FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Seth, A Ourmanov, I Kuroda, MJ Schmitz, JE Carroll, MW Wyatt, LS Moss, B Forman, MA Hirsch, VM Letvin, NL AF Seth, A Ourmanov, I Kuroda, MJ Schmitz, JE Carroll, MW Wyatt, LS Moss, B Forman, MA Hirsch, VM Letvin, NL TI Recombinant modified vaccinia virus Ankara-simian immunodeficiency virus gag pol elicits cytotoxic T lymphocytes in rhesus monkeys detected by a major histocompatibility complex class I peptide tetramer SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ATTENUATED MVA STRAIN; MHC-CLASS-I; HOST-RANGE; VECTOR; EXPRESSION; EPITOPE; GENES; MODEL AB The utility of modified vaccinia virus Ankara (MVA) as a vector for eliciting AIDS virus-specific cytotoxic T lymphocytes (CTL) was explored in the simian immunodeficiency virus (SIV)/rhesus monkey model. After two intramuscular immunizations with recombinant MVA-SIVSM gag pal, the monkeys developed a Gag epitope-specific CTL response readily detected in peripheral blood lymphocytes by using a functional killing assay. Moreover, those immunizations also elicited a population of CD8+ T lymphocytes in the peripheral blood that bound a specific major histocompatibility complex class I/peptide tetramer. These Gag epitope-specific CD8+ T lymphocytes also were demonstrated by using both functional and tetramer-binding assays in lymph nodes of the immunized monkeys. These observations suggest that MVA may prove a useful vector for an HIV-1 vaccine. They also suggest that tetramer staining may be a useful technology for monitoring CTL generation in vaccine trials in nonhuman primates and in humans. C1 Harvard Univ, Sch Med, Div Viral Pathogenesis,Dept Med, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NIAID, Viral Dis Lab, NIH, Rockville, MD 20852 USA. Beckman Coulter Inc, Miami, FL 33116 USA. RP Letvin, NL (reprint author), Harvard Univ, Sch Med, Div Viral Pathogenesis,Dept Med, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. FU NIAID NIH HHS [AI26507, AI35166, U01 AI026507, P01 AI026507] NR 29 TC 99 Z9 101 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 AUG 18 PY 1998 VL 95 IS 17 BP 10112 EP 10116 DI 10.1073/pnas.95.17.10112 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 112BX UT WOS:000075475200072 PM 9707609 ER PT J AU Bewley, CA Faulkner, DJ AF Bewley, CA Faulkner, DJ TI Lithistid sponges: Star performers or hosts to the stars SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Review DE antifungal agents; antitumor agents; macrocycles; natural products; peptides ID OKINAWAN MARINE SPONGE; ACTIVE TRIDECAPEPTIDE LACTONES; POTENT CYTOTOXIC MACROLIDES; ANTIFUNGAL CYCLIC-PEPTIDES; DEMOSPONGE CORALLISTES-SP; THEONELLA-SP THEONELLIDAE; BLUE-GREEN-ALGA; SWINHOLIDE-A; STRUCTURE ELUCIDATION; DISCODERMIA-KIIENSIS C1 Univ Calif San Diego, Scripps Inst Oceanog, La Jolla, CA 92093 USA. NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Faulkner, DJ (reprint author), Univ Calif San Diego, Scripps Inst Oceanog, La Jolla, CA 92093 USA. EM bewley@speck.niddk.nih.gov; jfaulkner@ucsd.edu NR 140 TC 34 Z9 36 U1 0 U2 11 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 1433-7851 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PD AUG 17 PY 1998 VL 37 IS 16 BP 2163 EP 2178 PG 16 WC Chemistry, Multidisciplinary SC Chemistry GA 118VE UT WOS:000075860500001 ER PT J AU Quan, N Whiteside, M Herkenham, M AF Quan, N Whiteside, M Herkenham, M TI Cyclooxygenase 2 mRNA expression in rat brain after peripheral injection of lipopolysaccharide SO BRAIN RESEARCH LA English DT Article DE prostaglandin; endotoxin; blood-brain barrier; endothelial ID PROSTAGLANDIN ENDOPEROXIDE SYNTHASE; C-FOS EXPRESSION; MESSENGER-RNA; MOUSE-BRAIN; INDUCIBLE CYCLOOXYGENASE; BACTERIAL-ENDOTOXIN; ACTH-SECRETION; INDUCED FEVER; HIPPOCAMPUS; ACTIVATION AB Inducible cyclooxygenase 2 (COX 2) converts arachidonic acid to prostaglandins, which are thought to mediate various peripheral Lipopolysaccharide (LPS)-induced central effects, including generation of fever and activation of the hypothalamic-pituitary-adrenal axis. To localize prostaglandin production in the brain following peripheral LPS administration, COX 2 mRNA expression was examined by in situ hybridization histochemistry in rats injected intraperitoneally (i.p.) or intravenously (i.v.) with various doses of LPS or saline. Constitutive expression of COX 2 mRNA was found in neurons of cortex, hippocampus, and amygdala, but not in cells of the blood vessels. COX 2 mRNA levels were not altered in saline-injected animals as compared to non-injected controls. In LPS-injected animals, no consistent changes of neuronal COX 2 mRNA expression were observed. COX 2 mRNA expression appeared ex novo at 0.5-h post-injection in cells closely associated with blood vessels, however, ex novo labeling of the number of labeled cells increased to a peak at 2 h and subsided gradually to basal levels by 24 h. Initially, labeling was observed in cells comprising major surface-lying blood vessels and meninges. Later, vascular and perivascular cells associated with smaller penetrating blood vessels were labeled. This pattern of COX 2 mRNA induction is independent of the route and dose of the LPS injection. The induced COX 2 mRNA producing cells are identified as endothelial and leptomeningeal cells. Changes in COX 2 mRNA expression were not observed in circumventricular organs. These results suggest that peripheral LPS induces a rapid increase in COX 2 production throughout the vasculatures of the brain, which could affect the neuronal activity of widespread brain regions by elevating the levels of prostaglandins. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIMH, Funct Neuroanat Sect, Bethesda, MD 20892 USA. RP Quan, N (reprint author), NIMH, Funct Neuroanat Sect, Bldg 36,Room 2D15, Bethesda, MD 20892 USA. OI Herkenham, Miles/0000-0003-2228-4238 NR 27 TC 127 Z9 128 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD AUG 17 PY 1998 VL 802 IS 1-2 BP 189 EP 197 DI 10.1016/S0006-8993(98)00402-8 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 115BY UT WOS:000075644700021 PM 9748570 ER PT J AU Rajan, P Gearan, T Fink, JS AF Rajan, P Gearan, T Fink, JS TI Leukemia inhibitory factor and NGF regulate signal transducers and activators of transcription activation in sympathetic ganglia: convergence of cytokine- and neurotrophin-signaling pathways SO BRAIN RESEARCH LA English DT Article DE sympathetic ganglion; axotomy; intracellular signaling; LIF; STAT; NGF ID NERVE GROWTH-FACTOR; VASOACTIVE-INTESTINAL-PEPTIDE; ADULT SENSORY NEURONS; SUPERIOR CERVICAL-GANGLION; STAT PROTEINS; NEUROPEPTIDE EXPRESSION; PHENOTYPIC PLASTICITY; SUBSTANCE-P; IN-VIVO; CULTURE AB We have used the response of the superior cervical ganglia (SCG) to axotomy to investigate interactions between neuropoietic cytokines and neurotrophins. Postganglionic sympathetic axotomy leads to a prolonged leukemia inhibitory factor (LIF)-dependent activation of signal transducers and activators of transcription (STAT) factors. To study regulation of LIF-dependent activation of STAT proteins and to mimic the loss of target-derived NGF resulting from postganglionic axotomy in vivo, SCG were explanted into media lacking NGF and activation of STAT proteins was assessed by electrophoretic mobility shift assay. Like postganglionic axotomy in vivo, STAT proteins were activated for up to 8 days after explantation of SCG in vitro. SCG cultured in the presence of NGF showed decreased STAT binding when compared to ganglia cultured in NGF-free media. This inhibition of STAT activation by NGF was only present in ganglia cultured for more than 5 days and was mimicked by brain-derived neurotrophic factor (BDNF). The serine kinase inhibitor H7 augmented the increase of STAT binding produced by explantation, suggesting the presence of a labile repressor of STAT activation in the SCG. These data indicated that the neuropoietic cytokine-signaling pathway interacts with neurotrophin and H7-sensitive-signaling pathways to regulate activation of STAT proteins in sympathetic neurons. Moreover, these data suggest that one of the mechanisms leading to prolonged activation of STAT proteins after postganglionic axotomy in vivo is loss of target-derived neurotrophins. (C) 1998 Elsevier Science B.V. All rights reserved. C1 Massachusetts Gen Hosp, Mol Neurobiol Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Rajan, P (reprint author), NINDS, Mol Biol Lab, NIH, Bldg 36,Room 3C09, Bethesda, MD 20892 USA. EM rajan@codon.nih.gov FU NIMH NIH HHS [MH-11205]; NINDS NIH HHS [NS-27514] NR 41 TC 28 Z9 28 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 AUG 17 PY 1998 VL 802 IS 1-2 BP 198 EP 204 DI 10.1016/S0006-8993(98)00611-8 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 115BY UT WOS:000075644700022 PM 9748576 ER PT J AU Toth, ZE Palkovits, M AF Toth, ZE Palkovits, M TI Distributions of periventricular projections of the paraventricular nucleus to the median eminence and arcuate nucleus SO BRAIN RESEARCH LA English DT Article DE paraventricular nucleus; median eminence; arcuate nucleus; Phaseolus vulgaris leucoagglutinin; rat ID THYROTROPIN-RELEASING-HORMONE; LEUKOAGGLUTININ PHA-L; IMMUNOHISTOCHEMICAL LOCALIZATION; CYTOARCHITECTONIC SUBDIVISIONS; RAT HYPOTHALAMUS; SPINAL-CORD; NEURONS; FIBERS; PITUITARY; SYSTEM AB Neuronal projections from the periventricular subnucleus of the hypothalamic paraventricular nucleus to the median eminence and the arcuate nucleus were investigated in the rat by the anterograde tract-tracer, Phaseolus vulgaris leucoagglutinin. The vast majority of labeled fibers coursed ventrally along the third ventricle and distributed in the external layer of the median eminence bilaterally, with ipsilateral predominance moving caudalwards. Periventricular fibers also terminated in the arcuate nucleus, but this innervation was exclusively ipsilateral. (C) 1998 Elsevier Science B.V. All rights reserved. C1 Semmelweis Univ Med, Sch Med, Neuromorphol Lab, H-1094 Budapest, Hungary. RP Toth, ZE (reprint author), NIMH, Genet Sect, NIH, Bldg 36,3D06, Bethesda, MD 20892 USA. RI Palkovits, Miklos/F-2707-2013; OI Palkovits, Miklos/0000-0003-0578-0387 NR 26 TC 10 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD AUG 17 PY 1998 VL 802 IS 1-2 BP 294 EP 297 DI 10.1016/S0006-8993(98)00620-9 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 115BY UT WOS:000075644700035 PM 9748636 ER PT J AU Markus, MA Gerstner, RB Draper, RB Torchia, DA AF Markus, MA Gerstner, RB Draper, RB Torchia, DA TI The solution structure of ribosomal protein S4 Delta 41 reveals two subdomains and a positively charged surface that may interact with RNA SO EMBO JOURNAL LA English DT Article DE modular proteins; multidimensional NMR; protein-nucleic acid interactions; ribosome assembly; ribosomal proteins ID TRIPLE-RESONANCE NMR; ISOTOPICALLY ENRICHED PROTEINS; LIQUID-CRYSTALLINE MEDIUM; SIDE-CHAIN RESONANCES; MESSENGER-RNA; C-13/N-15-ENRICHED PROTEINS; ESCHERICHIA-COLI; C-13 MAGNETIZATION; LARGER PROTEINS; BACKBONE AMIDE AB S4 is one of the first proteins to bind to 16S RNA during assembly of the prokaryotic ribosome, Residues 43-200 of S4 from Bacillus stearothermophilus (S4 Delta 41) bind specifically to both 16S rRNA and to a pseudoknot within the a operon mRNA, As a first step toward understanding how S4 recognizes and organizes RNA, we have solved the structure of S4 Delta 41 in solution by multidimensional heteronuclear nuclear magnetic resonance spectroscopy. The fold consists of two globular subdomains, one comprised of four helices and the other comprised of a five-stranded antiparallel P-sheet and three helices, Although cross-linking studies suggest that residues between helices alpha 2 and alpha 3 are close to RNA, the concentration of positive charge along the crevice between the two subdomains suggests that this could be an RNA-binding site, In contrast to the L11 RNA-binding domain studied previously, S4 Delta 41 shows no fast local motions, suggesting that it has less capacity for refolding to fit RNA. The independently determined crystal structure of S4 Delta 41 shows similar features, although there is small rotation of the subdomains compared with the solution structure. The relative orientation of the subdomains in solution will be verified with further study. C1 NIDR, Struct Mol Biol Unit, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Chem, Baltimore, MD 21218 USA. RP Torchia, DA (reprint author), NIDR, Struct Mol Biol Unit, NIH, 30 Convent Dr,Room 132, Bethesda, MD 20892 USA. NR 47 TC 38 Z9 40 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD AUG 17 PY 1998 VL 17 IS 16 