniotic fluid placenta growth factor concentration decreased with advancing gestational age (r = -0.42; P < .001). Amniotic fluid placenta growth factor concentrations were significantly higher in women in midtrimester pregnancy than in those at term not in labor (midtrimester pregnancy: median, 43.1 pg/mL; range, 22.9-69.8 pg/mL; vs term not in labor: median, 28.7 pg/mL; range, 16.1-82.7 pg/mL; P < .01). Neither term nor preterm parturition was associated with a change in amniotic fluid placenta growth factor concentrations. Term premature rupture of membranes was associated with a significant decrease in amniotic fluid placenta growth factor concentration (term premature rupture of membranes: median, 16.5 pg/mL; range <5.2-195.1 pg/mL; vs term intact membranes: median, 28.7 pg/mL; range, 16.1-822.7 pg/mL; P < .005). Preterm premature rupture of membranes was not associated with changes in amniotic fluid placenta growth factor concentrations. Intra-amniotic infection in preterm labor, term labor with intact membranes, and preterm premature rupture of membranes were not associated with changes in amniotic fluid placenta growth factor concentrations. CONCLUSION: Placenta growth factor is a physiologic constituent of amniotic fluid. Amniotic fluid concentrations of placenta growth factor decrease with advancing gestational age. Neither parturition nor infection affects amniotic fluid placenta growth factor concentrations. C1 Wayne State Univ, Hutzel Hosp, NICHD, Perinatol Res Branch,Dept Obstet & Gynecol, Detroit, MI 48201 USA. Univ Tennessee, Med Ctr, Dept Obstet & Gynecol, Knoxville, TN USA. RP Romero, R (reprint author), Wayne State Univ, Hutzel Hosp, NICHD, Perinatol Res Branch,Dept Obstet & Gynecol, 4707 St Antoine Blvd, Detroit, MI 48201 USA. NR 25 TC 10 Z9 10 U1 0 U2 0 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JUN PY 2000 VL 182 IS 6 BP 1633 EP 1637 DI 10.1067/mob.2000.107437 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 330XY UT WOS:000087987800119 PM 10871490 ER PT J AU Weisz, J Fritz-Wolz, G Gestl, S Clawson, GA Creveling, CR Liehr, JG Dabbs, D AF Weisz, J Fritz-Wolz, G Gestl, S Clawson, GA Creveling, CR Liehr, JG Dabbs, D TI Nuclear localization of catechol-O-methyltransferase in neoplastic and nonneoplastic mammary epithelial cells SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID BREAST-CANCER RISK; AROMATASE ACTIVITIES; ESTROGEN METABOLISM; OXIDATIVE STRESS; 2-METHOXYESTRADIOL; EXPRESSION; INDUCTION; INVITRO; TISSUE; CATECHOLESTROGENS AB Catechol-O-methyltransferase (COMT) plays both a regulatory and protective role in catechol homeostasis. It contributes to the regulation of tissue levels of catecholamines and catecholestrogens (CEs) and, by blocking oxidative metabolism of catechols, prevents endogenous and exogenous catechols from becoming a source of potentially mutagenic electrophiles. Evidence implicating CEs in carcinogenesis, in particular in the hamster kidney model of estrogen-induced cancer, has focused attention on the protective role of COMT in estrogen target tissues. We have previously reported that treating hamsters with estrogens causes translocation of COMT to nuclei of epithelial cells in the renal cortex, the site of CE biosynthesis and where the cancers arise, This ending suggested that nuclear COMT may be a marker of a threat to the genome by catechols, including CEs. It is postulated that CEs play a role in the genesis of breast cancer by contributing to a state of chronic oxidative stress that is presumed to underlie the high incidence of this disease in the United States. Therefore, here we used immunocytochemistry to re-examine human breast parenchyma for nuclear COMT, In addition to confirming previous reports of cytoplasmic COMT in mammary epithelial cells, we identified nuclear COMT in foci of mammary epithelial cells in histologically normal breast tissue of virtually all control (macromastia) and cancer patients and in breast can-cer cells. There was no correlation between tissue histology and the numbers of cells with nuclear COMT, the size of foci containing such cells, or intensity of nuclear COMT immunostaining, The focal nature of the phenomenon suggests that nuclear COMT does not serve a housekeeping function but that it reflects a protective response to an increased local catechol load, presumably of CEs and, as such, that it may be a characteristic of the population of women studied who share the same major risk factor for developing breast cancer, that of living in the industrialized West. C1 Penn State Univ, Milton S Hershey Med Ctr, Dept Obstet & Gynecol, Coll Med, Hershey, PA 17033 USA. Penn State Univ, Milton S Hershey Med Ctr, Dept Biochem, Coll Med, Hershey, PA 17033 USA. Penn State Univ, Milton S Hershey Med Ctr, Dept Pathol, Coll Med, Hershey, PA 17033 USA. Penn State Univ, Milton S Hershey Med Ctr, Cell & Mol Biol Program, Coll Med, Hershey, PA 17033 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. Univ Texas, Med Branch, Dept Pharmacol & Toxicol, Galveston, TX USA. RP Weisz, J (reprint author), Penn State Univ, Milton S Hershey Med Ctr, Dept Obstet & Gynecol, Coll Med, H103,500 Univ Dr, Hershey, PA 17033 USA. FU NCI NIH HHS [CA65532] NR 51 TC 16 Z9 16 U1 0 U2 0 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JUN PY 2000 VL 156 IS 6 BP 1841 EP 1848 DI 10.1016/S0002-9440(10)65057-2 PG 8 WC Pathology SC Pathology GA 321ZH UT WOS:000087484900004 PM 10854207 ER PT J AU Hertz, L Chen, Y Spatz, M AF Hertz, L Chen, Y Spatz, M TI Effects of arginine vasopressin on water space in astrocytes and in whole brain SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Letter ID POTASSIUM HOMEOSTASIS; VOLUME REGULATION; CELLULAR-LEVEL; FUROSEMIDE; BLOOD; ENDOTHELIN-1; ACCUMULATION; RECEPTORS; NEURONS; SODIUM C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. Univ Saskatchewan, Dept Pharmacol, Saskatoon, SK S7N 5E5, Canada. RP Spatz, M (reprint author), NINDS, Stroke Branch, NIH, Bldg 36,Rm 4A03,36 Convent Dr,MSC 4128, Bethesda, MD 20892 USA. NR 21 TC 2 Z9 2 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD JUN PY 2000 VL 278 IS 6 BP E1175 EP E1176 PG 2 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 323NH UT WOS:000087571200026 PM 10905857 ER PT J AU Thornton, DJ Gray, T Nettesheim, P Howard, M Koo, JS Sheehan, JK AF Thornton, DJ Gray, T Nettesheim, P Howard, M Koo, JS Sheehan, JK TI Characterization of mucins from cultured normal human tracheobronchial epithelial cells SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE MUC2; mucin oligomerization; amino-terminal cleavage of MUC5B ID PORCINE SUBMAXILLARY MUCIN; CERVICAL-MUCUS GLYCOPROTEINS; DISULFIDE-BONDED DIMERS; VON-WILLEBRAND-FACTOR; C-TERMINAL CLEAVAGE; LARGE CENTRAL EXON; GENE-EXPRESSION; GENOMIC ORGANIZATION; RESPIRATORY-TRACT; RETINOIC ACID AB Early-passage normal human tracheobronchial epithelial (NHTBE) cells grown in air-liquid interface cultures in medium containing retinoids differentiate into a mucociliary epithelium over a 2- to 3-wk period and express increasing mRNA levels of the airway mucin genes MUC5AC and MUC5B as the cultures age; the levels of MUC2 mRNA were very low throughout the study. Using specific antibodies to MUC5AC and MUC5B mucins, we noted a gradual increase in these two mucins in the intracellular and apically secreted pools as a function of time. A low level of MUC2 mucin was detected, which did not change with time. The intracellular and apically secreted mucins isolated from day 14 and day 21 cultures by density gradient centrifugation were similar in density to those previously isolated from human respiratory mucus secretions. The sedimentation rate of the apically secreted mucins indicated that they were highly oligomerized, polydisperse macromolecules similar to those previously documented from in vivo secretions. In contrast, the cell-associated mucins from the cultured NHTBE cells were much smaller, possibly only monomers and dimers. Anion-exchange chromatography detected no differences in charge density between the reduced and carboxymethylated cell-associated and secreted forms of the MUC5AC and MUC5B mucins. The MUC5AC mucin was of similar charge density to its in vivo counterpart; however, MUC5B was more homogeneous than that found in vivo. Finally, evidence is presented for an intracellular NH2-terminal cleavage of the MUC5B mucins. These studies indicate that the mucins produced by cultured NHTBE cells are similar to those found in human airways, suggesting that this cell culture model is suited for studies of respiratory mucin biosynthesis, processing, and assembly. C1 Univ Manchester, Sch Biol Sci, Div Biochem, Wellcome Trust Ctr Cell Matrix Res, Manchester M13 9PT, Lancs, England. NIEHS, Pulm Pathobiol Lab, Res Triangle Pk, NC 27709 USA. RP Thornton, DJ (reprint author), Univ Manchester, Sch Biol Sci, Div Biochem, Wellcome Trust Ctr Cell Matrix Res, 2-205 Stopford Bldg, Manchester M13 9PT, Lancs, England. NR 41 TC 51 Z9 53 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD JUN PY 2000 VL 278 IS 6 BP L1118 EP L1128 PG 11 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 323PF UT WOS:000087573600002 PM 10835316 ER PT J AU Kwon, TH Frokiaer, J Han, JS Knepper, MA Nielsen, S AF Kwon, TH Frokiaer, J Han, JS Knepper, MA Nielsen, S TI Decreased abundance of major Na+ transporters in kidneys of rats with ischemia-induced acute renal failure SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE sodium transport; sodium-hydrogen exchanger; sodium-inorganic; phosphate cotransporter; sodium-potassium-2 chloride; transporter; sodium-chloride cotransporter ID THICK ASCENDING LIMB; MELANOCYTE-STIMULATING HORMONE; K-CL COTRANSPORTER; PROXIMAL TUBULE; MOLECULAR-CLONING; ALTERED EXPRESSION; REPERFUSION INJURY; ATPASE; LOCALIZATION; AQUAPORINS AB Ischemia-induced acute renal failure (ARF) is known to be associated with significant impairment of tubular Na reabsorption. We examined whether temporary bilateral renal ischemia (30, 40, or 60 min) and reperfusion (1-5 days) affect the abundance of several renal Na transporters and urinary Na excretion (UNaV) in rats. In rats with mild ARF (30 min), immunoblotting revealed that proximal tubule type 3 Na+/H+ exchanger (NHE-3) and type II Na-P-i cotransporter (NaPi-II) were significantly decreased to 28 +/- 6 and 14 +/- 6% of sham levels, respectively, at day 1. Moreover, Na+-K+-ATPase levels were also significantly decreased (51 +/- 11%), whereas there was no significant decrease in type 1 bumetanide-sensitive cotransporter (BSC-1) and thiazide-sensitive cotransporter (TSC) levels. Consistent with reduced Na transporter abundance, fractional urinary Na excretion (FENa) was significantly increased in mild ARF (30 min) and UNaV was unchanged, despite a marked reduction in glomerular filtration rate. Na transporter levels and renal Na handling were normalized within 5 days. Severe ischemic injury (60 min) resulted in a marked decrease in the abundance of Na+-K+-ATPase, NHE-3, NaPi-II, BSC-1, and TSC at both days 1 and 5. Consistent with this, FENa was significantly increased at days 1 and 5. Intravenous K-melanocyte-stimulated hormone treatment partially prevented the ischemia-induced downregulation of renal Na transporters and reduced the high FENa to control levels. We conclude that reduced levels of Na transporters along the nephron may play a critical role in the impairment of tubular Na reabsorption, and hence increased Na excretion, in ischemia-induced ARF. C1 Univ Aarhus, Inst Anat, Dept Cell Biol, DK-8000 Aarhus C, Denmark. Aarhus Univ Hosp, Dept Clin Physiol, DK-8200 Aarhus N, Denmark. Inst Expt Clin Res, DK-8200 Aarhus N, Denmark. Seoul Natl Univ Hosp, Dept Internal Med, Seoul 110744, South Korea. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Nielsen, S (reprint author), Univ Aarhus, Inst Anat, Dept Cell Biol, DK-8000 Aarhus C, Denmark. EM sn@ana.au.dk RI Han, Jin-Suk/J-5711-2012 FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 51 TC 90 Z9 90 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JUN PY 2000 VL 278 IS 6 BP F925 EP F939 PG 15 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 323PJ UT WOS:000087573900008 PM 10836980 ER PT J AU Vallon V Verkman, AS Schnermann, J AF Vallon, V Verkman, AS Schnermann, J TI Luminal hypotonicity in proximal tubules of aquaporin-1-knockout mice SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE water transport; kidney; micropuncture ID WATER PERMEABILITY; DRIVING FORCE; NULL MICE; ABSORPTION; TRANSPORT AB To examine the role of aquaporin-1 (AQP1) in near-isosmolar fluid reabsorption in the proximal tubule, we compared osmolalities in micropuncture samples of late proximal tubular fluid and plasma in wild-type (+/+) and AQP1-knockout (-/-) mice. Compared with matched wild-type mice, the -/- animals produce a relatively hypotonic urine (607 +/- 42 vs. 1,856 +/- 101 mosmol/kgH(2)O) and have a higher plasma osmolality under micropuncture conditions (346 +/- 11 vs. 318 +/- 5 mosmol/kgH(2)O; P < 0.05). Measurements of tubular fluid osmolality were done in three groups of mice, +/+, -/-, and hydrated -/- mice in which plasma osmolality was reduced to 323 +/- 1 mosmol/kgH(2)O. Late proximal tubular fluid osmolalities were 309 +/- 5 (+/+, n = 21), 309 +/- 4 (-/-, n = 24), and 284 +/- 3 mosmol/kgH(2)O (hydrated -/-, n = 19). Tubular fluid chloride concentration averaged 152 +/- 1 (+/+), 154 +/- 1 (-/-), and 140 +/- 1 mM (hydrated -/-). Transtubular osmotic gradients in untreated and hydrated AQP1 -/- mice were 39 +/- 4 (n = 25) and 39 +/- 3 mosmol/kgH(2)O (n = 19), values significantly higher than in +/+ mice (12 +/- 2 mosmol/kgH(2)O; n = 24; both P < 0.001). AQP1 deficiency in mice generates marked luminal hypotonicity in proximal tubules, resulting from the retrieval of a hypertonic absorbate and indicating that near-isosmolar fluid absorption requires functional AQP1. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, Cardiovasc Res Inst, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Cardiovasc Res Inst, Dept Physiol, San Francisco, CA 94143 USA. RP Schnermann, J (reprint author), NIDDKD, NIH, Bldg 10,Rm 4 D51,10 Ctr Dr,MSC 1370, Bethesda, MD 20892 USA. EM jurgens@intra.niddk.nih.gov FU NIDDK NIH HHS [DK-35124] NR 16 TC 69 Z9 70 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JUN PY 2000 VL 278 IS 6 BP F1030 EP F1033 PG 4 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 323PJ UT WOS:000087573900020 PM 10836992 ER PT J AU Devlin, MJ Yanovski, SZ Wilson, GT AF Devlin, MJ Yanovski, SZ Wilson, GT TI Obesity: What mental health professionals need to know SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Review ID BINGE-EATING DISORDER; BODY-MASS INDEX; TISSUE LIPOPROTEIN-LIPASE; MINIMIZE WEIGHT-GAIN; LOW CALORIE DIET; ENERGY-EXPENDITURE; SMOKING CESSATION; UNITED-STATES; BEHAVIORAL TREATMENT; CHILDHOOD OBESITY C1 New York State Psychiat Inst & Hosp, Unit 116, New York, NY 10032 USA. Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10027 USA. NIDDKD, Obes & Eating Disorders Program, Bethesda, MD 20892 USA. Rutgers State Univ, Rutgers Eating Disorder Clin, Piscataway, NJ USA. RP Devlin, MJ (reprint author), New York State Psychiat Inst & Hosp, Unit 116, 1051 Riverside Dr, New York, NY 10032 USA. EM mjd5@columbia.edu FU NIMH NIH HHS [MH-54612] NR 143 TC 104 Z9 105 U1 3 U2 14 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUN PY 2000 VL 157 IS 6 BP 854 EP 866 DI 10.1176/appi.ajp.157.6.854 PG 13 WC Psychiatry SC Psychiatry GA 320VJ UT WOS:000087421300002 PM 10831462 ER PT J AU Bloch, M Schmidt, PJ Danaceau, M Murphy, J Nieman, L Rubinow, DR AF Bloch, M Schmidt, PJ Danaceau, M Murphy, J Nieman, L Rubinow, DR TI Effects of gonadal steroids in women with a history of postpartum depression SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID POSTNATAL DEPRESSION; PREMENSTRUAL-SYNDROME; MOOD DISORDERS; ESTROGEN; PREVALENCE; CHILDBEARING; CHILDBIRTH AB Objective: Endocrine factors are purported to play a role in the etiology of postpartum depression, but direct evidence for this role is lacking. The authors investigated the possible role of changes in gonadal steroid levels in postpartum depression by simulating two hormonal conditions related to pregnancy and parturition in euthymic women with and without a history of postpartum depression. Method: The supraphysiologic gonadal steroid levels of pregnancy and withdrawal from these high levels to a hypogonadal state were simulated by inducing hypogonadism in euthymic women-eight with and eight without a history of postpartum depression-with the gonadotropin-releasing hormone agonist leuprolide acetate, adding back supraphysiologic doses of estradiol and progesterone for 8 weeks, and then withdrawing both steroids under double-blind conditions. Outcome measures were daily symptom self-ratings and standardized subjective and objective cross-sectional mood rating scales. Results: Five of the eight women with a history of postpartum depression (62.5%) and none of the eight women in the comparison group developed significant mood symptoms during the withdrawal period, analysis of variance with repeated measures of daily and cross-sectional ratings of mood showed significant phase-by-group, effects. These effects reflected significant increases in depressive symptoms in women with a history of postpartum depression hut not in the comparison group after hormone withdrawal (and during the end of the hormone replacement phase), compared with baseline. Conclusions: The data provide direct evidence in support of the involvement of the reproductive hormones estrogen and progesterone in the development of postpartum depression in a subgroup of women. Further, they suggest that women with a history of postpartum depression are differentially sensitive to mood-destabilizing effects of gonadal steroids. C1 NIMH, Behav Endocrinol Branch, Bethesda, MD 20892 USA. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Nursing, Bethesda, MD 20892 USA. RP Rubinow, DR (reprint author), NIMH, Behav Endocrinol Branch, Bldg 10,Room 3N238,10 Ctr Dr,MSC 1276, Bethesda, MD 20892 USA. NR 26 TC 340 Z9 351 U1 2 U2 18 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUN PY 2000 VL 157 IS 6 BP 924 EP 930 DI 10.1176/appi.ajp.157.6.924 PG 7 WC Psychiatry SC Psychiatry GA 320VJ UT WOS:000087421300012 PM 10831472 ER PT J AU Park, CG Chwae, YJ Kim, JI Lee, JH Hur, GM Jeon, BH Koh, JS Han, JH Lee, SJ Park, JW Kaslow, DC Strickman, D Roh, CS AF Park, CG Chwae, YJ Kim, JI Lee, JH Hur, GM Jeon, BH Koh, JS Han, JH Lee, SJ Park, JW Kaslow, DC Strickman, D Roh, CS TI Serologic responses of Korean soldiers serving in malaria-endemic areas during a recent outbreak of Plasmodium vivax SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID REPUBLIC-OF-KOREA; CIRCUMSPOROZOITE PROTEIN; ANTIBODY AB Anti-Pv200 antibody levels were assessed in samples from endemic areas of Plasmodium vivax malaria in the Republic of Korea (ROK), using an indirect enzyme-linked immunosorbent assay (ELISA) method. Asymptomatic carriers of P. vivax were detected using nested polymerase chain reaction (PCR) of blood samples. Anti-Pv200 antibody levels in 20 vivax malaria patients (optical density + standard deviation [OD +/- SD] values 1.85 +/-= 0.29 of IgG isotype and 1.33 +/- 1.33 of IgM isotype) were markedly higher than those of uninfected, malaria-naive controls (0.08 +/- 0.16 of IgG isotype and 0.04 +/- 0.04 of IgM isotype). Antibody levels for 7 out of 8 soldiers with a recent malaria infection were sustained above the cut-off values for 4 months after successful treatment. Analysis of serum collected from 40 healthy, asymptomatic soldiers who had a P. vivax malaria attack within 3 months after our sampling, revealed 11 antibody-positive samples (27.5%), compared to 5 positive samples (12.5%) collected from a random selection of 40 soldiers. Among a larger pool of 1.713 soldiers who had served in high-risk areas for P. vivax transmission, 15% were antibody positive. Among 1,000 blood samples from asymptomatic soldiers who had served in the high-risk areas, 4 samples (0.4%) were parasite positive, as determined by nested PCR. Our results show that anti-Pv200 antibody levels can provide useful information in the late diagnosis of P. vivax malaria infection in a previously naive population and also in large seroepidemiologic studies. Furthermore, our results suggest that asymptomatic P. vivax carriers could be important in the current outbreak of malaria in Korea. C1 Korean Armed Forces Cent Med Res Inst, Taejon 305153, South Korea. NIAID, Malaria Res Lab, NIH, Bethesda, MD 20892 USA. US Forces Korea, Med Detachment 5, Med Command 18, Seoul, South Korea. RP Park, CG (reprint author), Rockefeller Univ, Cellular Physiol & Immunol Lab, Box 176,1230 York Ave, New York, NY 10021 USA. RI KIM, JONG-IL/D-1019-2011; OI KIM, JONG-IL/0000-0002-7240-3744; Park, Chae Gyu/0000-0003-1906-1308 NR 15 TC 22 Z9 23 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JUN PY 2000 VL 62 IS 6 BP 720 EP 725 PG 6 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 419EU UT WOS:000167937000013 PM 11304063 ER PT J AU Barral, A Honda, E Caldas, A Costa, J Vinhas, V Rowton, ED Valenzuela, JG Charlab, R Barral-Netto, M Ribeiro, JMC AF Barral, A Honda, E Caldas, A Costa, J Vinhas, V Rowton, ED Valenzuela, JG Charlab, R Barral-Netto, M Ribeiro, JMC TI Human immune response to sand fly salivary gland antigens: A useful epidemiological marker? SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID AMERICAN VISCERAL LEISHMANIASIS; LUTZOMYIA-LONGIPALPIS; VIRUS TRANSMISSION; VECTOR SALIVA; TICK EXPOSURE; RISK FACTOR; ANTIBODIES; INFECTION; MAXADILAN; PEPTIDE AB Antibody (IgG) responses to salivary gland homogenate and to a recombinant salivary protein from the sand fly Lutzomyia longipalpis were investigated using sera from children living in an endemic area of visceral leishmaniasis in Brazil. We classified children into four groups according to their responses to Leishmania antigen: (Group I) positive serology and positive delayed type hypersensitivity (DTH), (Group II) positive serology and negative DTH, (Croup III) negative serology and positive DTH, and (Group IV) negative serology and negative DTH. A highly significant correlation was found between anti-salivary gland IgG levels and DTH responses. An L. longipalpis salivary recombinant protein used as an antigen in an enzyme-linked immune sorbent assay (ELISA) gave a significant but different result. A positive correlation was found between anti-leishmania IgG and anti-recombinant protein IgG titers. The results indicate that sand fly salivary proteins may be of relevance to the study the epidemiology of leishmaniasis. C1 NIAID, Sect Med Entomol, Parasit Dis Lab, Bethesda, MD 20892 USA. FIOCRUZ, Ctr Pesquisas Goncalo Moniz, BR-40295001 Salvador, BA, Brazil. Univ Fed Bahia, Hosp Univ Prof Edgard Santos, Serv Imunol, BR-40110040 Salvador, BA, Brazil. Univ Fed Maranhao, Dept Patol, Sao Luiz, Maranhao, Brazil. Walter Reed Army Inst Res, Dept Entomol, Bethesda, MD 20892 USA. RP Ribeiro, JMC (reprint author), NIAID, Sect Med Entomol, Parasit Dis Lab, Bldg 4 Rm 126,6 Ctr Dr,MSC 0425, Bethesda, MD 20892 USA. RI Barral Netto, Manoel/B-3904-2009; Barral, Aldina/B-4191-2009; Rowton, Edgar/A-1975-2011; Rowton, Edgar/A-4474-2012; OI Barral Netto, Manoel/0000-0002-5823-7903; Barral, Aldina/0000-0002-7177-464X; Rowton, Edgar/0000-0002-1979-1485; Ribeiro, Jose/0000-0002-9107-0818 NR 27 TC 108 Z9 112 U1 0 U2 10 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JUN PY 2000 VL 62 IS 6 BP 740 EP 745 PG 6 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 419EU UT WOS:000167937000016 PM 11304066 ER PT J AU Somerfield, MR McCrae, RR AF Somerfield, MR McCrae, RR TI Stress and coping research - Methodological challenges, theoretical advances, and clinical applications SO AMERICAN PSYCHOLOGIST LA English DT Article ID MENTAL-HEALTH; PERSONALITY; CHECKLIST AB Coping is among the most widely studied topics in contemporary psychology. However, the explosion of interest in coping has yielded little and the field is in crisis. This section offers a survey of the state of the art in theory and research on stress and adaptational processes. The four core articles in the section take up, respectively, problems in research design, the neglect of unconscious reactions to stress, the selection of adaptational outcomes, and the link between research on adaptational processes and clinical practice. The final article by Richard S. Lazarus offers a commentary. The present introduction provides the historical backdrop for the section. Then, after a brief overview of research on adaptational processes, the authors summarize the scope and yield of coping research and preview the four core articles in the section. The strengths and limits of individual coping efforts and the need for realistic expectations and redoubled efforts are discussed. C1 Amer Soc Clin Oncol, Hlth Serv Res Dept, Alexandria, VA 22314 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Somerfield, MR (reprint author), Amer Soc Clin Oncol, Hlth Serv Res Dept, 225 Reinekers Lane,Suite 650, Alexandria, VA 22314 USA. NR 65 TC 189 Z9 202 U1 3 U2 30 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0003-066X J9 AM PSYCHOL JI Am. Psychol. PD JUN PY 2000 VL 55 IS 6 BP 620 EP 625 DI 10.1037//0003-066X.55.6.620 PG 6 WC Psychology, Multidisciplinary SC Psychology GA 325DM UT WOS:000087661100005 PM 10892204 ER PT J AU Chung, TF Sipe, JD McKee, A Fine, RE Schreiber, BM Liang, JS Johnson, RJ AF Chung, TF Sipe, JD McKee, A Fine, RE Schreiber, BM Liang, JS Johnson, RJ TI Serum amyloid A in Alzheimer's disease brain is predominantly localized to myelin sheaths and axonal membrane SO AMYLOID-INTERNATIONAL JOURNAL OF EXPERIMENTAL AND CLINICAL INVESTIGATION LA English DT Article; Proceedings Paper CT Experimental Biology 98 Meeting CY APR 18-22, 1998 CL SAN FRANCISCO, CALIFORNIA SP Amer Soc Exper Biol DE serum amyloid A; acute phase protein; Alzheimer's disease; inflammation; myelin; immunohistochemistry ID AORTIC SMOOTH-MUSCLE; ACUTE-PHASE RESPONSE; MECHANISMS; PROTEIN; EXPRESSION; APOSAA; LIPIDS; CELLS AB Immunohistochemical localization of the injury specific apolipoprotein, acute phase serum amyloid A (A-apoSAA), was compared in brains of patients with neuropathologically confirmed Alzheimer's disease (AD) multiple sclerosis (MS), Parkinson's disease (PD), Pick's disease (Pick's), dementia with Lewy bodies (DLB), coronary artery disease (CAD), and schizophrenia. Affected regions of both AD and MS brains showed intense staining for A-apoSAA in comparison to an unaffected region and non-AD/MS brains. The major site of A-apoSAA staining in both diseases was the myelin sheaths of axons in layers V and VI of affected cortex. A-apoSAA contains a cholesterol binding site near its amino terminus and is likely to have a high affinity for cholesterol-rich myelin. These findings, along with our recent evidence that A-apoSAA can inhibit lipid synthesis in vascular smooth muscle cells suggest that A-apoSAA plays a role in the neuronal loss and white matter damage occurring in AD and MS. C1 Boston Univ, Sch Med, Dept Biochem K120, Boston, MA 02118 USA. NIH, Ctr Sci Review, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Edith Nourse Rogers Mem Vet Adm Hosp, Bedford, MA 01730 USA. Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. RP Johnson, RJ (reprint author), Boston Univ, Sch Med, Dept Biochem K120, 80 E Concord St, Boston, MA 02118 USA. FU NIA NIH HHS [AG 13846, AG 9006, AG 05894] NR 22 TC 22 Z9 23 U1 0 U2 2 PU PARTHENON PUBLISHING GROUP PI CARNFORTH LANCASHIRE PA CASTERTON HALL, CARNFORTH LANCASHIRE LA6 2LA, ENGLAND SN 1350-6129 J9 AMYLOID JI Amyloid-Int. J. Exp. Clin. Investig. PD JUN PY 2000 VL 7 IS 2 BP 105 EP 110 DI 10.3109/13506120009146246 PG 6 WC Biochemistry & Molecular Biology; Medicine, General & Internal; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; General & Internal Medicine; Research & Experimental Medicine GA 315NU UT WOS:000087120500004 PM 10842712 ER PT J AU Moser, AM Patel, M Yoo, H Balis, FM Hawkins, ME AF Moser, AM Patel, M Yoo, H Balis, FM Hawkins, ME TI Real-time fluorescence assay for O-6-alkylguanine-DNA alkyltransferase SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE real-time DNA-repair assay; fluorescent nucleoside analog; alkylation; pteridine ID RESTRICTION-ENDONUCLEASE INHIBITION; DNA-REPAIR; OLIGONUCLEOTIDES; CARCINOGENESIS; AGENTS AB O-6-Alkylguanine-DNA alkyltransferase (AGT) is a DNA-repair protein that reverses the effects of alkylating agents by removing DNA adducts from the O-6-position of guanine, We developed a real-time AGT assay that utilizes a fluorescent guanosine analog (3-methylisoxantopterin, 3-MI). 3-MI fluorescence is quenched in DNA and fluorescence intensity increases substantially with digestion of the oligonucleotide and release of 3-MI. The substrate is a doubled-stranded oligonucleotide with 3'-overhangs on each end and a PuvII recognition site. PvuII is inhibited by Op-methylguanine, positioned within the restriction site. 3-MI is incorporated in the opposite strand just outside of the PvuII restriction site. AGT repairs O-6-methylguanine; PvuII cleaves at its restriction site, yielding a blunt-ended double strand, which is then digested by exonuclease III. This releases 3-MI from the oligonucleotide, resulting in an increase in fluorescence intensity. All reaction components (100-mu L volume) are monitored in a single microcuvette. Rate of increase in fluorescence intensity is related to the amount of AGT in the reaction mixture. We measured AGT levels in extracts from a leukemia cell line, from leukemic lymphoblasts from patients, and from peripheral blood mononuclear cells from normal controls, This method may prove useful for mechanistic studies of AGT, (C) 2000 Academic Press. C1 Natl Canc Inst, Pediat Oncol Branch, Bethesda, MD 20892 USA. Childrens Canc Ctr, San Antonio, TX 78229 USA. RP Hawkins, ME (reprint author), Natl Canc Inst, Pediat Oncol Branch, Bethesda, MD 20892 USA. RI MOSER, ASHER/F-1873-2012 NR 19 TC 19 Z9 19 U1 0 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD JUN 1 PY 2000 VL 281 IS 2 BP 216 EP 222 DI 10.1006/abio.2000.4554 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 320FL UT WOS:000087391100011 PM 10870838 ER PT J AU Ridnour, LA Sim, JE Hayward, MA Wink, DA Martin, SM Buettner, GR Spitz, DR AF Ridnour, LA Sim, JE Hayward, MA Wink, DA Martin, SM Buettner, GR Spitz, DR TI A spectrophotometric method for the direct detection and quantitation of nitric oxide, nitrite, and nitrate in cell culture media SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE nitric oxide; quantitation; chemiluminescence; spectrophotometric assay; nitrite; nitrate; cell culture ID AGENT AB A method for the spectrophotometric determination of nitric oxide, nitrite, and nitrate in tissue culture media is presented. The method is based on the nitric oxide-mediated nitrosative modification of sulfanilic acid that reacts with N-(1-naphthyl)ethylenediamine dihydrochloride forming an orange-colored product absorbing at 496 nm, Nitric oxide levels were determined in culture media from this absorbance measurement using chemiluminescence standardization. Extinction coefficients of 5400 and 6600 M-1 cm(-1) were determined for the nitric oxide product in assay solutions containing 0.1 or 100 mM KPO4 buffer (pH 7.4), respectively, with a limit of detection of 1 mu M. Acidification of these reactions (pH 2.4) generated a pink-colored product absorbing at 540 nm allowing for quantitation of total nitric oxide/nitrite levels using extinction coefficients of 38,000 and 36,900 M-1 cm(-1), for the assay solutions described, The limit of detection of this assay was approximately 300 nM, Using the 100 mM KPO4 buffer system, nitrate levels were determined following reduction to nitrite using a copper-coated cadmium reagent with an extinction coefficient of 29,500 M-1 cm(-1) and a detection limit of 0.5 mu M. The utility of these assays was demonstrated in the standardization of nitric oxide-saturated cell culture media, and the release of nitric oxide by the NONOate compound DEA/NO. (C) 2000 Academic Press. C1 Washington Univ, Radiat Oncol Ctr, Sect Canc Biol, St Louis, MO 63108 USA. NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. Univ Iowa, Free Radical Res Inst, Iowa City, IA 52242 USA. Med Coll Wisconsin, Dept Biochem, Milwaukee, WI 53226 USA. RP Ridnour, LA (reprint author), MetaPhore Pharmaceut, 1910 Innerbelt Business Ctr Dr, St Louis, MO 63114 USA. OI Buettner, Garry/0000-0002-5594-1903 FU NCI NIH HHS [P01 CA66081]; NHLBI NIH HHS [R01 HL51469]; NIEHS NIH HHS [F32 ES05781] NR 8 TC 70 Z9 74 U1 3 U2 19 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD JUN 1 PY 2000 VL 281 IS 2 BP 223 EP 229 DI 10.1006/abio.2000.4583 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 320FL UT WOS:000087391100012 PM 10870839 ER PT J AU Lin, SH Long, SR Ramirez, SM Cotter, RJ Woods, AS AF Lin, SH Long, SR Ramirez, SM Cotter, RJ Woods, AS TI Characterization of the "helix clamp" motif of HIV-1 reverse transcriptase using MALDI-TOF MS and surface plasmon resonance SO ANALYTICAL CHEMISTRY LA English DT Article ID ANGSTROM RESOLUTION; THUMB SUBDOMAIN; BINDING; MUTAGENESIS AB A helix-turn-helix motif in the crystal structure of human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) was proposed to be a conserved nucleic acid binding domain among several nucleotide polymerizing enzymes (Hermann, T.; Meier, T,; Gotte, M.; Heumann, H. Nucleic Acids Res. 1994, 22, 4625-4633). The sequence of this domain is homologous to (259)KLVGKL- (X)(16)KLLR284 Of HIV-1 RT, which acts as a "helix clamp" grasping the template-primer (T-P) complex. We characterized the helix clamp motif using MALDI-TOF MS and surface plasmon resonance (BIAcore), Our studies showed that the "helix clamp" has a nucleic acid binding function that: may not be sequence specific,This evidence suggests that ionic interactions between the helix clamp and oligonucleotide backbone are not solely responsible for binding. Secondary and tertiary structures of the protein may also play a significant role in nucleic acid binding. The association and dissociation constants, k(a) and k(d), for the binding of single-stranded oligonucleotide to the helix clamp were determined to be 7.03 x 10(3) M-1 s(-1) and 1.22 x 10(3) s(-1), respectively. C1 Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. Biacore Inc, Piscataway, NJ 08854 USA. RP Woods, AS (reprint author), NIDA, Intramural Program, NIH, 5500 Nathan Shock Dr,Room 249, Baltimore, MD 21224 USA. FU NIGMS NIH HHS [GM-54882] NR 20 TC 28 Z9 28 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD JUN 1 PY 2000 VL 72 IS 11 BP 2635 EP 2640 DI 10.1021/ac991429f PG 6 WC Chemistry, Analytical SC Chemistry GA 320WZ UT WOS:000087425000052 PM 10857647 ER PT J AU Gangur, V Oppenheim, JJ AF Gangur, V Oppenheim, JJ TI Are chemokines essential or secondary participants in allergic responses? SO ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY LA English DT Review ID MONOCYTE CHEMOATTRACTANT PROTEIN; HISTAMINE-RELEASING FACTORS; C-C CHEMOKINES; HUMAN B-CELLS; T-CELLS; TISSUE EOSINOPHILIA; AIRWAY HYPERRESPONSIVENESS; RECEPTOR CXCR4; IFN-GAMMA; ENDOTHELIAL-CELLS AB Objectives: This review will provide a concise and critical overview of the rapidly evolving concepts in chemokine biology with a special relevance to allergic responses. The article is intended for clinicians with little or no expertise in chemokine biology. Data Sources: A detailed literature search was performed through MEDLINE (PubMed). Those reports considered important and relevant to the topic were critically reviewed and their conclusions included. Results: Chemokines are a group of structurally related small proteins with a common biological activity of inducing directional migration (chemotaxis) of various cell types. Chemokines such as eotaxins and MCP-4 play a key role in selective eosinophil recruitment to sites of inflammation in allergies and asthma. Several other chemokine activities relevant to allergic responses are: activation of basophils and eosinophils to release inflammatory mediators, regulation of IgE responses, and Th1/Th2-type cytokine balance. A number of therapeutic strategies aimed at inhibiting chemokine function are being tested in animal models of allergies and asthma. Conclusions: Chemokines have been widely viewed as pathogenic mediators of acute and chronic inflammation and tissue damage in allergies and asthma. On the other hand, recent evidence suggests that endogenous production of certain chemokines might be beneficial to the host in preventing allergic response. Met-RANTES, a modified antagonist of RANTES, and eotaxin receptor (CCR3) antagonists, represent promising novel therapeutic agents potentially useful in atopic disorders. Thus, suppression of chemokines may interrupt the sequence of signals culminating in an allergic response. Whether chemokines are actually essential for an allergic response awaits confirmation with gene knockout animal experiments. C1 NCI, Mol Immunoregulat Lab, Div Basic Sci, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Oppenheim, JJ (reprint author), NCI, Mol Immunoregulat Lab, Div Basic Sci, Frederick Canc Res & Dev Ctr, Bldg 560,Rm 31-40, Frederick, MD 21702 USA. NR 104 TC 42 Z9 43 U1 0 U2 0 PU AMER COLL ALLERGY ASTHMA IMMUNOLOGY PI ARLINGTON HTS PA 85 WEST ALGONQUIN RD SUITE 550, ARLINGTON HTS, IL 60005 USA SN 1081-1206 J9 ANN ALLERG ASTHMA IM JI Ann. Allergy Asthma Immunol. PD JUN PY 2000 VL 84 IS 6 BP 569 EP 579 PG 11 WC Allergy; Immunology SC Allergy; Immunology GA 326VL UT WOS:000087757600004 PM 10875484 ER PT J AU Lindsay, BG Pilla, RS Basak, P AF Lindsay, BG Pilla, RS Basak, P TI Moment-based approximations of distributions using mixtures: Theory and applications SO ANNALS OF THE INSTITUTE OF STATISTICAL MATHEMATICS LA English DT Article DE cumulants; cumulative distribution function; gamma mixtures; mixture distribution; moment matrix; p-point mixture; tail probability; weighted sums of chi-squares ID LINEAR COMBINATION; RANDOM-VARIABLES; MATRICES; SUM AB There are a number of cases where the moments of a distribution are easily obtained, but theoretical distributions are not available in closed form. This paper shows how to use moment methods to approximate a theoretical univariate distribution with mixtures of known distributions. The methods are illustrated with gamma mixtures. It is shown that for a certain class of mixture distributions, which include the normal and gamma mixture families, one can solve for a p-point mixing distribution such that the corresponding mixture has exactly the same first 2p moments as the targeted univariate distribution. The gamma mixture approximation to the distribution of a positive weighted sums of independent central chi(2) variables is demonstrated and compared with a number of existing approximations. The numerical results show that the new approximation is generally superior to these alternatives. C1 Penn State Univ, Dept Stat, University Pk, PA 16802 USA. NIH, Bethesda, MD 20892 USA. Penn State Univ, Eiche Lib 120, Altoona, PA 16601 USA. NR 23 TC 27 Z9 27 U1 0 U2 4 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0020-3157 J9 ANN I STAT MATH JI Ann. Inst. Stat. Math. PD JUN PY 2000 VL 52 IS 2 BP 215 EP 230 DI 10.1023/A:1004105603806 PG 16 WC Statistics & Probability SC Mathematics GA 329YL UT WOS:000087936000002 ER PT J AU Venkateswaran, A McFarlan, SC Ghosal, D Minton, KW Vasilenko, A Makarova, K Wackett, LP Daly, MJ AF Venkateswaran, A McFarlan, SC Ghosal, D Minton, KW Vasilenko, A Makarova, K Wackett, LP Daly, MJ TI Physiologic determinants of radiation resistance in Deinococcus radiodurans SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID IONIZING-RADIATION; STREPTOCOCCUS-EQUISIMILIS; REPAIR; DNA; RECOMBINATION; DAMAGE AB Immense volumes of radioactive wastes, which were generated during nuclear weapons production, were disposed of directly in the ground during the Cold War, a period when national security priorities often surmounted concerns over the environment, The bacterium Deinococcus radiodurans is the most radiation-resistant organism known and is currently being engineered for remediation of the toxic metal and organic components of these environmental wastes. Understanding the biotic potential of D. radiodurans and its global physiological integrity in nutritionally restricted radioactive environments is important in development of this organism for in situ bioremediation, We have previously shown that D. radiodurans can grow on rich medium in the presence of continuous radiation (6,000 rads/h) without lethality. In this study we developed a chemically defined minimal medium that can be used to analyze growth of this organism in the presence and in the absence of continuous radiation; whereas cell growth was not affected in the absence of radiation, cells did not grow and were killed in the presence of continuous radiation. Under nutrient-limiting conditions, DNA repair was found to be limited by the metabolic capabilities of D. radiodurans and not by any nutritionally induced defect in genetic repair. The results of our growth studies and analysis of the complete D. radiodurans genomic sequence support the hypothesis that there are several defects in D, radiodurans global metabolic regulation that limit carbon, nitrogen, and DNA metabolism. We identified key nutritional constituents that restore growth of D. radiodurans in nutritionally limiting radioactive environments. C1 Uniformed Serv Univ Hlth Sci, Dept Pathol, Bethesda, MD 20814 USA. Univ Minnesota, Dept Biochem, Biol Proc Technol Inst, St Paul, MN 55108 USA. Univ Minnesota, Gortner Lab, Ctr Biodegradat Res & Informat, St Paul, MN 55108 USA. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Daly, MJ (reprint author), Uniformed Serv Univ Hlth Sci, Dept Pathol, Rm B3153,4301 Jones Bridge Rd, Bethesda, MD 20814 USA. FU NIGMS NIH HHS [5R01-GM39933-09] NR 33 TC 76 Z9 80 U1 2 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD JUN PY 2000 VL 66 IS 6 BP 2620 EP 2626 DI 10.1128/AEM.66.6.2620-2626.2000 PG 7 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 319TP UT WOS:000087358700047 PM 10831446 ER PT J AU Kaufman, D Dickersin, K Kelman, S Langenberg, P Newman, N Wilson, PD Kennerdell, J Bruchis, A Chung, S Govreau, D Holds, J Selhorst, J Malton, M Rogers, A Saunders, T Kosmorsky, G King, K Fecko, T Ross, D Feldon, S Levin, L Zimmerman, K Friedberg, K Sadaati, N Newman, NJ Loupe, D Wojno, T Skarf, B Croswell, M Gilroy, W Ponka, G Tang, R Hamlin, M Curtis, J Mack, K Tello, P Arnold, A Buckley, J Goldberg, R Gordon, L Krauss, H Stalling, R Cornblath, W Michael, M Johnson, LN Baker, G Cobb, C Turner, S Younge, B Leavitt, J Nielsen, R Eickhoff, B Garrity, J Ladsten, J Lebarron, K Link, T Rostvold, J Weber, K Felton, W Anderson, T Sanborn, G Kaufman, D Eggenberger, E Bickert, S Granadier, R Holliday, S Moore, T Friedman, D Jones, P Bersani, T Horton, J Chang, H Aber, LA Seiff, S Guy, J Zam, ZS Burke, R Goodwin, J Putterman, A Baker, R Beck, J Hanson, M Scoggins, T Kelman, S Frank, C Kalsi, R Chalam, K Hackett, S Digre, K Erickson, J Blackburn, T Anderson, R Langer, P Morris, P Osborn, S Patel, B Staker, S Warner, J Newman, S Evans, C Harrell, C Overstreet, H Scott, J Tyler, L Linberg, J Ellis, B Campbell, C McGregor, G Cohn, E Cummings, K Manatrey, P Casey, S Granadier, R Regan, V Roehr, D Streasick, P Elman, M Frank, C Dickersin, K Hooper, F Scherer, R Crawley, B Hiner, C Howard, L Langenberg, P Lurye, O Masiero, J McCarter, R Riedel, S Sotos, M Spioch, L Starr, J Urban, J Waring, M Wilson, PD Zhu, J Zhu, Q Dickersin, RK Spioch, L Zhu, J Zhu, Q Everett, D Crawley, B Kaufman, D Newman, NJ Zam, ZS Baker, R Feldon, S Granadier, R Kosmorsky, G Seiff, SR AF Kaufman, D Dickersin, K Kelman, S Langenberg, P Newman, N Wilson, PD Kennerdell, J Bruchis, A Chung, S Govreau, D Holds, J Selhorst, J Malton, M Rogers, A Saunders, T Kosmorsky, G King, K Fecko, T Ross, D Feldon, S Levin, L Zimmerman, K Friedberg, K Sadaati, N Newman, NJ Loupe, D Wojno, T Skarf, B Croswell, M Gilroy, W Ponka, G Tang, R Hamlin, M Curtis, J Mack, K Tello, P Arnold, A Buckley, J Goldberg, R Gordon, L Krauss, H Stalling, R Cornblath, W Michael, M Johnson, LN Baker, G Cobb, C Turner, S Younge, B Leavitt, J Nielsen, R Eickhoff, B Garrity, J Ladsten, J Lebarron, K Link, T Rostvold, J Weber, K Felton, W Anderson, T Sanborn, G Kaufman, D Eggenberger, E Bickert, S Granadier, R Holliday, S Moore, T Friedman, D Jones, P Bersani, T Horton, J Chang, H Aber, LA Seiff, S Guy, J Zam, ZS Burke, R Goodwin, J Putterman, A Baker, R Beck, J Hanson, M Scoggins, T Kelman, S Frank, C Kalsi, R Chalam, K Hackett, S Digre, K Erickson, J Blackburn, T Anderson, R Langer, P Morris, P Osborn, S Patel, B Staker, S Warner, J Newman, S Evans, C Harrell, C Overstreet, H Scott, J Tyler, L Linberg, J Ellis, B Campbell, C McGregor, G Cohn, E Cummings, K Manatrey, P Casey, S Granadier, R Regan, V Roehr, D Streasick, P Elman, M Frank, C Dickersin, K Hooper, F Scherer, R Crawley, B Hiner, C Howard, L Langenberg, P Lurye, O Masiero, J McCarter, R Riedel, S Sotos, M Spioch, L Starr, J Urban, J Waring, M Wilson, PD Zhu, J Zhu, Q Dickersin, RK Spioch, L Zhu, J Zhu, Q Everett, D Crawley, B Kaufman, D Newman, NJ Zam, ZS Baker, R Feldon, S Granadier, R Kosmorsky, G Seiff, SR CA IONDT Res Grp TI Ischemic optic neuropathy decompression trial - Twenty-four-month update SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID ASPIRIN AB Objective: To describe visual acuity outcomes of patients in the Ischemic Optic Neuropathy Decompression Trial (IONDT) after 24 months of follow-up. Design: The IONDT is a single-masked, multicenter, randomized clinical trial. Settings: Patients were evaluated and followed up at 25 clinical centers located throughout the United States. Data were sent to and analyzed at a central coordinating center. Patients: Two hundred fifty-eight patients SO years or older with nonarteritic anterior ischemic optic neuropathy and visual acuity of 20/64 or worse, but better than no light perception, were randomized to either a careful follow-up group (n=131) or an optic nerve decompression surgery (ONDS) group (n=127). Of these, 174 continued participation for at least 24 months, 89 in the careful follow-up group and 85 in the ONDS group. Methods: Randomized patients underwent a standard visual acuity examination at 3, 6, 12, 18, and 24 months of follow-up. The primary outcome was a change of 3 lines or more of visual acuity, defined as a difference of 0.3 in logMAR scores, between baseline and 6 months of followup. A secondary outcome was mean change in visual acuity (in logMAR units) at 3, 6, 12, 18, and 24 months following baseline. These changes were estimated using available data from all randomized patients for whom we had data. Results: Of the 258 patients randomized, 143 (55.4%) were male, and 169 (65.5%) were 65 years or older. Mean visual acuity was statistically significantly improved from baseline value at all study visits and for both treatment groups, although visual acuity declined gradually in both groups after the 3-month visit. There were no significant differences between careful follow-up and ONDS in mean change in vision from the baseline and any follow-up time point. At 24 months of follow-up, 31.0% of patients in the careful follow-up group and 29.4% of patients in the ONDS group experienced an increase of 3 or more lines of vision compared with baseline acuity; 21.8% of patients in the careful follow-up group and 20.0% of patients in the ONDS group experienced a decrease of 3 or more lines. In patients who could read at least 1 letter on the Lighthouse chart, there wets a gradual decline in mean visual acuity noted over time for both treatment groups, although acuity remained significantly better than at baseline. Conclusion: Analysis of visual acuity data from patients enrolled in the IONDT at 24 months of follow-up confirms that there is no benefit of ONDS compared with careful follow-up in patients with nonarteritic anterior ischemic optic neuropathy. C1 Brown Univ, Sch Med, Dept Community Hlth, Providence, RI 02912 USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. St Louis Univ, Hlth Sci Ctr, Inst Eye, St Louis, MO 63103 USA. Carolinas Med Ctr, Charlotte, NC 28203 USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Doheny Eye Inst, Los Angeles, CA 90033 USA. Emory Univ, Atlanta, GA 30322 USA. Henry Ford Hosp, Detroit, MI 48202 USA. Univ Texas, Houston, TX USA. Jules Stein Eye Inst, Los Angeles, CA 90024 USA. Univ Michigan, WK Kellogg Eye Ctr, Ann Arbor, MI 48109 USA. Univ Missouri, Mason Inst Ophthalmol, Columbia, MO 65212 USA. Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. Virginia Commonwealth Univ, Med Coll Virginia, Richmond, VA 23298 USA. Michigan State Univ, E Lansing, MI 48824 USA. SUNY Syracuse, Syracuse, NY USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Florida, Gainesville, FL USA. Univ Illinois, Chicago, IL USA. Univ Kentucky, Lexington, KY USA. Univ Maryland, Sch Med, Coordinating Ctr, Baltimore, MD 21201 USA. Univ S Carolina, Columbia, SC 29208 USA. Univ Utah, Salt Lake City, UT USA. Univ Virginia, Charlottesville, VA USA. W Virginia Univ, Morgantown, WV 26506 USA. William Beaumont Hosp, Royal Oak, MI 48072 USA. Brown Univ, Sch Med, Coordinating Ctr, Providence, RI 02912 USA. NEI, Bethesda, MD 20892 USA. RP Dickersin, K (reprint author), Brown Univ, Sch Med, Dept Community Hlth, 169 Angell St,Box G-S, Providence, RI 02912 USA. RI Dickersin, Kay/A-4576-2008 NR 18 TC 34 Z9 34 U1 1 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD JUN PY 2000 VL 118 IS 6 BP 793 EP 798 PG 6 WC Ophthalmology SC Ophthalmology GA 322HB UT WOS:000087503200007 ER PT J AU Jeong, HJ Chang, LC Kim, HK Kim, IH Kinghorn, AD Pezzuto, JM AF Jeong, HJ Chang, LC Kim, HK Kim, IH Kinghorn, AD Pezzuto, JM TI Aromatase inhibitors from Isodon excisus var. coreanus SO ARCHIVES OF PHARMACAL RESEARCH LA English DT Article DE aromatase inhibition; inflexin; ursolic acid ID ENT-KAURENE DITERPENOIDS; CONSTITUENTS AB The diethyl ether extract of Isodon excisus var. coreanus exhibited significant inhibitory activity in aromatase assay. Bioactivity-guided fractionation of the extract led to the isolation of three active compounds: inflexin (ent-1 alpha-hydroxy-3 beta,6a-diacetoxykaur-16-en-11,15-dione) (1), ursolic acid (2), and ursolic acid 3-O-acetate (3). C1 Univ Illinois, Coll Pharm, Program Collaborat Res Pharmaceut Sci, Chicago, IL 60612 USA. Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, Chicago, IL USA. RP Jeong, HJ (reprint author), NIH, Bldg 21,Room 136, Bethesda, MD 20892 USA. OI Kinghorn, A. Douglas/0000-0002-6647-8707 FU NCI NIH HHS [P01 CA48112] NR 18 TC 10 Z9 10 U1 0 U2 1 PU PHARMACEUTICAL SOCIETY KOREA PI SEOUL PA 1489-3 SUHCHO-DONG, SUHCHO-KU, SEOUL 137-071, SOUTH KOREA SN 0253-6269 J9 ARCH PHARM RES JI Arch. Pharm. Res. PD JUN PY 2000 VL 23 IS 3 BP 243 EP 245 DI 10.1007/BF02976453 PG 3 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 329DG UT WOS:000087890400010 PM 10896056 ER PT J AU Klein, R Sharrett, AR Klein, BEK Chambless, LE Cooper, LS Hubbard, LD Evans, G AF Klein, R Sharrett, AR Klein, BEK Chambless, LE Cooper, LS Hubbard, LD Evans, G TI Are retinal arteriolar abnormalities related to atherosclerosis? The atherosclerosis risk in communities study SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE arteriosclerosis; atherosclerosis; epidemiology; inflammation; risk factors ID CORONARY-HEART-DISEASE; VON-WILLEBRAND-FACTOR; ARTERY WALL THICKNESS; MIDDLE-AGED ADULTS; CAROTID ATHEROSCLEROSIS; CARDIOVASCULAR-DISEASE; DIABETES-MELLITUS; BLOOD-PRESSURE; ASSOCIATIONS; MECHANISMS AB The objective of this study was to describe associations of retinal arteriolar abnormalities with clinical and subclinical manifestations of atherosclerosis and a broad group of risk factors for vascular disease. A biracial population of 8772 adults (aged 48 to 72 years) living in 4 communities was examined from 1993 to 1995 were studied for that purpose. Retinal arteriovenous nicking and focal arteriolar narrowing were determined by light-box grading of a 45 degrees fundus photograph by use of a standardized protocol. Diameters of arterioles and venules were measured in digitized photographs, and a summary arteriolar-to-venular ratio was derived as an index of generalized arteriolar narrowing, Focal arteriolar narrowing was associated only with hypertension, Generalized arteriolar narrowing was associated with carotid plaque but not with any other evidence of atherosclerosis, either clinical (cardiovascular disease or stroke) or subclinical (carotid or popliteal artery thickness or lower limb obstructive disease), or with plasma cholesterol. It was also associated with smoking, with inflammatory markers (white blood cell count, fibrinogen, and reduced albumin), and with the triglyceride and high density lipoprotein cholesterol changes associated with inflammation. Arteriovenous nicking was inconsistently associated with subclinical atherosclerosis, It was not associated with cardiovascular disease, stroke, or plasma cholesterol. Arteriovenous nicking was associated with markers of inflammation and vascular endothelial dysfunction (von Willebrand factor and factor VIII), Arteriolar narrowing and nicking appear to be related to hypertension and inflammatory factors. Nicking may also be related to endothelial dysfunction, Results suggest that these arteriolar changes are pathologically distinct from atherosclerosis. Including their measurement in population studies may permit evaluation of the independent contribution of arteriolar disease to various ischemic diseases of the heart, brain, and other organs. C1 Univ Wisconsin, Dept Ophthalmol & Visual Sci, Sch Med, Madison, WI 53705 USA. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Sch Publ Hlth, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27109 USA. RP Klein, R (reprint author), Univ Wisconsin, Dept Ophthalmol & Visual Sci, Sch Med, 610 N Walnut St,460 WARF, Madison, WI 53705 USA. FU NEI NIH HHS [EYO6594]; NHLBI NIH HHS [HL-59259]; PHS HHS [N01-C-55015] NR 56 TC 186 Z9 188 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD JUN PY 2000 VL 20 IS 6 BP 1644 EP 1650 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 322NP UT WOS:000087515900036 PM 10845884 ER PT J AU Danning, CL Illei, GG Hitchon, C Greer, MR Boumpas, DT McInnes, IB AF Danning, CL Illei, GG Hitchon, C Greer, MR Boumpas, DT McInnes, IB TI Macrophage-derived cytokine and nuclear factor kappa B p65 expression in synovial membrane and skin of patients with psoriatic arthritis SO ARTHRITIS AND RHEUMATISM LA English DT Article ID NECROSIS-FACTOR-ALPHA; RHEUMATOID-ARTHRITIS; T-CELL; MESSENGER-RNA; INTERLEUKIN-15; IL-15; ACTIVATION; PATHOGENESIS; THERAPY; NUMBERS AB Objective. Monocyte-derived cytokines are important mediators in synovitis and represent novel therapeutic targets, This study was undertaken to analyze their expression in synovial membrane (SM) of patients with psoriatic arthritis (PsA) compared with that in skin of patients with Psii and (SM) of patients with rheumatoid arthritis (RA). Methods. Multiple synovial biopsy samples (24 from patients with PsA 20 from patients with RA 5 from patients with osteoarthritis [OA]) and skin biopsy samples (lesional and perilesional skin from 25 PsA patients) were obtained, Standard leukocyte antigens, cytokines (tumor necrosis factor alpha [TNF alpha], interleukin-1 alpha [IL-1 alpha], IL-1 beta, IL-15, and IL-10) and the transcription factor nuclear factor kappa B (NF-kappa B; active p65 subunit) were localized and quantified immunohistochemically by light microscopy and digital image analysis, Results. Sublining cellular infiltration, lymphoid aggregation, and vascularity were similar in PsA and Ri SM, Lining layer thickness was greater in RA SM associated with more CD68+ macrophages, In PsA SM, TNF alpha, IL-1 alpha; IL-1 beta, IL-15, and IL-10 were primarily localized to lining layer and perivascular macrophages, as were cells expressing the active subunit of NF-KB (p65), TNF alpha, IL-1 beta, and IL-15 expression in PsA lining laver was less than that in Ri lining Iq er, likely reflecting lower macrophage numbers. in sublining areas, levels of TNF alpha and IL-15 were loner in PsA patients than in Ri patients, whereas IL-1 alpha and IL-1 beta expression was equivalent, IL-10 was identified at similar levels in RA and PsA SM lining layer and sublining, Expression of NF-kappa B (p65) was equal in lining layer from both patient groups, but lower in PsA than RA sublining. Histologic findings did not correlate with clinical parameters of disease. Cytokine expression in skin did not correlate directly with that in SM. Cytokine expression was greater in PsA and Ri SM than in OA SM. Conclusion. This study shows, for the first time, that monocyte derived cytokines are found in PsA SR I and demonstrates the relative paucity of the antiinflammatory cytokine IL-10 in PsA skin and SM. Significant divergence from Ri SM expression was observed, despite similar clinical and demographic features in the 2 patient groups. C1 NIAMSD, NIH, Bethesda, MD 20892 USA. RP Danning, CL (reprint author), Gundersen Lutheran Med Ctr, Dept Rheumatol, 1836 South Ave, La Crosse, WI 54601 USA. NR 46 TC 137 Z9 141 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD JUN PY 2000 VL 43 IS 6 BP 1244 EP 1256 DI 10.1002/1529-0131(200006)43:6<1244::AID-ANR7>3.0.CO;2-2 PG 13 WC Rheumatology SC Rheumatology GA 322HC UT WOS:000087503300007 PM 10857783 ER PT J AU Griffiths, MM Wang, JP Joe, B Dracheva, S Kawahito, Y Shepard, JS Reese, VA McCall-Vining, S Hashiramoto, A Cannon, GW Remmers, EF Wilder, RL AF Griffiths, MM Wang, JP Joe, B Dracheva, S Kawahito, Y Shepard, JS Reese, VA McCall-Vining, S Hashiramoto, A Cannon, GW Remmers, EF Wilder, RL TI Identification of four new quantitative trait loci regulating arthritis severity and one new quantitative trait locus regulating autoantibody production in rats with collagen-induced arthritis SO ARTHRITIS AND RHEUMATISM LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; GENOME-WIDE LINKAGE; RHEUMATOID-ARTHRITIS; SUSCEPTIBILITY LOCI; GENETIC DISSECTION; DISEASE SEVERITY; IMMUNE-RESPONSE; GK RAT; BB RAT; COMPLEX AB Objective. Collagen-induced arthritis (CIA) is a polygenic model of experimentally induced autoimmunity and chronic joint inflammation. This study maps genetic loci that regulate CW susceptibility in DA/Bkl (Dt) and BN/SsNHsd (BN) rats. Methods. Genome scans covering chromosomes 1-20 and internal mapping techniques using 159 simple sequence-length polymorphism markers were used to identify quantitative trait loci (QTLs) that regulate CIA in (DA x BN)F-2 hybrids. Serum antibody titers to type II collagen were determined by enzyme-linked immunosorbent assay. Results. DA rats were high responders to porcine type II collagen (PII) and developed severe CIA (100%). BN rats were low responders to PII and resistant to CIA (0%). BN genes strongly repressed PII-induced CIA. Only 12% of (DA x BN)F-I rats (7 of 60) and 31% of (DA x BN)F-2 rats (307 of 1,004) developed CIA. Three new QTLs (Cia11, Cia12, and Cia13) with significant logarithm of odds (LOD) scores of 5.6, 4.6, and 4.5, respectively plus a suggestive QTL (Cia14*, LOD 3.0) regulating arthritis severity were identified on chromosomes,7, 12, 1, and 19, A new QTL, Ciaa3, associating with anticollagen antibody titer (antibody to PII LOD 6.5; antibody to rat type Il collagen LOD 5.2) mapped to chromosome 9. Of 10 CIA QTLs previously identified in (DA x F344) and (DA x ACI) rats, only Cia1 in the major histocompatibility complex and a region coincident to Cia5 on chromosome 10 (LOD >8.0) influenced CIA severity in (DA x BN)F-2 rats. Conclusion. Since CIA. exhibits many of the pathologic features of rheumatoid arthritis, the data indicate that the variety of genetic elements regulating human autoimmune and rheumatic diseases may be much larger and more varied than originally envisioned. C1 Univ Utah, Hlth Sci Ctr, Sch Med, Dept Med,Div Rheumatol, Salt Lake City, UT 84132 USA. Dept Vet Affairs Med Ctr, Salt Lake City, UT USA. NIAMSD, NIH, Bethesda, MD 20892 USA. RP Griffiths, MM (reprint author), Univ Utah, Hlth Sci Ctr, Sch Med, Dept Med,Div Rheumatol, Room 4B200,50 N Med Dr, Salt Lake City, UT 84132 USA. NR 73 TC 67 Z9 68 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD JUN PY 2000 VL 43 IS 6 BP 1278 EP 1289 DI 10.1002/1529-0131(200006)43:6<1278::AID-ANR10>3.0.CO;2-S PG 12 WC Rheumatology SC Rheumatology GA 322HC UT WOS:000087503300010 PM 10857786 ER PT J AU Li, RL Boerwinkle, E Olshan, AF Chambless, LE Pankow, JS Tyroler, HA Bray, M Pittman, GS Bell, DA Heiss, G AF Li, RL Boerwinkle, E Olshan, AF Chambless, LE Pankow, JS Tyroler, HA Bray, M Pittman, GS Bell, DA Heiss, G TI Glutathione S-transferase genotype as a susceptibility factor in smoking-related coronary heart disease (vol 149, pg 451, 2000) SO ATHEROSCLEROSIS LA English DT Correction C1 Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. Univ Texas, Hlth Sci Ctr, Ctr Human Genet, Houston, TX 77225 USA. Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. Collaborat Studies Coordinating Ctr, Chapel Hill, NC 27514 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Heiss, G (reprint author), Univ N Carolina, Dept Epidemiol, Suite 306n NationsBank Plaza,137 E Franklin St, Chapel Hill, NC 27514 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD JUN PY 2000 VL 150 IS 2 BP 447 EP 449 DI 10.1016/S0021-9150(00)00507-4 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 324NW UT WOS:000087629100028 ER PT J AU Siahpush, M Singh, GK AF Siahpush, M Singh, GK TI Public health surveys and the measurement of social capital - Response to letter titled "Social capital should not be incorporated into surveys designed to monitor population health" SO AUSTRALIAN AND NEW ZEALAND JOURNAL OF PUBLIC HEALTH LA English DT Letter C1 La Trobe Univ, Wodanga, Vic 3689, Australia. NCI, NIH, Bethesda, MD 20892 USA. RP Siahpush, M (reprint author), La Trobe Univ, POB 821,Parkers Rd, Wodanga, Vic 3689, Australia. NR 2 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC HEALTH ASSOC AUSTRALIA INC PI CURTIN PA PO BOX 319, CURTIN, ACT 2600, AUSTRALIA SN 1326-0200 J9 AUST NZ J PUBL HEAL JI Aust. N. Z. Publ. Health PD JUN PY 2000 VL 24 IS 3 BP 342 EP 342 DI 10.1111/j.1467-842X.2000.tb01584.x PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 354YK UT WOS:000089358700025 PM 10937420 ER PT J AU Al-Amin, HA Weinberger, DR Lipska, BK AF Al-Amin, HA Weinberger, DR Lipska, BK TI Exaggerated MK-801-induced motor hyperactivity in rats with the neonatal lesion of the ventral hippocampus SO BEHAVIOURAL PHARMACOLOGY LA English DT Article DE dizocilpine; hippocampus; animal model; schizophrenia; behavior; neuroleptics; AMPA antagonist; LY293558; rat ID NMDA ANTAGONIST DIZOCILPINE; EXTRACELLULAR DOPAMINE LEVELS; INDUCED LOCOMOTOR-ACTIVITY; IN-VIVO MICRODIALYSIS; NUCLEUS-ACCUMBENS; PREFRONTAL CORTEX; TEGMENTAL AREA; RECEPTOR ANTAGONISTS; SOCIAL-BEHAVIOR; GLUTAMATERGIC NEUROTRANSMISSION AB Neonatal lesions of the ventral hippocampus in rats produce changes in spontaneous and pharmacologically induced dopamine-dependent behaviors that emerge in early adulthood. Neural mechanisms underlying these changes may have implications for understanding the neurobiology of schizophrenia, putatively a neurodevelopmental disorder. In this study, we evaluated the effects of MK-801 (dizocilpine), on automated measures of distance traveled and stereotypies in adult rats with neonatal (postnatal day 7) lesions, and tested the effects of haloperidol, clozapine and an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) antagonist LY293558 on the MK-801-induced behaviors. The lesioned rats showed significantly greater increases in motor activity after 0.05 and 0.1 mg/kg of MK-801 than did controls. Both haloperidol (0.1 and 0.4 mg/kg) and clozapine (4 and 10 mg/kg) reduced hyperlocomotion elicited by 0.2 mg/kg MK-801 in the ventral hippocampus (VH)-lesioned and sham rats. Haloperidol was more potent than clozapine in decreasing MK-801-induced stereotypy, especially in the lesioned rats. Moreover, an AMPA antagonist normalized exaggerated MK-801-induced hyperolocomotion in the lesioned rats at doses that had no effect in controls. These results demonstrate that the lesioned rats are more sensitive to MK-801 during adulthood than control rats, and that antidopaminergic drugs as well as AMPA antagonists antagonize the MK-801-induced behaviors. The neonatal lesion rat model may be useful to further our understanding of the interactions between dopamine and glutamate and their role in the pathophysiology of schizophrenia. (C) 2000 Lippincott Williams & Wilkins. C1 NIMH, Clin Brain Disorders Branch, Intramural Res Programs, NIH, Bethesda, MD 20892 USA. RP Lipska, BK (reprint author), NIMH, Clin Brain Disorders Branch, Intramural Res Programs, NIH, Bldg 10,Rm 4N306, Bethesda, MD 20892 USA. RI Lipska, Barbara/E-4569-2017; OI Al-Amin, Hassen/0000-0001-6358-1541 NR 82 TC 64 Z9 65 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD JUN PY 2000 VL 11 IS 3-4 BP 269 EP 278 PG 10 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 329WZ UT WOS:000087932600010 PM 11103881 ER PT J AU Brown, KE AF Brown, KE TI Haematological consequences of parvovirus B19 infection SO BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY LA English DT Article DE parvovirus B19 infection; erythrovirus; haematopoiesis; bone marrow disease; red cell aplasia ID NONIMMUNE HYDROPS-FETALIS; ERYTHROCYTE-P-ANTIGEN; MARROW CELL-CULTURES; BONE-MARROW; SIMIAN PARVOVIRUS; APLASTIC-ANEMIA; HEMOPHAGOCYTIC SYNDROME; MONOCLONAL-ANTIBODIES; RHEUMATOID-ARTHRITIS; FULMINANT-HEPATITIS AB Parvovirus B19, a member of the Erythrovirus genus, is the only member of the Parvoviridae family known to be pathogenic in humans. Erythroviruses are so named because of their tropism and selective replication in erythroid progenitor cells. Haematological consequences of B19 infection arise due to a direct cytotoxic effect on erythroid progenitors in bone marrow with interruption of erythrocyte production. In addition, the physiology of host haematopoiesis and competence of the immune response each determines clinical manifestations of B19 infection: in individuals with underlying haemolytic disorders, B19 infection causes transient aplastic crisis; in immunocompromised patients, persistent B19 infection may develop that manifests as pure red cell aplasia and chronic anaemia; B19 infection in utero may result in fetal death, hydrops fetalis, or congenital anaemia. Diagnosis is based on examination of bone marrow and B19 virological studies. Treatment of persistent infection with immunoglobulin leads to a prompt resolution of the anaemia. C1 NHLBI, Hematol Branch, Bethesda, MD 20892 USA. RP Brown, KE (reprint author), NHLBI, Hematol Branch, Bethesda, MD 20892 USA. NR 79 TC 40 Z9 42 U1 0 U2 1 PU BAILLIERE TINDALL PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1521-6926 J9 BEST PRACT RES CL HA JI Best Pract. Res. Clin. Haematol. PD JUN PY 2000 VL 13 IS 2 BP 245 EP 259 DI 10.1053/beha.1999.0071 PG 15 WC Hematology SC Hematology GA 344NA UT WOS:000088764700008 PM 10942624 ER PT J AU Fisher, A Shi, Y Ritter, A Ferretti, JA Perez-Lamboy, G Shah, M Shiloach, J Taniuchi, H AF Fisher, A Shi, Y Ritter, A Ferretti, JA Perez-Lamboy, G Shah, M Shiloach, J Taniuchi, H TI Functional correlation in amino acid residue mutations of yeast iso-2-cytochrome c that is consistent with the prediction of the concomitantly variable codon theory in cytochrome c evolution SO BIOCHEMICAL GENETICS LA English DT Article DE cytochrome c evolution; functional correlation; covarion phenomenon; yeast iso-2-cytochrome c mutation ID SACCHAROMYCES-CEREVISIAE; RANDOM MUTAGENESIS; FERRICYTOCHROME-C; TERMINAL HELIX; MUTANT PROTEIN; GENE; ISO-1-CYTOCHROME-C; RESOLUTION; REPLACEMENT; EXPRESSION AB Fitch and Markowitz' theory of concomitantly variable codons (covarions) in evolution predicted the existence of functional correlation in amino acid residue mutations among present-day cytochromes c. Mutational analysis was carried out on yeast iso-2-cytochrome c, where hydrophobic core residues 120, M64, L85, and M98 and surface residue L9 were mutated in selected combinations, to those found in mammalian and bird cytochromes c, The functionality assay is based upon the ability of yeast cells to grow in YPGE medium. Furthermore, experiments on the single M64L and M98L mutations as well as the double M64L/M98L mutation using NMR showed that the effects of these mutations are to perturb the structural integrity of the protein, We identified functional correlation in two cases of a pair of residue mutations, the 120 --> V and M98 --> L pair and the L9 --> I and L85 --> I pair. In both cases, only one of the two alternative, putative evolutionary pathways leads to a functional protein and the corresponding pairs of residue mutations are among those found in present-day cytochromes c. Since valine is predicted to be at position 20 in the ancestral form of cytochrome c, the present data provide an explanation for the ancient requirement of leucine rather than methionine in position 98. The present data provide further evidence for the role of those specific atom-atom interactions in directing a pathway in the evolutionary changes of the amino acid sequence that have taken place in cytochrome c, in accordance with Fitch and Markowitz. C1 NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Taniuchi, H (reprint author), NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. NR 63 TC 3 Z9 3 U1 0 U2 0 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0006-2928 J9 BIOCHEM GENET JI Biochem. Genet. PD JUN PY 2000 VL 38 IS 5-6 BP 181 EP 200 PG 20 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 369FV UT WOS:000165056000006 PM 11091908 ER PT J AU Jumana, S Hasan, CM Rashid, MA AF Jumana, S Hasan, CM Rashid, MA TI Alakaloids from the stem bark of Miliusa velutina SO BIOCHEMICAL SYSTEMATICS AND ECOLOGY LA English DT Article DE Miliusa velutina; Annonaceae; aporphines; benzylisoquinoline; chemotaxonomy ID APORPHINE ALKALOIDS C1 Univ Dhaka, Fac Pharm, Phytochem Res Lab, Dhaka 1000, Bangladesh. RP Rashid, MA (reprint author), NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Bldg 560,Rm 32-63B,Post Box B, Frederick, MD 21702 USA. NR 13 TC 14 Z9 15 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0305-1978 J9 BIOCHEM SYST ECOL JI Biochem. Syst. Ecol. PD JUN PY 2000 VL 28 IS 5 BP 483 EP 485 DI 10.1016/S0305-1978(99)00083-6 PG 3 WC Biochemistry & Molecular Biology; Ecology; Evolutionary Biology SC Biochemistry & Molecular Biology; Environmental Sciences & Ecology; Evolutionary Biology GA 310ZM UT WOS:000086859700007 ER PT J AU Andric, SA Kostic, TS Stojilkovic, SS Kovacevic, RZ AF Andric, SA Kostic, TS Stojilkovic, SS Kovacevic, RZ TI Inhibition of rat testicular androgenesis by a polychlorinated biphenyl mixture Aroclor 1248 SO BIOLOGY OF REPRODUCTION LA English DT Article ID PREPUBERTAL FEMALE RATS; LEYDIG-CELLS; PCB CONGENERS; ACUTE STRESS; IN-VITRO; STEROIDOGENESIS; 3,4,5,3',4',5'-HEXACHLOROBIPHENYL; 17-ALPHA-HYDROXYLASE; CYTOCHROME-P-450; REPRODUCTION AB Polychlorinated biphenyls (PCBs) are complex mixtures of congeners that exhibit carcinogenic and toxicant activities in a variety of mammalian tissues. Here, we studied the acute in vivo and in vitro effects of a commercially used PCB product, Aroclor 1248 (A1248), a mixture of tri-, tetra-, and pentachloro congeners. Single intraperitoneal (i.p.) or bilateral intratesticular (i.t.) injections of A1248 decreased serum androgen levels in both groups 24 h after injection. Chorionic gonadotropin-stimulated androgen production by acute testicular cultures from both groups was also reduced, and progesterone production was attenuated in cultures from i.t.-treated animals. The capacity of the postmitochondrial fractions from testes of i.t.-treated animals to convert pregnenolone to progesterone and progesterone to testosterone was reduced as well. in vitro studies revealed that a 10- to 15-min exposure of postmitochondrial testicular fractions and intact interstitial cells from normal animals to A1248 in a subnanomolar concentration range was sufficient to attenuate the conversion of pregnenolone to progesterone and progesterone to testosterone. At micromolar concentrations, A1248 added in vitro also inhibited the conversion of Delta(4)-androstendione to testosterone without affecting the viability of interstitial cells. These results indicate that A1248 down-regulates the testicular androgenesis by an acute inhibition of 3 beta-hydroxysteroid dehydrogenase, 17 alpha-hydroxylase/lyase, and 17 beta-hydroxysteroid dehydrogenase activities. C1 NICHD, Endocrinol & Reprod Res Branch, Bethesda, MD 20892 USA. Univ Novi Sad, Fac Sci, Inst Biol, YU-21000 Novi Sad, Yugoslavia. RP Kovacevic, RZ (reprint author), NICHD, Endocrinol & Reprod Res Branch, Bldg 49,Room 6A-36,49 Convent Dr, Bethesda, MD 20892 USA. NR 41 TC 56 Z9 64 U1 0 U2 3 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD JUN PY 2000 VL 62 IS 6 BP 1882 EP 1888 DI 10.1095/biolreprod62.6.1882 PG 7 WC Reproductive Biology SC Reproductive Biology GA 317QZ UT WOS:000087239600051 PM 10819796 ER PT J AU Nam, JM AF Nam, JM TI Interval estimation of the kappa coefficient with binary classification and an equal marginal probability model SO BIOMETRICS LA English DT Article DE expected coverage probability; expected length of interval; interval estimation; intraclass; correlation; kappa coefficient of agreement; score method AB We derive a likelihood score method for interval estimation of the intraclass version of the kappa coefficient of agreement with binary classification using a general theory of Bartlett (1953, Biometrika 40, 306-317). By exact evaluation, we investigate statistical properties of the score method, the chi-square goodness-of-fit procedure (Donner and Eliasxiw, 1992, Statistics in Medicine 11, 1511-1519; Hale and Fleiss, 1993, Biometrics 49, 523-534), and a crude confidence interval for small and medium sample sizes. Actual coverage percentages of the score and chi-square methods are satisfactorily close to the nominal confidence coefficient, while that of the crude method is quite unsatisfactory. The expected length of the score method is shorter than that of the chi-square procedure when the response rate is very small or very large. C1 NCI, Biostat Branch, Bethesda, MD 20892 USA. RP Nam, JM (reprint author), NCI, Biostat Branch, Execut Plaza S,Room 8028,6120 Execut Blvd,MSC 736, Bethesda, MD 20892 USA. NR 7 TC 15 Z9 15 U1 0 U2 1 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD JUN PY 2000 VL 56 IS 2 BP 583 EP 585 DI 10.1111/j.0006-341X.2000.00583.x PG 3 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 325LR UT WOS:000087677500035 PM 10877320 ER PT J AU Albert, PS AF Albert, PS TI A transitional model for longitudinal binary data subject to nonignorable missing data SO BIOMETRICS LA English DT Article DE EM algorithm; episodic data; hidden Markov models; Markov models; missing data; opiate addiction; repeated binary data ID INFORMATIVE DROP-OUT; LIKELIHOOD AB Binary longitudinal data are often collected in clinical trials when interest is on assessing the effect of a treatment over time. Our application is a recent study of opiate addiction that examined the effect of a new treatment on repeated urine tests to assess opiate use over an extended follow-up. Drug addiction is episodic, and a new treatment may affect various features of the opiate-use process such as the proportion of positive urine tests over follow-up and the time to the first occurrence of a positive test. Complications in this trial were the large amounts of dropout and intermittent missing data and the large number of observations on each subject. We develop a transitional model for longitudinal binary data subject to nonignorable missing data and propose an EM algorithm for parameter estimation. We use the transitional model to derive summary measures of the opiate-use process that can be compared across treatment groups to assess treatment effect. Through analyses and simulations, we show the importance of property accounting for the missing data mechanism when assessing the treatment effect in our example. C1 NCI, Biometr Res Branch, Bethesda, MD 20892 USA. RP Albert, PS (reprint author), NCI, Biometr Res Branch, Execut Plaza N,Room 739, Bethesda, MD 20892 USA. NR 16 TC 33 Z9 33 U1 0 U2 0 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD JUN PY 2000 VL 56 IS 2 BP 602 EP 608 DI 10.1111/j.0006-341X.2000.00602.x PG 7 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 325LR UT WOS:000087677500038 PM 10877323 ER PT J AU Huster, D Arnold, K Gawrisch, K AF Huster, D Arnold, K Gawrisch, K TI Strength of Ca2+ binding to retinal lipid membranes: Consequences for lipid organization SO BIOPHYSICAL JOURNAL LA English DT Article ID ROD OUTER SEGMENT; CALCIUM-INDUCED FUSION; MAGNETIC-RESONANCE; ACYL-CHAIN; PHOSPHATIDYLCHOLINE BILAYERS; PHOSPHATIDYLSERINE VESICLES; DIVALENT-CATIONS; PHASE-SEPARATION; IONS; CHOLESTEROL AB There is evidence that membranes of rod outer segment (ROS) disks are a high-affinity Ca2+ binding site. We were interested to see if the high occurrence of sixfold unsaturated docosahexaenoic acid in ROS lipids influences Ca2+-membrane interaction. Ca2+ binding to polyunsaturated model membranes that mimic the lipid composition of ROS was studied by microelectrophoresis and H-2 NMR. Ca2+ association constants of polyunsaturated membranes were found to be a factor of similar to 2 smaller than constants of monounsaturated membranes. Furthermore, strength of Ca2+ binding to monounsaturated membranes increased with the addition of cholesterol, while binding to polyunsaturated lipids was unaffected. The data suggest that the lipid phosphate groups of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS) in PC/PE/PS (4:4:1, mol/mol) are primary targets for Ca2+. Negatively charged serine in PS controls Ca2+ binding by lowering the electric surface potential and elevating cation concentration at the membrane/water interface. The influence of hydrocarbon chain unsaturation on Ca2+ binding is secondary compared to membrane PS content. Order parameter analysis of individual lipids in the mixture revealed that Ca2+ ions did not trigger lateral phase separation of lipid species as long as all lipids remained liquid-crystalline. However, depending on temperature and hydrocarbon chain unsaturation, the lipid with the highest chain melting temperature converted to the gel state, as observed for the monounsaturated phosphatidylethanolamine (PE) in PC/PE/PS (4.4.1, mol/mol) at 25 degrees C. C1 NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. Univ Leipzig, Inst Med Phys & Biophys, D-04103 Leipzig, Germany. RP Gawrisch, K (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, 12420 Parklawn Dr,Rm 158, Rockville, MD 20852 USA. NR 44 TC 56 Z9 58 U1 0 U2 15 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUN PY 2000 VL 78 IS 6 BP 3011 EP 3018 PG 8 WC Biophysics SC Biophysics GA 323TE UT WOS:000087580400022 PM 10827979 ER PT J AU Dibrov, P Murtazina, R Kinsella, J Fliegel, L AF Dibrov, P Murtazina, R Kinsella, J Fliegel, L TI Characterization of a histidine rich cluster of amino acids in the cytoplasmic domain of the Na+/H+ exchanger SO BIOSCIENCE REPORTS LA English DT Article DE Na+/H+ exchanger; proton sensing; histidine residues ID MOLECULAR-CLONING; ESCHERICHIA-COLI; H+ EXCHANGER; PH-SENSOR; PROTEIN; GROWTH; ANTIPORTER; CELLS; EXPRESSION; ACTIVATION AB We examined the function of a highly conserved Histidine rich sequence of amino acids found in the carboxyl-terminal of the Na+/H+ exchanger (NHE1). A fusion protein containing the sequence HYGHHH (540-545) and the balance of the carboxyl terminal of the protein did not bind calcium but bound to an immobilized metal affinity column and could be used to partially purify the exchanger protein. Mutation of the sequence to either HYGAAA or HYGRRR did not affect activity of the intact protein. Mutation to HHHHHH did not affect proton activation of the Na+/H+ exchanger or localization but caused a decreased maximal velocity suggesting that this conserved sequence is important in maximal activity of the Na+/H+ exchanger. C1 Univ Alberta, Fac Med, Dept Biochem, Edmonton, AB T6G 2H7, Canada. NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Fliegel, L (reprint author), Univ Alberta, Fac Med, Dept Biochem, 347 Med Sci Bldg, Edmonton, AB T6G 2H7, Canada. NR 38 TC 7 Z9 7 U1 1 U2 3 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0144-8463 J9 BIOSCIENCE REP JI Biosci. Rep. PD JUN PY 2000 VL 20 IS 3 BP 185 EP 197 DI 10.1023/A:1005567519792 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 368DW UT WOS:000090103300006 PM 11095118 ER PT J AU Barrett, AJ Ringden, O Zhang, MJ Bashey, A Cahn, JY Cairo, MS Gale, RP Gratwohl, A Locatelli, F Martino, R Schultz, KR Tiberghien, P AF Barrett, AJ Ringden, O Zhang, MJ Bashey, A Cahn, JY Cairo, MS Gale, RP Gratwohl, A Locatelli, F Martino, R Schultz, KR Tiberghien, P CA GVHD GVL Working Com Int Bon TI Effect of nucleated marrow cell dose on relapse and survival in identical twin bone marrow transplants for leukemia SO BLOOD LA English DT Article ID HOST DISEASE; ACUTE GRAFT; RECOVERY; RECIPIENTS; DONORS AB The impact of cell dose (number of nucleated donor cells per kilogram recipient weight) on transplantation outcome is controversial and may differ for allogeneic and identical twin (syngeneic) bone marrow transplants. We studied the association between cell dose end outcome in 100 unmanipulated identical twin bone marrow transplantations for leukemia, reported to the International Bone Marrow Transplant Registry between 1985 and 1994, using Cox proportional hazards regression for multivariate analyses. Cell doses ranged from 0.3 to 7.4 x 10(8) nucleated cetls/kg (median, 3.0 x 10(8) cells/kg). Median follow-up was 75 months. Five-year cumulative incidences of transplant-related mortality with high (more than 3 x 10(8) cells/kg) versus low (less than or equal to 3 x 10(8) cells/kg) cell doses were 2% (95% confidence interval [CI], 0% to 8%) versus 10% (95% CI, 4% to 20%), respectively. Five-year probabilities of leukemia-free survival were 53% (95% CI, 39% to 67%) and 37% (95% CI, 23% to 52%), respectively. In multivariate analysis, among patients surviving in remission at least 9 months after transplantation, those receiving high cell doses were at significantly lower risk for treatment failure (relapse or death) than those receiving low cell doses (RR, 0.27; 95% CI, 0.12 to 0.6; P=.001). Lower treatment failure resulted from fewer relapses in the high cell dose group (RR for relapse, 0.28; 95% CI, 1.2 to 0.66; P =.003). These findings suggest that outcomes after syngeneic bone marrow transplantation could be improved by transplanting more than 3 x 10(8) nucleated cells per kilogram. The benefit of high cell dose on relapse may represent a delayed graft-versus-leukemia effect. (Blood. 2000;95:3323-3327) (C) 2000 by The American Society of Hematology. C1 Med Coll Wisconsin, Int Bone Marrow Transplant Registry, Hlth Policy Inst, Milwaukee, WI 53226 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. Huddinge Univ Hosp, Dept Transplantat Surg, S-14186 Huddinge, Sweden. Univ Calif San Diego, Dept Hematol Oncol, San Diego, CA 92103 USA. Georgetown Univ, Med Ctr, Dept Pediat, Washington, DC 20007 USA. Ctr Adv Studies Leukemia, Los Angeles, CA USA. Kantonsspital, Dept Hematol, CH-4031 Basel, Switzerland. Univ Pavia, I-27100 Pavia, Italy. Hosp St Pau, Serv Hematol Clin, Barcelona, Spain. Univ British Columbia, Dept Pediat, Vancouver, BC V6T 1W5, Canada. Etablissement Transfus Sanguine Franche Comte, Cell & Gene Therapy Unit, Besancon, France. RP Barrett, AJ (reprint author), Med Coll Wisconsin, Int Bone Marrow Transplant Registry, Hlth Policy Inst, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. FU NCI NIH HHS [U24CA76518, P01CA40053] NR 21 TC 44 Z9 44 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 JUN 1 PY 2000 VL 95 IS 11 BP 3323 EP 3327 PG 5 WC Hematology SC Hematology GA 319QA UT WOS:000087351600007 PM 10828011 ER PT J AU Kuwata, T Wang, IM Tamura, T Ponnamperuma, RM Levine, R Holmes, KL Morse, HC De Luca, LM Ozato, K AF Kuwata, T Wang, IM Tamura, T Ponnamperuma, RM Levine, R Holmes, KL Morse, HC De Luca, LM Ozato, K TI Vitamin A deficiency in mice causes a systemic expansion of myeloid cells SO BLOOD LA English DT Article ID RETINOIC ACID RECEPTORS; SEQUENCE-BINDING PROTEIN; BONE-MARROW CELLS; RAR-ALPHA; GRANULOCYTIC DIFFERENTIATION; BCL-2 EXPRESSION; GENE-EXPRESSION; X RECEPTORS; BCR-ABL; APOPTOSIS AB To examine the role of retinoids in hematopoietic cell growth in vivo, we studied female SENCAR mice made vitamin A deficient by dietary restriction. Deficient mice exhibited a dramatic increase in myeloid cells in bone marrow, spleen, and peripheral blood. The abnormal expansion of myeloid cells was detected from an early stage of vitamin A deficiency and contrasted with essentially normal profiles of T and B lymphocytes. This abnormality was reversed on addition of retinoic acid to the vitamin A-deficient diet, indicating that the myeloid cell expansion is a direct result of retinoic acid deficiency. TUNEL analysis indicated that spontaneous apoptosis, a normal process in the life cycle of myeloid cells, was impaired in vitamin A-deficient mice, which may play a role in the increased myeloid cell population. Quantitative reverse transcriptase-polymerase chain reaction analysis of purified granulocytes showed that expression of not only RAR, but RXRs, 2 nuclear receptors that mediate biologic activities of retinoids, was significantly reduced in cells of deficient mice, This work shows that retinoids critically control the homeostasis of myeloid cell population in vivo and suggests that deficiency in this signaling pathway may contribute to various myeloproliferative disorders, (Blood, 2000;95: 3349-3356) (C) 2000 by The American Society of Hematology. C1 NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. NCI, Lab Cellular Carcinogenesis & Tumor Promot, Bethesda, MD 20892 USA. NIAID, Immunopathol Lab, Bethesda, MD 20892 USA. NIAID, FLow Cytometry Unit, Bethesda, MD 20892 USA. RP Ozato, K (reprint author), NICHHD, Lab Mol Growth Regulat, NIH, Bldg 6,Rm 2A01, Bethesda, MD 20892 USA. OI Morse, Herbert/0000-0002-9331-3705 NR 50 TC 93 Z9 99 U1 0 U2 2 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 JUN 1 PY 2000 VL 95 IS 11 BP 3349 EP 3356 PG 8 WC Hematology SC Hematology GA 319QA UT WOS:000087351600011 PM 10828015 ER PT J AU Posey, SC Martelli, MP Azuma, T Kwiatkowski, DJ Bierer, BE AF Posey, SC Martelli, MP Azuma, T Kwiatkowski, DJ Bierer, BE TI Failure of gelsolin overexpression to regulate lymphocyte apoptosis SO BLOOD LA English DT Article ID PROTEIN GELSOLIN; IN-VIVO; ACTIN; PATHWAYS AB The actin regulatory protein gelsoiin cleaves actin filaments in a calcium- and polyphosphoinositide-dependent manner. Gelsolin has recently been described as a novel substrate of the cysteinyl protease caspase-3, an effector protease activated during apoptosis. Cleavage by caspase-3 generates an amino-terminal fragment of gelsolin that can sever actin filaments independently of calcium regulation. The disruption of the actin cytoskeleton by cleaved gelsolin is hypothesized to mediate many of the downstream morphological changes associated with apoptosis. In contrast, overexpression of full-length gelsolin has also been re-ported to inhibit apoptotic cell death upstream of the activation of caspase-3, suggesting that gelsolin may also act prior to commitment to cell death. The authors previously observed that actin stabilization by the cell permeant agent jasplakinolide enhanced cell death upon interleukin (IL)-2 or IL-3 withdrawal from growth-factor-dependent lymphocyte cell lines, and hypothesized that actin polymerization could alter the activity of gelsolin, thus enhancing apoptosis. Here the authors show that constitutive overexpression of gelsolin did not, however, inhibit or dramatically enhance apoptotic cell death upon growth-factor withdrawal, nor did it modify sensitivity to jasplakinolide, in contrast to previous reports, overexpression of gelsolin in Jurkat T cells did not prevent or delay apoptosis induced by Fas ligation or ceramide treatment. Overexpressed gelsolin protein was cleaved during apoptosis, as seen previously in this and other cell types. In these model systems, therefore, the level of gelsolin expression was not a rate-limiting determinant in commitment to or time to the morphological changes of apoptosis. (Blood. 