BP 4559 EP 4571 DI 10.1093/emboj/17.16.4559 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 114ML UT WOS:000075613200002 PM 9707416 ER PT J AU Caffrey, M Cai, ML Kaufman, J Stahl, SJ Wingfield, PT Covell, DG Gronenborn, AM Clore, GM AF Caffrey, M Cai, ML Kaufman, J Stahl, SJ Wingfield, PT Covell, DG Gronenborn, AM Clore, GM TI Three-dimensional solution structure of the 44 kDa ectodomain of SIV gp41 SO EMBO JOURNAL LA English DT Article DE cell fusion; ectodomain; gp41; HIV; SIV ID HUMAN-IMMUNODEFICIENCY-VIRUS; HEMAGGLUTININ MEMBRANE GLYCOPROTEIN; MAGNETIC-RESONANCE SPECTROSCOPY; PROTEIN-STRUCTURE DETERMINATION; ISOTOPICALLY ENRICHED PROTEINS; INFLUENZA-VIRUS; HIV-1 GP41; ENVELOPE GLYCOPROTEIN; TRANSMEMBRANE PROTEIN; EXTRACELLULAR DOMAIN AB The solution structure of the ectodomain of simian immunodeficiency virus (SIV) gp41 (e-gp41), consisting of residues 27-149, has been determined by multidimensional heteronuclear NMR spectroscopy. SN e-gp41 is a symmetric 44 kDa trimer with each subunit consisting of antiparallel N-terminal (residues 30-80) and C-terminal (residues 107-147) helices connected by a 26 residue loop (residues 81-106), The N-terminal helices of each subunit form a parallel coiled-coil structure in the interior of the complex which is surrounded by the C-terminal helices located on the exterior of the complex, The loop region is ordered and displays numerous intermolecular and non-sequential intramolecular contacts. The helical core of SIV e-gp41 is similar to recent X-ray structures of truncated constructs of the helical core of HIV-1 e-gp41. The present structure establishes unambiguously the connectivity of the N- and C-terminal helices in the trimer, and characterizes the conformation of the intervening loop, which has been implicated by mutagenesis and antibody epitope mapping to play a key role in gp120 association, In conjunction with previous studies, the solution structure of the SIV e-gp41 ectodomain provides insight into the binding site of gp120 and the mechanism of cell fusion. The present structure of SIV e-gp41 represents one of the largest protein structures determined by NMR to date. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. EM gronenborn@vger.niddk.nih.gov; clore@speck.niddk.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 NR 66 TC 342 Z9 345 U1 1 U2 20 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD AUG 17 PY 1998 VL 17 IS 16 BP 4572 EP 4584 DI 10.1093/emboj/17.16.4572 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 114ML UT WOS:000075613200003 PM 9707417 ER PT J AU Lim, MJ Chae, HZ Rhee, SG Yu, DY Lee, KK Yeom, RI AF Lim, MJ Chae, HZ Rhee, SG Yu, DY Lee, KK Yeom, RI TI The type II peroxiredoxin gene family of the mouse: molecular structure, expression and evolution SO GENE LA English DT Article DE type II peroxiredoxin; antioxidant enzyme; family gene; retrotransposition ID THIOL-SPECIFIC ANTIOXIDANT; MURINE ERYTHROLEUKEMIA-CELLS; CLONING; PROTEIN; BRAIN; REDUCTASE; HOMOLOGY; PRODUCT AB Peroxiredoxins (Prxs) are a newly defined family of antioxidant proteins that have been implicated, via their antioxidant activity, in a number of cellular functions, including cell proliferation and differentiation, protection of other proteins from oxidative damage, and intracellular signaling. We isolated genomic DNA sequences of the type II Pix (PI x II) gene from the mouse and analyzed their molecular genetic characteristics. In the mouse, the Prx II is found to form a small multigene family with three members. One of them, the Prx II-I gene, is actively transcribed in a variety of adult tissues as well as in the developing embryos to produce a 1.1-kb mRNA. The Prx II-1 gene consists of six exons and five introns, and the whole transcription unit occupies about 4.5 kb in the mouse genome. The other two genes, Prx II-2 and Prx II-3, are encoded by single exons, and show 97.5 and 87% of nucleotide sequence homology with the Prx II-I gene, respectively. Structural features of these genes and the results of RT-PCR analysis on RNAs from various tissue sources indicate that the Prx II-2 and Prx II-3 genes could be pseudogenes derived from the Prx II-1 gene by a mechanism involving retrotransposition. These results strongly suggest that only the Prx III gene might be relevant for studying the function of the Prx II gene in the murine system. (C) 1998 Elsevier Science B.V. All rights reserved. C1 Korea Res Inst Biosci & Biotechnol, Mol & Cellular Biol Res Div, Taejon 305600, South Korea. Chonnam Natl Univ, Dept Biol, Kwangju 500757, South Korea. NHLBI, Cell Signaling Lab, NIH, Bethesda, MD 20892 USA. Korea Res inst Biosci & Biotechnol, Plant & Anim Cell Technol Res Div, Taejon 305600, South Korea. RP Yeom, RI (reprint author), Korea Res Inst Biosci & Biotechnol, Mol & Cellular Biol Res Div, POB 115, Taejon 305600, South Korea. NR 25 TC 37 Z9 41 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD AUG 17 PY 1998 VL 216 IS 1 BP 197 EP 205 DI 10.1016/S0378-1119(98)00290-X PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 114JY UT WOS:000075606600023 PM 9714804 ER PT J AU Duensing, TD van Putten, JPM AF Duensing, TD van Putten, JPM TI Vitronectin binds to the gonococcal adhesin OpaA through a glycosaminoglycan molecular bridge SO BIOCHEMICAL JOURNAL LA English DT Article ID PLASMINOGEN-ACTIVATOR INHIBITOR-1; EXPRESSING NEISSERIA-GONORRHOEAE; THROMBIN-ANTITHROMBIN-III; OUTER-MEMBRANE PROTEINS; SOMATOMEDIN-B DOMAIN; STAPHYLOCOCCUS-AUREUS; EPITHELIAL-CELLS; S-PROTEIN; COLLAGEN-BINDING; ANTIBODY-BINDING AB Several bacterial pathogens including Neisseria gonorrhoeae bind the human serum glycoprotein vitronectin. We aimed at defining the gonococcal receptor for vitronectin. Ligand blots demonstrated that vitronectin bound specifically to the heparin-binding outer-membrane protein OpaA, but that coating OpaA with the sulphated polysaccharide heparin was required for the interaction to occur. Bound vitronectin could be dissociated from OpaA-heparin-vitronectin complexes by the addition of excess heparin, indicating that sulphated polysaccharides provided the main linkage between the two proteins. Binding assays with intact micro-organisms substantiated the requirement of sulphated polysaccharides such as heparin and dextran sulphate for the efficient binding of vitronectin to OpaA(+) gonococci. This was underscored by the increased binding of vitronectin to gonococci that had been preincubated with saturating concentrations of dextran sulphate, as opposed to the inhibition of vitronectin binding observed when bacteria were incubated simultaneously with vitronectin and saturating concentrations of dextran sulphate. Binding assays with dextran sulphates of various sizes indicated that vitronectin binding correlated with the size of the polysaccharide rather than with the amount of OpaA produced by the bacteria. The inability of zero-length crosslinking agents to couple vitronectin to OpaA provided further evidence that sulphated polysaccharides formed the linkage between vitronectin and OpaA. Infection experiments demonstrated that proteoglycan-deficient Chinese hamster ovary cells efficiently internalized dextran sulphate/vitronectin-coated gonococci, suggesting that soluble sulphated polysaccharides could substitute for cell surface glycosaminoglycans in the internalization process. On the basis of our results, we propose a novel mechanism of vitronectin binding in which sulphated polysaccharides act as molecular bridges, linking the glycosaminoglycan-binding sites of vitronectin and gonococcal OpaA. C1 NIAID, Rocky Mt Labs, Microbial Struct & Funct Lab, NIH, Hamilton, MT 59840 USA. RP Duensing, TD (reprint author), NIAID, Rocky Mt Labs, Microbial Struct & Funct Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM tduensing@nih.gov OI van Putten, Jos/0000-0002-4126-8172 NR 54 TC 28 Z9 30 U1 0 U2 2 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON, ENGLAND W1N 3AJ SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD AUG 15 PY 1998 VL 334 BP 133 EP 139 PN 1 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 113NM UT WOS:000075558200019 PM 9693112 ER PT J AU Hibbeln, JR Linnoila, M Umhau, JC Rawlings, R George, DT Salem, N AF Hibbeln, JR Linnoila, M Umhau, JC Rawlings, R George, DT Salem, N TI Essential fatty acids predict metabolites of serotonin and dopamine in cerebrospinal fluid among healthy control subjects, and early- and late-onset alcoholics SO BIOLOGICAL PSYCHIATRY LA English DT Article DE alcoholism; cholesterol; docosahexaenoic acid; polyunsaturated fatty acids; serotonin; suicide; violence; 5-hydroxyindoleacetic acid; arachidonic acid; essential fatty acids ID 5-HYDROXYINDOLEACETIC ACID; DOCOSAHEXAENOIC ACID; VIOLENT OFFENDERS; FIRE SETTERS; HUMAN CSF; CHOLESTEROL; DEPRESSION; PERFORMANCE; RELIABILITY; VOLUNTEERS AB Background: Impulsive violence, suicide, and depression are strongly associated with low concentrations of cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA). increased suicide and trauma reported in some cholesterol-lowering trials may be related to altered concentrations of polyunsaturated fatty acids rather than cholesterol, a possible surrogate marker. Methods: CSF 5-HIAA and homovanillic acid (HVA), total cholesterol, and plasma fatty acid concentrations were examined in 176 subjects, including 49 healthy volunteers, and 88 early- and 39 late-onset alcoholics. Results: Among each group, polyunsaturated fatty acids predicted both CSF 5-HIAA and CSF HVA concentrations, but total cholesterol was unrelated to either neurotransmitter metabolite. The relationships between plasma 22: 6n3 and CSF 5-HIAA were significantly different when healthy volunteers (r =.35) were compared to early-onset alcoholics (r = -.38) (p <.0002), Conclusions: Dietary studies are indicated to determine if essential fatty acid supplementation can influence central nervous system serotonin and dopamine metabolism and modify impulsive behaviors related to these neurotransmitters. Biol Psychiatry 1998;44:235-242 (C) 1998 Society of Biological Psychiatry. C1 NIAAA, Outpatient Clin, Lab Membrane Biochem & Biophys, Rockville, MD 20852 USA. NIAAA, Clin Studies Lab, Rockville, MD 20852 USA. RP Hibbeln, JR (reprint author), NIAAA, Outpatient Clin, Lab Membrane Biochem & Biophys, Pk 5,Room 158,12420 Parklawn Dr, Rockville, MD 20852 USA. NR 44 TC 132 Z9 137 U1 5 U2 14 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 AUG 15 PY 1998 VL 44 IS 4 BP 235 EP 242 DI 10.1016/S0006-3223(98)00141-3 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 110CP UT WOS:000075362800001 PM 9715354 ER PT J AU Hibbeln, JR Umhau, JC Linnoila, M George, DT Ragan, PW Shoaf, SE Vaughan, MR Rawlings, R Salem, N AF Hibbeln, JR Umhau, JC Linnoila, M George, DT Ragan, PW Shoaf, SE Vaughan, MR Rawlings, R Salem, N TI A replication study of violent and nonviolent subjects: Cerebrospinal fluid metabolites of serotonin and dopamine are predicted by plasma essential fatty acids SO BIOLOGICAL PSYCHIATRY LA English DT Article DE alcoholism; cholesterol; docosahexaenoic acid; polyunsaturated fatty acids; serotonin; suicide; violence; 5-hydroxyindoleacetic acid; arachidonic acid; essential fatty acids; depression ID DOCOSAHEXAENOIC ACID; 5-HYDROXYINDOLEACETIC ACID; HUMAN CSF; ALCOHOL; RELIABILITY; DEFICIENCY; VOLUNTEERS; OFFENDERS; TURNOVER; BRAIN AB Background: Among an independent group of subjects selected for their history of violent, impulsive behaviors and nonviolent control subjects, we attempted to replicate the finding that plasma docosahexaenoic acid concentrations were negatively correlated with cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) concentrations. Methods: CSF 5-HIAA and homovanillic acid (HVA), fasting total cholesterol, and plasma fatty acid concentrations were examined in violent and nonviolent subjects matched for their severity of alcohol dependence. Results: Violent subjects had significantly higher lifetime violence and hostility ratings and lower concentrations of CSF 5-HIAA than nonviolent subjects, Plasma docosahexaenoic acid was negatively correlated with CSF 5-HIAA only among violent subjects. Conclusions: This observational study suggests that dietary essential fatty acids may change neurotransmitter concentrations. Prospective dietary intervention trials will be required to determine if increasing dietary intake of docosahexaenoic acid will increase or decrease either CSF 5-HIAA concentrations or impulsive and violent behaviors. Biol Psychiatry 1998;44:243-249 (C) 1998 Society of Biological Psychiatry. C1 NIAAA, Outpatient Clin, Lab Membrane Biochem & Biophys, Rockville, MD 20852 