2000;95:3483-3488) (C) 2000 by The American Society of Hematology. C1 NHLBI, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Div Med Sci, Comm Immunol, Boston, MA USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. Brigham & Womens Hosp, Div Hematol, Genet Lab, Boston, MA 02115 USA. RP Bierer, BE (reprint author), NHLBI, NIH, Bldg 10,Rm 5D49,10 Ctr Dr, Bethesda, MD 20892 USA. RI Martelli, Maria Paola/I-5618-2012 FU NHLBI NIH HHS [HL54188] NR 16 TC 16 Z9 18 U1 0 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 1 PY 2000 VL 95 IS 11 BP 3483 EP 3488 PG 6 WC Hematology SC Hematology GA 319QA UT WOS:000087351600029 PM 10828033 ER PT J AU Husain, SR Puri, RK AF Husain, SR Puri, RK TI Interleukin-13 fusion cytotoxin as a potent targeted agent for AIDS-Kaposi's sarcoma xenograft SO BLOOD LA English DT Article ID PSEUDOMONAS EXOTOXIN; GROWTH-FACTOR; SIGNAL-TRANSDUCTION; CARCINOMA-CELLS; IL-13 RECEPTOR; IN-VITRO; PROTEIN; EXPRESSION; CYTOKINES; PATHOGENESIS AB Clinically advanced and rapidly progressive AIDS-associated Kaposi sarcoma (AIDS-KS) tumors require an aggressive tumor-directed therapy. We have observed that AIDS-KS cells express high levels of receptors for immune regulatory cytokine, interleukin-13 (IL-13). Two tumorigenic AIDS-KS cell lines, KS Y-1 and KS-imm, expressed 4560 and 9480 IL-13 binding sites per cell with an affinity (kd) of similar to 0.9 and 3.7 nmol/L, respectively. IL-13 cytotoxin IL13-PE38QQR, consisting of human IL-13 and a derivative of Pseudomonas exotoxin, is specifically cytotoxic to KS tumor cells. Systemic and loco regional administration of IL13-PE38QQR in immunodeficient mice with established human KS tumors produced remarkable antitumor activity. Three intratumoral (IT) injections of IL-13 toxin (250 mu g/kg per dose) on alternate days (qod) or 5 daily (qd) IT injections with lower doses (50 or 100 mu g/kg per dose) resulted in a complete regression of established subcutaneous tumors in most animals. Daily IT treatment with 250 mu g/kg of IL-13 toxin in another KS-derived cell line also produced complete responses. Twice daily intraperitoneal injections of IL13-PE38QQR (25 or 50 mu g/kg per dose) for 10 days (total injections = 20) also completely eradicated KS Y-1 tumors, Intravenous administration of IL13-PE38QQR also suppressed tumor growth; however, complete responses were not observed. All animals tolerated the therapeutic doses of IL-13 toxin without any visible signs of toxicity. The efficacy of receptor-directed IL13-PE38QQR therapy in mice warrants further exploration of this drug for AIDS-KS treatment. (Blood, 2000;95: 3506-3513) (C) 2000 by The American Society of Hematology. C1 US FDA, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res,NIH, Bethesda, MD 20892 USA. RP Puri, RK (reprint author), US FDA, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res,NIH, Bldg 29B,Rm 2NN10,29 Lincoln Dr,MSC 4555, Bethesda, MD 20892 USA. NR 38 TC 58 Z9 61 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 1 PY 2000 VL 95 IS 11 BP 3506 EP 3513 PG 8 WC Hematology SC Hematology GA 319QA UT WOS:000087351600032 PM 10828036 ER PT J AU Leocani, L Cohen, LG Wassermann, EM Ikoma, K Hallett, M AF Leocani, L Cohen, LG Wassermann, EM Ikoma, K Hallett, M TI Human corticospinal excitability evaluated with transcranial magnetic stimulation during different reaction time paradigms SO BRAIN LA English DT Article DE motor cortex; human; reaction time; transcranial magnetic stimulation ID CEREBRAL EVOKED-POTENTIALS; IPSILATERAL MOTOR CORTEX; VOLUNTARY MOVEMENT; HUMAN-BRAIN; ELECTRICAL-STIMULATION; HEMISPHERIC-ASYMMETRY; PYRAMIDAL TRACT; CORPUS-CALLOSUM; ARM MOVEMENTS; HUMAN WRIST AB The aim of this study was to evaluate corticospinal excitability of both hemispheres during the reaction time (RT) using transcranial magnetic stimulation (TMS), Nine right-handed subjects performed right and left thumb extensions in simple (SRT), choice (CRT) and go/no-go auditory RT paradigms, TMS, inducing motor-evoked potentials (MEPs) simultaneously in the extensor pollicis brevis muscles bilaterally, was applied at different latencies from the tone, For all paradigms, MEP amplitudes on the side of movement increased progressively in the 80-120 ms before EMG onset, while the resting side showed inhibition. The inhibition was significantly more pronounced for right than for left thumb movements. For the left SRT, significant facilitation occurred on the right after EMG onset, Initial bilateral facilitation occurred in SRT trials with slow RT, After no-go tones, bilateral inhibition occurred at a time corresponding to the mean RT to go tones. The timing of the corticospinal rise in excitability on the side of movement was independent of task difficulty and RT, This suggests that corticospinal activation is, to some extent, in series and not in parallel with stimulus processing and response selection. Corticospinal inhibition on the side not to be moved implies that suppression of movement is an active process. This inhibition is more efficient for right- than for left-side movements in right-handed subjects, possibly because of left hemispheric dominance for movement. C1 NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. Univ Milan, Hosp San Raffaele, Dept Clin Neurophysiol, Milan, Italy. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10,Room 5N226,10 Ctr Dr MSC 1428, Bethesda, MD 20892 USA. RI Ikoma, Katsunori/D-8158-2012 NR 52 TC 211 Z9 212 U1 1 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD JUN PY 2000 VL 123 BP 1161 EP 1173 DI 10.1093/brain/123.6.1161 PN 6 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 324BZ UT WOS:000087603100009 PM 10825355 ER PT J AU Murphy, EJ Zhang, H Sorbi, S Rapoport, SI Gibson, GE AF Murphy, EJ Zhang, H Sorbi, S Rapoport, SI Gibson, GE TI Phospholipid composition and levels are not altered in fibroblasts bearing presenilin-1 mutations SO BRAIN RESEARCH BULLETIN LA English DT Article DE Alzheimer disease; presenilin-1; fibroblasts; phospholipids; plasmalogen; cholesterol ID PERFORMANCE LIQUID-CHROMATOGRAPHY; ALZHEIMERS-DISEASE FIBROBLASTS; ALPHA-KETOGLUTARATE DEHYDROGENASE; CULTURED SKIN FIBROBLASTS; AMYLOID PRECURSOR PROTEIN; STIMULATED CAMP FORMATION; ENHANCED INOSITOL UPTAKE; FATTY-ACID COMPOSITION; KINASE-C-ALPHA; APP670/671 MUTATION AB Lipid alterations have been reported in brain regions affected by Alzheimer disease (AD). The mechanisms causing these changes are poorly understood because it is difficult to study dynamic, biochemical processes in post-mortem brain. Fibroblasts derived from AD patients offer an alternative model to study disease-related alterations in lipid metabolism. Therefore, we measured the phospholipid levels and composition of fibroblasts from individuals bearing two different presenilin-1 mutations and compared these values to appropriate control fibroblasts. There were no differences between groups in phospholipid composition or in individual phospholipid levels, including the plasmalogens. Cholesterol levels and the cholesterol/phospholipid ratio were not different between presenilin-1 mutation bearing and control fibroblasts. Although these presenilin-1 mutation bearing fibroblasts have a number of biochemical changes related to AD, the absence of a change in phospholipid levels suggests that under these conditions, these cells are not useful in studying the mechanisms underlying the alterations in brain phospholipid levels associated with AD. However, these results do not preclude the possible use of other fibroblasts bearing AD-related mutations, e.g., APP mutations, to examine AD-related changes in brain lipid metabolism, or of these fibroblasts under different conditions. (C) 2000 Elsevier Science Inc. C1 NIA, Sect Brain Physiol & Metab, NIH, Bethesda, MD 20892 USA. Cornell Univ, Weill Med Coll, Burke Med Res Inst, Dept Neurol & Neurosci, White Plains, NY USA. Univ Florence, Dept Neurol & Psychiat Sci, Florence, Italy. RP Murphy, EJ (reprint author), NIA, Sect Brain Physiol & Metab, NIH, Bldg 10,Room 6C103, Bethesda, MD 20892 USA. OI sorbi, sandro/0000-0002-0380-6670 FU NIA NIH HHS [AG14930, AG11921] NR 65 TC 3 Z9 3 U1 2 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD JUN PY 2000 VL 52 IS 3 BP 207 EP 212 DI 10.1016/S0361-9230(00)00257-4 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 318HG UT WOS:000087277400007 PM 10822162 ER PT J AU Jemal, A Devesa, SS Fears, TR Fraumeni, JF AF Jemal, A Devesa, SS Fears, TR Fraumeni, JF TI Retinoblastoma incidence and sunlight exposure SO BRITISH JOURNAL OF CANCER LA English DT Article DE retinoblastoma; sunlight; race; economic development; tropical climate; SEER ID CHILDHOOD-CANCER; MELANOMA AB To evaluate positive findings from an earlier report, we studied the relation between retinoblastoma incidence and ultraviolet (UV-B) radiation levels in the Surveillance, Epidemiology, and End Results (SEER) programme areas of the USA using weighted regression, as well as in international data after adjusting for race, economic development, and climate. The association was not statistically significant within the USA (P > 0.20). At an international level, the relation was significant overall and after adjusting for economic development, but it was not significant after adjusting for race and tropical climate, suggesting that environmental factors other than UV-B may be responsible for the geographic patterns of retinoblastoma. (C) 2000 Cancer Research Campaign. C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. RP Jemal, A (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd EPS 8049, Rockville, MD 20892 USA. NR 15 TC 13 Z9 13 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUN PY 2000 VL 82 IS 11 BP 1875 EP 1878 DI 10.1054/bjoc.2000.1215 PG 4 WC Oncology SC Oncology GA 315UY UT WOS:000087132400020 PM 10839306 ER PT J AU Eanes, ED Hailer, AW AF Eanes, ED Hailer, AW TI Anionic effects on the size and shape of apatite crystals grown from physiological solutions SO CALCIFIED TISSUE INTERNATIONAL LA English DT Article DE apatite; albumin; calcification; citrate; mineralization ID CONSTANT COMPOSITION; BONE TISSUE; OSTEOGENESIS IMPERFECTA; ELECTRON-DIFFRACTION; DISSOLVED ALBUMIN; ORGANIC MATRIX; SEEDED GROWTH; HYDROXYAPATITE; CRYSTALLIZATION; COLLAGEN AB Comparatively little is known of the role tissue fluid electrolytes have in establishing the size and shape of apatite crystals deposited in skeletal tissues. In vitro accretion experiments using synthetic apatite seed crystals comparable in size to bone apatite were performed to assess the extent to which these crystalline features may be affected by direct electrolyte/mineral interactions. A constant composition method was used to maintain the accretion reactions under physiological-like solution conditions (1.33 mmol/liter Ca2+, 1.0 mmol/liter total inorganic phosphate, (0 or 26) mmol/liter carbonate, 270 mmol/kg osmolality, pH 7.4, 37 degrees C). When the mass of the new accretions equaled the initial seed mass, the solids were harvested and the net change in crystal size resulting from the new accretions was assessed by X-ray diffraction line-broadening analysis. All the electrolytes examined in this study inhibited the accretion rate. The order of effectiveness was phosvitin > polyaspartate approximate to polyglutamate > 1-hydroxyethylidene-1,1-bisphosphonate (HEBP) > bovine serum albumin (BSA) > citrate. Citrate and BSA also reduced the mean crystal size of the harvested solids compared with those harvested in the absence of added electrolyte, a finding that suggests that citrate and BSA suppressed growth of the seed crystals in favor of the proliferation of new smaller crystals. In contrast, a net increase in size following accretion compared with controls suggests that the other more strongly inhibiting electrolytes stimulated growth of the primary seed crystals and/or of the secondary crystals. These size changes, however, were anisotropic, with the anions effecting primarily increases in crystal width/thickness rather than in length. The effects were also more pronounced in the presence of carbonate. Our findings suggest that the strength of the interaction with the crystal surface may be relatively more important than molecular size or conformational complexity in establishing the effect that electrolytes have on apatite growth and proliferation. The results also suggest that adsorbed electrolytes may be a significant factor in controlling the size of apatite crystals in skeletal tissues by inducing proliferation of new crystals and/or affecting crystal shape by selectively modifying growth of the lateral dimensions. C1 Natl Inst Stand & Technol, Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, Res Associate Program, Gaithersburg, MD 20899 USA. RP Eanes, ED (reprint author), Natl Inst Stand & Technol, Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, Res Associate Program, 100 Bur Dr,Stop 8545, Gaithersburg, MD 20899 USA. NR 38 TC 16 Z9 16 U1 2 U2 9 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0171-967X J9 CALCIFIED TISSUE INT JI Calcif. Tissue Int. PD JUN PY 2000 VL 66 IS 6 BP 449 EP 455 DI 10.1007/s002230010090 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 317VR UT WOS:000087248100010 PM 10821882 ER PT J AU Kennel, SJ Chappell, LL Dadachova, K Brechbiel, MW Lankford, TK Davis, IA Stabin, M Mirzadeh, S AF Kennel, SJ Chappell, LL Dadachova, K Brechbiel, MW Lankford, TK Davis, IA Stabin, M Mirzadeh, S TI Evaluation of Ac-225 for vascular targeted radioimmunotherapy of lung tumors SO CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS LA English DT Article DE Ac-225; HEHA; vascular targeting; radiotoxicity ID ALPHA-PARTICLE EMITTER; MONOCLONAL-ANTIBODY; ACETIC ACIDS; BI-213; COMPLEXES; RADIOTOXICITY; ACTINIUM-225 AB Several alpha particle emitting radioisotopes have been studied for use in radioimmunotherapy. Ac-225 has the potential advantages of a relatively long half life of 10 days, and a yield of 4 alpha emissions in its decay chain with a total energy release of similar to 28 MeV. A new, 12 coordination site chelating ligand, HEHA, has been chemically modified for coupling to targeting proteins without loss of chelating ability. HEHA was coupled with MAb 201B which binds to thrombomodulin and accumulates efficiently in murine lung. Ac-225 was bound to the HEHA-MAb 201B conjugate and injected into BALB/c mice bearing lung tumor colonies of EMT-6 mammary carcinoma. Biodistribution data at 1 and 4 h postinjection indicated that, as expected, Ac-225 was delivered to lung efficiently (>300 % ID/g). The Ac-225 was slowly released from the lung with an initial t(1/2) = 49 h, and the released Ac-225 accumulated in the liver. Injection of free HEHA was only partially successful in scavenging free Ac-225. I, addition to the slow release of Ac-225 from the chelate, data indicated that decay daughters of Ac-225 were also released from the lung. Immediately after organ harvest, the level of Bi-213, the third alpha-decay daughter was found to be deficient in the lungs and to be in excess in the kidney, relative to equilibrium values. Injected doses of Ac-225 MAb 201B of 1.0 mu Ci, delivering a minimum calculated absorbed dose of about 6 Gy to the lungs, was effective in killing lung tumors, but also proved acutely radiotoxic. Animals treated with 1.0 mu Ci or move of the Ac-225 radioconjugate died of a wasting syndrome within days with a dose dependent relationship. We conclude that the potential for Ac-225 as a radioimmunotherapeutic agent is compromised not only by the slow release of Ac-225 from the HEHA chelator, but most importantly by the radiotoxicity associated with decay daughter radioisotopes released from the target organ. C1 Oak Ridge Natl Lab, Div Life Sci, Oak Ridge, TN 37831 USA. NCI, Div Clin Sci, NIH, Bethesda, MD 20892 USA. UFPE, Dept Nucl Energy, Recife, PE, Brazil. RP Kennel, SJ (reprint author), Oak Ridge Natl Lab, Div Life Sci, POB 2008,Bldg 4500S,Rm F150,Bethel Valley Rd, Oak Ridge, TN 37831 USA. RI Dadachova, Ekaterina/I-7838-2013 FU NHLBI NIH HHS [HL09718] NR 29 TC 38 Z9 40 U1 3 U2 9 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1084-9785 J9 CANCER BIOTHER RADIO JI Cancer Biother. Radiopharm. PD JUN PY 2000 VL 15 IS 3 BP 235 EP 244 DI 10.1089/108497800414329 PG 10 WC Oncology; Medicine, Research & Experimental; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Research & Experimental Medicine; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging GA 339HM UT WOS:000088471700003 PM 10941530 ER PT J AU Mariani, G Villa, G Gipponi, M Bianchi, P Buffoni, F Agnese, G Vecchio, C Tomei, D Carli, F Nicolo, G Canavese, G AF Mariani, G Villa, G Gipponi, M Bianchi, P Buffoni, F Agnese, G Vecchio, C Tomei, D Carli, F Nicolo, G Canavese, G TI Mapping sentinel lymph node in breast cancer by combined lymphoscintigraphy, blue-dye, and intraoperative gamma-probe SO CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS LA English DT Article DE breast cancer; sentinel lymph node; axillary dissection; lymphoscintigraphy; gamma-probe guided surgery ID AXILLARY DISSECTION; BIOPSY; LYMPHADENECTOMY; SURGERY AB The purpose of the present work was two-fold: I) to evaluate the predictive value of the sentinel lymph node (sLN) versus the axillary-node status in patients with T-1-T-2 breast cancer and 2) to form an experimental basis for a randomized trial in which one group of patients with non-metastatic sLN will not have axillary dissection. Of a group of 284 patients considered for this analysis, 264 had a T-1 cancer (16 T-1a, 37 T-1b and 211 T-1c), while 20 had a T-2 cancer; 243 patients were in clinical stage N-0 and 41 were N-1. All patients underwent lymphoscintigraphy 18 hr before surgery: 10 MBq in 0.15 mt of Tc-99m-human albumin nanocolloids (particle size between 50-80 nm) was injected subdermally at the cutaneous projection of the tumor. Static gamma-camera images were acquired every 10-15 minutes until scintigraphic identification of the sLN. At surgery, 1-2 mt of Patent-Blue Violet was injected subdermally, and the sLN was searched by gamma-probe and by the dye method. The surgically isolated sLN was processed for intraoperative Hematoxylin & Eosin (H&E) histology, then for delayed histological and immunohistochemical examinations. The sLN was successfully identified by the combined radioisotopic procedure and Patent-Blue dye technique in 278/284 cases (97.9%). The Patent-Blue dye technique alone identified fewer sLNs than the ra dioisotopic procedure alone (56.3% versus 97.2%). Analysis of the predictive value of the sLN as to the status of axillary lymph nodes was limited to 197 patients undergoing standard axillary dissection irrespective of the sLN status. Overall, 63/191 (33%) identified sLNs were metastatic, the sLN alone being involved in 37/63 (58.7%) patients; a positive axilla status with negative sLN was found in 10/73 patients with metastatic involvement (13.7% false-negative rate). In conclusion, subdermal lymphoscintigraphy was confirmed to be an effective technique for sLN mapping; the addition of Patent-BLue dye minimally improved intra-surgical identification of the sLN. There was a high, but not absolute, correlation between a negative sLN and a negative axilla. C1 Univ Genoa, DIMI, Nucl Med Serv, Sch Med, I-16132 Genoa, Italy. Natl Canc Inst, Div Surg Oncol, Genoa, Italy. Natl Canc Inst, Div Pathol, Genoa, Italy. RP Mariani, G (reprint author), Univ Genoa, DIMI, Nucl Med Serv, Sch Med, Viale Benedetto XV N 6, I-16132 Genoa, Italy. NR 33 TC 13 Z9 13 U1 0 U2 2 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1084-9785 J9 CANCER BIOTHER RADIO JI Cancer Biother. Radiopharm. PD JUN PY 2000 VL 15 IS 3 BP 245 EP 252 DI 10.1089/108497800414338 PG 8 WC Oncology; Medicine, Research & Experimental; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Research & Experimental Medicine; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging GA 339HM UT WOS:000088471700004 PM 10941531 ER PT J AU Nielsen, MB Marincola, FM AF Nielsen, MB Marincola, FM TI Melanoma vaccines: the paradox of T cell activation without clinical response SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article; Proceedings Paper CT 15thy Bristol-Myers Squibb Nagoya International Cancer Treatment Symposium CY SEP 10-11, 1999 CL NAGOYA, JAPAN DE tumor immunity; vaccination; cytotoxic T lymphocytes; localization; human leukocyte antigen tetramers ID IMMUNE-RESPONSE; ELISPOT ASSAY; REACTIVE CTL; LYMPHOCYTES; TUMOR; FREQUENCY; ANTIGENS; IMMUNIZATION; VACCINATION; EXPRESSION AB In recent years significant progress in the understanding of the immune biology of melanoma has evolved from the identification of melanoma antigens (MAs) recognized by T cells. MAs consist of intracellular proteins that are expressed on the surface of cancer cells in association with human leukocyte antigen (HLA) class I molecules and therefore are suitable targets for cytotoxic T lymphocytes (CTLs). Several new monitoring strategies have been implemented to evaluate the status of activation and localization of vaccine-induced T cells in the peripheral circulation as well as the tumor site, including limiting dilution, in vitro sensitization, and ELISPOT. Previous studies aimed at monitoring patients receiving vaccination have utilized mainly those three methods. These methods have demonstrated that antigen-specific vaccination can elicit immune responses detectable in the peripheral blood of immunized patients. These assays, however, have been faulted by their requirement for in vitro expansion of T cells (limiting dilution or in vitro sensitization) or for limited sensitivity (ELISPOT). More recently, the use of soluble HLA/peptide complex tetramers, intracellular fluorescence-activated cell sorting (FACS) analysis, and real-time polymerase chain reaction (PCR) has been proposed for the monitoring of vaccine trials. These methods have the appeal of allowing direct enumeration of T cells specific for a particular epitope within relevant samples such as peripheral blood lymphocytes, lymph nodes, and tumors. We are evaluating whether utilizing a combination of HLA/peptide tetramer (tHLA) together with Taqman-based real-time reverse-transcription (RT)-PCR and intracellular FACS analysis could establish a direct and comprehensive strategy for the assessment of epitope-specific immune response in vivo. In conditions close to those of the tumor microenviroment or in peripheral blood lymphocytes, however, a different status of T cell activation call be expected due to a direct stimulation of T cells by tumor or antigen-presenting cells. We observed that activated T cells can easily be detected ill the peripheral blood of patients who have received MA-specific vaccines. However, when T cells are stimulated with their relevant epitope, a high level of T cell receptor downregulation occurs that does not allow identification of vaccine-specific T cells directly with tHLA. Thus evaluation of epitope-specific T cells at the tumor site, where they might be exposed to stimulation by interaction with tumor cells and/or in bulk peripheral blood mononuclear cells, might be more efficiently analyzed with functional methods such as intracellular FACS and Taqman-based real time RT-PCR. C1 NCI, Surg Branch, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), NCI, Surg Branch, Bldg 10,Room 2B42,10 Ctr Dr MSC 1502, Bethesda, MD 20892 USA. NR 28 TC 27 Z9 29 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD JUN PY 2000 VL 46 SU S BP S62 EP S66 DI 10.1007/PL00014052 PG 5 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 340KY UT WOS:000088532700013 PM 10950150 ER PT J AU Keir, ST Dolan, ME Pegg, AE Lawless, A Moschel, RC Bigner, DD Friedman, HS AF Keir, ST Dolan, ME Pegg, AE Lawless, A Moschel, RC Bigner, DD Friedman, HS TI O-6-benzylguanine-mediated enhancement of nitrosourea activity in Mer(-) central nervous system tumor xenografts - implications for clinical trials SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE nitrosourea; glioma; brain tumors ID O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; ALKYLATING-AGENTS; CHEMOTHERAPY; 1,3-BIS(2-CHLOROETHYL)-1-NITROSOUREA; MEDULLOBLASTOMA; RESISTANCE; PROTEIN; CELLS AB Purpose: To evaluate the role of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) plus O-6-benzylguanine (O-6-BG) in the treatment of both Mer(+) and Mer(-) tumors. Methods: The effect of pretreatment with O-6-BG on the activity of BCNU against Mer(-) human central nervous tumor xenografts D-54 MG and D-245 MG was evaluated in athymic nude mice. Results: BCNU (1.0 LD10; dose lethal to 10% of treated animals) produced growth delays of 8.9 days and 7.5 days and tumor regressions in six of ten and one of nine animals against D-54 MG, which was derived from a human malignant glioma xenograft, Dose reduction of BCNU to 0.38 LD10 eliminated antitumor activity. The combination of BCNU (0.38 LD10) plus O-6-BG produced growth delays of 8.8 days and 7.9 days, with tumor regressions in four of tell and two of nine animals, respectively. BCNU (1.0 LD10) produced a growth delay of 49.8 days and tell of ten tumor regressions against D-245 MG, which was derived from a glioblastoma multiforme. BCNU (0.38 LD10) produced a growth delay of 19.4 days, with nine of ten tumor regressions. The combination of BCNU (0.38 LD10) plus O-6-BG produced a growth delay of 65.7 days and seven of eight tumor regressions. Conclusion: These results suggest that the combination of BCNU plus O-6-BG may be a rational intervention for both Mer(+) as well as Mer(-) tumors. C1 Duke Univ, Med Ctr, Dept Pediat, South Hosp, Durham, NC 27710 USA. Univ Chicago, Dept Med, Chicago, IL 60637 USA. Penn State Univ, Milton S Hershey Med Ctr, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. NCI, Chem Carcinogenesis Lab, Frederick, MD 21702 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. RP Friedman, HS (reprint author), Duke Univ, Med Ctr, Dept Pediat, South Hosp, Box 3624, Durham, NC 27710 USA. NR 21 TC 12 Z9 12 U1 1 U2 2 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD JUN PY 2000 VL 45 IS 6 BP 437 EP 440 DI 10.1007/s002800051016 PG 4 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 321LA UT WOS:000087455900001 PM 10854129 ER PT J AU Chie, L Amar, S Kung, HF Lin, MCM Chen, H Chung, DL Adler, V Ronai, Z Friedman, FK Robinson, RC Kovac, C Brandt-Rauf, PW Yamaizumi, Z Michl, J Pincus, MR AF Chie, L Amar, S Kung, HF Lin, MCM Chen, H Chung, DL Adler, V Ronai, Z Friedman, FK Robinson, RC Kovac, C Brandt-Rauf, PW Yamaizumi, Z Michl, J Pincus, MR TI Induction of oocyte maturation by jun-N-terminal kinase (JNK) on the oncogenic ras-p21 pathway is dependent on the raf-MEK signal transduction pathway SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE oncogenic ras-p21; oocyte maturation; dominant negative mutant of raf ID ACTIVATED PROTEIN-KINASES; MOLECULAR-DYNAMICS; BINDING DOMAIN; XENOPUS OOCYTES; RAF-P74 PROTEIN; P21 PROTEIN; MAP KINASE; WILD-TYPE; INHIBITION; COMPLEXES AB Purpose: We have previously found that microinjection of activated MEK (mitogen activated kinase kinase) and ERK (mitogen-activated protein; MAP kinase) fails to induce oocyte maturation, but that maturation, induced by oncogenic ras-p21 and insulin-activated cell ras-p21, is blocked by peptides from the ras-binding domain of raf. We also found that jun kinase (JNK), on the stress-activated protein (SAP) pathway, which is critical to the oncogenic ras-p21 signal transduction pathway, is a strong inducer of oocyte maturation. Our purpose in this study was to determine the role of the raf-MEK-MAP kinase pathway in oocyte maturation and how it interacts with JNK from the SAP pathway. Methods: We microinjected raf dominant negative mutant mRNA (DN-raf) and the MEK-specific phosphatase, MKP-T4, either together with oncogenic p21 or c-raf mRNA, into oocytes or into oocytes incubated with insulin to determine the effects of these raf-MEK-MAP kinase pathway inhibitors. Results: We found that oocyte maturation induced by both oncogenic and activated normal p21 is inhibited by both DN-raf and by MKP-T4. The latter more strongly blocks the oncogenic pathway. Also an mRNA encoding a constitutively activated MEK strongly induces oocyte maturation that is not inhibited by DN-raf or by MKP-T4. Surprisingly, we found that oocyte maturation induced by JNK is blocked both by DN-raf and MKP-T4. Furthermore, we discovered that c-raf induces oocyte maturation that is inhibited by glutathione-S-transferase (GST), which we have found to be a potent and selective inhibitor of JNK. Conclusion: We conclude that there is a strong reciprocal interaction between the SAP pathway involving JNK and the raf-MEK-MAP kinase pathway and that oncogenic ras-p21 can be preferentially inhibited by MEK inhibitors. The results imply that blockade of both MEK and JNK-oncogenic ras-p21 interactions may constitute selective synergistic combination chemotherapy against oncogenic ras-induced tumors. C1 Vet Adm Med Ctr, Dept Pathol & Lab Med, Brooklyn, NY 11209 USA. Long Isl Univ, Dept Biol, Brooklyn, NY 11201 USA. Long Isl Univ, Dept Chem, Brooklyn, NY 11201 USA. NCI, Lab Biochem Physiol, Frederick, MD 21702 USA. CUNY, Mt Sinai Med Ctr, Ruttenberg Canc Ctr, New York, NY 10029 USA. NCI, Mol Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. Columbia Univ, Sch Publ Hlth, Div Environm Hlth Sci, New York, NY 10032 USA. NCI, Tokyo, Japan. SUNY Hlth Sci Ctr, Dept Pathol, Brooklyn, NY 11203 USA. Dept Microbiol, Brooklyn, NY USA. Dept Anat & Cell Biol, Brooklyn, NY USA. RP Pincus, MR (reprint author), Vet Adm Med Ctr, Dept Pathol & Lab Med, 800 Poly Pl, Brooklyn, NY 11209 USA. RI Friedman, Fred/D-4208-2016; OI RONAI, ZEEV/0000-0002-3859-0400 FU NCI NIH HHS [CA 42500, CA 69243] NR 35 TC 24 Z9 24 U1 0 U2 1 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD JUN PY 2000 VL 45 IS 6 BP 441 EP 449 DI 10.1007/s002800051017 PG 9 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 321LA UT WOS:000087455900002 PM 10854130 ER PT J AU Millikan, R Pittman, G Tse, CK Savitz, DA Newman, B Bell, D AF Millikan, R Pittman, G Tse, CK Savitz, DA Newman, B Bell, D TI Glutathione S-transferases M1, T1, and P1 and breast cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CATECHOL-O-METHYLTRANSFERASE; GENETIC POLYMORPHISMS; RISK; SUSCEPTIBILITY; GSTM1; ASSOCIATION; GSTT1; EPIDEMIOLOGY; GENOTYPES; FREQUENCY AB We examined associations for glutathione S-transferases M1 (GSTM1), T1 (GSTT1), and P1 (GSTP1) genotypes and breast cancer in the Carolina Breast Cancer Study, a population-based, case-control study in North Carolina. Odds ratios mere close to the null value for each GST locus among African-American women (278 cases and 271 controls) and white women (410 cases and 392 controls), as well as pre- and postmenopausal women. For women with a history of breast cancer in one or more first-degree relatives, odds ratios were 2.1 (95% confidence interval, 1.0-4.2) for GSTM1 null and 1.9 (0.8-4.6) for GSTT1 null genotypes, Among women with a family history, age at diagnosis was significantly earlier for those with the GSTM1 null genotype, We did not observe strong evidence for modification of odds ratios for smoking according to GST genotypes, There was no evidence for combined effects of GSTM1, GSTT1, and GSTP1 genotypes, and there were no combined effects for GST genotypes and the catechol O-methyltransferase genotype, We conclude that GSTM1, GSTT1, and GSTP1 genotypes do not play a strong role in susceptibility to breast cancer. However, the role of GST genotypes in age at onset and risk of breast cancer among women with a family history merits further investigation. C1 Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Med, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. Natl Inst Environm Hlth Sci, Genet Risk Grp, Res Triangle Pk, NC 27709 USA. Queensland Univ Technol, Sch Publ Hlth, Brisbane, Qld 4059, Australia. RP Millikan, R (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, CB 7400, Chapel Hill, NC 27599 USA. FU NCI NIH HHS [P50-CA58223, R21-CA66201]; NIEHS NIH HHS [R01-ES07128] NR 31 TC 81 Z9 85 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2000 VL 9 IS 6 BP 567 EP 573 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 324RC UT WOS:000087634300006 PM 10868690 ER PT J AU Kabuto, M Akiba, S Stevens, RG Neriishi, K Land, CE AF Kabuto, M Akiba, S Stevens, RG Neriishi, K Land, CE TI A prospective study of estradiol and breast cancer in Japanese women SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CASE-CONTROL INTERVIEW; SEX-HORMONE LEVELS; A-BOMB SURVIVORS; POSTMENOPAUSAL WOMEN; SERUM ESTROGEN; RISK; GUERNSEY AB Few studies have prospectively examined endogenous hormone levels as risk factors for breast cancer, The present study compares prediagnostic hormone levels using stored serum from breast cancer cases and controls selected from the Life Span Study population of the Radiation Effects Research Foundation in Hiroshima and Nagasaki, Japan. Stored serum samples collected in 1968-1970 were assayed for 72 women subsequently diagnosed with breast cancer and 150 control subjects in 72 case-control sets matched on age, date of blood collection, exposure, radiation dose, and city, Serum levels were determined for sex hormone binding globulin, total estradiol (E-2), bioavailable E-2, dehydroepiandrosterone sulfate, and prolactin, Matched case-control comparisons of hormone levels were carried out by conditional logistic regression and were adjusted for menopausal status at the time of blood drawing. The odds ratio per unit log change in bioavailable E-2 was 2.2 [95% confidence interval (CI), 1.02-5.3] for all subjects, and 2.3 (95% CI, 0.55-6.8) and 2.1 (95% CI, 0.55-9.7), respectively, based only on premenopausal or postmenopausal serum. The estimated odds ratios in each quintile of bioavailable E2 level, using the lowest quintile as referent, were 1.00, 1.89, 1.43, 3.45, and 3.37 (P for trend = 0.035), For sex hormone binding globulin, the overall odds ratio was 0.58 (95% CI, 0.14-2.26), and 1.00 (95% CI, 0.19-5.45) and 0.21 (95% CI, 0.02-1.88) based on premenopausal and postmenopausal serum, respectively, This study offers further prospective support for the hypothesis that a high level of biologically available E-2 is a risk factor for the subsequent development of breast cancer. C1 Radiat Effects Res Fdn, Dept Clin Studies, Minami Ku, Hiroshima 7320815, Japan. Radiat Effects Res Fdn, Dept Epidemiol, Hiroshima, Japan. Natl Inst Environm Studies, Environm Risk Res Div, Tsukuba, Ibaraki 3050053, Japan. Kagoshima Univ, Fac Med, Dept Publ Hlth, Kagoshima 8900075, Japan. Pacific NW Natl Lab, Richland, WA 99352 USA. NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. RP Neriishi, K (reprint author), Radiat Effects Res Fdn, Dept Clin Studies, Minami Ku, Hiroshima 7320815, Japan. NR 22 TC 118 Z9 121 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2000 VL 9 IS 6 BP 575 EP 579 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 324RC UT WOS:000087634300007 PM 10868691 ER PT J AU Lan, Q He, XZ Costa, DJ Tian, LW Rothman, N Hu, GZ Mumford, JL AF Lan, Q He, XZ Costa, DJ Tian, LW Rothman, N Hu, GZ Mumford, JL TI Indoor coal combustion emissions, GSTM1 and GSTT1 genotypes, and lung cancer risk: A case-control study in Xuan Wei, China SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID TRANSFERASE SUPERGENE FAMILY; BLADDER-CANCER; M1 GSTM1; GLUTATHIONE; SUSCEPTIBILITY; COUNTY AB The lung cancer mortality rate in Xuan Wei County, China is among the highest in the country and has been associated with exposure to indoor smoky coal emissions that contain high levels of polycyclic aromatic hydrocarbons, This risk may be modified by variation in metabolism genes, including GSTM1, which encodes an enzyme known to detoxify polycyclic aromatic hydrocarbons. To investigate the relationship between GST genotypes and lung cancer risk in Xuan Wei County, we analyzed GSTM1 and GSTT1 genotypes in a population-based case-control study. A total of 122 lung cancer patients and 122 controls, individually matched by age, sex, and home fuel type, were studied. Compared to subjects who used less than 130 tons of smoky coal during their lifetime, heavier users (greater than or equal to 130 tons) had a 2.4-fold (95% confidence interval, 1.3-4.4) increased risk of lung cancer. The GSTM1-null genotype was associated with a 2.3-fold (95% confidence interval, 1.3-4.2) increased risk of lung cancer. Furthermore, there was some evidence that smoky coal use was more strongly associated with lung cancer risk among GSTM1-null versus GSTM1-positive individuals. In contrast, the GSTT1 genotype was not significantly associated with lung cancer risk. Our data suggest that the GSTM1-null genotype may enhance susceptibility to air pollution from indoor coal combustion emissions. C1 NIH, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, NCI, Bethesda, MD 20892 USA. Univ N Carolina, Ctr Environm Med & Lung Biol, Chapel Hill, NC 27599 USA. Chinese Acad Prevent Med, Beijing 100050, Peoples R China. Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. Biomar Int, Chapel Hill, NC 27514 USA. US EPA, Res Triangle Pk, NC 27711 USA. RP Lan, Q (reprint author), NIH, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, NCI, MSC 7240,6120 Execut Blvd,EPS 8109, Bethesda, MD 20892 USA. RI Tian, Linwei/A-9736-2009 OI Tian, Linwei/0000-0002-4739-1534 NR 22 TC 106 Z9 112 U1 2 U2 10 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2000 VL 9 IS 6 BP 605 EP 608 PG 4 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 324RC UT WOS:000087634300012 PM 10868696 ER PT J AU Probst-Hensch, NM Bell, DA Watson, MA Skipper, PL Tannenbaum, SR Chan, KK Ross, RK Yu, MC AF Probst-Hensch, NM Bell, DA Watson, MA Skipper, PL Tannenbaum, SR Chan, KK Ross, RK Yu, MC TI N-acetyltransferase 2 phenotype but not NAT1*10 genotype affects aminobiphenyl-hemoglobin adduct levels SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BLADDER-CANCER; N-ACETYLTRANSFERASE-1 NAT1; DNA-ADDUCTS; IN-VIVO; POLYMORPHISMS; SMOKING; ACETYLATION; RISK; CARCINOGENS; BENZIDINE AB Aminobiphenyls (ABPs) in tobacco have been implicated in bladder cancer etiology in smokers. N-Acetylation of ABPs in the liver, predominantly by the N-acetyltransferase 2 (NAT2) isozyme, represents a detoxification pathway, whereas O-acetylation of N-hydroxy-ABPs in the bladder, predominantly by the N-acetyltransferase 1 (NAT1) isozyme, represents a bioactivation pathway, We and others have demonstrated that NAT2 phenotype affects 3- and 4-ABP-hemoglobin adduct levels (higher levels in slow acetylators), which are considered valid biomarkers of the internal dose of ABP to the bladder, We have also shown that NAT1 genotype (NAT1*10 allele) is associated with increased DNA adduct levels in urothelial tissue and higher risk of bladder cancer among smokers. It is not known whether NAT1*10 genotype influences ABP-hemoglobin adduct levels. Therefore, me assessed 403 primarily non-Hispanic white residents of Los Angeles County for their NAT2 acetylator phenotype, NAT1*10 acetylator genotype, and 3- and 1-ABP-hemoglobin adduct levels. Eighty-two subjects were current tobacco smokers of varying intensities, Tobacco smokers had significantly higher mean 3- and I-ABP-hemoglobin adduct levels relative to nonsmokers. The levels increased with increased amounts smoked per day (two-sided, P < 0.0001 in all cases). With adjustment for NAT1 genotype and race, the smoking-adjusted geometric mean level of 3-ABP-hemoglobin adducts in NAT2 slow acetylators was 47% higher than that in NAT2 rapid acetylators (P = 0.01), The comparable value for 4-ABP-hemoglobin adducts was 17% (P = 0.02). In contrast, no association between NAT1*10 genotype and 3- or 4 ABP-hemoglobin adduct levels was observed after adjustment for NAT2 phenotype, smoking, and race. The present study suggests that the impact of the NAT1*10 genotype on 3- and 4-ABP-hemoglobin adducts is noninformative on the possible association between NAT1 activity and bladder cancer risk. C1 Univ Basel, Inst Social & Prevent Med, CH-4051 Basel, Switzerland. Univ So Calif, Dept Prevent Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. MIT, Div Toxicol, Cambridge, MA 02139 USA. NIEHS, Lab Computat Biol & Risk Anal, Res Triangle Pk, NC 27709 USA. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. RP Probst-Hensch, NM (reprint author), Univ Basel, Inst Social & Prevent Med, Steinengraben 49, CH-4051 Basel, Switzerland. FU NCI NIH HHS [R01 CA65726, R35 CA53890]; NIEHS NIH HHS [P01 ES05622] NR 24 TC 38 Z9 38 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2000 VL 9 IS 6 BP 619 EP 623 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 324RC UT WOS:000087634300014 PM 10868698 ER PT J AU Tseng, M Greenberg, ER Sandler, RS Baron, JA Haile, RW Blumberg, BS McGlynn, KA AF Tseng, M Greenberg, ER Sandler, RS Baron, JA Haile, RW Blumberg, BS McGlynn, KA TI Serum ferritin concentration and recurrence of colorectal adenoma SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BODY IRON STORES; DIETARY IRON; ELDERLY POPULATION; PLASMA FERRITIN; WHOLE DIET; RISK; CANCER; POLYPS; ABSORPTION; COLON AB Both body iron stores and dietary iron intake have been reported to increase risk of colorectal neoplasms. We assessed whether serum ferritin concentration was associated with recurrence of colorectal adenomas among 733 individuals with baseline determinations of ferritin as part of a multicenter clinical trial of antioxidant supplements for adenoma prevention. All study participants had at least one adenoma removed within 3 months before enrollment, and 269 of them developed one or more adenomas between follow-up colonoscopies conducted 1 and 4 years after enrollment. Baseline serum ferritin concentrations were analyzed both as a log-transformed continuous variable and as a categorical variable, defined as whether iron stores mere nonreplete and low (ferritin less than or equal to 30 mu g/liter), nonreplete and borderline (31-70 mu g/liter), replete and adequate (71-160 mu g/liter), or replete and high (>160 mu g/liter). Analyses were based on multiple logistic regression models, including age, sex, study center, energy, alcohol, fiber, folate, and total fat intake, number of months between colonoscopic examinations, smoking status, and aspirin use. Overall, there was no statistically significant linear association between log ferritin concentration and adenoma recurrence (P = 0.33). Risk of adenoma recurrence was modestly increased among participants with ferritin concentrations >70 mu g/liter relative to those with lower ferritin (odds ratio, 1.39; 95% confidence interval, 0.96-2.02), This result seemed more pronounced among women than men. Dietary intake of iron and red meat was inversely associated with adenoma recurrence among participants with replete iron stores but not consistently associated among those with nonreplete stores. Our findings suggest that any role of iron stores and dietary iron in influencing risk of colorectal adenoma recurrence is likely complex. C1 Fox Chase Canc Ctr, Div Populat Sci, Philadelphia, PA 19111 USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Dartmouth Med Sch, Dept Med, Hanover, NH 03755 USA. Dartmouth Med Sch, Dept Community & Family Med, Hanover, NH 03755 USA. Dartmouth Med Sch, Norris Cotton Canc Ctr, Hanover, NH 03755 USA. Univ N Carolina, Ctr Gastrointestinal Biol & Dis, Chapel Hill, NC 27599 USA. Univ So Calif, Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. NCI, Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Tseng, M (reprint author), Fox Chase Canc Ctr, Div Populat Sci, 7701 Burholme Ave, Philadelphia, PA 19111 USA. RI Tseng, Marilyn/B-9334-2016 OI Tseng, Marilyn/0000-0002-9969-9055 NR 36 TC 18 Z9 20 U1 2 U2 6 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2000 VL 9 IS 6 BP 625 EP 630 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 324RC UT WOS:000087634300015 PM 10868699 ER PT J AU Shiao, YH Palli, D Caporaso, NE Alvord, WG Amorosi, A Nesi, G Saieva, C Masala, G Fraumeni, JF Rice, JM AF Shiao, YH Palli, D Caporaso, NE Alvord, WG Amorosi, A Nesi, G Saieva, C Masala, G Fraumeni, JF Rice, JM TI Genetic and immunohistochemical analyses of p53 independently predict regional metastasis of gastric cancers SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID TUMOR-SUPPRESSOR GENE; ACCUMULATION; CONFORMATION; PROGNOSIS; MUTATIONS; PROTEIN; LIFE AB Either p53 gene mutation or immunohistochemical detection of p53 protein has not been consistently shown to have prognostic significance in human cancers, including gastric carcinomas. One hypothesis to explain this inconsistency is that some p53 mutations and p53 protein accumulation are not indicative of tumor progression. To test this hypothesis, we categorized p53 status in 105 gastric carcinomas according to types of mutations, numerical scores of immunohistochemical staining (MC), or combinations thereof. The p53 status was then correlated with metastasis to liver or peritoneum, Gastric cancers with no p53 mutations were significantly less likely to metastasize than tumors with mutations, Intermediate MC scores were inversely associated with metastasis. A substantial number of gastric cancers (31 of 105) showed positive p53 immunostaining without detectable mutations (p53-/IHC+), which suggested an accumulation of wild-type p53 protein, and also a significantly lon er risk for metastasis. After adjusting for depth of invasion and lymph node involvement, the p53-/IHC+ combination predicted low metastatic risk better than either p53- or IHC+ with intermediate scores. These findings suggest that an accumulation of wild-type p53 protein occurs in gastric cancer cells and represents a stress-response mechanism that lowers metastatic potential. C1 NIH, Comparat Carcinogenesis Lab, Natl Canc Inst, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NIH, Data Management Serv Inc, Natl Canc Inst, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Ctr Studio & Prevenz Oncol, Epidemiol Unit, I-50131 Florence, Italy. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Florence, Dept Pathol, I-50134 Florence, Italy. Int Agcy Res Canc, F-69372 Lyon 08, France. RP Shiao, YH (reprint author), NIH, Comparat Carcinogenesis Lab, Natl Canc Inst, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. OI saieva, calogero/0000-0002-0117-1608; PALLI, Domenico/0000-0002-5558-2437; Masala, Giovanna/0000-0002-5758-9069 NR 21 TC 28 Z9 30 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2000 VL 9 IS 6 BP 631 EP 633 PG 3 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 324RC UT WOS:000087634300016 PM 10868700 ER PT J AU Walther, W Stein, U Fichtner, I Alexander, M Shoemaker, RH Schlag, PM AF Walther, W Stein, U Fichtner, I Alexander, M Shoemaker, RH Schlag, PM TI mdr1 promoter-driven tumor necrosis factor-alpha expression for a chemotherapy-controllable combined in vivo gene therapy and chemotherapy of tumors SO CANCER GENE THERAPY LA English DT Article DE gene therapy; inducible expression; conditional vector; tumor necrosis factor; chemotherapy ID COLON-CARCINOMA CELLS; MULTIDRUG-RESISTANCE; TNF-ALPHA; CANCER; LINES; INDUCTION; CYTOKINES; DOXORUBICIN; ACTIVATION; ANTITUMOR AB Cancer gene therapy approaches are often designed as single-agent treatments; however, greater therapeutic effect might be obtained if combined with an established conventional treatment regimen such as chemotherapy. In this context, conditional promoters are useful tools, because they may be induced by therapeutic modalities. The human multidrug resistance gene (mdr1) promoter is inducible by cytostatic drugs and can be employed for the chemotherapy-regulated expression of therapeutic genes. In this in vivo study, the human mdr1 promoter fragment (-207 to +158) was used for drug-inducible expression of human tumor necrosis factor-alpha (TNF-alpha) in the vector construct pM3mdr-p-hTNF. The single doxorubicin and vincristine treatment of nude mice xenografted with pM3mdr-p-hTNF-transduced MCF-7 mammary tumors resulted in drug-induced and time-dependent elevation of intratumoral TNF-alpha expression at the mRNA and protein level. The highest drug induction was achieved at 2 days after drug application, as reflected by a maximum 25-fold increase in TNF-alpha secretion in the tumor. This drug-induced TNF-alpha expression is more effective in inhibiting tumor growth compared with the growth of tumors transduced with constitutively TNF-a-expressing vectors in combination with chemotherapy. C1 Max Delbruck Ctr Mol Med, D-13092 Berlin, Germany. NCI, Frederick Canc Res & Dev Ctr, Lab Drug Discovery Res & Dev, Frederick, MD 21702 USA. Humboldt Univ, Berlin, Germany. RP Walther, W (reprint author), Max Delbruck Ctr Mol Med, Robert Rossle Str 10, D-13092 Berlin, Germany. NR 29 TC 23 Z9 29 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD JUN PY 2000 VL 7 IS 6 BP 893 EP 900 DI 10.1038/sj.cgt.7700196 PG 8 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 326LU UT WOS:000087737700010 PM 10880020 ER PT J AU Shiao, YH Resau, JH Nagashima, K Anderson, LM Ramakrishna, G AF Shiao, YH Resau, JH Nagashima, K Anderson, LM Ramakrishna, G TI The von Hippel-Lindau tumor suppressor targets to mitochondrial SO CANCER RESEARCH LA English DT Article ID GENE-PRODUCT; HUMAN TISSUES; PROTEIN; LOCALIZATION; RAT AB Subcellular localization of von Hippel-Lindau (VHL) tumor suppressor may clarify its role in tumorigenesis. In rat kidney, we observed a granular cytoplasmic immunostaining of VHL, as seen in human tissues. The green fluorescent protein (GFP)-tagged VHL also appeared as cytoplasmic granules in vitro and was colocalized with a mitochondrion-selective dye. Immunogold electron microscopy localized VHL specifically to the mitochondrion. Mitochondria retaining GFP-VHL fusion protein, mimicking an insertional VHL mutant, displayed abnormal phenotypes. Among these, small mitochondria have been observed in clear cell renal carcinomas known to have frequent VHL alterations. Thus, VHL may contribute to tumorigenesis through mitochondria-based action. C1 NCI, Comparat Carcinogenesis Lab, Frederick Canc Res & Dev Ctr, NIH, Frederick, MD 21702 USA. NCI, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, NIH, Frederick, MD 21702 USA. NCI, Lab Cell & Mol Struct, Sci Applicat Int Corp Frederick, Frederick Canc Res & Dev Ctr,NIH, Frederick, MD 21702 USA. RP Shiao, YH (reprint author), NCI, Comparat Carcinogenesis Lab, Frederick Canc Res & Dev Ctr, NIH, Bldg 538,Room 205, Frederick, MD 21702 USA. FU NCI NIH HHS [N01CO56000] NR 20 TC 31 Z9 32 U1 0 U2 0 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 JUN 1 PY 2000 VL 60 IS 11 BP 2816 EP 2819 PG 4 WC Oncology SC Oncology GA 321BH UT WOS:000087434700015 PM 10850420 ER PT J AU Boley, SE Anderson, EE French, JE Donehower, LA Walker, DB Recio, L AF Boley, SE Anderson, EE French, JE Donehower, LA Walker, DB Recio, L TI Loss of p53 in benzene-induced thymic lymphomas in p53+/- mice: Evidence of chromosomal recombination SO CANCER RESEARCH LA English DT Article ID WILD-TYPE P53; P53-DEFICIENT MICE; INDUCED TUMORIGENESIS; A LOCUS; HETEROZYGOSITY; TUMORS; GENE; MUTATIONS; CANCER; DELETION AB The purpose of this study was to examine the role of chromosomal recombination in mediating p53 loss in benzene-induced thymic lymphomas in C57BL/6-Trp53 haploinsufficient (N5) mice (p53+/- mice). We characterized loss of heterozygosity (LOH) on chromosome 11 using seven microsatellite markers in 27 benzene-induced and 6 spontaneous thymic lymphomas, Eleven patterns of LOH were found between the induced and spontaneous tumors,,vith only one pattern being in common between the tumor groups. Nearly 90% (24 of 27) of benzene-induced tumors exhibited loss of the functional p53 allele locus, and 83% (20 of 24) of these tumors retained two copies of the disrupted p53 allele, The results indicate that benzene induces a high frequency of LOH on chromosome 11 in p53+/- mice, likely mediated by aberrant chromosomal recombination. C1 Chem Ind Inst Toxicol, Res Triangle Pk, NC 27709 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Baylor Coll Med, Div Mol Virol, Houston, TX 77030 USA. US EPA, Res Triangle Pk, NC 27709 USA. RP Recio, L (reprint author), Chem Ind Inst Toxicol, 6 Davis Dr, Res Triangle Pk, NC 27709 USA. NR 25 TC 37 Z9 37 U1 0 U2 0 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 JUN 1 PY 2000 VL 60 IS 11 BP 2831 EP 2835 PG 5 WC Oncology SC Oncology GA 321BH UT WOS:000087434700018 PM 10850423 ER PT J AU Anna, CH Sills, RC Foley, JF Stockton, PS Ton, TV Devereux, TR AF Anna, CH Sills, RC Foley, JF Stockton, PS Ton, TV Devereux, TR TI beta-Catenin mutations and protein accumulation in all hepatoblastomas examined from B6C3F1 mice treated with anthraquinone or oxazepam SO CANCER RESEARCH LA English DT Article ID HEPATOCELLULAR CARCINOMAS; E-CADHERIN; N-NITROSODIETHYLAMINE; MOUSE; GENE; APC; TUMORS; DIETHYLNITROSAMINE; FREQUENCY; PROMOTION AB The molecular pathogenesis of hepatoblastomas in the B6C3F1 mouse is unclear but may involve alterations in the beta-catenin/Wnt signaling pathway as was recently described for chemically induced hepatocellular neoplasms and human liver cancers. The objective of this study was to characterize the mutation frequency and spectrum of beta-catenin mutations and the intracellular localization of beta-catenin protein accumulation in chemically induced hepatoblastomas. In this study, beta-catenin mutations were identified in all 19 anthraquinone-induced hepatoblastomas and all 8 oxazepam induced hepatoblastomas examined. Although several hepatoblastomas had multiple deletion and/or point mutations, the pattern of mutations in the hepatoblastomas did not differ from that identified in hepatocellular neoplasms. In a majority of the hepatoblastomas (six of seven) examined by immunohistochemical methods, both nuclear and cytoplasmic localization of beta-catenin protein were detected, whereas in hepatocellular adenomas, carcinomas, and normal liver only membrane staining was observed. Our data suggest that beta-catenin mutations and the subsequent translocation of beta-catenin protein from the cell membrane to the cytoplasm and nucleus may be critical steps in providing hepatocellular proliferative lesions with the growth advantage to progress to hepatoblastomas. C1 NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, NIH, Res Triangle Pk, NC 27709 USA. RP Devereux, TR (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 27 TC 38 Z9 40 U1 0 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 JUN 1 PY 2000 VL 60 IS 11 BP 2864 EP 2868 PG 5 WC Oncology SC Oncology GA 321BH UT WOS:000087434700024 PM 10850429 ER PT J AU Wargovich, MJ Jimenez, A McKee, K Steele, VE Velasco, M Woods, J Price, R Gray, K Kelloff, GJ AF Wargovich, MJ Jimenez, A McKee, K Steele, VE Velasco, M Woods, J Price, R Gray, K Kelloff, GJ TI Efficacy of potential chemopreventive agents on rat colon aberrant crypt formation and progression SO CARCINOGENESIS LA English DT Article ID HUMAN PROSTATE-CANCER; 6-PHENYLHEXYL ISOTHIOCYANATE; PRENEOPLASTIC LESIONS; SOLID TUMORS; MOUSE SKIN; FOCI; APOPTOSIS; PROLIFERATION; DIFFERENTIATION; PHENYLBUTYRATE AB We assessed the effects of 78 potential chemopreventive agents in the F344 rat using two assays in which the inhibition of carcinogen-induced aberrant crypt foci (ACF) in the colon was the measure of efficacy. In both assays ACF were induced by the carcinogen azoxymethane (AOM) in F344 rats by two sequential weekly injections at a dose of 15 mg/kg. Two weeks after the last AOM injection, animals were evaluated for the number of aberrant crypts detected in methylene blue stained whole mounts of rat colon. In the initiation phase protocol agents were given during the period of AOM administration, whereas in the post-initiation assay the chemopreventive agent was introduced during the last 4 weeks of an 8 week assay, a time when ACF had progressed to multiple crypt clusters. The agents were derived from a priority listing based on reports of chemopreventive activity in the literature and/ or efficacy data from in vitro models of carcinogenesis. During the initiation phase carboxyl amidoimidazole, p-chlorphenylacetate, chlorpheniramine maleate, D609, diclofenac, etoperidone, eicosatetraynoic acid, farnesol, ferulic acid, lycopene, meclizine, methionine, phenylhexylisothiocyanate, phenylbutyrate, piroxicam, 9-cis-retinoic acid, S-allylcysteine, taurine, tetracycline and verapamil were strong inhibitors of ACF. During the post-initiation phase aspirin, calcium glucarate, ketoprofen, piroxicam, 9-cis-retinoic acid, retinol and rutin inhibited the outgrowth of ACF into multiple crypt clusters. Based on these data, certain phytochemicals, antihistamines, non-steroidal antiinflammatory drugs and retinoids show unique preclinical promise for chemoprevention of colon cancer, with the latter two drug classes particularly effective in the post-initiation phase of carcinogenesis. C1 S Carolina Canc Ctr, Div Basic Res, Columbia, SC 29203 USA. Univ Texas, MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol & Digest Dis, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Div Vet Med & Surg, Houston, TX 77030 USA. NCI, Chemoprevent Agent Dev Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. RP Wargovich, MJ (reprint author), S Carolina Canc Ctr, Div Basic Res, Columbia, SC 29203 USA. RI Ain, Kenneth/A-5179-2012 OI Ain, Kenneth/0000-0002-2668-934X FU NCI NIH HHS [CA-16672, N01-CN-35570-01, N01-CN-85151-03] NR 48 TC 203 Z9 212 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD JUN PY 2000 VL 21 IS 6 BP 1149 EP 1155 DI 10.1093/carcin/21.6.1149 PG 7 WC Oncology SC Oncology GA 327XE UT WOS:000087819100011 PM 10837003 ER PT J AU Tudor, G Aguilera, A Halverson, DO Laing, ND Sausville, EA AF Tudor, G Aguilera, A Halverson, DO Laing, ND Sausville, EA TI Susceptibility to drug-induced apoptosis correlates with differential modulation of Bad, Bcl-2 and Bcl-x(L) protein levels SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE apoptosis; taxol (paclitaxel); thiotepa; Bad; Bcl-2; Bcl-2 cleavage; Bcl-x(L) ID PROGRAMMED CELL-DEATH; TAXOL-INDUCED APOPTOSIS; BREAST-CANCER CELLS; NORMAL P53 FUNCTION; CYTOCHROME-C; PHOSPHORYLATION; INDUCTION; LINES; ACTIVATION; EXPRESSION AB To define the responses of apoptotic regulatory proteins to different chemotherapeutic agents, we investigated the expression of Bcl-2 family gene products, the release of cytochrome c, and the activation of pro-caspase-3 during apoptosis induced by Taxol and Thiotepa, in the MCF-7 breast carcinoma and the HL-60 leukemia cell lines. The earliest event induced by drug exposure was increase in Bad protein levels, followed by Bcl-2 down-regulation, cytochrome c release, and Bcl-x(L) and Bar up-regulation. Bak accumulation was a late event. Activation of pro-caspase-3 and cleavage of Bcl-2 protein occurred in the HL-60 cells only, and followed the cytochrome c release. The overall responses were qualitatively similar in both cell types, but MCF-7 cells treated with Taxol showed a significant delay in apoptosis, correlating with early up-regulation of Bcl-2 and delayed release of cytochrome c, We conclude that Bad up-regulation is an early indicator of a cellular response that will lead to cell death, but may be modulated by survival mechanisms, which cumulatively govern the ultimate susceptibility to apoptosis. C1 NCI, Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp, Frederick, MD 21702 USA. NCI, Div Canc Treatment, Dev Therapeut Program, Rockville, MD 20892 USA. RP Tudor, G (reprint author), NCI, Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp, POB B, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 59 TC 98 Z9 100 U1 0 U2 3 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD JUN PY 2000 VL 7 IS 6 BP 574 EP 586 DI 10.1038/sj.cdd.4400688 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 313NU UT WOS:000087006400008 PM 10822281 ER PT J AU Vymazal, J Urgosik, D Bulte, JWM AF Vymazal, J Urgosik, D Bulte, JWM TI Differentiation between hemosiderin- and ferritin-bound brain iron using nuclear magnetic resonance and magnetic resonance imaging SO CELLULAR AND MOLECULAR BIOLOGY LA English DT Article DE brain iron; ferritin; hemosiderin; MRI ID DIFFERENT FIELD STRENGTHS; MR RELAXATION-TIMES; PARKINSONS-DISEASE; FREQUENCY-DEPENDENCE; T2 RELAXATION; BASAL GANGLIA; RELAXOMETRY; INCREASE; PRIMATES; IMAGES AB MRI is an optimal clinical (research) tool to provide information on brain morphology and pathology and to detect metal ions that possess intrinsic magnetic properties. Non-heme iron is abundantly present in the brain in three different forms: "low molecular weight" complexes, iron bound to "medium mollecular weight complexes" metalloproteins such as transferrin, and "high molecular weight" complexes as ferritin and hemosiderin. The total amount and form of iron may differ in health and disease, and MRT. can possibly quantify and monitor such changes. Ferritin-bound iron is the main storage form of iron and is present predominantly in the extrapyramidal nuclei where its amounts normally increase as a function of age. Ferritin is water soluble and shortens both, T-1 and T-2 relaxation, with as result a signal change on the MR images. Hemosiderin, a degradation product of ferritin, is water-insoluble with a stronger T-2 shortening effect than ferritin. The larger cluster size of hemosiderin and its water-insolubility also explain a lack of significant T-1-shortening effect on T-1-weighted images. Using both in vitro specimens and intact brain tissue in vivo we demonstrate here that MRT may be able to distinguish between ferritin- and hemosiderin-bound iron. C1 Hosp Homolce, Dept Radiol, Prague 15119, Czech Republic. NIH, Lab Diagnost Radiol Res, Ctr Clin, Bethesda, MD 20892 USA. RP Vymazal, J (reprint author), Hosp Homolce, Dept Radiol, Prague 15119, Czech Republic. EM vymazal@cesnet.cz RI Bulte, Jeff/A-3240-2008 OI Bulte, Jeff/0000-0003-1202-1610 NR 34 TC 37 Z9 40 U1 0 U2 4 PU C M B ASSOC PI POITIERS PA 40 AVENUE RECTEUR PINEAU, BAT MECANIQUE, 86022 POITIERS, FRANCE SN 0145-5680 J9 CELL MOL BIOL JI Cell. Mol. Biol. PD JUN PY 2000 VL 46 IS 4 BP 835 EP 842 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 324QW UT WOS:000087633700013 PM 10875444 ER PT J AU Usdin, K Grabczyk, E AF Usdin, K Grabczyk, E TI DNA repeat expansions and human disease SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE repeat expansion; DNA instability; DNA structure; triplet repeats; polyglutamine toxicity ID FRAGILE-X-SYNDROME; PROGRESSIVE MYOCLONUS EPILEPSY; DYSTROPHY PROTEIN-KINASE; CYSTATIN-B GENE; CENTER-DOT-CAG; PALLIDOLUYSIAN ATROPHY DRPLA; UNINTERRUPTED CGG REPEATS; FRAXE MENTAL-RETARDATION; MACHADO-JOSEPH DISEASE; REPLICATION IN-VIVO AB The repeat expansion diseases are genetic disorders caused by intergenerational expansions of a specific tandem DNA repeat. These disorders range from mildly to severely debilitating or fatal, and all have limited treatment options, How expansion occurs and causes disease is only now beginning to be understood. Efforts to model expansion in mice have so far met with only limited success, perhaps due to a requirement for specific cis- or trans-acting factors. In vitro studies and data from bacteria and yeast suggest that in addition to secondary structures formed by the repeats, components of the DNA replication and recombination machinery are important determinants of instability. The consequences of expansion differ depending on where in the gene the repeat tract is located, and range from reduction of transcription initiation to protein toxicity. Recent advances are beginning to make rational approaches to the development of therapies possible. C1 NIDDK, Sect Genom Struct & Funct, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. RP Usdin, K (reprint author), NIDDK, Sect Genom Struct & Funct, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. NR 161 TC 77 Z9 81 U1 1 U2 5 PU BIRKHAUSER VERLAG AG PI BASEL PA VIADUKSTRASSE 40-44, PO BOX 133, CH-4010 BASEL, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD JUN PY 2000 VL 57 IS 6 BP 914 EP 931 DI 10.1007/PL00000734 PG 18 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 340CD UT WOS:000088514800006 PM 10950307 ER PT J AU Werner, H Le Roith, D AF Werner, H Le Roith, D TI New concepts in regulation and function of the insulin-like growth factors: implications for understanding normal growth and neoplasia SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE insulin-like growth factors; IGF-I receptor; cancer; receptor signaling ID FACTOR-I RECEPTOR; ROUND-CELL TUMOR; MOUSE EMBRYO FIBROBLASTS; TYPE-1 IGF RECEPTOR; DISTAL LONG ARM; GENE-EXPRESSION; WILMS-TUMOR; PHOSPHATIDYLINOSITOL 3'-KINASE; TYROSINE PHOSPHORYLATION; INDUCED APOPTOSIS AB The insulin-like growth factors (IGFs) are a ubiquitous family of growth factors, binding proteins and receptors that are involved in normal growth and development. They are also implicated in numerous pathological states, including malignancy. IGF-II is a commonly expressed growth factor in many tumors and may enhance tumor growth. acting via the overexpressed IGF-I receptor, a cell-surface tyrosine kinase receptor. The IGF-I receptor may be overexpressed due to mutations in tumor suppression gene products such as p53 and WT-1 or growth factors such as bFGF and PDGF. Thus, this family of growth factors, especially the IGF-I receptor, may present an excellent target for new therapeutic agents in the treatment of cancer and other disorders of excessive cellular proliferation. C1 NIH, Clin Endocrinol Branch, Bethesda, MD 20892 USA. Tel Aviv Univ, Sackler Fac Med, Dept Clin Biochem, IL-69978 Tel Aviv, Israel. RP Le Roith, D (reprint author), NIH, Clin Endocrinol Branch, Room 8D12,Bldg 10,MSC 1758, Bethesda, MD 20892 USA. NR 82 TC 112 Z9 120 U1 0 U2 0 PU BIRKHAUSER VERLAG AG PI BASEL PA VIADUKSTRASSE 40-44, PO BOX 133, CH-4010 BASEL, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD JUN PY 2000 VL 57 IS 6 BP 932 EP 942 DI 10.1007/PL00000735 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 340CD UT WOS:000088514800007 PM 10950308 ER PT J AU Maric, D Maric, I Barker, JL AF Maric, D Maric, I Barker, JL TI Developmental changes in cell calcium homeostasis during neurogenesis of the embryonic rat cerebral cortex SO CEREBRAL CORTEX LA English DT Article ID SPINAL NEURONS; HIPPOCAMPAL-NEURONS; MONOCLONAL-ANTIBODY; VENTRICULAR ZONE; ION CHANNELS; CA2+ INFLUX; DIFFERENTIATION; CYCLE; TELENCEPHALON; TRANSIENTS AB We quantified cytoplasmic Ca2+ (Ca-c(2+)) levels in cells dissociated from the embryonic (E) rat cortex during neurogenesis. Dual-recordings by flow cytometry using calcium- and voltage-sensitive dyes revealed that, at the beginning of cortical development (E11-12), precursor cells exhibited either low (<100 nM), moderate (similar to 250 nM) or high (>1 mu M) resting Ca-c(2+) levels and well polarized (-70 mV) or less-polarized (-40 mV) resting membrane potentials which reflected postmitotic or proliferative stages of the cell cycle. Ca-c(2+) levels of all cells included a Ca-o(2+) entry component, which was also Mn2+-permeant in actively proliferating precursors. Postmitotic, but not premitotic, precursors exhibited thapsigargin-sensitive intracellular Ca2+ (Ca-i(2+)) stores, which had similar capacities throughout neuronal lineage development. Differentiating neurons, but not precursors expressed Ca-i(2+) stores with ryanodine and caffeine sensitivity and baseline Ca-c(2+) levels that depended on Na+-Ca-2 exchange activity. Voltage-dependent Ca-o(2+) entry was not detected in precursors, but emerged during neuronal differentiation, with most of the neurons expressing functional L-type Ca2+ channels. Ca2+ imaging of individually immunoidentified cells acutely recovered in culture confirmed that precursors differentiate into neurone which stereotypically exhibit Ca-o(2+) entry at the level of the membrane with increased Ca-i(2+) release mechanisms on Ca-i(2+) stores, Na+-Ca2+ exchange activity and expression of voltage-dependent Ca2+ channels. C1 NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Maric, D (reprint author), NINDS, Neurophysiol Lab, NIH, Bldg 36,Room 2C02, Bethesda, MD 20892 USA. NR 45 TC 33 Z9 34 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD JUN PY 2000 VL 10 IS 6 BP 561 EP 573 DI 10.1093/cercor/10.6.561 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 320AX UT WOS:000087379800003 PM 10859134 ER PT J AU Goldman, R Day, BW Carver, TA Mauthe, RJ Turteltaub, KW Shields, PG AF Goldman, R Day, BW Carver, TA Mauthe, RJ Turteltaub, KW Shields, PG TI Quantitation of benzo[a]pyrene-DNA adducts by postlabeling with C-14-acetic anhydride and accelerator mass spectrometry SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE molecular epidemiology; carcinogenesis; C-14-postlabeling; DNA adduct; benzo[a]pyrene ID CANCER-SUSCEPTIBILITY GENES; HYDROCARBON-DNA ADDUCTS; BREAST-CANCER; CIGARETTE-SMOKING; MOLECULAR EPIDEMIOLOGY; HUMAN-LUNG; RISK; POLYMORPHISMS; BIOMARKERS; PREVENTION AB Quantitation of carcinogen-DNA adducts provides an estimate of the biologically effective dose of a chemical carcinogen reaching the target tissue. In order to improve exposure-assessment and cancer risk estimates, we are developing an ultrasensitive procedure for the detection of carcinogen-DNA adducts. The method is based upon postlabeling of carcinogen-DNA adducts by acetylation with C-14-acetic anhydride combined with quantitation of C-14 by accelerator mass spectrometry (AMS). For this purpose, adducts of benzo[a]pyrene-r-7,t-8-dihydrodiol-t-9,10-epoxide (BPDE) with DNA and deoxyguanosine (dG) were synthesized. The most promutagenic adduct of BPDE, 7R,8S,9X-trihydroxy-10S-(N-2-deoxyguanosyl)-7,8,9,10-tetrahydrobenzo[a]pyrene (BPdG). was HPLC purified and structurally characterized. Postlabeling of the BPdG adduct with acetic anhydride yielded a major product with a greater than 60% yield. The postlabeled adduct was identified by liquid chromatography-mass spectrometry as pentakis(acetyl) BPdG (AcBPdG). Postlabeling of the BPdG adduct with C-14-acetic anhydride yielded a major product coeluting with an AcBPdG standard. Quantitation of the C-14-postlabeled adduct by AMS promises to allow detection of attomolar amounts of adducts. The method is now being optimized and validated for use in human samples. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Environm & Occupat Hlth, Pittsburgh, PA 15238 USA. Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15238 USA. Univ Calif Lawrence Livermore Natl Lab, Livermore, CA 94551 USA. Pfizer Inc, Groton, CT 06340 USA. RP Shields, PG (reprint author), Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Canc Genet & Epidemiol Program, Res Bldg W301,3970 Reservoir Rd NW, Washington, DC 20007 USA. RI Shields, Peter/I-1644-2012 NR 34 TC 18 Z9 18 U1 0 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD JUN 1 PY 2000 VL 126 IS 3 BP 171 EP 183 DI 10.1016/S0009-2797(00)00160-5 PG 13 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 326LZ UT WOS:000087738200001 PM 10862816 ER PT J AU Purkerson-Parker, SL Fieber, LA Rein, KS Podona, T Baden, DG AF Purkerson-Parker, SL Fieber, LA Rein, KS Podona, T Baden, DG TI Brevetoxin derivatives that inhibit toxin activity SO CHEMISTRY & BIOLOGY LA English DT Article DE brevetoxins; brevetoxin antagonists; marine neurotoxins; sodium channel ID SENSITIVE SODIUM-CHANNELS; RAT-BRAIN SYNAPTOSOMES; LIPID BILAYERS; BINDING; NERVE AB Background: The brevetoxins are marine neurotoxins that interfere with the normal functions of the voltage-gated Na+ channel. We have identified two brevetoxin derivatives that do not exhibit pharmacological properties typical of the brevetoxins and that function as brevetoxin antagonists. Results: PbTx-3 and benzoyl-PbTx-3 elicited Na+ channel openings during steady-state depolarizations; however, two PbTx-3 derivatives retained their ability to bind to the receptor, but did not elicit Na+ channel openings. alpha-Naphthoyl-PbTx-3 acted as a PbTx-3 antagonist but did not affect Na+ channels that were not exposed to PbTx-3. beta-Naphthoyl-PbTx-3 reduced openings of Na+ channels that were not exposed to PbTx-3. Conclusions: Some modifications to the brevetoxin molecule do not alter either the binding properties or the activity of these toxins. Larger modifications to the K-ring sidechain do not interfere with binding but have profound effects on their pharmacological properties. This implies a critical function for the K-ring sidechain of the native toxin. C1 Florida Int Univ, Dept Chem, Miami, FL 33199 USA. Univ N Carolina Curriculum Toxicol, US EPA, Div Neurotoxicol, Res Triangle Pk, NC 27711 USA. Univ Miami, Rosenstiel Sch Marine & Atmospher Sci, Div Marine Biol & Fisheries, NIEHS Marine & Freshwater Biomed Sci Ctr, Miami, FL 33149 USA. Univ N Carolina, Marine Sci Res Ctr, Wilmington, NC 28403 USA. RP Rein, KS (reprint author), Florida Int Univ, Dept Chem, Miami, FL 33199 USA. OI Fieber, Lynne/0000-0002-7717-2260 FU NIEHS NIH HHS [ES05785, ES05853] NR 24 TC 32 Z9 34 U1 1 U2 2 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD JUN PY 2000 VL 7 IS 6 BP 385 EP 393 DI 10.1016/S1074-5521(00)00119-8 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 325NT UT WOS:000087683100004 PM 10873835 ER PT J AU Orbach, Y Hershkowitz, I Lamb, ME Sternberg, KJ Esplin, PW Horowitz, D AF Orbach, Y Hershkowitz, I Lamb, ME Sternberg, KJ Esplin, PW Horowitz, D TI Assessing the value of structured protocols for forensic interviews of alleged child abuse victims SO CHILD ABUSE & NEGLECT LA English DT Article DE sexual abuse; forensic interviews; open-ended questions; child witnesses; interview processes ID INVESTIGATIVE UTTERANCE TYPES; SEXUAL ABUSE; EYEWITNESS-MEMORY; DEVELOPMENTAL PATTERNS; COGNITIVE INTERVIEW; PRESCHOOL-CHILDREN; YOUNG-CHILDREN; EVENT REPORTS; AMICUS BRIEF; WITNESSES AB Objective: To evaluate the effectiveness of a structured interview protocol (NICHD Investigative Interview Protocol) operationalizing universally recommended guidelines for forensic interviews. Method: The NICHD Investigative Protocol was designed to maximize the amount of information obtained using recall memory probes, which are likely to elicit more accurate information than recognition memory probes. Forensic investigators were trained to use the NICHD protocol while conducting feedback-monitored simulation interviews. The utility of the protocol was then evaluated by comparing 55 protocol interviews with 50 prior interviews by the same investigators, matched with respect to characertistics likely to affect the richness of the children's accounts. The comparison was based on an analysis of the investigators' utterance types, distribution, and timing, as well as quantitative and qualitative characteristics of the information produced. Results: As predicted, protocol interviews contained more open-ended prompts overall as well as before the first option-posing utterance than non-protocol interviews did. More details were obtained using open-ended invitations and fewer were obtained using focused questions in protocol interviews than in non-protocol interviews, although the total number of details elicited did not differ significantly. In both conditions, older children provided more details than younger children did. Conclusion: The findings confirmed that implementation of professionally recommended practices affected the behavior of interviewers in both the pre-substantive and substantive phases of their interviews and enhanced the quality (i.e., likely accuracy) of information elicited from alleged victims. (C) 2000 Elsevier Science Ltd. C1 NICHHD, Sect Social & Environm Dev, Bethesda, MD 20892 USA. Univ Haifa, IL-31999 Haifa, Israel. Israeli Minist Labor & Social Affairs, Jerusalem, Israel. RP Lamb, ME (reprint author), NICHHD, Sect Social & Environm Dev, 9190 Rockville Pike, Bethesda, MD 20892 USA. NR 100 TC 179 Z9 182 U1 7 U2 28 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2134 J9 CHILD ABUSE NEGLECT JI Child Abuse Negl. PD JUN PY 2000 VL 24 IS 6 BP 733 EP 752 DI 10.1016/S0145-2134(00)00137-X PG 20 WC Family Studies; Psychology, Social; Social Work SC Family Studies; Psychology; Social Work GA 314MC UT WOS:000087059000001 PM 10888015 ER PT J AU Uijtdehaage, SHJ Thayer, JF AF Uijtdehaage, SHJ Thayer, JF TI Accentuated antagonism in the control of human heart rate SO CLINICAL AUTONOMIC RESEARCH LA English DT Article DE heart rate; parasympathetic; accentuated antagonism; respiratory sinus arrhythmia ID PARASYMPATHETIC CARDIAC CONTROL; RESPIRATORY SINUS ARRHYTHMIA; INDEX AB Invasive animal models indicate that the accelerative effects of the sympathetic nervous system on heart rate are highly dependent on the background level of vagal activity. A noninvasive, parasympathetic chronotropic index (respiratory sinus arrhythmia) and a sympathetic chronotropic index (left ventricular ejection time) were used to evaluate autonomic control of human heart rate. A strong interaction, previously called accentuated antagonism, was found. Sympathetic heart rate effects were substantially smaller with high levels of vagal tone than with low vagal background activity. Furthermore, vagal effects became progressively stronger with increasing sympathetic background activity, demonstrating the predominance of parasympathetic control of human heart rate. This finding implies that changes in cardiac activity resulting from changes in sympathetic control cannot be interpreted accurately unless concurrent vagal activity is taken into account, as well. C1 Univ Calif Los Angeles, Dept Psychiat & Behav Sci, Los Angeles, CA 90024 USA. Univ Missouri, Dept Psychol, Columbia, MO USA. RP Thayer, JF (reprint author), NIA, Gerontol Res Ctr, LPC, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Uijtdehaage, Sebastian/0000-0001-8598-4683 NR 24 TC 47 Z9 49 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-9851 J9 CLIN AUTON RES JI Clin. Auton. Res. PD JUN PY 2000 VL 10 IS 3 BP 107 EP 110 DI 10.1007/BF02278013 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 330PT UT WOS:000087971000001 PM 10954067 ER PT J AU Rand, RW Kreitman, RJ Patronas, N Varricchio, F Pastan, I Puri, RK AF Rand, RW Kreitman, RJ Patronas, N Varricchio, F Pastan, I Puri, RK TI Intratumoral administration of recombinant circularly permuted interleukin-4-Pseudomonas exotoxin in patients with high-grade glioma SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL-CARCINOMA-CELLS; PSEUDOMONAS EXOTOXIN; CHIMERIC PROTEIN; INTERLEUKIN 4-TOXIN; CANCER-CELLS; BRAIN-TUMORS; PHASE-I; IMMUNOTOXIN; THERAPY; TOXIN AB Human glioblastoma but not normal brain cells express numerous receptors for the cytokine interleukin (IL)-4. To target these receptors, we have investigated the safety and activity of directly infusing IL-4(38-37)-PE38KDEL, a chimeric protein composed of circularly permuted IL-4 and a truncated form of Pseudomonas exotoxin (PE), into recurrent malignant high-grade gliomas, IL-4(38-37)-PE38KDEL (IL-4-toxin) was infused over a 4-8-day period into gliomas of nine patients by one to three stereotactically placed catheters, No apparent systemic toxicity occurred in any patient. The infusion of IL-4-toxin in six of nine patients showed glioma necrosis as evidenced by diminished gadolinium enhancement on magnetic resonance imaging. Seven of nine patients underwent craniotomy because of increased intracranial pressure at 16-101 days after the beginning of infusion. In six of these seven patients, partial-to-extensive tumor necrosis with edema was confirmed pathologically. No histological evidence of neurotoxicity to normal brain was identified in any patient. Two patients were not operated on; by magnetic resonance imaging, one showed mottled gadolinium enhancement, and the other showed extensive necrosis of tumor leading to complete remission; this patient remains disease-free >18 months after the procedure. We conclude that direct glioma injection of IL-4(38-37)-PE38KDEL is safe without systemic toxicity. Local toxicity seemed attributable mainly to tumor necrosis or occasionally to the volume of infusion. Histological evidence of toxicity to normal brain was not observed and in many patients, could be pathologically excluded. Additional patients are being treated to determine the maximal tolerated concentration and volume of IL-4(38-37)-PE38KDEL. C1 NIH, Lab Mol Tumor Biol, Div Cellullar & Gene Therapies, Ctr Biol Evaluat & Res,UD FDA, Bethesda, MD 20892 USA. John Wayne Canc Inst, Dept Neurooncol, Santa Monica, CA 90404 USA. NCI, Mol Biol Lab, Div Basic Sci, NCI, Bethesda, MD 20892 USA. NIH, Dept Neuroradiol, Bethesda, MD 20892 USA. US FDA, Div Biostat & Epidemiol, Ctr Biol Evaluat & Res, Rockville, MD 20850 USA. RP Puri, RK (reprint author), NIH, Lab Mol Tumor Biol, Div Cellullar & Gene Therapies, Ctr Biol Evaluat & Res,UD FDA, Bldg 29B,Room 2NN10,29 Lincoln Dr,MSC 4555, Bethesda, MD 20892 USA. NR 36 TC 171 Z9 177 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN PY 2000 VL 6 IS 6 BP 2157 EP 2165 PG 9 WC Oncology SC Oncology GA 322ZR UT WOS:000087540300006 PM 10873064 ER PT J AU von Mehren, M Arlen, P Tsang, KY Rogatko, A Meropol, N Cooper, HS Davey, M McLaughlin, S Schlom, J Weiner, LM AF von Mehren, M Arlen, P Tsang, KY Rogatko, A Meropol, N Cooper, HS Davey, M McLaughlin, S Schlom, J Weiner, LM TI Pilot study of a dual gene recombinant avipox vaccine containing both carcinoembryonic antigen (CEA) and B7.1 transgenes in patients with recurrent CEA-expressing adenocarcinomas SO CLINICAL CANCER RESEARCH LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; T-LYMPHOCYTE RESPONSES; ANTITUMOR IMMUNITY; STIMULATING FACTOR; COLORECTAL-CANCER; DENDRITIC CELLS; BREAST-CANCER; PHASE-I; INDUCTION; MOLECULES AB Coordinated presentation of antigen and costimulatory molecules has been shown to result in the induction of an antigen-specific T-cell response rather than the development of anergy. This study evaluated the vaccine ALVAC-CEA B7.1, a canary pox virus that has been engineered to encode the gene for the tumor-associated antigen carcinoembryonic antigen (CEA) and B7.1, a T-cell costimulatory molecule. Patients with CEA-expressing tumors were immunized with 2.5 x 10(7) (n = 3), 1.0 x 10(8) (n = 6), and 4.5 x 10(8) (n = 30) plaque-forming units intradermally every other week for 8 weeks. Patients with stable or responding disease received monthly boost injections. Biopsies of vaccine sites were obtained 48 h after vaccination to evaluate leukocytic infiltration and CEA expression, Induction of CPA-specific T-cell precursors was assessed by an ELISPOT assay looking for the production of IFN-gamma. Therapy was well tolerated, without significant toxicity attributable to vaccine. All patients had evidence of leukocytic infiltration and CEA expression in vaccine biopsy sites. Six patients with elevated serum CEA values at baseline had declines in their levels lasting 4-12 weeks. These patients all had stable disease after four vaccinations, After four vaccinations, patients who were HLA-A-2-positive demonstrated increases in their CEA-specific T-cell precursor frequencies to a CEA-A2-binding peptide from baseline. The number of prior chemotherapy regimens was inversely correlated with the ability to generate a T-cell response. ALVAC-CEA B7.1 is safe in patients with advanced, recurrent adenocarcinomas that express CEA, and it is associated with the induction of a CEA-specific T-cell response. C1 Fox Chase Canc Ctr, Dept Med Oncol, Philadelphia, PA 19111 USA. Fox Chase Canc Ctr, Dept Biostat, Philadelphia, PA 19111 USA. Fox Chase Canc Ctr, Dept Pathol, Philadelphia, PA 19111 USA. NIH, Lab Tumor Immunol, NCI, Bethesda, MD 20892 USA. RP von Mehren, M (reprint author), Fox Chase Canc Ctr, Dept Med Oncol, 7701 Burholme Ave, Philadelphia, PA 19111 USA. RI Rogatko, Andre/A-8099-2008 FU NCI NIH HHS [P0 CA06927, K12 CA01728] NR 45 TC 120 Z9 128 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN PY 2000 VL 6 IS 6 BP 2219 EP 2228 PG 10 WC Oncology SC Oncology GA 322ZR UT WOS:000087540300013 PM 10873071 ER PT J AU Streckfus, C Bigler, L Dellinger, T Dai, XL Kingman, A Thigpen, JT AF Streckfus, C Bigler, L Dellinger, T Dai, XL Kingman, A Thigpen, JT TI The presence of soluble c-erbB-2 in saliva and serum among women with breast carcinoma: A preliminary study SO CLINICAL CANCER RESEARCH LA English DT Article ID CANCER PATIENTS; CARCINOEMBRYONIC ANTIGEN; EXPRESSION; TUMORS; HER-2/NEU; PROTEIN; CA-15-3; TISSUE; ERBB-2 AB The protein c-erbB-2, also known as Her2/neu, is a prognostic breast cancer marker assayed in tissue biopsies from women diagnosed with malignant tumors. Present studies suggest that soluble fragments of the c-erbB-2 oncogene may be released from the cell surface and become detectable in patients with carcinoma of the breast. Consequently, the purpose of this study was to assay the c-erbB-2 protein in the saliva and serum of women with and without carcinoma of the breast and to determine whether the protein possesses any diagnostic value. To determine the diagnostic utility of this oncogene, the soluble form of the c-erbB-2 protein was assayed in the saliva and serum using ELISA in three different groups of women. The three groups consisted of 57 healthy women, 41 women with benign breast lesions, and 30 women diagnosed with breast cancer, To compare the relative diagnostic utility of the c-erbB-2 protein, CA 15-3 was also measured, The CA 15-3 measurements served as a "gold standard" by which to compare the c-erbB-2 protein's diagnostic effectiveness, We found c-erbB-2 protein in the saliva and serum of all three groups of women. The salivary and serological levels of c-erbB-2 in the cancer patients, however, were significantly higher (P < 0.001) than the salivary and serum levels of healthy controls and benign tumor patients. Additionally, the c-erbB-2 protein was found to be equal to or to surpass the ability of CA 15-3 to detect patients with carcinoma. The results of the pilot study suggest that the c-ErbB-2 protein may have potential use in the initial detection and/or follow-up screening for the recurrence of breast cancer in women. C1 Univ Mississippi, Med Ctr, Sch Dent, Dept Res, Jackson, MS 39216 USA. Univ Mississippi, Med Ctr, Dept Restorat Dent, Jackson, MS 39216 USA. Univ Mississippi, Med Ctr, Dept Med, Div Oncol, Jackson, MS 39216 USA. Natl Inst Dent & Craniofacial Res, Biostat Core, NIH, Bethesda, MD USA. RP Streckfus, C (reprint author), Univ Mississippi, Med Ctr, Sch Dent, Dept Res, 2500 N State St, Jackson, MS 39216 USA. FU NIDCR NIH HHS [1 R55 DE/OD12414-01] NR 28 TC 94 Z9 99 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN PY 2000 VL 6 IS 6 BP 2363 EP 2370 PG 8 WC Oncology SC Oncology GA 322ZR UT WOS:000087540300030 PM 10873088 ER PT J AU Sampson, ML Csako, G Remaley, AT AF Sampson, ML Csako, G Remaley, AT TI Estimation of serum apolipoprotein B by a modified homogeneous assay for HDL-cholesterol SO CLINICAL CHEMISTRY LA English DT Article ID ANALYZER C1 NIH, Ctr Clin, Dept Clin Pathol, Bethesda, MD 20892 USA. RP Remaley, AT (reprint author), NIH, Ctr Clin, Dept Clin Pathol, Bldg 10,Rm 2C-407, Bethesda, MD 20892 USA. NR 7 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2000 VL 46 IS 6 BP 869 EP 871 PN 1 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 325NL UT WOS:000087682500016 PM 10839781 ER PT J AU Cecco, SA Bolan, CD Remaley, AT Leitman, SF Rehak, NN AF Cecco, SA Bolan, CD Remaley, AT Leitman, SF Rehak, NN TI Effect of continuous citrate infusion on the concentration of serum calcium, magnesium, potassium, phosphorus and parathyroid hormone. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2000 VL 46 IS 6 SU S MA 222 BP A59 EP A59 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 326GU UT WOS:000087725600224 ER PT J AU Chan, YW Woods, JJ Nunes, J Garrity, M Lu, J Guthrie, E Remaley, AT AF Chan, YW Woods, JJ Nunes, J Garrity, M Lu, J Guthrie, E Remaley, AT TI Development of a rapid intraoperative ACTH assay on the Nichols Advantage analyzer. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. Nichols Inst Diagnost, San Juan Capistrano, CA USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2000 VL 46 IS 6 SU S MA 461 BP A120 EP A121 PN 2 PG 2 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 326GU UT WOS:000087725600461 ER PT J AU Costello, R Wang, J Csako, G AF Costello, R Wang, J Csako, G TI Effect of storage and freezing-thawing on the measurements of lipids and lipoproteins in human serum. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2000 VL 46 IS 6 SU S MA 401 BP A105 EP A105 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 326GU UT WOS:000087725600403 ER PT J AU Delgado, RM Wu, Y Sunderland, T Csako, G AF Delgado, RM Wu, Y Sunderland, T Csako, G TI Semi-automated PCR-SSCP detects a novel sequence polymorphism (IIe1000Val) in the human a2-macroglobulin gene. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2000 VL 46 IS 6 SU S MA 809 BP A208 EP A208 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 326GU UT WOS:000087725600808 ER PT J AU Hortin, GL King, C Kopp, J AF Hortin, GL King, C Kopp, J TI Quantification of rhesus monkey albumin with assays for human microalbumin. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2000 VL 46 IS 6 SU S MA 542 BP A140 EP A141 PN 2 PG 2 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 326GU UT WOS:000087725600542 ER PT J AU Murthy, JN George, MR Rehak, NN AF Murthy, JN George, MR Rehak, NN TI Short-term storage of serum at room temperature in gel separator tubes: Effect on common chemistry tests determined with Hitachi 917. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 1 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2000 VL 46 IS 6 SU S MA 141 BP A37 EP A37 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 326GU UT WOS:000087725600142 ER PT J AU Remaley, AT Hess, RA Fischer, S Sampson, ML Manak, M AF Remaley, AT Hess, RA Fischer, S Sampson, ML Manak, M TI Pre-analytical sterilization of serum by pressure-cycling treatment: A novel procedure to prevent laboratory acquired infections. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 BBI Biotech Res Labs Inc, Gaithersburg, MD USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2000 VL 46 IS 6 SU S MA 149 BP A39 EP A39 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 326GU UT WOS:000087725600150 ER PT J AU Sampson, ML Aubry, A Csako, G Remaley, AT AF Sampson, ML Aubry, A Csako, G Remaley, AT TI Sequential lipid testing: an automated single tube assay for HDL-cholesterol, total cholesterol, and triglycerides. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. Univ Niagara, Niagara, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2000 VL 46 IS 6 SU S MA 367 BP A97 EP A97 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 326GU UT WOS:000087725600369 ER PT J AU Sullivan, P Costello, RA Wesley, RA Csako, G AF Sullivan, P Costello, RA Wesley, RA Csako, G TI Relationship between vitamin E and lipids, lipoproteins, and apolipoproteins in human sera. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2000 VL 46 IS 6 SU S MA 421 BP A111 EP A111 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 326GU UT WOS:000087725600422 ER PT J AU Park, KY Dalakas, MC Semino-Mora, C Lee, HS Litvak, S Takeda, K Ferrans, VJ Goldfarb, LG AF Park, KY Dalakas, MC Semino-Mora, C Lee, HS Litvak, S Takeda, K Ferrans, VJ Goldfarb, LG TI Sporadic cardiac and skeletal myopathy caused by a de novo desmin mutation SO CLINICAL GENETICS LA English DT Article DE cardiomyopathy; de novo mutation; desmin gene; genotype-phenotype correlation; skeletal myopathy; sporadic disease ID DOMINANT DISTAL MYOPATHY; INTERMEDIATE FILAMENTS; ATRIOVENTRICULAR-BLOCK; MISSENSE MUTATION; BODY MYOPATHY; CARDIOMYOPATHY; GENE; ACCUMULATION; VIMENTIN; MUSCLE AB Desmin myopathy is a familial or sporadic disorder characterized by intracytoplasmic accumulation of desmin in the muscle cells. We and others have previously identified desmin gene mutations in patients with familial myopathy, but close to 45% of the patients do not report previous family history of the disease. The present study was conducted to determine the cause of desmin myopathy in a sporadic patient presenting with symmetrical muscle weakness and atrophy combined with atrioventricular conduction block requiring a permanent pacemaker. A novel heterozygous R406W mutation in the desmin gene was identified by sequencing cDNA anti genomic DNA. Expression of a construct containing the patient's mutant desmin cDNA in SW13 (vim-) cells demonstrated a high pathogenic potential of the R406W mutation. This mutation was not found in the patient's father, mother or sister by sequencing and restriction analysis. Testing with five microsatellite markers and four intragenic single nucleotide polymorphisms excluded alternative paternity. Haplotype analysis indicates that the patient's father was germ-line mosaic for the desmin mutation. We conclude that de novo mutations in the desmin gene may be the cause of sporadic forms of desmin-related cardiac and skeletal myopathy. C1 NINDS, Clin Neurogenet Unit, NIH, Bethesda, MD 20892 USA. NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. RP Goldfarb, LG (reprint author), NINDS, Clin Neurogenet Unit, NIH, Bldg 10,Room 4B37,10 Ctr Dr,MSC 1361, Bethesda, MD 20892 USA. NR 32 TC 28 Z9 30 U1 0 U2 1 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD JUN PY 2000 VL 57 IS 6 BP 423 EP 429 DI 10.1034/j.1399-0004.2000.570604.x PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 327MN UT WOS:000087797800006 PM 10905661 ER PT J AU Breiman, RF Ginsberg, AM AF Breiman, RF Ginsberg, AM TI An Overview of the Proceedings of the International Symposium on Tuberculosis Vaccine Development and Evaluation: Recognizing and addressing the barriers SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material C1 Ctr Dis Control & Prevent, Natl Vaccine Program Off, Atlanta, GA 30333 USA. NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. RP Breiman, RF (reprint author), Ctr Dis Control & Prevent, Natl Vaccine Program Off, 1600 Clifton Rd,MS C-12, Atlanta, GA 30333 USA. NR 0 TC 4 Z9 4 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN PY 2000 VL 30 SU 3 BP S199 EP S200 DI 10.1086/313882 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 341DR UT WOS:000088576200001 ER PT J AU Ginsberg, AM AF Ginsberg, AM TI A proposed national strategy for tuberculosis vaccine development SO CLINICAL INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT International Symposium on Tuberculosis Vaccine Development and Evaluation CY AUG 26-28, 1998 CL SAN FRANCISCO, CALIFORNIA SP Ctr Dis Control & Prevent, Amer Lung Assoc, Amer Thoracic Soc, Natl Inst Allergy & Infect Dis, Int Union Against Tuberculosis & Lung Dis, WHO AB The global tuberculosis epidemic causes similar to 5% of deaths worldwide. Despite recent concerted and largely successful tuberculosis control efforts, the incidence of tuberculosis in the United States remains 74-fold higher than the stated elimination goal of A and over-stretching conformational transitions, are compared with experimental data. These subtle conformational changes are critical to the functioning of the double helix, including its packaging in the close confines of the cell, the mutual fit of DNA and protein in nucleoprotein complexes, and the effective recognition of base pairs in recombination and transcription. C1 Rutgers State Univ, Wright Rieman Labs, Piscataway, NJ 08854 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Olson, WK (reprint author), Rutgers State Univ, Wright Rieman Labs, 610 Taylor Rd, Piscataway, NJ 08854 USA. EM olson@rutchem.rutgers.edu; zhurkin@nih.gov FU NIGMS NIH HHS [GM20861, GM34809] NR 84 TC 129 Z9 132 U1 1 U2 9 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD JUN PY 2000 VL 10 IS 3 BP 286 EP 297 DI 10.1016/S0959-440X(00)00086-5 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 325GC UT WOS:000087667000003 PM 10851199 ER PT J AU Clow, PA Chen, TLL Chisholm, RL McNally, JG AF Clow, PA Chen, TLL Chisholm, RL McNally, JG TI Three-dimensional in vivo analysis of Dictyostelium mounds reveals directional sorting of prestalk cells and defines a role for the myosin II regulatory light chain in prestalk cell sorting and tip protrusion SO DEVELOPMENT LA English DT Article DE Dictyostelium; morphogenesis; cell movement; myosin; prestalk cell ID OPTICAL-SECTIONING MICROSCOPY; PATTERN-FORMATION; TARGET RECOGNITION; PRESPORE PATTERN; C-ELEGANS; IN-VIVO; DISCOIDEUM; GENE; MORPHOGENESIS; EXPRESSION AB During cell sorting in Dictyostelium, we observed that GFP-tagged prestalk cells (ecmAO-expressing cells) moved independently and directionally to form a cluster. This is consistent with a chemotaxis model for cell sorting (and not differential adhesion) in which a long-range signal attracts many of the prestalk cells to the site of cluster formation. Surprisingly, the ecmAO prestalk cluster that we observed was initially found at a random location within the mound of this Ax3 strain, defining an intermediate sorting stage not widely reported in Dictyostelium. The cluster then moved en masse to the top of the mound to produce the classic, apical pattern of ecmAO prestalk cells. Migration of the cluster was also directional, suggesting the presence of another long-range guidance cue. Once at the mound apex, the cluster continued moving upward leading to protrusion of the mound's tip. To investigate the role of the cluster in tip protrusion, we examined ecmAO prestalk-cell sorting in a myosin II regulatory light chain (RLC) null in which tips fail to form. In RLC-null mounds, ecmAO prestalk cells formed an initial cluster that began to move to the mound apex, but then arrested as a vertical column that extended from the mound's apex to its base. Mixing experiments with wild-type cells demonstrated that the RLC-null ecmAO prestalk-cell defect is cell autonomous. These observations define a specific mechanism for myosin's function in tip formation, namely a mechanical role in the upward movement of the ecmAO prestalk cluster. The wild-type data demonstrate that cell sorting can occur in two steps, suggesting that, in this Ax3 strain, spatially and temporally distinct cues may guide prestalk cells first to an initial cluster and then later to the tip. C1 NCI, Lab Receptor Biol & Gene Express, Div Basic Sci, Bethesda, MD 20892 USA. Washington Univ, Dept Biol, St Louis, MO 63130 USA. Northwestern Univ, Sch Med, Dept Cell & Mol Biol, Chicago, IL 60611 USA. RP McNally, JG (reprint author), NCI, Lab Receptor Biol & Gene Express, Div Basic Sci, Bldg 41,Room C615,41 Lib Dr MSC 5055, Bethesda, MD 20892 USA. RI Chisholm, Rex/B-3418-2009 OI Chisholm, Rex/0000-0002-5638-3990 NR 60 TC 31 Z9 31 U1 0 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD JUN PY 2000 VL 127 IS 12 BP 2715 EP 2728 PG 14 WC Developmental Biology SC Developmental Biology GA 330EB UT WOS:000087948900019 PM 10821769 ER PT J AU Zahn-Waxler, C Klimes-Dougan, B Slattery, MJ AF Zahn-Waxler, C Klimes-Dougan, B Slattery, MJ TI Internalizing problems of childhood and adolescence: Prospects, pitfalls, and progress in understanding the development of anxiety and depression SO DEVELOPMENT AND PSYCHOPATHOLOGY LA English DT Review ID FIRST-GRADE CHILDREN; MAJOR DEPRESSION; ENVIRONMENTAL-INFLUENCES; ELECTRODERMAL ACTIVITY; BEHAVIORAL-INHIBITION; ATTRIBUTIONAL STYLE; ANXIOUS SYMPTOMS; MENTAL-DISORDERS; CONDUCT DISORDER; SEX-DIFFERENCES AB The focus of this article is on internalizing problems that are experienced by children and adolescents. We provide an historical perspective, selectively examine the current state of knowledge, consider advances and gaps in what is known, and identify new research directions. Diagnosis, epidemiology, theory, and research first are considered separately for anxiety and depressive disorders. These internalizing problems, however, whether clinical or subclinical, share many common features and show high comorbidity rates. We emphasize the importance of systematic analysis of comorbid anxiety and depression, including their comorbidity with externalizing problems. This could lead to more valid classification of subtypes of internalizing problems and further an understanding of the diverse conditions that constitute internalized distress. We highlight the need to study anxiety and depression within a developmental psychopathology framework, as well as to include both categorical and dimensional assessments of these problems in the same research designs. This will be essential for understanding the complex interplay of biological and environmental processes that contribute to the emergence, progression, and amelioration of internalizing problems over time. C1 NIMH, Child Psychiat Branch, Sect Dev Psychol, Bethesda, MD 20892 USA. RP Zahn-Waxler, C (reprint author), NIMH, Child Psychiat Branch, Sect Dev Psychol, 9000 Rockville Pike,Bldg 15-K,Rm 204-A, Bethesda, MD 20892 USA. NR 155 TC 265 Z9 269 U1 16 U2 77 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0954-5794 J9 DEV PSYCHOPATHOL JI Dev. Psychopathol. PD SUM PY 2000 VL 12 IS 3 BP 443 EP 466 DI 10.1017/S0954579400003102 PG 24 WC Psychology, Developmental SC Psychology GA 355DM UT WOS:000089370400010 PM 11014747 ER PT J AU Marenco, S Weinberger, DR AF Marenco, S Weinberger, DR TI The neurodevelopmental hypothesis of schizophrenia: Following a trail of evidence from cradle to grave SO DEVELOPMENT AND PSYCHOPATHOLOGY LA English DT Review ID JERUSALEM INFANT-DEVELOPMENT; HIGH-RISK PROJECT; CEREBRAL VENTRICULAR ENLARGEMENT; BRAIN MORPHOLOGICAL-CHANGES; PREFRONTAL WHITE-MATTER; POPULATION BIRTH COHORT; OBSTETRIC COMPLICATIONS; ADULT SCHIZOPHRENIA; ENTORHINAL CORTEX; LONG-TERM AB This is a critical review of the literature related to the neurodevelopmental hypothesis of schizophrenia which posits that the illness is related to abnormal brain development. The review focuses on data deriving from clinical studies, and it is organized according to the life phase from which the data were collected: conception and birth, infancy and childhood up to the onset of the illness, after illness onset, and postmortem. The neurodevelopmental hypothesis is supported by several pieces of evidence, including increased frequency of obstetric complications in patients with schizophrenia; the presence of minor physical anomalies; the presence of neurological, cognitive, and behavioral dysfunction long before illness onset; a course and outcome of the illness itself that is incompatible in most cases with a degenerative illness; the stability of brain structural measures over time; and the absence of postmortem evidence of neurodegeneration. A historical perspective on how this research accumulated and a section addressing important areas of future investigation are also provided. We conclude that schizophrenia is certainly not a degenerative brain disorder, and that it is likely that a brain insult in utero or at birth plays a role in its expression. Current evidence cannot completely exclude the role of environmental variables after birth. In addition, it is possible that other psychiatric disorders may also have a neurodevelopmental component. C1 NIMH, CBDB, NIH, Bethesda, MD 20892 USA. RP Weinberger, DR (reprint author), NIMH, CBDB, NIH, Bldg 10,4S235,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Marenco, Stefano/A-2409-2008 OI Marenco, Stefano/0000-0002-2488-2365 NR 170 TC 258 Z9 266 U1 7 U2 27 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0954-5794 J9 DEV PSYCHOPATHOL JI Dev. Psychopathol. PD SUM PY 2000 VL 12 IS 3 BP 501 EP 527 DI 10.1017/S0954579400003138 PG 27 WC Psychology, Developmental SC Psychology GA 355DM UT WOS:000089370400013 PM 11014750 ER PT J AU Liu, CQ Hunter, S Knezevic, V Thompson, K Mackem, S AF Liu, CQ Hunter, S Knezevic, V Thompson, K Mackem, S TI Does T (Brachyury) play a role in limb development? SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 NCI, Pathol Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2000 VL 222 IS 1 MA 38 BP 229 EP 229 PG 1 WC Developmental Biology SC Developmental Biology GA 323AN UT WOS:000087542500053 ER PT J AU Hallsson, JH Favor, J Gunnarsson, GJ Copeland, NG Jenkins, NA Steingrimsson, E AF Hallsson, JH Favor, J Gunnarsson, GJ Copeland, NG Jenkins, NA Steingrimsson, E TI Genomic, transcriptional, and mutational analysis of the mouse microphthalmia locus SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 Univ Iceland, Reykjavik, Iceland. NCI, FCRF, Mouse Canc Genet Program, Frederick, MD 21702 USA. GSF, Inst Mammalian Genet, D-85764 Neuherberg, Germany. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2000 VL 222 IS 1 MA 77 BP 235 EP 235 PG 1 WC Developmental Biology SC Developmental Biology GA 323AN UT WOS:000087542500092 ER PT J AU Chang, W Wu, DK AF Chang, W Wu, DK TI Bone morphogenetic proteins regulate morphogenesis of otic membrane, otic capsule chondrogenesis, and their interactions during chicken inner ear development SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 NIDCD, NIH, Rockville, MD 20850 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2000 VL 222 IS 1 MA 155 BP 248 EP 248 PG 1 WC Developmental Biology SC Developmental Biology GA 323AN UT WOS:000087542500168 ER PT J AU Weinstein, BM Lawson, ND AF Weinstein, BM Lawson, ND TI Analysis of blood vessel development using transgenic zebrafish. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 NICHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2000 VL 222 IS 1 MA 161 BP 249 EP 249 PG 1 WC Developmental Biology SC Developmental Biology GA 323AN UT WOS:000087542500174 ER PT J AU Perantoni, AO Plisov, S Dove, LF Higinbotham, KG Yoshino, K AF Perantoni, AO Plisov, S Dove, LF Higinbotham, KG Yoshino, K TI Leukemia inhibitory factor induces epithelial tubule formation in metanephric mesenchyme through activation of Wnt signaling. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 NCI, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2000 VL 222 IS 1 MA 168 BP 250 EP 250 PG 1 WC Developmental Biology SC Developmental Biology GA 323AN UT WOS:000087542500181 ER PT J AU Brody, T Stivers, C Odenwald, WF AF Brody, T Stivers, C Odenwald, WF TI Talin: A conserved cytoskeletal linker protein expressed in a subset of CNS neurons SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 NINDS, Neurochem Lab, Neurogenet Unit, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2000 VL 222 IS 1 MA 190 BP 254 EP 254 PG 1 WC Developmental Biology SC Developmental Biology GA 323AN UT WOS:000087542500202 ER PT J AU Stivers, C Kuzin, A Brody, T Odenwald, WF AF Stivers, C Kuzin, A Brody, T Odenwald, WF TI Nerfin-1, a new pan-neural Zn-finger gene is required for proper nervous system development in Drosophila SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 NINDS, Neurogenet Unit, Neurochem Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2000 VL 222 IS 1 MA 189 BP 254 EP 254 PG 1 WC Developmental Biology SC Developmental Biology GA 323AN UT WOS:000087542500201 ER PT J AU Lanford, PJ Kelley, MW AF Lanford, PJ Kelley, MW TI The role of histone deacetylase in the regulation of notch signaling in the mammalian cochlea. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 Natl Inst Deafness & Other Commun Disorders, NIH, Rockville, MD 20850 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2000 VL 222 IS 1 MA 200 BP 256 EP 256 PG 1 WC Developmental Biology SC Developmental Biology GA 323AN UT WOS:000087542500212 ER PT J AU Andreazzoli, M AF Andreazzoli, M TI Xrx1 in neural plate differentiation SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 NICHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. Univ Pisa, Lab Biol Cellulare & Sviluppo, I-56010 Pisa, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2000 VL 222 IS 1 MA 214 BP 258 EP 258 PG 1 WC Developmental Biology SC Developmental Biology GA 323AN UT WOS:000087542500225 ER PT J AU Miura, S Mishina, Y AF Miura, S Mishina, Y TI Establishment of region specific knockout for gastrulation stage mouse embryo SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 NIEHS, LRDT, Mol Dev Biol Grp, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2000 VL 222 IS 1 MA 260 BP 266 EP 266 PG 1 WC Developmental Biology SC Developmental Biology GA 323AN UT WOS:000087542500267 ER PT J AU Nguyen, MTT Arnheiter, H AF Nguyen, MTT Arnheiter, H TI Pattern formation in the mammalian optic vesicle SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 NINDS, Lab Dev Neurogenet, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2000 VL 222 IS 1 MA 266 BP 267 EP 267 PG 1 WC Developmental Biology SC Developmental Biology GA 323AN UT WOS:000087542500271 ER PT J AU Lawson, ND Kim, CH Chitnis, A Weinstein, BM AF Lawson, ND Kim, CH Chitnis, A Weinstein, BM TI Notch signaling is required for ephrinB2 expression and proper vascular development SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2000 VL 222 IS 1 MA 298 BP 272 EP 272 PG 1 WC Developmental Biology SC Developmental Biology GA 323AN UT WOS:000087542500302 ER PT J AU Ryan, J Garrett, L Deng, C Wang, XF Wynshaw-Boris, A Roberts, A Lechleider, R AF Ryan, J Garrett, L Deng, C Wang, XF Wynshaw-Boris, A Roberts, A Lechleider, R TI Smad1 is required for chorioallantoic placenta formation during murine development SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NIDDK, Bethesda, MD 20892 USA. NCHGR, Bethesda, MD 20892 USA. Duke Univ, Durham, NC 27710 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2000 VL 222 IS 1 MA 307 BP 274 EP 274 PG 1 WC Developmental Biology SC Developmental Biology GA 323AN UT WOS:000087542500311 ER PT J AU Hough, RB Piatigorsky, J AF Hough, RB Piatigorsky, J TI Transcriptional regulation OF two putative corneal enzyme-crystallins in the rabbit: ALDH1 and TKT SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 NEI, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2000 VL 222 IS 1 MA 322 BP 276 EP 276 PG 1 WC Developmental Biology SC Developmental Biology GA 323AN UT WOS:000087542500325 ER PT J AU Beanan, MJ Feledy, JA Sargent, TD AF Beanan, MJ Feledy, JA Sargent, TD TI beta-catenin regulates the early expression of the Xenopus anti-neural factor Dlx3 SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 NICHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2000 VL 222 IS 1 MA 331 BP 278 EP 278 PG 1 WC Developmental Biology SC Developmental Biology GA 323AN UT WOS:000087542500333 ER PT J AU Imperatore, G Knowler, WC Pettitt, DJ Kobes, S Bennett, PH Hanson, RL AF Imperatore, G Knowler, WC Pettitt, DJ Kobes, S Bennett, PH Hanson, RL TI Segregation analysis of diabetic nephropathy in Pima Indians SO DIABETES LA English DT Article; Proceedings Paper CT 47th Annual Meeting of the American-Society-of-Human-Genetics CY OCT 28-NOV 01, 1997 CL BALTIMORE, MARYLAND SP Amer Soc Human Genet ID ALBUMIN EXCRETION; BLOOD-PRESSURE; RENAL-DISEASE; RISK-FACTORS; MELLITUS; NIDDM; SUSCEPTIBILITY; HYPERGLYCEMIA; PROTEINURIA; TRAITS AB Familial aggregation of diabetic nephropathy suggests the existence of genes determining susceptibility to nephropathy in addition to those leading to diabetes. In the present study, complex segregation analysis was performed in diabetic members of Pima Indian families to determine whether familial aggregation of nephropathy in this population could reflect the action of a single major gene. Nephropathy, defined by a urinary protein-to-creatinine ratio (PCR) greater than or equal to 500 mg/g, was analyzed as a discrete trait in a class C regressive logistic model. Individuals with PCR <500 mg/g were considered unaffected. Segregation analysis was performed both for nephropathy at the last examination (prevalent cases) and for duration of diabetes at the onset of nephropathy (incident cases). The REGD program was used for the analysis of the prevalent cases and the REGTL program for the incident cases, both from the Statistical Analysis for Genetic Epidemiology package (Case Western University, Cleveland, OH). The analysis of prevalent cases included 2,107 Pima Indians from 715 nuclear families. A subset of 504 of these families containing 1,403 individuals was used in the analysis of incident cases. Analysis of prevalent cases supported the existence of a gene with a major role, in that hypotheses of no major effect and of no transmission of a major effect were rejected (P = 0.00001; P = 0.003), whereas Mendelian transmission was not rejected (P = 0.85). A dominant model provided the best fit, but a recessive model could not be rejected, The analysis of incident cases, however, did not support a major gene effect on duration of diabetes at the onset of nephropathy: and analyses of lifetime occurrence of nephropathy were inconclusive. The analysis of prevalent cases supports the hypothesis of a major genetic effect on susceptibility to diabetic nephropathy in Pima Indians, but the analysis of incident cases does not support a genetic effect on duration of diabetes at the onset of nephropathy. The discrepancy may reflect the difficulty in precisely dating onset of nephropathy. The parameters of the model derived from segregation analysis of prevalent cases may be useful in linkage studies to detect nephropathy susceptibility loci. C1 NIDDKD, Diabet Arthrit Epidemiol Sect, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ 85014 USA. Sansum Med Res Inst, Santa Barbara, CA USA. RP Hanson, RL (reprint author), NIDDKD, Diabet Arthrit Epidemiol Sect, Phoenix Epidemiol & Clin Res Branch, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU NCRR NIH HHS [1 P41 RR03655] NR 42 TC 57 Z9 58 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUN PY 2000 VL 49 IS 6 BP 1049 EP 1056 DI 10.2337/diabetes.49.6.1049 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 318ZG UT WOS:000087314100022 PM 10866059 ER PT J AU Harris, MI AF Harris, MI TI Health care and health status and outcomes for patients with type 2 diabetes SO DIABETES CARE LA English DT Article ID DENSITY-LIPOPROTEIN CHOLESTEROL; IMPROVE GLYCEMIC CONTROL; MEDICAL OUTCOMES; MELLITUS; RECOMMENDATIONS; IMPLEMENTATION; MANAGEMENT; COMMITTEE; ATTITUDES; ADHERENCE AB OBJECTIVE - To evaluate access and utilization of medical care, and health status and outcomes that would be influenced by recent medical care, in a representative sample of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS - A national sample of 733 adults with type 2 diabetes was studied from 1991 to 1994 in the Third National Health and Nutrition Examination Survey. Structured questionnaires and clinical and laboratory assessments were used to determine the frequencies of physician visits, health insurance coverage, screening for diabetes complications, treatment for hyperglycemia, hypertension, and dyslipidemia: and the proportion of patients who met treatment goals and established criteria for health outcome measures including hyperglycemia, albuminuria, obesity hypertension, and dyslipidemia. RESULTS - Almost all patients had 1 source of primary care (95%), 2 or more physician visits during the past year (88%), and health insurance coverage (91%). Most (76%) were treated with insulin or oral agents for their diabetes, and 45% of those patients taking insulin monitored their blood glucose at least once per day. The patients were frequently screened for retinopathy (52%), hypertension (88%), and dyslipidemia (84%). Of those patients with hypertension, 83% were diagnosed and treated with antihypertensive agents and only 17% were undiagnosed or untreated, most of the patients known to have dyslipidemia were treated with medication or diet (89%). Health status and outcomes were less than optimal: 58% had HbA(1), >7.0, 45% had BMI >30, 28% had microalbuminuria, and 8% had clinical proteinuria. Of those patients known to have hypertension and dyslipidemia, 60% were not controlled to accepted levels. In addition. 22% of patients smoked cigarettes, 26% had to be hospitalized during the previous year, and 42% assessed their health status as fair or poor. CONCLUSIONS - Rates of health care access and utilization, screening for diabetes: complications,, and treatment of hyperglycemia, hypertension, and dyslipidemia in type 2 diabetes are high: however, health status and outcomes are unsatisfactory. There are likely to be multiple reasons for this discordance, including intractability of diabetes to current therapies, patient self-care practices, physician medical care practices, and characteristics of U.S. health care systems. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. RP Harris, MI (reprint author), NIDDKD, NIH, 6707 Democracy Blvd,Room 695, Bethesda, MD 20892 USA. NR 28 TC 180 Z9 187 U1 3 U2 7 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD JUN PY 2000 VL 23 IS 6 BP 754 EP 758 DI 10.2337/diacare.23.6.754 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 318ZF UT WOS:000087314000009 PM 10840991 ER PT J AU Weyer, C Tataranni, PA Pratley, RE AF Weyer, C Tataranni, PA Pratley, RE TI Insulin action and insulinemia are closely related to the fasting complement C3, hot not acylation stimulating protein concentration SO DIABETES CARE LA English DT Article ID NECROSIS-FACTOR-ALPHA; TYPE-2 DIABETES-MELLITUS; INNATE IMMUNE-SYSTEM; MYOCARDIAL-INFARCTION; SERUM COMPLEMENT; ADIPOSE-TISSUE; DISEASE; RESISTANCE; OBESITY; ATHEROSCLEROSIS AB OBJECTIVE - An elevated C3 concentration has been reported in people with obesity type 2 diabetes, hypertension, and dyslipidemia, and has been proposed to play a role in the development of atherosclerosis. We hypothesized that an elevated C3 concentration might be linked to insulin resistance and/or hyperinsulinemia, abnormalities commonly observed in association with the above conditions. RESEARCH DESIGN AND METHODS - Fasting concentrations of C3 and acylation stimulating protein (ASP, C3adesarg), a cleavage product of C3 recently found to stimulate glucose uptake in vitro, were measured in 33 healthy nondiabetic Pima Indians (14 women and 19 men; age 27 +/- 1 and body fat 33 +/- 1%, means +/- SEM). Subjects were characterized for body composition dual-energy X-ray absorptiometry insulin action (insulin-stimulated glucose disposal [M], hyperinsulinemic glucose clamp), and glucose tolerance (75-g oral glucose tolerance test). RESULTS - Fasting C3 and ASP concentrations were positively correlated (r = 0.43, P < 0.05). Fasting C3 concentration was closely related to percent body fat (r = 0.77), M (r = -0.75), and lasting insulin concentration (r = 0.72) (all P < 0.0001). Fasting C3 concentrations remained significantly related to M and lasting insulin after adjusting for percent body fat (partial r = -0.53 and 0.33, both P < 0.05). In subjects with impaired glucose tolerance, fasting C3 concentrations were higher than in those with normal glucose tolerance-a difference that remained after adjustment for percent body fat and M. We found that fasting ASP concentrations were significantly related to percent body fat (r = 0.37. P < 0.05), but not to M or fasting insulin. CONCLUSIONS - In Pima Indians, fasting C3 concentration is closely related to adiposity insulin action, and lasting insulin levels and may thus be a mediator for the postulated link between obesity insulin resistance, hyperinsulinemia, and possibly atherosclerosis. C1 NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. RP Weyer, C (reprint author), NIDDKD, Clin Diabet & Nutr Sect, NIH, 4212 N 16th St,Room 5-41, Phoenix, AZ 85016 USA. NR 35 TC 73 Z9 82 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD JUN PY 2000 VL 23 IS 6 BP 779 EP 785 DI 10.2337/diacare.23.6.779 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 318ZF UT WOS:000087314000014 PM 10840996 ER PT J AU Dawson, DA AF Dawson, DA TI Drinking as a risk factor for sustained smoking SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE drinking; risk factor; sustained smoking ID GENERAL-POPULATION SAMPLE; ALCOHOL-USE DISORDERS; CIGARETTE-SMOKING; NICOTINE DEPENDENCE; MAJOR DEPRESSION; DRUG-USE; RELAPSE; CESSATION; PREDICTORS; EXPLORATION AB Data from a nationally representative sample of US adults (n = 42 862) were used to explore the associations between drinking and smoking, on a lifetime and past-year basis, and between drinking and smoking cessation for a subsample of past-year smokers (n = 12 586). Smoking cessation was defined as current nonsmoking (as of the time of interview) that had lasted at least 3 months. The proportions of both lifetime and past-year smokers increased with volume of alcohol intake and frequency of heavy drinking and were greater for individuals with DSM-IV alcohol abuse or dependence than for individuals without these disorders. For example, the proportion of past-year smokers rose from 22.5% of lifetime abstainers to 53.0%;, of heavy drinkers, from 23.8% of those who never drank 5 + drinks on any drinking day to 61.8% of those who drank 5 + drinks weekly or more often and from 27.6% of individuals without past-year DSM-IV alcohol abuse or dependence to 55.5% of those with either of these disorders. The proportion of past-year smokers who had stopped smoking decreased from 7.8% of former drinkers to 4.6% of heavy drinkers, from 7.3% of those who never drank 5 + drinks to 3.4% of those who did so weekly or more often and from 6.7% among individuals without past-year abuse or dependence compared to 4.4% among those with either disorder. In a multivariate analysis that adjusted for background variables and smoking history, average daily ethanol intake was not significantly associated with the odds of smoking cessation, but drinking 5 + drinks at least once a month reduced the odds of cessation by 42%. Having an alcohol use disorder increased the odds of smoking cessation below the age of 30 (an effect that disappeared after adjusting for the interaction between age group and having children in the home), but had an increasingly negative effect on smoking cessation at older ages. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 NIAAA, DBE, NIH, Bethesda, MD 20892 USA. RP Dawson, DA (reprint author), NIAAA, DBE, NIH, Willco Bldg,Suite 514,6000 Execut Blvd,MSC 7003, Bethesda, MD 20892 USA. NR 52 TC 133 Z9 137 U1 1 U2 6 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 JUN 1 PY 2000 VL 59 IS 3 BP 235 EP 249 DI 10.1016/S0376-8716(99)00130-1 PG 15 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 319GB UT WOS:000087332200004 PM 10812284 ER PT J AU Issaq, HJ AF Issaq, HJ TI A decade of capillary electrophoresis SO ELECTROPHORESIS LA English DT Article; Proceedings Paper CT 10th Annual Frederick Conference on Capillary Electrophoresis CY OCT 18-20, 1999 CL HOOD COLL, FREDERICK, MARYLAND SP Hood Coll HO HOOD COLL DE capillary electrophoresis; micellar electrokinetic chromatography; capillary electrochromatography; biomolecules; DNA fragments; proteins; natural products; review ID MICELLAR ELECTROKINETIC CHROMATOGRAPHY; INDUCED FLUORESCENCE DETECTION; PERFORMANCE LIQUID-CHROMATOGRAPHY; POLYMERASE-CHAIN-REACTION; ELECTROOSMOTIC FLOW ENVIRONMENT; OCTADECYL-SULFONATED-SILICA; SODIUM DODECYL-SULFATE; ZONE-ELECTROPHORESIS; FUSED-SILICA; AMINO-ACIDS AB Since the introduction of the first commercial capillary electrophoresis (CE) instrument a decade ago, CE applications have become widespread. Today, CE is a versatile analytical technique which is successfully used for the separation of small ions, neutral molecules, and large biomolecules and for the study of physicochemical parameters. It is being utilized in widely different fields, such as analytical chemistry, forensic chemistry, clinical chemistry, organic chemistry, natural products, pharamaceutical industry, chiral separations, molecular biology, and others. It is not only used as a separation technique but to answer physicochemical questions. In this review, we will discuss different modes of CE such as capillary zone electrophoresis, micellar electrokinetic chromatography, capillary gel electrophoresis, capillary isoelectric focusing, and capillary electrochromatography, and will comment on the future direction of CE, including array capillary electrophoresis and array microchip separations. C1 NCI, Frederick Canc Res & Dev Ctr, Separat Technol Grp, Chem Synth & Anal Lab,SAIC Frederick, Frederick, MD 21702 USA. RP Issaq, HJ (reprint author), NCI, Frederick Canc Res & Dev Ctr, Separat Technol Grp, Chem Synth & Anal Lab,SAIC Frederick, POB B, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 115 TC 80 Z9 88 U1 0 U2 15 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD JUN PY 2000 VL 21 IS 10 BP 1921 EP 1939 DI 10.1002/1522-2683(20000601)21:10<1921::AID-ELPS1921>3.0.CO;2-Y PG 19 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 326ZU UT WOS:000087767800002 PM 10879953 ER PT J AU Chan, KC Muschik, GM Issaq, HJ AF Chan, KC Muschik, GM Issaq, HJ TI Solid-state UV laser-induced fluorescence detection in capillary electrophoresis SO ELECTROPHORESIS LA English DT Article; Proceedings Paper CT 10th Annual Frederick Conference on Capillary Electrophoresis CY OCT 18-20, 1999 CL HOOD COLL, FREDERICK, MARYLAND SP Hood Coll HO HOOD COLL DE solid-state UV lasers; laser-induced fluorescence; capillary electrophoresis; native fluorescence; fluorescamine ID INDUCED NATIVE FLUORESCENCE; AMINO-ACIDS; PEPTIDES; PROTEINS; FLUORESCAMINE; DERIVATIZATION; SEPARATION; TRYPTOPHAN; CELLS; ASSAY AB Two solid-state UV lasers were applied to the laser-induced fluorescence (LIF) detection of various groups of compounds after separation by capillary electrophoresis. These lasers are thermoelectric-cooled, highly compact, and inexpensive. Such lasers provide few mW of quasi-continuous wave (CW) power which are sufficient and stable for LIF detection. Native fluorescence detection of tryptophan-containing proteins and peptides and related indoles was achieved at the nM level with the laser operating at 266 nm. Detection of fluorescamine-labeled amino acids and peptides was also possible at the nu level with the laser operating at 355 nm. Amino acids at a concentration as low as 10 ng/mL could be labeled with fluorescamine. Solid-state UV-LIF detection of the tryptic digest of cytochrome c after fluorescamine derivatization was demonstrated. C1 NCI, Frederick Canc Res & Dev Ctr, Analyt Chem Lab, SAIC Frederick, Frederick, MD 21702 USA. RP Chan, KC (reprint author), NCI, Frederick Canc Res & Dev Ctr, Analyt Chem Lab, SAIC Frederick, POB B, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 18 TC 54 Z9 57 U1 0 U2 6 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD JUN PY 2000 VL 21 IS 10 BP 2062 EP 2066 DI 10.1002/1522-2683(20000601)21:10<2062::AID-ELPS2062>3.0.CO;2-Z PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 326ZU UT WOS:000087767800016 PM 10879967 ER PT J AU Colvis, CM Duglas-Tabor, Y Werth, KB Vieira, NE Kowalak, JA Janjani, A Yergey, AL Garland, DL AF Colvis, CM Duglas-Tabor, Y Werth, KB Vieira, NE Kowalak, JA Janjani, A Yergey, AL Garland, DL TI Tracking pathology with proteomics: Identification of in vivo degradation products of alpha B-crystallin SO ELECTROPHORESIS LA English DT Article DE Soemmerring's ring; crystallin; proteolysis; lens; matrix-assisted laser desorption; ionization ID HUMAN LENS; MASS-SPECTROMETRY AB Soemmerring's ring is one form of "after cataract" that can occur following cataract surgery. The ring structure is formed by adherence of the anterior lens capsule to the posterior lens capsule. Epithelial cells remaining after surgery differentiate into lens fiber cells but the resulting tissue mass does not remain transparent. The protein in normal lens and in Soemmerring's rings from four individuals was analyzed using two-dimensional (2-D) gel electrophoresis, matrix assisted laser desorption/ionization-time of-flight-mass spectrometry (MALDI-TOF-MS) and image analysis with Phoretix software. The 2-D protein patterns of the Soemmerring's rings were generally similar to that of cortical fiber cells of normal human lens with some notable exceptions. Several posttranslationally modified forms of alpha beta-crystallin((1-175)) were identified. Two degradation products, alpha beta-crystallin((1-170)) and alpha beta-crystallin((1-174)), each make up 9.5-27% of the total alpha beta-crystallin in the Soemmerring's rings and less than 1% in the normal lenses. Other modified forms of alpha beta-crystallin are aberrant in the fiber cells of the Soemmerring rings relative to normal lens. C1 NEI, Bethesda, MD 20892 USA. NICHHD, Bethesda, MD 20892 USA. NIMH, Bethesda, MD 20892 USA. Univ Modena, Dept Ophthalmol, I-41100 Modena, Italy. RP Garland, DL (reprint author), 6 Ctr Dr MSC 2735, Bethesda, MD 20892 USA. NR 15 TC 16 Z9 20 U1 0 U2 2 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD JUN PY 2000 VL 21 IS 11 BP 2219 EP 2227 DI 10.1002/1522-2683(20000601)21:11<2219::AID-ELPS2219>3.0.CO;2-R PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 330RN UT WOS:000087975100014 PM 10892732 ER PT J AU Ornstein, DK Gillespie, JW Paweletz, CP Duray, PH Herring, J Vocke, CD Topalian, SL Bostwick, DG Linehan, WM Petricoin, EF Emmert-Buck, MR AF Ornstein, DK Gillespie, JW Paweletz, CP Duray, PH Herring, J Vocke, CD Topalian, SL Bostwick, DG Linehan, WM Petricoin, EF Emmert-Buck, MR TI Proteomic analysis of laser capture microdissected human prostate cancer and in vitro prostate cell lines SO ELECTROPHORESIS LA English DT Article DE pharmacoproteomics; prostate cancer; laser capture microdissection; cell culture; electrophoresis ID EXPRESSION; PROTEIN; ELECTROPHORESIS; PROGRESSION; CARCINOMAS; MEN AB Specific populations of normal and malignant epithelium from three radical prostatectomy tissue specimes were procured by laser capture microdissection (LCM) and analyzed by two-dimensional polyacrylamide gel electrophoresis (2-D PAGE). Six proteins that were only seen in malignant cells and two proteins that were only seen in benign epithelium were reproducibly observed in two of two cases examined. Furthermore, these proteins were not observed in the 2-D PAGE profiles from the patient-matched microdissected stromal cell populations, but were seen in the protein profiles from the undissected whole cryostat Sections. One of these proteins was determined to be prostate-specific antigen (PSA) by Western blot analysis, and intriguingly the remaining protein candidates were found to be at least as abundant as the PSA protein. Comparison of 2-D PAGE profiles of microdissected cell with matched in vitro cell lines from the same patient, and metastatic prostate cancer cell lines (LnCaP and PC3) showed striking differences between prostate cells in vivo and in vitro with less than 20% shared proteins. The data demonstrate that 2-D PAGE analysis of LCM-derived cells can reliably detect alterations in protein expression associated with prostate cancer, and that these differentially expressed proteins are produced in high enough levels which could allow for their clinical utility as new targets for therapeutic intervention, serum markers, and/or imaging markers. C1 US FDA, Ctr Biol Evaluat & Res, Div Therapeut Prod, Tissue Proteom Unit, Bethesda, MD 20892 USA. NCI, Pathol Lab, Pathogenet Unit, Bethesda, MD USA. NCI, Off Director, Canc Genome Anat Project, Bethesda, MD USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. NCI, Surg Branch, Bethesda, MD 20892 USA. Mayo Clin, Dept Pathol, Rochester, MN USA. Georgetown Univ, Dept Chem, Washington, DC 20057 USA. RP Petricoin, EF (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Therapeut Prod, Tissue Proteom Unit, Bldg 29A Room 2B01,8800 Rockville Pike, Bethesda, MD 20892 USA. NR 21 TC 201 Z9 215 U1 1 U2 13 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD JUN PY 2000 VL 21 IS 11 BP 2235 EP 2242 DI 10.1002/1522-2683(20000601)21:11<2235::AID-ELPS2235>3.3.CO;2-1 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 330RN UT WOS:000087975100016 PM 10892734 ER PT J AU Huang, K Louis, JM Donaldson, L Lim, FL Sharrocks, AD Clore, GM AF Huang, K Louis, JM Donaldson, L Lim, FL Sharrocks, AD Clore, GM TI Solution structure of the MEF2A-DNA complex: structural basis for the modulation of DNA bending and specificity by MADS-box transcription factors SO EMBO JOURNAL LA English DT Article DE DNA bending; MADS-box; MEF2; multidimensional NMR; transcription ID SERUM RESPONSE FACTOR; 3-DIMENSIONAL STRUCTURES; MUSCLE DEVELOPMENT; NMR-SPECTROSCOPY; MEF2 PROTEINS; BINDING; IDENTIFICATION; REFINEMENT; RESTRAINTS; EXPRESSION AB The solution structure of the 33 kDa complex between the dimeric DNA-blinding core domain of the transcription factor MEF2A (residues 1-85) and a 20mer DNA oligonucleotide comprising the consensus sequence CTA(A/T)(4)TAG has been solved by NMR, The protein comprises two domains: a MADS-box (residues 1-58) and a MEF2S domain (residues 59-73). Recognition and specificity are achieved by interactions between the MADS-box and both the major and minor grooves of the DNA. A number of critical differences in protein-DNA contacts observed in the MEF2A-DNA complex and the DNA complexes of the related MADS-box transcription factors SRF and MCM1 provide a molecular explanation for modulation of sequence specificity and extent of DNA bending (similar to 15 versus similar to 70 degrees), The structure of the MEF2S domain is entirely different from that of the equivalent SAM domain in SRF and MCM1, accounting for the absence of cross-reactivity with other proteins that interact with these transcription factors. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Univ Manchester, Sch Biol Sci, Manchester M13 9PT, Lancs, England. RP Clore, GM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. RI Clore, G. Marius/A-3511-2008; OI Clore, G. Marius/0000-0003-3809-1027; Lim, Fei Ling/0000-0002-7744-4836 NR 55 TC 61 Z9 64 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD JUN 1 PY 2000 VL 19 IS 11 BP 2615 EP 2628 DI 10.1093/emboj/19.11.2615 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 322ZH UT WOS:000087539300022 PM 10835359 ER PT J AU Natale, DA Li, CJ Sun, WH DePamphilis, ML AF Natale, DA Li, CJ Sun, WH DePamphilis, ML TI Selective instability of Orc1 protein accounts for the absence of functional origin recognition complexes during the M-G(1) transition in mammals SO EMBO JOURNAL LA English DT Article DE DNA replication; initiation; origin recognition complex ID REPLICATION LICENSING SYSTEM; CHORION GENE AMPLIFICATION; BETA-GLOBIN LOCUS; CELL-FREE SYSTEM; DNA-REPLICATION; S-PHASE; CDK PHOSPHORYLATION; EGG EXTRACTS; IN-VIVO; XENOPUS AB To investigate the events leading to initiation of DNA replication in mammalian chromosomes, the time when hamster origin recognition complexes (ORCs) became functional was related to the time when Orc1, Orc2 and Mcm3 proteins became stably bound to hamster chromatin, Functional ORCs, defined as those able to initiate DNA replication, were absent during mitosis and early G(1) phase, and reappeared as cells progressed through G(1) phase. Immunoblotting analysis revealed that hamster Orc1 and Orc2 proteins were present in nuclei at equivalent concentrations throughout the cell cycle, but only Orc2 was stably bound to chromatin, Orc1 and McmS were easily eluted from chromatin during mitosis and early G(1) phase, but became stably bound during mid-G(1) phase, concomitant with the appearance of a functional pre-replication complex at a hamster replication origin. Since hamster Ore proteins are closely related to their human and mouse homologs, the unexpected behavior of hamster Orc1 provides a novel mechanism in mammals for delaying assembly of prereplication complexes until mitosis is complete and a nuclear structure has formed. C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP DePamphilis, ML (reprint author), NICHHD, NIH, Bldg 6,Room 3A02, Bethesda, MD 20892 USA. NR 55 TC 61 Z9 62 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD JUN 1 PY 2000 VL 19 IS 11 BP 2728 EP 2738 DI 10.1093/emboj/19.11.2728 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 322ZH UT WOS:000087539300033 PM 10835370 ER PT J AU Garcia-Caballero, T Mertani, HM Lambert, A Gallego, R Fraga, M Pintos, E Forteza, J Chevallier, M Lobie, PE Vonderhaar, BK Beiras, A Morel, G AF Garcia-Caballero, T Mertani, HM Lambert, A Gallego, R Fraga, M Pintos, E Forteza, J Chevallier, M Lobie, PE Vonderhaar, BK Beiras, A Morel, G TI Increased expression of growth hormone and prolactin receptors in hepatocellular carcinomas SO ENDOCRINE LA English DT Article DE in situ hybridization; immunohistochemistry; mRNA expression; hepatocyte; liver ID HUMAN DIGESTIVE TISSUES; RAT-LIVER; GENE-EXPRESSION; MESSENGER-RNA; TYROSINE PHOSPHORYLATION; MONOCLONAL-ANTIBODY; ANTERIOR-PITUITARY; PROTEIN-KINASE; CELLS; LOCALIZATION AB The liver is an essential target tissue for growth hormone (CH) and prolactin (PRL). The aim of this study was to determine the in situ expression of growth hormone receptor (GHR) and prolactin receptor (PRLR) in hepatocellular carcinomas and to compare the results with normal liver. For this purpose, in situ hybridization (ISH)and immunohistochemical techniques were performed and several tests were conducted to validate the results. By radioactive ISH, all the hepatocellular carcinomas studied showed labeling for GHR and PRLR mRNAs, Relative expression levels, determined by computer-assisted microdensity, were higher in hepatocellular carcinomas than in normal liver. Immunohistochemistry led us to confirm the constant expression of both receptor proteins in hepatocellular carcinomas and normal liver and to demonstrate their localization not only in the cytoplasm but also in the nucleus. These results confirm that the liver is a major CH and PRL target tissue and suggest that in hepatocellular carcinomas the proliferative effects of these hormones may be increased by a higher expression of their receptors. C1 Univ Santiago, Sch Med, Dept Morphol Sci, Santiago De Compostela 15705, Spain. Univ Lyon 1, CNRS UMR 5578, F-69622 Villeurbanne, France. Univ Hosp, Sch Med, Dept Pathol & Forens Sci, Santiago De Compostela, Spain. Lab Marcel Merieux, Pathol Lab, Lyon, France. Natl Univ Singapore, Inst Mol & Cell Biol, Singapore 117548, Singapore. NCI, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. RP Garcia-Caballero, T (reprint author), Univ Santiago, Sch Med, Dept Morphol Sci, Santiago De Compostela 15705, Spain. EM cmhisihq@uscmail.usc.es RI ASTAR, IMCB/E-2320-2012; Garcia-Caballero, Tomas/H-7213-2015 NR 47 TC 29 Z9 34 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1355-008X EI 1559-0100 J9 ENDOCRINE JI Endocrine PD JUN PY 2000 VL 12 IS 3 BP 265 EP 271 DI 10.1385/ENDO:12:3:265 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 326EQ UT WOS:000087720100009 PM 10963047 ER PT J AU Kleer, CG Bryant, BR Giordano, TJ Sobel, M Merino, MJ AF Kleer, CG Bryant, BR Giordano, TJ Sobel, M Merino, MJ TI Genetic changes in chromosomes 1p and 17p in thyroid cancer progression SO ENDOCRINE PATHOLOGY LA English DT Article DE thyroid neoplasms; chromosome 1p; anaplastic thyroid carcinoma; genetic changes; p53 ID TUMOR-SUPPRESSOR-GENE; P53 MUTATIONS; PAPILLARY CARCINOMAS; HIGH-FREQUENCY; RET ONCOGENE; ACTIVATION; TRANSFORMATION; TUMORIGENESIS; PROTOONCOGENE; ASSOCIATION AB Little is known about the genetic alterations that occur during the progression of thyroid neoplasms. To understand better the biology of thyroid tumors, we investigated several genetic loci in benign and malignant thyroid neoplasms. Forty-one thyroid tumors (6 adenomas, 16 papillary, 14 follicular, and 5 anaplastic carcinomas) were studied. Normal and tumor cells were microdissected from paraffin-embedded tissues. DNA was used for polymerase chain reaction-based loss of heterozygosity (LOH) analysis with the following markers: D1S243 (1p35-36), D1S165 (1p36) and D1S162 (1p32), TP53 (17p13), and INT-2 (11q13). Immunohistochemistry for Ki-67 was performed. The Ki-67 labeling index (LI) was the percentage of positive tumor cells. LOH at Ip was seen in 2 of 5 (40%) informative cases of anaplastic carcinoma (2 of 2 at D1S162 and 1 of 2 at D1S165) and in 2 of 11 (18%) informative cases of follicular carcinoma (2 of 7 at D1S243, 2 of 7 at D1S165, and 1 of 6 at D1S162). One anaplastic (20%) and two follicular carcinomas (14%) had LOH in at least two of the Ip loci analyzed. None of the adenomas and papillary carcinomas had LOH at these loci. LOH at 17p and 11q13 were infrequent. Ki-67 LI was 1.4, 7, 16, and 65% in adenomas, papillary, follicular, and anaplastic carcinomas, respectively. Allelic loss at Ip may occur in aggressive types of thyroid carcinoma and may be a marker of poor prognosis. LOH at Ip may represent a late genetic event in thyroid carcinogenesis. LOH at 17p and 11q13 (MEN gene locus) is uncommon in thyroid neoplasms. C1 Univ Michigan, Ctr Med, Dept Pathol, Ann Arbor, MI 48109 USA. NCI, Pathol Lab, Bethesda, MD USA. RP Kleer, CG (reprint author), Univ Michigan Hosp, Dept Pathol 2G332, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. OI Giordano, Thomas/0000-0003-0641-8873 NR 28 TC 23 Z9 24 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1046-3976 J9 ENDOCR PATHOL JI Endocr. Pathol. PD SUM PY 2000 VL 11 IS 2 BP 137 EP 143 DI 10.1385/EP:11:2:137 PG 7 WC Endocrinology & Metabolism; Pathology SC Endocrinology & Metabolism; Pathology GA 338AR UT WOS:000088396400003 ER PT J AU Szayna, M Doyle, ME Betkey, JA Holloway, HW Spencer, RGS Greig, NH Egan, JM AF Szayna, M Doyle, ME Betkey, JA Holloway, HW Spencer, RGS Greig, NH Egan, JM TI Exendin-4 decelerates food intake, weight gain, and fat deposition in Zucker rats SO ENDOCRINOLOGY LA English DT Article ID GLUCAGON-LIKE PEPTIDE-1; INSULIN SENSITIVITY; RECEPTOR; GLP-1; ANTAGONIST; EXPRESSION; INJECTION; AGONIST; LEPTIN; MICE AB Exendin-4 is a 39 amino acid peptide produced in the salivary gland of the Gila monster lizard. It has a 53% amino acid homology to the incretin hormone glucagon-like peptide-1 (GLP-1). Exendin-4 induces insulin release through activation of the GLP-1 receptor but is a much more patent insulinotropic agent than GLP-1. Of critical importance for its potential use as a treatment for diabetes is its much longer biological effect in vivo. Previous studies involving once daily administration of exendin-4 over 13 weeks to db/db mice demonstrated that it lowers hemoglobin A(1c) (HbA(1c)), a marker of mean blood glucose levels. Food consumption in the treated animals dropped over the first 4 days and then increased to a level comparable with that of the untreated animals. In this study, we initially examined the effect of once daily injections (over 14 days) on the food consumption of Zucker fatty rats. We observed an immediate reduction in food intake which then leveled off (after 5 days) to match that of the untreated animals. Subsequently we injected the same animals twice daily (treatment period of 56 days in total) and observed a sustained reduction in food intake and weight-gain. This was matched by a reduction in the critical parameters of HbA(1c), fasting blood glucose and plasma insulin. MRI imaging of the abdominal regions of the animals showed that initially only the amount of fat deposited in the sc region was reduced after 4 weeks exendin-4 treatment. At the 8-week time point there was a corresponding decrease in the amount of visceral fat deposition. The combination of appetite reduction, decreased fat deposition and an improvement in the parameters associated with glucose intolerance makes a case for the use of exendin-4 as a treatment for diabetes. C1 NIA, GRC, Diabet Sect 23, NIH, Baltimore, MD 21224 USA. NIA, GRC, NMR Unit, NIH, Baltimore, MD 21224 USA. NIA, GRC, Drug Design & Dev Sect, NIH, Baltimore, MD 21224 USA. RP Egan, JM (reprint author), NIA, GRC, Diabet Sect 23, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM eganj@vax.grc.nia.nih.gov NR 23 TC 234 Z9 254 U1 1 U2 8 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD JUN PY 2000 VL 141 IS 6 BP 1936 EP 1941 DI 10.1210/en.141.6.1936 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 337WM UT WOS:000088386100006 PM 10830274 ER PT J AU Pinsky, PF AF Pinsky, PF TI Assessment of risk from long term exposure to waterborne pathogens SO ENVIRONMENTAL AND ECOLOGICAL STATISTICS LA English DT Article DE pathogen dose-response curve; model uncertainty; Poisson distribution; population risks ID DRINKING-WATER; IMMUNOLOGIC CONTROL; TYPHOID FEVER; VOLUNTEERS; CRYPTOSPORIDIUM; GIARDIA; VIRUSES; MODEL AB Disease due to waterborne pathogens, whether in outbreak or endemic form, continues to be a problem in both the developing and the developed world. Control of waterborne disease requires accurate assessment of the pathogen dose-response relation and of likely patterns of exposure. Heretofore, risk assessment of pathogen exposure has been done on the basis of several standard biologically plausible dose-response models. In this paper, the problem of estimating the long-term risk from waterborne pathogens is put into a rigorous mathematical and statistical framework. The implications of the biologic assumptions embedded in the dose-response models (e.g., heterogeneity in susceptibility) are fully considered, as are the likely patterns of long-term exposure (e.g., temporal correlations within individuals and heterogeneity of mean exposures). Two types of long-term risk are described, risk per person-time and risk per individual where the latter is the risk of infection at least once. The effects on these risks of heterogeneity in individuals' susceptibilities and mean exposures and of temporal correlations of exposures are described, both theoretically and empirically using a sample of experimental data sets. Because different models with equal plausibility may give very different results in the low-dose range but fit the experimental data equally well, we apply the model uncertainty algorithm of Buckland et al. (1997) on example data sets. Finally, the computational aspects of the general problem, which are often challenging, are discussed along with the conditions under which simplifying approximations may be utilized. C1 US EPA, Natl Ctr Environm Assessment, Washington, DC USA. RP Pinsky, PF (reprint author), NCI, EPN 330, 6130 Execut Blvd MSC 7354, Bethesda, MD 20892 USA. NR 32 TC 10 Z9 10 U1 1 U2 6 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 1352-8505 J9 ENVIRON ECOL STAT JI Environ. Ecol. Stat. PD JUN PY 2000 VL 7 IS 2 BP 155 EP 175 DI 10.1023/A:1009627012258 PG 21 WC Environmental Sciences; Mathematics, Interdisciplinary Applications; Statistics & Probability SC Environmental Sciences & Ecology; Mathematics GA 324EL UT WOS:000087608800003 ER PT J AU Anderson, LM Diwan, BA Fear, NT Roman, E AF Anderson, LM Diwan, BA Fear, NT Roman, E TI Critical windows of exposure for children's health: Cancer in human epidemiological studies and neoplasms in experimental animal models SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review DE cancer; chemical carcinogens; childhood; exposure; fetus; in utero; ionizing radiation; neonatal; postnatal; preconception ID INTRAMUSCULAR VITAMIN-K; NON-HODGKINS-LYMPHOMA; DEPENDENT TRANSPLACENTAL CARCINOGENESIS; ASSISTED REPRODUCTION TECHNOLOGY; FETAL MOUSE SUSCEPTIBILITY; PATERNAL X-IRRADIATION; NEONATAL RISK-FACTORS; LUNG-TUMOR INDUCTION; ETHYL-N-NITROSOUREA; HEPATITIS-B VIRUS AB In humans, cancer may be caused by genetics and environmental exposures; however, in the majority of instances the identification of the critical time window of exposure is problematic. The evidence for exposures occurring during the preconceptional period that have an association with childhood or adulthood cancers is equivocal. Agents definitely related to cancer in children, and adulthood if exposure occurs in utero, include: maternal exposure to ionizing radiation during pregnancy and childhood leukemia and certain other cancers, and maternal use of diethylstilbestrol during pregnancy and clear-cell adenocarcinoma of the vagina of their daughters. The list of environmental exposures that occur during the perinatal/postnatal period with potential to increase the risk of cancer is lengthening, but evidence available to date is inconsistent and inconclusive. In animal models, preconceptional carcinogenesis has been demonstrated for a variety of types of radiation and chemicals, with demonstrated sensitivity for all stages from fetal gonocytes to postmeiotic germ cells. Transplacental and neonatal carcinogenesis show marked ontogenetic stage specificity in some cases. Mechanistic factors include the number of cells at risk, the rate of cell division, the development of differentiated characteristics including the ability to activate and detoxify carcinogens, the presence of stem cells, and possibly others. Usefulness for human risk estimation would be strengthened by the study of these factors in more than one species, and by a focus on specific human risk issues. C1 NCI, Frederick Canc Res & Dev Ctr, SAIC, IRSP, Frederick, MD 21701 USA. NCI, Frederick Canc Res & Dev Ctr, Comparat Carcinogenesis Lab, Frederick, MD 21701 USA. Univ Leeds, Ctr Clin Epidemiol, Leukaemia Res Fund, Leeds, W Yorkshire, England. RP Anderson, LM (reprint author), NCI, Frederick Canc Res & Dev Ctr, SAIC, IRSP, Bldg 538, Frederick, MD 21701 USA. RI Fear, Nicola/A-1917-2012; huang, hongqi/N-1473-2014 NR 256 TC 209 Z9 216 U1 3 U2 20 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 2000 VL 108 SU 3 BP 573 EP 594 DI 10.2307/3454549 PG 22 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 326RK UT WOS:000087748400028 PM 10852857 ER PT J AU Olshan, AF Anderson, L Roman, E Fear, N Wolff, M Whyatt, R Vu, V Diwan, BA Potischman, N AF Olshan, AF Anderson, L Roman, E Fear, N Wolff, M Whyatt, R Vu, V Diwan, BA Potischman, N TI Workshop to identify critical windows of exposure for children's health: Cancer work group summary SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE adult; child; environmental; neoplasm ID ACUTE LYMPHOBLASTIC-LEUKEMIA; RETINOBLASTOMA; MUTATION; ORIGIN; GENE; RISK AB We considered whether there are discrete windows of vulnerability in the development of cancer and which time periods may be of the greatest importance. Cancer was considered broadly. including cancers in childhood as well as adult cancers that may have an in utero or childhood origin. We concluded that there was evidence from animal and epidemiologic studies for causal relationships for preconceptional, in utero, and childhood exposures and cancer occurrence in children and adults. However, the evidence is incomplete and all relevant critical windows may not have been identified. The comprehensive evaluation of the relative importance of specific time windows of exposure is limited. Improvements in the design of epidemiologic studies and additional animal studies of mechanisms are warranted. C1 Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. NCI, Comparat Carcinogenesis Lab, Frederick, MD USA. Univ Leeds, Inst Epidemiol, Leukaemia Res Fund, Leeds, W Yorkshire, England. Mt Sinai Sch Med, Div Environm Hlth Sci, New York, NY USA. Columbia Univ, Joseph L Mailman Sch Publ Hlth, Div Environm Hlth Sci, New York, NY USA. US EPA, Natl Ctr Environm Assessment, Washington, DC 20460 USA. Univ Massachusetts, Dept Biostat & Epidemiol, Amherst, MA 01003 USA. RP Olshan, AF (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, CB 7400, Chapel Hill, NC 27599 USA. RI Fear, Nicola/A-1917-2012 NR 16 TC 23 Z9 24 U1 0 U2 2 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 2000 VL 108 SU 3 BP 595 EP 597 DI 10.2307/3454550 PG 3 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 326RK UT WOS:000087748400029 PM 10852858 ER PT J AU Olden, K Guthrie, J AF Olden, K Guthrie, J TI Children's health: A mixed review SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Olden, K (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 18 TC 3 Z9 3 U1 0 U2 1 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 2000 VL 108 IS 6 BP A250 EP A251 DI 10.1289/ehp.108-a250 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 326EN UT WOS:000087719900001 PM 10856035 ER PT J AU Brawley, OW Parnes, H AF Brawley, OW Parnes, H TI Prostate cancer prevention trials in the USA SO EUROPEAN JOURNAL OF CANCER LA English DT Article; Proceedings Paper CT 1st International Conference on Tumour Genetics and Prevention CY FEB 17-19, 2000 CL UNIV ST GALLEN, ST GALLEN, SWITZERLAND SP European Journal Canc, Journal Clin Oncol HO UNIV ST GALLEN DE prostate; prostate cancer; chemoprevention; clinical trials; 5-alpha-reductase inhibitor; selenium; alpha tocopherol ID 5-ALPHA-REDUCTASE INHIBITOR; FINASTERIDE; CHEMOPREVENTION; ANTIGEN; CARCINOGENESIS; HYPERPLASIA; TUROSTERIDE; CARCINOMA; SELENIUM; EFFICACY AB There is dramatic international variation in prostate cancer mortality rates. The variation suggests that the disease has an environmental cause and encourages the search for a way to prevent it. Androgenic stimulation over a period of time, perhaps due to a high fat diet, has been suggested as a cause of prostate cancer. The corollary to this hypothesis is that lowering androgenic stimulation over time will prevent prostate cancer. 5-Alpha-reductase inhibition through drugs like finasteride have been shown to decrease androgenic stimulation or the prostate. A clinical trial is underway using finasteride to assess this hypothesis. Epidemiological and laboratory studies also suggest that those with high selenium and vitamin E intake have a lower risk of prostate cancer. Recent serendipitous findings of two randomised clinical trials support this. A study to assess these compounds is currently being designed. Other promising but less developed interventions in the chemoprevention of prostate cancer include vitamin D supplementation and diet modification. (C) 2000 Published by Elsevier Science Ltd. All rights reserved. C1 Natl Canc Inst, Bethesda, MD 20852 USA. NCI, Div Canc Prevent, Bethesda, MD 20852 USA. RP Brawley, OW (reprint author), Natl Canc Inst, 6120 Execut Blvd,EPS 320, Bethesda, MD 20852 USA. NR 30 TC 52 Z9 53 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUN PY 2000 VL 36 IS 10 BP 1312 EP 1315 DI 10.1016/S0959-8049(00)00105-2 PG 4 WC Oncology SC Oncology GA 327KJ UT WOS:000087792800020 PM 10882873 ER PT J AU Elahi, D Muller, DC AF Elahi, D Muller, DC TI Carbohydrate metabolism in the elderly SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT Workshop of the International-Dietary-Energy-Consultative-Group CY MAY, 1999 CL TUFS UNIV, USDA HUMAN NUTRIT RES CTR, BOSTON, MASSACHUSETTS SP Int Dietary Energy Consultat Grp HO TUFS UNIV, USDA HUMAN NUTRIT RES CTR DE aging; carbohydrate metabolism; glucose tolerance; diabetes ID IMPAIRED GLUCOSE-TOLERANCE; BODY-FAT DISTRIBUTION; INSULIN RESISTANCE; BETA-CELL; DIABETES-MELLITUS; PLASMA-GLUCOSE; AGE; INTOLERANCE; POPULATION; WOMEN AB In this short review we summarize the effect of age on glucose homeostasis. The concept of decreased glucose tolerance with increasing age is introduced, followed by evidence for this phenomenon. Specifically we review the evidence for changes in fasting glucose as a function of age and the effect of age on HbA1c. The role of age on hepatic glucose production and glucose uptake is then discussed in detail and we review the evidence that supports the concept that with advancing age hepatic glucose sensitivity to insulin is unaltered. We then review the large evidence for the role of age on the purported decrease in peripheral tissue sensitivity to insulin and conclude that the issue is unsettled. The decrease attributed to age is no longer significant when confounders are controlled for, the largest being obesity. We next present evidence that beta-cell sensitivity to glucose remains intact with aging. A review of age-related disorders due to hyperglycemia and confounding effects on the relationships of age and glucose tolerance is presented next. Finally we present new evidence that when the revised criteria for the diagnosis of type 2 diabetics as proposed by the American Diabetes Association and WHO are used, a greater percentage of the elderly will not be diagnosed. We conclude that, although glucose intolerance increases with aging, which is accompanied with other disorders, it is possible to ameliorate this effect with alteration of diet and exercise. C1 Massachusetts Gen Hosp, Geriat Res Lab, Boston, MA 02114 USA. NIA, Gerontol Res Ctr, Clin Invest Lab, Baltimore, MD 21224 USA. RP Elahi, D (reprint author), Massachusetts Gen Hosp, Geriat Res Lab, GRB SB 0015C,55 Fruit St, Boston, MA 02114 USA. NR 66 TC 23 Z9 23 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0954-3007 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD JUN PY 2000 VL 54 SU 3 BP S112 EP S120 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 333FG UT WOS:000088118600015 PM 11041082 ER PT J AU Henry, CJK Ritz, P Roth, GS Lane, M Solomons, NW AF Henry, CJK Ritz, P Roth, GS Lane, M Solomons, NW TI Report of the IDECG Working Group on the biology of aging SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Editorial Material C1 CESSIAM, Guatemala City, Guatemala. Oxford Brookes Univ, Sch Biol & Mol Sci, Oxford OX3 0BP, England. CHU Angers, Serv Med B, Angers, France. NIA, Francis Scott Key Med Ctr, NIH, Bethesda, MD 20892 USA. RP Solomons, NW (reprint author), CESSIAM, Sect Guatemala 3163, POB 02-5339, Miami, FL USA. NR 5 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0954-3007 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD JUN PY 2000 VL 54 SU 3 BP S157 EP S159 PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 333FG UT WOS:000088118600021 PM 11041088 ER PT J AU Roth, GS Ingram, DK Black, A Lane, MA AF Roth, GS Ingram, DK Black, A Lane, MA TI Effects of reduced energy intake on the biology of aging: the primate model SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT Workshop of the International-Dietary-Energy-Consultative-Group CY MAY, 1999 CL TUFS UNIV, USDA HUMAN NUTRIT RES CTR, BOSTON, MASSACHUSETTS SP Int Dietary Energy Consultat Grp HO TUFS UNIV, USDA HUMAN NUTRIT RES CTR DE aging; primates; energy restriction ID MONKEYS MACACA-MULATTA; TERM DIETARY RESTRICTION; MALE RHESUS-MONKEYS; CALORIC RESTRICTION; BODY-COMPOSITION; VOLUNTARY EXERCISE; BLOOD-CHEMISTRY; ADULT MALE; LIFE-SPAN; RATS AB Dietary energy restriction is the only proven method for extending lifespan and slowing aging in mammals, while maintaining health and vitality. Although the first experiments in this area were conducted over 60 y ago in rodents, possible applicability to primates has only been examined in controlled studies since 1987. Our project at the National Institute on Aging began with 3-0 male rhesus and 30 male squirrel monkeys of various ages over their respective life spans. Subsequently, it has been expanded to include female rhesus monkeys, and several other laboratories have initiated related studies. Experimental animals are generally fed 30% less than controls, and diets are supplemented with micronutrients to achieve undernutrition without malnutrition. These calorically restricted (CR) monkeys are lighter, with less fat and lean mass than controls. Bone mass is also slightly reduced, but in approximate proportion to the smaller body size. CR animals mature more slowly and achieve shorter stature than controls as well. Metabolically, CR monkeys have slightly lower body temperature and initial energy expenditure following onset of restriction, and better glucose tolerance and insulin sensitivity. The latter suggest a reduced predisposition towards diabetes as the animals age. Other potential anti-disease effects include biomarkers suggestive of lessened risk of cardiovascular disease and possibly cancer. Candidate biomarkers of aging, including the age-related decrease in plasma dehydroepiandrosterone sulfate (DHEAS), suggest that the CR animals may be aging more slowly than controls in some respects, although sufficient survival data will require more time to accumulate. In summary, nearly all CR effects detected in rodents, which have thus far been examined in primates, exhibit similar phenomenology. Potential applicability of these beneficial effects to humans is discussed. C1 NIA, Baltimore, MD 21224 USA. RP Roth, GS (reprint author), NIA, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Biguzzi, Felipe/E-4724-2015 NR 48 TC 33 Z9 33 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0954-3007 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD JUN PY 2000 VL 54 SU 3 BP S15 EP S20 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 333FG UT WOS:000088118600003 PM 11041070 ER PT J AU Monson, NL Dorner, T Lipsky, PE AF Monson, NL Dorner, T Lipsky, PE TI Targeting and selection of mutations in human V lambda rearrangements SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE human; B lymphocyte; antibody; generation of diversity, and evolution ID HEAVY-CHAIN GENES; SOMATIC HYPERMUTATION; GERMINAL-CENTERS; REPERTOIRE; SEQUENCES; MECHANISMS AB The impact of somatic hypermutation on the lambda light chain repertoire of individual IgM(+) peripheral B cells in the absence (nonproductive rearrangements) and presence (productive rearrangements) of selective influences was analyzed. In the 27 mutated nonproductive V lambda J lambda rearrangements obtained from individual peripheral B cells, a significantly greater mutational frequency was observed in the complementarity-determining region (CDR) in comparison to the framework region (FR), whereas the mutational frequencies in both the CDR and FR of the 100 mutated productive V lambda J lambda rearrangements were significantly greater R mutations were introduced comparably in CDR and FR of nonproductive V lambda J lambda rearrangements, but were significantly decreased in FR of productive V lambda J lambda rearrangements. The majority of codons defined as hot spots for R mutations were within CDR in both the nonproductive and productive V lambda J lambda, rearrangements. Targeting of mutations to RGYW/WRCY motifs was observed such that 38% of all mutations in the nonproductive V lambda J lambda rearrangements were within RGYW/WRCY motifs. Mutations in RGYW/WRCY motifs were positively selected and accounted for >50% of all mutations in the mutated productive V lambda J lambda rearrangements. These data indicate that targeting of the mutational machinery and selection of mutations in these targeted motifs play major roles in influencing nucleotide changes in V lambda J lambda rearrangements. C1 Univ Texas, SW Med Ctr, Dept Internal Med, Dallas, TX USA. Univ Texas, SW Med Ctr, Harold C Simmons Arthrit Res Ctr, Dallas, TX USA. RP Lipsky, PE (reprint author), NIAMSD, Bldg 10,Room 9N228,10 Ctr Dr MSC 1820, Bethesda, MD 20892 USA. FU NIAID NIH HHS [AI 31229] NR 17 TC 27 Z9 27 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUN PY 2000 VL 30 IS 6 BP 1597 EP 1605 DI 10.1002/1521-4141(200006)30:6<1597::AID-IMMU1597>3.0.CO;2-R PG 9 WC Immunology SC Immunology GA 322KA UT WOS:000087507700009 PM 10898495 ER PT J AU Fregonese, L Sacco, O Fregonese, B Verna, A Mereu, C Gambini, C Rossi, GA AF Fregonese, L Sacco, O Fregonese, B Verna, A Mereu, C Gambini, C Rossi, GA TI "Difficult-to-treat" asthma-like symptoms in a 12-yr-old atopic female SO EUROPEAN RESPIRATORY JOURNAL LA English DT Article DE bronchial stenosis; oxygen radicals; transition metals; YAG laser therapy ID TABLET C1 Ist Giannina Gaslini, Div Pulm Dis, I-16147 Genoa, Italy. Univ Genoa, Natl Canc Inst, Genoa, Italy. RP Rossi, GA (reprint author), Ist Giannina Gaslini, Div Pneumol, Largo G Gaslini 5, I-16147 Genoa, Italy. NR 10 TC 4 Z9 4 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0903-1936 J9 EUR RESPIR J JI Eur. Resp. J. PD JUN PY 2000 VL 15 IS 6 BP 1128 EP 1131 DI 10.1034/j.1399-3003.2000.01524.x PG 4 WC Respiratory System SC Respiratory System GA 327KA UT WOS:000087792000024 PM 10885435 ER PT J AU Xiao, XD Kinter, A Broder, CC Dimitrov, DS AF Xiao, XD Kinter, A Broder, CC Dimitrov, DS TI Interactions of CCR5 and CXCR4 with CD4 and gp120 in human blood monocyte-derived dendritic cells SO EXPERIMENTAL AND MOLECULAR PATHOLOGY LA English DT Article DE HIV-1; CD4; CXCR4; CCR5; gp120; dendritic cells; membrane fusion ID HUMAN-IMMUNODEFICIENCY-VIRUS; RECOMBINANT VACCINIA VIRUS; ENVELOPE GLYCOPROTEIN; SURFACE ASSOCIATION; HIV CORECEPTORS; TYPE-1; MACROPHAGES; INFECTION; RECEPTORS; ENTRY AB Dendritic cells (DC) and macrophages play an important role in the generation of immune responses and transmission of HIV infection. It has been recently found that, in the presence of gp120, CD4 can be efficiently coimmunoprecipitated by anti-CXCR4, antibodies from lymphocytes and monocytes but not from blood monocyte-derived macrophages. The gp 120-CD4-CXCR4 complex formation paralleled the ability for these cell types to support X4 (LAV) HIV-1 envelope glycoprotein (Env)-mediated fusion. Here we report that, unlike macrophages but similar to lymphocytes and monocytes, human blood monocyte-derived DC allow efficient complex formation among the HIV-1 coreceptor CXCR4, the primary receptor CD4, and the Env gp120 (LAV) which parallels their fusion ability with cells expressing HIV-1 Env (LAV). In addition, DC behaved similarly to macrophages, lymphocytes, and monocytes in their ability to support formation of complexes between CD4 and the other major HIV-1 coreceptor CCR5 even in the absence of gp 120 as demonstrated by CD4 coimmunoprecipitation with anti-CCR5 antibodies. Further, the amount of gp120-CD4-CXCR4 (or CCR5) complexes was proportional to the extent of cell fusion mediated by the HIV-1 Env (LAV or JRFL, respectively). These results demonstrate that of all the major types of host cells important for HIV-1 infection, the first central stage in the entry mechanism, the formation of gp120-CD4-coreceptor complexes, is not impaired except for the formation of the gp120-CD4-CXCR4 complex in macrophages. Therefore, for most CD4+ target cells restraint(s) on productive HIV-1 infection appears to occur at stages of the virus life cycle subsequent to the gp120-CD4-corecepror complex formation. C1 NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, NIH, Frederick, MD 21702 USA. RP Broder, CC (reprint author), NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, NIH, Bldg 469,Room 216,POB B,Miller Dr, Frederick, MD 21702 USA. FU NIAID NIH HHS [R21AI42599] NR 26 TC 16 Z9 16 U1 1 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4800 J9 EXP MOL PATHOL JI Exp. Mol. Pathol. PD JUN PY 2000 VL 68 IS 3 BP 133 EP 138 DI 10.1006/exmp.1999.2300 PG 6 WC Pathology SC Pathology GA 319PU UT WOS:000087351000001 PM 10816381 ER PT J AU Xiao, XD Norwood, D Feng, YR Moriuchi, M Jones-Trower, A Stantchev, TS Moriuchi, H Broder, CC Dimitrov, DS AF Xiao, XD Norwood, D Feng, YR Moriuchi, M Jones-Trower, A Stantchev, TS Moriuchi, H Broder, CC Dimitrov, DS TI Inefficient formation of a complex among CXCR4, CD4 and gp120 in U937 clones resistant to X4 gp120-gp41-mediated fusion SO EXPERIMENTAL AND MOLECULAR PATHOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; RECOMBINANT VACCINIA VIRUS; CELL-SURFACE ASSOCIATION; HIV CORECEPTORS; CCR-5; GLYCOPROTEINS; MACROPHAGES; INFECTIONS; RECEPTORS AB Certain subclones (designated as minus clones) of the promonocytic U937 cell line do not support efficient infection and fusion mediated by T cell line adapted (TCLA) X4 HIV-1 gp120-gp41 (Env) although the CXCR4 and CD4 concentrations at their surfaces are similar to those at the surfaces of clones susceptible to HIV-1 entry (plus clones) (H. Moriuchi et al., J. Virol. 71, 9664-9671, 1997). To test the hypothesis that inefficient formation of gp120-CD4-CXCR4 complexes could contribute to the mechanism of resistance to Env-mediated fusion in the minus clones, we incubated plus and minus cells with HIV-1 LAI gp120 and coimmunoprecipitated CD4 by using anti-CXCR4 antibodies. The gp120 induced inefficient coimmunoprecipitation of CD4 in the minus clones but not in the plus ones. Overexpression of CD4 resulted in significant restoration of the minus clones' susceptibility to fusion in parallel with an increase in the amount of the gp120-CD4-CXCR4 complexes. These results not only suggest that the resistance to TCLA X4 HIV-1 entry in the U937 minus clones is due to the inability of these cells to efficiently form complexes among CD4, gp120, and CXCR4, but also provide a direct evidence for the correlation between fusion and the cell surface concentration of the complexes among CXCR4, CD4, and gp120. These data and similar recent observations in macrophages suggest that inefficient complex formation among CXCR4, CD4, and gp120 could be a general mechanism of cell resistance to gp 120-gp41-mediated fusion and a major determinant of HIV-1 evolution in vivo. C1 NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, LELB,NIH, Frederick, MD 21702 USA. RP Broder, CC (reprint author), NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, LELB,NIH, Bldg 469,Room 216,POB B,Miller Dr, Frederick, MD 21702 USA. FU NIAID NIH HHS [R21AI414110, R01AI43885] NR 21 TC 12 Z9 12 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4800 J9 EXP MOL PATHOL JI Exp. Mol. Pathol. PD JUN PY 2000 VL 68 IS 3 BP 139 EP 146 DI 10.1006/exmp.1999.2299 PG 8 WC Pathology SC Pathology GA 319PU UT WOS:000087351000002 PM 10816382 ER PT J AU Moore, AB He, H Yoshida, A Rico, PJ Haseman, JK Dixon, D AF Moore, AB He, H Yoshida, A Rico, PJ Haseman, JK Dixon, D TI Transforming growth factor-alpha, epidermal growth factor receptor, and PCNA immunoexpression in uterine leiomyosarcomas and leiomyomas in B6C3F1 mice SO EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY LA English DT Article DE transforming growth factor-alpha; epidermal growth factor receptor; immunoexpression; growth factors; cell proliferation; uterine leiomyoma, leiomyosarcoma; proliferating cell nuclear antigen, PCNA ID CELL NUCLEAR ANTIGEN; MESSENGER-RNA; EXPRESSION; RAT; INDUCTION; SECRETION; ONCOGENE; ESTROGEN; CULTURES; PROTEIN AB The role of growth factors in the development of murine uterine mesenchymal tumors is unknown. In this study, immunohistochemical expression of transforming growth factor alpha (TGF-alpha) and its receptor epidermal growth factor (EGF-R) was assessed in spontaneous uterine leiomyomas and leiomyosarcomas in B6C3F1 mice. Cell proliferation, which has been induced by some growth factors, was evaluated by immunohistochemical detection of an endogenous marker of cell proliferation, proliferating cell nuclear antigen (PCNA). PCNA labeling indices were determined and compared to the intensity and distribution of TGF-alpha staining in sequential sections of control myometrium or tumor tissue. Results showed uterine leiomyosarcomas had positive cytoplasmic staining for TGF-alpha; however, all uterine leiomyomas evaluated were negative. Positive EGF-R staining was also observed in the uterine leiomyosarcomas, but not in the leiomyomas. EGFR immunoexpression was detected primarily within the cytoplasm of the leiomyosarcoma cells, with occasional nuclear immunoreactivity. Immunohistochemical staining for PCNA was more intense and there were increased numbers of positively staining nuclei in the leiomyosarcomas compared to samples of control myometrium or leiomyomas. The mean labeling index for the uterine leiomyosarcomas (7.40%) was significantly (p < 0.01) higher than that of leiomyomas (0.29%) and control uterine myometrium (0.13%). We conclude, that TGF-alpha and its receptor, EGFR, are expressed more intensely in uterine leiomyosarcomas, compared to leiomyomas in B6C3F1 mice. Immunoexpression of TGF-alpha may be an important biomarker of malignancy in uterine smooth muscle tumors in mice. Futhermore, TGF-alpha may play a critical role in increased proliferation of uterine smooth muscle tumor cells as suggested by increased immunolocalization of PCNA in rodent leiomyosarcomas expressing TGF-alpha, although other factors regulating cell replication can not be ruled out. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Dixon, D (reprint author), NIEHS, POB 12233,MD C2-09, Res Triangle Pk, NC 27709 USA. NR 34 TC 7 Z9 8 U1 0 U2 0 PU GUSTAV FISCHER VERLAG PI JENA PA VILLENGANG 2, D-07745 JENA, GERMANY SN 0940-2993 J9 EXP TOXICOL PATHOL JI Exp. Toxicol. Pathol. PD JUN PY 2000 VL 52 IS 3 BP 195 EP 200 PG 6 WC Pathology; Toxicology SC Pathology; Toxicology GA 339MB UT WOS:000088479900003 PM 10930119 ER PT J AU Brettler, SC Rude, SA Quinn, KJ Killian, JE Schweitzer, EC Baker, JF AF Brettler, SC Rude, SA Quinn, KJ Killian, JE Schweitzer, EC Baker, JF TI The effect of gravity on the horizontal and vertical vestibulo-ocular reflex in the rat SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE otolith organs; semicircular canals; eye movement; angular vestibulo-ocular reflex ID SQUIRREL-MONKEY; AXIS ROTATION; LINEAR ACCELERATION; OPTOKINETIC REFLEXES; SPATIAL-ORGANIZATION; SEMICIRCULAR CANALS; ANGULAR VELOCITY; NUCLEAR NEURONS; EYE-MOVEMENTS; PIGMENTED RAT AB Horizontal and vertical eye movements were recorded in alert pigmented rats using chronically implanted scleral search coils or temporary glue-on coils to test the dependence of the vestibule-ocular reflex (VOR) upon rotation axis and body orientation. The contributions of semicircular-canal versus otolith-organ signals to the VOR were investigated by providing canal-only (vertical axis) and canal plus otolith (horizontal axis) stimulation conditions. Rotations that stimulated canals only (upright yaw and nose-up roll) produced an accurate VOR during middle- and high-frequency rotations (0.2-2 Hz). However, at frequencies below 0.2 Hz, the canal-only rotations elicited a phase-advanced VOR. The addition of a changing gravity stimulus, and thus dynamic otolith stimulation, to the canal signal (nose-up yaw, on-side yaw, and upright roll) produced a VOR response with accurate phase down to the lowest frequency tested (0.02 Hz). In order to further test the dependence of the VOR on gravitational signals, we tested vertical VOR with the head in an inverted posture (inverted roll). The VOR in this condition was advanced in phase across all frequencies tested. At low frequencies, the VOR during inverted roll was anticompensatory, characterized by slow-phase eye movement in the same direction as head movement. The substantial differences between canal-only VOR and canal plus otolith VOR suggest an important role of otolith organs in rat VOR. Anticompensatory VOR during inverted roll suggests that part of the otolith contribution arises from static tilt signals that are inverted when the head is inverted. C1 Northwestern Univ, Inst Neurosci, Dept Physiol, Chicago, IL 60611 USA. Univ Washington, Dept Physiol & Biophys, Seattle, WA 98195 USA. NIMH, Rockville, MD 20857 USA. RP Baker, JF (reprint author), Northwestern Univ, Inst Neurosci, Dept Physiol, M211,303 E Chicago Ave, Chicago, IL 60611 USA. EM j-baker@nwu.edu FU NEI NIH HHS [EY07342]; NIDCD NIH HHS [DC01559] NR 61 TC 20 Z9 20 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0014-4819 EI 1432-1106 J9 EXP BRAIN RES JI Exp. Brain Res. PD JUN PY 2000 VL 132 IS 4 BP 434 EP 444 DI 10.1007/s002210000357 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 329MJ UT WOS:000087910500002 PM 10912824 ER PT J AU Denning, MF Dlugosz, AA Cheng, C Dempsey, PJ Coffey, RJ Threadgill, DW Magnuson, T Yuspa, SH AF Denning, MF Dlugosz, AA Cheng, C Dempsey, PJ Coffey, RJ Threadgill, DW Magnuson, T Yuspa, SH TI Cross-talk between epidermal growth factor receptor and protein kinase C during calcium-induced differentiation of keratinocytes SO EXPERIMENTAL DERMATOLOGY LA English DT Article DE protein kinase C; keratinocyte; differentiation; transforming growth factor alpha; tyrosine kinase; epidermal growth factor receptor ID TYROSINE PHOSPHORYLATION; FACTOR-ALPHA; TGF-ALPHA; TERMINAL DIFFERENTIATION; MOUSE KERATINOCYTES; SIGNALING PATHWAY; EGF RECEPTOR; MURINE KERATINOCYTES; GENE-EXPRESSION; ETA-ISOFORMS AB The induction of epidermal differentiation by extracellular Ca2+ involves activation of both tyrosine kinase and protein kinase C (PKC) signaling cascades. To determine if the differentiation-dependent activation of tyrosine kinase signaling can influence the PKC pathway, we examined the tyrosine phosphorylation status of PKC isoforms in primary mouse keratinocytes stimulated to terminally differentiate with Ca2+ Elevation of extracellular Ca2+ induced tyrosine phosphorylation of PKC-delta, but not the other keratinocyte PKC isoforms (alpha,epsilon, eta, zeta). We have previously demonstrated that activation of the epidermal growth factor receptor (EGFR) pathway induces PKC-delta tyrosine phosphorylation in basal keratinocytes (Denning M F, Dlugosz A A, Threadgill D W, Magnuson T, Yuspa S H (1996)J Biol Chern 271: 5325-5331). When basal keratinocytes were stimulated to differentiate by Ca2+, the level of cell-associated transforming growth factor-alpha (TGF-alpha) increased 30-fold, while no increase in secreted TGF-alpha was detected. Furthermore, Ca2+-induced tyrosine phosphorylation of PKC-delta and phosphotyrosine-association of the receptor adapter protein Shc was diminished in EGFR -/- keratinocytes, suggesting that EGFR activation may occur during keratinocyte differentiation. Tyrosine phosphorylated PKC-delta was also detected in mouse epidermis, suggesting that this differentiation-associated signaling pathway is physiological. These results establish a requirement for the EGFR in Ca2+-induced tyrosine phosphorylation of PKC-delta, and document the production of cell-associated TGF-alpha in differentiated keratinocytes which may function independent of its usual mitogenic effects. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. Vanderbilt Univ, Sch Med, Dept Cell Biol, Nashville, TN 37212 USA. Vet Affairs Med Ctr, Nashville, TN 37212 USA. Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA. RP Yuspa, SH (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bldg 37,Room 3B25,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. RI Threadgill, David/N-4425-2013 OI Threadgill, David/0000-0003-3538-1635 NR 52 TC 47 Z9 53 U1 0 U2 4 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0906-6705 J9 EXP DERMATOL JI Exp. Dermatol. PD JUN PY 2000 VL 9 IS 3 BP 192 EP 199 DI 10.1034/j.1600-0625.2000.009003192.x PG 8 WC Dermatology SC Dermatology GA 313QP UT WOS:000087010600005 PM 10839717 ER PT J AU Gelderman, MP Gonzalez-Fernandez, F Baer, CA Wiggert, B Chan, CC Vistica, BP Gery, I AF Gelderman, MP Gonzalez-Fernandez, F Baer, CA Wiggert, B Chan, CC Vistica, BP Gery, I TI Xenopus IRBP, a phylogenetically remote protein, is uveitogenic in Lewis rats SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE uveitis; phylogenetic remoteness; Lewis rat; Xenopus IRBP ID RETINOID-BINDING-PROTEIN; EXPERIMENTAL AUTOIMMUNE UVEORETINITIS; S-ANTIGEN; UVEITIS; MODEL; IDENTIFICATION; IMMUNODOMINANT; DETERMINANT; PINEALITIS; INDUCTION AB Mammalian interphotoreceptor retinoid-binding proteins (IRBPs) are highly uveitogenic in Lewis rats. Xenopus laevis IRBP resembles mammalian IRBP in its four-fold structure, and has similar to 70% amino acid sequence identity with the bovine protein. This study investigated the uveitogenicity of recombinant Xenopus IRBP and two of its derived peptides in Le Lewis rats. Rats immunized with Xenopus IRBP developed uveoretinitis as well as pineal inflammation. The Xenopus molecule was, however, less immunopathogenic than the bovine IRBP. Of the two Xenopus IRBP peptides tested, 1180-1191 was remarkably uveitogenic, whereas sequence 521-540 exhibited low activity. It is assumed, therefore, that as with bovine IRBP, peptide 1180-1191 is the major uveitogenic sequence in Xenopus IRBP. The role individual residues of these peptides play in the immunopathogenic process is discussed. Our data thus demonstrate that despite its being phylogenetically remote, Xenopus IRBP is uveitogenic in Lewis rats. C1 NEI, NIH, Bethesda, MD 20892 USA. Univ Virginia, Dept Ophthalmol, Charlottesville, VA 22903 USA. Univ Virginia, Grad Program Neurosci, Charlottesville, VA 22903 USA. RP Gery, I (reprint author), NEI, NIH, Bldg 10,Rm 10N112, Bethesda, MD 20892 USA. NR 19 TC 1 Z9 1 U1 0 U2 0 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 J9 EXP EYE RES JI Exp. Eye Res. PD JUN PY 2000 VL 70 IS 6 BP 731 EP 736 DI 10.1006/exer.2000.0839 PG 6 WC Ophthalmology SC Ophthalmology GA 325VG UT WOS:000087696700003 PM 10843777 ER PT J AU Andrews, KL Potdar, PD Nettesheim, P Ostrowski, LE AF Andrews, KL Potdar, PD Nettesheim, P Ostrowski, LE TI KPL1, which encodes a novel PH domain-containing protein, is induced during ciliated cell differentiation of rat tracheal epithelial cells SO EXPERIMENTAL LUNG RESEARCH LA English DT Article DE ciliogenesis; pleckstrin homology domain; tracheal epithelial cells; differentiation ID PLECKSTRIN HOMOLOGY DOMAIN; WISKOTT-ALDRICH SYNDROME; BRUTONS TYROSINE KINASE; GENE; IDENTIFICATION; CILIOGENESIS; EXPRESSION; PHENOTYPE; ADJACENT; ACID AB Using differential display, we have identified a novel gene, KPL1, induced in rat tracheal epithelial (RTE) cells grown under conditions which stimulate ciliogenesis. The KPL1 protein is Predicted to contain a pleckstrin homology (PH) domain, which has been found in numerous signal transduction and cytoskeletal proteins. These domains are thought to function by recruiting proteins to cellular membranes, and they have been shown to bind phosphoinositols and the beta/gamma subunit of G proteins. We have cloned rat and human KPL1; the predicted protein translations are 94% identical. Alternate transcripts exist in rat and human tracheal cells that predict a protein which contains a 35-amino acid insert. KPL1 was upregulated in RIE cultures undergoing mucociliary but not squamous differentiation; and in cultures undergoing mucociliary differentiation, KPL1 expression most closely paralleled that of a marker of ciliated cell differentiation (axonemal dynein heavy chain) and not a marker of mucous cell differentiation (mucin 5AC). As a new member of the family of PH domain-containing proteins, KPL1 may have a unique role in ciliated cell differentiation or function. C1 NIEHS, Pulm Pathobiol Lab, Res Triangle Pk, NC 27709 USA. RP Ostrowski, LE (reprint author), Univ N Carolina, Dept Med, Cyst Fibrosis Pulm Res Ctr, 927 Mary Ellen Jones Bldg, Chapel Hill, NC 27599 USA. NR 25 TC 5 Z9 7 U1 1 U2 2 PU HEMISPHERE PUBL CORP PI BRISTOL PA 1900 FROST ROAD, SUITE 101, BRISTOL, PA 19007-1598 USA SN 0190-2148 J9 EXP LUNG RES JI Exp. Lung Res. PD JUN PY 2000 VL 26 IS 4 BP 257 EP 271 PG 15 WC Respiratory System SC Respiratory System GA 327JU UT WOS:000087791400004 PM 10923244 ER PT J AU Isaacs, KR Wolpoe, ME Jacobowitz, DM AF Isaacs, KR Wolpoe, ME Jacobowitz, DM TI Vulnerability to calcium-induced neurotoxicity in cultured neurons expressing calretinin SO EXPERIMENTAL NEUROLOGY LA English DT Article DE cytotoxicity; PCREB; neuroprotection ID BINDING PROTEIN CALRETININ; CAJAL-RETZIUS CELLS; DOPAMINERGIC-NEURONS; PARKINSONS-DISEASE; HIPPOCAMPAL-NEURONS; CALBINDIN D-28K; CEREBRAL-CORTEX; IMMUNOHISTOCHEMICAL LOCALIZATION; GABAERGIC NEURONS; NERVOUS-SYSTEM AB Calretinin (CR) is a calcium-binding protein purported to have neuroprotective properties. This study was designed to characterize the types of neurons containing CR in two different primary cultures and to determine which, if any, CR-immunoreactive (CR-ir) neurons are resistant to excitotoxic insults. Calretinin-containing neurons in cortical primary cultures derived from E14 rat embryos were not resistant to either kainic acid or a brief calcium overload induced by the calcium ionophore A23187. Equal proportions of CR-ir and GABAergic cortical neurons were lost after a 24-h exposure to 100 or 500 mu M kainic acid. A 3 mu M, 3-h exposure to A23187 induced equivalent amounts of cell loss in both the total cell and CR-ir cortical neuron culture populations. Cortical cultures grown for 6-7 days were more vulnerable than 12- to 13-day-old cultures to short-term, low-concentration treatments of A23187. Older cultures, however, were more severely affected when examined 24 h after a 3-h exposure to A23187. Calretinin-immunoreactive neurons derived from the diencephalon were relatively more resistant than cortical neurons to kainic acid at 6-7 days in vitro. In cortical or diencephalic cultures, CR was rarely coexpressed with GABA or calbindin D-28k. No vasoactive intestinal peptide, substance P, or parvalbumin was detected in CR-ir neurons in either culture system. We suggest that the presence of CR alone is not sufficient to spare neurons from a toxic calcium overload. Calretinin may still buffer calcium at low concentrations or be a component in a calcium-based signal transduction system, (C) 2000 Academic Press. C1 NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. RP Isaacs, KR (reprint author), NIMH, Clin Sci Lab, Bldg 10,Rm 3D48, Bethesda, MD 20892 USA. NR 54 TC 22 Z9 22 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUN PY 2000 VL 163 IS 2 BP 311 EP 323 DI 10.1006/exnr.2000.7347 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 323CA UT WOS:000087546200001 PM 10833305 ER PT J AU Shakarian, AM Dwyer, DM AF Shakarian, AM Dwyer, DM TI Structurally conserved soluble acid phosphatases are synthesized and released by Leishmania major promastigotes SO EXPERIMENTAL PARASITOLOGY LA English DT Article DE human parasite; protozoan pathogen; phosphomonoesterase; histidine acid phosphatase; trypanosomatid; kinetoplastid ID DONOVANI PROMASTIGOTES AB Shakarian, A. M., and Dwyer, D. M. 2000. Structurally conserved soluble acid phosphatases are synthesized and released by Leishmania major promastigotes. Experimental Parasitology 95, 79-84. Previously it was reported that promastigotes of virtually all pathogenic Leishmania species, except Leishmania major; release a structurally conserved soluble acid phosphatase (AcP) activity during their growth in vitro (P. S. Doyle and D. M. Dwyer, Exp. Parasitol. 77, 435-444 1993). In the current study we used a highly sensitive fluorogenic detection method to demonstrate that soluble AcPs were in fact produced by promastigotes of several different strains of L. major: These L. major AcP activities were readily immunoprecipitated with a rabbit antibody previously generated against the L. donovani AcP. Results of metabolic labeling and immunoprecipitations demonstrated that AcPs produced by the L. majors strains examined had an apparent molecular mass of,77 kDa. Results of Southern hybridization analysis with an L. donovani AcP gene probe showed that the AcP gene loci were conserved in the L. I,major strains examined. Taken together, these results indicate that the AcP enzyme has been structurally and Functionally conserved throughout the evolution of pathogenic species of Leishmania. Such conservation suggests that the AcPs play a functional role in the growth and survival of this group of important human pathogens. C1 NIAID, Cell Biol Sect, Parasit Dis Lab, Div Intramural Res,NIH, Bethesda, MD 20892 USA. RP Dwyer, DM (reprint author), NIAID, Cell Biol Sect, Parasit Dis Lab, Div Intramural Res,NIH, Bldg 4,Room 126,4 Ctr Dr,MSC 0425, Bethesda, MD 20892 USA. NR 14 TC 23 Z9 23 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4894 J9 EXP PARASITOL JI Exp. Parasitol. PD JUN PY 2000 VL 95 IS 2 BP 79 EP 84 DI 10.1006/expr.2000.4511 PG 6 WC Parasitology SC Parasitology GA 343NM UT WOS:000088708500001 PM 10910708 ER PT J AU Kruger, EA Figg, WD AF Kruger, EA Figg, WD TI TNP-470: an angiogenesis inhibitor in clinical development for cancer SO EXPERT OPINION ON INVESTIGATIONAL DRUGS LA English DT Article DE AGM-1470; angiogenesis; cancer; fumagillin; neovascularisation; tumours; therapy ID ENDOTHELIAL-CELL GROWTH; O-(CHLOROACETYL-CARBAMOYL) FUMAGILLOL TNP-470; COLLAGEN-INDUCED ARTHRITIS; HUMAN COLON-CANCER; TUMOR-GROWTH; IN-VITRO; NUDE-MICE; AGENT TNP-470; PHASE-I; ANTIANGIOGENIC THERAPY AB TNP-470, an analogue of fumagillin, has been shown to inhibit angiogenesis in vitro and in vivo. In 1992, TNP-470 entered clinical development for I cancer as an anti-angiogenic agent. It is currently in Phase I/II trials in Kaposi's sarcoma, renal cell carcinoma, brain cancer, breast cancer, cervical cancer and prostate cancer. In early clinical reports, TNP-470 is tolerated up to 177 mg/m(2) with neurotoxic effects (fatigue, vertigo, ataxia, and loss of concentration) being the principal dose limiting toxicity (DLT). Terminal half-life values are short and have shown intermittent and intrapatient variation (range: 0.05 - 1.07 h). Recently, mechanistic studies have identified cell cycle mediators and the protein methionine aminopeptidase-2 (MetAP-2) as molecular targets of TNP-470 and fumagillin. Animal studies confirm some toxic effects on normal angiogenic processes such as the female reproductive system and wound healing, which will require caution and close monitoring in the clinic. TNP-470 is one of the first anti-angiogenic compounds to enter clinical trials, making it a valuable prototype for future trials of angiogenesis inhibitors in oncology. C1 NCI, Med Branch, NIH, Bethesda, MD 20892 USA. RP Kruger, EA (reprint author), NCI, Med Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 98 TC 91 Z9 97 U1 0 U2 6 PU ASHLEY PUBL LTD PI LONDON PA 1ST FL, THE LIBRARY, 1 SHEPHERDS HILL HIGHGATE, LONDON N6 5QJ, ENGLAND SN 1354-3784 J9 EXPERT OPIN INV DRUG JI Expert Opin. Investig. Drugs PD JUN PY 2000 VL 9 IS 6 BP 1383 EP 1396 DI 10.1517/13543784.9.6.1383 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 344VT UT WOS:000088780700016 PM 11060750 ER PT J AU Mei, JM Hord, NG Winterstein, DF Donald, SP Phang, JM AF Mei, JM Hord, NG Winterstein, DF Donald, SP Phang, JM TI Expression of prostaglandin endoperoxide H synthase-2 induced by nitric oxide in conditionally immortalized murine colonic epithelial cells SO FASEB JOURNAL LA English DT Article DE PGHS-2; NOSII; nitric oxide; colonic epithelial cells ID INFLAMMATORY BOWEL-DISEASE; FAMILIAL ADENOMATOUS POLYPOSIS; TRANSCRIPTION FACTOR LEF-1; TUMOR-SUPPRESSOR PROTEIN; BETA-CATENIN; CYCLOOXYGENASE-2 LEVELS; SMALL-INTESTINE; APC GENE; CANCER; ACTIVATION AB Increased expression of prostaglandin endoperoxide H synthase-2 (PGHS-2) has been implicated in pathological conditions such as inflammatory bowel diseases and colon cancer. Recently, it has been demonstrated that inducible nitric oxide synthase (NOS II) expression and nitric oxide (NO) production are up-regulated in these diseases as well. However, the apparent link between PGHS-2 and NOS II has not been thoroughly investigated in nontransformed and nontumorigenic colonic epithelial cells. In the present study, we examined the concomitant expression of PGHS-2 and NOS II as well as the production of prostaglandin E2 (PGE2) and NO in conditionally immortalized mouse colonic epithelial cells, namely YAMC (Apc(+/+)). We found that the induction of PGHS-2 and generation of PGE2 in these cells by IFN-gamma and lipopolysaccharide (LPS) were greatly reduced by two selective NOS II inhibitors, L-NIL and SMT. To ascertain the effect of NO on PGHS-2 overexpression, we tested NO-releasing compounds, NOR-1 and SNAP, and found that they caused PGHS-2 expression and PGE2 production. This effect was abolished by hemoglobin, a NO scavenger. Using electrophoretic mobility shift assays, we found that both NOR-1 and SNAP caused beta-catenin/LEF-1 DNA complex formation. Supershift by anti-beta-catenin antibody confirmed the presence of beta-catenin in the complex. Cell fractionation studies indicated that NO donors caused an increase in free soluble cytoplasmic beta-catenin. This is further corroborated by the immunocytochemistry data showing the redistribution of beta-catenin from the predominantly membrane localization into the cytoplasm and nucleus after treatment with NO donors. To further explore the possible connection between PGHS-2 expression and beta-catenin/LEF-1 DNA complex formation, we studied IMCE (Apc(Min/+)) cells, a sister cell line of YAMC with similar genetic background but differing in Ape genotype and, consequently, their beta-catenin levels. We found that IMCE cells, in comparison with YAMC cells, had markedly higher beta-catenin/LEF-1 DNA complex formation under both resting conditions as well as after induction with NO. In parallel fashion, IMCE cells ex pressed significantly higher levels of PGHS-2 mRNA and protein, and generated more PGE2. Overall, this study suggests that NO may be involved in PGHS-2 overexpression in conditionally immortalized mouse colonic epithelial cells. Although the molecular mechanism of the link is still under investigation, this effect of NO appears directly or indirectly to be a result of the increase in free soluble beta-catenin and the formation of nuclear beta-catenin/LEF-1 DNA complex.-Mei, J. M., Hord, N. G., Winterstein, D. F., Donald, S. P., and Phang, J. M. Expression of prostaglandin endoperoxide H synthase-2 induced by nitric oxide in conditionally immortalized murine colonic epithelial cells. C1 NCI, Metab & Canc Susceptibil Sect, Basic Res Lab, Div Basic Sci, Frederick, MD 21702 USA. NCI, Intramural Res Support Program, SAIC Frederick, FCRDC, Frederick, MD 21702 USA. RP Mei, JM (reprint author), NCI, Metab & Canc Susceptibil Sect, Basic Res Lab, Div Basic Sci, Rm 12-90,Bldg 560, Frederick, MD 21702 USA. NR 62 TC 39 Z9 39 U1 1 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUN PY 2000 VL 14 IS 9 BP 1188 EP 1201 PG 14 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 320XZ UT WOS:000087427300016 PM 10834941 ER PT J AU Offer, T Russo, A Samuni, A AF Offer, T Russo, A Samuni, A TI The pro-oxidative activity of SOD and nitroxide SOD mimics SO FASEB JOURNAL LA English DT Article DE papain; hydrogen peroxide; superoxide; oxidative damage; thiol ID SUPEROXIDE-DISMUTASE; HYDROGEN-PEROXIDE; LIPID-PEROXIDATION; CU,ZN-SUPEROXIDE DISMUTASE; RADICAL PRODUCTION; TOXICITY; CELLS; H2O2; INACTIVATION; MECHANISM AB Native Cu,Zn-SOD and synthetic SOD mimics sometimes demonstrate an apparently anomalous bell-shaped dose-response relationship when protecting various biological systems from oxidative stress. Several mechanisms have been proposed to account for such an effect, including: overproduction of H2O2, peroxidative activity of SOD, and opposing roles played by O-2(.-) in both initiation and termination of radical chain reactions. In the present study, ferrocyanide and thiols, which are susceptible to one-electron and two-electron oxidation, respectively, were subjected to a flux of superoxide in the presence and absence of SOD or SOD mimics. The results show that 1) either O-2(.-)/HO2. or H2O2 alone partially inactivates papain, whereas when combined they act synergistically; 2) nitroxide SOD mimics, but not SOD, exhibit a bell-shaped dose-response relationship in protecting papain from inactivation; 3) SOD, which at low dose inhibits superoxide-induced oxidation of ferrocyanide, loses its antioxidative effect as its concentration increases, These findings offer an additional explanation for the pro-oxidative activity of SOD and SOD mimics without invoking any dual activity of O-2(.-) or a combined effect of SOD and H2O2. The most significant outcome of an increase in SOD level is a decrease of [O-2(.-)](steady state), rather than any notable elevation of [H2O2](steady state). As a result, the reaction kinetics of the high oxidation state of each catalyst is altered. In the presence of ultra-low [O-2(.-)](steady state), the oxidized form of SOD [Cu(II),Zn-SOD] or SOD mimic (oxoammonium cation) does not react with O-2(.-) but rather oxidizes the target molecule that it was supposed to have protected. Consequently, these catalysts exert an anti- or pro-oxidative effect depending on their concentration.-Offer, T., Russo, A., Samuni, A. The pro-oxidative activity of SOD and nitroxide SOD mimics. C1 Hebrew Univ Jerusalem, Hadassah Med Sch, Fac Med, IL-91120 Jerusalem, Israel. NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Offer, T (reprint author), Hebrew Univ Jerusalem, Hadassah Med Sch, Fac Med, IL-91120 Jerusalem, Israel. NR 50 TC 76 Z9 79 U1 0 U2 6 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUN PY 2000 VL 14 IS 9 BP 1215 EP 1223 PG 9 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 320XZ UT WOS:000087427300018 PM 10834943 ER PT J AU Mondon, P Chang, YC Varma, A Kwon-Chung, KJ AF Mondon, P Chang, YC Varma, A Kwon-Chung, KJ TI A novel episomal shuttle vector for transformation of Cryptococcus neoformans with the ccdB gene as a positive selection marker in bacteria SO FEMS MICROBIOLOGY LETTERS LA English DT Article DE positive selection; vector; transformation; Cryptococcus neoformans ID VIRULENCE; DNA AB We report the engineering of a new shuttle vector featuring its episomal maintenance in Cryptococcus neoformans and the lethal Escherichia coli ccdB gene for positive selection in bacteria. Telomere-like sequences from C. neoformans and the STAB fragment confer episomal maintenance to the vector (pPM8) upon transformation in C. neoformans. The vector generated high transformation frequencies and each transformant was estimated to harbor thirty copies of the plasmid. The plasmids recovered in E. coli from the C. neoformans transformants showed no evidence of rearrangement. This construct will be very useful for cloning and studying the regulation of genes in C. neoformans. (C) 2000 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved. C1 NIAID, LCI, Mol Microbiol Sect, NIH, Bethesda, MD 20892 USA. RP Kwon-Chung, KJ (reprint author), NIAID, LCI, Mol Microbiol Sect, NIH, Bldg 10,11C304, Bethesda, MD 20892 USA. NR 14 TC 25 Z9 25 U1 0 U2 1 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 JUN 1 PY 2000 VL 187 IS 1 BP 41 EP 45 DI 10.1111/j.1574-6968.2000.tb09134.x PG 5 WC Microbiology SC Microbiology GA 320FZ UT WOS:000087392300008 PM 10828398 ER PT J AU Reiser, J AF Reiser, J TI Production and concentration of pseudotyped HIV-1-based gene transfer vectors SO GENE THERAPY LA English DT Article DE lentiviral vectors; pseudotypes; gene therapy ID HIGH-TITER; NONDIVIDING CELLS; RETROVIRAL VECTORS; DELIVERY; TRANSDUCTION AB Strategies to generate highly concentrated HIV-1 vector pseudotypes involving different envelope (Env) proteins including the vesicular stomatitis virus (VSV) G glycoprotein, the Moloney murine leukemia virus (MLV) 4070A amphotropic Env and the rabies G glycoprotein were established. Virus stocks were prepared by transient transfection using standard cell culture media or serum-free media. Such stocks were concentrated 50- to 300-fold by ultracentrifugation or by ultrafiltration using Centricon Plus-80 units yielding titers of up to 10(9) transducing units per milliliter. There was no loss in titer with any of the pseudotypes tested. Thus, like lentiviral vectors pseudotyped with VSV-G, HIV-1-based vectors pseudotyped with the MLV 4070A amphotropic Env and the rabies G glycoprotein resist inactivation during concentration. This opens up the possibility to generate highly concentrated HIV-1 vector stocks carrying alternative Env proteins on a large scale. C1 Louisiana State Univ, Sch Med, LSU Gene Therapy Program, New Orleans, LA 70112 USA. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Reiser, J (reprint author), Louisiana State Univ, Sch Med, LSU Gene Therapy Program, MEB 3205,1901 Perdido St, New Orleans, LA 70112 USA. NR 12 TC 116 Z9 128 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD JUN PY 2000 VL 7 IS 11 BP 910 EP 913 DI 10.1038/sj.gt.3301188 PG 4 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 320HN UT WOS:000087395900002 PM 10849549 ER PT J AU Stevceva, L Abimiku, AG Franchini, G AF Stevceva, L Abimiku, AG Franchini, G TI Targeting the mucosa: genetically engineered vaccines and mucosal immune responses SO GENES AND IMMUNITY LA English DT Review DE vaccine; naked DNA; mucosa; CTL; IgA ID IMMUNODEFICIENCY-VIRUS TYPE-1; MYCOBACTERIUM-BOVIS BCG; GLUTATHIONE-S-TRANSFERASE; CYTOTOXIC T-LYMPHOCYTES; CELL-MEDIATED-IMMUNITY; FEMALE GENITAL-TRACT; HERPES-SIMPLEX VIRUS; DNA VACCINE; RECOMBINANT VACCINE; PROTECTIVE IMMUNITY AB The discovery that inoculation of DNA leads to strong and long lasting immune responses generated enthusiasm to assess the efficacy of various genetically engineered vaccines against mucosally acquired infections. Various techniques have been used to generate the most suitable DNA vaccines, ranging from immunization with naked DNA to utilizing genetically engineered recombinant viruses and bacteria to deliver the DNA. Different DNA Vaccine modalities and mucosal immune responses to them have been discussed. It has been shown that even though intramuscular and intradermal immunization with these vaccines generates strong systemic responses, mucosal responses are not induced. It has been proposed that the site of immunization determines mucosal immune responses and that primed lymphocytes preferentially accumulate at sites where they have been induced thus generating the strongest cellular and antibody responses at the site of vaccination. The impact of the site of induction on mucosal immune responses to vaccines is discussed. It is possible to enhance desired vaccine effects in the mucosa and to modify the undesirable side effects. Cytokines such as IL-2, IL-12, IL-15 and IL-18 have been used to enhance CTL activity while IL-5, IL-6 and the chemokine MIP-1 alpha have shown the capacity to increase IgA responses to vaccines. C1 NCI, Div Basic Sci, Basic Res Lab, Bethesda, MD 20892 USA. Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. RP Stevceva, L (reprint author), NCI, Div Basic Sci, Basic Res Lab, Bldg 41, Bethesda, MD 20892 USA. NR 75 TC 23 Z9 23 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD JUN PY 2000 VL 1 IS 5 BP 308 EP 315 DI 10.1038/sj.gene.6363680 PG 8 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 342UB UT WOS:000088662600002 PM 11196691 ER PT J AU Moulds, JM Kassambara, L Middleton, JJ Baby, M Sagara, I Guindo, A Coulibaly, S Yalcouye, D Diallo, DA Miller, L Doumbo, O AF Moulds, JM Kassambara, L Middleton, JJ Baby, M Sagara, I Guindo, A Coulibaly, S Yalcouye, D Diallo, DA Miller, L Doumbo, O TI Identification of complement receptor one (CRI) polymorphisms in West Africa SO GENES AND IMMUNITY LA English DT Article DE malaria; blood groups; complement receptors ID SYSTEMIC LUPUS-ERYTHEMATOSUS; C3B/C4B RECEPTOR; SWAIN-LANGLEY; CR-1; ERYTHROCYTES; EXPRESSION; ANTIGENS; DISEASES; MARKERS; MALARIA AB Complement receptor one (CR1) is a ligand for the resetting of Plasmodium falciparum infected red cells with uninfected cells. Since CR1 exhibits three known polymorphisms, we studied European-Americans (n = 112) and African-Americans (n = 330) and Malians (n = 158) to determine if genetic differences existed in an area endemic for malaria that could offer a survival advantage. The frequencies of Knops blood group phenotypes McC(b+) and Sl(a-) were greatly increased in Africans vs Europeans. Although the frequency of McC(b+) was similar between Africans from the USA or Mali, the Sl(a-) phenotype was significantly higher in Mail (39% vs 65%, respectively). There was an increased frequency of the largest size (250 kD) of CR1 in Mail, but this did not differ significantly from the USA (P = 0.09). Both cohorts of Africans had higher expression of red cell CR1 than European-Americans but this showed little difference between the USA and Mali groups. Thus, the most important CR1 polymorphism relevant to resetting of malaria infected cells appears to be the Knops blood group. C1 Univ Texas, Sch Med, Houston, TX USA. Univ Mali, Bamako, Mali. NIAID, NIH, Bethesda, MD 20892 USA. RP Moulds, JM (reprint author), Med Coll Penn & Hahnemann Univ, Sch Med, Dept Microbiol & Immunol, 2900 Queen Lane,Room G44, Philadelphia, PA 19129 USA. FU NIAID NIH HHS [R01 AI 42367] NR 24 TC 30 Z9 31 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD JUN PY 2000 VL 1 IS 5 BP 325 EP 329 DI 10.1038/sj.gene.6363676 PG 5 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 342UB UT WOS:000088662600005 PM 11196694 ER PT J AU Krebs, LT Xue, YZ Norton, CR Shutter, JR Maguire, M Sundberg, JP Gallahan, D Closson, V Kitajewski, J Callahan, R Smith, GH Stark, KL Gridley, T AF Krebs, LT Xue, YZ Norton, CR Shutter, JR Maguire, M Sundberg, JP Gallahan, D Closson, V Kitajewski, J Callahan, R Smith, GH Stark, KL Gridley, T TI Notch signaling is essential for vascular morphogenesis in mice SO GENES & DEVELOPMENT LA English DT Article DE Notch signaling pathway; angiogenesis; vasculogenesis; ephrins ID ENDOTHELIAL GROWTH-FACTOR; MAMMARY EPITHELIAL-CELLS; CARDIOVASCULAR DEVELOPMENT; CAENORHABDITIS-ELEGANS; EMBRYONIC LETHALITY; MOUSE EMBRYO; GENE; HOMOLOG; PROTOONCOGENE; ANGIOGENESIS AB The Notch gene family encodes large transmembrane receptors that are components of an evolutionarily conserved intercellular signaling mechanism. To assess the role of the Notch4 gene, we generated Notch4-deficient mice by gene targeting. Embryos homozygous for this mutation developed normally, and homozygous mutant adults were viable and fertile. However, the Notch4 mutation displayed genetic interactions with a targeted mutation of the related Notch1 gene. Embryos homozygous for mutations of both the Notch4 and Notch1 genes often displayed a more severe phenotype than Notch1 homozygous mutant embryos. Both Notch1 mutant and Notch1/Notch4 double mutant embryos displayed severe defects in angiogenic vascular remodeling. Analysis of the expression patterns of genes encoding ligands for Notch family receptors indicated that only the D114 gene is expressed in a pattern consistent with that expected for a gene encoding a ligand for the Notch1 and Notch1 receptors in the early embryonic vasculature. These results reveal an essential role for the Notch signaling pathway in regulating embryonic vascular morphogenesis and remodeling, and indicate that whereas the Notch4 gene is not essential during embryonic development, the Notch4 and Notch1 genes have partially overlapping roles during embryogenesis in mice. C1 Jackson Lab, Bar Harbor, ME 04609 USA. Amgen Inc, Dept Mol Genet, Thousand Oaks, CA 91320 USA. NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. Columbia Univ Coll Phys & Surg, Dept Pathol & Obstet & Gynecol, New York, NY 10032 USA. RP Gridley, T (reprint author), Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. FU NCI NIH HHS [CA34196, P30 CA034196]; NHLBI NIH HHS [HL62454, R01 HL062454]; NINDS NIH HHS [NS36437, R01 NS036437] NR 43 TC 629 Z9 646 U1 4 U2 23 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUN 1 PY 2000 VL 14 IS 11 BP 1343 EP 1352 PG 12 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 321KP UT WOS:000087454900006 PM 10837027 ER PT J AU Kaler, SG Devaney, JM Pettit, EL Kirshman, R Marino, MA AF Kaler, SG Devaney, JM Pettit, EL Kirshman, R Marino, MA TI Novel method for molecular detection of the two common hereditary hemochromatosis mutations SO GENETIC TESTING LA English DT Article ID IRON; GENE AB We describe a novel molecular screening technique for hereditary hemochromatosis through which HFE genotypes at codon positions 282 and 63 are simultaneously detected. The technique combines multiplex PCR and denaturing high-performance liquid chromatography (DHPLC) and allows automated high-throughput analysis. We used this method to genotype 43 previously characterized anonymous DNA specimens in blinded fashion and found multiplex PCR/DHPLC 100% accurate when compared with PCR/restriction enzyme digestion, yet far more efficient. C1 Transgenom Inc, Gaithersburg, MD 20878 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. NINDS, Clin Neurosci Program, NIH, Bethesda, MD 20892 USA. Univ Oklahoma, Dept Med Genet, Oklahoma City, OK 73162 USA. RP Marino, MA (reprint author), Transgenom Inc, 11 Firstfield Rd,Suite E, Gaithersburg, MD 20878 USA. NR 14 TC 16 Z9 16 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1090-6576 J9 GENET TEST JI Genet. Test. PD SUM PY 2000 VL 4 IS 2 BP 125 EP 129 DI 10.1089/10906570050114821 PG 5 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA 344EZ UT WOS:000088747400007 PM 10953951 ER PT J AU Wiegant, J Bezrookove, V Rosenberg, C Tanke, HJ Raap, AK Zhang, HG Bittner, M Trent, JM Meltzer, P AF Wiegant, J Bezrookove, V Rosenberg, C Tanke, HJ Raap, AK Zhang, HG Bittner, M Trent, JM Meltzer, P TI Differentially painting human chromosome arms with combined binary ratio-labeling fluorescence in situ hybridization SO GENOME RESEARCH LA English DT Article ID INSITU HYBRIDIZATION; MULTIPLE; PROBES AB Recently we developed a novel strategy for differentially painting all 24 human chromosomes. It is termed COBRA-FISH, short for combined binary ratio labeling-fluorescence in situ hybridization. COBRA-FISH is distinct from the pure combinatorial approach in that only 4 instead of 5 fluorophores are needed to achieve color discrimination of 24 targets. Furthermore, multiplicity can be increased to 48 by introduction of a fifth Fluorophore. Here we show that color identification by COBRA-FISH of all of the p and q arms of human chromosomes is feasible, and we apply the technique for detecting and elucidating intra- and interchromosomal rearrangements. Compared with 24-color whole chromosome painting FISH, PQ-COBRA-FISH considerably enhances the ability to determine the composition of rearranged chromosomes as demonstrated by the identification of pericentric inversions and isochromosomes as well as the elucidation of the arm identity of chromosomal material involved in complex translocations that occur in solid tumors. C1 Leiden Univ, Ctr Med, Dept Mol Cell Biol, Lab Cytochem & Cytometry, Leiden, Netherlands. Natl Human Genome Res Inst, Canc Genet Lab, NIH, Bethesda, MD 20892 USA. RP Raap, AK (reprint author), Leiden Univ, Ctr Med, Dept Mol Cell Biol, Lab Cytochem & Cytometry, Leiden, Netherlands. RI rosenberg, carla/N-4148-2015 OI rosenberg, carla/0000-0003-3253-4448 NR 10 TC 47 Z9 47 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD JUN PY 2000 VL 10 IS 6 BP 861 EP 865 DI 10.1101/gr.10.6.861 PG 5 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 324TV UT WOS:000087638200012 PM 10854417 ER PT J AU Cmarik, JL Hegamyer, G Gerrard, B Dean, M Colburn, NH AF Cmarik, JL Hegamyer, G Gerrard, B Dean, M Colburn, NH TI cDNA cloning and mapping of mouse pleckstrin (Plek), a gene upregulated in transformation-resistant cells SO GENOMICS LA English DT Article ID PROMOTER-INDUCED TRANSFORMATION; ANCHORAGE-INDEPENDENT GROWTH; SENSITIVE JB6 CELLS; KINASE-C SUBSTRATE; G-BETA-GAMMA; PROTEIN-KINASE; NEOPLASTIC TRANSFORMATION; MOLECULAR-CLONING; PHOSPHOINOSITIDE 3-KINASE-GAMMA; AP-1 TRANSACTIVATION AB Changes that occur during tumor promotion, the rate-limiting phase of multistep carcinogenesis, may offer the best targets for prevention of cancer or reversal of early disease. The murine epidermal JB6 promotion-sensitive (P+) and -resistant (P-) cell lines provide a cell culture model for tumor promoter-induced neoplastic transformation ideally suited to the identification of molecular events that mediate or inhibit transformation. A differential display comparison of P+ and P- cell mRNAs yielded seven differentially expressed sequences. One of the sequences preferentially expressed in P- cells identified an similar to 3.6-kb message that was induced to higher levels in P- cells following exposure to the tumor promoter 12-O-tetradecanoylphorbol acetate than in P+ cells. The message was detected in mRNA from heart, lung, and spleen. cDNA cloning of the P- preferential sequence revealed a high degree of identity to human pleckstrin (PLEK), the major PKC substrate in platelets (Tyers et al., 1988, Nature 333: 470). We report the complete mouse cDNA sequence of pleckstrin and the localization of the gene to chromosome 11, its expression in a nonhematopoetic cell line, and its potential role in blocking neoplastic transformation. C1 NCI, Gene Regulat Sect, BRL, Frederick, MD 21701 USA. NCI, Intramural Res Support Program SAIC Frederick, Frederick, MD 21701 USA. NCI, Lab Genom Divers, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. RP Colburn, NH (reprint author), NCI, Gene Regulat Sect, BRL, Bldg 560,Room 21-89, Frederick, MD 21701 USA. RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 FU NCI NIH HHS [N01-CO-56000] NR 54 TC 7 Z9 8 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD JUN 1 PY 2000 VL 66 IS 2 BP 204 EP 212 DI 10.1006/geno.2000.6210 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 327PG UT WOS:000087801500009 PM 10860665 ER PT J AU Riley, MW Riley, JW AF Riley, MW Riley, JW TI Age integration: Conceptual and historical background SO GERONTOLOGIST LA English DT Article; Proceedings Paper CT 53rd Annual Scientific Meeting of the Gerontological -Society-of-America CY NOV 17-21, 2000 CL WASHINGTON, D.C. SP Gerontol Soc Amer C1 NIA, NIH, Bethesda, MD 20892 USA. RP Riley, MW (reprint author), NIA, NIH, Gateway Bldg 2C227,7201 Wisconsin Ave, Bethesda, MD 20892 USA. NR 13 TC 46 Z9 47 U1 0 U2 3 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD JUN PY 2000 VL 40 IS 3 BP 266 EP 270 PG 5 WC Gerontology SC Geriatrics & Gerontology GA 331VC UT WOS:000088038500003 PM 10853514 ER PT J AU Poopalasundaram, S Knott, C Shamotienko, OG Foran, PG Dolly, JO Ghiani, CA Gallo, V Wilkin, GP AF Poopalasundaram, S Knott, C Shamotienko, OG Foran, PG Dolly, JO Ghiani, CA Gallo, V Wilkin, GP TI Glial heterogeneity in expression of the inwardly rectifying K+ channel, Kir4.1, in adult rat CNS SO GLIA LA English DT Article DE astrocytes; oligodendrocytes; K+ inward rectifiers; rat brain; immunohistochemistry ID POTASSIUM CHANNEL; ION CHANNELS; CELLS; OLIGODENDROCYTES; CEREBELLUM; ASTROCYTES; BRAIN; HIPPOCAMPAL; INTERNEURONS; ANTIBODIES AB Previous electrophysiological evidence has indicated that astrocytes and oligodendrocytes express inwardly rectifying K+ channels both in vitro and in vivo. Here, for the first time, we have undertaken light microscopic immunohistochemical studies demonstrating the location of one such channel, Kir4.1, in both cell types in regions of the rat CNS. Some astrocytes such as those in the deep cerebellar nuclei, Bergmann glia, retinal Muller cells, and a subset in hippocampus express Kir4.1 immunoreactivity, but not others including those in white matter. Oligodendrocytes also express this protein, strongly in perikarya and to a lesser extent in their processes. Expression of Kir4.1 in astrocytes and oligodendrocytes would enable these cells to clear extracellular K+ through this channel, whereas nonexpressors might use other mechanisms. (C) 2000 Wiley-Liss, Inc. C1 Univ London Imperial Coll Sci Technol & Med, Dept Biochem, London SW7 2AZ, England. NIH, Lab Cellular & Mol Neurophysiol, Bethesda, MD 20892 USA. RP Wilkin, GP (reprint author), Univ London Imperial Coll Sci Technol & Med, Dept Biochem, London SW7 2AZ, England. RI Dolly, Oliver/G-1532-2012; OI Dolly, Oliver/0000-0002-0861-5320; Ghiani, Cristina/0000-0002-9867-6185 NR 37 TC 115 Z9 117 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0894-1491 J9 GLIA JI Glia PD JUN PY 2000 VL 30 IS 4 BP 362 EP 372 DI 10.1002/(SICI)1098-1136(200006)30:4<362::AID-GLIA50>3.0.CO;2-4 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 318MD UT WOS:000087287200005 PM 10797616 ER PT J AU Kossaczka, Z Szu, SC AF Kossaczka, Z Szu, SC TI Evaluation of synthetic schemes to prepare immunogenic conjugates of Vibrio cholerae O139 capsular polysaccharide with chicken serum albumin SO GLYCOCONJUGATE JOURNAL LA English DT Article DE Vibrio cholerae O139; O139 capsular polysaccharide; cholera O139 vaccine; vibriocidal activity to serotype O139 ID IMMUNOLOGICAL PROPERTIES; VIRULENCE DETERMINANTS; MOLECULAR ANALYSIS; BENGAL; RESPONSES; LIPOPOLYSACCHARIDE; EMERGENCE; MICE AB Vibrio cholerae serotype O139 is a new etiologic agent of epidemic cholera. There is no vaccine available against cholera caused by this serotype. V. cholerae O139 is an encapsulated bacterium, and its polysaccharide capsule is an essential virulent factor and likely protective antigen. This study evaluated several synthetic schemes for preparation of conjugates of V. cholerae O139 capsular polysaccharide (CPS) with chicken serum albumin as the carrier protein (CSA) using 1-ethyl-3(3-dimethylaminopropyl)carbodiimide (EDC) or 1-cyano-4-dimethylaminopyridinium tetrafluoroborate (CDAP) as activating agents. Four conjugates described here as representative of many experiments were synthesized in 2 steps: 1) preparation of adipic acid hydrazide derivative of CPS (CPSAH) or of CSA (CSA(AH)), and 2) binding of CPSAH to CSA or of CPS to CSA(AH). Although all conjugates induced CPS antibodies, the conjugate prepared by EDC-mediated binding of CPS and CSA(AH) (EDC:CPS-CSA(AH)) was statistically significantly less immunogenic than the other three conjugates. Representative sera from mice injected with these three conjugates contained antibodies that mediated the lysis of V. cholerae O139 inoculum. Evaluation of the different synthetic schemes and reaction conditions in relation to the immunogenicity of the resultant conjugates provided the basis for the preparation of a V. cholerae O139 conjugate vaccine with a medically useful carrier protein such as diphtheria toxin mutant. C1 NICHHD, Dev & Mol Immun Lab, NIH, Bethesda, MD 20892 USA. RP Kossaczka, Z (reprint author), NICHHD, Dev & Mol Immun Lab, NIH, Bldg 6A,Room 424, Bethesda, MD 20892 USA. NR 23 TC 10 Z9 10 U1 0 U2 2 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0282-0080 J9 GLYCOCONJUGATE J JI Glycoconjugate J. PD JUN PY 2000 VL 17 IS 6 BP 425 EP 433 DI 10.1023/A:1007164216202 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 403MB UT WOS:000167046100008 PM 11294508 ER PT J AU Zhou, J Bievre, M Bondy, CA AF Zhou, J Bievre, M Bondy, CA TI Reduced GLUT1 expression in Igf1-I- null oocytes and follicles SO GROWTH HORMONE & IGF RESEARCH LA English DT Article DE glucose transporter; oestrogen; IGF1; oocyte; folliculogenesis; infertility ID GROWTH-FACTOR-I; TRANSPORTER GENE-EXPRESSION; INSULIN; RECEPTOR; RAT AB Granulosa cells provide nutritional and trophic support for growing oocytes in ovarian follicles. The granulosa cells closest to the oocyte produce abundant insulin-like growth factor 1 (IGF1) and the IGF1 receptor is highly expressed by oocytes, suggesting that granulosa-derived IGF1 may have trophic effects on oocyte growth and development. To investigate this possibility, in the present study we used in situ hybridization and immunohistochemistry to examine glucose transporter (GLUTs 1, 3 & 4) expression in follicles from pre-pubertal Igf1-/- and littermate wildtype (wt) mice. Pre-pubertal mice were used for this study because the Igf1 null mice do not mature sexually. GLUT1 mRNA and immunoreactivity were most abundant in oocytes and in granulosa cells immediately surrounding the oocyte. Expression of this transporter was significantly reduced in Igf1 null oocytes and granulosa cells and was restored by exogenous IGF1 treatment to wt levels. These effects on GLUT expression were significant at both the mRNA and immunoreactive protein levels. Oestrogen treatment significantly increased GLUT1 levels in oocytes and granulosa from both wt and Igf1-/-, although the latter were still significantly lower than wt. Oocyte glycogen stores, determined by PAS staining, did not appear different in Igf1-/- and wt mice. GLUT3 was expressed in thecal cells surrounding growing follicles and was not appreciably different in Igf1 null compared with wt ovaries. GLUT4 expression was not detected in the prepubertal mouse ovary. Together with observations from previous studies showing that ovulation is blocked in Igf1 null mice, the present data suggest that IGF1's augmentation of granulosal and oocyte GLUT1 expression may be essential for oocyte maturation and successful ovulation. (C) 2000 Harcourt Publishers Ltd. C1 NICHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Zhou, J (reprint author), BG 10,RM 10N262,10 Ctr Dr 1862, Bethesda, MD 20892 USA. NR 16 TC 34 Z9 34 U1 0 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1096-6374 J9 GROWTH HORM IGF RES JI Growth Horm. IGF Res. PD JUN PY 2000 VL 10 IS 3 BP 111 EP 117 DI 10.1054/ghir.2000.0147 PG 7 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 350UT UT WOS:000089120100002 PM 10942631 ER PT J AU Schmitz, MJ Hendricks, DT Farley, J Taylor, RR Geradts, J Rose, GS Birrer, MJ AF Schmitz, MJ Hendricks, DT Farley, J Taylor, RR Geradts, J Rose, GS Birrer, MJ TI P27 and cyclin D1 abnormalities in uterine papillary serous carcinoma SO GYNECOLOGIC ONCOLOGY LA English DT Article DE uterine papillary serous carcinoma; endometrial cancer; p27; cyclin D1; p53; p16; Rb; K-ras ID DEPENDENT KINASE INHIBITOR; EPITHELIAL OVARIAN-TUMORS; RETINOBLASTOMA PROTEIN EXPRESSION; ENDOMETRIAL CARCINOMA; IMMUNOHISTOCHEMICAL DETECTION; REDUCED EXPRESSION; P53 OVEREXPRESSION; PROGNOSTIC FACTOR; GENE-PRODUCT; P15 GENES AB Objective, The expression status of p27 and cyclin D1 was examined in 21 uterine papillary serous carcinoma (UPSC) specimens to determine the role of these genes in the development of this disease. The status of p53, p16, Rb, and K-ras was also determined in these tissues so that a marker profile for UPSC could be compared with the published marker profile for other forms of endometrial and ovarian cancer. Methods. Immunohistochemistry was performed on 21 UPSC tissue sections to determine the expression status of p27, cyclin D1, p53, p16, and Rb, K-ras mutations were identified by restriction fragment length polymorphism analysis of DNA isolated from the UPSC sections. Results. All specimens displayed at least one molecular abnormality. A high incidence of p27 alterations were observed, with reduced p27 expression measured in 16 of 21 (76%) tumors, followed by p53 alterations observed in 13 of 21 (62%) tumors. The p27 abnormalities occur at an early stage of the disease, with 63% (5/8) of Stage I cases displaying reduced p27 expression. Cyclin D1 overexpression was observed in 4 of 21 (19%) specimens, whereas p16, Rb, and K-ras abnormalities were each observed in 2 of 21 specimens (10%). Both K-ras mutations were at codon 12. The p16 and Rb abnormalities coexisted in the same specimens. Conclusion. UPSC tumors display a high incidence of p27 abnormalities, suggesting that p27 abnormalities play an important role in the development of this disease. Our results also indicate that cyclin D1 overexpression is involved in the development of a small number of UPSC cases. A comparison of our results with reports by other authors suggests that UPSC shares molecular marker alterations with both ovarian cancer and endometrioid adenocarcinoma. (C) 2000 Academic Press. C1 NCI, Cell & Canc Biol Dept, Med Branch,Mol Mechanisms Sect, Div Clin Sci,NIH, Rockville, MD 20850 USA. Walter Reed Army Med Ctr, Div Gynecol Oncol, Washington, DC 20307 USA. Univ Oxford, John Radcliffe Hosp, Nuffield Dept Pathol & Bacteriol, Oxford OX3 9DU, England. RP Birrer, MJ (reprint author), NCI, Cell & Canc Biol Dept, Med Branch,Mol Mechanisms Sect, Div Clin Sci,NIH, 9610 Med Ctr Dr,Room 300, Rockville, MD 20850 USA. NR 41 TC 25 Z9 27 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD JUN PY 2000 VL 77 IS 3 BP 439 EP 445 DI 10.1006/gyno.2000.5814 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 323CH UT WOS:000087546900017 PM 10831356 ER PT J AU Metcalfe, DD Soter, NA AF Metcalfe, DD Soter, NA TI Mast cell disorders - Preface SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Editorial Material C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20842 USA. NYU, Med Ctr, Ronald O Perelman Dept Dermatol, New York, NY 10016 USA. RP Metcalfe, DD (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C205,10 Ctr Dr,MSC 1881, Bethesda, MD 20842 USA. NR 1 TC 0 Z9 0 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 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD JUN PY 2000 VL 14 IS 3 BP XI EP XIII DI 10.1016/S0889-8588(05)70292-6 PG 3 WC Oncology; Hematology SC Oncology; Hematology GA 333BA UT WOS:000088107800001 ER PT J AU Kirshenbaum, A AF Kirshenbaum, A TI Regulation of mast cell number and function SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Review ID CONNECTIVE-TISSUE-TYPE; C-KIT LIGAND; NERVE GROWTH-FACTOR; MURINE BONE-MARROW; COLONY-STIMULATING FACTOR; UMBILICAL-CORD BLOOD; FETAL LIVER-CELLS; FC-EPSILON-RI; TYROSINE KINASE RECEPTOR; BASOPHIL-LIKE CELLS AB Since the original identification by Ehrlich in 1877(23) of mast cells in human connective tissues, the understanding of the origin, regulation of mast cell growth, differentiation, survival, and apoptosis, mediator release and function and more recently, signal transduction events has increased considerably. Indeed, studies of rodent and human mast cells show that mast cells are complex, well-engineered, multifunctional cells that are central to innate and acquired immunity rather than involved solely in host responses against parasitic infections or allergic inflammation.(80, 84) Furthermore, one can no longer draw conclusions concerning human mast cells from studies involving rodent mast cells, because there are phenotypic differences or differences in regulation of mast cell number and function. Rodent mast cells, for example, have been classified as connective tissue (atypical) and mucosal (typical) based on metachromatic staining with acidic toluidine blue and alcian blue, on granule proteoglycan and protease content, and location within tissues.(16) Immunocytochemical studies of human tissues initially showed the presence of two mast cell (MC) phenotypes distinguishable by their neutral protease content: the MC, phenotype containing only tryptase, and the MCTC phenotype containing both tryptase and chymase. Initially these subtypes were thought to be the equivalents of the rodent mucosal and connective-tissue mast cells, respectively. It is now realized that variable amounts of both mast cell subtypes are present within any given tissue and that their relative abundance changes with disease states such as allergy or fibrosis.(16) A third mast cell phenotype, the MCC cell that rodent mast cell cultures expand in the presence of interleukin (IL)-3(44) and IL-4.(9) In contrast, primary long-term human mast cell cultures require stem cell factor (SCF) which is synergistic with IL-3(22) but is inhibited by IL-4.(127) The classification, therefore, of human mast cells, based on phenotype and regulation of growth characteristics, is unique and does not conform to the rodent model. These important differences must be cortsidered when engaging in human mast cell research. Two additional developments are significant for the understanding of the regulation of mast cell numbers and function. First, the characterization and cloning of SCE the ligand to the receptor encoded by the proto-oncogene c-kit and produced primarily by stromal cells, endothelial cells, fibroblasts, and keratinocytes, has enabled large numbers of human mast cells to be cultured from CD34+ progenitors for studies of various aspects of mast cell biology (Arnold Kirshenbaum, MD, unpublished observations, October 1999). Second, mast cell numbers may be controlled by agents that increase the cell divisions and also by factors that prevent apoptosis. Indeed, no report describes any growth factor in mast cells that does not have an antiapoptotic capability.(8) Therefore, much of the effect of the mast cell growth factors might be caused by the suppression of mast cell apoptosis as well as by a proliferative and differentiation capacity. The action of growth factors will differ, depending on culture conditions and on whether primary cultures or mast cell lines are studied. It is therefore important to describe the biologic system in which the effects of growth factors on mast cell numbers and function were evaluated. This review presents recent advances in the understanding of cytokine regulation of mast cell numbers and function in rodents and humans and in some of the cellular growth control networks which may occur in vivo at sites of mast cell growth. C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Kirshenbaum, A (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. NR 139 TC 6 Z9 6 U1 1 U2 7 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 2000 VL 14 IS 3 BP 497 EP + DI 10.1016/S0889-8588(05)70293-8 PG 21 WC Oncology; Hematology SC Oncology; Hematology GA 333BA UT WOS:000088107800002 PM 10909037 ER PT J AU Taylor, ML Metcalfe, DD AF Taylor, ML Metcalfe, DD TI Kit signal transduction SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Review ID STEM-CELL FACTOR; RECEPTOR TYROSINE KINASE; ACTIVATED PROTEIN-KINASE; HEMATOPOIETIC GROWTH-FACTORS; LIGAND-INDEPENDENT ACTIVATION; INOSITOL PHOSPHATASE SHIP; BLOOD MONONUCLEAR-CELLS; PROTOONCOGENE C-KIT; MAST-CELLS; BINDING-SITE AB The proto-oncogene c-kit was first identified as the cellular homologue of the oncogene v-kit, isolated from the retrovirus HZ-4-feline sarcoma, which causes multicentric fibrosarcomas.(2) This proto-oncogene encodes a transmembrane type III tyrosine kinase receptor (molecular weight 145-160 kd) which displays extensive homology with other members of this tyrosine kinase receptor family, such as platelet-derived growth factor (PDGF) and colony-stimulating factor-1 (CSF-1 or c-fms).(104) In humans, the c-kit gene maps to chromosome 4 (4q11 12), which is in close proximity to the PDGF receptor and to the epidermal growth factor (EGF) receptor. Kit protein has also been shown to be identical to the product of the murine dominant white-spotting W locus on chromosome 5 and as such is integral to the development of mast cells and hematopoiesis.(18) Alternative splicing results in two naturally occurring isoforms of kit that contain (kit A) or lack (kit) four amino acids (Gly Asn Asn Lys) at codon 510 just outside the transmembrane domain.(85) The biologic significance of these isoforms, however, remains unclear. These two isoforms have been reported to coexist in normal tissues at a ratio of 1:5 (kit A:kit). This ratio varies considerably in patients with acute myelogenous leukemia. Kit is expressed on mast cells, hematopoietic stem cells, melanocytes, gametocytes, intraepithelial lymphocytes, and interstitial cells of cajal. C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Taylor, ML (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C-207,10 Ctr Dr,MSC 1881, Bethesda, MD 20892 USA. NR 111 TC 90 Z9 93 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD JUN PY 2000 VL 14 IS 3 BP 517 EP + DI 10.1016/S0889-8588(05)70294-X PG 20 WC Oncology; Hematology SC Oncology; Hematology GA 333BA UT WOS:000088107800003 PM 10909038 ER PT J AU Jensen, RT AF Jensen, RT TI Gastrointestinal abnormalities and involvement in systemic mastocytosis SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Review ID MAST-CELL DISEASE; ZOLLINGER-ELLISON SYNDROME; CHRONIC MYELOMONOCYTIC LEUKEMIA; GASTRIC-ACID HYPERSECRETION; ORAL DISODIUM-CROMOGLYCATE; MAJOR URINARY METABOLITE; PORTAL-HYPERTENSION; URTICARIA PIGMENTOSA; INTERFERON-ALPHA; GENERALIZED MASTOCYTOSIS AB In 1869, Nettleship and Tay(159) described a 2-year-old child with hyperpigmented, urticarial skin lesions. Their report is credited as being the first description of urticaria pigmentosa. It was not until 1877(54) that mast cells were first described by Ehrlich, who found cells possessing cytoplasmic granules that stained metachromatically with aniline dyes. He called these cells "mastzellen" because they were distended with granules. Subsequently, in 1878, Sangster(191) described a patient with a pigmented, urticarial rash which he called "urticaria pigmentosa." In 1887,(226) Unna demonstrated the presence of mast cells in the skin lesions of affected patients. It was not until 50 years later, in 1933, that Touraine and co-workers(217) suggested that the disease might involve internal organs and 16 years later, in 1949, that Ellis et al(55) established this fact on an autopsy study in a 1-year-old child. In this first description of systemic mastocytosis by Ellis et al(55) the patient had urticaria pigmentosa from birth and developed diarrhea with voluminous, foul-smelling stools. Autopsy revealed hepatomegaly, splenomegaly, and lymphadenopathy, with microscopic infiltration by mast cells of the bone marrow, liver, spleen, lymph node, kidney, and pancreas.(55) Therefore, in both the clinical description and histologically, there was clear evidence for gastrointestinal involvement in the first established case of systemic mastocytosis.(55) In 1936, Sezary(200) proposed the name mastocytosis for this generalized involvement by mast cells. C1 NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Jensen, RT (reprint author), NIDDK, Digest Dis Branch, NIH, Bldg 10,Room 9C-103,10 Ctr Dr MSC 1804, Bethesda, MD 20892 USA. NR 238 TC 70 Z9 70 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD JUN PY 2000 VL 14 IS 3 BP 579 EP + DI 10.1016/S0889-8588(05)70298-7 PG 47 WC Oncology; Hematology SC Oncology; Hematology GA 333BA UT WOS:000088107800007 PM 10909042 ER PT J AU Hartmann, K Metcalfe, DD AF Hartmann, K Metcalfe, DD TI Pediatric mastocytosis SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article ID PROTOONCOGENE C-KIT; RECEPTOR TYROSINE KINASE; MAST-CELL LEUKEMIA; LIGAND-INDEPENDENT ACTIVATION; URTICARIA-PIGMENTOSA; SYSTEMIC MASTOCYTOSIS; CUTANEOUS MASTOCYTOSIS; BONE-MARROW; MONOZYGOTIC TWINS; MYELOPROLIFERATIVE DISORDER AB Mastocytosis is a rare disorder characterized by accumulation of mast cells in tissues. Sixty-five percent of patients with mastocytosis are children. Whereas mastocytosis in adults is usually persistent or progressive, pediatric mastocytosis is often transient and limited. Recent studies suggest that childhood-onset and adult-onset mastocytosis also differ in their pathogenesis. This article reviews the various forms of pediatric mastocytosis with a special focus on new pathogenetic findings. C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20842 USA. Univ Cologne, Dept Dermatol, D-5000 Cologne, Germany. RP Hartmann, K (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C205,10 Ctr Dr,MSC 1881, Bethesda, MD 20842 USA. RI Hartmann, Karin/N-4865-2015 OI Hartmann, Karin/0000-0002-4595-8226 NR 70 TC 52 Z9 53 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD JUN PY 2000 VL 14 IS 3 BP 625 EP + DI 10.1016/S0889-8588(05)70299-9 PG 17 WC Oncology; Hematology SC Oncology; Hematology GA 333BA UT WOS:000088107800008 PM 10909043 ER PT J AU Worobec, AS AF Worobec, AS TI Treatment of systemic past cell disorders SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Review ID BONE-MARROW TRANSPLANTATION; C-KIT MUTATION; DIFFUSE CUTANEOUS MASTOCYTOSIS; INTERNAL-MEDICINE CONFERENCE; MACULARIS ERUPTIVA PERSTANS; ORAL DISODIUM-CROMOGLYCATE; ACUTE MYELOID-LEUKEMIA; MAST-CELL; URTICARIA PIGMENTOSA; INTERFERON-ALPHA AB Despite recent advances in research on mastocytosis and new information about its pathophysiology, treatment of all categories of mastocytosis continues to be based primarily on symptom control because no current therapeutic modality is curative.* Because of the heterogeneous nature of disease manifestations in this group of disorders, therapy should be individualized to each patient's clinical presentation and prognosis. The mainstay of treatment for most categories of mastocytosis are H-1 and H-2 antihistamine blockade to control anaphylactic symptoms, cutaneous manifestations such as pruritus and flushing, and gastric hypersecretion, and corticosteroids to control malabsorption, ascites, and bone pain and to prevent or ameliorate anaphylaxis.(11, 115-118) Epinephrine is used to treat acute episodes of anaphylaxis.(138,159, 172) This article presents the accepted regimens for amelioration of the various mast cell mediator-related symptoms that may be seen in all categories of mastocytosis (Box 1).(114, 117) For patients with more aggressive forms of disease (categories II-IV),(114) greater understanding of the molecular basis of mastocytosis may afford new treatment strategies. Past and current approaches in dealing with the three more severe categories of mastocytosis are summarized, and future therapeutic directions for this enigmatic group of diseases are also discussed. C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Worobec, AS (reprint author), NIAID, Lab Allerg Dis, NIH, 10 Ctr Dr MSC 1881,Room 11C205, Bethesda, MD 20892 USA. NR 174 TC 84 Z9 87 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 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD JUN PY 2000 VL 14 IS 3 BP 659 EP + DI 10.1016/S0889-8588(05)70301-4 PG 30 WC Oncology; Hematology SC Oncology; Hematology GA 333BA UT WOS:000088107800010 PM 10909045 ER PT J AU Longley, BJ Metcalfe, DD AF Longley, BJ Metcalfe, DD TI A proposed classification of mastocytosis incorporating molecular genetics SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article ID STEM-CELL FACTOR; C-KIT RECEPTOR; LIGAND-INDEPENDENT ACTIVATION; CATALYTIC DOMAIN; TYROSINE KINASE; GROWTH-FACTOR; POINT MUTATION; SI-LOCUS; IDENTIFICATION; PROTOONCOGENE AB Recent studies have suggested that mutations in c-kit are a probable cause of some forms of mastocytosis.(10) C-kit is a proto-oncogene that encodes a receptor tyrosine kinase (kit), which is the receptor for stem cell factor (SCF, also known as mast cell growth factor).(2, 4, 5, 8, 12, 17, 19) Because neoplastic mast cells expressing specific c-kit mutations may be susceptible to different forms of therapy,(10, 11) we decided to reconsider previous classification schemes for mastocytosis in light of the developing knowledge of c-kit mutations and their relationship to different clinical forms of the disease. In this article, a classification system based on a combination of molecular, genetic, and clinical features is outlined. The goal is to develop a classification, as shown in Box 1, that will be relevant to researchers and to practitioners caring for patients and that is flexible enough to accommodate current and future molecular genetic data regarding the pathogenesis of mastocytosis. This scheme can be related to previous classification systems for retrospective with adult-onset mastocytosis. In patients with atypical pediatric-onset disease, the mutation can be found in multiple cell lineages, indicating involvement of an early, multipotent cell in the development of mastocytosis.(1, 14) Furthermore, although the authors have not detected juxtamembrane mutations in human material other than the HMC-1 cell line, they have found a number of juxtamembrane mutations present in canine mast cell neoplasms.(10, 11, 14) Taken together, these data suggest that c-kit activation mutations have a causal role in essentially ail cases of sporadic adult mastocytosis and in cases of pediatric mastocytosis with diffuse cutaneous mastocytosis and atypical urticaria pigmentosa. The clinical correlate of these activating mutations is disease which is persistent or progressive and which may require therapy that specifically inhibits activated kit. Detecting and defining the specific type of mutation in an individual patient is useful, especially for pediatric patients, because it allows assignment into a prognostic category. Furthermore, because activation loop mutations are more resistant to inhibition than are juxtamembrane mutations,(11) subclassification based on specific types of mutations will be important to slide therapy. C1 Columbia Univ, Coll Phys & Surg, Dept Dermatol, Vanderbilt Clin 15 208, New York, NY 10031 USA. Columbia Univ, Coll Phys & Surg, Dept Pathol, New York, NY USA. NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Longley, BJ (reprint author), Columbia Univ, Coll Phys & Surg, Dept Dermatol, Vanderbilt Clin 15 208, 630 W 168th St, New York, NY 10031 USA. FU NIAMS NIH HHS [P30AR44535, R01 AR43356] NR 19 TC 32 Z9 32 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 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD JUN PY 2000 VL 14 IS 3 BP 697 EP + DI 10.1016/S0889-8588(05)70303-8 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA 333BA UT WOS:000088107800012 PM 10909047 ER PT J AU Mastana, SS Reddy, PH Das, MK Reddy, P Das, K AF Mastana, SS Reddy, PH Das, MK Reddy, P Das, K TI Molecular genetic diversity in 5 populations of Madhya Pradesh, India SO HUMAN BIOLOGY LA English DT Article ID APOLIPOPROTEIN-B GENE; POLYMERASE CHAIN-REACTION; DEFINED HUMAN-POPULATIONS; HYPERVARIABLE REGION; VARIABLE NUMBER; VNTR LOCI; POLYMORPHISM; PCR AB This paper presents data on the distribution of 3 amplified fragment length polymorphisms (D1S80, APOB, and YNZ22) in 5 populations of Central India. Using the polymerase chain reaction technique, 3 caste (Brahmin, Khatri, and Dhimer) and 2 tribal (Gond and Baiga) populations. were studied for the 3 loci. The allelic variations observed in the caste populations are compatible with those of many Caucasian populations, but the caste populations showed significant overall and interpopulation variability within the region. D1S80 allele *24 varied from 32% (Dhimers) to 42% (Brahmins). Allele *18 was not observed in Baiga tribal populations, but in caste populations it varied from 11% (Dhimers) to 244b (Brahmins). Both tribal populations showed higher frequencies of allele *31 (17%-18%). For APOB, caste populations again showed bimodal distribution of alleles *35 and *37, but in tribal populations higher allele numbers (*47, *49) were also frequent. For YNZ22, extensive variation was observed for all populations studied. Allele *4 was the most common in caste populations, while alleles *2, *7, and *10 were prominent in tribal populations. The level of gene differentiation is not very high for the 3 systems studied in the 5 populations. Overall, allele frequency distribution, heterozygosity, and genetic diversity analysis show that the genetic diversity observed is socially and geographically structured. C1 Loughborough Univ Technol, Dept Human Sci, Human Genet Lab, Loughborough LE11 3TU, Leics, England. NHGRI, Lab Gene Transfer, NIH, Bethesda, MD USA. Kothari Med Ctr, Calcutta, W Bengal, India. Indian Stat Inst, Anthropol & Human Genet Unit, Calcutta 700035, W Bengal, India. RP Mastana, SS (reprint author), Loughborough Univ Technol, Dept Human Sci, Human Genet Lab, Loughborough LE11 3TU, Leics, England. NR 17 TC 6 Z9 6 U1 0 U2 0 PU WAYNE STATE UNIV PRESS PI DETROIT PA 4809 WOODWARD AVE, DETROIT, MI 48201-1309 USA SN 0018-7143 J9 HUM BIOL JI Hum. Biol. PD JUN PY 2000 VL 72 IS 3 BP 499 EP 510 PG 12 WC Biology; Genetics & Heredity SC Life Sciences & Biomedicine - Other Topics; Genetics & Heredity GA 334MF UT WOS:000088189700009 PM 10885195 ER PT J AU Takuma, N Sengoku, K Kimura, S Horikawa, M Komori, H Tsuchiya, K Ishikawa, M AF Takuma, N Sengoku, K Kimura, S Horikawa, M Komori, H Tsuchiya, K Ishikawa, M TI T/ebp is the essential gene for pituitary morphogenesis during mouse embryogenesis SO HUMAN REPRODUCTION LA English DT Meeting Abstract C1 Asahikawa Med Coll, Dept Obstet & Gynecol, Asahikawa, Hokkaido 078, Japan. NCI, Lab Metab, Natl Inst Hlth, 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 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD JUN PY 2000 VL 15 SI A1 MA P213 BP 180 EP 181 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 337JV UT WOS:000088355100455 ER PT J AU Cardillo, CM Kilcoyne, CM Cannon, RO Panza, JA AF Cardillo, CM Kilcoyne, CM Cannon, RO Panza, JA TI Interactions between nitric oxide and endothelin in the regulation of vascular tone of human resistance vessels in vivo SO HYPERTENSION LA English DT Article DE endothelin; nitric oxide; vascular tone; receptors, endothelin; blood flow ID RELAXING FACTOR; ESSENTIAL-HYPERTENSION; RECEPTOR ANTAGONIST; IN-VIVO; INHIBITION; ET(A); VASOCONSTRICTION; BLOCKADE; ET(B); RELAXATION AB Endothelial release of nitric oxide (NO) contributes to the regulation of vascular tone by inducing vascular relaxation. In addition, NO may inhibit the synthesis and hemodynamic effects of endothelin-1 (ET-1), a powerful endothelium-derived vasoconstrictor peptide that may stimulate NO production. However, whether NO and ET-1 physiologically interact to regulate vascular tone in humans has not been defined. In this study, the interactions between the L-arginine NO pathway and the ET-1 system in the regulation of vascular tone in human forearm resistance vessels were examined in vivo. Vasomotor response to the NO synthase inhibitor N-G-monomethyl-L-arginine (L-NMMA, 4 mu mol/min for 30 minutes) was measured during either saline infusion or blockade of ET-1 receptors, Endothelin-A (ETA) and endothelin-B (ETB) receptor blockade was achieved by infusion of BQ-123 (100 nmol/min) and BQ-788 (50 nmol/min), respectively, separately and in combination. Drugs were infused into the brachial artery, and the forearm blood flow (FBF) response was measured by strain-gauge plethysmography. During saline infusion, L-NMMA administration significantly decreased FBF (25%, P<0.01 versus baseline). This effect was significantly blunted during nonselective blockade of ET-1 receptors (7% decrease in FBF, P=0.02 versus the effect of L-NMMA during saline infusion). Selective ETA blockade did not modify the vasoconstrictor response to L-NMMA (26% decrease in FBF, P=0.66 versus the effect of L-NMMA during saline infusion), but selective ETB receptor antagonism caused significant diminution of the hemodynamic response to NO inhibition (8% decrease in FBF, P=0.04 versus the effect of L-NMMA during saline infusion), Thus ET-1 contributes to the regulation of vascular tone by stimulating NO activity. This effect is mediated through endothelial ETB receptors and may be relevant in conditions associated with endothelial dysfunction. C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. RP Panza, JA (reprint author), NHLBI, Cardiol Branch, NIH, Bldg 10,Room 7B-15, Bethesda, MD 20892 USA. NR 29 TC 91 Z9 96 U1 0 U2 2 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 2000 VL 35 IS 6 BP 1237 EP 1241 PG 5 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 327RN UT WOS:000087806700013 PM 10856270 ER PT J AU Clarke, LP AF Clarke, LP TI NCI initiative: Development of novel imaging technologies SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Editorial Material C1 NCI, Biomed Imaging Program, Div Canc Treatment & Diagnosis, NIH, Bethesda, MD 20892 USA. RP Clarke, LP (reprint author), NCI, Biomed Imaging Program, Div Canc Treatment & Diagnosis, NIH, 6130 Execut Blvd,EPN 800,MSC 7400, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017-2394 USA SN 0278-0062 J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD JUN PY 2000 VL 19 IS 6 BP 565 EP 567 DI 10.1109/TMI.2000.870660 PG 3 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 360KL UT WOS:000089666700001 PM 11026459 ER PT J AU Yim, PJ Choyke, PL Summers, RM AF Yim, PJ Choyke, PL Summers, RM TI Gray-scale skeletonization of small vessels in magnetic resonance angiography SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE magnetic resonance angiography; skeletonization; visualization ID 3-DIMENSIONAL MR-ANGIOGRAPHY; MEDICAL IMAGES; SEGMENTATION; VISUALIZATION; ENHANCEMENT AB Interpretation of magnetic resonance angiography (MRA) is problematic due to complexities of vascular shape and to artifacts such as the partial volume effect. We present new methods to assist in the interpretation of MRA. These include methods for detection of vessel paths and for determination of branching patterns of vascular trees. They are based on the ordered region growing (ORG) algorithm that represents the image as an acyclic graph, which can be reduced to a skeleton by specifying vessel endpoints or by a pruning process. Ambiguities in the vessel branching due to vessel overlap are effectively resolved by heuristic methods that incorporate a priori knowledge of bifurcation spacing. Vessel paths are detected at interactive speeds on a 500-MHz processor using vessel endpoints, These methods apply best to smaller vessels where the image intensity peaks at the center of the lumen which, for the abdominal MRA, includes vessels whose diameter is less than 1 cm. C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Yim, PJ (reprint author), NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 29 TC 97 Z9 100 U1 1 U2 7 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017-2394 USA SN 0278-0062 J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD JUN PY 2000 VL 19 IS 6 BP 568 EP 576 DI 10.1109/42.870662 PG 9 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 360KL UT WOS:000089666700002 PM 11026460 ER PT J AU Wolpaw, JR Birbaumer, N Heetderks, WJ McFarland, DJ Peckham, PH Schalk, G Donchin, E Quatrano, LA Robinson, CJ Vaughan, TM AF Wolpaw, JR Birbaumer, N Heetderks, WJ McFarland, DJ Peckham, PH Schalk, G Donchin, E Quatrano, LA Robinson, CJ Vaughan, TM TI Brain-computer interface technology: A review of the first international meeting SO IEEE TRANSACTIONS ON REHABILITATION ENGINEERING LA English DT Article DE brain-computer interface (BCI); electroencephalography (EEG); augmentative communication ID REAL-TIME; MOTOR CORTEX; EEG; FEEDBACK; SIGNALS; DESIGN; ARRAY AB Over the past decade, many laboratories have begun to explore brain-computer interface (BCI) technology as a radically new communication option for those with neuromuscular impairments that prevent them from using conventional augmentative communication methods. BCI's provide these users with communication channels that do not depend on peripheral nerves and muscles. This article summarizes the first international meeting devoted to BCI research and development. Current BCI's use electroencephalographic (EEG) activity recorded at the scalp or single-unit activity recorded from within cortex to control cursor movement, select letters or icons, or operate a neuroprosthesis. 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 which recognizes the commands contained in the input and expresses them in device control. Current BCI's have maximum information transfer rates of 5-25 b/min. Achievement of greater speed and accuracy depends on improvements in signal processing, translation algorithms, and user training. These improvements depend on increased interdisciplinary cooperation between neuroscientists, engineers, computer programmers, psychologists, and rehabilitation specialists, and on adoption and widespread application of objective methods for evaluating alternative methods. The practical use of BCI technology depends on the development of appropriate applications, identification of appropriate user groups, and careful attention to the needs and desires of individual users. BCI research and development will also benefit from greater emphasis on peer-reviewed publications, and from adoption of standard venues for presentations and discussion. C1 New York State Dept Hlth, Wadsworth Ctr, Lab Nervous Syst Disorders, Albany, NY 12201 USA. SUNY Albany, Albany, NY 12201 USA. Univ Tuebingen, Inst Med Psychol & Behav Neurobiol, Tuebingen, Germany. NINDS, Div Fundamental Neurosci, NIH, Bethesda, MD 20892 USA. Case Western Reserve Univ, Metro Hlth Ctr, Rehabil Engn Ctr, Cleveland, OH 44106 USA. Univ Illinois, Beckman Inst, Champaign, IL 61820 USA. NICHHD, Natl Ctr Med Rehabil Res, NIH, Bethesda, MD 20892 USA. Louisiana Tech Univ, Ctr Biomed Engn & Rehabil Sci, Ruston, LA 71270 USA. Overton Brooks VA Med Ctr, Shreveport, LA 71101 USA. RP Wolpaw, JR (reprint author), New York State Dept Hlth, Wadsworth Ctr, Lab Nervous Syst Disorders, Albany, NY 12201 USA. NR 52 TC 695 Z9 770 U1 10 U2 249 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017-2394 USA SN 1063-6528 J9 IEEE T REHABIL ENG JI IEEE Trans. Rehabil. Eng. PD JUN PY 2000 VL 8 IS 2 BP 164 EP 173 DI 10.1109/TRE.2000.847807 PG 10 WC Engineering, Biomedical; Rehabilitation SC Engineering; Rehabilitation GA 330TF UT WOS:000087976700002 PM 10896178 ER PT J AU Lauer, RT Peckham, PH Kilgore, KL Heetderks, WJ AF Lauer, RT Peckham, PH Kilgore, KL Heetderks, WJ TI Applications of cortical signals to neuroprosthetic control: A critical review SO IEEE TRANSACTIONS ON REHABILITATION ENGINEERING LA English DT Article DE cortical interface; electroencephalogram (EEG); neuroprosthesis ID UPPER EXTREMITY NEUROPROSTHESES; EEG; RESTORATION; INTERFACE AB Cortical signals might provide a potential means of interfacing with a neuroprosthesis. Guidelines regarding the necessary control features in terms of both performance characteristics and user requirements are presented, and their implications for the design of a first generation cortical control interface for a neuroprosthesis are discussed. C1 Case Western Reserve Univ, Metrohlth Med Ctr, Louis Stokes Cleveland VA Med Ctr, Cleveland FES Ctr, Cleveland, OH 44109 USA. NINCDS, NIH, Bethesda, MD 20892 USA. RP Lauer, RT (reprint author), Case Western Reserve Univ, Metrohlth Med Ctr, Louis Stokes Cleveland VA Med Ctr, Cleveland FES Ctr, Cleveland, OH 44109 USA. OI Kilgore, Kevin/0000-0002-2642-9855 FU NCRR NIH HHS [M01 RR00080-31]; NINDS NIH HHS [N01-NS-6-2338] NR 29 TC 56 Z9 57 U1 0 U2 3 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1063-6528 J9 IEEE T REHABIL ENG JI IEEE Trans. Rehabil. Eng. PD JUN PY 2000 VL 8 IS 2 BP 205 EP 208 DI 10.1109/86.847817 PG 4 WC Engineering, Biomedical; Rehabilitation SC Engineering; Rehabilitation GA 330TF UT WOS:000087976700012 PM 10896188 ER PT J AU Love, PE Shores, EW AF Love, PE Shores, EW TI ITAM multiplicity and thymocyte selection: How low can you go? SO IMMUNITY LA English DT Review ID T-CELL DEVELOPMENT; TCR-ZETA-CHAIN; EPSILON-RI-GAMMA; RECEPTOR SIGNAL-TRANSDUCTION; NEGATIVE SELECTION; POSITIVE SELECTION; ANTIGEN-RECEPTOR; MICE LACKING; CD4(+)CD8(+) THYMOCYTES; INTRAEPITHELIAL LYMPHOCYTES C1 US FDA, Div Therapeut Prot, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Shores, EW (reprint author), US FDA, Div Therapeut Prot, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. NR 76 TC 62 Z9 62 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUN PY 2000 VL 12 IS 6 BP 591 EP 597 DI 10.1016/S1074-7613(00)80210-1 PG 7 WC Immunology SC Immunology GA 329ZA UT WOS:000087937300001 PM 10894159 ER PT J AU Tudge, JRH Hogan, DM Snezhkova, IA Kulakova, NN Etz, KE AF Tudge, JRH Hogan, DM Snezhkova, IA Kulakova, NN Etz, KE TI Parents' child-rearing values and beliefs in the United States and Russia: The impact of culture and social class SO INFANT AND CHILD DEVELOPMENT LA English DT Article; Proceedings Paper CT Annual Meetings of the Society-for-Cross-cultural-Research CY FEB 15, 1996 CL PITTSBURGH, PENNSYLVANIA DE beliefs; child-rearing; Russia; SES; USA; values ID AGGRESSION AB Parents' values for their children and their beliefs about appropriate child-rearing practices contribute to the ways in which they try to shape their children's development. This paper examines the values and beliefs of 71 parents (37 mothers and 34 fathers) from two cities in the United States and Russia. Half of the families were middle class (determined by education and occupation criteria) and half were working class. The results revealed no cross-societal differences in value for self-direction in the children; perhaps reflecting the recent economic and ideological changes in Russia. In contrast, significant social class differences, for both mothers and fathers, were found in childrearing values and beliefs. Middle class parents in both societies were more likely to value self-direction and believe that children should have freedom in and around the home, whereas working class parents were more likely to believe that children should be expected to conform to rules. The results of this study underscore the role of within-society heterogeneity, as a function of social class, in parents' values and beliefs about child-rearing. Copyright (C) 2000 John Wiley & Sons, Ltd. C1 Univ N Carolina, Dept Human Dev & Family Studies, Greensboro, NC 27402 USA. Univ Dublin Trinity Coll, Dublin 2, Ireland. Russian Acad Sci, Moscow, Russia. Natl Inst Drug Abuse, Lexington, KY USA. RP Tudge, JRH (reprint author), Univ N Carolina, Dept Human Dev & Family Studies, POB 26170, Greensboro, NC 27402 USA. NR 49 TC 33 Z9 35 U1 0 U2 10 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 1522-7227 J9 INFANT CHILD DEV JI Infant Child Dev. PD JUN PY 2000 VL 9 IS 2 BP 105 EP 121 DI 10.1002/1522-7219(200006)9:2<105::AID-ICD222>3.0.CO;2-Y PG 17 WC Psychology, Developmental SC Psychology GA 331DG UT WOS:000088001600005 ER PT J AU Chaussee, MS Cole, RL van Putten, JPM AF Chaussee, MS Cole, RL van Putten, JPM TI Streptococcal erythrogenic toxin B abrogates fibronectin-dependent internalization of Streptococcus pyogenes by cultured mammalian cells SO INFECTION AND IMMUNITY LA English DT Article ID GROUP-A STREPTOCOCCI; EXTRACELLULAR CYSTEINE PROTEASE; FREQUENCY INTRACELLULAR INVASION; RESPIRATORY EPITHELIAL-CELLS; PYROGENIC EXOTOXIN-B; STAPHYLOCOCCUS-AUREUS; BINDING PROTEIN; IN-VITRO; ENTRY; INACTIVATION AB Streptococcus pyogenes secretes several proteins that influence host-pathogen interactions. A tissue-culture model was used to study the influence of the secreted cysteine protease streptococcal erythrogenic toxin B (SPE B) on the interaction between S. pyogenes strain NZ131 (serotype M49) and mammalian cells. Inactivation of the speB gene enhanced fibronectin-dependent uptake of the pathogen by Chinese hamster ovary (CHO-K1) cells compared to that in the isogenic wild-type strain. Preincubation of the NZ131 speB mutant with purified SPE B protease significantly inhibited fibronectin-dependent uptake by bath CHO-K1 and CHO-pgs745 cells. The effect was attributed to an abrogation of fibronectin binding to the surface of the bacteria that did not involve either the M49 protein or the streptococcal fibronectin-binding protein SfbI. In contrast, pretreatment of the NZ131 speB mutant with SPE B did not influence sulfated polysaccharide-mediated uptake by CHO-pgs745 cells. The results indicate that the SPE B protease specifically alters bacterial cell surface proteins and thereby influences pathogen uptake. C1 NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. Univ Utrecht, Inst Infect Dis & Immunol, NL-3584 CL Utrecht, Netherlands. RP Chaussee, MS (reprint author), NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, 903 South 4th St, Hamilton, MT 59840 USA. OI van Putten, Jos/0000-0002-4126-8172 NR 45 TC 30 Z9 30 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 2000 VL 68 IS 6 BP 3226 EP 3232 DI 10.1128/IAI.68.6.3226-3232.2000 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 316LF UT WOS:000087167900023 PM 10816467 ER PT J AU Gubba, S Cipriano, V Musser, JM AF Gubba, S Cipriano, V Musser, JM TI Replacement of histidine 340 with alanine inactivates the group A Streptococcus extracellular cysteine protease virulence factor SO INFECTION AND IMMUNITY LA English DT Article ID GROUP-A STREPTOCOCCUS; PYROGENIC EXOTOXIN-B; GENETIC INACTIVATION; PROTEOLYTIC ACTIVITY; PYOGENES; CELLS; DISSEMINATION; PURIFICATION; MECHANISM; PRECURSOR AB Streptococcus pyogenes expresses a highly conserved extracellular cysteine protease that is a virulence factor for invasive disease, including soft tissue infection. Site-directed mutagenesis was used to generate a His340Ala recombinant mutant protein that was made as a stable 40-kDa zymogen by Escherichia coli, Purified His340Ala protein was proteolytically inactive when bovine casein and human fibronectin were used as substrates, Wild-type 28-kDa streptococcal protease purified from S, pyogenes processed the 40-kDa mutant zymogen to a 28-kDa mature form, a result suggesting that the derivative protein retained structural integrity. The data are consistent with the hypothesis that His340 is an enzyme active site residue, an idea confirmed by recent solution of the zymogen crystal structure (T. F, Kagawa, J, C, Cooney, H, M. Baker, S, McSweeney, M, Liu, S, Gubba, J, M. Musser, and E, N, Baker, Proc. Natl, Acad, Sci, USA 97:2235-2240, 2000), The data provide additional insight into structure-function relationships in this S. pyogenes virulence factor. C1 NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. Baylor Coll Med, Dept Pathol, Inst Study Human Bacterial Pathogenesis, Houston, TX 77030 USA. RP Musser, JM (reprint author), NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, 903 S 4th St, Hamilton, MT 59840 USA. FU NIAID NIH HHS [AI-33119] NR 30 TC 11 Z9 11 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD JUN PY 2000 VL 68 IS 6 BP 3716 EP 3719 DI 10.1128/IAI.68.6.3716-3719.2000 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 316LF UT WOS:000087167900089 PM 10816533 ER PT J AU Moore, DF Tsenova, L Corral, L Freedman, VH Kaplan, G AF Moore, DF Tsenova, L Corral, L Freedman, VH Kaplan, G TI HUMAN alpha-1-acid glycoprotein inhibits TNF production in the CNS of rabbits with meningitis: A report of preliminary observations SO INFLAMMATION LA English DT Article ID TUMOR-NECROSIS-FACTOR; EXPERIMENTAL BACTERIAL-MENINGITIS; CEREBROSPINAL-FLUID; FACTOR-ALPHA; CORTICOSTEROID-THERAPY; INFLAMMATORY RESPONSE; HUMAN MONOCYTES; LIPOPOLYSACCHARIDE; INTERLEUKIN-10; THALIDOMIDE AB Bacterial meningitis is accompanied by an acute inflammatory response which may be exacerbated by antibiotic treatment and subsequent killing of bacteria. Bacterial cell products induce the release of cytokines including TNF alpha, which contribute to the inflammatory process. Alpha-1-acid glycoprotein (AAG), an acute phase reactant, is elevated during inflammation. To test whether AAG has anti-inflammatory activity we examined its effect on lipopolysaccharide-stimulated human peripheral blood mononuclear cells. Treatment of the cells with AAG in vitro resulted in reduced TNF alpha production. To test the effects of the molecule in vivo, AAG was administered intrathecally to rabbits with Haemophilus influenzae B lysate induced meningitis. Human AAG reduced TNF alpha production and leukocytosis in the cerebrospinal fluid. Histopathology of the leptomeninges showed markedly attenuated inflammation. These results indicate that AAG can reduce inflammation in rabbits with experimental meningitis and that the effect may be directly on TNF alpha production by stimulated mononuclear leukocytes. C1 Cornell Univ, Med Ctr, New York Hosp, Dept Neurol, New York, NY 10021 USA. Rockefeller Univ, Cellular Physiol & Immunol Lab, New York, NY 10021 USA. RP Moore, DF (reprint author), NINCDS, Dev & Metab Branch, NIH, Bldg 10,Room 3D04,10 Ctr Dr MSC 1260, Bethesda, MD 20892 USA. NR 30 TC 2 Z9 2 U1 1 U2 1 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0360-3997 J9 INFLAMMATION JI Inflammation PD JUN PY 2000 VL 24 IS 3 BP 265 EP 275 DI 10.1023/A:1007065514142 PG 11 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 318ZX UT WOS:000087315500007 ER PT J AU Ferdig, MT Taft, AS Smartt, CT Lowenberger, CA Li, J Zhang, J Christensen, BM AF Ferdig, MT Taft, AS Smartt, CT Lowenberger, CA Li, J Zhang, J Christensen, BM TI Aedes aegypti dopa decarboxylase: gene structure and regulation SO INSECT MOLECULAR BIOLOGY LA English DT Article DE Aedes aegypti; dopa decarboxylase; gene structure; gene expression; ovary development ID DROSOPHILA-MELANOGASTER; HORMONAL-CONTROL; BROAD-COMPLEX; BLOOD-MEAL; MOSQUITO; EXPRESSION; RNA; IDENTIFICATION; TRANSCRIPTION; SEQUENCE AB Dopa decarboxylase converts L-dopa to dopamine, a precursor molecule for diverse biological activities in insects including neurotransmission and a variety of tanning reactions required for development, reproduction and defence against parasites. Herein, we report the cloning and sequencing of the Aedes aegypti Ddc gene, including 2.1 kb of the upstream promoter region. The transcribed region of the gene spans more than 16 kb and contains five exons. In site hybridization localizes the blood-meal-induced ovarian transcription of this gene to the follicular epithelial cells surrounding individual oocytes. Ovary tissue transcription of Ddc is increased in response to injection of 20-hydroxyecdysone to levels equal to those observed for blood-fed controls, however coinjection with the translational inhibitor cycloheximide negates the effect, indicating an indirect regulatory role for this hormone. Clusters of putative ecdysone-responsive elements and zinc-finger binding domains for the products of Broad-Complex gene family are identified in the 5'-promoter region. These elements are discussed in the context of common insect Ddc regulatory mechanisms. C1 Univ Wisconsin, Dept Anim Hlth & Biomed Sci, Madison, WI 53706 USA. NIAID, Malaria Genet Sect, NIH, LPD, Bethesda, MD 20892 USA. Univ Illinois, Coll Vet Med, Dept Pathobiol, Urbana, IL 61801 USA. RP Christensen, BM (reprint author), Univ Wisconsin, Dept Anim Hlth & Biomed Sci, 1656 Linden Dr, Madison, WI 53706 USA. RI Ferdig, Michael/C-6627-2016 FU NIAID NIH HHS [AI 37789, AI 19769] NR 38 TC 16 Z9 16 U1 1 U2 8 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0962-1075 J9 INSECT MOL BIOL JI Insect Mol. Biol. PD JUN PY 2000 VL 9 IS 3 BP 231 EP 239 DI 10.1046/j.1365-2583.2000.00187.x PG 9 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 334CM UT WOS:000088167600002 PM 10886406 ER PT J AU Kenny, JJ Derby, EG Yoder, JA Hill, SA Fischer, RT Tucker, PW Claflin, JL Longo, DL AF Kenny, JJ Derby, EG Yoder, JA Hill, SA Fischer, RT Tucker, PW Claflin, JL Longo, DL TI Positive and negative selection of antigen-specific B cells in transgenic mice expressing variant forms of the V(H)1 (T15) heavy chain SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE antigen binding; B lymphocytes; generation of diversity; H chain transgenic mice; idiotype; positive selection; phosphocholine ID PHOSPHOCHOLINE-SPECIFIC ANTIBODIES; IMMUNE-DEFICIENT MICE; LYMPHOCYTES-B; BONE-MARROW; STREPTOCOCCUS-PNEUMONIAE; PHOSPHATIDYL CHOLINE; TARGETED DISRUPTION; PROTEUS-MORGANII; ESCAPE TOLERANCE; MEMBRANE EXON AB Four variant forms of the V1 (T15-H chain) gene are synthesized in mice. Each V1 variant pairs with a distinct L chain to produce a binding site having specificity for phosphocholine (PC), Transgenic mice expressing variant forms of the V1 gene were analyzed to elucidate the factors driving a cell selection into the peripheral repertoire. In all four lines of H chain transgenic mice analyzed, transgene expression caused complete allelic exclusion of endogenous H chains in the bone marrow (BM), whereas most splenic B cells expressed endogenous H chains. The number of sigM(+) BM a cells and their sig receptor number was reduced compared to that of normal transgene-negative controls, suggesting that a cells expressing transgene-encoded H chains were being negatively selected in the BM, Mice expressing autoreactive forms of the V1 transgene with lower affinity for PC (M603H and M167H) exhibit positive selection of PC-specific a cells into the spleen, whereas mice expressing the higher affinity T15H variant exhibited elevated PC-specific a cells in the peritoneal cavity but few V(H)1(+) splenic a cells. These data suggest that the higher affinity T15-id(+) B cells preferentially survive in the peritoneal cavity, When these H chain transgenes were crossed into the mu MT knockout mouse in which surface expression of endogenous H chains is blocked, the percent of splenic V(H)1(+) PC-specific B cells increased up to 5-fold and T15-id(+) a cells were detectable in the spleen of T15H mice. This implies that T15-id(+) PC-specific a cells can be selected into the periphery, but they compete poorly with follicular a cells expressing endogenous Ig. C1 NIA, NIH, Gerontol Res Ctr, Baltimore, MD 21224 USA. NCI, Intramural Res Support Program, SAIC, Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA. Univ Texas, Inst Mol & Cellular Biol, Austin, TX 78712 USA. Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. RP Kenny, JJ (reprint author), NIA, NIH, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. FU NIAID NIH HHS [AI-18016] NR 58 TC 10 Z9 11 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD JUN PY 2000 VL 12 IS 6 BP 873 EP 885 DI 10.1093/intimm/12.6.873 PG 13 WC Immunology SC Immunology GA 329JQ UT WOS:000087904200015 PM 10837415 ER PT J AU Ward, MH Pan, WH Cheng, YJ Li, FH Brinton, LA Chen, CJ Hsu, MM Chen, IH Levine, PH Yang, CS Hildesheim, A AF Ward, MH Pan, WH Cheng, YJ Li, FH Brinton, LA Chen, CJ Hsu, MM Chen, IH Levine, PH Yang, CS Hildesheim, A TI Dietary exposure to nitrite and nitrosamines and risk of nasopharyngeal carcinoma in Taiwan SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID N-NITROSO COMPOUNDS; CHINESE SALTED FISH; EXPERIMENTAL CARCINOGENESIS; MALAYSIAN CHINESE; PRESERVED FOODS; CANCER; NPC; PRECURSORS; GUANGXI AB Previous studies of nasopharyngeal carcinoma (NPC) have found elevated risks with higher consumption of salted fish and preserved foods, particularly during childhood. These foods can contain high levels of nitrosamines; however, most studies have not estimated exposure to nitrosamines directly. We conducted a case-control study in Taiwan to evaluate dietary intakes and NPC risk. A total of 375 cases (99% response rate) and 327 controls (88% response rate) were interviewed about their diet as an adult and at age In using a food-frequency questionnaire. We interviewed mothers of participants about their child's diet at age 10, age 3 and during weaning and the mother's diet while she was breastfeeding. Mothers of 96 cases and 120 controls were interviewed. Nitrosamine and nitrite levels were assigned to 66 foods based on published values, Intake of nitrosamines and nitrite as an adult was not associated with risk of NPC. High intakes of nitrosamines and nitrite during childhood and weaning were associated with increased risks of NPC for foods other than soy products. Adjusted odds ratios for the highest quartile were 2.2 [95% confidence interval (CI) 0.8-5.6] for age in, 2.6 (95% CI 1.0-7.0) for age 3 and 3.9 (95% CI 1.4-10.4) for weaning diet. Intakes of nitrite and nitrosamines from soybean products during childhood and weaning were inversely associated with risk. Soybeans contain known inhibitors of nitrosation, and thus may explain the inverse association we observed. Our results suggest that nitrosamine and nitrite intake during childhood may play a role in the development of NPC. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Acad Sinica, Taipei, Taiwan. Natl Taiwan Univ, Coll Publ Hlth, Inst Epidemiol, Taipei, Taiwan. Natl Taiwan Univ Hosp, Taipei, Taiwan. Natl Taiwan Univ, Coll Med, Inst Microbiol, Taipei, Taiwan. RP Ward, MH (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS-8104, Bethesda, MD 20892 USA. EM wardm@exchange.nih.gov RI Chen, Chien-Jen/C-6976-2008; Pan, Wen-Harn /F-9972-2010; Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 36 TC 75 Z9 80 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUN 1 PY 2000 VL 86 IS 5 BP 603 EP 609 DI 10.1002/(SICI)1097-0215(20000601)86:5<603::AID-IJC1>3.0.CO;2-H PG 7 WC Oncology SC Oncology GA 311PL UT WOS:000086893000001 PM 10797279 ER PT J AU Kang, SH Choi, HH Kim, SG Jong, HS Kim, NK Kim, SJ Bang, YJ AF Kang, SH Choi, HH Kim, SG Jong, HS Kim, NK Kim, SJ Bang, YJ TI Transcriptional inactivation of the tissue inhibitor of metalloproteinase-3 gene by DNA hypermethylation of the 5 '-CPG island in human gastric cancer cell lines SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID TUMOR-SUPPRESSOR GENE; GROWTH-FACTOR; METHYLATION; EXPRESSION; INDUCTION; CARCINOMA; PROMOTER AB The tissue inhibitor of metalloproteinase-3 (TIMP-3), a recently cloned member of TIMP gene family, has been implicated in the negative regulation of tumor cell invasion and tumor growth. Down-regulation of this gene has been shown to occur in a mouse carcinogenesis model, suggesting that it might play a role in the tumor progression of some cancers. In this study, we used human gastric cancer cell lines to investigate whether TIMP-3 gene expression is suppressed in human gastric cancer. We examined whether aberrant DNA methylation of the 5'-CpG island of the TIMP-3 gene is involved in this cancer. Nine of 10 human gastric cancer cell lines completely lost TIMP-3 gene expression compared with normal samples. Southern blot analysis and bisulfite genomic sequencing revealed aberrant hypermethylation near the transcription-start site of the TIMP-3 gene in all cell lines lacking TIMP-3 expression. Treatment of these cell lines with the demethylating agent 5-aza-2'-deoxycytidine restored TIMP-3 gene expression. Our results suggest that the TIMP-3 gene is another early target of tumor-associated aberrant DNA methylation in human gastric carcinogenesis. Consequently, genetic silencing of TIMP-3 may lead to a more malignant and invasive phenotype in these cancer cells. (C) 2000 Wiley-Liss. Inc. C1 Seoul Natl Univ Hosp, Dept Internal Med, Chongno Ku, Seoul 110744, South Korea. Seoul Natl Univ, Coll Med, Ctr Canc Res, Seoul, South Korea. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Bang, YJ (reprint author), Seoul Natl Univ Hosp, Dept Internal Med, Chongno Ku, 28 Yongon Dong, Seoul 110744, South Korea. RI Bang, Yung Jue/J-2759-2012 NR 21 TC 51 Z9 53 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 JUN 1 PY 2000 VL 86 IS 5 BP 632 EP 635 DI 10.1002/(SICI)1097-0215(20000601)86:5<632::AID-IJC5>3.0.CO;2-5 PG 4 WC Oncology SC Oncology GA 311PL UT WOS:000086893000005 PM 10797283 ER PT J AU Sasaki, CY Lin, HC Passaniti, A AF Sasaki, CY Lin, HC Passaniti, A TI Expression of E-cadherin reduces Bcl-2 expression and increases sensitivity to etoposide-induced apoptosis SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID RNA HYBRIDIZATION TECHNIQUE; COLON-CARCINOMA CELLS; BETA-CATENIN; BREAST-CANCER; V-SRC; TYROSINE PHOSPHORYLATION; DRUG-RESISTANCE; GASTRIC-CANCER; EGF RECEPTOR; GROWTH AB Expression of Ed-a is important in determining cancer cell resistance to chemotherapy. However, it is not clear whether cell-cell interactions regulate Bcl-2 expression. Using rat breast carcinoma cells selected for loss of hormone responsiveness, we found that parental E-cadherin-expressing cells (E cells) were more sensitive to etoposide-induced apoptosis than hormone-non-responsive cells (F cells), which failed to express E-cadherin. Expression of beta-catenin and ppl20 src substrate proteins, which associate with E-cadherin, was unaffected. To determine whether re-expression of E-cadherin in F cells would restore etoposide sensitivity, F cells were transfected with an expression vector coding for the mouse E-cadherin gene. Stable clonal isolates expressing E-cadherin (F,Cad) showed increased sensitivity to etoposide treatment compared with control clones (F,Neo). Expression of E-cadherin resulted in a redistribution of beta-catenin from the cytoskeletal/nuclear fraction Co the cytoplasmid/membrane fraction of the cells. E-cadherin-expressing clones also showed reduced invasion through basement membrane. Etoposide-induced apoptosis was characterized by morphological changes (nuclear blebbing) and DNA fragmentation. Induction of CPP32-like caspase activity was also observed in F,Cad transfectants but not F,Neo cells. Unlike F cells, F,Cad transfectants were not able to express Bcl-2, but transient transfection of bcl-2 resulted in re-expression and resistance to etoposide treatment, Therefore, E-cadherin may negatively regulate Bcl-2 expression by altering the availability of nuclear beta-catenin, Loss of E-cadherin in invasive tumor cells may lead to increased Bcl-2 expression and resistance to chemotherapeutic drugs. Published 2000 Wiley-Liss, Inc.dagger C1 Univ Maryland, Greenebaum Canc Ctr, Dept Pathol, Baltimore, MD 21201 USA. NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. NIA, Biol Chem Lab, NIH, Baltimore, MD 21224 USA. RP Passaniti, A (reprint author), Univ Maryland, Greenebaum Canc Ctr, Dept Pathol, Bressler Res Bldg 7-021,655 W Baltimore St, Baltimore, MD 21201 USA. NR 43 TC 23 Z9 32 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 JUN 1 PY 2000 VL 86 IS 5 BP 660 EP 666 DI 10.1002/(SICI)1097-0215(20000601)86:5<660::AID-IJC9>3.0.CO;2-X PG 7 WC Oncology SC Oncology GA 311PL UT WOS:000086893000009 PM 10797287 ER PT J AU Weed, DL AF Weed, DL TI Interpreting epidemiological evidence: how meta-analysis and causal inference methods are related SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE causation; epidemiology; inference; meta-analysis; systematic reviews ID BREAST-CANCER; BLACK-BOX; METAANALYSIS; HETEROGENEITY; REVIEWS; GUIDELINES; ABORTION; CRITERIA; RISK AB Interpreting observational epidemiological evidence can involve both the quantitative method of meta-analysis and the qualitative criteria-based method of causal inference. The relationships between these two methods are examined in terms of the capacity of meta-analysis to contribute to causal claims, with special emphasis on the most commonly used causal criteria: consistency, strength of association, dose-response, and plausibility. Although meta-analysis alone is nor sufficient for making causal claims, it can provide a reproducible weighted average of the estimate of effect that seems better than the rules-of-thumb (e.g. majority rules and all-or-none) often used to assess consistency. A finding of statistical heterogeneity, however, need not preclude a conclusion of consistency (e.g. consistently greater than 1.0). For the criteria of strength of association and dose-response, meta-analysis provides more precise estimates, but the causal relevance of these estimates remains a matter of judgement. Finally, metaanalysis may be used to summarize evidence from biological, clinical, and social levels of knowledge, bur combining evidence across levels is beyond its current capacity. Meta-analysis has a real but limited role in causal inference, adding to an understanding of some causal criteria. Meta-analysis may also point to sources of confounding or bias in its assessment of heterogeneity. C1 NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Weed, DL (reprint author), NCI, Div Canc Prevent, EPS T-41,6130 Execut Blvd,MSC 7105, Bethesda, MD 20892 USA. NR 44 TC 62 Z9 63 U1 0 U2 6 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 2000 VL 29 IS 3 BP 387 EP 390 DI 10.1093/ije/29.3.387 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 334WD UT WOS:000088207900001 PM 10869307 ER PT J AU You, WC Ma, JL Liu, WD Gail, MH Chang, YS Zhang, L Hu, YR Fraumeni, JF Xu, GW AF You, WC Ma, JL Liu, WD Gail, MH Chang, YS Zhang, L Hu, YR Fraumeni, JF Xu, GW TI Blood type and family cancer history in relation to precancerous gastric lesions SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE precancerous gastric lesions; ABO blood type; family stomach cancer history ID CARCINOGENESIS; RISK AB Background The increased odds of stomach cancer among subjects with blood type A have been reported in epidemiological studies. Aim To study the relation of family history of gastric cancer and ABO blood type with precancerous gastric lesions in a high-risk area for stomach cancer. Subjects and setting We examined 3400 adults aged 35-64 in a population-based gastric endoscopic screening in a county in China with one of the highest rates of stomach cancer in the world. Methods In this cross-sectional study, data on family cancer history, ABO blood type and other characteristics of the participants were obtained by interview and blood test. Responses were compared between those with the most advanced gastric lesions, dysplasia (DYS) or intestinal metaplasia (IM), versus those with chronic atrophic gastritis (CAG) or superficial gastritis (SG). Results The prevalence odds ratio (OR) for blood type A relative to other types was 1.39 (95% CI : 1.12-1.73) for DYS and 1.28 (95% CI : 1.06-1.53) for IM. The OR associated with parental history of stomach cancer was 1.88 (95% CI : 1.20-2.95) for DYS, but the numbers were too small to evaluate aggregation among siblings. The combined OR associated with blood type A and a parental of history of gastric cancer was 2.61 (95% CI : 1.59-4.30) for DYS and 1.46 (95% CI : 0.93-2.31) for IM. Conclusions The findings suggest that genetic factors play a role in developing precancerous gastric lesions. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Beijing Med Univ, Beijing Inst Canc Res, Beijing 100034, Peoples R China. Beijing Med Univ, Sch Oncol, Beijing 100034, Peoples R China. Linqu Publ Hlth Bur, Shandong 262600, Peoples R China. Westat Inc, Rockville, MD 20850 USA. RP You, WC (reprint author), NCI, Div Canc Epidemiol & Genet, EPS Room 8030, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CP-15620, N01-CP-21009, N01-CP-05613] NR 10 TC 27 Z9 31 U1 0 U2 6 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 2000 VL 29 IS 3 BP 405 EP 407 DI 10.1093/ije/29.3.405 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 334WD UT WOS:000088207900004 PM 10869310 ER PT J AU Chrousos, GP AF Chrousos, GP TI The role of stress and the hypothalamic-pituitary-adrenal axis in the pathogenesis of the metabolic syndrome: neuro-endocrine and target tissue-related causes SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article; Proceedings Paper CT 8th International Congress on Endocrinology of Obesity Basic, Clinical and Therapeutic Aspects CY SEP, 1998 CL VENICE, ITALY DE CRH; HPA; glucocorticoids; cortisol; Cushing's syndrome ID CORTICOTROPIN-RELEASING HORMONE; GLUCOCORTICOID RECEPTOR GENE; BODY-FAT DISTRIBUTION; CORTISOL SECRETION; BIOCHEMICAL MANIFESTATIONS; CUSHINGS-SYNDROME; PLASMA-CORTISOL; OBESE WOMEN; WEIGHT-LOSS; DEPRESSION AB The stress system coordinates the adaptive response of the organism to real or perceived stressors. The main components of the stress system are the corticotropin-releasing hormone (CRH) and locus ceruleus-norepinephrine/autonomic (LC/NE) systems and their peripheral effectors, the hypothalamic-pituitary-adrenal (HPA) axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival. Thus, CRH and the LC/NE system stimulate arousal and attention, as well as the mesocorticolimbic dopaminergic system, which is involved in anticipatory and reward phenomena, and the amygdala, which are responsible for the generation of fear. Hypothalamic CRH plays an important role in inhibiting gonadotropin-releasing hormone secretion during stress, while via somatostatin it also inhibits growth hormone, thyrotropin-releasing hormone and thyrotropin secretion, suppressing thus reproduction, growth and thyroid function. Glucocorticoids directly inhibit pituitary gonadotropin, growth hormone and thyrotropin secretion and make the target tissues of sex steroids and growth factors resistant to these substances. In addition, glucocorticoids stimulate hepatic gluconeogenesis, and inhibit or potentiate insulin actions on skeletal muscle and adipose tissue respectively, ultimately promoting visceral adiposity and the metabolic syndrome. Glucocorticoids also have direct effects on the bone, inhibiting osteoblastic activity and causing osteoporosis. Obese subjects with psychiatric manifestations ranging from those of melancholic depression to anxiety with perception of 'uncontrollable' stress, frequently have mild hypercortisolism, while carefully screened obese subjects with no such manifestations are eucortisolemic. The former may have stress-induced glucocorticoid-mediated visceral obesity and metabolic syndrome manifestations, which in the extreme may be called a pseudo-Cushing state that needs to be differentiated from frank Cushing syndrome. Stress-induced hypercortisolism and visceral obesity and their cardiovascular and other sequelae increase the all-cause mortality risk of affected subjects by 2-3-fold and curtail their life expectancy by several years. C1 Nichhd, Pediat Endocrinol Sect, PREB, NIH, Bethesda, MD 20892 USA. RP Chrousos, GP (reprint author), Nichhd, Pediat Endocrinol Sect, PREB, NIH, 10 Ctr Dr MSC 1583,Bldg 10,Room 1D42, Bethesda, MD 20892 USA. NR 38 TC 281 Z9 296 U1 6 U2 28 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD JUN PY 2000 VL 24 SU 2 BP S50 EP S55 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 335NW UT WOS:000088250400012 PM 10997609 ER PT J AU Patel, J Coppack, SW Rawesh, A Miles, JM Eisenhofer, G AF Patel, J Coppack, SW Rawesh, A Miles, JM Eisenhofer, G TI Regional and total body changes in sympathoadrenal activity in response to eating SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article; Proceedings Paper CT 8th International Congress on Endocrinology of Obesity Basic, Clinical and Therapeutic Aspects CY SEP, 1998 CL VENICE, ITALY DE noradrenaline; adipose tissue ID INVIVO C1 UCL, Sch Med, Dept Med, London W1N 8AA, England. St Lukes Hosp, Kansas City, MO USA. NIH, Clin Neurosci Branch, Bethesda, MD 20892 USA. RP Coppack, SW (reprint author), Royal London Hosp, Acad Med Unit, London E1 1BB, England. EM s.w.coppack@qmw.ac.uk NR 5 TC 3 Z9 3 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD JUN PY 2000 VL 24 SU 2 BP S156 EP S157 PG 2 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 335NW UT WOS:000088250400046 PM 10997643 ER PT J AU Van Waes, C Enamorado-Ayala, I Hecht, D Sulica, L Chen, Z Batt, DG Mousa, S AF Van Waes, C Enamorado-Ayala, I Hecht, D Sulica, L Chen, Z Batt, DG Mousa, S TI Effects of the novel alpha(v) integrin antagonist SM256 and cis-platinum on growth of murine squamous cell carcinoma PAM LY8 SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE integrins; integrin alpha(v)beta(3); integrin alpha(v)beta(5); vitronectin; RGD; squamous cell carcinoma ID ANGIOGENESIS INHIBITOR TNP-470; TERMINAL DIFFERENTIATION; TUMOR-GROWTH; HUMAN BREAST; NECK-CANCER; HUMAN SKIN; EXPRESSION; AGM-1470; LINES; HEAD AB Increased density of proliferating and migrating tumor cells and neovascular endothelial cells has been associated with tumor progression and poor prognosis in patients with squamous cell carcinoma (SCC). Tumor and neovascular endothelial cells in squamous cell carcinoma have been reported to express integrin heterodimers containing the alpha(v) subunit, which binds to vitronectin and other extracellular matrix proteins that contain the amino acid recognition sequence Arg-Gly-Rsp (RGD). In the present study, we examined the effect of the novel non-peptide alpha(v) integrin antagonist SM256 on growth of SCC line PAM LY8 in BALB/c SCID mice, and determined whether SM256 has direct inhibitory effects on growth of murine endothelial and PAM LY8 SCC cells in vitro. SM256 inhibits cell adhesion of murine cells expressing alpha(v)beta(3) and alpha(v)beta(5) integrins in vitro with an IC50 of 35 nM and 30 nM, respectively. Growth of PAM LY8 tumors in vivo was inhibited with 14-day continuous administration of SM256 by subcutaneous osmotic diffusion pump, during which a mean serum concentration of 56 nM was detected. While both murine aortic endothelial cells and PAM LY8 were found to express alpha(v) integrins by fluorescence cytofluorometry, SM256 at 50 nM in MTT assay completely inhibited growth of endothelial cells, but had no significant direct effect on growth of PAM LY8 cells. We compared the effect on growth of PAM LY8 of SM256 infusion versus single agent or combination chemotherapy with a maximally tolerated dose of cis-platinum, which is used as a standard chemotherapy for SCC. When treatment was initiated at either 7 or 21 days following establishment of tumor, 14-day infusion of SM256 had an inhibitory effect on growth that was similar to that obtained with single dose cis-platinum, but no additive effect of concurrent therapy with SM256 and cis-platinum was observed. These results demonstrate the activity and feasibility of use of alpha(v) antagonists such as SM256 for therapy of SCC. C1 Natl Inst Deafness & Other Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD 20892 USA. Dupont Merck Pharmaceut Co, Expt Stn, Wilmington, DE 19880 USA. RP Van Waes, C (reprint author), Natl Inst Deafness & Other Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bldg 10,Rm 5D55, Bethesda, MD 20892 USA. FU NIDCD NIH HHS [DC-95-01, Z01-DC-0017] NR 35 TC 16 Z9 17 U1 1 U2 3 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD JUN PY 2000 VL 16 IS 6 BP 1189 EP 1195 PG 7 WC Oncology SC Oncology GA 314GA UT WOS:000087047000017 PM 10811994 ER PT J AU Baum, BJ Goldsmith, CM Hoque, ATMS Wellner, RB Baccaglini, L DIng, C Yamano, S Zheng, C Aframian, DJ O'Connell, BC AF Baum, BJ Goldsmith, CM Hoque, ATMS Wellner, RB Baccaglini, L DIng, C Yamano, S Zheng, C Aframian, DJ O'Connell, BC TI Salivary glands as a model for craniofacial applications of gene transfer SO INTERNATIONAL JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Review DE gene therapy; gene therapeutics; molecular medicine; salivary glands ID IN-VIVO; MEDIATED TRANSFER; GROWTH-HORMONE; WATER CHANNEL; THERAPY; DELIVERY; SECRETION; CELLS; EXPRESSION; BARRIERS AB The potential applications of gene transfer technology to all branches of medicine are increasing. It is quite likely that within the next 10-20 years surgical practice routinely will utilize gene transfer, at least adjunctively. The purpose of this review is to familiarize the oral and maxillofacial surgeon with this technology. Studies performed with salivary glands in animal models are presented as examples of proof of concept. C1 NIDCR, GTTB, NIH, Bethesda, MD 20892 USA. RP Baum, BJ (reprint author), NIDCR, GTTB, NIH, Bldg 10,Room 1N113,MSC 1190, Bethesda, MD 20892 USA. OI O'Connell, Brian/0000-0003-4529-7664; Yamano, Seiichi/0000-0003-2056-4359 NR 29 TC 8 Z9 8 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0901-5027 J9 INT J ORAL MAX SURG JI Int. J. Oral Maxillofac. Surg. PD JUN PY 2000 VL 29 IS 3 BP 163 EP 166 DI 10.1034/j.1399-0020.2000.290302.x PG 4 WC Dentistry, Oral Surgery & Medicine; Surgery SC Dentistry, Oral Surgery & Medicine; Surgery GA 346AH UT WOS:000088847600002 PM 10970076 ER PT J AU McCrae, RR AF McCrae, RR TI Cross-cultural trait psychology SO INTERNATIONAL JOURNAL OF PSYCHOLOGY LA English DT Meeting Abstract C1 NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 0020-7594 J9 INT J PSYCHOL JI Int. J. Psychol. PD JUN-AUG PY 2000 VL 35 IS 3-4 SI SI BP 183 EP 183 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 337XP UT WOS:000088388801790 ER PT J AU Ungerleider, L AF Ungerleider, L TI Mechanisms of visual attention in human cortex SO INTERNATIONAL JOURNAL OF PSYCHOLOGY LA English DT Meeting Abstract C1 NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 0020-7594 J9 INT J PSYCHOL JI Int. J. Psychol. PD JUN-AUG PY 2000 VL 35 IS 3-4 SI SI BP 295 EP 295 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 337XP UT WOS:000088388802890 ER PT J AU Thayer, JF Brosschot, JF AF Thayer, JF Brosschot, JF TI Perseverative thinking, vagal inhibition, and health SO INTERNATIONAL JOURNAL OF PSYCHOLOGY LA English DT Meeting Abstract C1 NIA, Baltimore, MD 21224 USA. Leiden Univ, NL-2300 RA Leiden, Netherlands. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 0020-7594 J9 INT J PSYCHOL JI Int. J. Psychol. PD JUN-AUG PY 2000 VL 35 IS 3-4 SI SI BP 309 EP 309 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 337XP UT WOS:000088388803026 ER PT J AU Higley, JD Bennett, A AF Higley, JD Bennett, A TI Impaired CNS serotonin functioning, and antisocial-like personality: A nonhuman primate model of genetic and environmental influences SO INTERNATIONAL JOURNAL OF PSYCHOLOGY LA English DT Meeting Abstract C1 NIAAA, Poolesville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 0020-7594 J9 INT J PSYCHOL JI Int. J. Psychol. PD JUN-AUG PY 2000 VL 35 IS 3-4 SI SI BP 314 EP 314 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 337XP UT WOS:000088388803073 ER PT J AU Fahlke, C Champoux, M Higley, D Long, J Lorenz, J Suomi, S AF Fahlke, C Champoux, M Higley, D Long, J Lorenz, J Suomi, S TI Rearing experiences and plasma cortisol as early risk factors for excessive alcohol intake in nonhuman primates SO INTERNATIONAL JOURNAL OF PSYCHOLOGY LA English DT Meeting Abstract C1 Gothenburg Univ, Dept Psychol, Gothenburg, Sweden. NIAAA, Lab Comperat Ethol, Bethesda, MD USA. NIAAA, Clin Studies Lab, Bethesda, MD 20892 USA. NIAAA, Neurogenet Lab, Bethesda, MD USA. NIH, Ethol Lab, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 0020-7594 J9 INT J PSYCHOL JI Int. J. Psychol. PD JUN-AUG PY 2000 VL 35 IS 3-4 SI SI BP 332 EP 332 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 337XP UT WOS:000088388803249 ER PT J AU Kozhich, AT Chan, CC Gery, I Whitcup, SM AF Kozhich, AT Chan, CC Gery, I Whitcup, SM TI Recurrent intraocular inflammation in endotoxin-induced uveitis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID RAT; CYTOKINES AB PURPOSE. Endotoxin-induced uveitis (EIU) in rats and mice peaks 24 hours after endotoxin injection and is commonly assumed to be a monophasic disease. This study examined intraocular inflammation at later time points to determine whether endotoxin injection can induce recurrent intraocular inflammation in strains of mice with high or moderate levels of susceptibility to EIU. METHODS. EIU was elicited in two mouse strains with high (C3H/HeN) and moderate (FVB/N) susceptibility, by means of intraperitoneal injections of Salmonella typhimurium endotoxin. Mammatory cells in the anterior and posterior segments of the eye were counted by a masked observer on histologic sections of eyes from 1 to 17 days after endotoxin injection. RESULTS. A bimodal distribution of inflammatory cell infiltration was noted in eyes from C3H/HeN mice. As previously reported, inflammation peaked at 24 hours after endotoxin injection. However a second, more pronounced peak of intraocular inflammation occurred approximately 5 days after endotoxin injection. FVB/N mice had a single peak of intraocular inflammation 4 days after injection. CONCLUSIONS. Endotoxin injection in C3H/HeN elicits recurrent intraocular inflammation. The previously unrecognized second peak of inflammation is more severe than the initial inflammatory disease. Studies on this second inflammatory peak may be useful in determining the pathogenesis of recurrent uveitis in humans. C1 NEI, NIH, Bethesda, MD 20892 USA. RP Whitcup, SM (reprint author), Allergan, 2525 Dupont Dr,POB 19534, Irvine, CA 92623 USA. NR 11 TC 14 Z9 19 U1 0 U2 0 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 2000 VL 41 IS 7 BP 1823 EP 1826 PG 4 WC Ophthalmology SC Ophthalmology GA 320DV UT WOS:000087387300030 PM 10845604 ER PT J AU Fee, E AF Fee, E TI How the idea of profession changed the writing of medical history. SO ISIS LA English DT Book Review C1 NIH, Hist Med Div, Natl Lib Med, Bethesda, MD 20892 USA. RP Fee, E (reprint author), NIH, Hist Med Div, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0021-1753 J9 ISIS JI Isis PD JUN PY 2000 VL 91 IS 2 BP 332 EP 333 DI 10.1086/384743 PG 2 WC History & Philosophy Of Science SC History & Philosophy of Science GA 343YA UT WOS:000088729400025 ER PT J AU Ewings, EL Gerschenson, M St Claire, MC Nagashima, K Skopets, B Harbaugh, SW Harbaugh, JW Poirier, MC AF Ewings, EL Gerschenson, M St Claire, MC Nagashima, K Skopets, B Harbaugh, SW Harbaugh, JW Poirier, MC TI Genotoxic and functional consequences of transplacental zidovudine exposure in fetal monkey brain mitochondria SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE nucleoside analogues; mitochondria; vertical transmission; brain; zidovudine; toxicity ID ANTIRETROVIRAL NUCLEOSIDE ANALOGS; HUMAN-IMMUNODEFICIENCY-VIRUS; MYOPATHY; DNA; THERAPY; DYSFUNCTION; INFECTION; TOXICITY; DISORDER; AIDS AB Mitochondrial toxicity was assessed in the brains of developing Erythrocebus patas monkey fetuses exposed in utero to the nucleoside analogue drug zidovudine (3'-azido-3' deoxythymidine or AZT). Pregnant E. patas monkeys were given 0 (n = 5), 10 (n = 3), and 40 (n = 3) mg of AZT/day, equivalent to 21 and 86% of the human daily dose, for the last half(about 10 weeks) of gestation. Mitochondria were isolated from fetal cerebrum and cerebellum at birth and mitochondrial morphology was examined in these tissues by transmission electron microscopy (TEM). Oxidative phosphorylation (OXPHOS) enzyme specific activities were measured spectrophotometrically. Mitochondrial DNA (mtDNA) integrity and quantity were determined by Southern blot and slot blot analysis. In the cerebral mitochondria, reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase (complex I) specific activity decreased by 25% in monkeys treated with 40 mg of AZT/day compared with unexposed monkeys (p greater than or equal to .05). At the same AZT dose in the cerebral mitochondria, succinate dehydrogenase (complex II) and cytochrome c reductase (complex IV)-specific activities showed dose-dependent increases (p greater than or equal to .05), compared with those in controls. In the cerebellum, no difference was seen in mitochondrial OXPHOS enzyme activities between unexposed and exposed fetuses. Furthermore, TEM demonstrated no difference in mitochondrial morphology in frontal cerebrum or cerebellum from unexposed and exposed fetuses, and all fetuses had similar amounts of mtDNA in both tissues. Cerebral mtDNA degradation was noted in the highest AZT dosage group, whereas mtDNA from cerebellum was uneffected. Thus, in fetal patas monkeys given a human equivalent daily dose of AZT during the last half of pregnancy, mitochondria in the fetal cerebrum appear to sustain moderate damage, while the fetal cerebellum mitochondria were not effected. C1 NCI, Div Basic Sci, NIH, Bethesda, MD 20892 USA. BioQual Inc, Rockville, MD USA. NCI, Frederick Canc Res & Dev Ctr, Lab Cell & Mol Struct, SAIC, Frederick, MD USA. RP Gerschenson, M (reprint author), NCI, Div Basic Sci, NIH, Bldg 37,Room 2A03,37 Convent Dr,MSC-4255, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CO-56000] NR 29 TC 25 Z9 26 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. PD JUN 1 PY 2000 VL 24 IS 2 BP 100 EP 105 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 339QU UT WOS:000088490100002 PM 10935684 ER PT J AU Sichieri, R Taddei, JA Everhart, JE AF Sichieri, R Taddei, JA Everhart, JE TI Influence of parental height and sociodemographic factors on adolescent height in Brazil SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE adolescent health; anthropometry; national surveys; underdeveloped countries; Brazil ID GROWTH; CHILDREN; BIRTH AB Objective: To analyze the influence of parental stature and environmental factors on the stature of adolescents from a national survey sample. Methods: A nationwide survey was carried out in 1989 among a stratified, two-stage, probability cluster sample of 14,455 Brazilian households to provide estimates of anthropometric deficits for urban and rural populations from the five regions of the country. Stature was measured for 5681 boys and girls age 14-18 years, 78.9% of their fathers, and 93.8% of their mothers. Associations between explanatory variables and adolescent height in centimeters were assessed by fitting multiple linear models to the data. Results: The predicted effects of parental stature and environmental conditions together sum to a total of 17 cm when comparing a boy born to parents with stature below the median and living in the underdeveloped rural Northeast region (1.56 m) with one born to parents with stature above the median and living in the partially industrialized urban South region (1.73 m). For girls, this estimated difference was 12 cm. For boys, the overall influence of parents' stature was 10 cm (R-2 = 0.40) and the sociodemographic factors had an overall influence of 7 cm (R-2 = 0.29). For girls, these values were 7 cm (R-2 = 0.35) for the parental influence and 5 cm (R-2 = 0.11) for the sociodemographic factors. Conclusions: Mother's stature had the same influence on adolescent's stature as father's stature. Independent of parental stature, environmental factors have a strong influence on adolescent stature, particularly among boys. 0 Society for Adolescent Medicine, 2000. C1 Univ Estadual Rio de Janeiro, Inst Social Med, Dept Social Med, BR-20550012 Rio De Janeiro, Brazil. Emory Univ, Dept Int Hlth, Atlanta, GA 30322 USA. NIDDK, NIH, Bethesda, MD USA. RP Sichieri, R (reprint author), Univ Estadual Rio de Janeiro, Inst Social Med, Dept Social Med, Rua S Francisco Xavier 524,7o Andar,Bloco E, BR-20550012 Rio De Janeiro, Brazil. RI TADDEI, JOSE AUGUSTO/D-8216-2015 OI TADDEI, JOSE AUGUSTO/0000-0003-3833-392X NR 23 TC 14 Z9 19 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD JUN PY 2000 VL 26 IS 6 BP 414 EP 419 DI 10.1016/S1054-139X(99)00004-X PG 6 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 316VP UT WOS:000087189000007 PM 10822183 ER PT J AU Ochs, RL Muro, Y Si, YZ Ge, H Chan, EKL Tan, EM AF Ochs, RL Muro, Y Si, YZ Ge, H Chan, EKL Tan, EM TI Autoantibodies to DFS 70 kd/transcription coactivator p75 in atopic dermatitis and other conditions SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE atopic dermatitis; autoantibodies; antinuclear antibodies; asthma; interstitial cystitis; transcription coactivator ID INTERSTITIAL CYSTITIS; TRANSCRIPTIONAL ACTIVATION; LENS EPITHELIUM; GENES; PATHOGENESIS; ANTIBODIES; DIAGNOSIS; SEQUENCE; PROTEINS; CLONING AB Background: Sera of patients with atopic dermatitis (AD) were found to have autoantibodies that reacted with tissue culture cell substrates in immunohistochemistry to display a characteristic pattern of nuclear distribution of dense fine speckles. The sera also recognized a 70-kd protein on Western immunoblots, and the antigen was termed dense fine speckles 70 kd (DSF70). Objective: Because spontaneously occurring autoantibodies could be immune responses to proteins that might be participating in the disease process, it was of interest to identify the antigens driving the autoimmune antibody response. Methods: A serum containing high-titer antibodies to DFS70 was used to immunoscreen a complementary (c)DNA expression library to isolate cDNA encoding the antigen. After the cDNA was isolated, this was used to express recombinant protein to determine the prevalence of antibody in AD and other conditions. Results: Thirty percent of patients with AD were found to have antibody to recombinant DFS70 in Western immunoblots. Sixteen percent of patients with asthma and 9% of patients with interstitial cystitis had antibodies of the same specificities. The cDNA encoding DFS70 was identical to a transcription coactivator called p75, which had been shown to be required for RNA polymerase II-dependent transcription. Another important finding was that IgE antibodies to DFS70 were also present in AD sera. Conclusion: It is suggested that a common basis for the presence of autoantibodies to DFS70 might be related to AD in asthma, interstitial cystitis, and other conditions. A possible role of this antigen-antibody system in pathogenesis remains to be demonstrated, but it appears to be a marker for a subset of patients with AD. C1 Scripps Res Inst, WM Keck Autoimmune Dis Ctr, Dept Mol & Expt Med, La Jolla, CA 92037 USA. NICHHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. RP Tan, EM (reprint author), Scripps Res Inst, WM Keck Autoimmune Dis Ctr, Dept Mol & Expt Med, MEM 131,10550 N Torrey Pines Rd, La Jolla, CA 92037 USA. RI Chan, Edward/B-5671-2009; MURO, Yoshinao/M-8883-2014; OI Chan, Edward/0000-0003-3938-9503; Muro, Yoshinao/0000-0003-2329-8375 FU NIAMS NIH HHS [AR32063]; NIDDK NIH HHS [DK49413] NR 33 TC 96 Z9 103 U1 0 U2 2 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUN PY 2000 VL 105 IS 6 BP 1211 EP 1220 DI 10.1067/mai.2000.107039 PN 1 PG 10 WC Allergy; Immunology SC Allergy; Immunology GA 327EX UT WOS:000087781800024 PM 10856157 ER PT J AU Reynolds, TH Brozinick, JT Larkin, LM Cushman, SW AF Reynolds, TH Brozinick, JT Larkin, LM Cushman, SW TI Transient enhancement of GLUT-4 levels in rat epitrochlearis muscle after exercise training SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE glucose transporters; detraining; glucose metabolism; training cessation; insulin action ID HUMAN SKELETAL-MUSCLE; GLUCOSE-TRANSPORT CAPACITY; PROTEIN-CONTENT; INSULIN; INCREASES; STIMULATION; CESSATION AB The purpose of the present study was to examine the effect of detraining on the glucose transport system after short-term swim training (5 days), long-term swim training (5 wk), and treadmill run training (5 wk). Skeletal muscles were isolated from female Wistar rats at 24 or 48 h posttraining. SST produces a 48% increase in GLUT-4 mRNA, a 30% increase in GLUT-4 protein, and a 60% increase in insulin-stimulated glucose transport activity at 24 h posttraining but not at 48 h posttraining. Similar to SST, long-term swim training produces a 60% increase in GLUT-4 mRNA and a 30% increase in GLUT-4 protein content at 24 h posttraining but not at 48 h posttraining. Finally, treadmill run training produces a transient 35% increase in GLUT-4 protein content that is completely reversed at 48 h after the last bout of exercise. These results demonstrate that the increase in GLUT-4 mRNA and GLUT-4 protein occurs during the first week of exercise training and is rapidly lost after training cessation. We believe that the transient enhancement in GLUT-4 protein after exercise training is due to a short GLUT-4 half-life, a process that is primarily regulated by pretranslational mechanisms. C1 Univ Michigan, Geriatr Ctr, Div Geriatr Med, Ann Arbor, MI 48109 USA. NIDDKD, Expt Diabet Metab & Nutr Sect, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Reynolds, TH (reprint author), Univ Michigan, Geriatr Ctr, Div Geriatr Med, 5131 CCGC,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. FU NIA NIH HHS [K01 AG000701-04, AG-00710, K01 AG000701, T32 AG000114, T32-AG00114] NR 34 TC 12 Z9 15 U1 0 U2 0 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 2000 VL 88 IS 6 BP 2240 EP 2245 PG 6 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 324CA UT WOS:000087603200040 PM 10846041 ER PT J AU Kozmin, SG Pavlov, YI Dunn, RL Schaaper, RM AF Kozmin, SG Pavlov, YI Dunn, RL Schaaper, RM TI Hypersensitivity of Escherichia coli Delta(uvrB-bio) mutants to 6-hydroxylaminopurine and other base analogs is due to a defect in molybdenum cofactor biosynthesis SO JOURNAL OF BACTERIOLOGY LA English DT Article ID BIOTIN SULFOXIDE REDUCTASE; SACCHAROMYCES-CEREVISIAE; XANTHINE DEHYDROGENASE; SALMONELLA-TYPHIMURIUM; MUTAGENIC ACTIVITY; DNA-REPLICATION; PHYSICAL MAP; MUTT PROTEIN; GENE; 6-N-HYDROXYLAMINOPURINE AB We have shown previously that Escherichia coli and Salmonella enterica serovar Typhimurium strains carrying a deletion of the uvrB-bio region are hypersensitive to the mutagenic and toxic action of 6-hydroxylaminopurine (HAP) and related base analogs. This sensitivity is not due to the uvrB excision repair defect associated with this deletion because a uvrB point mutation or a uvrA deficiency does not cause hypersensitivity, In the present work, we have investigated which gene(s) within the deleted region may be responsible for this effect. Using independent approaches, we isolated both a point mutation and a transposon insertion in the moeA gene, which is located in the region covered by the deletion, that conferred HAP sensitivity equal to that conferred by the uvrB-bio deletion. The moeAB operon provides one of a large number of genes responsible for biosynthesis of the molybdenum cofactor. Defects in other genes in the same pathway, such as moa or mod, also lead to the same HAP-hypersensitive phenotype. We propose that the molybdenum cofactor is required as a cofactor for an as Set unidentified enzyme (or enzymes) that acts to inactivate HAP and other related compounds. C1 NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. Sankt Petersburg State Univ, Dept Genet, St Petersburg 199034, Russia. RP NIEHS, Mol Genet Lab, MD E3-01,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM schaaper@niehs.nih.gov RI Kozmin, Stanislav/J-6849-2012 OI Kozmin, Stanislav/0000-0002-4128-4447 NR 64 TC 29 Z9 30 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD JUN PY 2000 VL 182 IS 12 BP 3361 EP 3367 DI 10.1128/JB.182.12.3361-3367.2000 PG 7 WC Microbiology SC Microbiology GA 318WM UT WOS:000087307700007 PM 10852865 ER PT J AU Behr, MA Schroeder, BG Brinkman, JN Slayden, RA Barry, CE AF Behr, MA Schroeder, BG Brinkman, JN Slayden, RA Barry, CE TI A point mutation in the mma3 gene is responsible for impaired methoxymycolic acid production in Mycobacterium bovis BCG strains obtained after 1927 SO JOURNAL OF BACTERIOLOGY LA English DT Article ID CALMETTE-GUERIN VACCINES; TUBERCULOSIS COMPLEX; MYCOLIC ACIDS; DNA; BIOSYNTHESIS; SEQUENCE; IDENTIFICATION; POLYMORPHISM; VACCINATION AB BCG vaccines are substrains of Mycobacterium bovis derived by attenuation in vitro. After the original attenuation (1908 to 1921), BCG strains were maintained by serial propagation in different BCG laboratories (1921 to 1961). As a result, various BCG substrains developed which are now known to differ in a number of genetic and phenotypic properties. However, to date, none of these differences has permitted a direct phenotype-genotype link. Since BCG strains differ in their abilities to synthesize methoxymycolic acids and since recent work bras shown that the mma3 gene is responsible for O-methylation of hydroxymycolate precursors to form methoxymycolic acids, we analyzed methoxymycolate production and mma3 gene sequences for a genetically defined collection of BCG strains. We found that BCG strains obtained from the Pasteur Institute In 1927 and earlier produced methoxymycolates in vitro but that those obtained from the Pasteur Institute in 1931 and later all failed to synthesize methoxymycolates, and furthermore, the mma3 sequence of the latter strains differs from that of Mycobacterium tuberculosis H37Rv by a point mutation at bp 293, Site-specific introduction of this guanine-to-adenine mutation into wild-type mma3 (resulting in the replacement of glycine 98 with aspartic acid) eliminated the ability of this enzyme to produce O-methylated mycolic acids when the mutant was cloned in tandem with mma4 into Mycobacterium smegmatis. These findings indicate that a point mutation in mma3 occurred between 1927 and 1931, and that this mutant population became the dominant clone of BCG at the Pasteur Institute. C1 McGill Univ, Ctr Hlth, Montreal, PQ H3G 1A4, Canada. NIAID, Host Def Lab, TB Res Sect, Rockville, MD 20852 USA. RP Behr, MA (reprint author), Montreal Gen Hosp, A5-156,1650 Cedar Ave, Montreal, PQ H3G 1A4, Canada. RI Barry, III, Clifton/H-3839-2012; Slayden, Richard/O-8626-2016 OI Slayden, Richard/0000-0001-6857-7277 FU Intramural NIH HHS [Z01 AI000783-11] NR 29 TC 53 Z9 55 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD JUN PY 2000 VL 182 IS 12 BP 3394 EP 3399 DI 10.1128/JB.182.12.3394-3399.2000 PG 6 WC Microbiology SC Microbiology GA 318WM UT WOS:000087307700011 PM 10852869 ER PT J AU Hartsough, MT Steeg, PS AF Hartsough, MT Steeg, PS TI Nm23/nucleoside diphosphate kinase in human cancers SO JOURNAL OF BIOENERGETICS AND BIOMEMBRANES LA English DT Article DE NDP kinase; Nm23; loss of heterozygosity; metastasis suppressor; NME genes ID HUMAN BREAST-CANCER; NM23 GENE-PRODUCT; SQUAMOUS-CELL CARCINOMA; HUMAN HEPATOCELLULAR-CARCINOMA; NERVE GROWTH-FACTOR; PROTEIN EXPRESSION; OVARIAN-CANCER; IMMUNOHISTOCHEMICAL ANALYSIS; MESSENGER-RNA; ADENOCARCINOMA CELLS AB Tumor metastasis is the leading cause of death in cancer patients. From a series of tumor cohort studies, low expression of Nm23/NDP kinase has been correlated with poor patient prognosis and survival, lymph node infiltration, and histopathological indicators of high metastatic potential in a number of cancer types, including mammary and ovarian carcinomas and melanoma. In other tumor types, no correlation has been established. Transfection of Nm23/NDP kinase cDNA into highly metastatic breast, melanoma, prostrate and squamous cell carcinomas, and colon adenocarcinoma cells significantly reduced the metastatic competency of the cells in vivo. In culture, cell motility, invasion, and colonization were inhibited, whereas tumorigenicity and cellular proliferation were not affected, indicating that Nm23/NDP kinase acts as a metastasis suppressor. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Hartsough, MT (reprint author), NCI, Pathol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 81 TC 147 Z9 157 U1 1 U2 2 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0145-479X J9 J BIOENERG BIOMEMBR JI J. Bioenerg. Biomembr. PD JUN PY 2000 VL 32 IS 3 BP 301 EP 308 DI 10.1023/A:1005597231776 PG 8 WC Biophysics; Cell Biology SC Biophysics; Cell Biology GA 354QA UT WOS:000089340100011 PM 11768314 ER PT J AU McMahon, JB Beutler, JA O'Keefe, BR Goodrum, CBB Myers, MA Boyd, MR AF McMahon, JB Beutler, JA O'Keefe, BR Goodrum, CBB Myers, MA Boyd, MR TI Development of a Cyanovirin-N-HIV-1 gp120 binding assay for high throughput screening of natural product extracts by time-resolved fluorescence SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article ID VIRUS-INACTIVATING PROTEIN; HOLSTII NRRL Y-2448; EXTRACELLULAR POLYSACCHARIDE; BIOLOGICAL-ACTIVITY; HIV VACCINES; CD4 BINDING; CYANOBACTERIUM; TECHNOLOGIES; FERMENTATION; INHIBITORS AB The unique, high-affinity binding of cyanovirin-N (CV-N), a potent anti-human immunodeficiency virus (HIV) protein, to the HIV envelope glycoprotein gp120, was exploited to develop an HTS assay in an attempt to discover small-molecule mimetics of CV-N. A competition binding assay was developed using CV-N labeled with europium (Eu3+). The labeling protocol did not significantly alter the gp120 binding properties or the antiviral activity of CV-N. This report describes the assay development, validation, and results of screening a large library of aqueous and organic natural product extracts. The extracts were incubated with immobilized recombinant gp120 in 96-well plates prior to the addition of Eu3+-labeled CV-N. Following a wash step, bound CV-N was measured by dissociation-enhanced time-resolved fluorometry of Eu3+. The assay proved to be robust, rapid, and reproducible, and was used to screen over 50,000 natural product extracts, and has resulted in the identification of several aqueous natural product extracts that inhibited CV-N-gp120 binding and also had anti-HIV activity. C1 NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program,Div Canc Treatment & Diag, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. RP Boyd, MR (reprint author), NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program,Div Canc Treatment & Diag, Frederick Canc Res & Dev Ctr, Bldg 1052,Room 121, Frederick, MD 21702 USA. RI Beutler, John/B-1141-2009 OI Beutler, John/0000-0002-4646-1924 NR 38 TC 12 Z9 12 U1 2 U2 8 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1087-0571 J9 J BIOMOL SCREEN JI J. Biomol. Screen PD JUN PY 2000 VL 5 IS 3 BP 169 EP 176 DI 10.1177/108705710000500309 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA 329QT UT WOS:000087919800008 PM 10894760 ER PT J AU Bertram, R Sherman, A AF Bertram, R Sherman, A TI Dynamical complexity and temporal plasticity in pancreatic beta-cells SO JOURNAL OF BIOSCIENCES LA English DT Review DE bursting; coupled oscillators; mathematical model ID BURSTING ELECTRICAL-ACTIVITY; CYTOPLASMIC FREE CA2+; 2 CALCIUM CURRENTS; B-CELLS; (I) OSCILLATIONS; INSULIN-SECRETION; COUPLED BURSTERS; EXCITABLE CELL; ISLET CELLS; GLUCOSE AB We discuss some of the biological and mathematical issues involved in understanding and modelling the bursting electrical activity in pancreatic beta-cells. These issues include single-cell versus islet behaviour, parameter heterogeneity, channel noise, the effects of hormones, neurotransmitters, and ions, and multiple slow biophysical processes. Some of the key experimental and modelling studies are described, and some of the major open questions are discussed. C1 Florida State Univ, Inst Mol Biophys, Tallahassee, FL 32306 USA. NIDDKD, Mathat Res Branch, NIH, Bethesda, MD 20892 USA. RP Bertram, R (reprint author), Florida State Univ, Inst Mol Biophys, Tallahassee, FL 32306 USA. NR 59 TC 23 Z9 25 U1 0 U2 2 PU INDIAN ACADEMY SCIENCES PI BANGALORE PA P B 8005 C V RAMAN AVENUE, BANGALORE 560 080, INDIA SN 0250-5991 J9 J BIOSCIENCE JI J. Biosci. PD JUN PY 2000 VL 25 IS 2 BP 197 EP 209 PG 13 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 325JT UT WOS:000087673000011 PM 10878861 ER PT J AU Merrill, RM Hankey, BE AF Merrill, RM Hankey, BE TI Monitoring progress against cancer with age-adjusted rates and trends: What role does the standard population play? SO JOURNAL OF CANCER EDUCATION LA English DT Article ID MORTALITY AB Background. Age-adjusted rates and statistical measures used to assess these rates are commonly used in cancer research to monitor progress against this disease. Trends in age-adjusted rates and related summary statistics may depend on the standard population used for age adjustment. Hence, knowledge of how the selected standard population influences such rates is essential for analysis and interpretation of the results. Methods. The current paper evaluates age-specific and age adjusted trends for the three leading causes of cancer mortality in the United States: lung and prostate cancers for males, and lung and breast cancers for females. Results, Conclusions. The analysis shows that the choice of the standard population for age adjustment of the rates can influence one's perception of the progress being made against cancer. C1 Brigham Young Univ, Dept Hlth Sci, Provo, UT 84602 USA. Univ Utah, Coll Med, Dept Family & Prevent Med, Div Epidemiol, Salt Lake City, UT USA. NCI, Div Canc Control & Populat Sci, Canc Stat Branch, Canc Control Res Program, Bethesda, MD USA. RP Merrill, RM (reprint author), Brigham Young Univ, Dept Hlth Sci, 213 Richards Bldg, Provo, UT 84602 USA. NR 17 TC 0 Z9 0 U1 0 U2 0 PU HANLEY & BELFUS INC PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA SN 0885-8195 J9 J CANCER EDUC JI J. Cancer Educ. PD SUM PY 2000 VL 15 IS 2 BP 99 EP 107 PG 9 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 343AX UT WOS:000088680500010 PM 10879900 ER PT J AU MacGowan, GA Koretsky, AP AF MacGowan, GA Koretsky, AP TI Inotropic and energetic effects of altering the force-calcium relationship: Mechanisms, experimental results, and potential molecular targets SO JOURNAL OF CARDIAC FAILURE LA English DT Review DE inotropy; energetics; calcium ID PROTEIN-KINASE-C; BRIDGE TURNOVER KINETICS; FAILING HUMAN MYOCARDIUM; CANINE LEFT-VENTRICLE; TROPONIN-I; HEART-FAILURE; DILATED CARDIOMYOPATHY; OXYGEN-CONSUMPTION; CARDIAC MYOCYTES; 2,3-BUTANEDIONE MONOXIME AB Conventional positive inotropy with beta-adrenergic agonists or phosphodiesterase inhibitors increases the amplitude of the calcium transient and is associated with increases in myocardial oxygen consumption that may not be desirable when used in heart failure. Alternatively, agents that increase the sensitivity of the contractile apparatus without increasing the amplitude of the calcium transient have been shown to increase contractility without increasing energy consumption. Also, agents that result in negative inotropy while maintaining the amplitude of the calcium transient result in more energy-inefficient negative inotropy in comparison with agents that cause negative inotropy though a decrease in the amplitude of the calcium transient. These experiments suggest that calcium handling is responsible for a large proportion of the total energy expenditure associated with changes in inotropy. Problems that remain with the use of calcium-sensitizing agents include uncertainty regarding the site of action, adverse effects on systemic and coronary vasculature and diastolic function, and concomitant phosphodiesterase-inhibiting activity. One alternative is to use genetically engineered mouse models in which specific mutations selective to the myocyte can he produced. Potential molecular targets include the protein kinase A and C phosphorylation sites on troponin I, which, when phosphorylated, mediate a reduction in calcium sensitivity and a reduction in maximal actomyosin adenosinebriphosphatase activity, respectively. Mutations at these sites, by altering the relationship between force and calcium, may provide significant insights into the molecular mechanisms controlling the energetics of positive inotropy. C1 Univ Pittsburgh, Med Ctr, Cardiovasc Inst, Pittsburgh, PA 15213 USA. Pittsburgh Nucl Magnet Resonance Inst Biomed Res, Pittsburg, PA USA. Carnegie Mellon Univ, Dept Biol Sci, Pittsburg, PA USA. NINDS, Lab Funct & Mol Imaging, Bethesda, MD 20892 USA. RP MacGowan, GA (reprint author), Univ Pittsburgh, Med Ctr, Cardiovasc Inst, 200 Lothrop St,S550 Scaife Hall, Pittsburgh, PA 15213 USA. RI Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU NCRR NIH HHS [RR-03631]; NHLBI NIH HHS [HL-03826, HL-40354] NR 70 TC 10 Z9 10 U1 0 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD JUN PY 2000 VL 6 IS 2 BP 144 EP 156 DI 10.1054/jcaf.2000.7863 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 331TA UT WOS:000088033700012 PM 10908089 ER PT J AU Misteli, T AF Misteli, T TI Cell biology of transcription and pre-mRNA splicing: nuclear architecture meets nuclear function SO JOURNAL OF CELL SCIENCE LA English DT Review DE pre-mRNA splicing; transcription; nuclear architecture; phosphorylation ID RNA-POLYMERASE-II; CARBOXY-TERMINAL DOMAIN; CHINESE-HAMSTER CELLS; DISEASE GENE-PRODUCT; MESSENGER-RNA; IN-VIVO; SR PROTEINS; COILED BODIES; SITE SELECTION; CENTROMERIC HETEROCHROMATIN AB Gene expression is a fundamental cellular process. The basic mechanisms involved in expression of genes have been characterized at the molecular level, A major challenge is now to uncover how transcription, RNA processing and RNA export are organized within the cell nucleus, how these processes are coordinated with each other and how nuclear architecture influences gene expression and regulation. A significant contribution has come from cell biological approaches, which combine molecular techniques with microscopy methods, These studies have revealed that the mammalian cell nucleus is a complex but highly organized organelle, which contains numerous subcompartments. I discuss here how two essential nuclear processes - transcription and pre-mRNA splicing - are spatially organized and coordinated in vivo, and how this organization might contribute to the control of gene expression. The dynamic nature of nuclear proteins and compartments indicates a high degree of plasticity in the cellular organization of nuclear functions, The cellular organization of transcription and splicing suggest that the morphology of nuclear compartments is largely determined by the activities of the nucleus. C1 NCI, NIH, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, NIH, 41 Lib Dr, Bethesda, MD 20892 USA. NR 125 TC 167 Z9 171 U1 1 U2 11 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 PY 2000 VL 113 IS 11 BP 1841 EP 1849 PG 9 WC Cell Biology SC Cell Biology GA 326KM UT WOS:000087734700001 PM 10806095 ER PT J AU Litman, T Brangi, M Hudson, E Fetsch, P Abati, A Ross, DD Miyake, K Resau, JH Bates, SE AF Litman, T Brangi, M Hudson, E Fetsch, P Abati, A Ross, DD Miyake, K Resau, JH Bates, SE TI The multidrug-resistant phenotype associated with overexpression of the new ABC half-transporter, MXR (ABCG2) SO JOURNAL OF CELL SCIENCE LA English DT Article DE atypical multidrug resistance; mitoxantrone; MXR; ABC half-transporter; confocal microscopy; cancer ID CARCINOMA CELL-LINE; BREAST-CANCER CELLS; DECREASED DRUG ACCUMULATION; COLON ADENOCARCINOMA CELLS; ORGANIC ANION TRANSPORTER; GLUTATHIONE S-CONJUGATE; P-GLYCOPROTEIN; PROTEIN MRP; MITOXANTRONE; GENE AB Mechanisms of drug resistance other than P-glycoprotein are of increasing interest as the list of newly identified members of the ABC transport family has grown, We sought to characterize the phenotype of the newly discovered ABC transporter encoded by the mitoxantrone resistance gene, MXR, also known as ABCP1 or BCRP, The pharmacodynamics of mitoxantrone and 12 other fluorescent drugs were evaluated by confocal microscopy in four multidrug-resistant human colon (S1) and breast (MCF-7) cancer cell lines, We utilized two sublines, MCF-7 AdVp3000 and S1-M1-80, and detected overexpression of MXR by PCR, immunoblot assay and immunohistochemistry. These MXR overexpressing sublines were compared to cell lines with P-glycoprotein and MRP-mediated resistance. High levels of cross-resistance were observed for mitoxantrone, the anthracyclines, bisantrene and topotecan. Reduced levels of mitoxantrone, daunorubicin, bisantrene, topotecan, rhodamine 123 and prazosin were observed in the two sublines with high MXR expression, Neither the P-glycoprotein substrates vinblastine, paclitaxel, verapamil and calcein-AM, nor the MRP substrate calcein, were extruded from MCF-7 AdVp3000 and S1-M1-80 cells, Thus, the multidrug-resistant phenotype due to MXR expression is overlapping with, but distinct from, that due to P-glycoprotein. Further, cells that overexpress the MXR protein seem to be more resistant to mitoxantrone and topotecan than cells with P-glyeoprotein-mediated multidrug resistance, Our studies suggest that the ABC half-transporter, MXR, is a potent, new mechanism for conferring multiple drug resistance, Definition of its mechanism of transport and its role in clinical oncology is required. C1 NCI, Med Branch, NIH, Bethesda, MD 20892 USA. Univ Maryland, Baltimore, MD 21201 USA. RP Bates, SE (reprint author), NCI, Med Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 59 TC 376 Z9 397 U1 3 U2 17 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 PY 2000 VL 113 IS 11 BP 2011 EP 2021 PG 11 WC Cell Biology SC Cell Biology GA 326KM UT WOS:000087734700018 PM 10806112 ER PT J AU Satomura, K Krebsbach, P Bianco, P Robey, PG AF Satomura, K Krebsbach, P Bianco, P Robey, PG TI Osteogenic imprinting upstream of marrow stromal cell differentiation SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE bone marrow stromal cell; differentiation; phenotype; osteoblast; chondroblast; adipocyte ID HUMAN BONE-MARROW; MESENCHYMAL PROGENITOR CELLS; DIFFUSION CHAMBER METHOD; IN-VIVO; OSTEOBLAST DIFFERENTIATION; PRECURSOR CELLS; STEM-CELLS; FIBROBLASTIC CELLS; ADULT-RATS; INVITRO AB Five spontaneously transformed cell lines were established from a population of murine bone marrow stromal cells (BMSCs) and the expression profiles of phenotype-characteristic genes, patterns of in vitro differentiation, and osteogenic capacity after in vivo transplantation were determined for each. All the clones expressed stable levels of cbfa1, the osteogenic "master" gene, whereas the levels of individual phenotypic mRNAs were variable within each, suggestive of both maturational and phenotypic plasticity in vitro. Varying levels of collagen type I and alkaline phosphatase (AP) were expressed in all the clonal lines. The clonal lines with proven in vivo osteogenic potential (3 out of 5) had a high proliferation rate and expressed bone sialoprotein (BSP), whereas the two nonosteogenic clones proliferated more slowly and never expressed BSP. Bone nodules were only observed in 2 out of 3 of the osteogenic lines, and only 1 out of three formed cartilage-like matrix in vitro. There was no evidence of chondrogenesis in the nonosteogenic lines. By contrast, LPL was expressed in two osteogenic and in two nonosteogenic lines. These results demonstrate the presence of multipotential and restricted progenitors in the murine stromal system, cbfa1, collagen type I, and AP expression were common to all, and therefore presumably early, basic traits of stromal cell lines that otherwise significantly differ with respect to growth and differentiation potential. This finding suggests that an osteogenic imprinting lies upstream of diversification, modulation, and restriction of stromal cell differentiation potential. Published 2000 Wiley-Liss, Inc. C1 NIDR, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. Univ Michigan, Sch Dent, Dept Oral Med Pathol Surg, Ann Arbor, MI USA. Univ Aquila, Dipartimento Med Sperimentale, I-67100 Laquila, Italy. RP Robey, PG (reprint author), Bldg 30,Room 228,30 Convent Dr,MSC-4320, Bethesda, MD 20892 USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU Telethon [E.1029] NR 51 TC 97 Z9 107 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 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD JUN PY 2000 VL 78 IS 3 BP 391 EP 403 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 336GJ UT WOS:000088293300005 PM 10861838 ER PT J AU Watabe, H Channing, MA Der, MG Adams, HR Jagoda, E Herscovitch, P Eckelman, WC Carson, RE AF Watabe, H Channing, MA Der, MG Adams, HR Jagoda, E Herscovitch, P Eckelman, WC Carson, RE TI Kinetic analysis of the 5-HT(2A) ligand [(11)C]MDL 100,907 SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE 5-HT(2A) receptors; modeling; positron emission tomography; serotonin ID POSITRON EMISSION TOMOGRAPHY; SEROTONIN RECEPTORS; HUMAN-BRAIN; F-18 ALTANSERIN; PET; RADIOLIGAND; BINDING; SETOPERONE; INVIVO; SYSTEM AB The goal of this study was to develop a suitable kinetic analysis method for quantification of 5-HT(2A) receptor parameters with [(11)C]MDL 100,907. Twelve control studies and foul preblocking studies (400 nmol/kg unlabeled MDL 100,907) were performed in isoflurane-anesthetized rhesus monkeys. The plasma input function was determined from arterial blood samples with metabolite measurements by extraction in ethyl acetate. The preblocking studies showed that a two-tissue compartment model was necessary to fit the time activity curves of all brain regions including the cerebellum-in other words, the need fur two compartments is not proof of specific binding. Therefore, a three-tissue compartment model was used to analyze the control studies, with three parameters fixed based on the preblocking data. Reliable fits of control data could be obtained only if no more than three parameters were allowed to vary. For routine use of [(11)C]MDL 100,907, several simplified methods were evaluated. A two-tissue (2T') compartment with one fixed parameter was the most reliable compartmental approach: a one-compartment model failed to fit the data adequately. The Logan graphical approach was also tested and produced comparable results to the 2T' model. However, a simulation study showed that Logan analysis produced a larger bias at higher noise levels. Thus, the 2T' model is the best choice for analysis of [(11)C]MDL 100,907 studies. C1 NIH, PET Dept, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Carson, RE (reprint author), NIH, PET Dept, Warren G Magnuson Clin Ctr, Bldg 10,Room 1C-401,10 Ctr Dr,MSC 1180, Bethesda, MD 20892 USA. RI Carson, Richard/H-3250-2011 OI Carson, Richard/0000-0002-9338-7966 NR 35 TC 58 Z9 58 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUN PY 2000 VL 20 IS 6 BP 899 EP 909 PG 11 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 320XL UT WOS:000087426100002 PM 10894173 ER PT J AU Kohanoff, J Koval, S Estrin, DA Laria, D Abashkin, Y AF Kohanoff, J Koval, S Estrin, DA Laria, D Abashkin, Y TI Concertedness and solvent effects in multiple proton transfer reactions: The formic acid dimer in solution SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; BARRIER HYDROGEN-BONDS; LIQUID WATER; HYBRID QUANTUM; ENERGY; CLUSTERS; SURFACE; MALONALDEHYDE AB The issue of multiple proton transfer (PT) reactions in solution is addressed by performing molecular dynamics simulations for a formic acid dimer embedded in a water cluster. The reactant species is treated quantum mechanically, within a density functional approach, while the solvent is represented by a classical model. By constraining different distances within the dimer we analyze the PT process in a variety of situations representative of more complex environments. Free energy profiles are presented, and analyzed in terms of typical solvated configurations extracted from the simulations. A decrease in the PT barrier height upon solvation is rationalized in terms of a transition state which is more polarized than the stable states. The dynamics of the double PT process is studied in a low-barrier case and correlated with solvent polarization fluctuations. Cooperative effects in the motion of the two protons are observed in two different situations: when the solvent polarization does not favor the transfer of one of the two protons and when the motion of the two protons is not synchronized. This body of observations is correlated with local structural and dynamical properties of the solvent in the vicinity of the reactant. (C) 2000 American Institute of Physics. [S0021-9606(00)51121-0]. C1 Abdus Salaam Int Ctr Theoret Phys, I-34014 Trieste, Italy. Queens Univ Belfast, Atom Simulat Grp, Belfast BT7 1NN, Antrim, North Ireland. Univ Nacl Rosario, Inst Fis Rosario, RA-2000 Rosario, Argentina. Univ Buenos Aires, Fac Ciencias Exactas & Nat, INQUIMAE, RA-1428 Buenos Aires, DF, Argentina. Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Quim Inorgan Analit & Quim Fis, RA-1428 Buenos Aires, DF, Argentina. Comis Nacl Energia Atom, Unidad Actividad Quim, RA-1429 Buenos Aires, DF, Argentina. NCI, Adv Biomed Comp Ctr, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Abdus Salaam Int Ctr Theoret Phys, POB 586, I-34014 Trieste, Italy. EM j.kohanoff@qub.ac.uk RI Kohanoff, Jorge/H-9874-2015; OI Kohanoff, Jorge/0000-0002-8237-7543; Estrin, Dario/0000-0002-5006-7225 NR 40 TC 23 Z9 23 U1 0 U2 4 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD JUN 1 PY 2000 VL 112 IS 21 BP 9498 EP 9508 AR PII [S0021-9606(00)51121-0] DI 10.1063/1.481585 PG 11 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 315YC UT WOS:000087139700035 ER PT J AU Bornstein, MH Haynes, OM Painter, KM Genevro, JL AF Bornstein, MH Haynes, OM Painter, KM Genevro, JL TI Child language with mother and with stranger at home and in the laboratory: a methodological study SO JOURNAL OF CHILD LANGUAGE LA English DT Article ID UTTERANCE LENGTH; AGE; VALIDITY; SPEECH; PLAY AB This methodological study in 33 two-year-olds shows that child speech (total utterances, word roots, MLU) occurs at about the same level in different settings (the familiar home vs. the unfamiliar laboratory), but that children speak more and in more differentiated ways with different people (mother vs, stranger). Child speech also shows significant shortterm stability. Girls use more different word roots and speak in longer utterances than do boys. In spontaneous child speech, cross-context generalizations appear warranted, but they also depend on conversational partner and gender of child. C1 NICHHD, Bethesda, MD 20892 USA. RP Bornstein, MH (reprint author), NICHHD, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM Marc_H_Bornstein@nih.gov NR 36 TC 34 Z9 34 U1 1 U2 10 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0305-0009 J9 J CHILD LANG JI J. Child Lang. PD JUN PY 2000 VL 27 IS 2 BP 407 EP 420 DI 10.1017/S0305000900004165 PG 14 WC Psychology, Developmental; Linguistics; Psychology, Experimental SC Psychology; Linguistics GA 335VK UT WOS:000088265300009 PM 10967894 ER PT J AU Bosek, V AF Bosek, V TI Myths in anesthesiology SO JOURNAL OF CLINICAL ANESTHESIA LA English DT Editorial Material C1 Univ S Florida, Coll Med, Dept Anesthesiol, H Lee Moffitt Canc Ctr & Res Inst,NCI, Tampa, FL 33612 USA. RP Bosek, V (reprint author), Univ S Florida, Coll Med, Dept Anesthesiol, H Lee Moffitt Canc Ctr & Res Inst,NCI, 12901 Bruce B Downs Blvd, Tampa, FL 33612 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0952-8180 J9 J CLIN ANESTH JI J. Clin. Anesth. PD JUN PY 2000 VL 12 IS 4 BP 263 EP 264 DI 10.1016/S0952-8180(00)00157-4 PG 2 WC Anesthesiology SC Anesthesiology GA 345QZ UT WOS:000088827800001 PM 10960195 ER PT J AU Akamizu, T Kohn, LD Hiratani, H Saijo, M Tahara, K Nakao, K AF Akamizu, T Kohn, LD Hiratani, H Saijo, M Tahara, K Nakao, K TI Hashimoto's thyroiditis with heterogeneous antithyrotropin receptor antibodies: Unique epitopes may contribute to the regulation of thyroid function by the antibodies SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID HUMAN THYROTROPIN RECEPTOR; GRAVES-DISEASE; TSH RECEPTOR; STIMULATING ANTIBODY; PRIMARY MYXEDEMA; IGG ANTIBODIES; AUTOANTIBODIES; IMMUNOGLOBULINS; LYMPHOCYTES; EXPRESSION AB Blocking-type TSH-binding inhibitor Igs (TBIIs) are known to cause hypothyroidism and an atrophic thyroid gland in patients with primary myxedema. They can block the activity of thyroid-stimulating antibodies (TSAbs) in Graves' patients as well as the activity of TSH. The majority of the epitopes for these blocking-type TBIIs have been, and are shown herein, to be present on the C-terminal region of the extracellular domain of the human TSH receptor (TSHR), whereas those for Graves' TSAbs are on the N-terminus. We report on a patient with Hashimoto's thyroiditis who suffered from mild hypothyroidism and a moderately sized goiter. Her serum had a potent blocking-type TBII and a weak TSAb in human and porcine TSHR systems. Using human TSHR/lutropin-CG receptor chimeras, we determined that the functional epitope of her blocking-type TBII was uniquely present on the N-terminal, rather than the C-terminal, region of the extracellular domain of the TSHR, unlike the case for blocking-type TBIIs in primary myxedema patients. The epitope of her TSAb was also unusual. Although the functional epitopes of most TSAbs are known to involve the N-terminal region of the receptor, her TSAb epitope did not seem to be present solely on the N- or C-terminus of the extracellular domain of the receptor. Blocking-type TBIIs from patients with primary myxedema blocked her TSAb activity as well as stimulation by TSH; her blocking-type TBII was able to only partially block her TSAb. In contrast, her blocking-type TBII almost completely blocked TSAbs from Graves' patients. Thus, we suggest that the unique epitopes of this patient's heterogeneous population of TSH receptor antibodies, at least in part, contribute to regulation of her thyroid function. C1 Kyoto Univ, Sch Med, Dept Med & Clin Sci, Sakyo Ku, Kyoto 6068507, Japan. NIDDKD, Cell Regulat Sect, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Akamizu, T (reprint author), Kyoto Univ, Sch Med, Dept Med & Clin Sci, Sakyo Ku, 54 Shogoin Kawaharacho, Kyoto 6068507, Japan. EM akataka@kuhp.kyoto-u.ac.jp NR 23 TC 13 Z9 14 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2000 VL 85 IS 6 BP 2116 EP 2121 DI 10.1210/jc.85.6.2116 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 339CR UT WOS:000088460500009 PM 10852437 ER PT J AU de Beur, SMJ Ding, CL Labuda, MC Usdin, TB Levine, MA AF de Beur, SMJ Ding, CL Labuda, MC Usdin, TB Levine, MA TI Pseudohypoparathyroidism 1b: Exclusion of parathyroid hormone and its receptors as candidate disease genes SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ALBRIGHT HEREDITARY OSTEODYSTROPHY; NUCLEOTIDE REGULATORY PROTEIN; STIMULATORY G-PROTEIN; LINKAGE ANALYSIS; ALPHA-SUBUNIT; IB PSEUDOHYPOPARATHYROIDISM; BLOMSTRAND CHONDRODYSPLASIA; SKELETAL RESPONSIVENESS; INACTIVATING MUTATION; DEOXYRIBONUCLEIC-ACID AB Pseudohypoparathyroidism 1b (PHP 1b) is characterized by specific resistance of target tissues to PTH, but no mutations in the PTH/PTH-related peptide (PTHrP) receptor gene have been identified. To investigate the basis for defective PTH signaling, we used polymorphic markers in or near the genes encoding PTH and its receptors to perform linkage analysis between these loci and PHP 1b. Two multiplex PHP 1b families (families M and K) were informative for an intragenic polymorphism in exon 13 of the PTH/PTHrP receptor gene detected by PCR amplification and resolved by denaturing gradient gel electrophoresis. Linkage analysis revealed discordance of the PTH/PTHrP receptor with PHP1b. One PHP 1b kindred (family M) was informative for a intragenic polymorphism in exon 3 of the PTH gene detected by PCR amplification and resolved by denaturing gradient gel electrophoresis. The PTH gene polymorphism segregation was discordant with PHP 1b. Probands from each family had normal PTH genes by direct sequence analysis. In three PHP 1b kindreds, we analyzed simple sequence polymorphisms in three microsatellite markers flanking the PTH type 2 receptor locus located at 2q33. Linkage analysis demonstrated no linkage. In conclusion, neither the PTH gene nor the PTH receptor genes (type 1 and 2) are linked to PHP 1b. C1 Johns Hopkins Univ, Sch Med, Div Endocrinol & Metab, Dept Med, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21287 USA. NIMH, NIH, Bethesda, MD 20892 USA. RP de Beur, SMJ (reprint author), Johns Hopkins Univ, Sch Med, Div Endocrinol & Metab, Dept Med, 1830 E Monument St,Suite 333, Baltimore, MD 21287 USA. OI Levine, Michael/0000-0003-0036-7809 NR 51 TC 16 Z9 16 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2000 VL 85 IS 6 BP 2239 EP 2246 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 339CR UT WOS:000088460500029 ER PT J AU Robey, PG AF Robey, PG TI Stem cells near the century mark SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material C1 Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. RP Robey, PG (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bldg 30,Room 228,30 Convent Dr MSC 4320, Bethesda, MD 20892 USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 17 TC 57 Z9 57 U1 0 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN PY 2000 VL 105 IS 11 BP 1489 EP 1491 DI 10.1172/JCI10256 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 322WJ UT WOS:000087532000001 PM 10841501 ER PT J AU Yamada, KM AF Yamada, KM TI Fibronectin peptides in cell migration and wound repair SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID MURINE MELANOMA-CELLS; EXPERIMENTAL METASTASIS; SIGNAL-TRANSDUCTION; SYNTHETIC PEPTIDES; ADHESIVE FUNCTION; INTEGRINS; BETA-1; SITES C1 Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. RP Yamada, KM (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bldg 30,Room 421,30 Convent Dr MSC 4370, Bethesda, MD 20892 USA. OI Yamada, Kenneth/0000-0003-1512-6805 NR 18 TC 47 Z9 49 U1 1 U2 2 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN PY 2000 VL 105 IS 11 BP 1507 EP 1509 DI 10.1172/JCI10119 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 322WJ UT WOS:000087532000006 PM 10841505 ER PT J AU Murphy, PM AF Murphy, PM TI Viral antichemokines: from pathogenesis to drug discovery SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID SERINE PROTEINASE-INHIBITOR; CHEMOKINES; RECEPTOR; HOMOLOG; ATHEROSCLEROSIS; INFECTION; RABBITS; MICE; M-T7 C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Murphy, PM (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Room 11N113, Bethesda, MD 20892 USA. NR 22 TC 20 Z9 20 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN PY 2000 VL 105 IS 11 BP 1515 EP 1517 DI 10.1172/JCI10211 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 322WJ UT WOS:000087532000008 PM 10841507 ER PT J AU Abe, A Gregory, S Lee, L Killen, PD Brady, RO Kulkarni, A Shayman, JA AF Abe, A Gregory, S Lee, L Killen, PD Brady, RO Kulkarni, A Shayman, JA TI Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivation SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID GLUCOSYLCERAMIDE SYNTHASE; N-BUTYLDEOXYNOJIRIMYCIN; GLYCOSPHINGOLIPID DEPLETION; ALPHA-GALACTOSIDASE; IMPROVED INHIBITORS; CERAMIDE-GLYCANASE; POTENT INHIBITORS; PURIFICATION; METABOLISM; ENZYME AB We used a potent inhibitor of glucosylceramide synthase to test whether substrate deprivation could lower globotriaosylceramide levels in alpha-galactosidase A (alpha-galA) knockout mice, a model of Fabry disease. C57BL/6 mice treated twice daily for 3 days with D-threo- 1-ethylendioxyphenyl-2-palmitoylamino-3-pyrrolidino-propanol (D-t-EtDO-P4) showed a concentration-dependent decrement in glucpsylceramide levels in kidney, liver, and spleen. A single intraperitoneal injection of D-t-EtDO-P4 resulted in a 55% reduction in renal glucosylceramide, consistent with rapid renal glucosylceramide metabolism. A concentration-dependent decrement in renal and hepatic globotriaosylceramide levels was observed in alpha-GalA(-) males treated for 4 weeks with D-t-EtDO-P4. When S-week-old alpha-Gal A(-) males were treated for 8 weeks with 10 mg/kg twice daily, renal globotriaosylceramide fell to below starting levels, consistent with an a-galactosidase A-independent salvage pathway for globotriaosylceramide degradation. Complications observed with another glucosylceramide synthase inhibitor, N-butyldeoxynojirimycin, including weight loss and acellularity of lymphatic organs, were not observed with D-t-EtDO-P4. These data suggest that Fabry disease may be amenable to substrate deprivation therapy. C1 Univ Michigan, Dept Internal Med, Div Nephrol, Med Ctr, Ann Arbor, MI 48109 USA. Univ Michigan, Med Ctr, Dept Pathol, Ann Arbor, MI 48109 USA. NINDS, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Shayman, JA (reprint author), Univ Michigan, Dept Internal Med, Div Nephrol, Med Ctr, Box 0676,Room 1560 MSRBII,1150 W Med Ctr Dr, Ann Arbor, MI 48109 USA. FU NIDDK NIH HHS [R01 DK41487]; PHS HHS [R0139255] NR 29 TC 102 Z9 106 U1 0 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN PY 2000 VL 105 IS 11 BP 1563 EP 1571 DI 10.1172/JCI9711 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 322WJ UT WOS:000087532000016 PM 10841515 ER PT J AU Bianco, P Robey, PG AF Bianco, P Robey, PG TI Marrow stromal stem cells SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID HUMAN-BONE-MARROW; IN-VITRO; PROGENITOR CELLS; TRANSPLANTATION; MICE; DIFFERENTIATION; FIBROBLASTS; PRECURSORS; EXPRESSION; VIVO C1 Univ Aquila, Dipartimento Med Sperimentale, I-67100 Laquila, Italy. Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. RP Bianco, P (reprint author), Univ Aquila, Dipartimento Med Sperimentale, Via Vetoio Coppito 2, I-67100 Laquila, Italy. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU Telethon [E.1029] NR 28 TC 410 Z9 462 U1 0 U2 11 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN PY 2000 VL 105 IS 12 BP 1663 EP 1668 DI 10.1172/JCI10413 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 326VJ UT WOS:000087757400001 PM 10862779 ER PT J AU Fuchimoto, Y Huang, CA Yamada, K Shimizu, A Kitamura, H Colvin, RB Ferrara, V Murphy, MC Sykes, M White-Scharf, M Neville, DM Sachs, DH AF Fuchimoto, Y Huang, CA Yamada, K Shimizu, A Kitamura, H Colvin, RB Ferrara, V Murphy, MC Sykes, M White-Scharf, M Neville, DM Sachs, DH TI Mixed chimerism and tolerance without whole body irradiation in a large animal model SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID BONE-MARROW TRANSPLANTATION; MAJOR HISTOCOMPATIBILITY COMPLEX; IDENTICAL LITTERMATE DOGS; CLASS-I-DISPARATE; T-CELL DEPLETION; MINIATURE SWINE; RENAL-ALLOGRAFTS; MONOCLONAL-ANTIBODIES; PHARMACOLOGICAL IMMUNOSUPPRESSION; HEMATOPOIETIC CHIMERISM AB Mixed hematopoietic chimerism may provide a treatment for patients with nonmalignant hematologic diseases, and may tolerize patients to organ allografts without requiring chronic immunosuppression. However, the toxicity of the usual conditioning regimens has limited the clinical applicability of this approach. These regimens generally include some level of whole body irradiation (WBI), which is thought to facilitate engraftment either by making room for donor hematopoietic stem cells or by providing sufficient host immunosuppression to enable donor cells to engraft. Here, we have established mixed chimerism across both minor and major histocompatibility barriers in swine, by using high doses of peripheral blood stem cells in the absence of WBI. After mixed chimerism was established, swine leukocyte antigen-matched (SLA-matched) donor skin grafts were tolerated and maintained for a prolonged period, whereas third-party SLA-matched skin was rejected promptly. Donor-matched kidney allografts were also accepted without additional immunosuppression. Because of its low toxicity, this approach has potential for a wide range of clinical applications. Our data may indicate that niches for engrafting stem cells are filled by mass action and that WBI, which serves to empty some of these niches, can be omitted if the donor inoculum is sufficiently large and if adequate host T-cell depletion is achieved before transplant. C1 Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. BioTransplant Inc, Boston, MA USA. NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Sachs, DH (reprint author), Massachusetts Gen Hosp, Transplantat Biol Res Ctr, MGH East,Bldg 149-9019,13th St, Boston, MA 02129 USA. FU NHLBI NIH HHS [2PO1 HL-18646, P01 HL018646]; NIAID NIH HHS [5RO1 AI-39755, P01 AI039755] NR 57 TC 142 Z9 145 U1 0 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN PY 2000 VL 105 IS 12 BP 1779 EP 1789 DI 10.1172/JCI8721 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 326VJ UT WOS:000087757400015 PM 10862793 ER PT J AU Fiscus, SA Brambilla, D Coombs, RW Yen-Lieberman, B Bremer, J Kovacs, A Rasheed, S Vahey, M Schutzbank, T Reichelderfer, PS AF Fiscus, SA Brambilla, D Coombs, RW Yen-Lieberman, B Bremer, J Kovacs, A Rasheed, S Vahey, M Schutzbank, T Reichelderfer, PS CA AIDS Clin Trials Grp Genital Secre TI Multicenter evaluation of methods to quantitate human immunodeficiency virus type 1 RNA in seminal plasma SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID POLYMERASE CHAIN-REACTION; SEROPOSITIVE MEN; DISEASE STAGE; HIV-1 RNA; SEMEN; INFECTION; THERAPY; AMPLIFICATION; CULTURE; LOAD AB We have evaluated two commercially available kits (AMPLICOR MONITOR [Roche] and NASBA HIV-1 QT or NucliSens HIV-1 QT [Organon Teknika]) and two noncommercial methods for the accurate quantitation of human immunodeficiency virus type 1 (HIV-1) RNA in seminal plasma. The same panels of coded specimens were tested on four separate occasions. Laboratories using the commercial assays employed silica beads to isolate HIV-1 RNA, which removed inhibitory factors sometimes found in seminal plasma. Sensitivities and specificities, respectively, for each assay were as follows: AMPLICOR MONITOR 100 and 73%; NASBA HIV-1 QT, 84 and 100%; NucliSens HIV-1 QT, 99 and 98%; and noncommercial assays, 91 and 73%. When results from the laboratory that was inexperienced with the silica bead extraction method were excluded from the analysis, specificity for the Roche assay increased to 100%. The commercial assays demonstrated highly reproducible results, with intra-assay standard deviations (measured in log,, RNA copies/milliliter of seminal plasma) ranging from 0.11 to 0.32; those of the noncommercial assays ranged from 0.12 to 0.75, Differences in mean estimated HIV-1 RNA concentrations were less than or equal to 0.67 lag(10) and were greater at low viral loads. Suspension matrices that used blood plasma or seminal plasma did not make a difference in recovery of HIV-1 RNA, which suggested that blood plasma specimens can be used as external controls for seminal plasma assays. More variation in the HIV-1 RNA viral toads was observed in the seminal plasma values than in the blood plasma values when paired specimens from HIV-1-infected men were tested. Quantitation of HIV-1 RNA in seminal plasma can be reliably accomplished using two commercially available assays, and may be incorporated into the evaluations of HIV-1 seropositive men enrolled in clinical studies. C1 Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. New England Res Inst, Watertown, MA 02472 USA. Univ Washington, Seattle, WA 98104 USA. Cleveland Clin, Cleveland, OH 44195 USA. Rush Presbyterian Hosp, Chicago, IL 60612 USA. Univ So Calif, Los Angeles, CA 90033 USA. Walter Reed Army Hosp, Rockville, MD 20852 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. NICHHD, Bethesda, MD 20892 USA. RP Fiscus, SA (reprint author), Univ N Carolina, Dept Microbiol & Immunol, CB 7140, Chapel Hill, NC 27599 USA. FU NIAID NIH HHS [U01 AI025868, U01 AI027664, AI27757, P01 AI030731, AI-27664, AI-30731, P30 AI027757]; NIDDK NIH HHS [R37 DK049381, R01 DK049381] NR 19 TC 25 Z9 25 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 2000 VL 38 IS 6 BP 2348 EP 2353 PG 6 WC Microbiology SC Microbiology GA 320YR UT WOS:000087428600054 PM 10835001 ER PT J AU Walsh, TJ Gonzalez, CE Piscitelli, S Bacher, JD Peter, J Torres, R Shetti, D Katsov, V Kligys, K Lyman, CA AF Walsh, TJ Gonzalez, CE Piscitelli, S Bacher, JD Peter, J Torres, R Shetti, D Katsov, V Kligys, K Lyman, CA TI Correlation between in vitro and in vivo antifungal activities in experimental fluconazole-resistant oropharyngeal and esophageal candidiasis SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; AMPHOTERICIN-B-RESISTANT; HIV-INFECTED PATIENTS; IN-VITRO; ORAL CAVITIES; TISSUE PENETRATION; ALBICANS; PHARMACOKINETICS; ITRACONAZOLE; AIDS AB Oropharyngeal and esophageal candidiasis (OPEC) is a frequent opportunistic mycosis in immunocompromised patients. Azole-resistant OPEC is a refractory form of this infection occurring particularly in human immunodeficiency virus (HIV)-infected patients. The procedures developed by the Antifungal Subcommittee of the National Committee for Clinical Laboratory Standards (NCCLS) are an important advance in standardization of in vitro antifungal susceptibility methodology. In order to further understand the relationship between NCCLS methodology and antifungal therapeutic response, we studied the potential correlation between in vitro susceptibility to fluconazole and in vivo response in a rabbit model of fluconazole-resistant OPEC MICs of fluconazole were determined by NCCLS methods. Three fluconazole-susceptible (FS) (MIC, less than or equal to 0.125 mu g/ml) and three fluconazole-resistant (FR) (MIC, greater than or equal to 64 mu g/ml) isolates of Candida albicans from prospectively monitored HIV-infected children with OPEC were studied, FR isolates were recovered from children with severe OPEC refractory to fluconazole, and FS isolates were recovered from those with mucosal candidiasis responsive to fluconazole. Fluconazole at 2 mg/kg of body weight/day was administered to infected animals for 7 days. The concentrations of fluconazole in plasma were maintained above the MICs for FS isolates throughout the dosing interval. Fluconazole concentrations in the esophagus were greater than or equal to those in plasma. Rabbits infected with FS isolates and treated with fluconazole had significant reductions in oral mucosal quantitative cultures (P < 0.001) and tissue burden of C, albicans in tongue, soft palate, and esophagus (P < 0.001). In comparison, rabbits infected with FR isolates were unresponsive to fluconazole and had no reduction in oral mucosal quantitative cultures or tissue burden of C. albicans versus untreated controls. We conclude that there is a strong correlation between in vitro fluconazole susceptibility by NCCLS methods and in vivo response to fluconazole therapy of OPEC due to C. albicans. C1 NCI, Pediat Oncol Branch, Immunocompromised Hosp Sect, NIH, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Pharm, Bethesda, MD 20892 USA. NIH, Nation Ctr Res Resources, Vet Resources Program, Bethesda, MD 20892 USA. RP Walsh, TJ (reprint author), NCI, Pediat Oncol Branch, Immunocompromised Hosp Sect, NIH, Bldg 10,Rm 13N-240, Bethesda, MD 20892 USA. NR 28 TC 35 Z9 36 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 2000 VL 38 IS 6 BP 2369 EP 2373 PG 5 WC Microbiology SC Microbiology GA 320YR UT WOS:000087428600058 PM 10835005 ER PT J AU Kimura, H Kido, S Ozaki, T Tanaka, N Ito, Y Williams, RK Morishima, T AF Kimura, H Kido, S Ozaki, T Tanaka, N Ito, Y Williams, RK Morishima, T TI Comparison of quantitations of viral load in varicella and zoster SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID VIRUS-INFECTION; CHILDREN; VIREMIA AB The pathogenesis of varicella and tester and the effects of antiviral treatment were investigated using realtime PCR for varicella-zoster virus (VZV) DNA in skin lesions and peripheral blood. A higher occurrence of viremic VZV DNA was observed in varicella than in tester. Acyclovir treatment resulted in marked suppression of viremia in varicella. C1 Nagoya Univ, Sch Med, Dept Pediat, Showa Ku, Nagoya, Aichi 4668550, Japan. Showa Hosp, Dept Pediat, Aichi, Japan. NIAID, Med Virol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Kimura, H (reprint author), Nagoya Univ, Sch Med, Dept Pediat, Showa Ku, 65 Tsuruma Cho, Nagoya, Aichi 4668550, Japan. RI Kimura, Hiroshi/I-2246-2012 NR 7 TC 37 Z9 38 U1 2 U2 2 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 2000 VL 38 IS 6 BP 2447 EP 2449 PG 3 WC Microbiology SC Microbiology GA 320YR UT WOS:000087428600082 PM 10835029 ER PT J AU Bishop, MR Tarantolo, SR Pavletic, ZS Lynch, JC Morris, ME Zacharias, D Armitage, JO Kessinger, A AF Bishop, MR Tarantolo, SR Pavletic, ZS Lynch, JC Morris, ME Zacharias, D Armitage, JO Kessinger, A TI Filgrastim as an alternative to donor leukocyte infusion for relapse after allogeneic stern-cell transplantation SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BONE-MARROW TRANSPLANTATION; VERSUS-HOST DISEASE; CHRONIC MYELOGENOUS LEUKEMIA; CHRONIC MYELOID-LEUKEMIA; IMMUNOTHERAPY AB Purpose: Donor leukocyte infusion (DLI) effectively treats relapse after allogeneic stem-cell transplantation (alloSCT), but the response may require several months and may be associated with significant toxicity. Filgrastim has also been observed to effectively treat leukemic relapse after alloSCT. A retrospective analysis was performed to determine the effectiveness of filgrastim in treating relapses after alloSCT. Patients and Methods: Fourteen patients with hematologic malignancies were treated with filgrastim at relapse after alloSCT. Filgrastim was given at 5 mcg/kg/d subcutaneously for 21 consecutive days. Response was evaluated at 7 days after completion of filgrastim. Immunosuppressants, if present, were rapidly tapered to complete discontinuation at the time of relapse. Results: Three patients were not assessable for response because additional therapy was necessary before completion of filgrastim. Six patients (43%) achieved a complete response on an intent-to-treat basis. When response was evaluated based on relapse type, three of four cytogenetic relapses, two of three morphologic relapses, and one of four hematologic relapses achieved a complete remission. Two responses were observed in patients who were completely off of any immunosuppression at the time of relapse. Six patients developed chronic graft-versus-host disease. The event-free and overall survival rates for all 14 patients are 43% and 73%, respectively, Conclusion: The use of filgrastim with rapid discontinuation of immunosuppression results in response rates that are similar to results using DLI. Filgrastim could be considered as an alternative or an adjunct to DLI for relapses after alloSCT. J Clin Oncol 18:2269-2272. (C) 2000 by American Society of Clinical Oncology. C1 Univ Nebraska, Med Ctr, Dept Internal Med, Hematol Oncol Sect, Omaha, NE USA. Univ Nebraska, Med Ctr, Dept Prevent & Societal Med, Omaha, NE USA. RP Bishop, MR (reprint author), NCI, Bldg 10,Room 12N226,10 Ctr Dr,MSC 1906, Bethesda, MD 20892 USA. NR 14 TC 18 Z9 20 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN PY 2000 VL 18 IS 11 BP 2269 EP 2272 PG 4 WC Oncology SC Oncology GA 320JQ UT WOS:000087398400011 PM 10829047 ER PT J AU Shields, PG Harris, CC AF Shields, PG Harris, CC TI Cancer risk and low-penetrance susceptibility genes in gene-environment interactions SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID SQUAMOUS-CELL CARCINOMA; FRAGMENT-LENGTH-POLYMORPHISM; GERM-LINE POLYMORPHISMS; TUMOR-SUPPRESSOR GENE; S-TRANSFERASE GENES; DNA ADDUCT LEVELS; FOLLOW-UP CARE; LUNG-CANCER; P53 GENE; MOLECULAR EPIDEMIOLOGY AB Purpose: To provide a concise review for human cancer risk related to low-penetrance genes and their effects on environmental carcinogen exposure. Methods: Citation of relevant and recent references for molecular epidemiology, focusing on lung cancer, ethical issues, and some clinical implications of recent molecular epidemiology studies. Results: Law-penetrance genes contribute to cancer risk by augmenting the effects of carcinogen exposures. These exposures can be measured in the body through molecular dosimetry (ie, the amount of DNA damage), which reflects ct biologically effective dose. The examination of tumors and the mutations within tumor suppressor genes, such as p53, can provide etiologic clues for both exposure and susceptibility. Although many studies have focused on carcinogen metabolism and cancer risk, more recent studies are considering DNA repair, Also, we are learning that behavior, such as tobacco addiction, also may be genetically controlled. Conclusion: Sporadic cancers are caused by gene(n)-environment(n) interactions rather than a dominant effect by a specific gene, environmental exposure, or gene-environment interaction. New paradigms, where we categorize genes as caretaker or gatekeeper genes, will allow for new hypotheses to be tested and will require advanced methods of analysis. The goal of molecular epidemiology is to develop risk assessment models for individuals, but currently the most achievable goal will be population risk assessment and a better understanding of carcinogenesis. J Clin Oncol 18:2309-2315. (C) 2000 by American Society of Clinical Oncology. C1 NCI, Human Carcinogenesis Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Canc Genet & Epidemiol Program, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Div Basic Sci, NIH, Bldg 37,Rm 2C01,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. RI Shields, Peter/I-1644-2012 NR 65 TC 197 Z9 200 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN PY 2000 VL 18 IS 11 BP 2309 EP 2315 PG 7 WC Oncology SC Oncology GA 320JQ UT WOS:000087398400016 PM 10829052 ER PT J AU Metayer, C Lynch, CF Clarke, EA Glimelius, B Storm, H Pukkala, E Joensuu, T van Leeuwen, FE van't Veer, MB Curtis, RE Holowaty, EJ Andersson, M Wiklund, T Gospodarowicz, M Travis, LB AF Metayer, C Lynch, CF Clarke, EA Glimelius, B Storm, H Pukkala, E Joensuu, T van Leeuwen, FE van't Veer, MB Curtis, RE Holowaty, EJ Andersson, M Wiklund, T Gospodarowicz, M Travis, LB TI Second cancers among long-term survivors of Hodgkin's disease diagnosed in childhood and adolescence SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ATOMIC-BOMB SURVIVORS; POPULATION-BASED COHORT; SALIVARY-GLAND TUMORS; 2ND MALIGNANT-TUMORS; BREAST-CANCER; RISK-FACTORS; FOLLOW-UP; ESOPHAGEAL ADENOCARCINOMA; OVARIAN-CANCER; THYROID-CANCER AB Purpose: To quantify the risk of second cancers among long-term survivors of Hodgkin's disease (HD) diagnosed before 21 years of age and to explore sex-, age-, and site-related differences. Patients and Methods: We analyzed data from 5,925 pediatric HD patients, including 2,646 10-year and 755 20-year survivors, who were reported to 16 population-based cancer registries in North America and Europe between 1935 and 1994. Results: A total of 157 solid tumors (observed/expected ratio [O/E] = 7.0; 95% confidence interval [CI], 5.9 to 8.2.) and 26 acute leukemias (O/E = 27.4; 95% CI, 17.9 to 40.2) were reported. Risk of solid tumors remained significantly increased among 20-year survivors (O/E = 6.6, observed [O] = 40, cumulative risk = 6.5%) and persisted for 25 years (O/E = 4.6, O = 15, cumulative risk = 11.7%). Temporal trends for cancers of thyroid, female breast, bone/connective tissue, stomach, and esophagus were consistent with the late effects of radiotherapy. Greater than 50-fold increased risks were observed for tumors of the thyroid and respiratory tract tone lung and one pleural among children treated before age 10. At older ages (10 to 16 years), the largest number of second cancers occurred in the digestive tract (O/E = 19.3) and breast (O/E = 22.9). Risk of solid tumors increased with decreasing age at HD on a relative but not absolute scale, Conclusion: Children and adolescents treated for HD experience significantly increased risks of second cancers at various sites for 2 to 3 decades. Although our results reflect the late effects of past therapeutic modalities, they underscore the importance of lifelong fallow-up of pediatric HD patients given early more aggressive treatments. J Clin Oncol 18:2435-2443. (C) 2000 by American Society of Clinical Oncology. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Iowa, Iowa City, IA USA. Canc Care Ontario, Toronto, ON, Canada. Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. Univ Hosp, Dept Oncol, Uppsala, Sweden. Danish Canc Soc, Copenhagen, Denmark. Finnish Canc Registry, FIN-00170 Helsinki, Finland. Univ Helsinki, Cent Hosp, Helsinki, Finland. Netherlands Canc Inst, Amsterdam, Netherlands. Dr Daniel den Hoed Canc Ctr, Rotterdam, Netherlands. RP Metayer, C (reprint author), NCI, Div Canc Epidemiol & Genet, Execut Plaza S,Suite 7084, Bethesda, MD 20892 USA. NR 60 TC 206 Z9 207 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN PY 2000 VL 18 IS 12 BP 2435 EP 2443 PG 9 WC Oncology SC Oncology GA 325ZY UT WOS:000087708300012 PM 10856104 ER PT J AU Gallo, JM Laub, PB Rowinsky, EK Grochow, LB Baker, SD AF Gallo, JM Laub, PB Rowinsky, EK Grochow, LB Baker, SD TI Population pharmacokinetic model for topotecan derived from phase I clinical trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID INHIBITOR TOPOTECAN; CONTINUOUS-INFUSION; SERUM CREATININE; CANCER; PHARMACODYNAMICS; PREDICTION; PERFORMANCE; CARBOPLATIN; DOCETAXEL; CLEARANCE AB Purpose: To characterize the pharmacokinetics of topotecan in a population model that would identify patient variables or covariates that appreciably impacted on its disposition. Patients and Methods: All data were collected from 82 patients entered in four different phase I trials that were previously reported as separate studies from 1992 to 1996. All patients received topotecan as a 30-minute constant-rate infusion on a daily-times-five schedule and were selected for this study because their daily dose did not exceed 2.0 mg/m(2). Among the 82 patients were 30 patients classified as having renal insufficiency and 13 patients with hepatic dysfunction. The population pharmacokinetic model was built in sequential manner, starting with a covariate-free model and progressing to a covariate model with the aid of generalized additive modeling. Results: A linear two-compartment model characterized total topotecan plasma concentrations (n = 899). Four primary pharmacokinetic parameters (total clearance, volume of the central compartment, distributional clearance, and volume of the peripheral compartment) were related to various combinations of covariates. The relationship for total clearance (TVCL [L/h] = 32.0 +/- [0.356(WT - 71) + 0.308(HT - 168.5) - 8.42(SCR - 1.1)] x [1 + 0.671 sex]) was dependent on the patients' weight (WT), height (HT), serum creatinine (SCR), and sex and had a moderate ability to predict (r(2) = 0.64) each patient's individual clearance value. The addition of covariates to the population model improved the prediction errors, particularly for clearance. Removal of 10 outlying patients from the analysis improved the ability of the model to predict individual clearance values (r(2) = 0.77). Conclusion: A population pharmacokinetic model for total topotecan has been developed that incorporates measures of body size and renal function to predict total clearance. The model can be used prospectively to obtain a revised and validated model that can then be used to design individualized dosing regimens. J Clin Oncol 18:2459-2467. (C) 2000 by American Society of Clinical Oncology. C1 Fox Chase Canc Ctr, Dept Pharmacol, Philadelphia, PA 19111 USA. Canc Therapy & Res Ctr, Inst Drug Dev, San Antonio, TX 78229 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Gallo, JM (reprint author), Fox Chase Canc Ctr, Dept Pharmacol, 7701 Burholme Ave, Philadelphia, PA 19111 USA. FU NCI NIH HHS [CA76254] NR 33 TC 45 Z9 46 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN PY 2000 VL 18 IS 12 BP 2459 EP 2467 PG 9 WC Oncology SC Oncology GA 325ZY UT WOS:000087708300014 PM 10856106 ER PT J AU Cagnoni, PJ Walsh, TJ Prendergast, MM Bodensteiner, D Hiemenz, S Greenberg, RN Arndt, CAS Schuster, M Seibel, N Yeldandi, V Tong, KB AF Cagnoni, PJ Walsh, TJ Prendergast, MM Bodensteiner, D Hiemenz, S Greenberg, RN Arndt, CAS Schuster, M Seibel, N Yeldandi, V Tong, KB TI Pharmacoeconomic analysis of liposomal amphotericin B versus conventional amphotericin B in the empirical treatment of persistently febrile neutropenic patients SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 35th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 15-18, 1999 CL ATLANTA, GEORGIA SP Amer Soc Clin Oncol AB Purpose: In a randomized, double-blind, comparative, multicenter trial, liposomal amphotericin B was equivalent to conventional amphotericin a for empirical antifungal therapy in febrile neutropenic patients, using a composite end paint, but was more effective in reducing proven emergent fungal infections, infusion-related toxicities, and nephrotoxicity, The purpose of this study was to compare the pharmacoeconomics of liposomal versus conventional therapy. Patients and Methods: Itemized hospital billing data were collected on 414 patients from 19 of the 32 centers that participated in the trial. Hospital length of stay and costs from the first dose of study medication to the rime of hospital discharge were assessed. Results: Hospital costs from the time of first dose to discharge were significantly higher for all patients who received liposomal amphotericin B ($48,962 v $43,183; P = .022). However, hospital costs were highly sensitive to the cost of study medication ($39,648 v $43,048 when drug costs were not included; P = .416). Using decision analysis models and sensitivity analyses to vary the cost of study medications and the risk of nephrotoxicity, the break-even points for the cost of liposomal therapy were calculated to range from $72 to $87 per 50 mg for all patients and $83 to $112 per 50 mg in allogeneic bone marrow transplant patients, Conclusion: The cost of liposomal amphotericin B and patient risk for developing nephrotoxicity piety large roles in determining whether liposomal amphotericin B is cast-effective as first-line empirical therapy in persistently febrile neutropenic patients. J Clin Oncol 18:2476-2483. (C) 2000 by American Society of Clinical Oncology. C1 Quorum Consulting Inc, San Francisco, CA 94102 USA. Univ Colorado, Hlth Sci Ctr, Bone Marrow Transplant Program, Denver, CO USA. NCI, Immunocompromised Host Sect, Bethesda, MD 20892 USA. Fujisawa Healthcare Inc, Deerfield, IL USA. Univ Kansas, Med Ctr, Div Hematol & Bone Marrow Transplantat, Kansas City, MO USA. Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. Univ Kentucky, Div Infect Dis, Lexington, KY USA. Mayo Clin, Div Pediat Hematol Oncol, Rochester, MN USA. Univ Penn, Div Infect Dis, Philadelphia, PA 19104 USA. Childrens Natl Med Ctr, Div Hematol Oncol, Washington, DC 20010 USA. Loyola Univ, Med Ctr, Div Infect Dis, Maywood, IL 60153 USA. RP Tong, KB (reprint author), Quorum Consulting Inc, 442 Post St,9th Floor, San Francisco, CA 94102 USA. NR 9 TC 103 Z9 108 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN PY 2000 VL 18 IS 12 BP 2476 EP 2483 PG 8 WC Oncology SC Oncology GA 325ZY UT WOS:000087708300016 PM 10856108 ER PT J AU Marshall, J Rodarte, A Blumer, J Khoo, KC Akbari, B Kearns, G AF Marshall, J Rodarte, A Blumer, J Khoo, KC Akbari, B Kearns, G CA Pediat Pharmacology Res Unit Netwo TI Pediatric pharmacodynamics of midazolam oral syrup SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article ID PHARMACOLOGICAL PROPERTIES; CHILDREN; PREMEDICATION; PHARMACOKINETICS; BENZODIAZEPINES; SEPARATION; MANAGEMENT; SEDATION AB In this study, the authors evaluate the pharmacodynamics, safety, and acceptability of a new cherry-flavored oral syrup formulation of midazolam. This randomized, double-blind, parallel-group, dose-ranging clinical trial of oral midazolam rr cts conducted at seven U.S, health care institutions focused on pediatric clinical pharmacology research (i.e., the PPRU Network). Pediatric patients (n = 85, ages 6 months through 15 years) underwent invasive procedures and were randomized to a single oral dose of midazolam syrup (0.25, 0.5, or 1.0 mg/kg). Patient taste acceptability of midazolam syrup was evaluated at the time of oral administration. Pharmacodynamic measurements included (1) sedation score using a 5-point scale at baseline and 10-, 20-, and 30-minute postdose intervals and (2) anxiety score using a 5-point scale at the time of separation from caretakers and, when applicable, at the time of mask anesthetic induction. Midazolam and alpha-hydroxymidazolam plasma concentrations were measured at all pharmacodynamic measurement time points. Adverse events were monitored continuously during the study. Most patients (99%) accepted the syrup without difficulty. Satisfactory sedation was achieved within 30 minutes by 81% of patients. The anxiety score at the time of caretaker separation and mask anesthetic induction was satisfactory for 87% and 91% of patients, respectively. A significant linear relationship between plasma drug concentration and maximal sedation score, but not anxiety score, was observed. The occurrence of adverse events was consistent with the known safety profile of midazolam. The most commonly reported adverse events were hiccoughing, hypoxemia, nausea, and emesis. It was concluded that a new oral syrup formulation of midazolam, 0.25 to 1.0 mg/kg, effectively induced rapid-onset, dose-related, adequate, and safe sedation and anxiolysis in pediatric pa tien ts who underwent operative procedures. Sedative effects were related to plasma concentrations of both midazolam and the primary metabolite, alpha-hydroxymidazolam. Oral midazolam, 1.0 mg/kg, administered within 30 minutes of the expected procedure or anesthetic induction should provide safe and effective sedation to a majority of children ages 6 months to 16 years. C1 Childrens Mercy Hosp, Sect Crit Care Med, Pediat Clin Pharmacol & Expt Therapeut, Kansas City, MO 64108 USA. Univ Missouri, Dept Pediat, Kansas City, MO 64110 USA. Univ Missouri, Dept Pharmacol, Kansas City, MO 64110 USA. Childrens Hosp & Hlth Ctr, Div Anesthesia & Crit Care, San Diego, CA USA. Univ Calif San Diego, Dept Anesthesia, San Diego, CA 92103 USA. Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA. Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Div Pediat Pharmacol & Crit Care Med, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Pediat, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Pharmacol, Cleveland, OH 44106 USA. Roche Labs Inc, Nutley, NJ USA. NICHHD, Bethesda, MD 20892 USA. RP Marshall, J (reprint author), Childrens Mercy Hosp, Sect Crit Care Med, Pediat Clin Pharmacol & Expt Therapeut, 2401 Gillham Rd, Kansas City, MO 64108 USA. FU NICHD NIH HHS [1-U01-HD31313-05] NR 32 TC 26 Z9 26 U1 1 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0091-2700 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD JUN PY 2000 VL 40 IS 6 BP 578 EP 589 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 316FE UT WOS:000087156300005 PM 10868308 ER PT J AU Coulter, ID Marcus, M Freed, JR Der-Martirosian, C Cunningham, WE Andersen, RM Maas, WR Garcia, I Schneider, DA Genovese, B Shapiro, MF Bozzette, SA AF Coulter, ID Marcus, M Freed, JR Der-Martirosian, C Cunningham, WE Andersen, RM Maas, WR Garcia, I Schneider, DA Genovese, B Shapiro, MF Bozzette, SA TI Use of dental care by HIV-infected medical patients SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE HIV; use of dental care ID SERVICE USE; DENTISTS ATTITUDES; SELF-DISCLOSURE; AIDS; SIMILARITIES; EXPERIENCE; KNOWLEDGE; ACCESS; PEOPLE; RISK AB Although increasing attention has been paid to the use of dental care by HIV patients, the existing studies do not use probability samples, and no accurate population estimates of use can be made from this work. The intent of the present study was to establish accurate population estimates of the use of dental services by patients under medical care. The study, part of the HIV Cost and Services Utilization Study (HCSUS), created a representative national probability sample, the first of its kind, of HN-infected adults in medical care. Both bivariate and logistic regressions were conducted, with use of dental care in the preceding 6 months as the dependent variable and demographic, social, behavioral, and disease characteristics as independent variables. Forty-two percent of the sample had seen a dental health professional in the preceding 6 months. The bivariate logits for use of dental care show that African-Americans, those whose exposure to HIV was caused by hemophilia or blood transfusions, persons with less education, and those who were employed were less likely to use dental care (p < 0.05). Sixty-five percent of those with a usual source of care had used dental care in the preceding 6 months. Use was greatest among those obtaining dental care from an AIDS clinic (74%) and lowest among those without a usual source of dental care (12%). We conclude that, in spite of the high rate of oral disease in persons with HIV, many do not use dental care regularly, and that use varies by patient characteristics and availability of a regular source of dental care. C1 Univ Calif Los Angeles, Sch Dent, Los Angeles, CA 90024 USA. RAND Corp, Santa Monica, CA 90407 USA. Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90024 USA. Ctr Dis Control, Atlanta, GA 30333 USA. Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. US Hlth Care Financing Adm, Baltimore, MD 21207 USA. Vet Affairs San Diego Hlth Care Syst, La Jolla, CA USA. Univ Calif San Diego, San Diego, CA 92103 USA. RP Coulter, ID (reprint author), Univ Calif Los Angeles, Sch Dent, Los Angeles, CA 90024 USA. FU AHRQ HHS [U01 HS 08578] NR 33 TC 23 Z9 23 U1 1 U2 1 PU AMER ASSOC DENTAL RESEARCH PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUN PY 2000 VL 79 IS 6 BP 1356 EP 1361 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 325TZ UT WOS:000087693600002 PM 10890713 ER PT J AU Kawahara, Y Zillikens, D Yancey, KB Marinkovich, MP Nie, Z Hashimoto, T Nishikawa, T AF Kawahara, Y Zillikens, D Yancey, KB Marinkovich, MP Nie, Z Hashimoto, T Nishikawa, T TI Subepidermal blistering disease with autoantibodies against a novel dermal 200-kDa antigen SO JOURNAL OF DERMATOLOGICAL SCIENCE LA English DT Article DE Autoantigen; Autoimmune bullous disease; basement membrane zone ID BULLOUS PEMPHIGOID ANTIGEN; BASEMENT-MEMBRANE ZONE; SYSTEMIC LUPUS-ERYTHEMATOSUS; LAMINA-LUCIDA AUTOANTIGEN; EPIDERMAL JUNCTION; CIRCULATING IGA; TARGET ANTIGEN; HUMAN-SKIN; IDENTIFICATION; LOCALIZATION AB A number of autoimmune subepidermal blistering diseases are characterized by the distinct autoantigens of the cutaneous basement membrane zone. Recently, a few cases with autoantibodies against a novel 200-kDa dermal protein have been reported. We collected nine cases of subepidermal blistering disease with IgG antibodies against this 200-kDa antigen. In this report, we describe the clinical and immunological appearances in these cases. Five cases showed bullous pemphigoid-like features, one case resembled dermatitis herpetiformis, and another case showed mixed features of bullous pemphigoid and linear IgA bullous dermatosis. It was interesting to note that psoriasis coexisted in four cases. By indirect immunofluorescence on 1 M NaCl split skin, IgG antibodies from all sera reacted with the dermal side of the split. By immunoblot analysis, IgG antibodies recognized a 200-kDa protein of dermal extract. IgG affinity-purified antibodies on the 200-kDa immunoblot membrane stained the dermal side of 1 M NaCl split skin. Various examinations suggested that the 200-kDa antigen is not identical to any chains of laminins-1. -5 or -6. This autoimmune subepidermal blistering disease against the dermal 200-kDa protein may form a new distinct entity, which often associates with psoriasis. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 Keiyu Hosp, Dept Dermatol, Nishi Ku, Yokohama, Kanagawa 2200012, Japan. Univ Wurzburg, Dept Dermatol, D-8700 Wurzburg, Germany. NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. Stanford Univ, Med Ctr, Sch Med, Dept Dermatol,Dermatol Serv, Stanford, CA 94305 USA. Kurume Univ, Sch Med, Dept Dermatol, Fukuoka, Japan. Keio Univ, Sch Med, Dept Dermatol, Tokyo, Japan. RP Kawahara, Y (reprint author), Keiyu Hosp, Dept Dermatol, Nishi Ku, 3-7-3 Minatomirai, Yokohama, Kanagawa 2200012, Japan. RI Zillikens, Detlef/C-8572-2011 FU NIAMS NIH HHS [AR44012] NR 36 TC 35 Z9 36 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0923-1811 J9 J DERMATOL SCI JI J. Dermatol. Sci. PD JUN PY 2000 VL 23 IS 2 BP 93 EP 102 DI 10.1016/S0923-1811(99)00093-6 PG 10 WC Dermatology SC Dermatology GA 320XA UT WOS:000087425100003 PM 10808126 ER PT J AU Hoagwood, K AF Hoagwood, K TI Research on youth violence: Progress by replacement, not addition SO JOURNAL OF EMOTIONAL AND BEHAVIORAL DISORDERS LA English DT Article ID DISORDER C1 NIMH, Off Director, Bethesda, MD 20892 USA. RP Hoagwood, K (reprint author), NIMH, Off Director, 6001 Execut Blvd, Bethesda, MD 20892 USA. NR 10 TC 11 Z9 11 U1 0 U2 0 PU PRO-ED INC PI AUSTIN PA 8700 SHOAL CREEK BLVD, AUSTIN, TX 78757-6897 USA SN 1063-4266 J9 J EMOT BEHAV DISORD JI J. Emot. Behav. Disord. PD SUM PY 2000 VL 8 IS 2 BP 67 EP 70 DI 10.1177/106342660000800202 PG 4 WC Education, Special; Psychology, Educational; Psychology, Multidisciplinary SC Education & Educational Research; Psychology GA 315RR UT WOS:000087127200002 ER PT J AU Collins, MT Remaley, AT Csako, G Pucino, F Skarulis, MC Balow, JE Sarlis, NJ AF Collins, MT Remaley, AT Csako, G Pucino, F Skarulis, MC Balow, JE Sarlis, NJ TI Increased levothyroxine requirements presenting as "inappropriate" TSH secretion syndrome in a patient with nephrotic syndrome SO JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION LA English DT Article; Proceedings Paper CT 72nd Annual Meeting of the American-Thyroid-Association CY SEP 29-OCT 01, 1999 CL PALM BEACH, FLORIDA SP Amer Thyroid Assoc DE "inappropriate" TSH secretion; nephrotic syndrome; levothyroxine; hypothyroidism; proteinuria ID THYROID-STIMULATING HORMONE; THYROXINE-BINDING GLOBULIN; INSTITUTES-OF-HEALTH; GRAVES-DISEASE; MONOCLONAL-ANTIBODIES; FREE TRIIODOTHYRONINE; THYROTROPIN; PITUITARY; SERUM; RESISTANCE AB Patients with primary thyroid failure on levothyroxine (LT4) replacement who develop nephrotic syndrome (NS) may rarely present with an increase in LT4 requirements. In this report, we describe a patient with thyroid failure following radioactive iodine ablation for Graves' disease who required an escalation of LT4 doses following the onset of NS. The case presented with disproportionately elevated TSH levels in the presence of normal(or slightly subnormal) thyroid hormone levels, thus, masquerading as a state of "inappropriate" TSH secretion. This pattern of extreme dysregulation in thyroid function indices due to urinary loss of thyroid hormones has not been previously described in NS, and, therefore, extends the spectrum of endocrine manifestations of NS. (C)2000, Editrice Kurtis. C1 NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Cranofacial Res, Bethesda, MD 20892 USA. NIDDK, Dept Clin Pathol, NIH, Bethesda, MD 20892 USA. NIDDK, Dept Pharm, Ctr Clin, NIH, Bethesda, MD 20892 USA. NIDDK, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Sarlis, NJ (reprint author), NIDDK, Clin Endocrinol Branch, NIH, Bldg 10,Room 8D12C,10 Ctr Dr,MSC 1758, Bethesda, MD 20892 USA. NR 74 TC 2 Z9 2 U1 0 U2 0 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 0391-4097 J9 J ENDOCRINOL INVEST JI J. Endocrinol. Invest. PD JUN PY 2000 VL 23 IS 6 BP 383 EP 392 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 330WN UT WOS:000087984300006 PM 10908166 ER PT J AU Mayfield, JA Reiber, GE Nelson, RG Greene, T AF Mayfield, JA Reiber, GE Nelson, RG Greene, T TI Do foot examinations reduce the risk of diabetic amputation? SO JOURNAL OF FAMILY PRACTICE LA English DT Article DE diabetic foot; foot examinations [non-MESH]; foot ulcer; amputation ID PIMA-INDIANS; CARE; PREVENTION; MELLITUS; EDUCATION; SYSTEM AB BACKGROUND Foot examinations are widely recommended as a means to reduce amputation risk, but no investigators have studied their independent effect on this outcome. METHODS We conducted a population-based case-control study of primary care provided to Pima Indians from the Gila River Indian Community. Sixty-one Pima Indians with type 2 diabetes and a first lower-extremity amputation between January 1, 1985, and December 31, 1992, were compared with 183 people who had no amputation by December 31, 1992. The type of foot examination conducted, comorbid conditions, and foot risk factors present in the 36 months before the pivotal event were abstracted front medical records. AU ulcer care was excluded. The independent effect of foot examinations on the risk of amputation was assessed by logistic regression. RESULTS During the 36 study months, 1857 fool examinations were performed on 244 subjects. The median number of preventive foot examinations was 7 for case patients and 3 for control patients. After controlling for differences in comorbid conditions and foot risk conditions, the risk of amputation for persons with 1 or more foot examinations was an odds ratio (OR) of 0.55 (95% confidence interval [CI], 0.2-1.7; P=.31). The risk of amputation associated with written comments of nonadherence with therapeutic foot care recommendations or diabetic medication was an OR of 1.9 (95% CZ, 0.9-4.3; P=.10). CONCLUSIONS Our study failed to demonstrate that foot examinations decrease the risk of amputation in Pima Indians with type 2 diabetes. However, foot examinations detect high-risk conditions for which specific interventions have been shown to be effective in reducing amputation risk. C1 Vet Affairs Puget Sound Hlth Care Syst, Hlth Serv Res Ctr, Seattle, WA USA. NIDDKD, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ USA. Indiana Univ, Dept Family Med, Bowen Res Ctr, Indianapolis, IN 46204 USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. RP Mayfield, JA (reprint author), 1660 So Columbia way,MS 152, Seattle, WA 98108 USA. RI Nelson, Robert/B-1470-2012 FU AHRQ HHS [HS07238] NR 21 TC 15 Z9 17 U1 0 U2 0 PU DOWDEN PUBLISHING CORP PI MONTVALE PA 110 SUMMIT AVE, MONTVALE, NJ 07645-1712 USA SN 0094-3509 J9 J FAM PRACTICE JI J. Fam. Pract. PD JUN PY 2000 VL 49 IS 6 BP 499 EP 504 PG 6 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 324ZT UT WOS:000087652400001 PM 10923547 ER PT J AU Appelbaum, M Belsky, J Booth, C Bradley, R Brownell, C Burchinal, M Caldera, Y Caldwell, B Campbell, S Clarke-Stewart, A Cox, M Friedman, S Huston, A Knoke, B Marshall, N O'Brien, M Owen, MT Phillips, D Pianta, R Spieker, S Stright, A Vandell, DL AF Appelbaum, M Belsky, J Booth, C Bradley, R Brownell, C Burchinal, M Caldera, Y Caldwell, B Campbell, S Clarke-Stewart, A Cox, M Friedman, S Huston, A Knoke, B Marshall, N O'Brien, M Owen, MT Phillips, D Pianta, R Spieker, S Stright, A Vandell, DL CA NICHD Early Child Care Res Network TI Factors associated with fathers' caregiving activities and sensitivity with young children SO JOURNAL OF FAMILY PSYCHOLOGY LA English DT Article ID SINGLE-EARNER FAMILIES; DUAL-EARNER; PATERNAL INVOLVEMENT; CARE; DETERMINANTS; INFANCY; PARTICIPATION; ANTECEDENTS; EXPERIENCE; ADJUSTMENT AB A multifactorial model was used to identify child, sociodemographic, paternal, and maternal characteristics associated with 2 aspects of fathers' parenting. Fathers were interviewed about their caregiving responsibilities at 6, 15, 24, and 36 months, and a subset was videotaped during father-child play at 6 and 36 months. Caregiving activities and sensitivity during play interactions were predicted by different factors. Fathers were more involved in caregiving when fathers worked fewer hours and mothers worked more hours, when fathers and mothers were younger, when fathers had more positive personalities, when mothers reported greater marital intimacy, and when children were boys. Fathers who had less traditional child-rearing beliefs, were older, and reported more marital intimacy were more sensitive during play. These findings are consistent with a multifactorial and multidimensional view of fathering. C1 NICHD, Early Child Care Res Network, CRMC, Rockville, MD 20852 USA. RP Appelbaum, M (reprint author), NICHD, Early Child Care Res Network, CRMC, 6100 Execut Blvd,4B05, Rockville, MD 20852 USA. RI Marshall, Nancy/C-3428-2012 NR 59 TC 8 Z9 9 U1 4 U2 14 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 2000 VL 14 IS 2 BP 200 EP 219 DI 10.1037//0893-3200.14.2.200 PG 20 WC Psychology, Clinical; Family Studies SC Psychology; Family Studies GA 325LD UT WOS:000087676300003 ER PT J AU Li-Smerin, Y Swartz, KJ AF Li-Smerin, Y Swartz, KJ TI Localization and molecular determinants of the hanatoxin receptors on the voltage-sensing domains of a K+ channel SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Article DE gating modifier toxin; scanning mutagenesis; voltage-dependent gating; protein-protein interaction ID POTASSIUM CHANNEL; TRANSMEMBRANE SEGMENTS; ELECTROSTATIC INTERACTIONS; STREPTOMYCES-LIVIDANS; CHARYBDOTOXIN BLOCK; PEPTIDE INHIBITOR; GATING MODIFIER; SCORPION TOXIN; MUTANT CYCLES; S4 SEGMENT AB Hanatoxin inhibits voltage-gated K+ channels by modifying the energetics of activation. We studied the molecular determinants and physical location of the Hanatoxin receptors on the drk1 voltage-gated K+ channel. First, we made multiple substitutions at three previously identified positions in the COOH terminus of S3 to examine whether these residues interact intimately with the toxin. We also examined a region encompassing S1-S3 using alanine-scanning mutagenesis to identify additional determinants of the toxin receptors. Finally, guided by the structure of the KcsA K+ channel, we explored whether the toxin interacts with the peripheral extracellular surface of the pore domain in the drk1 K+ channel. Our results argue for an intimate interaction between the toxin and the COOH terminus of S3 and suggest that the Hanatoxin receptors are confined within the voltage-sensing domains of the channel, at least 20-25 Angstrom away from the central pore axis. C1 NINDS, Mol Physiol & Biophys Unit, NIH, Bethesda, MD 20892 USA. RP Swartz, KJ (reprint author), NINDS, Mol Physiol & Biophys Unit, NIH, Bldg 36,Rm 2C19,36 Convent Dr,MSC 4066, Bethesda, MD 20892 USA. EM swartzk@ninds.nih.gov FU Intramural NIH HHS [ZIA NS002945-13] NR 62 TC 101 Z9 102 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1295 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD JUN PY 2000 VL 115 IS 6 BP 673 EP 684 DI 10.1085/jgp.115.6.673 PG 12 WC Physiology SC Physiology GA 323QR UT WOS:000087576900001 PM 10828242 ER PT J AU Hoshino, Y Kapikian, AZ AF Hoshino, Y Kapikian, AZ TI Rotavirus serotypes: Classification and importance in epidemiology, immunity, and vaccine development SO JOURNAL OF HEALTH POPULATION AND NUTRITION LA English DT Review DE rotavirus; serotyping : epidemiology; immunity; vaccine development ID POLYMERASE CHAIN-REACTION; LINKED IMMUNOSORBENT-ASSAY; MONOCLONAL-ANTIBODIES; BOVINE ROTAVIRUS; ENZYME-IMMUNOASSAY; NEUTRALIZING ANTIBODY; RHESUS ROTAVIRUS; YOUNG-CHILDREN; P-TYPE; REASSORTANT ROTAVIRUSES AB The development and implementation of safe and effective vaccines to prevent the enormous health burden of rotavirus-associated disease: is a global public health goal. Human rotaviruses, the major aetiological agents of severe infantile diarrhoea worldwide, display surprisingly diverse and complex serotypic specificities. Ten VP7 serotypes and 7 VP4 serotypes have so far been detected. An increasing number of observations, obtained from analyses of (i) natural rotavirus infections in infants and young children, (ii) experimental rotavirus infections in laboratory animals, and (iii) extensive rotavirus vaccine field trials performed in different populations of various parts of the world, appears to support the concept that serotype-specific antibodies to rotaviruses play an important role in protection against rotavirus-associated illnesses. Thus, the first licensed rotavirus vaccine (RRV-based quadrivalent vaccine) was designed to cover the epidemiologically important VP7 serotype 1, 2, 3, and 4. C1 NIAID, Infect Dis Lab, Epidemiol Sect, NIH, Bethesda, MD 20892 USA. RP Hoshino, Y (reprint author), NIAID, Infect Dis Lab, Epidemiol Sect, NIH, Bldg 7,Room 105,7 Ctr Dr MSC 0729, Bethesda, MD 20892 USA. EM THOSHINO@niaid.nih.gov NR 115 TC 101 Z9 106 U1 0 U2 4 PU I C D D R B-CENTRE HEALTH POPULATION RESEARCH PI DHAKA PA MOHAKHALI, 1212 DHAKA, BANGLADESH SN 1606-0997 J9 J HEALTH POPUL NUTR JI J. Heatlh Popul. Nutr. PD JUN PY 2000 VL 18 IS 1 BP 5 EP 14 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 366RY UT WOS:000090019400002 PM 11014764 ER PT J AU Barrett, J Childs, R AF Barrett, J Childs, R TI The benefits of an alloresponse: Graft-versus-tumor SO JOURNAL OF HEMATOTHERAPY & STEM CELL RESEARCH LA English DT Review ID BONE-MARROW TRANSPLANTATION; MINOR HISTOCOMPATIBILITY ANTIGENS; RESTRICTED TISSUE DISTRIBUTION; CHRONIC MYELOID-LEUKEMIA; T-CELL; BREAST-CANCER; LUNG METASTASES; HOST DISEASE; IMMUNOTHERAPY; LYMPHOCYTES C1 NHLBI, Hematol Branch, Stem Cell Allotransplantat Unit, NIH, Bethesda, MD 20892 USA. RP Barrett, J (reprint author), NHLBI, Hematol Branch, Stem Cell Allotransplantat Unit, NIH, Bldg 10,Room 7C103,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Ain, Kenneth/A-5179-2012 OI Ain, Kenneth/0000-0002-2668-934X NR 61 TC 8 Z9 8 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1525-8165 J9 J HEMATOTH STEM CELL JI J. Hematother. Stem Cell Res. PD JUN PY 2000 VL 9 IS 3 BP 347 EP 354 DI 10.1089/15258160050079452 PG 8 WC Hematology; Medicine, Research & Experimental; Transplantation SC Hematology; Research & Experimental Medicine; Transplantation GA 332YQ UT WOS:000088102300008 PM 10894356 ER PT J AU Petersson, M Rundqvist, B Johansson, M Eisenhofer, G Jenssen, G Herlitz, H Friberg, P AF Petersson, M Rundqvist, B Johansson, M Eisenhofer, G Jenssen, G Herlitz, H Friberg, P TI Increased cardiac sympathetic activity in hypertensive patients with renovascular disease SO JOURNAL OF HYPERTENSION LA English DT Meeting Abstract C1 Univ Gothenburg, Dept Cardiol, Gothenburg, Sweden. Univ Gothenburg, Dept Clin Physiol, Gothenburg, Sweden. Univ Gothenburg, Dept Nephrol, Gothenburg, Sweden. NINDS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 2000 VL 18 SU 2 BP S138 EP S138 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 323YY UT WOS:000087593800485 ER PT J AU Segal, BM Chang, JT Shevach, EM AF Segal, BM Chang, JT Shevach, EM TI CPG oligonucleotides are potent adjuvants for the activation of autoreactive encephalitogenic T cells in vivo SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; MYELIN BASIC-PROTEIN; IFN-GAMMA PRODUCTION; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; IMMUNOSTIMULATORY DNA-SEQUENCES; MULTIPLE-SCLEROSIS; BACTERIAL-DNA; INTERFERON-GAMMA; IN-VITRO; DENDRITIC CELLS AB The mechanism of action of microbial adjuvants in promoting the differentiation of autoimmune effector cells remains to be elucidated. We demonstrate that CpG-containing oligodeoxynucleotides (ODN) can completely substitute for heat-killed mycobacteria in the priming of encephalitogenic myelin-reactive T cells in vivo. The adjuvanticity of the CpG ODN was secondary to their direct ability to induce IL-12 or to act synergistically with endogenous IL-12 to promote Th1 differentiation and encephalitogenicity. T cells primed in the absence of CpG with Ag and IFA alone appeared to be in a transitional state and had not undergone differentiation along a conventional Th pathway. Unlike Th2 cells, they expressed low levels of the IL-12R beta 2 subunit and retained the ability to differentiate into encephalitogenic effectors when reactivated in vitro under Th1-polarizing conditions. These results support the use of CpG ODN as adjuvants but also suggest that they could potentially trigger autoimmune disease in a susceptible individual. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. Howard Hughes Med Inst, Res Scholars Program, NIH, Bethesda, MD USA. RP Shevach, EM (reprint author), NIAID, Immunol Lab, NIH, Bldg 10,Room 11N315, Bethesda, MD 20892 USA. OI Segal, Benjamin/0000-0002-0906-6319 NR 54 TC 126 Z9 131 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 JUN 1 PY 2000 VL 164 IS 11 BP 5683 EP 5688 PG 6 WC Immunology SC Immunology GA 316EN UT WOS:000087154800018 PM 10820244 ER PT J AU Marovich, MA McDowell, MA Thomas, EK Nutman, TB AF Marovich, MA McDowell, MA Thomas, EK Nutman, TB TI IL-12p70 production by Leishmania major-harboring human dendritic cells is a CD40/CD40 ligand-dependent process SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EPIDERMAL LANGERHANS CELLS; COLONY-STIMULATING FACTOR; PROTECT SUSCEPTIBLE MICE; ANTIGEN-PRESENTING CELLS; NECROSIS-FACTOR-ALPHA; CUTANEOUS LEISHMANIASIS; IN-VIVO; INTERLEUKIN-12 PRODUCTION; T-CELLS; MEDIATED-IMMUNITY AB Leishmaniasis, a vector-borne parasitic disease, is transmitted during a sandfly blood meal as the parasite is delivered into the dermis, The parasite displays a unique immune evasion mechanism: prevention of IL-12 production within its host cell, the macrophage (i.e., where it differentiates and multiplies). Given the close proximity of skin dendritic tells (DC) to the site of parasite delivery, their critical role in initiating immune responses and the self-healing nature of Leishmania major (Lm) infection, we examined the interaction between myeloid-derived human DC and Lm metacyclic promastigotes (infectious-stage parasites) to model the early "natural" events of infection. We found that DC can take up Lm and, after this internalization, undergo changes in surface phenotype suggesting "maturation". Despite the intracellular location of the parasite and resultant up-regulation of costimulatory and class II molecules, there was no detectable cytokine release by these Lm-harboring DC. However, using intracellular staining and flow cytometry to analyze cytokine production at the single-cell level, we found that Lm-harburing DC, but not monocytes, produce large amounts of IL-12p70 in a CD40 ligand (CD40L)-dependent manner. Finally, DC generated from mononuclear cells from patients with cutaneous leishmaniasis (Lm), once loaded with live metacyclic promastigotes, were found to reactivate autologous primed T lymphocytes and induce a CD40L-dependent IFN-gamma response. Our results link the required CD40/CD40L interactions for healing with DC-derived IL-12p70 production and provide a mechanism to explain the genesis of a protective T cell-mediated response in the face of local immune evasion within the macrophage at the site of Leishmania delivery. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Immunex Corp, Seattle, WA 98101 USA. RP Marovich, MA (reprint author), NIAID, Parasit Dis Lab, NIH, 4 Ctr Dr,Bldg 4,Room 126, Bethesda, MD 20892 USA. NR 50 TC 92 Z9 95 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 2000 VL 164 IS 11 BP 5858 EP 5865 PG 8 WC Immunology SC Immunology GA 316EN UT WOS:000087154800039 PM 10820265 ER PT J AU Yamamoto, JH Vallochi, AL Silveira, C Kalil, J Nussenblatt, RB Cunha-Neto, E Gazzinelli, RT Belfort, R Rizzo, LV AF Yamamoto, JH Vallochi, AL Silveira, C Kalil, J Nussenblatt, RB Cunha-Neto, E Gazzinelli, RT Belfort, R Rizzo, LV TI Discrimination between patients with acquired toxoplasmosis and congenital toxoplasmosis on the basis of the immune response to parasite antigens SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID T-CELL RECEPTOR; POLYMERASE CHAIN-REACTION; OCULAR TOXOPLASMOSIS; IFN-GAMMA; DEFICIENCY SYNDROME; CD8+ LYMPHOCYTES; PROTECTIVE ROLE; IN-VIVO; GONDII; ALPHA AB Many persons infected with Toxoplasma gondii develop ocular lesions, Immunologic parameters in the response to I gondii were evaluated in infected persons with and without ocular lesions and in noninfected controls. Subjects were divided into groups on the basis of presence of serum antibodies to I: gondii, presence of ocular lesions, and clinical history. Production of interleukin-2 and interferon-gamma by peripheral blood mononuclear cells from patients with probable congenital toxoplasmosis was decreased, compared with that in persons with presumed acquired infection. Cell proliferation and delayed-type skin reaction induced by soluble toxoplasma tachyzoite antigen followed the same pattern. Asymptomatic persons showed high levels of interleukin-12 and interferon-gamma, whereas persons with ocular lesions had high interleukin-1 and tumor necrosis factor-alpha responses toward soluble toxoplasma tachyzoite antigen. These data suggest that patients with ocular disease due to congenital infection show tolerance toward the parasite. Furthermore, susceptibility to ocular lesions after acquired toxoplasmosis is associated with high levels of interleukin-1 and tumor necrosis factor-alpha, whereas resistance is associated with high levels of interleukin-12 and interferon-gamma. C1 Univ Sao Paulo, ICB, Dept Immunol, BR-05509890 Sao Paulo, Brazil. Univ Sao Paulo, Inst Heart, Lab Transplant Immunol, Sao Paulo, Brazil. Univ Sao Paulo, Fac Med, Dept Ophthalmol, Sao Paulo, Brazil. Univ Fed Sao Paulo, Dept Ophthalmol, Sao Paulo, Brazil. Univ Sao Paulo, Sch Med, Div Clin Immunol & Allergy, Lab Med Invest, Sao Paulo, Brazil. Fundacao EJ Zerbini, Sao Paulo, Brazil. Univ Fed Minas Gerais, Dept Biochem & Immunol, Belo Horizonte, MG, Brazil. Fundacao Osvaldo Cruz, Ctr Pesquisas Rene Rachou, Belo Horizonte, MG, Brazil. NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Rizzo, LV (reprint author), Univ Sao Paulo, ICB, Dept Immunol, Av Prof Lineu Prestes 1730, BR-05509890 Sao Paulo, Brazil. RI Rizzo, Luiz Vicente/B-4458-2009; Cunha-Neto, Edecio/B-4157-2009; Belfort Jr, Rubens/E-2252-2012; Yamamoto, Joyce/B-6192-2015; OI Belfort Jr, Rubens/0000-0002-8422-3898; Cunha-Neto, Edecio/0000-0002-3699-3345 NR 23 TC 50 Z9 52 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN PY 2000 VL 181 IS 6 BP 2018 EP 2022 DI 10.1086/315494 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 329TH UT WOS:000087923900020 PM 10837184 ER PT J AU Maloney, EM Morgan, OS Widner, B Werner, ER Fuchs, D AF Maloney, EM Morgan, OS Widner, B Werner, ER Fuchs, D TI Central nervous system activation of the indoleamine-2,3-dioxygenase pathway in human T cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID TRYPTOPHAN CATABOLISM; IMMUNE ACTIVATION; INFECTION; PROLIFERATION; KYNURENINE; NEOPTERIN; NITRATE; NITRITE AB Human T cell lymphotropic virus type I (HTLV-I) is associated with a chronic neurologic disease called HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The potential mechanisms of HAM/TSP pathogenesis were assessed by examination of 2 pathways initiated by interferon-gamma, a predominant cytokine in HAM/TSP. Jamaican HAM/TSP patients (n = 17) were compared with patients with other neurologic diseases (ONDs; n = 13) with respect to cerebrospinal fluid levels of the following: neopterin; nitrite plus nitrate, a stable indicator of nitric oxide; and tryptophan and kynurenine, metabolites of the indoleamine-2,3-dioxygenase (IDO) pathway. HAM/TSP patients had significantly elevated levels of neopterin (P = .003) and kynurenine (P = .05) and a significantly decreased level of tryptophan (P = .003), compared with patients with ONDs, These results support immune activation within the central nervous system and activation of the IDO pathway. Thus, activation of the IDO pathway may play a role in HAM/TSP. C1 NCI, Viral Epidemiol Branch, Bethesda, MD 20892 USA. Univ W Indies, Dept Med, Kingston 7, Jamaica. Univ Innsbruck, Inst Med Chem & Biochem, A-6020 Innsbruck, Austria. Ludwig Boltzmann Inst AIDS Res, Innsbruck, Austria. RP Maloney, EM (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,MSC 7248, Rockville, MD 20822 USA. EM maloneyb@epndce.nci.nih.gov NR 16 TC 9 Z9 9 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN PY 2000 VL 181 IS 6 BP 2037 EP 2040 DI 10.1086/315483 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 329TH UT WOS:000087923900024 PM 10837188 ER PT J AU Moriuchi, H Moriuchi, M Mizell, SB Ehler, LA Fauci, AS AF Moriuchi, H Moriuchi, M Mizell, SB Ehler, LA Fauci, AS TI In vitro reactivation of human immunodeficiency virus 1 from latently infected, resting CD4(+) T cells after bacterial stimulation SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 6th Conference on Retroviruses and Opportunistic in fections CY FEB, 1999 CL CHICAGO, ILLINOIS ID ACTIVE ANTIRETROVIRAL THERAPY; HIV-1 REPLICATION; IN-VIVO; COINFECTION; MACROPHAGES; RESERVOIR AB Microbial coinfections have been associated with transient bursts of human immunodeficiency virus (HIV) viremia in patients. In this study, we have investigated whether microbial coinfections can induce replication of HIV-1 in latently infected CD4(+) T cells derived from HIV-infected patients who are receiving highly active antiretroviral therapy and in whom plasma viremia is undetectable by sensitive assays. We demonstrate that supernatants from macrophages exposed to the bacterial product lipopolysaccharide can induce in vitro activation of HIV-1 from latently infected, resting CD4(+) T cells obtained from HIV-infected individuals, Depletion of proinflammatory cytokines from the supernatant markedly reduced-whereas depletion of beta chemokines increased-the ability of the supernatant to induce replication of HIV-1. Our results suggest that coinfection with microbial pathogens such as bacteria may induce viral replication in the latent viral reservoirs in vivo. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Moriuchi, H (reprint author), Nagasaki Univ, Sch Med, Dept Pediat, Nagasaki 8528501, Japan. NR 15 TC 31 Z9 31 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN PY 2000 VL 181 IS 6 BP 2041 EP 2044 DI 10.1086/315496 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 329TH UT WOS:000087923900025 PM 10837189 ER PT J AU Byrne, GI Skarlotos, SI Grunfeld, C Kalayoglu, MV Libby, P Saikku, P Summersgill, JT Wyrick, P AF Byrne, GI Skarlotos, SI Grunfeld, C Kalayoglu, MV Libby, P Saikku, P Summersgill, JT Wyrick, P TI Collaborative multidisciplinary workshop report: Interface of lipid metabolism, atherosclerosis, and Chlamydia infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material C1 Univ Wisconsin, Sch Med, Dept Med Microbiol & Immunol, Madison, WI 53706 USA. NIH, Bethesda, MD 20892 USA. San Francisco Vet Adm Ctr, San Francisco, CA USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. Natl Publ Hlth Inst, Oulu, Finland. Univ Louisville, Div Infect Dis, Louisville, KY 40292 USA. Univ N Carolina, Sch Med, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. RP Byrne, GI (reprint author), Univ Wisconsin, Sch Med, Dept Med Microbiol & Immunol, 250 Biochem Bldg, Madison, WI 53706 USA. FU NIAID NIH HHS [R01 AI019782] NR 0 TC 8 Z9 8 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN PY 2000 VL 181 SU 3 BP S490 EP S491 DI 10.1086/315600 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 331MY UT WOS:000088023900024 PM 10839745 ER PT J AU Fong, IW Quinn, T Blessing, E Kuo, CC Malinverni, R Lauer, M Mawhorter, S Bachmaier, K Rosenfeld, M Taylor, C Zhong, GM AF Fong, IW Quinn, T Blessing, E Kuo, CC Malinverni, R Lauer, M Mawhorter, S Bachmaier, K Rosenfeld, M Taylor, C Zhong, GM TI Collaborative multidisciplinary workshop report: What questions regarding the role of Chlamydia pneumoniae in atherosclerosis and cardiovascular disease need to be addressed utilizing animal models? SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material C1 Univ Toronto, St Michaels Hosp, Dept Med, Toronto, ON M5B 1W8, Canada. Amgen Inst, Toronto, ON, Canada. Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. Johns Hopkins Hosp, Div Infect Dis, Baltimore, MD 21287 USA. NIAID, NIH, Bethesda, MD 20892 USA. Univ Washington, Dept Pathobiol, Seattle, WA 98195 USA. Univ Washington, Dept Pathobiol & Pathol, Seattle, WA 98195 USA. Hop Cadolles, Dept Med, Neuchatel, Switzerland. Cleveland Clin Fdn, Dept Cardiol, Cleveland, OH 44195 USA. Cleveland Clin Fdn, Dept Infect Dis, Cleveland, OH 44195 USA. RP Fong, IW (reprint author), Univ Toronto, St Michaels Hosp, Dept Med, 30 Bond St,Room 4-179V, Toronto, ON M5B 1W8, Canada. RI Bachmaier, Kurt/B-6331-2014 OI Bachmaier, Kurt/0000-0002-0299-2707 NR 0 TC 1 Z9 1 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN PY 2000 VL 181 SU 3 BP S519 EP S520 DI 10.1086/315637 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 331MY UT WOS:000088023900030 PM 10839751 ER PT J AU Lee, K Overwijk, WW O'Toole, M Swiniarski, H Restifo, NP Dorner, AJ Wolf, SF Sturmhoefel, K AF Lee, K Overwijk, WW O'Toole, M Swiniarski, H Restifo, NP Dorner, AJ Wolf, SF Sturmhoefel, K TI Dose-dependent and schedule-dependent effects of interleukin-12 on antigen-specific CD8 responses SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Article ID EXPERIMENTAL VIRAL-INFECTIONS; IN-VIVO; IMMUNE-RESPONSES; LYMPHOCYTES-T; TUMOR; IL-12; CELL; REJECTION; SUPPRESSION; ADJUVANT AB Interleukin-12 (IL-12) has been shown to play a central role in the innate and acquired immune responses. Its activities include enhancement of natural killer (NK) and cytotoxic T lymphocyte (CTL) activity and promotion of CD4 Th1 cell development. It has also been shown to provide potent activity as a vaccine adjuvant in generating antibody and T cell responses. We have investigated the efficacy of IL-12 protein in promoting CD8 T cell responses when it is used as an adjuvant for immunization. Studies using, as antigen, cDNA from an autologous antigen (P1A) as well as studies of responses to vaccinia virus-delivered self (gp100) and non-self (beta-galactosidase) antigens show that the dose and schedule of IL-12 administration can significantly affect adjuvant activity, leading to enhancement or suppression of antigen-specific responses. C1 Genet Inst, Andover, MA 01810 USA. NCI, Bethesda, MD 20892 USA. RP Wolf, SF (reprint author), Genet Inst, 1 Burtt Rd, Andover, MA 01810 USA. RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z99 CA999999, Z01 BC010763-01] NR 24 TC 9 Z9 9 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1079-9907 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD JUN PY 2000 VL 20 IS 6 BP 589 EP 596 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 329CC UT WOS:000087887700007 PM 10888115 ER PT J AU Hofman, K AF Hofman, K TI The Global Forum for Bioethics in Research: Report of a meeting, November 1999 SO JOURNAL OF LAW MEDICINE & ETHICS LA English DT Article C1 NIH, John E Fogarty Int Ctr, Div Adv Studies & Policy Anal, Bethesda, MD 20892 USA. RP Hofman, K (reprint author), NIH, John E Fogarty Int Ctr, Div Adv Studies & Policy Anal, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC LAW MEDICINE ETHICS PI BOSTON PA 765 COMMONWEALTH AVE, 16TH FL, BOSTON, MA 02215 USA SN 0277-8459 J9 J LAW MED ETHICS JI J. Law Med. Ethics PD SUM PY 2000 VL 28 IS 2 BP 174 EP 175 DI 10.1111/j.1748-720X.2000.tb00007.x PG 2 WC Ethics; Law; Medical Ethics; Medicine, Legal SC Social Sciences - Other Topics; Government & Law; Medical Ethics; Legal Medicine GA 373UL UT WOS:000165307600007 PM 11185033 ER PT J AU Bodor, J Bodorova, J Gress, RE AF Bodor, J Bodorova, J Gress, RE TI Suppression of T cell function: a potential role for transcriptional repressor ICER SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Review DE interleukin-2; cAMP; CREB; CREM; CBP ID BINDING PROTEIN; CYCLIC-AMP; GENE-EXPRESSION; C-FOS; RHYTHMIC TRANSCRIPTION; AUTOREGULATORY LOOPS; COACTIVATORS P300; NUCLEAR FACTOR; DNA-BINDING; CREB AB In this article, we review the inducible cAMP early repressor (ICER) and its possible critical involvement in modulation of T cell responsiveness by its capacity to transcriptionally attenuate interleukin-2 (IL-2) gene expression, It seems clear that the failure to produce the IL-2 is an important determinant of anergy induction, It is important that the CD28-responsive element (CD28RE), a composite DNA binding element consisting of NFAT and cyclic AMP-responsive (CRE)-like motifs in position of -160 of IL-2 promoter has the high affinity for ICER binding as well as NFAT/ICER complex formation. Moreover, CD28RE with adjacent DNA sequences was also shown to be essential for conferring anergy in T lymphocytes, Because ICER does not possess a transactivation domain required for the recruitment of CBP/p300, the binding of ICER to CD28RE and/or composite motifs containing CRE-like DNA motifs may lead to uncoupling of CBP/p300 thus extinguishing IL-2 expression as well as expression of numderous other cytokines and chemokines. C1 NCI, Expt Immunol Branch, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NCI, Transplantat Therapy Sect, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Gress, RE (reprint author), NCI, Expt Immunol Branch, Div Basic Sci, NIH, Bldg 10,Rm 4B14,10 Ctr Dr, Bethesda, MD 20892 USA. NR 46 TC 40 Z9 41 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JUN PY 2000 VL 67 IS 6 BP 774 EP 779 PG 6 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 323WU UT WOS:000087588600003 PM 10857848 ER PT J AU Blazevic, V Pinto, LA Mac Trubey, C Shearer, GM AF Blazevic, V Pinto, LA Mac Trubey, C Shearer, GM TI Alloantigenic stimulation bypasses CD28-B7 costimulatory blockade by an interleukin-2-dependent mechanism SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE costimulatory molecules; CTLA4Ig; CTL; human ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-INFECTED INDIVIDUALS; T-CELLS; INFLUENZA-VIRUS; LYMPHOCYTES-T; B7 MOLECULES; EXPRESSION; MODEL; MONOCYTES; RESPONSES AB Allogeneic leukocytes have been used as biological adjuvants for T cell-specific responses to tumor and recall antigens, but the mechanisms underlying this effect have not been fully understood, The present study investigates whether alloantigen stimulation of human T cells would bypass an in vitro T cell costimulatory dysfunction induced by CTLA4Ig blockage of CD28-B7 interaction. Here, we demonstrate that costimulation with intact allogeneic leukocytes plus viral antigen circumvented the inhibition of this costimulatory pathway via interleukin-2 (IL-2) production, resulting in the generation of influenza-specific cytotoxic T lymphocytes (CTL). The alloantigen-induced help for influenza-specific CTL generation did not require cell-to-cell contact between responding and allogeneic stimulator cells. These results suggest that alloantigens can be used to bypass defects in the CD28-B7 costimulatory pathway and, therefore, may contribute to understanding the mechanisms of alloantigen-induced restoration of T cell-mediated immunity. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, SAIC Frederick, FCRDC, Intramural Res Support Program, Frederick, MD USA. RP Shearer, GM (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Room 4B36, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CO-56000] NR 47 TC 4 Z9 4 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JUN PY 2000 VL 67 IS 6 BP 817 EP 824 PG 8 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 323WU UT WOS:000087588600009 PM 10857854 ER PT J AU de Alba, E Tjandra, N AF de Alba, E Tjandra, N TI Protein backbone N-15 relaxation rates as a tool for the diagnosis of structure quality SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE NMR; N-15 relaxation; protein structure; dipolar couplings; liquid crystal ID ROTATIONAL DIFFUSION ANISOTROPY; LIQUID-CRYSTALLINE MEDIUM; SUGAR PHOSPHOTRANSFERASE SYSTEM; DIPOLAR COUPLINGS; BIOLOGICAL MACROMOLECULES; ORIENTED MACROMOLECULES; CONFORMATIONAL EXCHANGE; NMR-SPECTROSCOPY; ALIGNMENT TENSOR; TERMINAL DOMAIN AB In the work reported herein we define a structure validation factor that depends on protein backbone N-15 relaxation rates. This is an alternative method to the previously defined quality factors derived from anisotropic chemical shifts or residual dipolar couplings. We have used the structure dependence of N-15 relaxation rates of anisotropically tumbling proteins to calculate this structure diagnosis factor and have used it to demonstrate the improvement of protein structures refined with residual dipolar couplings. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Tjandra, N (reprint author), NHLBI, Biophys Chem Lab, NIH, Bldg 3,Room 418, Bethesda, MD 20892 USA. NR 32 TC 8 Z9 8 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD JUN PY 2000 VL 144 IS 2 BP 367 EP 371 DI 10.1006/jmre.2000.2063 PG 5 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 322RZ UT WOS:000087523700019 PM 10828204 ER PT J AU Frattali, C AF Frattali, C TI Health Care Forum - Cost containment as mother-of-invention SO JOURNAL OF MEDICAL SPEECH-LANGUAGE PATHOLOGY LA English DT Editorial Material ID APHASIA; ADULTS C1 NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Frattali, C (reprint author), NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NR 14 TC 0 Z9 0 U1 0 U2 0 PU SINGULAR PUBLISHING GROUP INC PI SAN DIEGO PA 401 WEST A ST, STE 325, SAN DIEGO, CA 92101-7904 USA SN 1065-1438 J9 J MED SPEECH-LANG PA JI J. Med. Speech-Lang. Pathol. PD JUN PY 2000 VL 8 IS 2 BP XIII EP XV PG 3 WC Audiology & Speech-Language Pathology; Clinical Neurology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology GA 322LM UT WOS:000087511100003 ER PT J AU Moss, SE Tomoeda, CK Bayles, KA AF Moss, SE Tomoeda, CK Bayles, KA TI Comparison of the cognitive-linguistic profiles of Down syndrome adults with and without dementia to individuals with Alzheimer's disease SO JOURNAL OF MEDICAL SPEECH-LANGUAGE PATHOLOGY LA English DT Article ID TANGLES AB Although Down syndrome (DS) adults frequently develop Alzheimer's disease (AD), clinicians are challenged to identify loss of cognitive-linguistic functioning because of a lack of information about the typical cognitive-linguistic capabilities of adults with DS who vary in mental age and ability to read. The purpose of this study was to investigate the relation of age to neuropsychological test performance in 22 nondemented DS adults and two with dementia for whom mental age and reading ability were specified. Thereafter, the performance profiles of the demented and nondemented adults with DS were compared to those of individuals with mild and moderate AD. Chronologic age was found to have a significant inverse relation to both mental age and test performance. The performance of nondemented adults with DS was poorer on measures of linguistic comprehension and visuospatial construction than individuals with mild and moderate AD. Nonetheless, they were superior to patients with mild AD in performance on an episodic memory test. Considerable performance variation was observed in the nondemented adults with DS as a function of reading ability and mental age. The scores of the demented adults with DS were poorer than the mean scores of all individuals with AD. Study results demonstrate the importance of considering chronologic age, mental age, and reading ability in the assessment of cognitive-linguistic skills of individuals with DS. C1 NIH, Ctr Clin, Dept Rehabil Med, Bethesda, MD 20892 USA. Univ Arizona, Natl Ctr Neurogen Commun Disorders, Tucson, AZ 85721 USA. Univ Arizona, Natl Ctr Neurogen Commun Disorders, Dept Speech & Hearing Sci, Tucson, AZ 85721 USA. RP Moss, SE (reprint author), Amer Speech Language Hearing Assoc, Res Resources & Advocacy, 10801 Rockville Pike, Rockville, MD 20852 USA. NR 21 TC 2 Z9 2 U1 0 U2 2 PU SINGULAR PUBLISHING GROUP INC PI SAN DIEGO PA 401 WEST A ST, STE 325, SAN DIEGO, CA 92101-7904 USA SN 1065-1438 J9 J MED SPEECH-LANG PA JI J. Med. Speech-Lang. Pathol. PD JUN PY 2000 VL 8 IS 2 BP 69 EP 81 PG 13 WC Audiology & Speech-Language Pathology; Clinical Neurology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology GA 322LM UT WOS:000087511100004 ER PT J AU Bolin, DR Swain, AL Sarabu, R Berthel, SJ Gillespie, P Huby, NJS Makofske, R Orzechowski, L Perrotta, A Toth, K Cooper, JP Jiang, N Falcioni, F Campbell, R Cox, D Gaizband, D Belunis, CJ Vidovic, D Ito, K Crowther, R Kammlott, U Zhang, XL Palermo, R Weber, D Guenot, J Nagy, Z Olson, GL AF Bolin, DR Swain, AL Sarabu, R Berthel, SJ Gillespie, P Huby, NJS Makofske, R Orzechowski, L Perrotta, A Toth, K Cooper, JP Jiang, N Falcioni, F Campbell, R Cox, D Gaizband, D Belunis, CJ Vidovic, D Ito, K Crowther, R Kammlott, U Zhang, XL Palermo, R Weber, D Guenot, J Nagy, Z Olson, GL TI Peptide and peptide mimetic inhibitors of antigen presentation by HLA-DR class II MHC molecules. Design, structure-activity relationships, and X-ray crystal structures SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID T-CELL RECEPTOR; TETRAPEPTIDE DERIVED INHIBITORS; SOLID-PHASE SYNTHESIS; BETA-D-GLUCOSE; 3-DIMENSIONAL STRUCTURE; BINDING PEPTIDES; PROTEIN HLA-DR1; CATHEPSIN-B; COMPLEX; ACIDS AB Molecular features of ligand binding to MHC class II HLA-DR molecules have been elucidated through a combination of peptide structure-activity studies and structure-based drug design, resulting in analogues with nanomolar affinity in binding assays. Stabilization of lead compounds against cathepsin B cleavage by N-methylation of noncritical backbone NH groups or by dipeptide mimetic substitutions has generated analogues that compete effectively against protein antigens in cellular assays, resulting in inhibition of T-cell proliferation. Crystal structures of four ternary complexes of different peptide mimetics with the rheumatoid arthritis-linked MHC DRB1*0401 and the bacterial superantigen SEB have been obtained. Peptide-sugar hybrids have also been identified using a structure-based design approach in which the sugar residue replaces a dipeptide. These studies illustrate the complementary roles played by phage display library methods, peptide analogue SAR, peptide mimetics substitutions, and structure-based drug design in the discovery of inhibitors of antigen presentation by MHC class II HLA-DR molecules. C1 Hoffmann La Roche Inc, Roche Res Ctr, Nutley, NJ 07110 USA. RP Swain, AL (reprint author), NIH, Natl Ctr Res Resources, 6705 Rockledge Dr, Bethesda, MD 20892 USA. NR 49 TC 64 Z9 65 U1 3 U2 19 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUN 1 PY 2000 VL 43 IS 11 BP 2135 EP 2148 DI 10.1021/jm000034h PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 320XG UT WOS:000087425700007 PM 10841792 ER PT J AU Jacobson, KA Ji, XD Li, AH Melman, N Siddiqui, MA Shin, KJ Marquez, VE Ravi, RG AF Jacobson, KA Ji, XD Li, AH Melman, N Siddiqui, MA Shin, KJ Marquez, VE Ravi, RG TI Methanocarba analogues of purine nucleosides as potent and selective adenosine receptor agonists SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID NECROSIS-FACTOR-ALPHA; A(1) RECEPTOR; A(3) RECEPTORS; SUGAR RING; N-6-BENZYLADENOSINE-5'-URONAMIDES; PHARMACOLOGY; INHIBITION; ACTIVATION; RAT AB Adenosine receptor agonists have cardioprotective, cerebroprotective, and antiinflammatory properties. We report that a carbocyclic modification of the ribose moiety incorporating ring constraints is a general approach for the design of A(1) and A(3) receptor agonists having favorable pharmacodynamic properties. While simple carbocyclic substitution of adenosine agonists greatly diminishes potency, methanocarba-adenosine analogues have now defined the role of sugar puckering in stabilizing the active adenosine receptor-bound conformation and thereby have allowed identification of a favored isomer. In such analogues a fused cyclopropane moiety constrains the pseudosugar ring of the nucleoside to either a Northern (N) or Southern (S) conformation, as defined in the pseudorotational cycle. In binding assays at A(1), A(2A), and A(3) receptors, (N)-methanocarba-adenosine was of higher affinity than the (S)-analogue, particularly at the human A(3) receptor (N/S affinity ratio of 150). (N)-Methanocarba analogues of various N-6-substituted adenosine derivatives, including cyclopentyl and 3-iodobenzyl, in which the parent compounds are potent agonists at either A(1) or A(3) receptors, respectively, were synthesized. The N-6-cyclopentyl derivatives were A(1) receptor-selective and maintained high efficacy at recombinant human but not rat brain A(1) receptors, as indicated by stimulation of binding of [S-35] GTP-gamma-S. The (N)-methanocarba-N-6-(3-iodobenzyl)adenosine and its 2-chloro derivative had K-i values of 4.1 and 2.2 nM at A(3) receptors, respectively, and were highly selective partial agonists. Partial agonism combined with high functional potency at A(3) receptors (EC50 < 1 nM) may produce tissue selectivity. In conclusion, as for P2Y(1) receptors, at least three adenosine receptors favor the ribose (N)-conformation. C1 NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NCI, Med Chem Lab, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031117-20, Z99 DK999999] NR 41 TC 101 Z9 102 U1 0 U2 5 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 JUN 1 PY 2000 VL 43 IS 11 BP 2196 EP 2203 DI 10.1021/jm9905965 PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 320XG UT WOS:000087425700013 PM 10841798 ER PT J AU Paz, K Boura-Halfon, S Wyatt, LS LeRoith, D Zick, Y AF Paz, K Boura-Halfon, S Wyatt, LS LeRoith, D Zick, Y TI The juxtamembrane but not the carboxyl-terminal domain of the insulin receptor mediates insulin's metabolic functions in primary adipocytes and cultured hepatoma cells SO JOURNAL OF MOLECULAR ENDOCRINOLOGY LA English DT Article ID PROTEIN-KINASE-B; FACTOR-I RECEPTORS; GLUCOSE-TRANSPORT; TYROSINE KINASE; ADIPOSE-CELLS; ISOLATED RAT; PHOSPHATIDYLINOSITOL 3'-KINASE; PHOSPHOTYROSINE PROTEIN; GLUT4 TRANSLOCATION; 3T3-L1 ADIPOCYTES AB Insulin-stimulated signaling pathways are activated upon interactions between the intracellular domains of the receptor and its downstream effecters. Insulin receptor substrate proteins (IRS-1, -2, -3 and -4) are the best-studied substrates for the insulin receptor kinase (IRK). We have previously shown that IRS-1 and IRS-2 interact with the juxtamembrane (JM) but not with the carboxyl-terminal (CT) region of the insulin receptor (IR) in vitro. However, the precise role of these IR regions in mediating insulin's bioeffects is still unresolved. In the present work we made use of vaccinia virus as a vector for quantitative expression of the JM and CT domains within the cytoplasm of physiologically insulin-responsive primary rat adipocytes and rat hepatoma Fao cells. We could demonstrate that overexpression of either the JM or the CT domains did not inhibit either insulin binding or insulin-stimulated receptor autophosphorylation. In contrast, metabolic effects such as insulin-induced glucose utilization in adipocytes, and insulin-induced amino acid utilization in Fao hepatoma cells were inhibited (70-80%) in cells over-expressing the JM but not the CT domains of IR. The inhibitory effects of the overexpressed JM domain were accompanied by inhibition of insulin-stimulated IRS-1 phosphorylation, decreased IRS-1-associated PI3K activity, and decreased phosphorylation of the downstream effectors of PI3K, PKB and p70 S6K. Insulin-stimulated thymidine incorporation in Fao cells was also inhibited (40%) upon overexpression of the JM but not the CT region of IR. Our findings suggest that interactions between the JM region of IR and its downstream effecters are obligatory for insulin-stimulated metabolic functions in physiologically relevant insulin responsive cells. They also rule out the possibility that interaction of proteins, including PI3K, with the CT domain can provide an alternative pathway. C1 Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Mol & Cellular Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Zick, Y (reprint author), Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. NR 57 TC 7 Z9 7 U1 1 U2 1 PU SOC ENDOCRINOLOGY PI BRISTOL PA 17/18 THE COURTYARD, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4NQ, ENGLAND SN 0952-5041 J9 J MOL ENDOCRINOL JI J. Mol. Endocrinol. PD JUN PY 2000 VL 24 IS 3 BP 419 EP 432 DI 10.1677/jme.0.0240419 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 325WV UT WOS:000087700200015 PM 10828835 ER PT J AU Matthews, CC Figueiredo, DM Wollack, JB Fairweather, NF Dougan, G Hallewell, RA Cadet, JL Fishman, PS AF Matthews, CC Figueiredo, DM Wollack, JB Fairweather, NF Dougan, G Hallewell, RA Cadet, JL Fishman, PS TI Protective effect of supplemental superoxide dismutase on survival of neuronal cells during starvation - Requirement for cytosolic distribution SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE Cu2+/Zn2+ superoxide dismutase; tetanus toxin C fragment; green fluorescent protein; neurons; cultured; N18-RE-105 ID RETROGRADE AXONAL-TRANSPORT; CENTRAL-NERVOUS-SYSTEM; TETANUS TOXIN; TRANSGENIC MICE; TRANSSYNAPTIC TRANSFER; FREE-RADICALS; FRAGMENT-C; OXYGEN; ATTENUATION; ENZYME AB There is evidence that raising cellular levels of Cu2+/Zn2+ superoxide dismutase (SOD1) can protect neurons from oxidative injury. We compared a novel method of elevating neuronal SOD activity using a recombinant hybrid protein composed of the atoxic neuronal binding domain of tetanus toxin (C fragment or TTC) and human SOD1 (hSOD1) with increasing cellular SOD levels through overexpression. Fetal murine cortical neurons or N18-RE-105 cells were incubated with the TTC-hSOD1 hybrid protein and compared to cells constitutively expressing hSOD1 for level of SOD activity, cellular localization of hSOD1, and capacity to survive glucose and pyruvate starvation. Cells incubated with TTC-hSOD1 showed a threefold increase in cellular SOD activity over control cells. This level of increase was comparable to Petal cortical neurons from transgenic mice constitutively expressing hSOD1 and transfected N18-RE-205 cells expressing a green fluorescent protein-hSOD1 fusion protein (GFP-hSOD1). Human SOD1 was distributed diffusely throughout the cytoplasm of the transgenic murine neurons and transfected N18-RE-105 cells. In contrast, cells incubated with TTC-hSOD1 showed hSOD1 localized to the cell surface and intra-cytoplasmic vesicles. The cells expressing hSOD1 showed enhanced survival in glucose- and pyruvate-free medium. Neither cortical neurons nor N18-RE-105 cells incubated in TTC-hSOD1 showed increased survival during starvation. Access to the site where toxic superoxides are generated or their targets may be necessary for the protective function of SOD1. C1 Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. Vet Affairs Med Ctr, Baltimore, MD 21201 USA. Imperial Coll, Dept Biochem, London SW7 2AZ, England. Natl Inst Drug Abuse, Baltimore, MD 21224 USA. RP Matthews, CC (reprint author), Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. FU NIA NIH HHS [1-P01-AG12992-01] NR 46 TC 9 Z9 10 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD JUN PY 2000 VL 14 IS 3 BP 155 EP 166 DI 10.1385/JMN:14:3:155 PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 345QX UT WOS:000088827600004 PM 10984191 ER PT J AU Mattson, MP Haddon, RC Rao, AM AF Mattson, MP Haddon, RC Rao, AM TI Molecular functionalization of carbon nanotubes and use as substrates for neuronal growth SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE brain; growth cones; hippocampus; hydroxynonenal; nanotechnology ID CONE GUIDANCE; LIPID-PEROXIDATION; CALCIUM REGULATION; CHEMISTRY; PROTEINS; PRODUCT AB Carbon nanotubes are strong, flexible, conduct electrical current, and can be functionalized with different molecules, properties that may be useful in basic and applied neuroscience research. We report the first application of carbon nanotube technology to neuroscience research. Methods were developed for growing embryonic rat-brain neurons on multiwalled carbon nanotubes. On unmodified nanotubes, neurons extend only one or two neurites, which exhibit very few branches. In contrast, neurons grown on nanotubes coated with the bioactive molecule 4-hydroxynonenal elaborate multiple neurites, which exhibit extensive branching. These findings establish the feasability of using nanotubes as substrates for nerve cell growth and as probes of neuronal function at the nanometer scale. C1 Univ Kentucky, Sanders Brown Res Ctr Aging, Lexington, KY 40536 USA. Univ Kentucky, Dept Anat & Neurobiol, Lexington, KY 40536 USA. NIA, Neurosci Lab, Baltimore, MD 21224 USA. Univ Kentucky, Dept Chem & Phys, Lexington, KY 40506 USA. Univ Kentucky, Ctr Appl Energy Res, Lexington, KY 40511 USA. Univ Kentucky, Dept Phys & Astron, Lexington, KY 40511 USA. RP Mattson, MP (reprint author), Univ Kentucky, Sanders Brown Res Ctr Aging, Lexington, KY 40536 USA. RI Haddon, Robert/A-2528-2008; Mattson, Mark/F-6038-2012 OI Haddon, Robert/0000-0002-7903-5139; NR 27 TC 440 Z9 455 U1 4 U2 67 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD JUN PY 2000 VL 14 IS 3 BP 175 EP 182 DI 10.1385/JMN:14:3:175 PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 345QX UT WOS:000088827600006 PM 10984193 ER PT J AU Pettit, GR Knight, JC Collins, JC Herald, DL Pettit, RK Boyd, MR Young, VG AF Pettit, GR Knight, JC Collins, JC Herald, DL Pettit, RK Boyd, MR Young, VG TI Antineoplastic agents 430. Isolation and structure of cribrostatins 3, 4, and 5 from the Republic of Maldives Cribrochalina species SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID MARINE SPONGE CRIBROCHALINA; RENIERA SP; ANTIMICROBIAL METABOLITES; ACETYLENIC ALCOHOLS; ANTITUMOR-ACTIVITY; SAFRAMYCIN-A; VASCULUM; ECTEINASCIDIN-743; OLEMDA; STEREOCHEMISTRY AB Continued investigation of cancer-cell growth-inhibitory constituents of the blue marine sponge Cribrochalina sp. has led to discovery of cribrostatins 3 (4a), 4 (5), and 5 (4b) in 10(-5) to 10(-7) % of the wet weight. The structure of cribrostatin 3 (4a) was determined by results of high field (500 MHz) H-1 and C-13 NMR and HRMS interpretations. The same general approach to the structures of cribrostatins 4 (5) and 5 (4b) was completed by X-ray crystal structure determinations. Cribrostatins 3, 4, and 5 provided significant cancer cell line inhibitory activities. Cribrostatins 1 and 2(2) and the newly isolated cribrostatins 3-5 displayed antibacterial and/or antifungal activities. C1 Arizona State Univ, Canc Res Inst, Tempe, AZ 85287 USA. Arizona State Univ, Dept Chem & Biochem, Tempe, AZ 85287 USA. NCI, Lab Drug Discovery Res & Dev, DTP, DCTD,Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Univ Minnesota, Dept Chem, Minneapolis, MN 55455 USA. RP Pettit, GR (reprint author), Arizona State Univ, Canc Res Inst, Tempe, AZ 85287 USA. FU NCI NIH HHS [CA44344-01-10] NR 40 TC 73 Z9 74 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD JUN PY 2000 VL 63 IS 6 BP 793 EP 798 DI 10.1021/np990618q PG 6 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 329TA UT WOS:000087922900013 PM 10869203 ER PT J AU Nakamura, K Wright, DA Wiatr, T Kowlessur, D Milstien, S Lei, XG Kang, UJ AF Nakamura, K Wright, DA Wiatr, T Kowlessur, D Milstien, S Lei, XG Kang, UJ TI Preferential resistance of dopaminergic neurons to the toxicity of glutathione depletion is independent of cellular glutathione peroxidase and is mediated by tetrahydrobiopterin SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE Parkinson's disease; glutathione; L-buthionine-[S,R]-sulfoximine; tert-butyl hydroperoxide; tetrahydrobiopterin; monochlorobimane; sepiapterin ID NITRIC-OXIDE SYNTHASE; PARKINSONIAN SUBSTANTIA-NIGRA; DOPA-RESPONSIVE DYSTONIA; LEWY-BODY-DISEASE; OXIDATIVE STRESS; RAT-BRAIN; BUTYL HYDROPEROXIDE; SELECTIVE INCREASE; HYDROGEN-PEROXIDE; KINETIC-ANALYSIS AB Depletion of glutathione in the substantia nigra is one of the earliest changes observed in Parkinson's disease (PD) and could initiate dopaminergic neuronal degeneration, Nevertheless, experimental glutathione depletion does not result in preferential toxicity to dopaminergic neurons either in vivo or in vitro. Moreover, dopaminergic neurons in culture are preferentially resistant to the toxicity of glutathione depletion, possibly owing to differences in cellular glutathione peroxidase (GPx1) function. However, mesencephalic cultures from GPx1 -knockout and wild-type mice were equally susceptible to the toxicity of glutathione depletion, indicating that glutathione also has GPx1-independent functions in neuronal survival. In addition, dopaminergic neurons were more resistant to the toxicity of both glutathione depletion and treatment with peroxides than nondopaminergic neurons regardless of their GPx1 status. To explain this enhanced antioxidant capacity, we hypothesized that tetrahydrobiopterin (BH(4)) may function as an antioxidant in dopaminergic neurons. In agreement, inhibition of BH(4) synthesis increased the susceptibility of dopaminergic neurons to the toxicity of glutathione depletion, whereas increasing BH(4) levels completely protected nondopaminergic neurons against it. Our results suggest that BH(4) functions as a complementary antioxidant to the glutathione/glutathione peroxidase system and that changes in BH(4) levels may contribute to the pathogenesis of PD. C1 Univ Chicago, Dept Neurol, Chicago, IL 60637 USA. Univ Chicago, Dept Neurobiol, Chicago, IL 60637 USA. Univ Chicago, Dept Pharmacol, Chicago, IL 60637 USA. Univ Chicago, Dept Physiol, Chicago, IL 60637 USA. Univ Chicago, Comm Neurobiol, Chicago, IL 60637 USA. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. Cornell Univ, Dept Anim Sci, Ithaca, NY 14853 USA. RP Kang, UJ (reprint author), Univ Chicago, Dept Neurol, 5841 S Maryland Ave,MC 2030,S225B, Chicago, IL 60637 USA. EM u-kang@uchicago.edu RI Wright, David/K-7898-2012 OI Wright, David/0000-0002-2785-0254 FU NIDDK NIH HHS [R01 DK53018]; NIMH NIH HHS [F30 MH11986] NR 70 TC 37 Z9 37 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUN PY 2000 VL 74 IS 6 BP 2305 EP 2314 DI 10.1046/j.1471-4159.2000.0742305.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 312XG UT WOS:000086968800009 PM 10820190 ER PT J AU Zatz, M Gastel, JA Heath, JR Klein, DC AF Zatz, M Gastel, JA Heath, JR Klein, DC TI Chick pineal melatonin synthesis: Light and cyclic AMP control abundance of serotonin N-acetyltransferase protein SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE pineal; circadian rhythms; proteosomal proteolysis; cyclic AMP; melatonin; photoreceptors; serotonin N-acetyltransferase ID MESSENGER-RNA; PHOTOENDOCRINE TRANSDUCTION; MOLECULAR REGULATION; CELLS; RHYTHM; GLAND; NOREPINEPHRINE; OSCILLATOR; PACEMAKER; CULTURE AB Melatonin production in the pineal gland is high at night and low during the day. This rhythm reflects circadian changes in the activity of serotonin N-acetyltransferase [arylalkylamine N-acetyltransferase (AA-NAT); EC 2.3.1.87], the penultimate enzyme in melatonin synthesis. The rhythm is generated by an endogenous circadian clock. In the chick, a clock is located in the pinealocyte, which also contains two phototransduction systems. One controls melatonin production by adjusting the clock and the other acts distal to the clock, via cyclic AMP mechanisms, to switch melatonin synthesis on and off. Unlike the clock in these cells, cyclic AMP does not appear to regulate activity by altering AA-NAT mRNA levels. The major changes in AA-NAT mRNA levels induced by the clock seemed likely (but not certain) to generate comparable changes in AA-NAT protein levels and AA-NAT activity. Cyclic AMP might also regulate AA-NAT activity via changes in protein levels, or it might act via other mechanisms, including posttranslational changes affecting activity. We measured AA-NAT protein levels and enzyme activity in cultured chick pineal cells and found that they correlated well under all conditions, They rose and fell spontaneously with a circadian rhythm. They also rose in response to agents that increase cyclic AMP. They were raised by agents that increase cyclic AMP, such as forskolin, and lowered by agents that decrease cyclic AMP, such as light and norepinephrine. Thus, both the clock and cyclic AMP can control AA-NAT activity by altering the total amount of AA-NAT protein. Effects of proteosomal proteolysis inhibitors suggest that changes in AA-NAT protein levels, in turn, reflect changes in the rate at which the protein is destroyed by proteosomal proteolysis. It is likely that cyclic AMP-induced changes in AA-NAT protein levels mediate rapid changes in chick pineal AA-NAT activity. Our results indicate that light can rapidly regulate the abundance of a specific protein (AA-NAT) within a photoreceptive cell. C1 NIMH, SBP, LCMR, Bethesda, MD 20892 USA. NICHHD, Sect Neuroendocrinol, Dev Neurobiol Lab, Bethesda, MD 20892 USA. RP Zatz, M (reprint author), NIMH, SBP, LCMR, Bldg 36,Room 2A-11,36 Convent Dr,MSC 4068, Bethesda, MD 20892 USA. NR 28 TC 41 Z9 41 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUN PY 2000 VL 74 IS 6 BP 2315 EP 2321 DI 10.1046/j.1471-4159.2000.0742315.x PG 7 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 312XG UT WOS:000086968800010 PM 10820191 ER PT J AU Key, S Wray, S AF Key, S Wray, S TI Two olfactory placode derived galanin subpopulations: Luteinizing hormone-releasing hormone neurones and vomeronasal cells SO JOURNAL OF NEUROENDOCRINOLOGY LA English DT Article DE gonadotrophin releasing hormone; olfactory placode; vomeronasal organ; mRNA; in situ hybridization histochemistry ID CENTRAL-NERVOUS-SYSTEM; GENE-EXPRESSION; MESSENGER-RNA; GNRH NEURONS; EXPLANT CULTURES; NEUROPEPTIDE-Y; LHRH NEURONS; FEMALE RAT; C-FOS; GONADOTROPIN AB In adult rodents, the peptide galanin is expressed in a subpopulation of hypothalamic luteinizing hormone-releasing hormone (LHRH) neurones in an activity-dependent manner. in this investigation, we examined whether galanin mRNA expression in mice was activated coincident with LHRH mRNA expression, as LHRH neurones differentiate from the olfactory placode. Using in situ hybridization, we show (i) that galanin mRNA is coexpressed in LHRH neurones prenatally, (ii) that there is a decrease in galanin mRNA expression relative to LHRH mRNA expression once LHRH mRNA positive/galanin mRNA positive neurones migrate out of the olfactory pit and into the nasal septum, and (iii) the presence of a novel population of galanin mRNA positive/LHRH mRNA negative expressing neurones in the olfactory pit/vomeronasal organ which do not migrate into the central nervous system (CNS). This study demonstrates that there are at least two populations of galanin mRNA expressing neurones arising from the olfactory placode; one that remains in nasal regions, is LHRH mRNA negative and whose function is unknown, and one which is coexpressed with LHRH, In addition, the temporal expression of galanin mRNA in LHRH cells indicates that initial activation and subsequent inactivation of galanin mRNA expression is independent of synaptic CNS connections. C1 NINDS, Cellular & Dev Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Wray, S (reprint author), NINDS, Cellular & Dev Neurobiol Sect, NIH, Bldg 36,Room 5A-25, Bethesda, MD 20892 USA. OI wray, susan/0000-0001-7670-3915 NR 57 TC 16 Z9 16 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0953-8194 J9 J NEUROENDOCRINOL JI J. Neuroendocrinol. PD JUN PY 2000 VL 12 IS 6 BP 535 EP 545 DI 10.1046/j.1365-2826.2000.00486.x PG 11 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 320VA UT WOS:000087420000010 PM 10844582 ER PT J AU Singer, BA Tresser, NJ Frank, JA McFarland, HF Biddison, WE AF Singer, BA Tresser, NJ Frank, JA McFarland, HF Biddison, WE TI Induction of experimental allergic encephalomyelitis in the NIH minipig SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE experimental allergic encephalomyelitis; minipig; magnetic resonance imaging; demyelination; multiple sclerosis; lymphocyte ID MULTIPLE-SCLEROSIS; OLIGODENDROCYTES; IMMUNOPEROXIDASE; CELLS; BLOOD AB Experimental allergic encephalomyelitis (EAE) was induced in the NIH minipig to create a large animal model of multiple sclerosis with a well-characterized immune system. Sixteen NIH minipigs were inoculated with minipig spinal cord homogenate (SCH). The clinical course was primarily monophasic, but re-induction was possible. CNS and blood lymphocytes specifically proliferated to SCH. Flow cytometry of CNS-isolated cells and SCH-stimulated PBMC revealed a shift to CD4(+) CD8(+) cells. Pathology demonstrated demyelination in the CNS white matter with perivascular mononuclear cell infiltrates of CD3(+)CD4(+)CD45(-) lymphocytes with a subset CD8(+). Pathology and in vitro SCH responses implicate a central role of CD4(+) lymphocytes in swine EAE. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. NIH, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. RP Singer, BA (reprint author), 1 Barnes Jewish Plaza,Suite 16304, St Louis, MO 63110 USA. NR 23 TC 10 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD JUN 1 PY 2000 VL 105 IS 1 BP 7 EP 19 DI 10.1016/S0165-5728(99)00275-1 PG 13 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 310HV UT WOS:000086821200002 PM 10713359 ER PT J AU Baxter, MG Parker, A Lindner, CCC Izquierdo, AD Murray, EA AF Baxter, MG Parker, A Lindner, CCC Izquierdo, AD Murray, EA TI Control of response selection by reinforcer value requires interaction of amygdala and orbital prefrontal cortex SO JOURNAL OF NEUROSCIENCE LA English DT Article DE amygdala; crossed-lesion technique; decision-making; orbital prefrontal cortex; reinforcer devaluation; representation; rhesus monkey ID ORBITOFRONTAL CORTEX; RHESUS-MONKEYS; DECISION-MAKING; BASOLATERAL AMYGDALA; RHINAL CORTEX; FRONTAL-LOBE; LESIONS; PREFERENCE; MACACA; DAMAGE AB Goal-directed actions are guided by expected outcomes of those actions. Humans with bilateral damage to ventromedial prefrontal cortex, or the amygdala, are deficient in their ability to use information about positive and negative outcomes to guide their choice behavior. Similarly, rats and monkeys with orbital prefrontal or amygdala damage have been found to be impaired in their responses to changing values of outcomes. In the present study, we tested whether direct, functional interaction between the amygdala and the orbital prefrontal cortex is necessary for guiding behavior based on expected outcomes. Unlike control monkeys, rhesus monkeys with surgical disconnection of these two structures, achieved by crossed unilateral lesions of the amygdala in one hemisphere and orbital prefrontal cortex in the other, combined with forebrain commissurotomy, were unable to adjust their choice behavior after a change in the outcome (here, a reduction in the value of a particular reinforcer). The lesions did not affect motivation to work for a food reinforcer, or food preferences, per se. Hence, the amygdala and orbital prefrontal cortex act as part of an integrated neural system guiding decision-making and adaptive response selection. C1 NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. Univ Nottingham, Sch Psychol, Nottingham NG7 2RD, England. George Washington Univ, Dept Psychol, Washington, DC 20052 USA. RP Murray, EA (reprint author), NIMH, Neuropsychol Lab, Bldg 49,Room 1B80,49 Convent Dr, Bethesda, MD 20892 USA. OI Murray, Elisabeth/0000-0003-1450-1642 NR 37 TC 373 Z9 375 U1 6 U2 23 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 1 PY 2000 VL 20 IS 11 BP 4311 EP 4319 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 317ZA UT WOS:000087257300042 PM 10818166 ER PT J AU Kouri, JG Chen, MY Watson, JC Oldfield, EH AF Kouri, JG Chen, MY Watson, JC Oldfield, EH TI Resection of suprasellar tumors by using a modified transsphenoidal approach - Report of four cases SO JOURNAL OF NEUROSURGERY LA English DT Article DE suprasellar tumor; craniopharyngioma; hemangioblastoma; von Hippel-Lindau disease; transsphenoidal approach ID SURGICAL-MANAGEMENT; CRANIOPHARYNGIOMA; HEMANGIOBLASTOMA; CHILDHOOD; CHILDREN; SURGERY; MICROSURGERY; POPULATION; ENDOCRINE; ADENOMAS AB Generally accepted contraindications to using a transsphenoidal approach for resection of turners that arise in or extend into the suprasellar region include a normal-sized sella turcica, normal pituitary function, and adherence of tumor to viral intracranial structures. Thus, the transsphenoidal approach has traditionally been restricted to the removal of tumors involving the pituitary fossa and, occasionally, to suprasellar extensions of such tumors if the sella is enlarged. However, conventional transcranial approaches to the suprasellar region require significant brain retraction and offer limited visualization of contralateral tumor extension and the interface between the turner and adjacent structures, such as the hypothalamus, third ventricle, optic apparatus, and major arteries. In this paper the authors describe successful removal of suprasellar tumors by using a modified transsphenoidal approach that circumvents some of the traditional contraindications to transsphenoidal surgery, while avoiding some of the disadvantages of transcranial surgery. Four patients harbored tumors (two craniopharyngiomas and two hemangioblastomas) that arose in the suprasellar region and were located either entirely (three patients) or primarily (one patient) within the suprasellar space. All patients had a normal-sized sella turcica. Preoperatively, three of the four patients had significant endocrinological deficits signifying involvement of the hypothalamus, pituitary stalk, or pituitary gland. Two patients exhibited preoperative visual field defects. For tumor excision. a recently described modification of the traditional transsphenoidal approach was used. Using this modification, one removes the posterior portion of the planum sphenoidale, allowing access to the suprasellar region. Total resection of tumor was achieved (including absence of residual tumor on follow-up imaging) in three of the four patients. In the remaining patient, total removal was not possible because of adherence of tumor to the hypothalamus and midbrain. One postoperative cerebrospinal fluid leak occurred. postoperative endocrinological function was worse than preoperative function in one patient. No other new postoperative endocrinological or neurological deficits were encountered. This study demonstrates the feasibility of using a modified transsphenoidal approach for resection of certain suprasellar, nonpituitary tumors. C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Oldfield, EH (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,Room 5D37-1414, Bethesda, MD 20892 USA. NR 41 TC 124 Z9 131 U1 0 U2 1 PU AMER ASSOC NEUROLOGICAL SURGEONS PI CHARLOTTESVILLE PA UNIV VIRGINIA, 1224 WEST MAIN ST, STE 450, CHARLOTTESVILLE, VA 22903 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD JUN PY 2000 VL 92 IS 6 BP 1028 EP 1035 DI 10.3171/jns.2000.92.6.1028 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 318XJ UT WOS:000087309700018 PM 10839266 ER PT J AU Heiss, JD Oldfield, EH AF Heiss, JD Oldfield, EH TI Pathophysiology of syringomyelia - Response SO JOURNAL OF NEUROSURGERY LA English DT Letter ID I MALFORMATION C1 NINDS, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. RP Heiss, JD (reprint author), NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 14 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI CHARLOTTESVILLE PA UNIV VIRGINIA, 1224 WEST MAIN ST, STE 450, CHARLOTTESVILLE, VA 22903 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD JUN PY 2000 VL 92 IS 6 BP 1071 EP 1073 PG 3 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 318XJ UT WOS:000087309700035 ER PT J AU Croft, BY AF Croft, BY TI NCI biomedical imaging program initiatives SO JOURNAL OF NUCLEAR MEDICINE LA English DT News Item C1 NCI, Biomed Imaging Program, Bethesda, MD 20892 USA. RP Croft, BY (reprint author), NCI, Biomed Imaging Program, Bethesda, MD 20892 USA. RI Croft, Barbara/D-1248-2013 OI Croft, Barbara/0000-0003-2544-150X NR 0 TC 0 Z9 0 U1 0 U2 0 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 2000 VL 41 IS 6 BP 34N EP 34N PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 364JE UT WOS:000089888600010 ER PT J AU Karamychev, VN Panyutin, IG Kim, MK Le, N Paik, CH Carrasquillo, JA Reed, MW Neumann, RD AF Karamychev, VN Panyutin, IG Kim, MK Le, N Paik, CH Carrasquillo, JA Reed, MW Neumann, RD TI DNA cleavage by In-111-labeled oligodeoxyribonucleotide SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE Auger electrons; In-111; DNA double-strand breaks ID TRIPLEX-FORMING-OLIGONUCLEOTIDES; I-125 LABELED OLIGONUCLEOTIDES; DECAY; DAMAGE; OLIGODEOXYNUCLEOTIDES; MODEL; I125 AB We studied the fine structure of DNA damage produced by the decay of In-111 incorporated into duplex and tripler DNA strands to evaluate the usefulness of this radionuclide for sequence-specific DNA cleavage. Methods: Oligodeoxyribonucleotides (ODNs) were prepared with In-111 attached by diethylenetriaminepentaacetic acid (DTPA) at the 5' end or 3' end through a long chemical linker or to an internal nucleotide position through a short linker. Subsequent formation of DNA duplexes and triplexes was confirmed by gel electrophoresis. The In-111-induced breaks were assayed in denaturing polyacrylamide gel electrophoresis with a single-nucleotide resolution. Results: In-111-labeled oligonucleotides of high specific activity (740-1554 TBq/mmol) were synthesized. The presence of the bulky In-111-DTPA group did not impede duplex or tripler formation. Localized DNA breaks were observed in all duplexes and triplexes formed. The majority of DNA breaks in duplex formations were located within +/-10 nucleotides from the site of attachment of the In-111-bearing linker. The yield of DNA breaks per decay was 0.38 in a duplex with internally modified ODNs. This is nearly 2 times less than the yield of DNA breaks in the same duplex with I-125 attached through the same linker. The yield of DNA breaks in the pyrimidine and purine strands of DNA triplexes with In-111 attached to the tripler-forming ODNs through the linkers of different length varied from 0.05 to 0.10. The distribution of DNA breaks was wider in comparison with the duplex experiment. The lower yields of breaks per In-111 decay compared with I-125 may be not only the result of lower deposited energy but also of the ionic repulsion of the negatively charged In-111-DTPA group from the DNA strands. Conclusion: We have shown that decay of In-111 produces highly localized DNA breaks. In-111 introduced into triplex- and duplex-forming ODNs through hydrocarbon linkers produces sequence-specific DNA strand breaks with an efficiency nearly comparable with that of I-125. These findings are supportive of our proposed use of In-111-ODNs for gene-specific radiotherapy. C1 NIH, Warren G Magnuson Clin Ctr, Dept Nucl Med, Bethesda, MD 20892 USA. Epoch Pharmaceut Inc, Bothell, WA USA. Novosibirsk Bioorgan Chem Inst, Novosibirsk 630090, Russia. RI Carrasquillo, Jorge/E-7120-2010 NR 32 TC 15 Z9 16 U1 0 U2 4 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD JUN PY 2000 VL 41 IS 6 BP 1093 EP 1101 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 364JE UT WOS:000089888600033 PM 10855641 ER PT J AU Cocco, P Rice, CH Chen, JQQ McCawley, M McLaughlin, JK Dosemeci, M AF Cocco, P Rice, CH Chen, JQQ McCawley, M McLaughlin, JK Dosemeci, M TI Non-malignant respiratory diseases and lung cancer among Chinese workers exposed to silica SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID AIRWAYS OBSTRUCTION; NONSMOKING WOMEN; POTTERY WORKERS; MORTALITY; RISK; MINERS AB The objective of this study was to explore whether a medical history for non-malignant respiratory disease contributes to an increased lung cancer risk among workers exposed to silica. We analyzed data from a nested case-control study in 29 dusty workplaces in China. The study population consisted of 316 lung cancer cases and 1356 controls matched to cases by facility type and decade of birth who were alive at the time of diagnosis of the index case and who were identified in a follow-up study of about 68, 000 workers. Age at first exposure and cigarette smoking were accounted for in the analysis, Smoking was the main risk factor for both lung cancer and chronic bronchitis. Lung cancer risk showed a modest association with silicosis and with cumulative silica exposure, which did not vary by history of previous pulmonary tuberculosis. Among subjects without a medical history for chronic bronchitis or asthma, lung cancer risk was associated with silicosis (odds ratio [OR] 1.6; 95% confidence interval [CI] 1.1 to 2.2), and it was increased in each quartile of cumulative silica exposure However, risk was not elevated in the highest quartile (OR, 1.3 1.6, 1.8, 1.4). Among subjects with a medical history for chronic bronchitis or asthma, lung cancer risk was associated with neither silicosis (subjects with chronic bronchitis: OR, 0.6; subjects with asthma: OR, 0.4) nor with silica exposure. In this Study population, we observed a modest association of both silicosis and cumulative exposure to silica with lung cancer among subjects who were not previously diagnosed with chronic bronchitis or asthm, but not among subjects who had a medical history for either disease. Risk of lung cancer associated with silicosis or cumulative exposure to silica did not vary by previous medical history of pulmonary tuberculosis. C1 NCI, Occupat Epidemiol Branch, Bethesda, MD 20892 USA. Univ Cagliari, Ist Med Lavoro, I-09124 Cagliari, Italy. Univ Cincinnati, Dept Environm Hlth, Cincinnati, OH 45221 USA. Tongji Med Univ, Dept Labor Hlth & Occupat Dis, Wuhan, Peoples R China. NIOSH, Morgantown, WV USA. Int Epidemiol Inst, Rockville, MD USA. RP Dosemeci, M (reprint author), NCI, Occupat Epidemiol Branch, 6120 Execut Blvd,EPS Room 8002, Bethesda, MD 20892 USA. NR 19 TC 18 Z9 18 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-2752 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD JUN PY 2000 VL 42 IS 6 BP 639 EP 644 DI 10.1097/00043764-200006000-00014 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 325ZC UT WOS:000087706300012 PM 10874657 ER PT J AU Park, J Banaji, MR AF Park, J Banaji, MR TI Mood and heuristics: The influence of happy and sad states on sensitivity and bias in stereotyping SO JOURNAL OF PERSONALITY AND SOCIAL PSYCHOLOGY LA English DT Article ID OUT-GROUP HOMOGENEITY; SOCIAL JUDGMENT; POSITIVE AFFECT; CATEGORIZATION; RECOGNITION; PERCEPTION; PERSUASION; COGNITION; IMPACT; EXPERT AB The influence of mood states on the propensity to use heuristics as expressed in stereotypes was examined using signal detection statistics. Participants experienced happy, neutral, or sad moods and "remembered" whether names connoting race (African American, European American) belonged to social categories (criminal, politician, basketball player). Positive mood increased reliance on heuristics, indexed by higher false identification of members of stereotyped groups. Positive mood lowered sensitivity (d'), even among relative experts, and shifted bias (beta) or criterion to be more lenient for stereotypical names. in contrast, sad mood did not disrupt sensitivity and, in fact, revealed the use of a stricter criterion compared with baseline mood. Results support theories that characterize happy mood as a mental state that predisposes reliance on heuristics and sad mood as dampening such reliance. C1 NICHHD, Child & Family Res, Bethesda, MD 20892 USA. Yale Univ, Dept Psychol, New Haven, CT 06520 USA. RP Park, J (reprint author), NICHHD, Child & Family Res, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. FU NIMH NIH HHS [MH57672] NR 56 TC 109 Z9 116 U1 3 U2 21 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-3514 J9 J PERS SOC PSYCHOL JI J. Pers. Soc. Psychol. PD JUN PY 2000 VL 78 IS 6 BP 1005 EP 1023 DI 10.1037//0022-3514.78.6.1005 PG 19 WC Psychology, Social SC Psychology GA 322LZ UT WOS:000087512200001 PM 10870905 ER PT J AU Hayashi, T Maurice, T Su, TP AF Hayashi, T Maurice, T Su, TP TI Ca2+ signaling via sigma(1)-receptors: Novel regulatory mechanism affecting intracellular Ca2+ concentration SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID METHYL-D-ASPARTATE; INDUCED NEURONAL ACTIVATION; SIGMA-LIGANDS; BINDING PROTEIN; SIGMA(1)-BINDING SITE; DORSAL HIPPOCAMPUS; CARDIAC MYOCYTES; NEUROPEPTIDE-Y; IMMUNE-SYSTEMS; RAT-BRAIN AB The sigma(1)-receptor is a one-transmembrane endoplasmic reticulum protein that binds neurosteroids and dextrorotatory benzomorphans. The roles of sigma(1)-receptors in regulating intracellular Ca2+ in NG108 cells were examined in this study. sigma(1)-Ligands pregnenolone sulfate, (+)-pentazocine, and 2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate hydrochloride modulate Ca2+ signaling in NG108 cells via two modes of action. First, nanomolar concentrations of the ligands, without effect by themselves, potentiated the bradykinin-induced increase of the cytosolic free Ca2+ concentration in a bell-shaped manner. This effect of sigma(1)-ligands was unaffected by depletion of Ca2+ from perfusion buffer and was blocked by a 21-mer antisense oligodeoxynucleotide against the cloned sigma(1)-receptors. Second, after the cells were depleted of the endoplasmic reticulum Ca2+ stores, the depolarization (75 mM KCl)-induced increase in cytosolic free Ca2+ was potentiated by 2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate hydrochloride, whereas it was inhibited by pregnenolone sulfate and (+)-pentazocine. These effects, albeit opposite in direction, were blocked by both the 21-mer antisense oligodeoxynucleotide and pertussis toxin. Western blotting indicates that sigma(1)-receptors are increased on the plasma membrane and the nuclear membrane in the presence of sigma(1)-ligand. These results suggest that Ca-2+ signaling via sigma(1)-receptors may represent a novel mechanism that affects intracellular Ca2+ concentrations. C1 NIDA, Cellular Pathobiol Unit, Mol Neuropsychiat Sect, Intramural Res Program,NIH, Baltimore, MD 21224 USA. INSERM, U336, Unite Dev Vieillissement & Plast Syst Nerveux, Montpellier, France. RP Su, TP (reprint author), NIDA, Cellular Pathobiol Unit, Mol Neuropsychiat Sect, Intramural Res Program,NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Hayashi, Teruo/A-9690-2008 NR 43 TC 190 Z9 198 U1 0 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUN PY 2000 VL 293 IS 3 BP 788 EP 798 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 323FR UT WOS:000087554800011 PM 10869377 ER PT J AU Gozes, I Giladi, E Pinhasov, A Bardea, A Brenneman, DE AF Gozes, I Giladi, E Pinhasov, A Bardea, A Brenneman, DE TI Activity-dependent neurotrophic factor: Intranasal administration of femtomolar-acting peptides improve performance in a water maze SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID VASOACTIVE-INTESTINAL-PEPTIDE; E-DEFICIENT MICE; NEUROPROTECTIVE PEPTIDE; CELL-DEATH; FATTY NEUROPEPTIDE; ALZHEIMERS-DISEASE; DEVELOPING BRAIN; NERVOUS-SYSTEM; FACTOR ADNF; VIP AB Activity-dependent neurotrophic factor (ADNF) is a glia-derived protein that is neuroprotective at femtomolar concentrations. A nine-amino acid peptide derived from ADNF (Ser-Ala-Leu-Leu-Arg-Ser-lle-Pro-Ala; ADNF-9) captured the activity of the parent protein and has been reported to protect cultured neurons from multiple neurotoxins. Antibodies recognizing ADNF-9 produced neuronal apoptosis, and identified an additional, structurally related, glia-derived peptide, Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln (NAP). Previous comparative studies have characterized s.c.-injected NAP as most efficacious in protecting against developmental retardation and learning impairments in apolipoprotein E-deficient mice. This study was designed to assess 1) neuroprotection after intranasal administration of ADNF-9 and NAP to rats treated with the cholinotoxin ethylcholine aziridium; and 2) bioavailability and pharmacokinetics after intranasal administration. Results showed significant improvements in short-term spatial memory, as assessed in a water maze, after daily intranasal administration of 1 mu g of peptide (ADNF-9 or NAP) per animal. However, a 5-day pretreatment with ADNF-9 did not improve performance measured after cessation of treatment. Compared with rats treated with ADNF-9, NAP-pretreated animals exhibited a significantly better performance. Furthermore, NAP land not ADNF-9) protected against loss of choline acetyl transferase activity. Significant amounts of H-3-labeled NAP reached the brain, remained intact 30 min after administration, and dissipated 60 min after administration. This study revealed efficacy for ADNF-related peptides in rodent models far neurodegeneration. The small size of the molecules, the low dosage required, the noninvasive administration route, and the demonstrated activity in a relevant paradigm suggest NAP as a lead compound for future drug design. C1 Tel Aviv Univ, Sackler Sch Med, Dept Clin Biochem, IL-69978 Tel Aviv, Israel. NICHHD, Sect Dev & Mol Pharmacol, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Gozes, I (reprint author), Tel Aviv Univ, Sackler Sch Med, Dept Clin Biochem, IL-69978 Tel Aviv, Israel. NR 40 TC 123 Z9 124 U1 3 U2 8 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 2000 VL 293 IS 3 BP 1091 EP 1098 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 323FR UT WOS:000087554800048 PM 10869414 ER PT J AU O'Donovan, MJ Wenner, P Chub, N Tabak, J Whelan, PJ Rinzel, J AF O'Donovan, MJ Wenner, P Chub, N Tabak, J Whelan, PJ Rinzel, J TI The genesis of spontaneous activity in the developing spinal cord of the chick embryo SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Meeting Abstract ID NETWORK ACTIVITY C1 NINDS, Neural Control Lab, NIH, Bethesda, MD 20892 USA. NYU, Ctr Neural Sci, New York, NY 10003 USA. RI tabak, joel/K-1549-2013 NR 5 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD JUN PY 2000 VL 525 SU S BP 2S EP 2S PG 1 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 335HD UT WOS:000088237300125 ER PT J AU Tsutsui, A Yagi, M Horowitz, AM AF Tsutsui, A Yagi, M Horowitz, AM TI The prevalence of dental caries and fluorosis in Japanese communities with up to 1.4 ppm of naturally occurring fluoride SO JOURNAL OF PUBLIC HEALTH DENTISTRY LA English DT Article DE dental caries; dental fluorosis; epidemiology; fluoride; drinking water ID FOLLOW-UP SURVEY; WATER FLUORIDATION; WESTERN AUSTRALIA; DRINKING-WATER; AREAS; SCHOOLCHILDREN; EXPERIENCE; EXPOSURE AB Objectives: The purpose of this study was to determine the relationship between the concentration of fluoride in drinking wafer and the prevalence of dental caries and fluorosis in seven Japanese communities with different concentrations of fluoride occurring naturally in the drinking wafer. Methods: A total of 1,060 10- to 12-year-old lifetime residents were examined to determine the prevalence of dental caries and fluorosis in communities with trace amounts to 1.4 ppm fluoride in the drinking water in 1987 Systemic fluorides (drops or tablets) have never been available in Japan and the market share of fluoride-containing toothpaste was 12 percent at the time of the study. Results: The prevalence of dental caries was inversely related and the prevalence of fluorosis was directly related to the concentration of fluoride in the drinking wafer. The mean DMFS in the communities with 0.8 to 1.4 ppm fluoride was 53.9 percent to 62.4 percent lower than that in communities with negligible amounts of fluoride. Multivariate analysis showed that wafer fluoride level was the strongest factor influencing DMFS scores. The prevalence of fluorosis ranged from 1.7 percent to 15.4 percent, and the increase in fluorosis with increasing fluoride exposure was limited entirely to the milder forms. Conclusions: The findings of this study conducted in 1987 in Japan parallel those reported by Dean et al. in the early 1940s. C1 Fukuoka Dent Coll, Dept Prevent Dent, Sawara Ku, Fukuoka, Japan. Niigata Univ, Fac Dent, Dept Prevent Dent, Niigata, Japan. NIDCR, NIH, Bethesda, MD USA. RP Tsutsui, A (reprint author), Fukuoka Dent Coll, Dept Prevent Dent, Sawara Ku, 2-15-1 Tamura, Fukuoka, Japan. NR 44 TC 23 Z9 25 U1 0 U2 2 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 2000 VL 60 IS 3 BP 147 EP 153 DI 10.1111/j.1752-7325.2000.tb03320.x PG 7 WC Dentistry, Oral Surgery & Medicine; Public, Environmental & Occupational Health SC Dentistry, Oral Surgery & Medicine; Public, Environmental & Occupational Health GA 372KL UT WOS:000165232800003 PM 11109211 ER PT J AU Ling, SM Fried, LP Garrett, E Hirsch, R Guralnik, JM Hochberg, MC AF Ling, SM Fried, LP Garrett, E Hirsch, R Guralnik, JM Hochberg, MC CA Womens Hlth Aging Collaborative Re TI The accuracy of self-report of physician diagnosed rheumatoid arthritis in moderately to severely disabled older women SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE rheumatoid arthritis; elderly; disability ID VALIDITY AB Objective. To determine the accuracy of self-report of physician diagnosed rheumatoid arthritis (RA) in moderately to severely disabled older women. Methods. A total of 1002 participants in the Women's Health and Aging Study were included. These women were greater than or equal to 65 years old, had an average of 4 chronic illnesses, and represented the one-third most disabled women living in the community. Self-report of a physician's diagnosis of RA was compared to cases of "definite" RA that were adjudicated using an algorithm modeled on the American College of Rheumatology criteria for RA. Results. The sensitivity of self-report of physician diagnosed RA was 77%, with 90.6% specificity and 99% negative predictive value, kappa = 0.46. The positive predictive value was 34% and likely reflected the low prevalence of RA in this sample (3.1%). Five of the 6 women who did not correctly report RA were under the care of a rheumatologist. Conclusion, The accuracy of self-report of a physician's diagnosis of RA in this sample of disabled women with multiple chronic illnesses matched that observed in the general adult population of previous studies. Accuracy was enhanced by including report of receiving care by a rheumatologist. C1 Johns Hopkins Univ, Sch Med, Div Geriatr Med & Gerontol, Baltimore, MD 21218 USA. Johns Hopkins Univ, Sch Med, Div Rheumatol, Baltimore, MD 21218 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Biostat, Baltimore, MD USA. Ctr Aging & Hlth, Baltimore, MD USA. Natl Ctr Hlth Stat, Ctr Dis Control, Hyattsville, MD USA. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD USA. Univ Maryland, Div Rheumatol & Clin Immunol, Baltimore, MD 21201 USA. RP Ling, SM (reprint author), Johns Hopkins Geriatr Ctr, 5505 Hopkins Bayview Circle, Baltimore, MD 21224 USA. FU NIA NIH HHS [N01-AG-1-12112] NR 16 TC 25 Z9 25 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 2000 VL 27 IS 6 BP 1390 EP 1394 PG 5 WC Rheumatology SC Rheumatology GA 320BH UT WOS:000087380800012 PM 10852259 ER PT J AU Cabrera, JE Paz, JLP Genti-Raimondi, S AF Cabrera, JE Paz, JLP Genti-Raimondi, S TI Steroid-inducible transcription of the 3 beta/17 beta-hydroxysteroid dehydrogenase gene (3 beta/17 beta-hsd) in Comamonas testosteroni SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article ID PSEUDOMONAS-TESTOSTERONI; DELTA-5-3-KETOSTEROID ISOMERASE; HYDROXYSTEROID DEHYDROGENASE; MOLECULAR-CLONING; EXPRESSION; OVEREXPRESSION; SEQUENCE; PROTEIN AB The expression of the Comamonas testosteroni gene, encoding 3 beta/17 beta-hydroxysteroid dehydrogenase enzyme (3 beta/17 beta-HSD). was analyzed at the transcriptional level. Northern blot analysis detected a 1 kb transcript in bacterial cells grown in minimum media supplemented with Casamino acids and testosterone. Also this transcript was observed when cells were grown in presence of 1-dehydrotestosterone, androstenedione and 1,4-androstadien-3,17dione, but not in presence of acetate, citrate, cholic acid, cholesterol, and cortisol. In addition, this effect was dependent on the presence of another carbon source in the growth medium used, revealing catabolite repression. (C) 2000 Elsevier Science Ltd. All rights reserved. C1 Univ Nacl Cordoba, Fac Ciencias Quim, Dept Bioquim Clin, RA-5000 Cordoba, Argentina. NCI, Dev Genet Sect, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Genti-Raimondi, S (reprint author), Univ Nacl Cordoba, Fac Ciencias Quim, Dept Bioquim Clin, RA-5000 Cordoba, Argentina. NR 19 TC 18 Z9 19 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 2000 VL 73 IS 3-4 BP 147 EP 152 DI 10.1016/S0960-0760(00)00066-2 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 340PV UT WOS:000088544200007 PM 10925214 ER PT J AU Sipe, JD Cohen, AS AF Sipe, JD Cohen, AS TI Review: History of the amyloid fibril SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Review DE amyloid fibril; amyloid protein; amyloidosis; electron microscopy; history ID IMMUNOGLOBULIN LIGHT CHAINS; ALZHEIMERS-DISEASE; PRE-ALBUMIN; PROTEIN; POLYNEUROPATHY; FIBRILLOGENESIS; TRANSTHYRETIN; PROTEOGLYCANS; PRION AB Rudolph Virchow, in 1854, introduced and popularized the term amyloid to denote a macroscopic tissue abnormality that exhibited a positive iodine staining reaction. Subsequent light microscopic studies with polarizing optics demonstrated the inherent birefringence of amyloid deposits, a property that increased intensely after staining with Congo red dye. In 1959, electron microscopic examination of ultrathin sections of amyloidotic tissues revealed the presence of fibrils, indeterminate in length and, invariably, 80 to 100 Angstrom in width. Using the criteria of Congophilia and fibrillar morphology, 20 or more biochemically distinct forms of amyloid have been identified throughout the animal kingdom; each is specifically associated with a unique clinical syndrome. Fibrils, also 80 to 100 A in width, have been isolated from tissue homogenates using differential sedimentation or solubility. X-ray diffraction analysis revealed the fibrils to be ordered in the beta pleated sheet conformation, with the direction of the polypeptide backbone perpendicular to the fibril axis (cross beta structure). Because of the similar dimensions and tinctorial properties of the fibrils extracted from amyloid-laden tissues and amyloid fibrils in tissue sections, they have been assumed to be identical. However, the spatial relationship of proteoglycans and amyloid P component (AP), common to all forms of amyloid, to the putative protein only fibrils in tissues, has been unclear. Recently, it has been suggested that, in situ, amyloid fibrils are composed of proteoglycans and AP as well as amyloid proteins and thus resemble connective tissue microfibrils. Chemical and physical definition of the fibrils in tissues will be needed to relate the in vitro properties of amyloid protein fibrils to the pathogenesis of amyloid fibril formation in vivo. (C) 2000 Academic Press. C1 NIH, Ctr Sci Review, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Amyloid Program, Boston, MA 02118 USA. RP Sipe, JD (reprint author), NIH, Ctr Sci Review, 6701 Rockledge Dr,Room 4106,MSC 7814, Bethesda, MD 20892 USA. NR 45 TC 554 Z9 567 U1 5 U2 84 PU ACADEMIC PRESS INC 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 2000 VL 130 IS 2-3 BP 88 EP 98 DI 10.1006/jsbi.2000.4221 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 349BA UT WOS:000089022900002 PM 10940217 ER PT J AU Wickner, RB Taylor, KL Edskes, HK Maddelein, ML Moriyama, H Roberts, BT AF Wickner, RB Taylor, KL Edskes, HK Maddelein, ML Moriyama, H Roberts, BT TI Prions of yeast as heritable amyloidoses SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE amyloid; [Het-s]; Podospora; prion; [PSI+]; Saccharomyces cerevisiae; Sup35p; Ure2p; [URE3] ID DE-NOVO APPEARANCE; FUNGUS PODOSPORA-ANSERINA; CHAIN RELEASE FACTOR; SACCHAROMYCES-CEREVISIAE; SUP35 PROTEIN; IN-VITRO; VEGETATIVE INCOMPATIBILITY; PSI+ PRION; GENE; PROPAGATION AB Two infectious proteins (prions) of Saccharomyces cerevisiae have been identified by their unusual genetic properties: (1) reversible curability, (2) de novo induction of the infectious prion form by over-production of the protein, and (3) similar phenotype of the prion and mutation in the chromosomal gene encoding the protein. [URE3] is an altered infectious form of the Urea protein, a regulator of nitrogen catabolism, while [PSI] is a prion of the Sup35 protein, a subunit of the translation termination factor. The altered form of each is inactive in its normal function, but is able to convert the corresponding normal protein into the same altered inactive state. The N-terminal parts of Ure2p and Sup35p (the "prion domains") are responsible for prion formation and propagation and are rich in asparagine and glutamine residues. Ure2p and Sup35p are aggregated in vivo in [URE3]- and [PSI]-containing cells, respectively. The prion domains can form amyloid in vitro, suggesting that amyloid formation is the basis of these two prion diseases. Yeast prions can be cured by growth on millimolar concentrations of guanidine. An excess or deficiency of the chaperone Hsp104 cures the [PST] prion. Overexpression of fragments of Ure2p or certain fusion proteins leads to curing of [URE3]. (C) 2000 Academic Press. C1 NIDDKD, Biochem & Genet Lab, NIH, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), NIDDKD, Biochem & Genet Lab, NIH, Bethesda, MD 20892 USA. RI MADDELEIN, Marie-Lise/G-5395-2010; MORIYAMA, Hiromitsu/F-9256-2013 NR 67 TC 57 Z9 58 U1 0 U2 5 PU ACADEMIC PRESS INC 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 2000 VL 130 IS 2-3 BP 310 EP 322 DI 10.1006/jsbi.2000.4250 PG 13 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 349BA UT WOS:000089022900020 PM 10940235 ER PT J AU Condelli, WS Koch, MA Fletcher, B AF Condelli, WS Koch, MA Fletcher, B TI Treatment refusal/attrition among adults randomly assigned to programs at a drug treatment campus - The New Jersey Substance Abuse Treatment Campus, Seacaucus, NJ SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE substance abuse treatment; attrition; retention ID FOLLOW-UP OUTCOMES; THERAPEUTIC COMMUNITIES; TREATMENT RETENTION; ALCOHOL DEPENDENCY; TREATMENT SERVICES; MINNESOTA MODEL; TIME SPENT; DATOS; MANAGEMENT; MIRACLE AB The New Jersey Substance Abuse Treatment Campus was funded to assess the feasibility of establishing a new model for delivering substance abuse treatment services and to serve as a research laboratory for conducting comparative evaluations of those services. The 350-bed campus was designed to improve treatment effectiveness by providing special services needed by underserved populations, and reduce treatment costs by serving large numbers of clients, centralizing services, and sharing facilities. First-time clients who met preliminary eligibility requirements during phone screening were randomly assigned to therapeutic community and chemical dependency programs. We used data collected on 1,573 adults who were ultimately accepted for admission to analyze treatment refusals and attrition during the 25 days after admission. Only 6.4% of the clients refused admission when informed of their treatment assignment. Planned duration of the residential phase of treatment, gender, and language spoken (English/Spanish) interacted with one another and differentially predicted treatment refusal/attrition. These findings may be useful for understanding treatment refusal and attrition in substance abuse treatment programs. (C) 2000 Elsevier Science Inc. All rights reserved. C1 Res Triangle Inst, Div Stat Res, Res Triangle Pk, NC 27709 USA. NIDA, Bethesda, MD 20892 USA. Res Triangle Inst, Hlth & Social Policy Div, Res Triangle Pk, NC 27709 USA. RP Koch, MA (reprint author), Res Triangle Inst, Div Stat Res, POB 12194, Res Triangle Pk, NC 27709 USA. NR 64 TC 13 Z9 14 U1 2 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD JUN PY 2000 VL 18 IS 4 BP 395 EP 407 DI 10.1016/S0740-5472(99)00086-0 PG 13 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 314KW UT WOS:000087055800012 PM 10812314 ER PT J AU Berger, AC Feldman, AL Gnant, MFX Kruger, EA Sim, BKL Hewitt, S Figg, WD Alexander, HR Libutti, SK AF Berger, AC Feldman, AL Gnant, MFX Kruger, EA Sim, BKL Hewitt, S Figg, WD Alexander, HR Libutti, SK TI The angiogenesis inhibitor, endostatin, does not affect murine cutaneous wound healing SO JOURNAL OF SURGICAL RESEARCH LA English DT Article; Proceedings Paper CT Annual Meeting of the Association-for-Academic-Surgery CY NOV 18-22, 1999 CL PHILADELPHIA, PENNSYLVANIA SP Assoc Acad Surg DE angiogenesis; endostatin; tensile strength; endothelial cells ID TUMOR-GROWTH; EXPRESSION; MODEL AB Background. Endostatin is a potent angiogenesis inhibitor, which is currently being used in Phase I trials as an antitumor agent. The purpose of this study was to determine whether endostatin has an effect on wound healing in a murine model. Materials and methods. The function of endostatin was confirmed using a human microvascular endothelial cell (HMVEC) proliferation assay in which cells are treated for 4 days with growth media plus or minus endostatin, Full-thickness incisions were made on the dorsum of athymic nude mice and closed primarily with skin staples. PVA sponges were implanted in some wounds to determine vascular ingrowth. Subsequently, mice were treated with recombinant human endostatin at 20 mg/kg/day or 50 mg/kg/dose BID versus control for a total of 14 days. On Days 2, 4, 8, 12, and 16, three mice per group had serum samples drawn and were sacrificed. Perpendicular breaking strength (N) was determined using an Instron 5540 tensometer. Wound strength was determined by dividing breaking strength by wound area (N/cm(2)). Vascular density in sponges was determined using CD31 immunohistochemistry. Serum endostatin concentrations were determined using a commercially available ELISA kit. Results. Endostatin caused a significant reduction of endothelial cell proliferation after 4 days compared to media alone (72%, P = 0.031). At all time points tested, there was no statistical difference in the wound-breaking strength between endostatin and control-treated mice at either the low or high dose. Serum endostatin levels were consistently 10-fold higher in endostatin-treated mice than in controls. No differences in vascular density were seen in endostatin versus control-treated mice as determined by CD31 immunohistochemistry of PVA sponges. Conclusion. Therapy with human endostatin does not induce a significant decrease in breaking strength of cutaneous wounds in mice. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. EntreMed Inc, Rockville, MD 20850 USA. RP Libutti, SK (reprint author), NCI, Surg Branch, NIH, Bldg 10,Room 2B07,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Feldman, Andrew/D-5028-2012; Figg Sr, William/M-2411-2016; OI Hewitt, Stephen/0000-0001-8283-1788; Gnant, Michael/0000-0003-1002-2118 NR 18 TC 93 Z9 104 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 J9 J SURG RES JI J. Surg. Res. PD JUN 1 PY 2000 VL 91 IS 1 BP 26 EP 31 DI 10.1006/jsre.2000.5890 PG 6 WC Surgery SC Surgery GA 317QW UT WOS:000087239300005 PM 10816345 ER PT J AU Moolchan, ET Ernst, M Henningfield, JE AF Moolchan, ET Ernst, M Henningfield, JE TI A review of tobacco smoking in adolescents: Treatment implications SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Review DE tobacco; review; cessation; reduction ID DEFICIT HYPERACTIVITY DISORDER; NICOTINE PATCH THERAPY; DOPAMINE-RECEPTOR GENE; CIGARETTE-SMOKING; SUBSTANCE USE; FOLLOW-UP; DRUG-USE; PSYCHIATRIC COMORBIDITY; GENDER DIFFERENCES; MAJOR DEPRESSION AB Objective: To review current data on the tobacco epidemic in adolescents that impact treatment decisions, Method: Epidemiological and pharmacological data, risk factors, characteristics of nicotine use in adolescents, and treatment intervention reports from the literature are discussed. Results: Of students in grades 9 to 12, 42.7% have used tobacco; 75% of teenage smokers will smoke as adults. Environmental and biological factors influence adolescent smoking, including sociodevelopmental aspects of adolescence, psychiatric history, genetic background, ethnic and gender characteristics, drug effects, and regulatory factors. Criteria for nicotine dependence are currently based on the experience with adult smokers. Overall, smoking cessation treatment for adolescents has been disappointing because of low participation, high attrition, and low quit rates. Conclusion: Characterization of nicotine dependence and further assessment of the safety and efficacy of pharmacological treatment interventions in adolescents are needed given the formidable challenge of the tobacco epidemic in adolescents. C1 NIDA, IRP, Clin Pharmacol Branch, NIH, Baltimore, MD 21224 USA. Pinney Associates, Bethesda, MD USA. RP Moolchan, ET (reprint author), NIDA, IRP, Clin Pharmacol Branch, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 100 TC 83 Z9 83 U1 6 U2 12 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 2000 VL 39 IS 6 BP 682 EP 693 DI 10.1097/00004583-200006000-00006 PG 12 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 319FQ UT WOS:000087331200006 PM 10846302 ER PT J AU Goodman, SH Schwab-Stone, M Lahey, BB Shaffer, D Jensen, PS AF Goodman, SH Schwab-Stone, M Lahey, BB Shaffer, D Jensen, PS TI Major depression and dysthymia in children and adolescents: Discriminant validity and differential consequences in a community sample SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE major depression; dysthymia; discriminant validity; impairment ID PUBERTAL STATUS; FAMILY HISTORY; DISORDERS; CHILDHOOD; SYMPTOMS; RELIABILITY; COMPETENCE; HEALTH; MOOD; RISK AB Objectives: To evaluate evidence, in a community sample, for discriminant validity between major depression (MDD) and dysthymia (Dy) in children and adolescents and to examine differential consequences of the 2 disorders for functioning. Method: The National Institute of Mental Health (NIMH) Methods for the Epidemiology of Child and Adolescent Mental Disorders (MECA) study consists of probability samples of youths. Data for this study are derived from interviews with 1,285 complete parent-youth pairs aged 9 to 17 years from 4 geographic areas in the United States. Youths with MDD were contrasted with those with Dy and those with both (MDD-Dy) on the NIMH Diagnostic interview Schedule for Children, Non-Clinician Children's Global Assessment Scale, Columbia Impairment Scale, and the Service Utilization and Risk Factors Module. Results: Groups with MDD, Dy, or MDD-Dy did not differ on sociodemographic, clinical, or family and life event variables. Youths with combined MDD-Dy were significantly less competent and more impaired than youths with either disorder alone. Conclusions: The findings do not provide support for the differentiation of MDD and Dy but strongly suggest the importance of addressing the needs of youths who meet criteria for both MDD and Dy because this combination is likely to be both serious and disruptive of normal developmental processes. C1 Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. Yale Univ, New Haven, CT USA. Univ Chicago, Chicago, IL 60637 USA. Columbia Univ, New York, NY 10027 USA. NIMH, Bethesda, MD 20892 USA. RP Goodman, SH (reprint author), Emory Univ, Dept Psychol, 532 Kilgo Circle, Atlanta, GA 30322 USA. OI Jensen, Peter/0000-0003-2387-0650 FU NIMH NIH HHS [UO1 MH46717, UO1 MH46718, UO1 MH46725] NR 46 TC 29 Z9 32 U1 20 U2 22 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 2000 VL 39 IS 6 BP 761 EP 770 DI 10.1097/00004583-200006000-00015 PG 10 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 319FQ UT WOS:000087331200015 PM 10846311 ER PT J AU Fine, JD Eady, RAJ Bauer, EA Briggaman, RA Bruckner-Tuderman, L Christiano, A Heagerty, A Hintner, H Jonkman, MF McGrath, J McGuire, J Moshell, A Shimizu, H Tadini, G Uitto, J AF Fine, JD Eady, RAJ Bauer, EA Briggaman, RA Bruckner-Tuderman, L Christiano, A Heagerty, A Hintner, H Jonkman, MF McGrath, J McGuire, J Moshell, A Shimizu, H Tadini, G Uitto, J TI Revised classification system for inherited epidermolysis bullosa: Report of the Second International Consensus Meeting on diagnosis and classification of epidermolysis bullosa SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID PRENATAL-DIAGNOSIS C1 Univ N Carolina, Dept Dermatol, Chapel Hill, NC 27599 USA. Natl Epidermolysis Bullosa Registry, Chapel Hill, NC USA. St Thomas Hosp, Guys Kings & St Thomas Sch Med, St Johns Inst Dermatol, London, England. Stanford Univ, Stanford, CA 94305 USA. Univ Munster, D-4400 Munster, Germany. Columbia Univ, New York, NY USA. Gen Hosp, Salzburg, Austria. Univ Groningen Hosp, Groningen, Netherlands. Univ Birmingham, Birmingham, W Midlands, England. NIAMSD, NIH, Bethesda, MD 20892 USA. Hokkaido Univ, Sch Med, Sapporo, Hokkaido 060, Japan. Univ Milan, IRCCS, Politecn Milan, Milan, Italy. Thomas Jefferson Univ, Philadelphia, PA 19107 USA. RP Fine, JD (reprint author), Univ N Carolina, Dept Dermatol, 3100 Thurston-CB 7287, Chapel Hill, NC 27599 USA. RI Shimizu, Hiroshi/A-5193-2012; McGrath, John/D-6824-2012; Jonkman, Marcel/H-4647-2011 OI McGrath, John/0000-0002-3708-9964; FU NIAMS NIH HHS [K24 AR02098, N01 AR72233] NR 24 TC 266 Z9 290 U1 1 U2 4 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD JUN PY 2000 VL 42 IS 6 BP 1051 EP 1066 DI 10.1016/S0190-9622(00)90302-5 PG 16 WC Dermatology SC Dermatology GA 321GP UT WOS:000087448000016 PM 10827412 ER PT J AU Cooper, HA Exner, DV Domanski, MJ AF Cooper, HA Exner, DV Domanski, MJ TI Light-to-moderate alcohol consumption and prognosis in patients with left ventricular systolic dysfunction SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID MYOCARDIAL-INFARCTION; HEART-DISEASE; MORTALITY; INGESTION; ETHANOL; DEATH; RISK AB OBJECTIVES The study evaluated the relationship between light-to-moderate alcohol consumption and prognosis in patients with left ventricular (LV) systolic dysfunction. BACKGROUND Although chronic consumption of large amounts of alcohol can lead to cardiomyopathy, the effects of light-to-moderate alcohol consumption in patients with LV dysfunction are unknown. METHODS The relationship between light-to-moderate alcohol consumption and prognosis was assessed in participants in the Studies of Left Ventricular Dysfunction (SOLVD), all of whom had ejection fraction values less than or equal to 0.35. Baseline characteristics and event rates of patients who consumed 1 to 14 drinks per week (light-to-moderate drinkers, n = 2,594) were compared with those of patients who reported no alcohol consumption (nondrinkers, n = 3,719). The association between light-to-moderate alcohol consumption and prognosis was evaluated using Cox proportional hazards analysis, controlling for baseline differences and important covariates. RESULTS Mortality rates were lower among light-to-moderate drinkers than among nondrinkers (7.2 vs. 9.4 deaths/100 person-years, p < 0.001). Among patients with ischemic LV dysfunction, light-to-moderate alcohol consumption was independently associated with a reduced risk of all-cause mortality (RR [relative risk] 0.85, p = 0.01), particularly for death from myocardial infarction (RR 0.55, p < 0.001). The risks of cardiovascular death, death from progressive heart failure, arrhythmic death, and hospitalization for heart failure were similar for light-to-moderate drinkers and nondrinkers in this group. Among patients with nonischemic LV dysfunction, light-to-moderate alcohol consumption had no significant effect on mortality (RR 0.93, p = 0.5). CONCLUSIONS Light-to-moderate alcohol consumption is not associated with an adverse prognosis in patients with LV systolic dysfunction, and it may reduce the risk of fatal myocardial infarction in patients with ischemic LV dysfunction. (J Am Coll Cardiol 2000;35:1753-9) (C) 2000 by the American College of Cardiology. C1 NHLBI, Clin Trials Res Grp, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Washington, DC 20007 USA. RP Cooper, HA (reprint author), 2 Rockledge Ctr,Room 8149,6701 Rockledge Dr, MSC, Bethesda, MD 20892 USA. NR 25 TC 52 Z9 58 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN PY 2000 VL 35 IS 7 BP 1753 EP 1759 DI 10.1016/S0735-1097(00)00625-2 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 319ED UT WOS:000087327800007 PM 10841221 ER PT J AU Li, ST Tack, CJ Fananapazir, L Goldstein, DS AF Li, ST Tack, CJ Fananapazir, L Goldstein, DS TI Myocardial perfusion and sympathetic innervation in patients with hypertrophic cardiomyopathy SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID POSITRON EMISSION TOMOGRAPHY; CORONARY VASODILATOR RESERVE; BLOOD-FLOW; HUMAN-HEART; SYMPTOMATIC PATIENTS; ALPHA-TROPOMYOSIN; NEURONAL UPTAKE; N-13 AMMONIA; NOREPINEPHRINE; MUTATIONS AB OBJECTIVE This study assessed left ventricular myocardial perfusion and sympathetic innervation and function in hypertrophied and nonhypertrophied myocardial regions of patients with hypertrophic cardiomyopathy (HCM). BACKGROUND Patients with HCM often have clinical findings consistent with increased cardiac sympathetic outflow. Little is known about the status of sympathetic innervation specifically in hypertrophic regions. METHODS We conducted positron emission tomographic (PET) scanning using the perfusion imaging N-13-ammonia ((NH3)-N-13) and the sympathoneuronal imaging agent 6-[F-18]agent fluorodopamine (F-18-FDA) in 8 patients with HCM and 15 normal volunteers. Positron emission tomographic data corrected for attenuation and the partial volume effect were analyzed using the region-of-interest technique. RESULTS Myocardial (NH3)-N-13-derived radioactivity was similar in hypertrophied and nonhypertrophied regions of patients with HCM and in normal volunteers. At all time points, the F-18:N-13 ratio was lower in hypertrophied than in nonhypertrophied regions of HCM patients and in the F-18-FDA-derived radioactivity over time septum of normal volunteers (p = 0.001). Trends in were normal in both hypertrophied and nonhypertrophied myocardium. CONCLUSIONS The results are consistent with decreased neuronal uptake of catecholamines in hypertrophied but not in nonhypertrophied myocardium of patients with HCM. Other aspects of cardiac sympathoneural function seem normal. Decreased neuronal uptake could reflect local relative hypoinnervation, decreased numbers of neuronal uptake sites, or metabolic limitations on cell membrane transport. By enhancing norepinephrine delivery to adrenoceptors for a given amount of sympathetic nerve traffic, decreased neuronal uptake can explain major clinical features of HCM. (J Am Coll Cardiol 2000;35:1867-73) (C) 2000 by the American College of Cardiology. C1 NINCDS, Clin Neuroradiol Sect, NIH, Bethesda, MD 20892 USA. Univ Nijmegen Hosp, Dept Internal Med, NL-6500 HB Nijmegen, Netherlands. NHLBI, Cardiol Branch, Bethesda, MD 20892 USA. RP Li, ST (reprint author), NINCDS, Clin Neuroradiol Sect, NIH, Bldg 10,Room 6N252,10 Ctr Dr,MSC-1620, Bethesda, MD 20892 USA. RI Tack, Cees/A-2368-2014 NR 44 TC 24 Z9 25 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN PY 2000 VL 35 IS 7 BP 1867 EP 1873 DI 10.1016/S0735-1097(00)00626-4 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 319ED UT WOS:000087327800023 PM 10841237 ER PT J AU Slavkin, HC AF Slavkin, HC TI Maturity and oral health: Live longer and better SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article ID BACTERIA C1 Natl Inst Dent & Cranofacial REs, Bethesda, MD 20892 USA. RP Slavkin, HC (reprint author), Natl Inst Dent & Cranofacial REs, 31 Ctr Dr,Room 2C39, Bethesda, MD 20892 USA. NR 18 TC 3 Z9 4 U1 0 U2 1 PU AMER DENTAL ASSN PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD JUN PY 2000 VL 131 IS 6 BP 805 EP 808 PG 4 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 322KM UT WOS:000087508800034 PM 10860334 ER PT J AU Rantanen, T Penninx, BWJH Masaki, K Lintunen, T Foley, D Guralnik, JM AF Rantanen, T Penninx, BWJH Masaki, K Lintunen, T Foley, D Guralnik, JM TI Depressed mood and body mass index as predictors of muscle strength decline in old men SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE aging; disability; frailty; muscle; body weight ID MAXIMAL ISOMETRIC STRENGTH; PHYSICAL-ACTIVITY; DISABILITY; SYMPTOMS; WOMEN; TESTOSTERONE; ASSOCIATION; 75-YEAR-OLD; COMMUNITY AB OBJECTIVE: To study depressed mood as a predictor of strength decline within body weight categories over a 3-year follow-up period. DESIGN: A prospective cohort study over 3 years. SETTING: Honolulu, Hawaii. PARTICIPANTS: The subjects were 2275 men participating in the Honolulu Heart Program with an average age of 77.1 years (range 71-92 years), who were not cognitively impaired at baseline (Exam 4), and who participated in maximal hand grip strength measurements at baseline and 3 years later (Exam 5). MEASUREMENTS: Hand grip strength was measured using a dynamometer. Depressive symptoms were studied using an Ii-item version of Center for Epidemiologic Studies Depression Scale with 9 as a cutoff. Body weight categories were formed on the basis of body mass index (BMI) (BMI = weight/height(2); underweight: BMI < 20; normal weight: BMI 20-24.99, overweight: BMI greater than or equal to 25). MAIN RESULTS: At baseline, 9.4% of the participants were rated as having depressed mood. The mean individual strength change over 3 years was -6.9% (standard deviation 14.0). Steep strength decline was determined as losing greater than or equal to 14% (lowest quartile). The proportions of those with steep strength decline in the groups based on combined distributions of BMI and depressed mood were: underweight/ depressed (n = 22) 41%, underweight/not depressed (n 200) 28%, normal weight/depressed (n = 127) 30%, normal weight/not depressed (n = 1181) 25%, overweight/depressed (n = 55) 31%, overweight/not depressed (n = 675, referent) 21%. After adjusting for baseline strength, age, height, sociodemographic variables and diseases, the odds ratio for steep strength decline was more than four rimes greater among those who were depressed and underweight, and twice as great among people who were depressed and normal weighs compared with those who were nondepressed and over-weight. The risks of nondepressed under- and normal weight people and depressed overweight people did not differ from the reference group. CONCLUSIONS: Depressed mood was associated with increased risk of steep strength decline, in particular in older men with low body weight. Low body weight in combination with depressed mood may be an indicator of frailty or severe disease status that leads to accelerated strength loss and disability. C1 Univ Jyvaskyla, Dept Hlth Sci, Jyvaskyla 403510, Finland. NIA, Epidemiol Demog & Biometry Program, NIH, Bethesda, MD 20892 USA. Vrije Univ Amsterdam, Fac Med, Inst Res Extramural Med, Amsterdam, Netherlands. Kuakini Med Ctr, Honolulu Asia Aging Study, Honolulu Heart Program, Honolulu, HI 96817 USA. Univ Jyvaskyla, Dept Phys Educ, Jyvaskyla 403510, Finland. RP Rantanen, T (reprint author), Univ Jyvaskyla, Dept Hlth Sci, POB 35, Jyvaskyla 403510, Finland. RI Lintunen, Taru/G-2838-2011; Rantanen, Taina/O-6579-2016 OI Lintunen, Taru/0000-0001-5191-2251; Rantanen, Taina/0000-0002-1604-1945 NR 29 TC 67 Z9 72 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUN PY 2000 VL 48 IS 6 BP 613 EP 617 PG 5 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 321YV UT WOS:000087483700002 PM 10855595 ER PT J AU Bassen, CR AF Bassen, CR TI Humor and psyche: Psychoanalytic perspectives. SO JOURNAL OF THE AMERICAN PSYCHOANALYTIC ASSOCIATION LA English DT Book Review C1 NICHD, LCE, SSED, NIH, Bethesda, MD 20814 USA. RP Bassen, CR (reprint author), NICHD, LCE, SSED, NIH, BSA Bldg,Rm 331,9190 Rockville Pike, Bethesda, MD 20814 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHOANALYTIC ASSOC PI HILLSDALE PA 101 WEST STREET, HILLSDALE, NJ 07642 USA SN 0003-0651 J9 J AM PSYCHOANAL ASS JI J. Am. Psychoanal. Assoc. PD SUM PY 2000 VL 48 IS 3 BP 1005 EP 1007 DI 10.1177/00030651000480030301 PG 3 WC Psychiatry; Psychology, Psychoanalysis SC Psychiatry; Psychology GA 366XW UT WOS:000090032400025 ER PT J AU Ono, A Demirov, D Freed, EO AF Ono, A Demirov, D Freed, EO TI Relationship between human immunodeficiency virus type 1 Gag multimerization and membrane binding SO JOURNAL OF VIROLOGY LA English DT Article ID HIV-1 CAPSID PROTEIN; ASSEMBLY INTERMEDIATE COMPLEXES; C-TERMINAL DOMAIN; MATRIX PROTEIN; PARTICLE FORMATION; NUCLEOCAPSID DOMAIN; DIMERIZATION DOMAIN; CRYSTAL-STRUCTURE; AMINO-TERMINUS; LIFE-CYCLE AB The human immunodeficiency virus type I (HIV-I) Gag precursor, Pr55(Gag), is necessary and sufficient far the assembly and release of viruslike particles. Binding of Gag to membrane and Gag multimerization are both essential steps in virus assembly, get the domains responsible for these events have not been fully defined. In addition, the relationship between membrane binding and Gag-Gag interaction remains to be elucidated. To investigate these issues, we analyzed, in vivo, the membrane-binding and assembly properties of a series of C-terminally truncated Gag mutants. Pr-55Gag was truncated at the C terminus of matrix (MAstop), between the N- and C-terminal domains of capsid (CA146stop), at the C terminus of capsid (p41stop), at the C terminus of p2 (p43stop), and after the N-terminal 35 amino acids of nucleocapsid (NC35stop). The ability of these truncated Gag molecules to assemble and release viruslike particles and their capacity to copackage into particles when coexpressed with full-length Gag were determined. We demonstrate that the amount of truncated Gag incorporated into particles is incrementally increased by extension from CA416 to NC35, suggesting that multiple sites in this region are involved in Gag multimerization, Using membrane Botation centrifugation, we observe that MA shows significantly reduced membrane binding relative to full-length Gag but that CA146 displays steady-state membrane-binding properties comparable to those of Pr55(Gag). The finding that the CA146 mutant, which contains only matrix and the N-terminal domain of capsid, exhibits levels of steady-state membrane binding equivalent to those of full-length Gag indicates that strong Gag-Gag interaction domains are not required for the efficient binding of HIV-1 Gag to membrane. C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Freed, EO (reprint author), NIAID, Mol Microbiol Lab, NIH, 9000 Rockville Pike,Bldg 4,Rm 307, Bethesda, MD 20892 USA. NR 63 TC 93 Z9 94 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 2000 VL 74 IS 11 BP 5142 EP 5150 DI 10.1128/JVI.74.11.5142-5150.2000 PG 9 WC Virology SC Virology GA 312MX UT WOS:000086948000023 PM 10799589 ER PT J AU van Dinten, LC van Tol, H Gorbalenya, AE Snijder, EJ AF van Dinten, LC van Tol, H Gorbalenya, AE Snijder, EJ TI The predicted metal-binding region of the arterivirus helicase protein is involved in subgenomic mRNA synthesis, genome replication, and virion biogenesis SO JOURNAL OF VIROLOGY LA English DT Article ID EQUINE ARTERITIS VIRUS; MESSENGER-RNA SYNTHESIS; MOUSE HEPATITIS-VIRUS; SYSTEMATIC MUTATIONAL ANALYSIS; POSITIVE REGULATORY GENE; MURINE LEUKEMIA-VIRUS; NSP4 SERINE-PROTEASE; ZINC-FINGER; SACCHAROMYCES-CEREVISIAE; KLUYVEROMYCES-LACTIS AB Equine arteritis virus (EAV), the prototype Arterivirus, is a positive-stranded RNA virus that expresses its replicase in the form of two large polyproteins of 1,727 and 3,175 amino acids. The functional replicase subunits (nonstructural proteins), which drive EAV genome replication and subgenomic mRNA transcription, are generated by extensive proteolytic processing. Subgenomic mRNA transcription involves an unusual discontinuous step and generates the mRNAs for structural protein expression, Previously, the phenotype of mutant EAV030F, which carries a single replicase point mutation (Ser-2429-->Pro), had implicated the nsp10 replicase subunit (51 kDa) in viral RNA synthesis, and in particular in subgenomic mRNA transcription. nsp10 contains an N-terminal (putative) metal-binding domain (MBD), located just upstream of the Ser-2429-->Pro mutation, and a helicase activity in its C-terminal part. We hare now analyzed the N-terminal domain of nsp10 in considerable detail. A total of 38 mutants, most of them carrying specific single point mutations, were tested in the contest of an EAV infectious cDNA clone. Variable effects on viral genome replication and subgenomic mRNA transcription mere observed. In general, our results indicated that the MBD region, and in particular a set of 13 conserved Cgs and His residues that are assumed to be involved in zinc binding, is essential for viral RNA synthesis. On the basis of these data and comparative sequence analyses, we postulate that the MBD may employ a rather unusual mode of zinc binding that could result in the association of up to four zinc cations with this domain. The region containing residue Ser-2429 mag play the role of "hinge spacer," which connects the MBD to the rest of nsp10. Several mutations in this region specifically affected subgenomic mRNA synthesis. Furthermore, one of the MBD mutants was replication and transcription competent but did not produce infectious progeny virus. This suggests that nsp10 is involved in an as yet unidentified step of virion biogenesis. C1 Leiden Univ, Med Ctr, Dept Virol, Ctr Infect Dis, NL-2300 RC Leiden, Netherlands. NCI, Frederick Canc Res & Dev Ctr, Adv Biomed Comp Ctr, SAIC, Frederick, MD 21702 USA. RP Snijder, EJ (reprint author), Leiden Univ, Med Ctr, Dept Virol, Ctr Infect Dis, LUMC P4-26,POB 9600, NL-2300 RC Leiden, Netherlands. RI Gorbalenya, Alexander/J-4818-2012 OI Gorbalenya, Alexander/0000-0002-4967-7341 FU NCI NIH HHS [N01-CO-56000] NR 73 TC 62 Z9 66 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 2000 VL 74 IS 11 BP 5213 EP 5223 DI 10.1128/JVI.74.11.5213-5223.2000 PG 11 WC Virology SC Virology GA 312MX UT WOS:000086948000031 PM 10799597 ER PT J AU Grivel, JC Penn, ML Eckstein, DA Schramm, B Speck, RF Abbey, NW Herndier, B Margolis, L Goldsmith, MA AF Grivel, JC Penn, ML Eckstein, DA Schramm, B Speck, RF Abbey, NW Herndier, B Margolis, L Goldsmith, MA TI Human immunodeficiency virus type 1 coreceptor preferences determine target T-cell depletion and cellular tropism in human lymphoid tissue SO JOURNAL OF VIROLOGY LA English DT Article ID CHEMOKINE RECEPTORS; INFECTION; HIV-1; LYMPHOCYTES; REPLICATION; STRAINS; MICE AB The present study sought to determine how usage of coreceptors by human immunodeficiency virus type 1 dictates cell tropism and depletion of CD4(+) T cells in human lymphoid tissues cultured ex vivo. We found that coreceptor preferences control the marked, preferential depletion of coreceptor-expressing CD4(+) lymphocytes. In addition, there was a strong, but not absolute, preference shown by CXCR4-using strains for lymphocytes and by CCR5-using strains for macrophages. C1 Univ Calif San Francisco, Sch Med, Gladstone Inst Virol & Immunol, San Francisco, CA 94141 USA. Univ Calif San Francisco, Sch Med, Dept Med, San Francisco, CA 94141 USA. Univ Calif San Francisco, Sch Med, Dept Pathol, San Francisco, CA 94141 USA. NICHHD, Lab Mol & Cellular Biophys, NIH, Bethesda, MD 20892 USA. RP Goldsmith, MA (reprint author), Univ Calif San Francisco, Sch Med, Gladstone Inst Virol & Immunol, POB 419100, San Francisco, CA 94141 USA. RI Speck, Roberto/O-2433-2016 FU NIAID NIH HHS [R01-AI43695] NR 14 TC 51 Z9 51 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 2000 VL 74 IS 11 BP 5347 EP 5351 DI 10.1128/JVI.74.11.5347-5351.2000 PG 5 WC Virology SC Virology GA 312MX UT WOS:000086948000046 PM 10799612 ER PT J AU Peterson, KE Iwashiro, M Hasenkrug, KJ Chesebro, B AF Peterson, KE Iwashiro, M Hasenkrug, KJ Chesebro, B TI Major histocompatibility complex class I gene controls the generation of gamma interferon-producing CD4(+) and CD8(+) T cells important for recovery from friend retrovirus-induced leukemia SO JOURNAL OF VIROLOGY LA English DT Article ID HOST IMMUNE-RESPONSE; VIRUS LEUKEMIA; RFV-1 GENE; MICE; INFECTION; RESPONSIVENESS; H-2; IDENTIFICATION; CYTOKINES; DISEASE AB Recovery from leukemia induced by Friend virus complex (FV) requires strong CD4(+) helper, CD8(+) cytotoxic T-lymphocyte, and B-cell responses. The development of these immune responses is dependent on the major histocompatibility complex (MHC) (H-2) genotype of the mouse, In H-2(b/b) mice, which spontaneously recover from FV-induced erythroleukemia, neutralization of gamma interferon (IFN-gamma) in vivo inhibited recovery, which indicated that IFN-gamma was a necessary component of the immune response to FV. Furthermore, in H-2(b/b) mice, high numbers of IFN-gamma producing cells were detected after FV infection, whereas in H-2(a/b) mice, which have a low-recovery phenotype, only low numbers of IFN-gamma-producing cells were detected, Similarly, H-2(bm14/b) mice, which cannot recover from FV infection due to a point mutation in one allele of the H-2D(b) gene, also had low numbers of IFN-gamma-producing T cells. Surprisingly, this effect was observed for both CD8(+) and CD4(+) T cells, These findings reveal a novel influence of MHC class I genes on CD4(+) T-cell responses to viral infection, Furthermore, the influence of MHC class I genotype on the generation of both IFN-gamma-producing CD4(+) and CD8(+) T cells helps explain the major impact of the H-2D gene on recovery from FV disease, C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. RP Chesebro, B (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. RI Peterson, Karin/D-1492-2016 OI Peterson, Karin/0000-0003-4177-7249 NR 32 TC 24 Z9 24 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 2000 VL 74 IS 11 BP 5363 EP 5367 DI 10.1128/JVI.74.11.5363-5367.2000 PG 5 WC Virology SC Virology GA 312MX UT WOS:000086948000049 PM 10799615 ER PT J AU Weng, YK Yang, ZN Weiss, CD AF Weng, YK Yang, ZN Weiss, CD TI Structure-function studies of the self-assembly domain of the human immunodeficiency virus type 1 transmembrane protein gp41 SO JOURNAL OF VIROLOGY LA English DT Article ID SIV GP41; ENVELOPE GLYCOPROTEIN; MUTATIONAL ANALYSIS; CRYSTAL-STRUCTURE; ATOMIC-STRUCTURE; LEUCINE ZIPPER; CORE STRUCTURE; COILED-COIL; HIV-1 GP41; ECTODOMAIN AB The coiled-coil region of the human immunodeficiency virus type 1 transmembrane protein (gp41) makes up the interior core of the six-helix bundle structure of the gp41 self-assembly domain. We extended our previous study of this domain (Y. Weng and C. D. Weiss, J. Virol. 72:9676-9682, 1998) by analyzing 23 additional mutants at positions that lie at the interface of the interior core and outer helices. We found nine new functional mutants. For most mutants, the activity could be explained by the ability of the modeled mutants to stabilize the six-helix bundle structure. The present study provides insights into the envelope glycoprotein fusion mechanism and information for rational drug and vaccine design. C1 US FDA, CBER, Bethesda, MD 20892 USA. NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. RP Weiss, CD (reprint author), US FDA, CBER, HFM 466,NIH Bldg 29,Room 532,29 Lincoln Dr, Bethesda, MD 20892 USA. RI Weiss, Carol/F-6438-2011 OI Weiss, Carol/0000-0002-9965-1289 NR 19 TC 36 Z9 36 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 2000 VL 74 IS 11 BP 5368 EP 5372 DI 10.1128/JVI.74.11.5368-5372.2000 PG 5 WC Virology SC Virology GA 312MX UT WOS:000086948000050 PM 10799616 ER PT J AU Jung, YT Kozak, CA AF Jung, YT Kozak, CA TI A single amino acid change in the murine leukemia virus capsid gene responsible for the Fv1(nr) phenotype SO JOURNAL OF VIROLOGY LA English DT Article ID LOCUS AFFECTING RESISTANCE; HOST-RANGE RESTRICTIONS; NUCLEOTIDE-SEQUENCE; CELL-CULTURES; FV-1 TROPISM; MOUSE EMBRYO; BALB-C; INFECTION; GENOMES; MICE AB The nr allele at the mouse Fv1 restriction locus governs resistance to B-tropic and some N-tropic murine leukemia viruses (MLVs). Sequence analysis and site-specific mutagenesis of N-tropic MLVs identified a single amino acid difference responsible for this restriction that is distinct from the site that governs N or B tropism. Viruses with other substitutions at this site were evaluated for altered replication patterns. C1 NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. RP Kozak, CA (reprint author), NIAID, Mol Microbiol Lab, Bldg 4,Room 329, Bethesda, MD 20892 USA. NR 21 TC 21 Z9 21 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 2000 VL 74 IS 11 BP 5385 EP 5387 DI 10.1128/JVI.74.11.5385-5387.2000 PG 3 WC Virology SC Virology GA 312MX UT WOS:000086948000054 PM 10799620 ER PT J AU Beringue, V Adjou, KT Lamoury, F Maignien, T Deslys, JP Race, R Dormont, D AF Beringue, V Adjou, KT Lamoury, F Maignien, T Deslys, JP Race, R Dormont, D TI Opposite effects of dextran sulfate 500, the polyene antibiotic MS-8209, and Congo red on accumulation of the protease-resistant isoform of PrP in the spleens of mice inoculated intraperitoneally with the scrapie agent SO JOURNAL OF VIROLOGY LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; BOVINE SPONGIFORM ENCEPHALOPATHY; PRION PROTEIN; INCUBATION PERIOD; AMPHOTERICIN-B; DIFFERENT ROUTES; AMYLOID PLAQUES; MOUSE SCRAPIE; INFECTION; REPLICATION AB The mode and the site of action of the major antiscrapie drugs have been studied by investigating their effects on the abnormal protease-resistant isoform of PrP (PrPres) and on its accumulation in mouse spleen. Day-by-day PrPres accumulation in the spleen and in other peripheral organs was first monitored to describe the early steps of scrapie pathogenesis. Three phases were identified: the detection of scrapie inoculum on the day of scrapie infection, a clearance phase, and then the peripheral accumulation of PrPres, In a second step, the effects of the polyene antibiotic MS-8209, the polyanion dextran sulfate 500 (DS500), and Congo red were assessed on these phases, after the drugs were coincubated,vith scrapie inoculum. Highly different mechanisms and sites of action were apparent. MS-8209 had a weak effect on the accumulation of PrPres in spleen, suggesting another site of intervention for this drug. DS500 delayed the beginning of the clearance phase but then blocked PrPres synthesis for a long period of time, probably because of its immunological effects on the spleen, Surprisingly, Congo red suppressed the clearance phase of scrapie inoculum and then increased transiently accumulation of PrPres in spleen. We showed in vitro that this effect was related to a direct enhancement of the protease resistance of PrPres by the drug. C1 CEA, Serv Neurovirol, DRM, DSV,CRSSA, Fontenay Aux Roses, France. NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. RP Beringue, V (reprint author), St Marys Hosp, Imperial Coll, Sch Med, Dept Neurogenet,Neuroimmunol Grp, Norfolk Pl, London W2 1PG, England. NR 50 TC 53 Z9 57 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 2000 VL 74 IS 12 BP 5432 EP 5440 DI 10.1128/JVI.74.12.5432-5440.2000 PG 9 WC Virology SC Virology GA 317RL UT WOS:000087240700005 PM 10823847 ER PT J AU Schofield, DJ Glamann, J Emerson, SU Purcell, RH AF Schofield, DJ Glamann, J Emerson, SU Purcell, RH TI Identification by phage display and characterization of two neutralizing chimpanzee monoclonal antibodies to the hepatitis E virus capsid protein SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; COMBINATORIAL LIBRARIES; VIRAL-HEPATITIS; CYNOMOLGUS MONKEYS; MOLECULAR-CLONING; PROTOTYPE STRAIN; ANIMAL VIRUSES; INSECT CELLS; RISK-FACTORS; INFECTION AB Two monoclonal antibodies (MAbs) against the ORF2 protein of the SAR-55 strain of hepatitis E virus (HEV) were isolated by phage display from a cDNA library of chimpanzee (Pan troglodytes) gamma 1/kappa antibody genes. Both MAbs, HEV#4 and HEV#31, bound to reduced, denatured open reading frame 2 (ORF2) protein in a Western blot, suggesting that they recognize linear epitopes, The affinities (equilibrium dissociation constants, K-d) for the SAR-55 ORF2 protein were 1.7 nM for HEV#4 and 5.4 nM for HEV#31, The two MAbs also reacted in an enzyme-linked immunosorbent assay,vith recombinant ORF2 protein from a heterologous HEV, the Meng strain. Each MAb blocked the subsequent binding of the other MAb to homologous ORF2 protein in indirect competition assays, suggesting that they recognize the same or overlapping epitopes, Radioimmunoprecipitation assays suggested that at least part of the linear epitope(s) recognized by the two MAbs is located between amino acids 578 and 607. MAbs were mixed with homologous HEV in vitro and then inoculated into rhesus monkeys (Macaca mulatta) to determine their neutralizing ability. Whereas all control animals developed hepatitis (elevated liver enzyme levels in serum) and seroconverted to HEV, those receiving an inoculum incubated with either HEV#4 or HEV#31 were not infected. Therefore, each MAb neutralized the SAR-55 strain of HEV in vitro. C1 NIAID, Infect Dis Lab, Hepatitis Viruses Sect, NIH, Bethesda, MD 20892 USA. NIAID, Infect Dis Lab, Mol Hepatitis Sect, NIH, Bethesda, MD 20892 USA. NIAID, Mol Microbiol Lab, Immunodeficiency Viruses Sect, NIH, Bethesda, MD 20892 USA. RP NIAID, Infect Dis Lab, Hepatitis Viruses Sect, NIH, Bldg 7,Rm 200,7 Ctr Dr,MSC-0740, Bethesda, MD 20892 USA. EM DSCHOFIELD@NIAID.NIH.GOV NR 64 TC 103 Z9 111 U1 1 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUN PY 2000 VL 74 IS 12 BP 5548 EP 5555 DI 10.1128/JVI.74.12.5548-5555.2000 PG 8 WC Virology SC Virology GA 317RL UT WOS:000087240700019 PM 10823861 ER PT J AU Takeda, N Thomas, GR Ludlow, CL AF Takeda, N Thomas, GR Ludlow, CL TI Aging effects on motor units in the human thyroarytenoid muscle SO LARYNGOSCOPE LA English DT Article DE electromyography; aging; recurrent laryngeal nerve; thyroarytenoid muscle; motor unit; neuropathy ID VOCAL CORD PARALYSIS; LARYNGEAL ELECTROMYOGRAPHY; ACTION-POTENTIALS; OLD-AGE; HEALTHY AB Objectives: To determine whether age differences are present in the human laryngeal thyroarytenoid muscle that would indicate that different normative values would be needed for identifying motor unit abnormalities. Study Design: Twenty-six consecutively recruited healthy subjects between the ages of 21 and 72 years participated in a laryngeal electromyography study. Methods: Bipolar needle electrodes were used to record motor unit action potentials from several locations in the right and left thyroarytenoid muscles of each subject. The duration of a motor unit was measured when at least 10 firings of the same motor unit could be identified. On the average, four units were measured per muscle. Results: In the subjects less than 60 years of age, motor unit duration did not increase significantly with age. However, motor units from subjects greater than 60 years of age had longer durations than those from subjects less than 60 years of age (P < .00005), and 25% of the units measured in subjects greater than 60 years of age had longer durations than any of the units measured in subjects less than 60 years of age. Further, the older subjects differed from each other in their mean unit durations (P < .0001). In subjects less than 60 years of age, significantly longer durations were found for units innervated by the longer, left-side recurrent laryngeal nerve in comparison with the right-side nerve (P = .005). Conclusions: Different mean and SD values should be used for patients less than and greater than 60 years of age and for the right and left sides, when evaluating motor units in the thyroarytenoid muscles. C1 NINDS, Laryngeal & Speech Sect, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, Tumor Biol Sect, NIH, Bethesda, MD USA. RP Ludlow, CL (reprint author), NINDS, Laryngeal & Speech Sect, Bldg 10,Room 5D38,10 Ctr Dr,MSC 1416, Bethesda, MD 20892 USA. OI Ludlow, Christy/0000-0002-2015-6171 NR 42 TC 34 Z9 36 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD JUN PY 2000 VL 110 IS 6 BP 1018 EP 1025 DI 10.1097/00005537-200006000-00025 PG 8 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 322DL UT WOS:000087494900025 PM 10852524 ER PT J AU Kovalchuk, AL Kishimoto, T Janz, S AF Kovalchuk, AL Kishimoto, T Janz, S TI Lymph nodes and Peyer's patches of IL-6 transgenic BALB/c mice harbor T(12;15) translocated plasma cells that contain illegitimate exchanges between the immunoglobulin heavy-chain mu locus and c-myc SO LEUKEMIA LA English DT Article DE chromosomal translocation; plasmacytomagenesis; tumor precursor ID CHROMOSOMAL TRANSLOCATION; MURINE PLASMACYTOMAS; V-ABL; INTERLEUKIN-6; SWITCH; DNA; RECOMBINATIONS; ACTIVATION; INDUCTION; PRISTANE AB Hyperplastic plasmacytotic lymph nodes and Peyer's patches of 12 of 25 (48%) BALB/c mice that carried a human IL-6 transgene under the transcriptional control of the histocompatibility H-2L(D) promoter (BALB/c,IL-6 mice) were found to harbor 15 cell clones that contained in their T(12;15) translocation breakpoint regions illegitimate genetic recombinations between the upstream flank of the immunoglobulin heavy-chain C mu locus (5'-C mu) and c-mye (5'-C mu/c-myc(+) clones). Similar 5'-C mu/c-myc(+) clones were also detected in prlstane-induced peritoneal granulomata (a significant source of IL-6 In situ) of three of 13 (13%) conventional BALB/c mice, but not in lymphoid tissues of pristane-treated BALB/c mice, nor in any tissue of untreated BALB/c mice. These findings provided strong evidence that IL-6 may be able to promote the growth andlor survival of clones that contained rearrangements between 5'-C mu and c-myc, Taken in conjunction with our previous observation that 5'-C mu/c-myc(+) clones are the precursors for prlstane-induced BALB/c plasmacytomas, the findings further suggested that IL-6 may play a pivotal role in the early stage of plasmacytoma development, by promoting tumor precursor cells. The BALB/c.IL-6 model of plasmacytomagenesis may be superior to the conventional BALA/c model because the putative plasmacytoma precursors appear to be more prevalent and in their development independent of treating the mice with inflammation-inducing plasmacytomagenic agents, such as pristane or silicone polymers. C1 NCI, Genet Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Osaka Univ, Sch Med, Inst Mol & Cellular Biol, Osaka, Japan. RP Janz, S (reprint author), NCI, Genet Lab, Div Basic Sci, NIH, Bldg 37,Rm 2B10, Bethesda, MD 20892 USA. RI Kishimoto, Tadamitsu/C-8470-2009 NR 34 TC 18 Z9 19 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD JUN PY 2000 VL 14 IS 6 BP 1127 EP 1135 DI 10.1038/sj.leu.2401767 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 322DJ UT WOS:000087494700018 PM 10865979 ER PT J AU Deutsch, J Kalderon, B Purdon, AD AF Deutsch, J Kalderon, B Purdon, AD TI Evaluation of brain long-chain acylcarnitines during cerebral ischemia SO LIPIDS LA English DT Article ID FREE FATTY-ACID; CARNITINE PALMITOYLTRANSFERASE; ERYTHROCYTE-MEMBRANE; POOL; METABOLISM; RAT; PHOSPHOLIPIDS; TURNOVER; PATHWAY AB Concentration and distribution of long-chain acylcarnitines in control microwaved and ischemic (decapitated) rat brain were measured by electrospray ionization tandem mass spectrometry. The total acylcarnitine concentration from control rat brains equaled 7-8 nmol/g wet weight brain, about one-fourth the total concentration of long-chain acyl-CoA, indicating a small role in buffering the total acyl-CoA pool concentration. Furthermore, acylcarnitine did not differ between ischemic and control rat brain with regard to total concentration or concentrations of molecular species of acylcarnitine. Therefore, the size of the acylcarnitine pool in brain is not affected by the dramatic increase in unesterified fatty acids (similar to 4x) that occurs in ischemia. C1 Hebrew Univ Jerusalem, Fac Med, Dept Med Chem, IL-91120 Jerusalem, Israel. Hebrew Univ Jerusalem, Fac Med, Dept Human Nutr & Metab, IL-91120 Jerusalem, Israel. NIA, Sect Brain Physiol & Metab, NIH, Bethesda, MD 20892 USA. RP Deutsch, J (reprint author), Hebrew Univ Jerusalem, Sch Pharm, Dept Med Chem, IL-91120 Jerusalem, Israel. NR 19 TC 4 Z9 4 U1 0 U2 0 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 2000 VL 35 IS 6 BP 693 EP 696 DI 10.1007/s11745-000-0575-1 PG 4 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 331FR UT WOS:000088008100016 PM 10901433 ER PT J AU Velan, SS Spencer, RGS Zweier, JL Kuppusamy, P AF Velan, SS Spencer, RGS Zweier, JL Kuppusamy, P TI Electron paramagnetic resonance oxygen mapping (EPROM): Direct visualization of oxygen concentration in tissue SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE EPR; EPR imaging; oximetry; nitroxide ID FREE-RADICALS; BIOLOGICAL SAMPLES; MAGNETIC-RESONANCE; SPECTROSCOPY; HEART; PROBE; METABOLISM; FREQUENCY; OXIMETRY; TENSION AB Tissue oxygen content is a central parameter in physiology but is difficult to measure. We report a novel procedure for spatial mapping of oxygen by electron paramagnetic resonance (EPR) utilizing a spectral-spatial imaging data set, in which an EPR spectrum is obtained from each image volume element. From this data set, spatial maps corresponding to local spin density and maximum EPR spectral line amplitude are generated. A map of local EPR spectral linewidth is then computed. Because linewidth directly correlates with oxygen concentration, the linewidth image provides a map of oxygenation. This method avoids a difficulty inherent in other oxygen content mapping techniques using EPR, that is, the unwanted influence of local spin probe density on the image. We provide simulation results and data from phantom studies demonstrating the validity of this method. We then apply the method to map oxygen content in rat tail tissue and vasculature. This method provides a new, widely applicable, approach to direct visualization of oxygen concentration in living tissue. Magn Reson Med 43: 804-809, 2000, (C) 2000 Wiley-Liss, Inc. C1 Johns Hopkins Univ, Sch Med, EPR Ctr, Dept Med,Div Cardiol, Baltimore, MD 21224 USA. NIA, Nucl Magnet Resonance Unit, NIH, Baltimore, MD USA. RP Kuppusamy, P (reprint author), Johns Hopkins Univ, Sch Med, EPR Ctr, Dept Med,Div Cardiol, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 USA. RI Velan, S. Sendhil/B-6374-2017 OI Velan, S. Sendhil/0000-0002-4096-0722 FU NCI NIH HHS [CA-78886-01]; NCRR NIH HHS [RR-12190] NR 33 TC 58 Z9 59 U1 1 U2 4 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD JUN PY 2000 VL 43 IS 6 BP 804 EP 809 DI 10.1002/1522-2594(200006)43:6<804::AID-MRM5>3.0.CO;2-B PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 320ZG UT WOS:000087430000005 PM 10861874 ER PT J AU Yongbi, MN Tan, CX Frank, JA Duyn, JH AF Yongbi, MN Tan, CX Frank, JA Duyn, JH TI A protocol for assessing subtraction errors of arterial spin-tagging perfusion techniques in human brain SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE perfusion; subtraction error; slice profile; Gd-DTPA ID INVERSION FOCI PULSES; CEREBRAL BLOOD-FLOW; SLICE PROFILE; FREQUENCY; SIGNAL AB A protocol for assessing signal contributions from static tissue (subtraction errors) in perfusion images acquired with arterial spin-labeling (ASL) techniques in human brain is proposed. The method exploits the reduction of blood T-1 caused by the clinically available paramagnetic contrast agent, gadopentetate dimeglumine (Gd-DTPA), The protocol is demonstrated clinically with multislice FAIR images acquired before, during, and after Gd-DTPA administration using a range of selective inversion widths. Perfusion images acquired postcontrast for selective inversion widths targe enough (threshold) to avoid interaction with the imaging slice had signal intensities reduced to noise level, as opposed to subtraction errors manifested on images acquired using inversion widths below the threshold. The need for these experiments to be performed in vivo is further illustrated by comparison with phantom results. The protocol allows a one-time calibration of relevant ASL parameters (e.g., selective inversion widths) in vivo, which may otherwise cause subtraction errors. Magn Reson Med 43: 896-900, 2000, Published 2000 Wiley-Liss, Inc(dagger). C1 NIH, Ctr Clin, Lab Diagnost Radiol, Bethesda, MD 20892 USA. RP Duyn, JH (reprint author), NIH, Ctr Clin, Lab Diagnost Radiol, Bldg 10,Room B1N256,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Duyn, Jozef/F-2483-2010 NR 20 TC 3 Z9 3 U1 0 U2 0 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD JUN PY 2000 VL 43 IS 6 BP 896 EP 900 DI 10.1002/1522-2594(200006)43:6<896::AID-MRM17>3.0.CO;2-J PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 320ZG UT WOS:000087430000017 PM 10861886 ER PT J AU Duyn, JH AF Duyn, JH TI High-speed interlaced spin-echo magnetic resonance imaging SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE spin-echo; multi-slice; rapid imaging; T-2 contrast ID CONTRAST; BRAIN AB A new method is introduced for increasing the efficiency in multislice single spin-echo MRI. The method interlaces the excitation and measurement of different slices, resulting in an effective use of the echo delay time between RF excitation and reception. Under certain conditions, the method allows for scan time reduction compared to standard single spin-echo MRI, in particular for long echo times. The technique is demonstrated in examples of brain scans, indicating that a substantial increase is scan speed can be achieved without loss in image signal-to-noise ratio or contrast. Potential applications include perfusion imaging using T-2-contrast agents, as well as BOLD-based functional imaging. Magn Reson Med 43:905-908, 2000. Published 2000 Wiley-Liss, Inc(dagger). C1 NIH, Ctr Clin, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. RP Duyn, JH (reprint author), NIH, Ctr Clin, Lab Diagnost Radiol Res, Bldg 10,Room N1N-256,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Duyn, Jozef/F-2483-2010 NR 9 TC 0 Z9 1 U1 0 U2 1 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD JUN PY 2000 VL 43 IS 6 BP 905 EP 908 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 320ZG UT WOS:000087430000019 PM 10861888 ER PT J AU Pajevic, S Pierpaoli, C AF Pajevic, S Pierpaoli, C TI Color schemes to represent the orientation of anisotropic tissues from diffusion tensor data: Application to white matter fiber tract mapping in the human brain (vol 42, pg 526, 1999) SO MAGNETIC RESONANCE IN MEDICINE LA English DT Correction C1 NINDS, Neuroimaging Branch, NIH, Bethesda, MD 20892 USA. RP Pajevic, S (reprint author), NIH, Ctr Informat Technol, Math & Stat Comp Lab, Bldg 10, Bethesda, MD 20892 USA. RI Pierpaoli, Carlo/E-1672-2011 NR 2 TC 35 Z9 36 U1 0 U2 1 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD JUN PY 2000 VL 43 IS 6 BP 921 EP 921 DI 10.1002/1522-2594(200006)43:6<921::AID-MRM23>3.0.CO;2-I PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 320ZG UT WOS:000087430000023 ER PT J AU Danciger, M Matthes, MT Yasamura, D Akhmedov, NB Rickabaugh, T Gentleman, S Redmond, TM La Vail, MM Farber, DB AF Danciger, M Matthes, MT Yasamura, D Akhmedov, NB Rickabaugh, T Gentleman, S Redmond, TM La Vail, MM Farber, DB TI A QTL on distal Chromosome 3 that influences the severity of light-induced damage to mouse photoreceptors SO MAMMALIAN GENOME LA English DT Article ID AGE-RELATED MACULOPATHY; MACULAR DEGENERATION; VISUAL THRESHOLDS; MICE; EYE; MUTANT; SUSCEPTIBILITY; RHODOPSIN; ALBINO; RETINA AB C57BL/6J-c(2J) (c2J) albino mice showed much less damage to their photoreceptors after exposure to prolonged light than BALB/c mice and seven other albino strains tested. There were no Sender differences, and preliminary studies suggested that the c2J relative protective effect was a complex trait. A genome-wide scan using dinucleotide repeat markers was carried out for the analysis of 194 progeny of the backcross (c2J x BALB/c)F-1 x c2J and the thickness of the outer nuclear layer (ONL) of the retina was the quantitative trait reflecting retinal damage. Our results revealed a strong and highly significant quantitative trait locus (QTL) on mouse Chromosome (Chr) 3 that contributes almost 50% of the c2J protective effect, and three other very weak but significant QTLs on Chrs 9, 12, and 14. Interestingly, the Chrs 9 and 12 QTLs corresponded to relative susceptibility alleles in c2J (Or relative protection alleles in BALB/c), the opposite of the relative protective effect of the QTLs on Chrs 3 and 14. We mapped the Rpe65 gene to the apex of the Chr 3 QTL (LOD score = 19.3). Northern analysis showed no difference in retinal expression of Rpe65 message between c2J and BALB/c mice. However, sequencing of the Rpe65 message revealed a single base change in codon 450, predicting a methionine in c2J and a leucine in BALB/c. When the retinas of aging BALB/c and c2J mice reared in normal cyclic light were compared, the BALB/c retinas showed a small but significant loss of photoreceptor cells, while the c2J retinas did not. Finding light damage-modifying genes in the mouse may open avenues of study for understanding age-related macular degeneration and other retinal degenerations, since light exposures may contribute to the course of these diseases. C1 Univ Calif Los Angeles, Sch Med, Jules Stein Eye Inst, Los Angeles, CA 90095 USA. Loyola Marymount Univ, Dept Biol, Los Angeles, CA 90045 USA. Univ Calif San Francisco, Sch Med, Beckman Vis Ctr, San Francisco, CA 94143 USA. NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Sch Med, Inst Mol Biol, Los Angeles, CA 90095 USA. RP Danciger, M (reprint author), Univ Calif Los Angeles, Sch Med, Jules Stein Eye Inst, Los Angeles, CA 90095 USA. OI Redmond, T. Michael/0000-0002-1813-5291 FU NEI NIH HHS [EY08285] NR 28 TC 89 Z9 89 U1 0 U2 1 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0938-8990 J9 MAMM GENOME JI Mamm. Genome PD JUN PY 2000 VL 11 IS 6 BP 422 EP 427 DI 10.1007/s003350010081 PG 6 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 316HF UT WOS:000087161000002 PM 10818205 ER PT J AU Chae, JJ Centola, M Aksentijevich, I Dutra, A Tran, M Wood, G Nagaraju, K Kingma, DW Liu, PP Kastner, DL AF Chae, JJ Centola, M Aksentijevich, I Dutra, A Tran, M Wood, G Nagaraju, K Kingma, DW Liu, PP Kastner, DL TI Isolation, genomic organization, and expression analysis of the mouse and rat homologs of MEFV, the gene for familial Mediterranean fever SO MAMMALIAN GENOME LA English DT Article ID CHROMOSOME 16P13.3; FREQUENCY; REGION; CONSTRUCTION; LOCALIZATION; HAPLOTYPE; MUTATIONS; LOCUS; FMF AB Familial Mediterranean fever (FMF) is a recessive disorder characterized by episodes of fever with serositis or synovitis. Recently the FMF gene (MEFV) was cloned; the protein product, pyrin/marenostrin, is thought to regulate inflammation in myeloid cells. In this manuscript we report the mouse and rat homologs of MEFV. The murine gene contains ten exons with a coding sequence of 2304 bp, while the rat homolog has nine exons with a coding sequence of 2253 bp. A considerable amino acid sequence homology was observed between the mouse and human (47.6% identity and 65.5% similarity) and between the mouse and rat genes (73.5% identity and 82.1% similarity). The predicted rodent proteins have several important domains and signals found in human pyrin, including a B-box zinc finger domain, Robbins-Dingwall nuclear localization signal, and coiled-coil domain. However, perhaps because of an ancient frame-shift mutation, nei ther the mouse nor the rat protein has an intact C-terminal B30.2 domain, in which most FMF-associated mutations have been found in human MEFV. Nevertheless, like the human gene, mouse Mefv is expressed in peripheral blood granulocytes but not lymphocytes. Consistent with its expression in granulocytes. Mefv was detected at high levels in the primary follicles and marginal zones of the splenic white pulp, Mefv is localized on mouse Chromosome (Chr) 16, region A3-B1, extending a region of synteny with human Chr 16p13.3. Development of knockout and knockin mouse models may provide further insights into the functional evolution of this gene. C1 NIAMSD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Cytogenet & Confocal Microscopy Core, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Kastner, DL (reprint author), NIAMSD, Arthrit & Rheumatism Branch, NIH, Bldg 10,Room 9N-214, Bethesda, MD 20892 USA. RI Liu, Paul/A-7976-2012 OI Liu, Paul/0000-0002-6779-025X NR 25 TC 32 Z9 34 U1 0 U2 4 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0938-8990 J9 MAMM GENOME JI Mamm. Genome PD JUN PY 2000 VL 11 IS 6 BP 428 EP 435 DI 10.1007/s003350010082 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 316HF UT WOS:000087161000003 PM 10818206 ER PT J AU Manickam, P Vogel, AM Agarwal, SK Oda, T Spiegel, AM Marx, SJ Collins, FS Weinstein, BM Chandrasekharappa, SC AF Manickam, P Vogel, AM Agarwal, SK Oda, T Spiegel, AM Marx, SJ Collins, FS Weinstein, BM Chandrasekharappa, SC TI Isolation, characterization, expression and functional analysis of the zebrafish ortholog MEN1 SO MAMMALIAN GENOME LA English DT Article ID ENDOCRINE NEOPLASIA TYPE-1; MURINE HOMOLOG; GENE AB Mutations in the MEN1 gene lead to an autosomal dominant disorder, multiple endocrine neoplasia type 1 (MEN1), which is characterized by tumors of the parathyroid, entero-pancreatic neuroendocrine, and pituitary tissues. The protein encoded by MEN1, 610-amino acid menin, resides primarily in the nucleus and binds to the transcription factor JunD, resulting in the repression of JunD-induced transcription. We report here a detailed characterization of the zebrafish men1 gene and its full-length (2551 nt) transcript, encoding a 617-amino acid protein with 67% identity and 80% similarity to human menin. Of the 81 missense mutations and in-frame deletions reported in MEN1 patients, 72 occur in residues that are identical in zebrafish, suggesting the importance of the conserved regions. The zebrafish men1 gene maps 61 cM from the top of linkage group 7 (LG7), a region that appears to show conserved synteny to the MEN1 loci at human 11q13. A 2.7-kb men1 message is detected at all stages of zebrafish development analyzed, from one-cell embryos to adult fish. Whole-mount in situ hybridization showed ubiquitous distribution of men1 message in zebrafish embryos at cleavage, blastula, gastrula, and early segmentation stages, with relatively abundant expression in blood cell progenitors (24 h post fertilization) and mesenchymal tissues (48 h post fertilization) at later stages. Zebrafish menin binds both human and mouse JunD, and represses JunD-induced transcription, indicating that the JunD-binding ability of menin is evolutionarily conserved. C1 Natl Human Genome Res Inst, Genet & Mol Biol Branch, Banaras Hindu Univ, Bethesda, MD 20892 USA. NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Chandrasekharappa, SC (reprint author), Natl Human Genome Res Inst, Genet & Mol Biol Branch, NIH, Bldg 49,Rm 3E13,49 Convent Dr, Bethesda, MD 20892 USA. RI Agarwal, Sunita/D-1428-2016 OI Agarwal, Sunita/0000-0002-7557-3191 NR 18 TC 32 Z9 32 U1 1 U2 4 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0938-8990 J9 MAMM GENOME JI Mamm. Genome PD JUN PY 2000 VL 11 IS 6 BP 448 EP 454 DI 10.1007/s003350010085 PG 7 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 316HF UT WOS:000087161000006 PM 10818209 ER PT J AU Wang, CC Brodnicki, T Copeland, NG Jenkins, NA Harvey, RP AF Wang, CC Brodnicki, T Copeland, NG Jenkins, NA Harvey, RP TI Conserved linkage of NK-2 homeobox gene pairs Nkx2-2/2-4 and Nkx2-1/2-9 in mammals SO MAMMALIAN GENOME LA English DT Article ID FOREBRAIN; REGION C1 St Vincents Hosp, Victor Chang Cardiac Res Inst, Darlinghurst, NSW 2010, Australia. Univ New S Wales, Fac Med, Kensington, NSW 2052, Australia. Univ New S Wales, Fac Life Sci, Kensington, NSW 2052, Australia. Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Genet & Bioinformat Grp, Parkville, Vic 3050, Australia. Cooperat Res Ctr Discovery Genes Common Human Dis, Richmond 3121, Australia. NCI, Mammalian Genet Lab, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Harvey, RP (reprint author), St Vincents Hosp, Victor Chang Cardiac Res Inst, 384 Victoria St, Darlinghurst, NSW 2010, Australia. NR 12 TC 15 Z9 17 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0938-8990 J9 MAMM GENOME JI Mamm. Genome PD JUN PY 2000 VL 11 IS 6 BP 466 EP 468 DI 10.1007/s003350010089 PG 3 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 316HF UT WOS:000087161000010 PM 10818213 ER PT J AU Viarengo, A Burlando, B Giordana, A Bolognesi, C Gabrielides, GP AF Viarengo, A Burlando, B Giordana, A Bolognesi, C Gabrielides, GP TI Networking and expert-system analysis: next frontier in biomonitoring SO MARINE ENVIRONMENTAL RESEARCH LA English DT Article DE biomarkers; biomonitoring; stress index; pollutant effects; data warehouse; expert system; data mining ID BIOMARKERS; INDICATORS; RESPONSES; POLLUTION; MOLLUSKS AB The extensive use of biomarkers in environment biomonitoring programmes has raised the problem of data management and intercomparison. A research project (Pollution Effect Network, PEN) is proposed here, consisting of the realisation of an on-line warehouse for biomarker data (http ://www.muf.unipmn.it/pen), The web site will contain repository sections and expert system procedures able to integrate information from different biomarkers and provide ranking of the organism health status in terms of synthetic stress syndrome indexes. Researchers accessing the site will be able to submit and process their own data. This will allow common criteria in the evaluation of the biological effects of pollutants, and an intercomparison of biomonitoring data among different geographic areas and sentinel species. (C) 2000 Elsevier Science Ltd. All rights reserved. C1 Univ Eastern Piedmont, Dept Sci & Adv Technol, I-15100 Alessandria, Italy. Natl Canc Inst, Toxicol Evaluat Unit, Genoa, Italy. UN, Environm Programme, Athens 11610, Greece. RP Viarengo, A (reprint author), Univ Eastern Piedmont, Dept Sci & Adv Technol, Corso Borsalino 54, I-15100 Alessandria, Italy. OI Viarengo, Aldo/0000-0002-1557-6526 NR 12 TC 36 Z9 38 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0141-1136 J9 MAR ENVIRON RES JI Mar. Environ. Res. PD JUN PY 2000 VL 49 IS 5 BP 483 EP 486 DI 10.1016/S0141-1136(00)00027-1 PG 4 WC Environmental Sciences; Marine & Freshwater Biology; Toxicology SC Environmental Sciences & Ecology; Marine & Freshwater Biology; Toxicology GA 315CH UT WOS:000087094700006 PM 11285725 ER PT J AU Kramer, PR Guerrero, G Krishnamurthy, R Mitchell, PJ Wray, S AF Kramer, PR Guerrero, G Krishnamurthy, R Mitchell, PJ Wray, S TI Ectopic expression of luteinizing hormone-releasing hormone and peripherin in the respiratory epithelium of mice lacking transcription factor AP-2 alpha SO MECHANISMS OF DEVELOPMENT LA English DT Article DE AP-2 alpha; transcription factor; cranial placode; gonadotropin releasing hormone; respiratory epithelium; homozygous mutant; olfactory axon ID CELL-ADHESION MOLECULE; FACTOR AP-2; OLFACTORY PLACODE; GENE-EXPRESSION; LHRH NEURONS; CHICK-EMBRYO; MURINE EMBRYOGENESIS; MOUSE EMBRYOGENESIS; BASAL EXPRESSION; NASAL PLACODE AB The vertebrate transcription factor activator protein-2 (AP-2 alpha) is involved in craniofacial morphogenesis. In the nasal placode AP-2 alpha expression delineates presumptive respiratory epithelia from olfactory epithelia, with AP-2 alpha expression restricted to the anterior region of the respiratory epithelium (absent from the olfactory epithelium) at later stages. To address the role AP-2 alpha plays in differentiation of cell groups in the nasal placode, the spatiotemporal expression pattern of four markers normally associated with olfactory epithelial structures was analyzed in mice lacking AP-2 alpha. These markers were the intermediate filament protein peripherin, the neuropeptide luteinizing hormone-releasing hormone (LHRH), the neural cell adhesion molecule (NCAM) and the olfactory transcription factor Olf-1. Development of cells expressing these markers was similar in both genotypes until embryonic day 12.5 (E12.5), indicating that the main olfactory epithelium and olfactory pit formation was normal. At E13.5 in mutant mice, ectopic LHRH neurons and peripherin axons were detected in respiratory epithelial areas, areas devoid of Olf-1 and NCAM staining. Over the next few days, an increase in total nasal LHRH neurons occurred. The increase in nasal LHRH neurons could be accounted for by LHRH neurons arising and migrating out of respiratory epithelial regions on peripherin-positive fibers. These results indicate that AP-2 alpha is not essential for the separation of the olfactory and respiratory epithelium from the nasal placode and is consistent with AP-2 alpha preventing recapitulation of developmental programs within the respiratory epithelium that lead to expression of LHRH and peripherin phenotypes. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 NINDS, Cellular & Dev Neurobiol Sect, NIH, Bethesda, MD 20895 USA. Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. RP Wray, S (reprint author), NINDS, Cellular & Dev Neurobiol Sect, NIH, Bldg 36,Room 5A-25, Bethesda, MD 20895 USA. OI Kramer, Phillip/0000-0003-0117-542X; Guerrero, Giovanna/0000-0003-4931-8530 NR 75 TC 29 Z9 29 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD JUN PY 2000 VL 94 IS 1-2 BP 79 EP 94 DI 10.1016/S0925-4773(00)00316-6 PG 16 WC Developmental Biology SC Developmental Biology GA 332AZ UT WOS:000088052000008 PM 10842061 ER PT J AU Ribeiro, JMC AF Ribeiro, JMC TI Blood-feeding in mosquitoes: probing time and salivary gland anti-haemostatic activities in representatives of three genera (Aedes, Anopheles, Culex) SO MEDICAL AND VETERINARY ENTOMOLOGY LA English DT Article DE Aedes aegypti; Anopheles albimanus; Culex quinquefasciatus; apyrase; blood; haematophagy; haemostasis; mosquito; platelet; probing; saliva; vasodilator ID YELLOW-FEVER MOSQUITO; CIMEX LECTULARIUS; AEGYPTI; PURIFICATION; ALBIMANUS; CLONING; TRANSFORMATION; OXIDASE; IGE AB Mosquitoes (Diptera: Culicidae) face their hosts' haemostatic mechanisms when attempting to feed on blood. Accordingly, they antagonize haemostasis by salivary agents that include anti-clotting, anti-platelet and vasodilatory compounds. Because haemostasis is a complex and redundant physiological response that varies between vertebrates, it is to be expected that haematophagous animals have a salivary armoury that most efficiently counteracts their preferred hosts. The mosquito Culex quinquefasciatus Say, which has a strong tendency to ornithophagy, appears to have only recently adapted to mammals and may not have evolved efficient mechanisms to counteract mammalian platelet responses, while birds only have relatively inefficient thrombocytes. Accordingly, we compared the probing behaviour of Cx. quinquefasciatus with two other mosquito species from different backgrounds: Aedes aegypti (L.) and Anopheles albimanus Weidemann, that have apparently had a longer evolutionary association with mammals. Culex takes much more time to find blood on a mammalian host (human or mouse) when compared to the two other mosquito species, but does not differ in probing behaviour when feeding on a chicken. Salivary anti-haemostatic components were also measured in those three species of mosquito and results are discussed in context with the probing behaviour. C1 NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Ribeiro, JMC (reprint author), NIAID, Parasit Dis Lab, Bldg 4 Rm 126,4 Ctr Dr MSC 0425, Bethesda, MD 20892 USA. OI Ribeiro, Jose/0000-0002-9107-0818 NR 36 TC 52 Z9 57 U1 2 U2 10 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0269-283X J9 MED VET ENTOMOL JI Med. Vet. Entomol. PD JUN PY 2000 VL 14 IS 2 BP 142 EP 148 DI 10.1046/j.1365-2915.2000.00227.x PG 7 WC Entomology; Veterinary Sciences SC Entomology; Veterinary Sciences GA 323JP UT WOS:000087562500004 PM 10872858 ER PT J AU Croft, BY Orton, CG Hendee, WR AF Croft, BY Orton, CG Hendee, WR TI With the expectation that cancer detection and treatment will occur increasingly at the molecular and gene levels, medical physics trainees should take courses in molecular biology and genetics SO MEDICAL PHYSICS LA English DT Editorial Material C1 NCI, Biomed Imaging Program, Bethesda, MD 20892 USA. Wayne State Univ, Karmanos Canc Inst, Gershenson Radiat Oncol Ctr, Detroit, MI 48201 USA. RP Croft, BY (reprint author), NCI, Biomed Imaging Program, 6130 Execut Blvd,EPN 800, Bethesda, MD 20892 USA. RI Croft, Barbara/D-1248-2013 OI Croft, Barbara/0000-0003-2544-150X NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2000 VL 27 IS 6 BP 1209 EP 1211 DI 10.1118/1.599012 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 326YN UT WOS:000087765000001 PM 10902548 ER PT J AU Sullivan, M Li, J Kumar, S Rogers, MJ McCutchan, TF AF Sullivan, M Li, J Kumar, S Rogers, MJ McCutchan, TF TI Effects of interruption of apicoplast function on malaria infection, development, and transmission SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE anti-malarial drugs; guanosine triphosphatase site; malaria transmission; plastid; thiopeptides; thiostrepton ID APICOMPLEXAN PARASITES; PLASMODIUM-FALCIPARUM; PROTEIN-SYNTHESIS; CLINDAMYCIN; ORGANELLE AB A chloroplast-like organelle is present in many species of the Apicomplexa phylum. We have previously demonstrated that the plastid organelle of Plasmodium falciparum is essential to the survival of the blood-stage malaria parasite in culture. One known function of the plastid organelle in another Apicomplexan, Toxoplasma gondii, involves the formation of the parasitophorous vacuole. The effects of interruption of plastid function on sporozoites and sexual-stage parasites have not been investigated. In our previous studies of the effects of thiostrepton, a polypeptide antibiotic from streptococcus spp., on erythrocytic schizongony of the human malaria P. falciparum we found that this antibiotic appears to interact with the guanosine triphosphatase (GTPase) binding domain of the organellar large subunit ribosomal RNA, as it does in bacteria. We investigate here the effects of this drug on life-cycle stages of the malaria parasite in vivo. Preincubation of mature infective sporozoites with thiostrepton has no observable effect on their infectivity. Sporozoite infection both by mosquito bite and sporozoite injection was prevented by pretreatment of mice with thiostrepton. Thiostrepton eliminates infection with erythrocytic forms of Plasmodium berghei in mice. Clearance of infected red blood cells follows the delayed kinetics associated with drugs that interact with the apicoplast. Thiostrepton treatment of. infected mice reduces transmission of parasites by more than ten-fold, indicating that the plastid has a role in sexual development of the parasite. These results indicate that the plastid function is accessible to drug action in vivo and important to the development of both sexual and asexual forms of the parasite. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NIAID, Growth & Dev Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. USN, Med Ctr, Malaria Program, Bethesda, MD 20814 USA. RP McCutchan, TF (reprint author), NIAID, Growth & Dev Sect, Parasit Dis Lab, NIH, Bldg 4,Rm B1-28, Bethesda, MD 20892 USA. NR 9 TC 41 Z9 46 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD JUN PY 2000 VL 109 IS 1 BP 17 EP 23 DI 10.1016/S0166-6851(00)00226-7 PG 7 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 331TU UT WOS:000088035400002 PM 10924753 ER PT J AU Cibotti, R Bhandoola, A Guinter, TI Sharrow, SO Singer, A AF Cibotti, R Bhandoola, A Guinter, TI Sharrow, SO Singer, A TI CD8 coreceptor extinction in signaled CD4(+) CD8(+) thymocytes: Coordinate roles for both transcriptional and posttranscriptional regulatory mechanisms in developing thymocytes SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID T-CELL DEVELOPMENT; POSITIVE SELECTION; TRANSGENIC MICE; MESSENGER-RNA; GENE-EXPRESSION; NEGATIVE SELECTION; THYMIC SELECTION; CD4+CD8+ CELLS; NUCLEAR-RNA; RECEPTOR AB T-cell development in the thymus is characterized by changing expression patterns of CD4 and CD8 coreceptor molecules and by changes in CD4 and CD8 gene transcription. In response to T-cell receptor (TCR) signals, thymocytes progress through developmental transitions, such as conversion of CD4(+)CD8(+) (double-positive [DP]) thymocytes into intermediate CD4(+)CD8(-) thymocytes, that appear to require more-rapid changes in coreceptor expression than can be accomplished by transcriptional regulation alone. Consequently, we considered the possibility that TCR stimulation of DP thymocytes not only affects coreceptor gene transcription but also affects coreceptor RNA stability. Indeed, we found that TCR signals in DP thymocytes rapidly destabilized preexisting CD4 and CD8 coreceptor RNAs, resulting in their rapid elimination. Destabilization of coreceptor RNA was shown for CD8 alpha to be dependent on target sequences in the noncoding region of the RNA. TCR signals also differentially affected coreceptor gene transcription in DP thymocytes, terminating CD8 alpha gene transcription but only transiently reducing CD4 gene transcription. Thus, posttranscriptional and transcriptional regulatory mechanisms act coordinately in signaled DP thymocytes to promote the rapid conversion of these cells into intermediate CD4+CD8- thymocytes. We suggest that destabilization of preexisting coreceptor RNAs is a mechanism by which coreceptor expression in developing thymocytes is rapidly altered at critical points in the differentiation of these cells. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Room 4B36, Bethesda, MD 20892 USA. NR 38 TC 16 Z9 17 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 2000 VL 20 IS 11 BP 3852 EP 3859 DI 10.1128/MCB.20.11.3852-3859.2000 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 313UF UT WOS:000087017100010 PM 10805728 ER PT J AU Strumberg, D Pilon, AA Smith, M Hickey, R Malkas, L Pommier, Y AF Strumberg, D Pilon, AA Smith, M Hickey, R Malkas, L Pommier, Y TI Conversion of topoisomerase 1 cleavage complexes on the leading strand of ribosomal DNA into 5 '-phosphorylated DNA double-strand breaks by replication runoff SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID HUMAN CELL EXTRACT; RNA GENES; LAGGING-STRAND; ILLEGITIMATE RECOMBINATION; DIFFERENTIAL REPLICATION; I TOPOISOMERASE; MAMMALIAN-CELLS; CAMPTOTHECIN; SITES; MECHANISM AB Topoisomerase I cleavage complexes can be induced by a variety of DNA damages and by the anticancer drug camptothecin. We have developed a ligation-mediated PCR (LM-PGR) assay to analyze replication-mediated DNA double-strand breaks induced by topoisomerase I cleavage complexes in human colon carcinoma HT29 cells at the nucleotide level. We found that conversion of topoisomerase I cleavage complexes into replication-mediated DNA double-strand breaks was only detectable on the leading strand for DNA synthesis, which suggests an asymmetry in the way that topoisomerase I cleavage complexes are metabolized on the two arms of a replication fork. Extension by Tag DNA polymerase was not required for ligation to the LM-PCR primer, indicating that the 3' DNA ends are extended by DNA polymerase in vivo closely to the 5' ends of the topoisomerase I cleavage complexes. These findings suggest that the replication-mediated DNA double-strand breaks generated at topoisomerase I cleavage sites are produced by replication runoff. We also found that the 5' ends of these DNA double-strand breaks are phosphorylated in vivo, which suggests that a DNA 5' kinase activity acts on the double-strand ends generated by replication runoff. The replication-mediated DNA double-strand breaks: were rapidly reversible after cessation of the topoisomerase I cleavage complexes, suggesting the existence of efficient repair pathways for removal of topoisomerase I-DNA covalent adducts in ribosomal DNA. C1 NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Univ Maryland, Dept Pharmacol & Expt Therapeut, Baltimore, MD 21201 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bldg 37,Rm 5D02, Bethesda, MD 20892 USA. NR 75 TC 203 Z9 205 U1 2 U2 15 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 2000 VL 20 IS 11 BP 3977 EP 3987 DI 10.1128/MCB.20.11.3977-3987.2000 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 313UF UT WOS:000087017100022 PM 10805740 ER PT J AU Jhappan, C Yusufzai, TM Anderson, S Anver, MR Merlino, G AF Jhappan, C Yusufzai, TM Anderson, S Anver, MR Merlino, G TI The p53 response to DNA damage in vivo is independent of DNA-dependent protein kinase SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; ATAXIA-TELANGIECTASIA GENE; COMBINED IMMUNE-DEFICIENCY; CATALYTIC SUBUNIT; V(D)J RECOMBINATION; SCID MOUSE; ENHANCED PHOSPHORYLATION; NONSENSE MUTATION; MICE; APOPTOSIS AB Ionizing radiation (IR) exposure causes mammalian cells to undergo p53-dependent cell cycle arrest and/or apoptosis. The in vivo role of DNA-dependent protein kinase (DNA-PK) in the transduction of the DNA damage signal to p53 remains unresolved. To determine the relationship between DNA-PK and p53, we studied the cell cycle and apoptotic responses to IR in mice deficient in DNA-PK. Using the slip mouse, which harbors an inactivating mutation of the DNA-PK catalytic subunit (DNA-PKcs), we demonstrated not only that these DNA-PKcs null mutants were highly radiosensitive but also that upon IR treatment, p53 accumulated in their cultured cells and tissue. Induced p53 was transcriptionally active and mediated the induction of p21 and Bar in slip cells. Examination of the thymic cell cycle response to IR treatment indicated that the slip G(1)/S-phase cell cycle checkpoint function was intact. We further show that slip mice exhibited a higher level of spontaneous thymic apoptosis as well as a more robust apoptotic response to IR than wild-type mice. Together, these data demonstrate that the p53-mediated response to DNA damage is intact in cells devoid of DNA-PK activity and suggest that other kinases, such as the product of the gene (ATM) mutated in ataxia telangiectasia, are better candidates for regulating IR-induced phosphorylation and accumulation of p53. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Pathol Histotechnol Lab, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NHGRI, Lab Gene Transfer, NIH, Bethesda, MD 20892 USA. RP Jhappan, C (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37,Room 2E22,37 Convent Dr MSC4255, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01CO56000] NR 48 TC 40 Z9 41 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 2000 VL 20 IS 11 BP 4075 EP 4083 DI 10.1128/MCB.20.11.4075-4083.2000 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 313UF UT WOS:000087017100031 PM 10805749 ER PT J AU Jung, S Aliberti, J Graemmel, P Sunshine, MJ Kreutzberg, GW Sher, A Littman, DR AF Jung, S Aliberti, J Graemmel, P Sunshine, MJ Kreutzberg, GW Sher, A Littman, DR TI Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID T-CELL AREAS; DENDRITIC CELLS; CX3C CHEMOKINE; MICROGLIA; FLOW; ADHESION; IDENTIFICATION; ACTIVATION; ARREST; BRAIN AB The seven-transmembrane receptor CX(3)CR1 is a specific receptor for the novel CX3C chemokine fractalkine (FKN) (neurotactin). In vitro data suggest that membrane anchoring of FKN, and the existence of a shed, soluble FKN isoform allow for both adhesive and chemoattractive properties. Expression on activated endothelium and neurons defines FKN as a potential target for therapeutic intervention in inflammatory conditions, particularly central nervous system diseases. To investigate the physiological function of CX(3)CR1-FKN interactions, we generated a mouse strain in which the CX,CRI gene was replaced by a green fluorescent protein (GFP) reporter gene. In addition to the creation of a mutant CX(3)CR1 locus, this approach enabled us to assign murine CX(3)CR1 expression to monocytes, subsets of NK and dendritic cells, and the brain microglia. Analysis of CX(3)CR1-deficient mice indicates that CX(3)CR1 is the only murine FKN receptor. Yet, defying anticipated FKN functions, absence of CX(3)CR1 interferes neither with monocyte extravasation in a peritonitis model nor with DC migration and differentiation in response to microbial antigens or contact sensitizers. Furthermore, a prominent response of CX(3)CR1-deficient microglia to peripheral nerve injury indicates unimpaired neuronal-glial cross talk in the absence of CX(3)CR1. C1 NYU, Med Ctr, Skirball Inst Biomol Med, Mol Pathogenesis Program, New York, NY 10016 USA. NYU, Med Ctr, Howard Hughes Med Inst, New York, NY 10016 USA. NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Max Planck Inst Neurobiol, Dept Neuromorphol, Martinsried, Germany. RP Jung, S (reprint author), NYU, Med Ctr, Skirball Inst Biomol Med, Mol Pathogenesis Program, 540 1st Ave, New York, NY 10016 USA. RI Aliberti, Julio/G-4565-2012; Aliberti, Julio/I-7354-2013; OI Aliberti, Julio/0000-0003-3420-8478; Jung, Steffen/0000-0003-4290-5716 NR 20 TC 983 Z9 1000 U1 58 U2 232 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 2000 VL 20 IS 11 BP 4106 EP 4114 DI 10.1128/MCB.20.11.4106-4114.2000 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 313UF UT WOS:000087017100034 PM 10805752 ER PT J AU Barrera-Hernandez, G Cultraro, CM Pianetti, S Segal, S AF Barrera-Hernandez, G Cultraro, CM Pianetti, S Segal, S TI Mad1 function is regulated through elements within the carboxy terminus SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MURINE ERYTHROLEUKEMIA-CELLS; MYC ANTAGONIST MAD1; C-MYC; DNA-BINDING; TRANSCRIPTIONAL REPRESSION; EPIDERMAL DIFFERENTIATION; PHOSPHORYLATION SITES; RAS COTRANSFORMATION; HISTONE DEACETYLASE; OPPOSITE REGULATION AB Myc and Mad are basic helix-loop-helix leucine zipper (bHLH-LZ) proteins that heterodimerize with Max to bind DNA and thereby influence the transcription of Mac-responsive genes. Myc-Max dimers transactivate whereas Mad-Max-mSin3 complexes repress Myc-mediated transcriptional activation. We have previously shown that the N-terminal mSin3 binding domain and the centrally located bHLH-LZ are required for Mad1 to function during a molecular switch from proliferation to differentiation. Here we demonstrate that the carboxy terminus (CT) of Mad1 contains previously unidentified motifs necessary for the regulation of Mad1 function. We show that removal of the last 18 amino acids of Mad1 (region V) abolishes the growth-inhibitory function of the protein and the ability to reverse a Myc-imposed differentiation block Moreover, deletion of region V results in a protein that binds DNA weakly and no longer represses Myc-dependent transcriptional activation. In contrast, deletion of the preceding 24 amino acids (region IV) together with region V restores DNA binding and transcriptional repression, suggesting a functional interplay between these two regions. Furthermore, phosphorylation within region IV appears to mediate this interplay. These findings indicate that novel regulatory elements are present in the Mad1 CT. C1 NCI, NCI Navy Med Branch, Dept Genet, NNMC,NIH, Bethesda, MD 20889 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20889 USA. RP Segal, S (reprint author), NCI, NCI Navy Med Branch, Dept Genet, NNMC,NIH, Bldg 8,Rm 5101,8901 Wisconsin Ave, Bethesda, MD 20889 USA. NR 58 TC 6 Z9 6 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 2000 VL 20 IS 12 BP 4253 EP 4264 DI 10.1128/MCB.20.12.4253-4264.2000 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 318NF UT WOS:000087289700007 PM 10825189 ER PT J AU Zhou, YJ Magnuson, KS Cheng, TP Gadina, M Frucht, DM Galon, J Candotti, F Geahlen, RL Changelian, PS O'Shea, JJ AF Zhou, YJ Magnuson, KS Cheng, TP Gadina, M Frucht, DM Galon, J Candotti, F Geahlen, RL Changelian, PS O'Shea, JJ TI Hierarchy of protein tyrosine kinases in interleukin-2 (IL2) signaling: Activation of Syk depends on Jak3; However, neither Syk nor Lck is required for IL-2-mediated STAT activation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RECEPTOR-BETA-CHAIN; SEVERE COMBINED IMMUNODEFICIENCY; T-CELL PROLIFERATION; MICE LACKING JAK3; IL-2 RECEPTOR; JANUS KINASE; C-MYC; GAMMA-CHAIN; LYMPHOID DEVELOPMENT; GENE INDUCTION AB Interleukin-2 (IL-2) activates several different families of tyrosine kinases, but precisely how these kinases interact is not completely understood. We therefore investigated the functional relationships among Jak3, Lck, and Syk in IL-2 signaling. We first observed that in the absence of Jak3, both Lck and Syk had the capacity to phosphorylate Stat3 and Stat5a. However, neither supported IL-2-induced STAT activation, nor did dominant negative alleles of these kinases inhibit. Moreover, pharmacological abrogation of Lck activity did not inhibit IL-2-mediated phosphorylation of Jak3 acid Stat5a. Importantly, ligand-dependent Syk activation was dependent on the presence of catalytically active Jak3, whereas Lck activation was not. Interestingly, Syk functioned as a direct substrate of Jak1 but not Jak3. Additionally, Jak3 phosphorylated Jak1, whereas the reverse was not the case. Taken together, our data support a model in which Lck functions in parallel with Jak3, while Syk functions as a downstream element of Jak3 in IL-2 signaling. Jak3 may regulate Syk catalytic activity indirectly via Jak1. However, IL-2-mediated Jak3/Stat activation is not dependent on Lck or Syk. While the essential roles of Jak1 and Jak3 in signaling by gamma c-utilizing cytokines are clear, it will be important to dissect the exact contributions of Lck and Syk in mediating the effects of IL-2 and related cytokines. C1 NIAMSD, Lymphocyte Cell Biol Sect, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Clin Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. Pfizer Inc, Cent Res, Dept Immunol, Groton, CT 06340 USA. Purdue Univ, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. RP Zhou, YJ (reprint author), NIAMSD, Lymphocyte Cell Biol Sect, Arthrit & Rheumatism Branch, NIH, 10-9N228,10 Ctr Dr,MSC 1820, Bethesda, MD 20892 USA. OI Geahlen, Robert/0000-0001-8400-2924 NR 55 TC 33 Z9 33 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 2000 VL 20 IS 12 BP 4371 EP 4380 DI 10.1128/MCB.20.12.4371-4380.2000 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 318NF UT WOS:000087289700018 PM 10825200 ER PT J AU Sleckman, BP Khan, WN Xu, WP Bassing, CH Malynn, BA Copeland, NG Bardon, CG Breit, TM Davidson, L Oltz, EM Jenkins, NA Berman, JE Alt, FW AF Sleckman, BP Khan, WN Xu, WP Bassing, CH Malynn, BA Copeland, NG Bardon, CG Breit, TM Davidson, L Oltz, EM Jenkins, NA Berman, JE Alt, FW TI Cloning and functional characterization of the early-lymphocyte-specific Pb99 gene SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; B-CELL; V(D)J RECOMBINATION; RECEPTOR SUPERFAMILY; SIGNAL-TRANSDUCTION; MESSENGER-RNA; T-CELLS; PROTEIN; MICE; EXPRESSION AB The Pb99 gene is specifically expressed in pre-B cells and thymocytes and not in mature B and T cells or nonlymphoid tissues, implying that it may function in early lymphoid development. We have previously described the cloning of an incomplete cDNA for Pb99. Here we report the isolation of full-length cDNAs and genomic clones for the murine Pb99 gene and the mapping of its location to mouse chromosome 8. Sequence analyses of different Pb99 cDNA clones suggest that there may be at least three forms of the Pb99 protein generated by differential processing of the Pb99 transcript. The cDNA with the longest open reading frame encodes a putative protein that has seven hydrophobic domains similar to those of seven membrane-spanning proteins, such as the classical G protein-coupled receptors. To directly address the role of the Pb99 protein in lymphoid development, Pb99-deficient mice were generated by gene targeting, and lymphocyte development in these mice was analyzed. C1 Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Ctr Blood Res, Boston, MA 02115 USA. Univ Maryland, Ctr Med Biotechnol, Baltimore, MD 21201 USA. Univ Maryland, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. Univ Maryland, Program Mol & Cell Biol, Baltimore, MD 21201 USA. NCI, Mammalian Genet Lab, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Alt, FW (reprint author), Childrens Hosp, Howard Hughes Med Inst, Longwood Ave, Boston, MA 02115 USA. FU NCI NIH HHS [CA61009]; NIAID NIH HHS [AI01297-01, AI20047] NR 35 TC 7 Z9 7 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 2000 VL 20 IS 12 BP 4405 EP 4410 DI 10.1128/MCB.20.12.4405-4410.2000 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 318NF UT WOS:000087289700021 PM 10825203 ER PT J AU Tanaka, K Matsumoto, Y Nakatani, F Iwamoto, Y Yamada, Y AF Tanaka, K Matsumoto, Y Nakatani, F Iwamoto, Y Yamada, Y TI A zinc finger transcription factor, alpha A-crystallin binding protein 1, is a negative regulator of the chondrocyte-specific enhancer of the alpha 1(II) collagen gene (Retracted Article) SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article; Retracted Publication ID MAJOR HISTOCOMPATIBILITY COMPLEX; AUTOSOMAL SEX REVERSAL; SRY-RELATED GENE; II COLLAGEN; CAMPOMELIC DYSPLASIA; FACTOR PRDII-BF1; CELL-LINE; MOUSE; SOX9; EXPRESSION AB Transcription of the type II collagen gene (Col2a1) is regulated by multiple cis-acting sites, The enhancer element, which is located in the first intron, is necessary for high-level and cartilage-specific expression of Col2a1. A mouse limb bud cDNA expression library was screened by the Saccharomyces cerevisiae one hybrid screening method to identify protein factors bound to the enhancer. A zinc finger protein, alpha A-crystallin binding protein 1 (CRYBP1), which had been reported to bind to the mouse alpha A-crystallin gene promoter, was isolated. We herein demonstrate that CRYBP1 is involved in the negative regulation of Col2a1 enhancer activity, CRYBP1 mRNA expression was downregulated during chondrocyte differentiation in vitro. In situ hybridization analysis of developing mouse cartilage showed that CRYBP1 mRNA was also downregulated during mesenchymal condensation and that CRYBP1 mRNA was highly expressed by hypertrophic chondrocytes, but at very low levels by resting and proliferating chondrocytes, Expression of recombinant CRYBP1 in a transfected rat chondrosarcoma cell line inhibited Col2a1 enhancer activity. Electrophoretic mobility shift assays showed that CRYBP1 bound a specific sequence within the Col2a1 enhancer and inhibited the binding of Sox9, an activator for Col2a1, to the enhancer. Cotransfection of CRYBP1 with Sox9 into BALB/c 3T3 cells inhibited activation of the Col2a1 enhancer by Sox9. These results suggest a novel mechanism that negatively regulates cartilage-specific expression of Col2a1. C1 NIDCR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. Kyushu Univ, Grad Sch Med Sci, Dept Orthopaed Surg, Fukuoka 8128582, Japan. RP Yamada, Y (reprint author), NIDCR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bldg 30,Room 405, Bethesda, MD 20892 USA. EM yoshi.yamada@nih.gov NR 48 TC 51 Z9 54 U1 2 U2 10 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 2000 VL 20 IS 12 BP 4428 EP 4435 DI 10.1128/MCB.20.12.4428-4435.2000 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 318NF UT WOS:000087289700024 PM 10825206 ER PT J AU Gonzalez-Villasenor, LI Wu, K Yang, L AF Gonzalez-Villasenor, LI Wu, K Yang, L TI A solid phase plate assay for HIV-1 genotyping SO MOLECULAR AND CELLULAR PROBES LA English DT Article DE human immunodeficiency virus; genotyping; clades; solid phase; PCR; probes; oligonucleotides ID IMMUNODEFICIENCY-VIRUS TYPE-1; NATURALLY-OCCURRING MUTATIONS; HETERODUPLEX MOBILITY ASSAY; POLYMERASE CHAIN-REACTION; REVERSE-TRANSCRIPTASE; GENETIC SUBTYPES; NEUTRALIZATION SEROTYPES; SEQUENCE; DIVERSITY; DISTINCT AB A prototype solid phase prate assay (SPPA) for the detection and genotyping of HIV-I subtypes was developed using a PCR-based capture hybridization format. Well characterized HIV-1 reference controls of known subtypes and subtype specific capture oligonucleotide probes targeting several regions of the envelope (env) gene of HIV-1 were selected to develop the assay. The subtype specific oligonucleotide probes were covalently bound to microtubes in an ordered pattern and biotin labelled primers were used to amplify the target sequences. The PCR products were hybridized to the corresponding oligonucleotide probes, and colorimetrically detected by a chromogenic reaction using a standard microplate reader. All the HIV-1 subtype reference controls specifically hybridized to the corresponding capture probes and negligible cross-hybridization between subtypes was observed. To demonstrate the performance and reproducibility of the SPPA system and its validation with clinical samples, several human plasma samples of unknown and known HIV-1 subtypes were tested. The SPPA is highly specific and unambiguously identify the major subtypes of the HIV-I M and O groups. This assay could be a useful method for subtyping samples of HIV-1 infected individuals and for disease management. (C) 2000 Academic Press. C1 BBI, Biotech Res Labs, Gaithersburg, MD 20877 USA. RP Gonzalez-Villasenor, LI (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. FU NIAID NIH HHS [R43AI041798, 2R44AI41798-02] NR 45 TC 1 Z9 1 U1 0 U2 2 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0890-8508 J9 MOL CELL PROBE JI Mol. Cell. Probes PD JUN PY 2000 VL 14 IS 3 BP 137 EP 147 DI 10.1006/mcpr.2000.0298 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology GA 330NL UT WOS:000087968100001 PM 10860711 ER PT J AU Boissinot, S Chevret, P Furano, AV AF Boissinot, S Chevret, P Furano, AV TI L1 (LINE-1) retrotransposon evolution and amplification in recent human history SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE L1/LINE-1; human; evolution; polymorphism; retrotransposon ID HIGH-FREQUENCY RETROTRANSPOSITION; POLYMORPHIC ALU INSERTIONS; HUMAN TRANSPOSABLE ELEMENT; REPETITIVE DNA-SEQUENCES; REVERSE-TRANSCRIPTASE; APOLIPOPROTEIN(A) GENE; REPEAT FAMILY; MOUSE GENOME; SUBFAMILY; RECOMBINATION AB L1 (LINE-I) elements constitute a large family of mammalian retrotransposons that have been replicating and evolving in mammals for more than 100 Myr and now compose 20% or more of the DNA of some mammals. Here, we investigated the evolutionary dynamics of the active human Ta L1 family and found that it arose similar to 4 MYA and subsequently differentiated into two major subfamilies, Ta-0 and Ta-l, each of which contain additional subsets. Ta-l, which has not heretofore been described, is younger than Ta-0 and now accounts for at least 50% of the Ta family. Although Ta-0 contains some active elements, the Ta-l subfamily has replaced it as the replicatively dominant subfamily in humans; 69% of the loci that contain Ta-l inserts are polymorphic for the presence or absence of the insert in human populations, as compared with 29% of the loci that contain Ta-0 inserts. This value is 90% for loci that contain Ta-ld inserts, which are the youngest subset of Ta-l and now account for about two thirds of the Ta-l subfamily. The successive emergence and amplification of distinct Ta L1 subfamilies shows that L1 evolution has been as active in recent human history as it has been found to be for rodent L1 families. In addition, Ta-l elements have been accumulating in humans at about the same rate per generation as recently evolved active rodent L1 subfamilies. C1 NIDDKD, Sect Genom Struct & Funct, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. RP Furano, AV (reprint author), NIDDKD, Sect Genom Struct & Funct, Mol & Cellular Biol Lab, NIH, Bldg 8,Room 203,8 Ctr Dr MSC 0830, Bethesda, MD 20892 USA. RI Chevret, Pascale/B-7299-2009 NR 56 TC 160 Z9 165 U1 0 U2 10 PU SOC MOLECULAR BIOLOGY EVOLUTION PI LAWRENCE PA PO BOX 1897, LAWRENCE, KS 66044-8897 USA SN 0737-4038 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD JUN PY 2000 VL 17 IS 6 BP 915 EP 928 PG 14 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 319FV UT WOS:000087331600009 PM 10833198 ER PT J AU Caterina, JJ Shi, J Kozak, CA Engler, JA Birkedal-Hansen, H AF Caterina, JJ Shi, J Kozak, CA Engler, JA Birkedal-Hansen, H TI Characterization, expression analysis and chromosomal mapping of mouse Matrix Metalloproteinase-19 (MMP-19) SO MOLECULAR BIOLOGY REPORTS LA English DT Article DE arthritis; Mely; MMP-18; RASI-1 ID EXTRACELLULAR-MATRIX; MOUSE-CHROMOSOME-10; IDENTIFICATION; METASTASIS; INVASION AB Using homology-based database screening, we have identified the mouse homologue for the recently described matrix metalloproteinase-19 (MMP-19). Sequencing of mouse MMP-19 resulted in a putative open reading frame (ORF) of 527 amino acids showing 84% identity to the human homologue. In mouse, MMP-19 appears to be most highly expressed in the liver; however, there is a detectable level of expression in all tissues analyzed. The major mouse MMP-19 transcript is almost twice as long as that of human. The COOH-terminal serine and threonine-rich domain is considerably longer in the mouse homologue. The mouse MMP-19 gene maps to very distal end of mouse chromosome 10. C1 Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. NIAID, Bethesda, MD 20892 USA. Univ Alabama, Dept Biochem & Mol Genet, Birmingham, AL USA. RP Caterina, JJ (reprint author), Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA13148]; NIDCR NIH HHS [DE08228, DE10631] NR 23 TC 3 Z9 4 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0301-4851 J9 MOL BIOL REP JI Mol. Biol. Rep. PD JUN PY 2000 VL 27 IS 2 BP 73 EP 79 DI 10.1023/A:1007196529604 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 373ZU UT WOS:000165320600002 PM 11092553 ER PT J AU Santora, KE Nelson, SA Lewis, KA LaRochelle, WJ AF Santora, KE Nelson, SA Lewis, KA LaRochelle, WJ TI Avidin- or streptavidin-biotin as a highly sensitive method to stain total protein on membranes SO MOLECULAR BIOTECHNOLOGY LA English DT Article DE streptavidin; avidin; biotin; protein blotting; nitrocellulose replica ID NITROCELLULOSE MEMBRANES; BIOTINYLATION AB A sensitive method for staining proteins after transfer from polyacrylamide gels to nitrocellulose paper is described. Transferred proteins are first derivatized by reaction of the nitrocellulose replica with sulfosuccinimidobiotin and are then reacted sequentially with streptavidin, rabbit anti-streptavidin, and horseradish peroxidase-conjugated goat anti-rabbit IgG antibody. Incubation with the enzyme substrate alpha-chloronaphthol, produces dark protein bands against a white background. The binding of streptavidin to the proteins is dependent on biotin derivatization as demonstrated by competition with biotinylated bovine serum albumin or 10 nM biotin. The procedure detects less than 5ng of transferred protein in a single band and is thus 5-10 times more sensitive than horseradish peroxidase-conjugated avidin alone. For bovine serum albumin, the method is comparable in sensitivity to silver staining of protein in polyacrylamide gels. C1 NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. FU NINDS NIH HHS [NS-14781] NR 24 TC 8 Z9 8 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1073-6085 J9 MOL BIOTECHNOL JI Mol. Biotechnol. PD JUN PY 2000 VL 15 IS 2 BP 161 EP 165 DI 10.1385/MB:15:2:161 PG 5 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 338ML UT WOS:000088423800009 PM 10949830 ER PT J AU Su, YA Bittner, ML Chen, YD Tao, L Jiang, Y Zhang, YH Stephan, DA Trent, JM AF Su, YA Bittner, ML Chen, YD Tao, L Jiang, Y Zhang, YH Stephan, DA Trent, JM TI Identification of tumor-suppressor genes using human melanoma cell lines UACC903, UACC903(+6), and SRS3 by comparison of expression profiles SO MOLECULAR CARCINOGENESIS LA English DT Article DE chromosome 6; anchorage-independent growth; cDNA microarray; gene expression profile; connexin 43 ID JUNCTIONAL INTERCELLULAR COMMUNICATION; CARCINOMA CELLS; TRANSFORMED-CELLS; CONNEXIN43; GROWTH; CANCER; TUMORIGENICITY; PHENOTYPE; CARCINOGENESIS; TRANSFECTION AB The development and progression of cancer are believed to be due to multiple genetic alterations resulting in complex changes in expression of many genes. The parental malignant melanoma cell line UACC903 displays anchorage-independent growth, and the chromosome 6-suppressed subline UACC903(+6) displays anchorage-dependent growth. The anchorage-independent revertant cell line SRS3 derived from UACC903(+6) by retroviral transduction resembles the phenotype of UACC903. In this study, we first compared the expression profiles of 3317 genes between these three cell lines in pairs by cDNA microarrays, resulting in identification of genes with known suppressor activities. We then demonstrated connexin 43 (Cx43)-suppressing anchorage-independent growth of UACC903 on overexpression. Of 3317 genes with informative expression detected by cDNA microarray, 321 (9.68%) showed expression changes between at least one pair of the three cell lines. Notably, 12 genes displayed higher levels of expression in UACC903(+6) than in both UACC903 and SRS3, providing candidates for further identification of melanoma-suppressor genes. Genes encoding Cx43 (suppressor activity), monocyte chemotactic protein 1 (suppressor activity), and cysteine proteinase P32 alpha(apoptotic activity) were all upregulated in UACC903(+6), in contrast to both UACC903 and SRS3. Transfection of Cx43, encoded on human chromosome 6q21-q23, a region frequently altered in malignant melanoma, resulted in its overexpression and the suppression of anchorage-independent growth of UACC903. Thus, our result proves the principle that the combination of the ability to alter cellular phenotype by successive genetic alterations and the ability to examine the global expression profiles facilitates the identification of tumor suppressor genes. Mel. Carcinog. 28:119-127, 2000. (C) 2000 Wiley-Liss. Inc. C1 Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Dept Oncol, Washington, DC 20007 USA. Natl Human Genome Res Inst, Canc Genet Branch, NIH, Bethesda, MD USA. RP Su, YA (reprint author), Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Dept Oncol, Res Bldg,Room E308,3970 Reservoir Rd NW, Washington, DC 20007 USA. NR 39 TC 49 Z9 56 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 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD JUN PY 2000 VL 28 IS 2 BP 119 EP 127 DI 10.1002/1098-2744(200006)28:2<119::AID-MC8>3.0.CO;2-N PG 9 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 330NH UT WOS:000087967800008 PM 10900469 ER PT J AU Hickman, AB Li, Y Mathew, SV May, EW Craig, NL Dyda, F AF Hickman, AB Li, Y Mathew, SV May, EW Craig, NL Dyda, F TI Unexpected structural diversity in DNA recombination: The restriction endonuclease connection SO MOLECULAR CELL LA English DT Article ID PATCH REPAIR ENDONUCLEASE; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; PVUII ENDONUCLEASE; ECORV ENDONUCLEASE; TN7 TRANSPOSITION; DIFFRACTION DATA; MISMATCH REPAIR; MU-TRANSPOSASE; ACTIVE-SITE AB Transposition requires a coordinated series of DNA breakage and joining reactions. The Tn7 transposase contains two proteins: TnsA, which carries out DNA breakage at the 5' ends of the transposon, and TnsB, which carries out breakage and joining at the 3' ends of the transposon. TnsB is a member of the retroviral integrase superfamily whose hallmark is a conserved DDE motif. We report here the structure of TnsA at 2.4 Angstrom resolution. Surprisingly, the TnsA fold is that of a type II restriction endonuclease. Thus, Tn7 transposition involves a collaboration between polypeptides, one containing a DDE motif and one that does not. This result indicates that the range of biological processes that utilize restriction enzyme-like folds also includes DNA transposition. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. RP Hickman, AB (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 49 TC 85 Z9 87 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell. PD JUN PY 2000 VL 5 IS 6 BP 1025 EP 1034 DI 10.1016/S1097-2765(00)80267-1 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 328HZ UT WOS:000087845900012 PM 10911996 ER PT J AU Li, BS Kramer, PR Zhao, WQ Ma, W Stenger, DA Zhang, L AF Li, BS Kramer, PR Zhao, WQ Ma, W Stenger, DA Zhang, L TI Molecular cloning, expression, and characterization of rat homolog of human AP-2 alpha that stimulates neuropeptide Y transcription activity in response to nerve growth factor SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID FACTOR AP-2; PANCREATIC-POLYPEPTIDE; SYMPATHETIC NEURONS; CALCIUM-CHANNELS; BINDING-PROTEINS; MESSENGER-RNAS; PC12 CELLS; PEPTIDE-YY; GENE; DNA AB Neuropeptide Y (NPY) plays an important role in the central regulation of neuronal activity, endocrine and sexual behavior, and food intake. Although transcription activity of the NPY gene in PC12 cells is regulated by a number of agents such as nerve growth factor (NGF), the mechanism responsible for the NGF-elicited increase in the transcription of the NPY gene remains to be explored. In this study, we isolated and characterized a nuclear protein that is bound to NGF-response elements (NGFRE) that lie between nucleotide -87 and -33 of the rat NPY promoter gene. This nuclear protein is identical to the rat homolog of human transcription factor AP-2 alpha. We further demonstrated that rat AP-2 alpha promotes efficient NPY transcription activity in response to NGF. Finally, we provide direct evidence that the mice lacking transcription factor AP-2a exhibit reduced expression of NPY mRNA compared with wild-type mice, further supporting the hypothesis that AP-2 alpha is an important transcription factor in regulating NPY transcription activity. C1 NIMH, Behav & Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NINCDS, Lab Neurochem, NIH, Bethesda, MD 20892 USA. NINCDS, Lab Adapt Syst, NIH, Bethesda, MD 20892 USA. USN, Res Lab, Ctr Biomol Sci & Engn, Washington, DC 20375 USA. RP Zhang, L (reprint author), NIMH, Behav & Endocrinol Branch, NIH, Bldg 36,Room 2C02, Bethesda, MD 20892 USA. EM zhangl@codon.nih.gov NR 44 TC 14 Z9 15 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD JUN PY 2000 VL 14 IS 6 BP 837 EP 847 DI 10.1210/me.14.6.837 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 320ZN UT WOS:000087430600009 PM 10847586 ER PT J AU Garayoa, M Martinez, A Lee, SM Pio, R An, WG Neckers, L Trepel, J Montuenga, LM Ryan, H Johnson, R Gassmann, M Cuttitta, F AF Garayoa, M Martinez, A Lee, SM Pio, R An, WG Neckers, L Trepel, J Montuenga, LM Ryan, H Johnson, R Gassmann, M Cuttitta, F TI Hypoxia-inducible factor-1 (HIF-1) up-regulates adrenomedullin expression in human tumor cell lines during oxygen deprivation: A possible promotion mechanism of carcinogenesis SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID FACTOR MESSENGER-RNA; RAT ENDOTHELIAL-CELLS; GROWTH-FACTOR GENE; FACTOR 1-ALPHA; TRANSCRIPTIONAL REGULATION; ERYTHROPOIETIN GENE; PROTEIN; BINDING; INDUCTION; ARNT AB Little is known about the molecular mechanisms that control adrenomedullin (AM) production in human cancers. We demonstrate here that the expression of AM mRNA in a variety of human tumor cell lines is highly induced in a time-dependent manner by reduced oxygen tension (1% O-2) or exposure to hypoxia mimetics such as desferrioxamine mesylate (DFX) or CoCl2. This AM expression seems to be under hypoxia-inducible factor-1 (HIF-1) transcriptional regulation, since HIF-1 alpha and HIF-1 beta knockout mouse cell lines had an ablated or greatly reduced hypoxia AM mRNA induction. Similarly, inhibition or enhancement of HIF-1 activity in human tumor cells showed an analogous modulation of AM mRNA. Under hypoxic conditions, immunohistochemical analysis of tumor eel lines revealed elevated levels of AM and HIF-1 alpha as compared with normoxia, and we also found an increase of immunoreactive AM in the conditioned medium of tumor cells analyzed by RIA. AM mRNA stabilization was shown to be partially responsible for the hypoxic up-regulated expression of AM. In addition, we have identified several putative hypoxia response elements (HREs) in the human AM gene, and reporter studies with selected HREs were capable of enhancing luciferase expression after exposure to DFX. Furthermore, transient coexpression of HIF-1 alpha resulted in an augmented transactivation of the reporter gene after DFX treatment. Given that most solid human tumors have focal hypoxic areas and that AM functions as a mitogen, angiogenic factor, and apoptosis-survival factor, our findings implicate the HIF-1/AM link as a possible promotion mechanism of carcinogenesis. C1 NCI, Cell & Canc Biol Dept, NIH, Bethesda, MD 20892 USA. Univ Navarra, Dept Histol & Pathol, E-31080 Pamplona, Spain. Univ Calif San Diego, Dept Biol, La Jolla, CA 92093 USA. Univ Zurich, Inst Physiol, CH-8057 Zurich, Switzerland. RP Garayoa, M (reprint author), NCI, Cell & Canc Biol Dept, NIH, Bldg 10-12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM garayoam@bprb.nci.nih.gov RI Martinez, Alfredo/A-3077-2013; Pio, Ruben/F-5353-2017; OI Martinez, Alfredo/0000-0003-4882-4044; Pio, Ruben/0000-0002-6831-6111; Johnson, Randall/0000-0002-4084-6639 NR 60 TC 200 Z9 210 U1 2 U2 9 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD JUN PY 2000 VL 14 IS 6 BP 848 EP 862 DI 10.1210/me.14.6.848 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 320ZN UT WOS:000087430600010 PM 10847587 ER PT J AU Lee, SK Na, SY Jung, SY Choi, JE Jhun, BH Cheong, J Meltzer, PS Lee, YC Lee, JW AF Lee, SK Na, SY Jung, SY Choi, JE Jhun, BH Cheong, J Meltzer, PS Lee, YC Lee, JW TI Activating protein-1, nuclear factor-kappa B, and serum response factor as novel target molecules of the cancer-amplified transcription coactivator ASC-2 SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID STEROID-RECEPTOR COACTIVATOR-1; CREB-BINDING PROTEIN; THYROID-HORMONE RECEPTOR; RETINOID-X-RECEPTOR; HISTONE ACETYLTRANSFERASE; BREAST-CANCER; MEDIATED TRANSACTIVATIONS; CO-REPRESSOR; P65 SUBUNIT; IN-VIVO AB ASC-2 was recently discovered as a cancer-amplified transcription coactivator molecule of nuclear receptors, which interacts with multifunctional transcription integrators steroid receptor coactivator-1 (SRC-1) and CREB-binding protein (CBP)/p300. Herein, we report the identification of three mitogenic transcription factors as novel target molecules of ASC-2. First, the C-terminal transactivation domain of serum response factor (SRF) was identified among a series of ASC-2-interacting proteins from the yeast two-hybrid screening. Second, ASC-2 specifically interacted with the activating protein-1 (AP-1) components c-Jun and c-Fos as well as the nuclear factor-kappa B (NF kappa B) components p50 and p65, as demonstrated by the glutathione S-transferase pull-down assays as well as the yeast two-hybrid tests. In cotransfection of mammalian cells, ASC-2 potentiated transactivations by SRF, AP-1, and NF kappa B in a dose-dependent manner, either alone or in conjunction with SRC-1 and p300. In addition, ASC-2 efficiently relieved the previously described transrepression between nuclear receptors and either AP-1 or NF kappa B. Overall, these results suggest that the nuclear receptor coactivator ASC-2 also mediates transactivations by SRF, AP-1, and NF kappa B, which may contribute to the putative, ASC-2-mediated tumorigenesis. C1 Chonnam Natl Univ, Ctr Ligand & Transript, Kwangju 500757, South Korea. Chonnam Natl Univ, Dept Biol, Kwangju 500757, South Korea. Chonnam Natl Univ, Hormone Res Ctr, Kwangju 500757, South Korea. Pusan Natl Univ, Coll Pharm, Pusan 609735, South Korea. NIH, Natl Human Genome Res Inst, Canc Genet Branch, Bethesda, MD 20892 USA. RP Lee, JW (reprint author), Chonnam Natl Univ, Ctr Ligand & Transript, Kwangju 500757, South Korea. EM jlee@chonnam.chonnam.ac.kr NR 46 TC 52 Z9 54 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD JUN PY 2000 VL 14 IS 6 BP 915 EP 925 DI 10.1210/me.14.6.915 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 320ZN UT WOS:000087430600015 PM 10847592 ER PT J AU Permana, PA Kahn, BB Huppertz, C Mott, DM AF Permana, PA Kahn, BB Huppertz, C Mott, DM TI Functional analyses of amino acid substitutions Arg883Ser and Asp905Tyr of protein phosphatase-1 G-subunit SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE PPP1R3; G-subunit; protein phosphatase-1; amino acid variants; adenovirus; Pima Indians; L6; glycogen synthase; glycogen synthesis ID GLYCOGEN-TARGETING SUBUNIT; PIMA-INDIANS; SKELETAL-MUSCLE; INSULIN-RESISTANCE; REGULATORY SUBUNIT; DIABETES-MELLITUS; GENE; CELLS; NIDDM; POLYMORPHISMS AB The PPP1R3 gene encoding the G-subunit of protein phosphatase-1 has three polymorphisms in linkage disequilibrium in the Pima Indians: an mRNA-destabilizing element in the 3'-untranslated region (ARE1/ARE2 alleles), Arg883Ser, and Asp905Tyr substitutions, The ARE2 allele, Arg883, and Asp905 variants are associated with insulin resistance and higher prevalence of type 2 diabetes in the Pima Indians, The ARE2 allele is associated with lower PPP1R3 transcript and protein levels in muscle tissue. Here we determined the functional contribution of the amino acid substitutions independent of the ARE alleles to insulin-stimulated glycogen synthesis by adenoviral-mediated gene expression in L6 myotubes. Similar overexpression levels of the G-subunit variants increased glycogen synthase fractional activity in the presence (similar to 1.5-fold) of insulin compared to control myotubes transduced with adenovirus encoding beta-galactosidase, The glycogen synthesis rate of myotubes overexpressing the G-subunit variants also increased by similar to 1.7-fold over the control with and without insulin. However, these measures were not significantly different among the variants. This study does not support a role for Arg883 and Asp905 variants independent of the ARE2 allele in the impaired insulin-stimulated glycogen synthesis in the muscle of Pima Indians, (C) 2000 Academic Press. C1 NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. Beth Israel Deaconess Med Ctr, Dept Med, Div Endocrinol & Metab, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. RP NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, NIH, 4212 N 16th St, Phoenix, AZ 85016 USA. EM ppermana@mail.nih.gov FU NIDDK NIH HHS [DK-43051] NR 25 TC 2 Z9 3 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 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JUN PY 2000 VL 70 IS 2 BP 151 EP 158 DI 10.1006/mgme.2000.3011 PG 8 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 333UW UT WOS:000088150000008 PM 10873397 ER PT J AU Alexandroff, AB Jackson, AM Paterson, T Haley, JL Ross, JA Longo, DL Murphy, WJ James, K Taub, DD AF Alexandroff, AB Jackson, AM Paterson, T Haley, JL Ross, JA Longo, DL Murphy, WJ James, K Taub, DD TI Role for CD40-CD40 ligand interactions in the immune response to solid tumours SO MOLECULAR IMMUNOLOGY LA English DT Article DE CD40; CD40-ligand; T-lymphocyte; carcinoma; melanoma; apoptosis ID INTERFERON-GAMMA PRODUCTION; BLADDER-CANCER CELLS; CD40 LIGAND; T-LYMPHOCYTES; COSTIMULATORY MOLECULE; FAS LIGAND; ADHESION MOLECULES; FUNCTIONAL CD40; DENDRITIC CELLS; CARCINOMA-CELLS AB CD40-mediated interactions play an important role in the response to infections, transplantation, and cancer by affecting the development, activation, proliferation and differentiation of a variety of immune cells. In the current study we examined the role of CD40-mediated interactions in immune responses to bladder, pancreatic and breast carcinomas as well as melanoma cell lines using soluble human CD40L (rhCD40L) or anti-CD40 mAb in vitro. CD40 expression was readily detected in a large proportion of the cell lines and was augmented but not induced de novo by treatment with IFN gamma. Treatment of CD40-positive cell lines with rhCD40L or anti-CD40mAb enhanced cell surface expression of ICAM-1 and FAS and stimulated the production of IL-6, IL-8, GRO alpha, GM-CSF and TNF alpha but not IL-4, IL-10, TGF beta, MCP-1, RANTES, MIP-1 beta, or IP-10. In addition, incubation of CD40 + tumour cell lines with immobilised rhCD40L or anti-CD40 mAb in vitro resulted in significant inhibition of proliferation and a corresponding decrease in viability. This CD40-mediated inhibition of cell growth was due, at least in part, to alterations in cell cycle and the induction of apoptosis. Transfection of CD40-negative tumour cell lines with the cDNA for CD40 conferred responsiveness to rhCD40L and anti-CD40 antibody. Finally, the presence of CD40 on the surface of carcinoma lines was found to be an important factor in the generation of tumour-specific T cell responses. (C) 2000 Elsevier Science Ltd. All rights reserved. C1 Univ Edinburgh, Royal Infirm, Lister Labs, Dept Clin & Surg Sci, Edinburgh EH3 9YW, Midlothian, Scotland. St James Univ Hosp, Imperial Canc Res Fund, Canc Med Res Unit, Leeds LS9 7TF, W Yorkshire, England. Scotland Natl Blood Transfus Serv, Edinburgh, Midlothian, Scotland. NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. NIA, Off Sci Director, NIH, Baltimore, MD 21224 USA. NCI, Lab Leukocyte Biol, SAIC Frederick, Frederick, MD 21701 USA. RP James, K (reprint author), Univ Edinburgh, Royal Infirm, Lister Labs, Dept Clin & Surg Sci, Lauriston Pl, Edinburgh EH3 9YW, Midlothian, Scotland. RI Jackson, Andrew/I-5929-2013 OI Jackson, Andrew/0000-0003-4739-4804 NR 40 TC 61 Z9 69 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD JUN PY 2000 VL 37 IS 9 BP 515 EP 526 DI 10.1016/S0161-5890(00)00079-1 PG 12 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 386GJ UT WOS:000166052300005 PM 11163401 ER PT J AU Itokawa, M Lin, ZC Cai, NS Wu, C Kitayama, S Wang, JB Uhl, GR AF Itokawa, M Lin, ZC Cai, NS Wu, C Kitayama, S Wang, JB Uhl, GR TI Dopamine transporter transmembrane domain polar mutants: Delta G and Delta Delta G values implicate regions important for transporter functions SO MOLECULAR PHARMACOLOGY LA English DT Article ID TRIPLE MUTANT; CONSTITUTIVE ACTIVATION; SEROTONIN TRANSPORTER; RECEPTOR ACTIVATION; COCAINE; BINDING; MUTATIONS; RESIDUES; AFFINITY; RECOGNITION AB Polar residues in dopamine transporter (DAT) transmembrane domains (TMs) are likely to act individually and even interactively in recognizing cocaine and dopamine. We initially evaluated the effects of alanine substitution mutants that remove the polar side chains from residues in each of the 12 putative DAT TMs on the recognition of dopamine and the cocaine analog CFT. Eleven combination mutants with multiple substitutions in DAT TMs 4, 5, 7, or 11 were then selected as candidates for more detailed evaluation based on mutation effects on dopamine and cocaine analog affinities. An evaluation of Gibbs free energy changes displayed by single and combined TM mutants (Delta G degrees and Delta Delta G(int)degrees) reveals three categories of potential interactions among mutants: 1) independent, noncooperative interactions (five influenced CFT and two influenced dopamine affinities), 2) synergistic influences (two for CFT and four for dopamine), and 3) complementation of influences on CFT recognition (four mutants) or on dopamine affinity (five). Combined mutations in TMs 4 and 5 yield the largest Delta Delta G(int)degrees values for dopamine uptake. TMs 4 and 11 mutants provide the largest Delta Delta G(int)degrees for CFT binding. Interactions between residues lying in DAT TMs 4 and 5 support current DAT structural models that suggest the juxtaposition of these two TMs. These data also support contributions of TM 4 and 11 residues to a polar pocket important for cocaine recognition. These candidate interactive DAT polar domains provide larger target sites for compounds that could modulate specific DAT functions than those provided by single mutations alone. C1 NIDA, Mol Neurobiol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Uhl, GR (reprint author), NIDA, Mol Neurobiol Branch, Intramural Res Program, NIH, POB 5180,5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 39 TC 36 Z9 36 U1 1 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUN PY 2000 VL 57 IS 6 BP 1093 EP 1103 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 318KL UT WOS:000087283100002 PM 10825379 ER PT J AU Heim, DA Hanazono, Y Giri, N Wu, T Childs, R Sellers, SE Muul, L Agricola, BA Metzger, ME Donahue, RE Tisdale, JF Dunbar, CE AF Heim, DA Hanazono, Y Giri, N Wu, T Childs, R Sellers, SE Muul, L Agricola, BA Metzger, ME Donahue, RE Tisdale, JF Dunbar, CE TI Introduction of a xenogeneic gene via hematopoietic stem cells leads to specific tolerance in a rhesus monkey model SO MOLECULAR THERAPY LA English DT Article DE hematopoietic stem cell transplantation; gene therapy; genetic vectors; immune tolerance; polymerase chain reaction ID GREEN FLUORESCENT PROTEIN; BONE-MARROW CELLS; HUMAN ADENOSINE-DEAMINASE; TERM RECONSTITUTED MICE; IN-VIVO EXPRESSION; APE LEUKEMIA-VIRUS; NONHUMAN-PRIMATES; HUMAN GLUCOCEREBROSIDASE; RETROVIRAL VECTORS; CD34(+) CELLS AB Host immune responses against foreign transgenes may be a major obstacle to successful gene therapy. To clarify the impact of an immune response to foreign transgene products on the survival of genetically modified cells, we! studied the in vivo persistence of cells transduced with a vector expressing a foreign transgene compared to cells transduced with a nonexpressing vector in the clinically predictive rhesus macaque model. We constructed retroviral vectors containing the neomycin phosphotransferase gene (neo) sequences modified to prevent protein expression (nonexpressing vectors). Rhesus monkey lymphocytes or hematopoietic stem cells (HSCs) were transduced with nonexpressing and neo-expressing vectors followed by reinfusion, and their in vivo persistence was studied. While lymphocytes transduced with a nonexpressing vector could be detected for more than 1 year, lymphocytes transduced with a neo-expressing vector were no longer detectable within several weeks of infusion. However, five of six animals transplanted with HSCs transduced with nonexpression or neo-expression vectors, and progeny lymphocytes marked with either vector persisted for more than 2 years. Furthermore, in recipients of transduced HSCs, infusion of mature lymphocytes transduced with a second neo-expressing vector did not result in elimination of the transduced lymphocytes. Our data show that introduction of a xenogeneic gene via HSCs induces tolerance to the foreign gene products. HSC gene therapy is therefore suitable for clinical applications where long-term expression of a therapeutic or foreign gene is required. C1 NHGRI, Clin Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Dunbar, CE (reprint author), Bldg 10,Room 7C103,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 50 TC 61 Z9 62 U1 0 U2 0 PU ACADEMIC PRESS INC 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 2000 VL 1 IS 6 BP 533 EP 544 DI 10.1006/mthe.2000.0072 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 367EF UT WOS:000090048200008 PM 10933978 ER PT J AU Aoki, K Akyurek, LM San, H Leung, K Parmacek, MS Nabel, EG Nabel, GJ AF Aoki, K Akyurek, LM San, H Leung, K Parmacek, MS Nabel, EG Nabel, GJ TI Restricted expression of an adenoviral vector encoding Fas ligand (CD95L) enhances safety for cancer gene therapy SO MOLECULAR THERAPY LA English DT Article DE cancer gene therapy; Fas ligand; CD95L; adenoviral vectors; leiomyosarcoma; SM22 alpha promoter; cleavage mutant; smooth muscle cell ID TRANSFORMING GROWTH FACTOR-BETA-1; SMOOTH-MUSCLE CELLS; INDUCED APOPTOSIS; DOWN-REGULATION; TUMOR-CELLS; IN-VIVO; MYOBLASTS; LIVER; DEATH; REPLICATION AB Gene transfer of Fas ligand (CD95L) using adenoviral vectors has been shown to generate apoptotic responses and potent inflammatory reactions that earn be used to induce the regression of malignancies in vivo, but these vectors also cause significant hepatotoxicity that may limit their clinical utility. Here we describe an adenoviral vector encoding CD95L with restricted gene expression that reduces its toxicity in vivo. Preclinical efficacy and gene expression studies of lineage-restricted CD95L adenoviral vectors were performed. To enhance its cytotoxicity and reduce potential systemic effects, a noncleavable CD95L was made by deleting a segment containing the cleavage site (CD95L Delta QP). Higher CD95L expression of this mutant was observed on the tumor cell surface, together with a reduction in the release of soluble CD95L. This CD95L cleavage mutant was then expressed under control of a smooth muscle-specific promoter, SM22 alpha, and analyzed for its ability to suppress the growth of tumors of smooth muscle origin in vivo. Growth of human leiomyosarcomas but not gliomas was inhibited after ADV gene transfer into tumor-bearing immunodeficient mice. In contrast to viral promoters, in which mortality was uniformly seen after injection of 10(12) particles, no significant hepatic injury or systemic toxicity was observed in mice, and the maximum tolerated dose was increased greater than or equal to 10- to 100-fold. These findings suggest that restricted specificity of adenoviral CD95L gene expression enhances the safety of this approach for cancer gene therapy. C1 NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. Univ Michigan, Med Ctr, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Michigan, Med Ctr, Dept Biol Chem, Ann Arbor, MI 48109 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Univ Penn Hlth Syst, Philadelphia, PA 19104 USA. RP Nabel, GJ (reprint author), NIH, Vaccine Res Ctr, 40 Convent Dr, Bethesda, MD 20892 USA. FU NCI NIH HHS [P01 CA59327] NR 40 TC 42 Z9 45 U1 0 U2 0 PU ACADEMIC PRESS INC 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 2000 VL 1 IS 6 BP 555 EP 565 DI 10.1006/mthe.2000.0076 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 367EF UT WOS:000090048200010 PM 10933980 ER PT J AU Lieberman, AP Fischbeck, KH AF Lieberman, AP Fischbeck, KH TI Triplet repeat expansion in neuromuscular disease SO MUSCLE & NERVE LA English DT Review DE Kennedy's disease; myotonic dystrophy; neuromuscular diseases; oculopharyngeal muscular dystrophy; triplet repeat expansion; X-linked spinal and bulbar muscular atrophy ID BULBAR MUSCULAR-ATROPHY; MYOTONIC-DYSTROPHY LOCUS; EXPANDED ANDROGEN RECEPTOR; RECESSIVE BULBOSPINAL NEURONOPATHY; TRINUCLEOTIDE REPEAT; CTG REPEAT; INTRANUCLEAR INCLUSIONS; CAG REPEAT; NEURODEGENERATIVE DISEASES; SPINOCEREBELLAR ATAXIA AB Expansions of unstable trinucleotide repeats cause at least 15 inherited neurologic diseases. Here we review what has been learned of three neuromuscular diseases caused by this type of mutation. X-linked spinal and bulbar muscular atrophy is a motor neuronopathy caused by a CAG repeat expansion in the androgen receptor gene. The mutated protein has an expanded polyglutamine tract, forms intranuclear aggregates, and mediates neurodegeneration through a toxic gain-of-function mechanism. Oculopharyngeal muscular dystrophy is a dominantly inherited myopathy caused by a GCG/polyalanine expansion in the gene encoding poly(A)binding protein 2. Myotonic dystrophy is a clinically variable multisystem disease caused by a CTG expansion in the 3' untranslated region of the myotonin gene. For each of these disorders, we summarize the clinical and pathologic features and review current understanding of the molecular mechanisms underlying their pathogenesis. (C) 2000 John Wiley & Sons, Inc.* C1 NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Lieberman, AP (reprint author), NINDS, Neurogenet Branch, NIH, Bldg 10,Rm 3B14,MSC 1250, Bethesda, MD 20892 USA. NR 81 TC 53 Z9 56 U1 1 U2 3 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-639X J9 MUSCLE NERVE JI Muscle Nerve PD JUN PY 2000 VL 23 IS 6 BP 843 EP 850 DI 10.1002/(SICI)1097-4598(200006)23:6<843::AID-MUS2>3.0.CO;2-8 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 319RP UT WOS:000087356000002 PM 10842259 ER PT J AU Boyington, JC Motyka, SA Schuck, P Brooks, AG Sun, PD AF Boyington, JC Motyka, SA Schuck, P Brooks, AG Sun, PD TI Crystal structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand SO NATURE LA English DT Article ID NATURAL-KILLER-CELLS; LEUKOCYTE ANTIGEN (HLA)-CW4; HLA-C MOLECULES; INHIBITORY RECEPTOR; MEDIATED LYSIS; DIRECT BINDING; AMINO-ACID; PEPTIDE; RECOGNITION; SELECTIVITY AB Target cell lysis is regulated by natural killer (NK) cell receptors that recognize class I MHC molecules, Here we report the crystal structure of the human immunoglobulin-like NK cell receptor KIR2DL2 in complex with its class I ligand HLA-Cw3 and peptide. KIR binds in a nearly orthogonal orientation across the alpha 1 and alpha 2 helices of Cw3 and directly contacts positions 7 acid 8 of the peptide. No significant conformational changes in KIR occur on complex formation. The receptor footprint on HCB overlaps with but is distinct from that of the T-cell receptor. Charge complementarity dominates the KIR/HLA interface and mutations that disrupt interface salt bridges substantially diminish binding. Most contacts in the complex are between hip and conserved HLA-C residues. but a hydrogen band between Lys 44 of KIR2DL2 and Asn 80 of Cw3 confers the allotype specificity. KIR contact requires position 8 of the peptide to be a residue smaller than valine, A second KIR/HLA interface produced an ordered receptor-ligand aggregation in the crystal which may resemble receptor clustering during immune synapse formation. C1 NIAAA, Struct Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. Johns Hopkins Univ, Sch Med, Biochem Cellular & Mol Biol Program, Bethesda, MD 20205 USA. NIH, Bioengn & Phys Sci Program, Bethesda, MD 20892 USA. Univ Melbourne, Dept Immunol & Microbiol, Parkville, Vic 3052, Australia. RP Sun, PD (reprint author), NIAAA, Struct Biol Sect, Immunogenet Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. NR 43 TC 264 Z9 274 U1 1 U2 15 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 1 PY 2000 VL 405 IS 6786 BP 537 EP 543 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 321HF UT WOS:000087449500041 PM 10850706 ER PT J AU Galperin, MY Koonin, EV AF Galperin, MY Koonin, EV TI Who's your neighbor? New computational approaches for functional genomics SO NATURE BIOTECHNOLOGY LA English DT Review DE protein function prediction; gene sequence; Rosetta Stone; clusters of orthologs; phylogenetic patterns ID TRANSFER-RNA SYNTHETASE; PROTEIN SEQUENCES; BACTERIAL GENOMES; GENE; EVOLUTION; FAMILIES; PERSPECTIVE; ARCHAEAL; DOMAIN AB Several recently developed computational approaches in comparative genomics go beyond sequence comparison. By analyzing phylogenetic profiles of protein families, domain fusions, gene adjacency in genomes, and expression patterns, these methods predict many functional interactions between proteins and help deduce specific functions for numerous proteins. Although some of the resultant predictions may not be highly specific, these developments herald a new era in genomics in which the benefits of comparative analysis of the rapidly growing collection of complete genomes will become increasingly obvious. C1 NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RI Galperin, Michael/B-5859-2013 OI Galperin, Michael/0000-0002-2265-5572 NR 38 TC 205 Z9 213 U1 1 U2 5 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD JUN PY 2000 VL 18 IS 6 BP 609 EP 613 DI 10.1038/76443 PG 5 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 325EK UT WOS:000087663200019 PM 10835597 ER PT J AU Bartlett, RJ Stockinger, S Denis, MM Bartlett, WT Inverardi, L Le, TT Man, NT Morris, GE Bogan, DJ Metcalf-Bogan, J Kornegay, JN AF Bartlett, RJ Stockinger, S Denis, MM Bartlett, WT Inverardi, L Le, TT Man, NT Morris, GE Bogan, DJ Metcalf-Bogan, J Kornegay, JN TI In vivo targeted repair of a point mutation in the canine dystrophin gene by a chimeric RNA/DNA oligonucleotide SO NATURE BIOTECHNOLOGY LA English DT Article DE dystrophin; chimeric RNA/DNA oligonucleotide; invivo gene repair; quantitative RT/PCR; in situ RT/PCR; canine ID RETRIEVER MUSCULAR-DYSTROPHY; MOUSE SKELETAL-MUSCLE; IN-VIVO; MDX MICE; MYOBLAST TRANSPLANTATION; IMMUNE-RESPONSES; VIRAL-ANTIGENS; EXPRESSION; INJECTION; TRANSCRIPTS AB In the canine model of Duchenne muscular dystrophy in golden retrievers (GRMD), a point mutation within the splice acceptor site of intron 6 leads to deletion of exon 7 from the dystrophin mRNA, and the consequent frameshift causes early termination of translation. We have designed a DNA and RNA chimeric oligonucleotide to induce host cell mismatch repair mechanisms and correct the chromosomal mutation to wild type. Direct skeletal muscle injection of the chimeric oligonucleotide into the cranial tibialis compartment of a six-week-old affected male dog, and subsequent analysis of biopsy and necropsy samples, demonstrated in vivo repair of the GRMD mutation that was sustained for 48 weeks. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of exons 5-10 demonstrated increasing levels of exon 7 inclusion with time. An isolated exon 7-specific dystrophin antibody confirmed synthesis of normal-sized dystrophin product and positive localization to the sarcolemma, Chromosomal repair in muscle tissue was confirmed by restriction fragment length polymorphism (RFLP)-PCR and sequencing the PCR product, This work provides evidence for the long-term repair of a specific dystrophin point mutation in muscle of a live animal using a chimeric oligonucleotide. C1 Univ Missouri, Coll Vet Med, Dept Vet Med & Surg, Dalton Cardiovasc Res Ctr, Columbia, MO 65202 USA. Univ Miami, Sch Med, Dept Med, Miami, FL 33136 USA. Univ Miami, Sch Med, Dept Neurol, Miami, FL 33136 USA. Ohio State Univ, Dept Med Biochem, Columbus, OH 43210 USA. NE Wales Inst, Wrexham LL11 2AW, Wales. RP Bartlett, RJ (reprint author), NIAMS, Grants Review Branch, Bethesda, MD 20892 USA. NR 32 TC 128 Z9 128 U1 0 U2 7 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD JUN PY 2000 VL 18 IS 6 BP 615 EP 622 DI 10.1038/76448 PG 8 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 325EK UT WOS:000087663200020 PM 10835598 ER PT J AU Lee, SH Lumelsky, N Studer, L Auerbach, JM McKay, RD AF Lee, SH Lumelsky, N Studer, L Auerbach, JM McKay, RD TI Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells SO NATURE BIOTECHNOLOGY LA English DT Article ID FETAL VENTRAL MESENCEPHALON; IN-VITRO; DOPAMINERGIC-NEURONS; MAMMALIAN BRAIN; PRECURSOR CELLS; NEURAL PLATE; PAX-GENES; TRANSPLANTATION; DIFFERENTIATION; EXPRESSION C1 NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP McKay, RD (reprint author), NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 34 TC 893 Z9 953 U1 5 U2 47 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD JUN PY 2000 VL 18 IS 6 BP 675 EP 679 DI 10.1038/76536 PG 5 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 325EK UT WOS:000087663200031 PM 10835609 ER PT J AU Misteli, T AF Misteli, T TI Different site, different splice SO NATURE CELL BIOLOGY LA English DT Article ID IN-VIVO AB The MKK3/6-p38 pathway has been found to induce the relocalization of premessenger-RNA splicing factors from the nucleus to the cytoplasm. This represents the first physiological mechanism that alters the nuclear ratios of splicing factors and modulates alternative splice-site choice in vivo. C1 NCI, NIH, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 10 TC 3 Z9 3 U1 0 U2 0 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD JUN PY 2000 VL 2 IS 6 BP E98 EP E100 DI 10.1038/35014091 PG 3 WC Cell Biology SC Cell Biology GA 321KE UT WOS:000087454000005 PM 10854335 ER PT J AU Gripp, KW Wotton, D Edwards, MC Roessler, E Ades, L Meinecke, P Richieri-Costa, A Zackai, EH Massague, J Muenke, M Elledge, SJ AF Gripp, KW Wotton, D Edwards, MC Roessler, E Ades, L Meinecke, P Richieri-Costa, A Zackai, EH Massague, J Muenke, M Elledge, SJ TI Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination SO NATURE GENETICS LA English DT Article ID BRAIN; GENE; PROTEINS; HEDGEHOG; LAYER AB Holoprosencephaly (HPE) is the most common structural defect of the developing forebrain in humans (1 in 250 conceptuses, 1 in 16,000 live-born infants(1-3)). HPE is aetiologically heterogeneous, with both environmental and genetic causes(4,5). So far, three human HPE genes are known: SHH at chromosome region 7q36 (ref. 6); ZIC2 at 13q32 (ref. 7); and SIX3 at 2p21 (ref. 8). In animal models, genes in the Nodal signalling pathway, such as those mutated in the zebrafish mutants cyclops (refs 9,10), squint (ref. Il)and one-eyed pinhead (oep: ref. 12), cause HPE. Mice heterozygous for null alleles of both Nodal and Smad2 have cyclopia(13) Here we describe the involvement of the TO-interacting factor (TGIF), a homeodomain protein, in human HPE. We mapped TGIF to the HPE minimal critical region in 18p11.3. Heterozygous mutations in individuals with HPE affect the transcriptional repression domain of TGIF, the DNA-binding domain or the domain that interacts with SMAD2. (The latter is an effector in the signalling path-way of the neural axis developmental factor NODAL, a member of the transforming growth factor-beta (TGF-beta) family.) Several of these mutations cause a loss of TGIF function. Thus, TGIF links the NODAL signalling pathway to the bifurcation of the human forebrain and the establishment of ventral midline structures. C1 Univ Penn, Sch Med, Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Childrens Hosp Philadelphia, Dept Genet & Neurol, Philadelphia, PA 19104 USA. Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, Cell Biol Program, New York, NY 10021 USA. Baylor Coll Med, Howard Hughes Med Inst, Dept Biochem & Mol Biol, Houston, TX 77030 USA. Natl Human Genome Res Inst, Dept Mol & Human Genet, NIH, Bethesda, MD USA. Natl Human Genome Res Inst, Med Genet Branch, NIH, Bethesda, MD USA. Royal Alexandra Hosp Children, Parramatta, Australia. Altonauer Kinderkrankenhaus, Hamburg, Germany. Univ Sao Paulo, Sao Paulo, Brazil. RP Muenke, M (reprint author), Univ Penn, Sch Med, Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. RI Richieri-Costa, Antonio/B-2514-2013 NR 24 TC 255 Z9 264 U1 1 U2 7 PU NATURE AMERICA INC 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 2000 VL 25 IS 2 BP 205 EP 208 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 321ML UT WOS:000087459200022 PM 10835638 ER PT J AU Altieri, AS Mazzulla, MJ Horita, DA Coats, RH Wingfield, PT Das, A Court, DL Byrd, RA AF Altieri, AS Mazzulla, MJ Horita, DA Coats, RH Wingfield, PT Das, A Court, DL Byrd, RA TI The structure of the transcriptional antiterminator NusB from Escherichia coli SO NATURE STRUCTURAL BIOLOGY LA English DT Article ID AMBIGUOUS DISTANCE RESTRAINTS; RIBOSOMAL-PROTEIN S10; SECONDARY-STRUCTURE; PHAGE-LAMBDA; CRYSTAL-STRUCTURE; NMR-SPECTROSCOPY; BINDING PROTEINS; RNA; RECOGNITION; DNA AB We have determined the solution structure of NusB, a transcription antitermination protein from Escherichia coli, The structure reveals a novel, all a-helical protein fold. NusB mutations that cause a loss of function (NusB5) or alter specificity for RNA targets (NusB101) are localized to surface residues and likely affect RNA-protein or protein-protein interactions. Residues that are highly conserved among homologs stabilize the protein core. The solution structure of E. coliNusB presented here resembles that of Mycobacterium tuberculosis NusB determined by X-ray diffraction, but differs substantially from a solution structure of E. coli NusB reported earlier. C1 NCI, Frederick Canc Res & Dev Ctr, Struct Biophys Lab, Frederick, MD 21702 USA. NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. Univ Connecticut, Ctr Hlth, Dept Microbiol, Farmington, CT 06030 USA. NCI, Frederick Canc Res & Dev Ctr, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. RP Byrd, RA (reprint author), NCI, Frederick Canc Res & Dev Ctr, Struct Biophys Lab, POB B,Bldg 538, Frederick, MD 21702 USA. EM rabyrd@ncifcrf.gov RI Byrd, R. Andrew/F-8042-2015; OI Byrd, R. Andrew/0000-0003-3625-4232; Horita, David/0000-0002-9563-107X NR 38 TC 19 Z9 20 U1 0 U2 2 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 2000 VL 7 IS 6 BP 470 EP 474 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 321ME UT WOS:000087458600013 PM 10881193 ER EF