USA. NIAAA, Clin Studies Lab, Rockville, MD 20852 USA. Georgetown Med Sch, Washington, DC USA. RP Hibbeln, JR (reprint author), NIAAA, Outpatient Clin, Lab Membrane Biochem & Biophys, Pk 5,Room 158,12420 Parklawn Dr, Rockville, MD 20852 USA. NR 35 TC 93 Z9 95 U1 5 U2 8 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 AUG 15 PY 1998 VL 44 IS 4 BP 243 EP 249 DI 10.1016/S0006-3223(98)00143-7 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 110CP UT WOS:000075362800002 PM 9715355 ER PT J AU Rubinow, DR AF Rubinow, DR TI Markku Linnoila - June 10, 1947 February 25, 1998 - In memoriam SO BIOLOGICAL PSYCHIATRY LA English DT Biographical-Item C1 NIMH, NIH, Bethesda, MD 20892 USA. RP Rubinow, DR (reprint author), NIMH, NIH, Bldg 10,Room 3N-238 MSC 1276,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD AUG 15 PY 1998 VL 44 IS 4 BP 307 EP 308 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 110CP UT WOS:000075362800012 ER PT J AU Tisdale, JF Hanazono, Y Sellers, SE Agricola, BA Metzger, ME Donahue, RE Dunbar, CE AF Tisdale, JF Hanazono, Y Sellers, SE Agricola, BA Metzger, ME Donahue, RE Dunbar, CE TI Ex vivo expansion of genetically marked rhesus peripheral blood progenitor cells results in diminished long-term repopulating ability SO BLOOD LA English DT Article ID COLONY-STIMULATING FACTOR; MEDIATED GENE-TRANSFER; BONE-MARROW TRANSPLANTATION; HUMAN HEMATOPOIETIC-CELLS; STEM-CELLS; NONHUMAN-PRIMATES; EXVIVO EXPANSION; CD34(+) CELLS; CYCLE STATUS; FLT3 LIGAND AB The possibility of primitive hematopoietic cell ex vivo expansion is of interest for both gene therapy and transplantation applications. The engraftment of autologous rhesus peripheral blood (PB) progenitors expanded 10 to 14 days were tracked in vivo using genetic marking. Stem cell factor(SCF)/granulocyte colony-stimulating factor (G-CSF)-mobilized and CD34-enriched PB cells were divided into two equal aliquots and transduced with one of two retroviral vectors carrying the neomycin-resistance gene (neo) for 4 days in the presence of interleukin-3 (IL-3), IL-6, and SCF in the first 5 animals, IL-3/1L-G/SCF/Flt-3 ligand (FLT) in 2 subsequent animals, or IL-3/IL-6/SCF/FLT plus an autologous stromal monolayer (STR) in the final 2. At the end of transduction period, one aliquot (nonexpanded) from each animal was frozen, whereas the other was expanded under the same conditions but without vector for a total of 14 days before freezing. After total body irradiation, both the nonexpanded and expanded transduced cells were reinfused. Despite 5- to 13-fold higher cell and colony-forming unit (CFU) doses from the expanded fraction of marked cells, there was greater short- and long-term marking from the nonexpanded cells in all animals. In animals receiving cells transduced and expanded in the presence of IL-3/IL-6/SCF/FLT, engraftment by the marked expanded cells was further diminished. This discrepancy was even more pronounced in the animals who received cells transduced and expanded in the presence of FLT and autologous stroma, with no marking detectable from the expanded cells. Despite lack of evidence for expansion of engrafting cells, we found that the addition of FLT and especially STR during the initial brief transduction period increased engraftment with marked cells into a clinically relevant range. Levels of marked progeny cells originating from the nonexpanded aliqouts were significantly higher than that seen in previous 4 animals receiving cells transduced in the presence of IL-3/IL-6/SCF, with levels of 10% to 20% confirmed by Southern blotting from the nonexpanded IL-3/IL-6/SCF/FLT/STR graft compared with 0.01% in the original IL-3/IL-6/SCF cohort. These results suggest that, although expansion of PB progenitors is feasible ex vivo, their contribution towards both short- and long-term engraftment is markedly impaired. However, a brief transduction in the presence of specific cytokines and stromal support allows engraftment with an encouraging number of retrovirally modified cells. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Tisdale, JF (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Room 7C208,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tisdalej@gwgate.nhlbi.nih.gov NR 48 TC 207 Z9 211 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 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 1998 VL 92 IS 4 BP 1131 EP 1141 PG 11 WC Hematology SC Hematology GA 109MR UT WOS:000075326800007 PM 9694700 ER PT J AU Krenacs, L Himmelmann, AW Quintanilla-Martinez, L Fest, T Riva, A Wellmann, A Bagdi, E Kehrl, JH Jaffe, ES Raffeld, M AF Krenacs, L Himmelmann, AW Quintanilla-Martinez, L Fest, T Riva, A Wellmann, A Bagdi, E Kehrl, JH Jaffe, ES Raffeld, M TI Transcription factor B-cell-specific activator protein (BSAP) is differentially expressed in B cells and in subsets of B-cell lymphomas SO BLOOD LA English DT Article ID PAIRED BOX GENE; ALVEOLAR RHABDOMYOSARCOMA; PAX-GENES; 3'ALPHA ENHANCER; CHROMOSOMAL TRANSLOCATION; HODGKINS-DISEASE; SWITCH REGIONS; IN-VIVO; NF-HB; IMMUNOGLOBULIN AB The paired box containing gene PAX-5 encodes the transcription factor BSAP (B-cell-specific activator protein), which plays a key role in B-lymphocyte development. Despite its known involvement in a rare subtype of non-Hodgkin's lymphoma (NHL), a detailed examination of BSAP expression in NHL has not been previously report-ed. In this study, we analyzed normal and malignant lymphoid tissues and cell lines, including 102 cases of B-cell NHL, 23 cases of T- and null-cell NHL, and 18 cases of Hodgkin's disease. Normal lymphoid tissues showed strong nuclear BSAP expression in mantle zone B cells, less intense reactivity in follicular center B cells, and no expression in cells of the T-cell-rich zones. Monocytoid B cells showed weak expression, whereas plasma cells and extrafollicular large transformed B cells were negative. Of the 102 B-cell NHLs, 83 (81%) demonstrated BSAP expression. All of the 13 (100%) B-cell chronic lymphocytic leukemias (B-CLLs), 21 of [100%) mantle cells (MCLs), and 20 of 21 (95%) follicular lymphomas (FLs) were positive. Moderate staining intensities were found in most B-CLL and FL cases, whereas most MCLs showed strong reactions, paralleling the strong reactivity of nonmalignant mantle cells. Eight of 12 (67%) marginal zone lymphoma cases showed negative or low BSAP levels, and 17 of 24 (71%) large B-cell lymphomas displayed moderate to strong expression. None of the 23 T- and null-cell lymphomas reacted with the BSAP antisera, whereas in Hodgkin's disease, 2 of 4 (50%) nodular lymphocytic predominance and 5 of 14 (36%) classical cases showed weak nuclear or nucleolar BSAP reactions in a fraction of the tumor cells. Western blot analysis showed a 52-kD BSAP band in B-cell lines, but not in non-B-cell or plasma cell lines. We conclude that BSAP expression is largely restricted to lymphomas of B-cell lineage and that BSAP expression varies in B-cell subsets and subtypes of B-cell NHL. The high levels of BSAP, especially those found in large-cell lymphomas and in some follicular lymphomas, may be a consequence of deregulated gene expression and suggest a possible involvement of PAX-5 in certain B-cell malignancies. C1 NCI, Hematopathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, B Cell Mol Immunol Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Albert Szent Gyorgyi Med Univ, Dept Pathol, H-6701 Szeged, Hungary. RP Raffeld, M (reprint author), NCI, Hematopathol Sect, Pathol Lab, NIH, Bldg 10,Room 2N110,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Krenacs, Laszlo/L-8063-2014; OI Krenacs, Laszlo/0000-0001-6541-3031; Kehrl, John/0000-0002-6526-159X NR 55 TC 91 Z9 98 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 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 1998 VL 92 IS 4 BP 1308 EP 1316 PG 9 WC Hematology SC Hematology GA 109MR UT WOS:000075326800026 PM 9694719 ER PT J AU Bessudo, A Rassenti, L Havlir, D Richman, D Feigal, E Kipps, TJ AF Bessudo, A Rassenti, L Havlir, D Richman, D Feigal, E Kipps, TJ TI Aberrant and unstable expression of immunoglobulin genes in persons infected with human immunodeficiency virus SO BLOOD LA English DT Article ID STAPHYLOCOCCAL PROTEIN-A; NON-HODGKINS-LYMPHOMA; B-CELLS; HIV-INFECTION; IN-VIVO; T-CELL; AIDS; REPERTOIRE; ORGANIZATION; LYMPHOCYTES AB We examined the IgM V-H gene subgroup use-distribution in serial blood samples of 37 human immunodeficiency virus (HIV)-infected patients and a group of HIV-seronegative healthy adults. The IgM V-H gene repertoires of healthy adults were relatively similar to one another and were stable over time. In contrast, individuals infected with HIV had IgM V-H gene repertoires that were significantly more heterogeneous and unstable. Persons at early stages of HIV infection generally had abnormal expression levels of Ig V(H)3 genes and frequently displayed marked fluctuations in the relative expression levels of this V-H gene subgroup over time. In contrast, persons with established acquired immunodeficiency syndrome (AIDS) had a significantly lower incidence of abnormalities in Ig V(H)3 expression levels, although continued to display abnormalities and instability in the expression levels of the smaller Ig V-H gene subgroups. Moreover, the skewing and/or fluctuations in the expressed-IgM V-H gene repertoire appeared greatest for persons at earlier stages of HIV infection. These studies show that persons infected with HIV have aberrant and unstable expression of immunoglobulin genes suggestive of a high degree humoral immune dysregulation and ongoing humoral immune responses to HIV-associated antigens and superantigens. (C) 1998 by The American Society of Hematology. C1 Univ Calif San Diego, Dept Med, Div Hematol Oncol, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Med, Div Infect Dis, La Jolla, CA 92093 USA. NCI, Bethesda, MD 20892 USA. RP Kipps, TJ (reprint author), Univ Calif San Diego, Dept Med, Div Hematol Oncol, La Jolla, CA 92093 USA. FU NCI NIH HHS [R01 CA 65408-03]; NIAID NIH HHS [AI27670, AI 36214] NR 46 TC 22 Z9 23 U1 1 U2 3 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 1998 VL 92 IS 4 BP 1317 EP 1323 PG 7 WC Hematology SC Hematology GA 109MR UT WOS:000075326800027 PM 9694720 ER PT J AU Guedez, L Courtemanch, L Stetler-Stevenson, M AF Guedez, L Courtemanch, L Stetler-Stevenson, M TI Tissue inhibitor of metalloproteinase (TIMP)-1 induces differentiation and an antiapoptotic phenotype in germinal center B Cells SO BLOOD LA English DT Article ID ERYTHROID-POTENTIATING ACTIVITY; BURKITT-LYMPHOMA CELLS; EXTRACELLULAR-MATRIX; LYMPHOCYTES-B; LATENT GENES; APOPTOSIS; EXPRESSION; ANTIGEN; METASTASIS; MECHANISM AB Tissue inhibitors of metalloproteinases (TIMPs) have been shown to be multifunctional factors. Contrasting with their enzyme-inhibitory activity, TIMPs also promote cell growth. Previously, we have reported an enhanced expression of TIMP-1 by normal reactive B cells and high-grade lymphomas. In the present study, a series of Burkitt's lymphoma (BL) cell lines were analyzed for their expression of TIMP-1. TIMP-1 expression correlates with upregulation of activation and survival markers. TIMP-1-negative cells express the phenotype associated with group I Bk lines and Epstein-Barr virus (EBV)-negative, nonendemic BLs (CD10(+), CD38(+), sIg(+), and CD77(+)). However, TIMP-1(+) BL lines showed group II/III BL phenotype, downregulation of the above markers, and upregulation and secretion of the activation marker CD23. Also, TIMP-1(+) cells have high levels of CD40 expression. To determine whether TIMP-1 is directly involved in the BL phenotype, an EBV-negative BL line JD38 was infected with timp-1-expressing retrovirus and analyzed. In the absence of EBV, upregulation of TIMP-1 is sufficient to induce the same phenotype seen in TIMP-1(+), EBV+ BL lines (CD10(-), CD38(-), sIg(-), CD77(-), CD23(+), CD40 bright). This study not only suggests a role for TIMP-1 in BLs, but also supports its value as a prognostic factor. C1 NCI, Hematopathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Stetler-Stevenson, M (reprint author), NCI, Hematopathol Sect, Pathol Lab, NIH, Bldg 10,Rm 2A33, Bethesda, MD 20892 USA. RI Guedez, Liliana/H-4951-2012 NR 46 TC 122 Z9 126 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 1998 VL 92 IS 4 BP 1342 EP 1349 PG 8 WC Hematology SC Hematology GA 109MR UT WOS:000075326800030 PM 9694723 ER PT J AU Torti, SV Torti, FM Whitman, SP Brechbiel, MW Park, G Planalp, RP AF Torti, SV Torti, FM Whitman, SP Brechbiel, MW Park, G Planalp, RP TI Tumor cell cytotoxicity of a novel metal chelator SO BLOOD LA English DT Article ID PYRIDOXAL ISONICOTINOYL HYDRAZONE; SUBUNIT MESSENGER-RNAS; TRANSFERRIN RECEPTOR; HEAVY-SUBUNIT; IRON; DEFEROXAMINE; GROWTH; PROLIFERATION; TRANSLATION; INHIBITION AB We have synthesized a novel six-coordinate metal chelator from the triamine cis-1,3,5-triaminocyclohexane by the addition of a 2-pyridylmethyl pendant arm on each nitrogen, which we term tachpyr. The experiments described here were designed to explore whether this compound exhibits potential antitumor activity When added to MBT2 or T24 cultured bladder cancer cells, tachpyr was profoundly cytotoxic, with an IC50 of approximately 4.6 mu mol/L compared with 70 mu mol/L for desferioxamine. To explore the mode of action of tachpyr, several metal complexes were prepared, including Fe(II), Ca(II), Mn(II), Mg(II), Cu(II), and Zn(II) tachpyr complexes. Of these, the Zn(II), Cu(II), and Fe(II) complexes were without toxic effect, whereas the Ca(II), Mn(II), and Mg(ll) complexes remained cytotoxic. To further probe the role of Zn(II) and Cu(II) chelation in the cytotoxicity of tachpyr, sterically hindered tachpyr derivatives were prepared through N-alkylation of tachpyr. These derivatives were unable to strongly bind Fe(III) or Fe(II) but were able to bind Zn(II) and Cu(II). When added to cells, these sterically hindered tachpyr derivatives were nontoxic, consistent with a role of iron depletion in the cytotoxic mechanism of tachpyr. Further, the addition of tachpyr to proliferating cultures resulted in an early and selective inhibition of ferritin synthesis, an iron storage protein whose translation is critically dependent on intracellular iron pools. Taken together, these experiments suggest that tachpyr is a cytotoxic metal chelator that targets intracellular iron, and that the use of tachpyr in cancer therapy deserves further exploration. (C) 1998 by The American Society of Hematology. C1 Wake Forest Univ, Bowman Gray Sch Med, Dept Biochem, Winston Salem, NC 27157 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Canc Biol, Winston Salem, NC 27157 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Winston Salem, NC 27157 USA. Wake Forest Univ, Ctr Comprehens Canc, Winston Salem, NC 27157 USA. NIH, Radiat Oncol Branch, Bethesda, MD 20892 USA. Univ New Hampshire, Dept Chem, Durham, NH 03824 USA. RP Torti, SV (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Biochem, Med Ctr Blvd, Winston Salem, NC 27157 USA. FU NIDDK NIH HHS [DK 42412, DK42412-09S1] NR 30 TC 86 Z9 87 U1 3 U2 9 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 1998 VL 92 IS 4 BP 1384 EP 1389 PG 6 WC Hematology SC Hematology GA 109MR UT WOS:000075326800034 PM 9694727 ER PT J AU Kammula, US White, DE Rosenberg, SA AF Kammula, US White, DE Rosenberg, SA TI Trends in the safety of high dose bolus interleukin-2 administration in patients with metastatic cancer SO CANCER LA English DT Article DE immunotherapy; interleukin-2; safety; toxicity; renal cell cancer; melanoma ID ACTIVATED KILLER-CELLS; PROSPECTIVE RANDOMIZED TRIAL; 199 CONSECUTIVE PATIENTS; RECOMBINANT INTERLEUKIN-2; IMMUNOTHERAPY; MELANOMA; CARCINOMA; TOXICITY; THERAPY AB BACKGROUND. Administration of recombinant high dose interleukin-2 (IL-2) can mediate tumor regression in patients with metastatic melanoma and renal carcinoma. Significant trends in the safety of high dose IL-2 administration at a single institution over a 12-year study period were reviewed. METHODS. A consecutive series of 1241 metastatic cancer patients treated with intravenous bolus infusions of IL-2 (720,000 IU/kg every 8 hours) were evaluated for the incidence of specific treatment-related toxicities, the maximum number of administered IL-2 doses, and objective response rates. RESULTS. Significant decreases in the incidence of Grade 3 and/or Grade 4 toxicities were found when the initial group of 155 patients was compared with the final group: Grade 3/4 line sepsis (18% vs. 4%), Grade 314 diarrhea (92% vs. 12%), Grade 4 neuropsychiatric toxicity (19% vs. 8%), pulmonary intubations (12% vs. 3%), Grade 314 hypotension (81% vs. 31%), and Grade 4 cardiac ischemia (3% vs. 0%). No treatment-related deaths were noted in the final 809 patients. Laboratory abnormalities, such as increased creatinine, hyperbilirubinemia, and thrombocytopenia, were less severe, whereas percent weight gain remained stable over the 12-year period. The maximum number of administered IL-2 doses during the first cycle of therapy decreased from an initial median of 13 doses to 7 doses per first treatment cycle. No significant differences in overall and ongoing complete response rates to high dose bolus IL-2 were observed for melanoma patients (two-tailed P value = 0.40 and 1.0, respectively), or renal carcinoma patients (two-tailed P value = 0.92 and 0.89, respectively) over the study period. CONCLUSIONS. Progressive reduction in morbidity and mortality was found with the systemic administration of high dose IL-2-based therapies over the 12-year study period, The improvement in safety most likely reflects the development of strategies to screen eligible patients, optimize therapeutic conditions, and judiciously terminate dosing when significant toxicities are noted. Despite these interventions, the overall and onging complete response rates for melanoma and renal carcinoma have not shown significant compromise. These trends suggest that high dose IL-2 can be safely administered to metastatic cancer patients under the current treatment guidelines and result in durable responses in a small subset of patients. Cancer 1998;83:797-805. (C) 1998 American Cancer Society. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, NIH, Bldg 10,Room 2B42,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 26 TC 107 Z9 108 U1 1 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER JI Cancer PD AUG 15 PY 1998 VL 83 IS 4 BP 797 EP 805 DI 10.1002/(SICI)1097-0142(19980815)83:4<797::AID-CNCR25>3.0.CO;2-M PG 9 WC Oncology SC Oncology GA 107QV UT WOS:000075221500025 PM 9708948 ER PT J AU Wang, RF Wang, X Johnston, SL Zeng, G Robbins, PF Rosenberg, SA AF Wang, RF Wang, X Johnston, SL Zeng, G Robbins, PF Rosenberg, SA TI Development of a retrovirus-based complementary DNA expression system for the cloning of tumor antigens SO CANCER RESEARCH LA English DT Article ID T-LYMPHOCYTES; HIGH-TITER; RAPID PRODUCTION; GENE-EXPRESSION; IDENTIFICATION; LIBRARIES; VECTORS; MELANOMA; THERAPY AB A new retroviral system has been developed for the generation of a cDNA library and the functional cloning of tumor antigens, These retroviral vectors contain a cytomegalovirus promoter in the 5' long terminal repeat, an extended packaging signal for rapid production of high-titer retroviral particles, and many convenient cloning sites for cDNA library construction. The vesicular stomatitis virus G protein has been used to generate pseudotype retroviral particles to enable efficient viral infection. Using this system, viral titers in the range of 10(6) colony-forming units/ml could be generated routinely, and a high transduction efficiency in human primary cells, including fibroblasts, was achieved. In addition, a new procedure has been devised for screening a retrovirus-based cDNA library without a functional selection. The utility of this system was demonstrated by constructing a retrovirus-based cDNA Library and re-isolating the NY-ESO-I tumor antigen from a cDNA library using an antigen-specific CTL. This approach can facilitate the identification of novel tumor antigens recognized by T cells without knowledge of MHC class I restriction elements and is generally applicable for the isolation of any gene as long as a biological assay is available. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Wang, RF (reprint author), NCI, Surg Branch, NIH, Bldg 10,2B42,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 29 TC 34 Z9 36 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 AUG 15 PY 1998 VL 58 IS 16 BP 3519 EP 3525 PG 7 WC Oncology SC Oncology GA 112EU UT WOS:000075481800008 PM 9721852 ER PT J AU Wang, JX Otsuki, T Youssoufian, H Lo ten Foe, J Kim, S Devetten, M Yu, JM Li, YL Dunn, D Liu, JM AF Wang, JX Otsuki, T Youssoufian, H Lo ten Foe, J Kim, S Devetten, M Yu, JM Li, YL Dunn, D Liu, JM TI Overexpression of the Fanconi anemia group C gene (FAC) protects hematopoietic progenitors from death induced by Fas-mediated apoptosis SO CANCER RESEARCH LA English DT Article ID IN-VITRO; INTERFERON-GAMMA; CELL-LINES; COMPLEMENTATION; EXPRESSION; SUPPRESSION; POLYPEPTIDE; PROTEINS; RECEPTOR; COMPLEX AB Fanconi anemia is a rare, inherited disorder characterized by hone marrow failure, congenital malformations, and cancer susceptibility. The group C Fanconi anemia gene, FAG, identified by expression cloning methods, encodes a protein of unknown function that may he involved in the response to apoptotic stimuli. Hematopoietic progenitor cells from Fac knock-out mice are hypersensitive to IFN-gamma, a molecule that can induce apoptosis through up-regulation of the Pas death receptor. Sn this study, we used FAC-overexpressing transgenic mice to examine the relationship between PAC and Pas-triggered cell death. Hematopoietic progenitors from FAC-transgenic mice mere up to 10-fold less sensitive to the cytolytic effect of Fas-ligation. Our experiments implicate FAC in the regulation of apoptosis mediated by the Pas death receptor. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. Free Univ Amsterdam, NL-1081 BT Amsterdam, Netherlands. Brigham & Womens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. RP Liu, JM (reprint author), NHLBI, Hematol Branch, NIH, 10-ACRF-7C103, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [HL52138] NR 20 TC 35 Z9 35 U1 1 U2 1 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 AUG 15 PY 1998 VL 58 IS 16 BP 3538 EP 3541 PG 4 WC Oncology SC Oncology GA 112EU UT WOS:000075481800012 PM 9721856 ER PT J AU Vaisman, A Varchenko, M Umar, A Kunkel, TA Risinger, JI Barrett, JC Hamilton, TC Chaney, SG AF Vaisman, A Varchenko, M Umar, A Kunkel, TA Risinger, JI Barrett, JC Hamilton, TC Chaney, SG TI The role of hMLH1, hMSH3, and hMSH6 defects in cisplatin and oxaliplatin resistance: Correlation with replicative bypass of platinum-DNA adducts SO CANCER RESEARCH LA English DT Article ID HUMAN MISMATCH REPAIR; OVARIAN-CANCER CELLS; TUMOR-CELLS; MICROSATELLITE INSTABILITY; POLYMERASE-DELTA; DRUG-RESISTANCE; MAMMALIAN-CELLS; EXCISION-REPAIR; CARRIER-LIGAND; IN-VITRO AB Defects in mismatch repair are associated with cisplatin resistance, and several mechanisms have been proposed to explain this correlation. It is hypothesized that futile cycles of translesion synthesis past cisplatin-DNA adducts followed by removal of the newly synthesized DNA by an active mismatch repair system may lead to cell death. Thus, resistance to platinum-DNA adducts could arise through loss of the mismatch repair pathway. However, no direct link between mismatch repair status and replicative bypass ability has been reported. In this study, cytotoxicity and steady-state chain elongation assays indicate that hMLH1 or hMSH6 defects result in 1.5-4.8-fold increased cisplatin resistance and 2.5-6-fold increased replicative bypass of cisplatin adducts, Oxaliplatin adducts are not recognized by the mismatch repair complex, and no significant differences in bypass of oxaliplatin adducts in mismatch repair-proficient and -defective cells were found, Defects in hMSH3 did not alter sensitivity to, or replicative bypass of, either cisplatin or oxaliplatin adducts, These observations support the hypothesis that mismatch repair defects in hMutL alpha and hMutS alpha, but not in hMutS beta, contribute to increased net replicative bypass of cisplatin adducts and therefore to drug resistance by preventing futile cycles of translesion synthesis and mismatch correction. C1 Univ N Carolina, Dept Biochem & Biophys, Lineberger Comprehens Canc Ctr, Curriculum Genet & Mol Biol,Sch Med, Chapel Hill, NC 27599 USA. NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. Fox Chase Canc Ctr, Dept Med Oncol, Philadelphia, PA 19111 USA. RP Chaney, SG (reprint author), Univ N Carolina, Dept Biochem & Biophys, Lineberger Comprehens Canc Ctr, Curriculum Genet & Mol Biol,Sch Med, 515 Mary Ellen Jones Bldg, Chapel Hill, NC 27599 USA. RI Vaisman, Alexandra/C-3766-2013 OI Vaisman, Alexandra/0000-0002-2521-1467 FU NCI NIH HHS [CA34082] NR 43 TC 224 Z9 231 U1 0 U2 8 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 AUG 15 PY 1998 VL 58 IS 16 BP 3579 EP 3585 PG 7 WC Oncology SC Oncology GA 112EU UT WOS:000075481800020 PM 9721864 ER PT J AU Ramljak, D Jones, AB Diwan, BA Perantoni, AO Hochadel, JF Anderson, LM AF Ramljak, D Jones, AB Diwan, BA Perantoni, AO Hochadel, JF Anderson, LM TI Epidermal growth factor and transforming growth factor-alpha-associated overexpression of cyclin D1, Cdk4, and c-Myc during hepatocarcinogenesis in Helicobacter hepaticus-infected A/JCr mice SO CANCER RESEARCH LA English DT Article ID TRANSGENIC MOUSE MODEL; SIGNAL-TRANSDUCTION; LIVER-REGENERATION; RESTRICTION POINT; CELL-CYCLE; IN-VITRO; EXPRESSION; GENE; AMPLIFICATION; G(1) AB Helicobacter hepaticus is a new bacterial species that is homologous to Helicobacter pylori, a human gastric carcinogen. H. hepaticus causes chronic active hepatitis, with progression to hepatocellular tumors. We hypothesized that chronic up-regulation of epidermal growth factor (EGF), transforming growth factor-alpha, and nuclear oncogenes (cyclin D1 and c-Myc), all known to transform by overexpression, might contribute to tumorigenesis. Livers from mice that were 6-18 months old mere analyzed, including nonneoplastic and preneoplastic tissues and turners, along with age-matched controls, by immunohistochemistry and immunoblotting. EGF and transforming growth factor-cr mere increased at the earliest stage, with a further increase in EGF in tumors. Cyclin D1, cyclin-dependent kinase 4, and c-Myc were strongly increased in all infected livers, with even greater increases in tumors. An increase in cyclin D1/cyclin-dependent kinase 4 complex was also demonstrated in tumors, and its functionality mas confirmed by an increase in the hyperphosphorylated:hypophosphorylated retinoblastoma protein ratio. Our findings suggest a possible cooperation of growth factors, cell cycle proteins, and transcription factors during the development of H. hepaticus-associated liver tumors and may have relevance to human cancers associated with bacterial, viral, or parasitic infections. C1 NCI, Frederick Canc Res & Dev Ctr, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21702 USA. RP Ramljak, D (reprint author), NCI, Frederick Canc Res & Dev Ctr, Comparat Carcinogenesis Lab, Bldg 538,Room 206, Frederick, MD 21702 USA. EM ramljak@mail.nfifcrf.gov NR 40 TC 17 Z9 19 U1 1 U2 2 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 AUG 15 PY 1998 VL 58 IS 16 BP 3590 EP 3597 PG 8 WC Oncology SC Oncology GA 112EU UT WOS:000075481800022 PM 9721866 ER PT J AU Taylor, JA Umbach, DM Stephens, E Castranio, T Paulson, D Robertson, C Mohler, JL Bell, DA AF Taylor, JA Umbach, DM Stephens, E Castranio, T Paulson, D Robertson, C Mohler, JL Bell, DA TI The role of N-acetylation polymorphisms in smoking-associated bladder cancer: Evidence of a gene-gene-exposure three-way interaction SO CANCER RESEARCH LA English DT Article ID N-ACETYLTRANSFERASE-1 NAT1; ACETYLTRANSFERASE; PHENOTYPES; BENZIDINE; GENOTYPE; RISK; SUSCEPTIBILITY; CARCINOGENS; ACTIVATION; WORKERS AB Arylamines are known bladder carcinogens and are an important constituent of tobacco smoke. The handling of arylamines in the body is complex and includes metabolism by NAT1 and NAT2, enzymes that play a role in both activation and detoxification of arylamines and their congeners. Both NAT1 and NAT2 are polymorphic, with alleles that have been shown to correlate with higher or lower enzyme activity. To explore the combined role of these genes and exposure on bladder cancer risk, we examined the NAT1 and NAT2 genotype in a case-control study of bladder cancer in which detailed exposure histories were available on all 230 cases and 203 frequency-matched controls. Using PCR-RFLP genotyping, we determined NAT2 genotype for the five most common alleles, NAT2*4, NAT2*5, NAT2*6, NAT2*7, NAT2*14 (frequently referred to as WT, M1, M2, M3, and M4, respectively). Similarly, the NAT1 genotype was determined for the four most common alleles NAT1*3, NAT1*4 and NAT1*11, and the putative high-activity allele, NAT1*10, No association between NAT2 genotype and bladder cancer risk was found whether genotype was considered alone or in combination with smoking, in either stratified or logistic regression analysis that adjusted for age, sex, and race. Stratified and logistic regression analysis both demonstrated an increased risk for individuals carrying the NAT1*10 allele among smokers. There was evidence of a gene-dosage effect, such that those who were homozygous for the NAT1*10 allele had the highest risks. There was also evidence of a statistically significant gene-environment interaction, such that bladder cancer risk depends on both NAT1 genotype and smoking exposure. Interestingly, although NAT2 genotype did not influence risk either alone or in combination with smoking exposure, there was evidence of a statistically significant gene-gene-environment three-way interaction. Bladder cancer risk from smoking exposure is particularly high in those who inherit NAT2 slow alleles in combination with one or two copies of the NAT1*10 allele. A biological mechanism for this finding is suggested. C1 NIEHS, Mol & Genet Epidemiol Sect, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Computat Biol & Risk Anal, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. Univ N Carolina, Dept Surg, Div Urol, Chapel Hill, NC 27599 USA. RP Taylor, JA (reprint author), NIEHS, Mol & Genet Epidemiol Sect, Epidemiol Branch, Mail Drop A3-05,POB 12233, Res Triangle Pk, NC 27709 USA. EM taylor@niehs.nih.gov OI taylor, jack/0000-0001-5303-6398 NR 29 TC 124 Z9 127 U1 2 U2 5 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 AUG 15 PY 1998 VL 58 IS 16 BP 3603 EP 3610 PG 8 WC Oncology SC Oncology GA 112EU UT WOS:000075481800024 PM 9721868 ER PT J AU Husain, SR Behari, N Kreitman, RJ Pastan, I Puri, RK AF Husain, SR Behari, N Kreitman, RJ Pastan, I Puri, RK TI Complete regression of established human glioblastoma tumor xenograft by interleukin-4 toxin therapy SO CANCER RESEARCH LA English DT Article ID CIRCULARLY PERMUTED INTERLEUKIN-4; KAPOSIS-SARCOMA CELLS; PSEUDOMONAS EXOTOXIN; CHIMERIC PROTEIN; FUSION PROTEIN; RECEPTOR; MULTIFORME; CARCINOMA; EFFICACY; GLIOMAS AB No curative therapy is available for malignant gliomas, We have discovered that human glioblastoma cells express high affinity interleukin-4 receptor (IL-4R), which is an attractive target for receptor-directed IL-4 toxin therapy. The IL-4 toxin, IL-4(38-37)-PE38KDEL, is a fusion protein containing translocation and enzymatic domains of Pseudomonas exotoxin and a circularly permuted human IL-4. The IL-4 toxin binds specifically to the IL-4R and is highly cytotoxic to glioblastoma cells, as determined by clonogenic and protein synthesis inhibition assays. Intratumoral administration of the IL-4 toxin given on alternate days for 3-4 doses into U251 glioblastoma flank tumors in nude mice, showed a complete remission of small (similar to 13 mm(3)) and large (similar to 60 mm(3)) tumors in all animals, without any evidence of toxicity. A significant antitumor activity was also observed when the IL-4 toxin was administered via i.p. and i.v. routes. These results demonstrate that the IL-4 toxin may be a new therapeutic drug for the treatment of human glioblastoma, Therefore, we have begun a Phase I clinical trial with IL-4(38-37)-PE38KDEL for treatment of human glioblastoma. C1 NIH, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res,Food & Drug Adm, Bethesda, MD 20892 USA. NCI, Mol Biol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Puri, RK (reprint author), NIH, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res,Food & Drug Adm, Bldg 29B,Room 2NN10,29 Lincoln Dr MSC 4555, Bethesda, MD 20892 USA. EM Puri@A1.CBER.FDA.GOV NR 22 TC 63 Z9 65 U1 0 U2 2 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 AUG 15 PY 1998 VL 58 IS 16 BP 3649 EP 3653 PG 5 WC Oncology SC Oncology GA 112EU UT WOS:000075481800030 PM 9721874 ER PT J AU Chen, Z Colon, I Ortiz, N Callister, M Dong, G Pegram, MY Arosarena, O Strome, S Nicholson, JC Van Waes, C AF Chen, Z Colon, I Ortiz, N Callister, M Dong, G Pegram, MY Arosarena, O Strome, S Nicholson, JC Van Waes, C TI Effects of interleukin-1 alpha, interleukin-1 receptor antagonist, and neutralizing antibody on proinflammatory cytokine expression by human squamous cell carcinoma lines SO CANCER RESEARCH LA English DT Article ID COLONY-STIMULATING FACTOR; MELANOMA-CELLS; NUDE-MICE; HEAD; NECK; TUMOR; CANCER; INHIBITION; PROLIFERATION; ANGIOGENESIS AB Proinflammatory cytokines interleukin (IL)-1 alpha, IL-6, IL-8, and granulocyte macrophage colony-stimulating factor (GM-CSF) have been detected in tumor specimens and primary cell cultures from patients with head and neck squamous cell carcinoma. IL-1 alpha has been reported to play an important role in inducing the expression of cytokines IL-6, IL-8, and GM-CSF during inflammation. We examined whether these cytokines are expressed together in Five primary and seven established UM-SCC cell lines, and we also examined the effects of IL-1 alpha, IL-1 receptor antagonist or neutralizing antibody (Ab) upon expression of this repertoire of proinflammatory cytokines in established UM-SCC lines. Secretion of proinflammatory cytokines IL-1 alpha, IL-6, IL-8, and GM-CSF was detected by ELISA in both the primary and established UM-SCC lines, Constitutive expression of specific mRNAs for these cytokines was confirmed in the UM-SCC lines by reverse transcriptase-PCR and Northern blot analysis, Addition of recombinant IE (rIL)-1 alpha but not rIL-6 induced a dose-dependent increase in IL-8 and GM-CSF production, IL-1 receptor antagonist (IL-RA) or anti-IL-1 neutralizing Ab could completely inhibit the rIL-1 alpha-inducible increase in IL-8 and GM-CSF expression, hut the inhibitors had a negligible effect on the constitutive Level of production of the cytokines,Transfer and expression of the IL-1 alpha gene in a low-cytokine-producing cell Line, UM-SCC-38, induced IL-8 and GM-CSP expression, but this expression was also not inhibited by IL-1RA or anti-IL-1 neutralizing Ab, We conclude that IL-1 alpha can enhance the expression of cytokines IL-8 and GM-CSF in UM-SCC cell lines but that constitutive expression of these cytokines by UM-SCC is not inhibited by exogenous IL-1RA or neutralizing Ab. C1 Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, Tumor Biol Sect, NIH, Bethesda, MD 20892 USA. Howard Hughes Med Inst, Bethesda, MD 20817 USA. Univ Michigan, Dept Otolaryngol Head & Neck Surg, Ann Arbor, MI 48109 USA. Natl Naval Med Ctr, Bethesda, MD 20889 USA. RP Van Waes, C (reprint author), Bldg 10,Room 5D55,MSC-1419, Bethesda, MD 20892 USA. FU NIDCD NIH HHS [Z01-DC-00016] NR 35 TC 63 Z9 63 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 AUG 15 PY 1998 VL 58 IS 16 BP 3668 EP 3676 PG 9 WC Oncology SC Oncology GA 112EU UT WOS:000075481800033 PM 9721877 ER PT J AU Chung, DC Brown, SB Graeme-Cook, F Tillotson, LG Warshaw, AL Jensen, RT Arnold, A AF Chung, DC Brown, SB Graeme-Cook, F Tillotson, LG Warshaw, AL Jensen, RT Arnold, A TI Localization of putative tumor suppressor loci by genome-wide allelotyping in human pancreatic endocrine tumors SO CANCER RESEARCH LA English DT Article ID PARATHYROID ADENOMAS; SOMATIC MUTATIONS; TRANSGENIC MICE; P53 MUTATIONS; FREQUENT LOSS; RAS ONCOGENE; GENE; DNA; ADENOCARCINOMA; TUMORIGENESIS AB Only two tumor suppressor gene loci, one on 3p25 and the MEN1 gene on 11q13, have thus far been implicated in the pathogenesis of sporadic human pancreatic endocrine tumors (PETs), A genome-wide allelotyping study of 28 human PETs was undertaken to identify other potential tumor suppressor gene loci. In addition to those on chromosomes 3p and 11q, frequent allelic deletions were identified on 3q (32%), 11p (36%), 16p (36%), and 22q (29%). Finer deletion mapping studies localized the smallest regions of common deletion to 3q27, 11p13, and 16p12.3-13.11. Potential candidate genes at these loci include WT1 (11p13), TSC2 (16p13), and NF2 (22q12), but no known tumor suppressor gene localizes to 3q27, The mean fractional allelic loss among these human PETs is 0.126, and no correlation was observed between allelic loss and clinical parameters, including age, sea, hormonal subtype, and disease stage. These findings highlight novel locations of tumor suppressor gene Loci that contribute to the pathogenesis of human PETs, and several of these on 3p, 3q, and 22q are syntenic with loci on mouse chromosomes 9 and 16 that are implicated in a murine transgenic model of PETs. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Lab Endocrine Oncol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA 02114 USA. Univ N Carolina, Div Digest Dis, Chapel Hill, NC 27599 USA. NIH, Digest Dis Branch, Bethesda, MD 20892 USA. RP Chung, DC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, GRJ 823,32 Fruit St, Boston, MA 02114 USA. FU NIDDK NIH HHS [DK01410-11] NR 35 TC 70 Z9 72 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 AUG 15 PY 1998 VL 58 IS 16 BP 3706 EP 3711 PG 6 WC Oncology SC Oncology GA 112EU UT WOS:000075481800038 PM 9721882 ER PT J AU Nicholson, JKA Stetler-Stevenson, M AF Nicholson, JKA Stetler-Stevenson, M TI Quantitative fluorescence: To count or not to count. Is that the question? SO CYTOMETRY LA English DT Editorial Material ID CANADIAN CONSENSUS RECOMMENDATIONS; IMMUNOPHENOTYPIC ANALYSIS; HEMATOLOGIC NEOPLASIA; FLOW-CYTOMETRY C1 Ctr Dis Control & Prevent, Div AIDS STD & TB Lab Res, Natl Ctr Infect Dis, Atlanta, GA 30333 USA. NCI, Dept Pathol, Div Clin Sci, Flow Cytometry Unit, Bethesda, MD 20892 USA. RP Nicholson, JKA (reprint author), 1-1202 A25,1600 Clifton Rd NE, Atlanta, GA 30333 USA. NR 6 TC 3 Z9 3 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 0196-4763 J9 CYTOMETRY JI Cytometry PD AUG 15 PY 1998 VL 34 IS 4 BP 203 EP 204 DI 10.1002/(SICI)1097-0320(19980815)34:4<203::AID-CYTO5>3.0.CO;2-G PG 2 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 111JU UT WOS:000075434200005 PM 9725461 ER PT J AU Kim, HS Swierczynski, SL Tuttle, JS Lai, WS Blackshear, PJ AF Kim, HS Swierczynski, SL Tuttle, JS Lai, WS Blackshear, PJ TI Transgenic complementation of MARCKS deficiency with a nonmyristoylatable, pseudo-phosphorylated form of MARCKS: Evidence for simultaneous positive and dominant-negative effects on central nervous system development SO DEVELOPMENTAL BIOLOGY LA English DT Article ID PROTEIN-KINASE-C; ABNORMAL BRAIN-DEVELOPMENT; MEMBRANE ASSOCIATION; MICE; CALMODULIN; SUBSTRATE; DEFECTS; BINDING; CELLS; EXPRESSION AB MARCKS is a widely expressed protein kinase C substrate that is essential for normal prenatal development of the central nervous system in mice. MARCKS-deficient mice exhibit universal perinatal mortality and numerous developmental abnormalities of the brain and retina. To determine which domains of the protein were important in complementing these neurodevelopmental anomalies, we have interbred MARCKS knockout mice with transgenic mice expressing an epitope-tagged human MARCKS transgene that can completely correct the MARCKS-deficient phenotype. Previous structure-function studies showed that a nonmyristoylatable form of MARCKS could correct all of the neuroanatomical abnormalities, and resulted in approximately 25% viable pups that grew to adulthood and were fertile. The present experiment attempted a similar complementation strategy in which a nonmyristoylatable, "pseudo-phosphorylated" form of the protein was used, which has been shown to be almost completely cytosolic in cell expression studies. Surprisingly, this transgene was able to complement almost all of the cerebral anatomical abnormalities characteristic of the knockout mice. However, these mice also exhibited a universal, novel phenotype: profound retinal ectopia, in which retinal tissue was often found in the vitreous humor as well as extraocularly. Retrospective evaluation of the original MARCKS knockout phenotype revealed that this anomaly was present in about 43% of the knockout mice, and was clearly detectable as early as embryonic day 12.5, before retinal cell differentiation begins. These data suggest that a nonmyristoylatable, pseudo-phosphorylated form of MARCKS can complement most if not all cerebral aspects of the MARCKS-deficient phenotype, but that it appears to worsen a retinal phenotype, perhaps by exerting a dominant-negative effect on a coexpressed MARCKS homologue. (C) 1998 Academic Press. C1 NIEHS, Off Clin Res, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Signal Transduct, 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, POB 12233, Res Triangle Pk, NC 27709 USA. NR 30 TC 10 Z9 10 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD AUG 15 PY 1998 VL 200 IS 2 BP 146 EP 157 DI 10.1006/dbio.1998.8952 PG 12 WC Developmental Biology SC Developmental Biology GA 117RK UT WOS:000075795400002 PM 9705223 ER PT J AU Robles, AI Rodriguez-Puebla, ML Glick, AB Trempus, C Hansen, L Sicinski, P Tennant, RW Weinberg, RA Yuspa, SH Conti, CJ AF Robles, AI Rodriguez-Puebla, ML Glick, AB Trempus, C Hansen, L Sicinski, P Tennant, RW Weinberg, RA Yuspa, SH Conti, CJ TI Reduced skin tumor development in cyclin D1-deficient mice highlights the oncogenic ras pathway in vivo SO GENES & DEVELOPMENT LA English DT Article DE knockout; Tg.AC; cell cycle; keratinocyte; two-stage carcinogenesis ID EPIDERMAL-KERATINOCYTES; D1 OVEREXPRESSION; LUNG-CANCER; CELL-LINES; MOUSE SKIN; EXPRESSION; P16(INK4); GROWTH; CARCINOGENESIS; TRANSFORMATION AB Cyclin D1 is part of a cell cycle control node consistently deregulated in most human cancers. However, studies with cyclin D1-null mice indicate that it is dispensable for normal mouse development as well as eel growth in culture. Here, rye provide evidence that ras-mediated tumorigenesis depends on signaling pathways that act preferentially through cyclin D1. Cyclin D1 expression and the activity of its associated kinase are up-regulated in keratinocytes in response to oncogenic ras. Furthermore, cyclin D1 deficiency results in up to an 80% decrease in the development of squamous tumors generated through either grafting of retroviral ras-transduced keratinocytes, phorbol ester treatment of ras transgenic mice, or two-stage carcinogenesis. C1 Univ Texas, MD Anderson Cancer Ctr, Sci Pk Res Div, Smithville, TX 78957 USA. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. NIEHS, Lab Environm Carcinogenesis & Mutagenesis, Res Triangle Pk, NC 27709 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. MIT, Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. MIT, Dept Biol, Cambridge, MA 02142 USA. RP Conti, CJ (reprint author), Univ Texas, MD Anderson Cancer Ctr, Sci Pk Res Div, Smithville, TX 78957 USA. EM SA83125@odin.mdacc.tmc.edu FU NCI NIH HHS [CA42157, R01 CA042157] NR 35 TC 181 Z9 184 U1 0 U2 0 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 AUG 15 PY 1998 VL 12 IS 16 BP 2469 EP 2474 DI 10.1101/gad.12.16.2469 PG 6 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 114JG UT WOS:000075604900003 PM 9716400 ER PT J AU Harfe, BD Gomes, AV Kenyon, C Liu, J Krause, M Fire, A AF Harfe, BD Gomes, AV Kenyon, C Liu, J Krause, M Fire, A TI Analysis of a Caenorhabditis elegans Twist homolog identifies conserved and divergent aspects of mesodermal patterning SO GENES & DEVELOPMENT LA English DT Article DE CeTwist; C-elegans; ceh-24; egl-15; mab-5; CeE/DA; NdE box ID C-ELEGANS; DROSOPHILA-TWIST; TRANSCRIPTION FACTOR; FGF-RECEPTOR; BODY REGION; GENE; EXPRESSION; SEQUENCE; PROTEIN; CELLS AB Mesodermal development is a multistep process in which cells become increasingly specialized to form specific tissue types. In Drosophila and mammals, proper segregation and patterning of the mesoderm involves the bHLH factor Twist. We investigated the activity of a Twist-related factor, CeTwist, during Caenorhabditis elegans mesoderm development. Embryonic mesoderm in C. elegans derives from a number of distinct founder cells that are specified during the early lineages! in contrast, a single blast cell (M) is responsible for all nongonadal mesoderm formation during postembryonic development. Using immunofluorescence and reporter fusions, we determined the activity pattern of the gene encoding CeTwist. No activity was observed during specification of mesodermal lineages in the early embryo; instead, the gene was active within the M lineage and in a number of mesodermal cells with nonstriated muscle fates. A role for CeTwist in postembryonic mesodermal cell fate specification was indicated by ectopic expression and genetic interference assays. These experiments showed that CeTwist was responsible for activating two target genes normally expressed in specific subsets of nonstriated muscles derived from the M lineage. In vitro and in vivo assays suggested that CeTwist cooperates with the C. elegans E/Daughterless homolog in directly activating these targets. The two target genes that we have studied, ceh-24 and eg1-15, encode an NK-2 class homeodomain and an FGF receptor (FGFR) homolog, respectively. Twist activates FGFR and NK-homeodomain target genes during mesodermal patterning of Drosophila and similar target interactions have been proposed to modulate mesenchymal growth during closure of the vertebrate skull. These results suggest the possibility that a conserved pathway may be used for diverse functions in mesodermal specification. C1 Carnegie Inst Washington, Dept Embryol, Baltimore, MD 21210 USA. Johns Hopkins Univ, Grad Program Biol, Baltimore, MD 21218 USA. NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA. RP Fire, A (reprint author), Carnegie Inst Washington, Dept Embryol, 115 W Univ Pkwy, Baltimore, MD 21210 USA. OI Krause, Michael/0000-0001-6127-3940 FU NICHD NIH HHS [F32 HD008331]; NIDDK NIH HHS [Z01 DK036117]; NIGMS NIH HHS [R01 GM037706, T32 GM007231, T32GM07231, R01GM37053, R01GM37706] NR 48 TC 122 Z9 134 U1 0 U2 3 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 AUG 15 PY 1998 VL 12 IS 16 BP 2623 EP 2635 DI 10.1101/gad.12.16.2623 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 114JG UT WOS:000075604900016 PM 9716413 ER PT J AU Schlessinger, D Ko, MSH AF Schlessinger, D Ko, MSH TI Developmental genomics and its relation to aging SO GENOMICS LA English DT Article ID GENE-EXPRESSION; MOUSE CELLS; STEM-CELLS; SENESCENCE; LONGEVITY; MUTATIONS; CHROMOSOME; PHENOTYPE; PROTEIN C1 NIA, Gerontol Res Ctr, Genet Lab, Baltimore, MD 21224 USA. RP Schlessinger, D (reprint author), NIA, Gerontol Res Ctr, Genet Lab, Box 31,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM SchlessingerD@grc.nia.nih.gov RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 NR 55 TC 6 Z9 6 U1 0 U2 1 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 AUG 15 PY 1998 VL 52 IS 1 BP 113 EP 118 DI 10.1006/geno.1998.5426 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 121TX UT WOS:000076031000017 PM 10348638 ER PT J AU Ghosh, S Hauser, ER Magnuson, VL Valle, T Ally, DS Karanjawala, ZE Rayman, JB Knapp, JI Musick, A Tannenbaum, J Te, C Eldridge, W Shapiro, S Musick, T Martin, C So, A Witt, A Harvan, JB Watanabe, RW Hagopian, W Eriksson, J Nylund, SJ Kohtamaki, K Tuomilehto-Wolf, E Toivanen, L Vidgren, G Ehnholm, C Bergman, RN Tuomilehto, J Collins, FS Boehnke, M AF Ghosh, S Hauser, ER Magnuson, VL Valle, T Ally, DS Karanjawala, ZE Rayman, JB Knapp, JI Musick, A Tannenbaum, J Te, C Eldridge, W Shapiro, S Musick, T Martin, C So, A Witt, A Harvan, JB Watanabe, RW Hagopian, W Eriksson, J Nylund, SJ Kohtamaki, K Tuomilehto-Wolf, E Toivanen, L Vidgren, G Ehnholm, C Bergman, RN Tuomilehto, J Collins, FS Boehnke, M TI A large sample of Finnish diabetic sib-pairs reveals no evidence for a non-insulin-dependent diabetes mellitus susceptibility locus at 2qter SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE gene mapping; affected sib-pairs; non-insulin-dependent diabetes mellitus fluorescent genotyping; linkage analysis ID LINKAGE ANALYSIS; MEXICAN-AMERICANS; COMPLEX TRAITS; CHROMOSOME 2Q; HUMAN GENOME; NIDDM; POPULATION; SECRETION; EXCLUSION; FAMILIES AB In the first reported positive result from a genome scan for non-insulin-dependent diabetes mellitus (NIDDM), Hanis et al. found significant evidence of linkage for NIDDM on chromosome 2q37 and named the putative disease locus NIDDM1 (Hanis et al. 1996. Nat. Genet. 13:161-166). Their total sample was comprised of 440 Mexican-American affected sib-pairs from 246 sibships. The strongest evidence for linkage was at marker D2S125 and best estimates of lambda(s) (risk to siblings of probands/population prevalence) using this marker were 1.37 under an additive model and 1.36 under a multiplicative model. We examined this chromosomal region using linkage analysis in a Finnish sample comprised of 709 affected sib-pairs from 472 sibships. We excluded this region in our sample (multipoint logarithm of odds score less than or equal to -2) for lambda(s) greater than or equal to 1.37. We discuss possible reasons why linkage to 2q37 was not found and conclude that this region is unlikely to be playing a major role in NIDDM susceptibility in the Finnish Caucasian population. C1 NIH, Genet & Mol Biol Branch, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. Natl Publ Hlth Inst, Diabet & Genet Epidemiol Unit, Dept Epidemiol & Hlth Promot, FIN-00300 Helsinki, Finland. Univ Washington, Dept Med, Seattle, WA 98195 USA. Univ So Calif, Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90033 USA. RP Ghosh, S (reprint author), NIH, Genet & Mol Biol Branch, Natl Human Genome Res Inst, Room 1W108,Bldg 9,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Addington, Anjene/C-3460-2008 FU NHGRI NIH HHS [T32 HG-00040, R01 HG-00376]; NIDDK NIH HHS [F32 DK-09525] NR 34 TC 20 Z9 24 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD AUG 15 PY 1998 VL 102 IS 4 BP 704 EP 709 DI 10.1172/JCI2512 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 113MX UT WOS:000075556500008 PM 9710438 ER PT J AU Ueda, H Howard, OMZ Grimm, MC Su, SB Gong, WH Evans, G Ruscetti, FW Oppenheim, JJ Wang, JM AF Ueda, H Howard, OMZ Grimm, MC Su, SB Gong, WH Evans, G Ruscetti, FW Oppenheim, JJ Wang, JM TI HIV-1 envelope gp41 is a potent inhibitor of chemoattractant receptor expression and function in monocytes SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE HIV-1; gp41; chemokines; receptors; suppression ID IMMUNODEFICIENCY-VIRUS TYPE-1; TUMOR-NECROSIS-FACTOR; MULTIPLE LEUKOCYTE RECEPTORS; PROTEIN-3 MCP3 INTERACTS; HUMAN CELL-LINES; CHEMOKINE RECEPTOR; MOLECULAR-CLONING; SIGNAL-TRANSDUCTION; FACTOR-ALPHA; CD4 LIGAND AB HIV-1 uses CD4 and chemokine receptors as cofactors for cellular entry. The viral envelope transmembrane protein gp41 is thought to participate in viral fusion with CD4(+) cells. We investigated whether gp41 interacts with chemokine receptors on human monocytes by testing its effect on the capacity of cells to respond to chemokine stimulation. Monocytes preincubated with gp41 of the MN strain showed markedly reduced binding, calcium mobilization, and chemotaxis in response to a variety of chemokines as well as to the bacterial peptide fMLP. This generalized inhibition of monocyte activation by chemoattractants required the presence of CD3, since the effect of gp41 was only observed in CD4(+) monocytes and in HEK293 cells cotransfected with chemokine receptors and an intact CD3, but not a CD4 lacking its cytoplasmic domain. Confocal microscopy showed that gp41 caused internalization of CXCR4 in HEK293 cells provided they were also cotransfected with intact CD4. In addition, pretreatment of monocytes with protein kinase C inhibitors partially reversed the inhibitory effect of gp41. Thus, gp41, which had not previously been implicated as interacting with HIV-1 fusion cofactors, downregulates chemoattractant receptors on monocytes by a CD4-dependent pathway. C1 NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Div Basic Sci, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Lab Leukocyte Biol, Div Basic Sci, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, AIDS Vaccine Program, SAIC Frederick, Frederick, MD 21702 USA. RP Wang, JM (reprint author), NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Div Basic Sci, Bldg 560,Room 31-40, Frederick, MD 21702 USA. EM wangji@mail.ncifcrf.gov RI Howard, O M Zack/B-6117-2012 OI Howard, O M Zack/0000-0002-0505-7052 NR 50 TC 24 Z9 24 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD AUG 15 PY 1998 VL 102 IS 4 BP 804 EP 812 DI 10.1172/JCI3273 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 113MX UT WOS:000075556500019 PM 9710449 ER PT J AU Deng, YP Gibbs, J Bacik, I Porgador, A Copeman, J Lehner, P Ortmann, B Cresswell, P Bennink, JR Yewdell, JW AF Deng, YP Gibbs, J Bacik, I Porgador, A Copeman, J Lehner, P Ortmann, B Cresswell, P Bennink, JR Yewdell, JW TI Assembly of MHC class I molecules with biosynthesized endoplasmic reticulum-targeted peptides is inefficient in insect cells and can be enhanced by protease inhibitors SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RECOMBINANT VACCINIA VIRUSES; HISTOCOMPATIBILITY COMPLEX-MOLECULES; CD8+ T-CELLS; INTRACELLULAR-TRANSPORT; ANTIGENIC PEPTIDES; LYMPHOCYTE-T; TAP; CALNEXIN; BINDING; BETA-2-MICROGLOBULIN AB To study the requirements for assembly of MHC class I molecules with antigenic peptides in the endoplasmic reticulum (ER), we studied Ag processing in insect cells. Insects lack a class I recognition system, and their cells therefore provide a "blank slate" for identifying the proteins that have evolved to facilitate assembly of class I molecules in vertebrate cells. H-2K(b) heavy chain, mouse beta(2)-microglobulin, and an ER-targeted version of a peptide corresponding to Ova(257-264) were expressed in insect cells using recombinant vaccinia viruses, Cell surface expression of K-b-OVA(257-264) complexes was quantitated using a recently described complex-specific mAb (25-D1.16), Relative to TAP deficient human cells, insect cells expressed comparable levels of native, peptide-receptive cell surface K-b molecules, but generated cell surface K-b-OVA(257-264) complexes at least 20-fold less efficiently from ER-targeted peptides. The inefficient assembly of K-b-OVA(257-264) complexes in the ER of insect cells cannot be attributed solely to a requirement for human tapasin, since first, human cells lacking tapasin expressed endogenously synthesized K-b-OVA(257-264) complexes at levels comparable to tapasin-expressing cells, and second, vaccinia virus-mediated expression of human tapasin in insect cells did not detectably enhance the expression of K-b-OVA(257-264) complexes, The assembly of K-b-OVA(257-264) complexes could be greatly enhanced in insect but not human cells by a nonproteasomal protease inhibitor, These findings indicate that insect cells lack one or more factors required for the efficient assembly of class I-peptide complexes in vertebrate cells and are consistent with the idea that the missing component acts to protect antigenic peptides or their immediate precursors from degradation. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Howard Hughes Med Inst, Immunobiol Sect, New Haven, CT 06510 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, NIH, Room 213,Bldg 4, Bethesda, MD 20892 USA. EM jbennink@nih.gov; jyewdell@nih.gov RI yewdell, jyewdell@nih.gov/A-1702-2012 NR 56 TC 14 Z9 14 U1 1 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 1998 VL 161 IS 4 BP 1677 EP 1685 PG 9 WC Immunology SC Immunology GA 109VV UT WOS:000075345400014 PM 9712031 ER PT J AU Ryan, JJ McReynolds, LJ Huang, H Nelms, K Paul, WE AF Ryan, JJ McReynolds, LJ Huang, H Nelms, K Paul, WE TI Characterization of a mobile Stat6 activation motif in the human IL-4 receptor SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MICE LACKING JAK3; INSULIN-RECEPTOR; INTERLEUKIN-4 RECEPTOR; CYTOKINE RECEPTORS; CELLS; PROTEIN; PHOSPHOTYROSINE; EXPRESSION; SUBSTRATE-1; RESPONSES AB The IL-4R induces proliferation and gene expression through the use of conserved tyrosine residues located in growth and gene regulation domains, respectively. We demonstrate that residues surrounding these conserved tyrosines (juxtatyrosine residues) are essential for the proper activation of the signaling molecules IRS-2 and Stat6, as well as for IL-4-induced gene expression. Further, we found that the IL-4R gene regulation domain (amino acids 557-657) contains a tyrosine-based sequence (EAGYKAF) that can convey Stat6 DNA binding and gene expression activities to a minimally active IL-4R mutant, Delta 557. Thus, this tyrosine-based sequence can function as a mobile Stat6 activation cassette. However, mutants bearing this sequence induced CD23 expression much less efficiently than did wild-type IL-4R, requiring 150-fold more IL-4 to reach maximal CD23 expression. Our results indicate the importance of juxtatyrosine residues in IL-4R signaling and argue for an essential role of extended domain structure in the recognition and function of juxtatyrosine sequences. C1 NIAID, Immunol Lab, Bethesda, MD 20892 USA. RP Ryan, JJ (reprint author), Virginia Commonwealth Univ, Dept Biol, Richmond, VA 23284 USA. NR 38 TC 27 Z9 29 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 1998 VL 161 IS 4 BP 1811 EP 1821 PG 11 WC Immunology SC Immunology GA 109VV UT WOS:000075345400031 PM 9712048 ER PT J AU Gilmore, EC Ohshima, T Goffinet, AM Kulkarni, AB Herrup, K AF Gilmore, EC Ohshima, T Goffinet, AM Kulkarni, AB Herrup, K TI Cyclin-dependent kinase 5-deficient mice demonstrate novel developmental arrest in cerebral cortex SO JOURNAL OF NEUROSCIENCE LA English DT Article DE neuronal migration; cdk5; reeler; cerebral cortical development; neuronal morphology; BrdU ID DIEKER LISSENCEPHALY GENE; CORTICAL DEVELOPMENT; EMBRYONIC MOUSE; PROTEIN-KINASE; REELER MICE; NEURONS; NEOCORTEX; NEUROGENESIS; EXPRESSION; ACTIVATOR AB The cerebral cortex of mice with a targeted disruption in the gene for cyclin-dependent kinase 5 (cdk5) is abnormal in its structure. Bromodeoxyuridine labeling reveals that the normal inside-out neurogenic gradient is inverted in the mutants; earlier born neurons are most often found superficial to those born later. Despite this, the early preplate layer separates correctly and neurons with a normal, pyramidal morphology can be found between true marginal zone and subplate. Consistent with their identity as layer VI corticothalamic neurons, they can be labeled by Dil injections into thalamus. The Dil injections also reveal that the trajectories of the cdk5(-/-) thalamocortical axons are oblique and cut across the entire cortical plate, instead of being oriented tangentially in the subcortical white matter. We propose a model in which the cdk5(-/-) defect blocks cortical development at a heretofore undescribed intermediate stage, after the splitting of the preplate, but before the migration of the full complement of cortical neurons. C1 Case Western Reserve Univ, Sch Med E504, Dept Neurosci, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Alzheimer Res Lab, Cleveland, OH 44106 USA. NINDS, NIH, Bethesda, MD 20892 USA. NIDR, Gene Targeting Res & Core Facil, NIH, Bethesda, MD 20892 USA. Fac Univ Notre Dame Paix, Dept Physiol, B-5000 Namur, Belgium. RP Gilmore, EC (reprint author), Case Western Reserve Univ, Sch Med E504, Dept Neurosci, 10900 Euclid Ave, Cleveland, OH 44106 USA. FU NINDS NIH HHS [NS20591] NR 44 TC 232 Z9 242 U1 1 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 15 PY 1998 VL 18 IS 16 BP 6370 EP 6377 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 108BQ UT WOS:000075246500029 PM 9698328 ER PT J AU Behar, TN Schaffner, AE Scott, CA O'Connell, C Jeffery, JL AF Behar, TN Schaffner, AE Scott, CA O'Connell, C Jeffery, JL TI Differential response of cortical plate and ventricular zone cells to GABA as a migration stimulus SO JOURNAL OF NEUROSCIENCE LA English DT Article DE development; chemotaxis; cortex; G-protein; depolarization; neuron; migration ID RAT SPINAL-CORD; NEURONAL MIGRATION; G-PROTEINS; CHEMOTAXIS; EXPRESSION; RECEPTORS; CALCIUM; CHEMOKINESIS; PROGENITORS; MECHANISMS AB A microdissection technique was used to separate differentiated cortical plate (cp) cells from immature ventricular zone cells (vz) in the rat embryonic cortex. The cp population contained >85% neurons (TUJ1(+)), whereas the vz population contained similar to 60% precursors (nestin(+) only). The chemotropic response of each population was analyzed in vitro, using an established microchemotaxis assay. Micromolar GABA (1-5 mu M) stimulated the motility of cp neurons expressing glutamic acid decarboxylase (GAD), the rate-limiting enzyme in GABA synthesis. In contrast, femtomolar GABA (500 fM) directed a subset of GAD(-) vz neurons to migrate. Thus, the two GABA concentrations evoked the motility of phenotypically distinct populations derived from different anatomical regions. Pertussis toxin (PTX) blocked GABA-induced migration, indicating that chemotropic signals involve G-protein activation. Depolarization by micromolar muscimol, elevated [K+](o), or micromolar glutamate arrested migration to GABA or GABA mimetics, indicating that migration is inhibited in the presence of excitatory stimuli, These results suggest that GABA, a single ligand, can promote motility via G-protein activation and arrest attractant-induced migration via GABA(A) receptor-mediated depolarization. C1 NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. RP NINDS, Neurophysiol Lab, NIH, Bldg 36,Room 2C02,36 Convent Dr, Bethesda, MD 20892 USA. NR 40 TC 151 Z9 153 U1 0 U2 5 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 AUG 15 PY 1998 VL 18 IS 16 BP 6378 EP 6387 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 108BQ UT WOS:000075246500030 PM 9698329 ER PT J AU Murray, EA Mishkin, M AF Murray, EA Mishkin, M TI Object recognition and location memory in monkeys with excitotoxic lesions of the amygdala and hippocampus SO JOURNAL OF NEUROSCIENCE LA English DT Article DE amygdala; hippocampus; limbic system; ibotenic acid; visual memory; delayed nonmatching-to-sample; spatial memory; recognition memory ID RHESUS-MONKEY; VISUAL RECOGNITION; PARAHIPPOCAMPAL CORTICES; CORTEX; IMPAIRMENT; CONNECTIONS; SEPARATE; ORGANIZATION; ABLATIONS; REMOVAL AB Earlier work indicated that combined but not separate removal of the amygdala and hippocampus, together with the cortex underlying these structures, leads to a severe impairment in visual recognition. More recent work, however, has shown that removal of the rhinal cortex, a region subjacent to the amygdala and rostral hippocampus, yields nearly the same impairment as the original removal. This raises the possibility that the earlier results were attributable to combined damage to the rostral and caudal portions of the rhinal cortex rather than to the combined amygdala and hippocampal removal. To test this possibility, we trained rhesus monkeys on delayed nonmatching-to-sample, a measure of visual recognition, gave them selective lesions of the amygdala and hippocampus made with the excitotoxin ibotenic acid, and then assessed their recognition abilities by using increasingly longer delays and list lengths, including delays as long as 40 min, Postoperatively, monkeys with the combined amygdala and hippocampal lesions performed as well as intact controls at every stage of testing, The same monkeys also were unimpaired relative to controls on an analogous test of spatial memory, delayed nonmatching-to-location. It is unlikely that unintended sparing of target structures can account for the lack of impairment; there was a significant positive correlation between the percentage of damage to the hippocampus and scores on portions of the recognition performance test, suggesting that, paradoxically, the greater the hippocampal damage, the better the recognition. The results show that, within the medial temporal lobe, the rhinal cortex is both necessary and sufficient for visual recognition. C1 NIMH, Neuropsychol Lab, Bethesda, MD 20892 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 48 TC 297 Z9 300 U1 0 U2 12 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 AUG 15 PY 1998 VL 18 IS 16 BP 6568 EP 6582 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 108BQ UT WOS:000075246500045 PM 9698344 ER PT J AU Ziemann, U Tergau, F Wassermann, EM Wischer, S Hildebrandt, J Paulus, W AF Ziemann, U Tergau, F Wassermann, EM Wischer, S Hildebrandt, J Paulus, W TI Demonstration of facilitatory I wave interaction in the human motor cortex by paired transcranial magnetic stimulation SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID CORTICOSPINAL DIRECT RESPONSE; ELECTRICAL-STIMULATION; VOLUNTARY CONTRACTION; SPINAL MOTONEURONS; BRAIN-STIMULATION; INHIBITION; EXCITABILITY; ACTIVATION; SURGERY; VOLLEYS AB 1. Transcranial magnetic stimulation (TMS) of the human motor cortex results in multiple discharges (D and I waves) in the corticospinal tract. We tested whether these volleys can be explored non-invasively with paired TMS. The intensity of the first stimulus (S1) was set to produce a motor-evoked potential (MEP) of 1 mV in the resting contralateral abductor digiti minimi (ADM) muscle; the second stimulus (S2) was set to 90% of the resting motor threshold. At interstimulus intervals of 1.1-1.5, 2.3-2.9 and 4.1-4.4 ms the MEP elicited by S1 plus S2 was larger than that produced by S1 alone. 2. Varying the S1 intensity between 70 and 130% resting motor threshold with S2 held constant at 90 % resting motor threshold showed that the threshold for the first MEP peak was less than or equal to 70% resting motor threshold. The second and third MEP peaks appeared only at higher S1 intensities. The latency of all peaks decreased with increasing S1 intensity. 3. Varying the S2 intensity with S1 held constant to produce a MEP of 1 mV on its own showed that the amplitude of all MEP peaks increased with S2 intensity, but that their timing remained unchanged. 4. Paired TMS in the active ADM (S1 clearly suprathreshold, SS just above threshold; interstimulus interval, 1 ms) produced strong MEP facilitation. The onset of this facilitation occurred later by about 1.5 ms than the onset of the MEP evoked by S2 alone. No MEP facilitation was seen if the magnetic S2 was replaced by anodal or cathodal transcranial electrical stimulation. 5. It is concluded that the MEP facilitation after paired TMS, at least for the first MEP peak, is due to facilitatory interaction between I waves, and takes place in the motor cortex at or upstream from the corticospinal neurone. C1 NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. Univ Gottingen, Dept Clin Neurophysiol, D-37075 Gottingen, Germany. RP Ziemann, U (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10,Room 5N242,10 Ctr Dr, Bethesda, MD 20892 USA. RI Paulus, Walter/A-3544-2009 OI Paulus, Walter/0000-0001-5549-8377 NR 37 TC 223 Z9 223 U1 1 U2 11 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 AUG 15 PY 1998 VL 511 IS 1 BP 181 EP 190 DI 10.1111/j.1469-7793.1998.181bi.x PG 10 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 121XD UT WOS:000076040400018 PM 9679173 ER PT J AU Hatanpaa, K Chandrasekaran, K Brady, DR Rapoport, SI AF Hatanpaa, K Chandrasekaran, K Brady, DR Rapoport, SI TI No association between Alzheimer plaques and decreased levels of cytochrome oxidase subunit mRNA, a marker of neuronal energy metabolism SO MOLECULAR BRAIN RESEARCH LA English DT Article DE amyloid beta-protein; cytochrome oxidase; immunohistochemistry; in situ hybridization; mitochondria; polyadenylated mRNA ID BETA-AMYLOID PROTEIN; NEUROFIBRILLARY TANGLES; SENILE PLAQUES; OXIDATIVE-PHOSPHORYLATION; DYSTROPHIC NEURITES; POSSIBLE MECHANISM; FIBRIL FORMATION; GENE-EXPRESSION; CEREBRAL-CORTEX; PC12 CELLS AB It has been proposed that neuritic plaques or toxic substances diffusing from them contribute to neurodegeneration in Alzheimer disease. We examined this hypothesis by looking for evidence of decreased neuronal energy metabolism in the proximity of neuritic plaques. Levels of mitochondrial DNA-encoded mRNA for subunit III of cytochrome oxidase, a marker of neuronal energy metabolism, were determined in post mortem brain samples. Consistent with earlier results, overall cytochrome oxidase subunit III mRNA levels were decreased in Alzheimer midtemporal cortex compared with controls. However, this reduction did not correlate with plaque density. In Alzheimer brains, cytochrome oxidase subunit III mRNA levels in neurons bearing neurofibrillary tangles were lower than in tangle-free neurons. However, neuronal cell bodies in close proximity of neuritic plaques showed no decrease in cytochrome oxidase subunit III mRNA or total polyadenylated mRNA compared with more distant neurons. Cytochrome oxidase enzyme activity in neuronal processes also showed no local reduction around neuritic plaques. These results suggest that neuritic plaques do not contribute to reduced neuronal energy metabolism in Alzheimer disease. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. RP Hatanpaa, K (reprint author), NIA, Neurosci Lab, NIH, Bldg 10,Rm 6C 103, Bethesda, MD 20892 USA. NR 62 TC 17 Z9 17 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD AUG 15 PY 1998 VL 59 IS 1 BP 13 EP 21 DI 10.1016/S0169-328X(98)00117-X PG 9 WC Neurosciences SC Neurosciences & Neurology GA 113NY UT WOS:000075559200002 ER PT J AU Lau, FC Abbott, LC Rhyu, IJ Kim, DS Chin, HM AF Lau, FC Abbott, LC Rhyu, IJ Kim, DS Chin, HM TI Expression of calcium channel alpha(1A) mRNA and protein in the leaner mouse (tg(la)/tg(la)) cerebellum SO MOLECULAR BRAIN RESEARCH LA English DT Article DE Purkinje cell; cerebellar granule cell; in situ hybridization histochemistry; immunocytochemistry; myoclonus; ataxia; ion channel mutation ID HYPOKALEMIC PERIODIC PARALYSIS; FAMILIAL HEMIPLEGIC MIGRAINE; BETA-GAMMA-SUBUNITS; CA2+ CHANNELS; TYROSINE-HYDROXYLASE; MUTANT MICE; TRANSMITTER RELEASE; PURKINJE-CELLS; RAT CEREBELLUM; N-TYPE AB Homozygous leaner mice carry an autosomal recessive mutation in the Ca2+ channel subunit gene, alpha(1A), causing them to exhibit severe ataxia, petit-mal-like epilepsy and a myoclonus-like movement disorder. Expression of alpha(1A) mRNA in cerebella from 20-day-old homozygous leaner mice was compared to control mice, using in situ hybridization histochemistry. Expression of alpha(1A) protein was examined in cerebella from 20-day-old homozygous leaner and control mice using immunocytochemistry. No differences in either mRNA or protein expression of the alpha(1A) subunit were observed when homozygous leaner mice were compared to age-matched controls. Therefore, functional alterations in P/Q-Type Ca2+ channels containing the alpha(1A) subunit need to be explored to further understand the relationship of mutations in the alpha(1A) gene to the pathogenesis of the neurologic disorders occurring in leaner mice. (C) 1998 Elsevier Science B.V. All rights reserved. C1 Texas A&M Univ, Coll Vet Med, Dept Vet Anat & Publ Hlth, College Stn, TX 77843 USA. Korea Univ, Coll Med, Dept Anat, Seoul 136705, South Korea. NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Abbott, LC (reprint author), Texas A&M Univ, Coll Vet Med, Dept Vet Anat & Publ Hlth, College Stn, TX 77843 USA. EM labbott@cvm.tamu.edu NR 44 TC 22 Z9 22 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD AUG 15 PY 1998 VL 59 IS 1 BP 93 EP 99 DI 10.1016/S0169-328X(98)00110-7 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 113NY UT WOS:000075559200012 ER PT J AU Aravind, L Koonin, EV AF Aravind, L Koonin, EV TI Phosphoesterase domains associated with DNA polymerases of diverse origins SO NUCLEIC ACIDS RESEARCH LA English DT Article ID NUCLEOTIDYLTRANSFERASE SUPERFAMILY; SEQUENCE DATABASES; ESCHERICHIA-COLI; ACTIVE-SITE; ALIGNMENT; SUBUNIT; DELTA; GENE; RECOMBINATION; RECOGNITION AB Computer analysis of DMA polymerase protein sequences revealed previously unidentified conserved domains that belong to two distinct superfamilies of phosphoesterases. The alpha subunits of bacterial DNA polymerase III and two distinct family X DNA polymerases are shown to contain an N-terminal domain that defines a novel enzymatic superfamily, designated PHP, after polymerase and histidinol phosphatase. The predicted catalytic site of the PHP superfamily consists of four motifs containing conserved histidine residues that are likely to be Involved in metal-dependent catalysis of phosphoester bond hydrolysis. The PHP domain is highly conserved in all bacterial polymerase ill alpha subunits, but in proteobacteria and mycoplasmas, the conserved motifs are distorted, suggesting a loss of the enzymatic activity. Another conserved domain, found in the small subunits of archaeal DNA polymerase II and eukaryotic DNA polymerases alpha and delta, is shown to belong to-the superfamily of calcineurin-like phosphoesterases, which unites a variety of phosphatases and nucleases, The conserved motifs required for phosphoesterase activity are intact in the archaeal DNA polymerase subunits, but are disrupted in their eukaryotic orthologs. A hypothesis is proposed that bacterial and archaeal replicative DNA polymerases possess intrinsic phosphatase activity that hydrolyzes the pyrophosphate released during nucleotide polymerization. As proposed previously, pyrophosphate hydrolysis may be necessary to drive the polymerization reaction forward, The phosphoesterase domains with disrupted catalytic motifs may assume an allosteric, regulatory function and/or bind other subunits of DNA polymerase holoenzymes. In these cases, the pyrophosphate may be hydrolyzed by a stand-alone phosphatase, and candidates for such a role were identified among bacterial PHP superfamily members. C1 NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Texas A&M Univ, Dept Biol, College Stn, TX 77843 USA. RP Koonin, EV (reprint author), NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. NR 35 TC 156 Z9 158 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD AUG 15 PY 1998 VL 26 IS 16 BP 3746 EP 3752 DI 10.1093/nar/26.16.3746 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 110YB UT WOS:000075408200018 PM 9685491 ER PT J AU Hacia, JG Edgemon, K Sun, B Stern, D Fodor, SPA Collins, FS AF Hacia, JG Edgemon, K Sun, B Stern, D Fodor, SPA Collins, FS TI Two color hybridization analysis using high density oligonucleotide arrays and energy transfer dyes SO NUCLEIC ACIDS RESEARCH LA English DT Article AB High density oligonucleotide arrays (DNA chips) have been used in two color mutational analysis of the 3.43 kb exon 11 of the hereditary breast and ovarian cancer gene BRCA1. Two color analysis allows competitive hybridization between a reference standard and an unknown sample, improving the performance of the assay. Fluorescein and phycoerythrin dyes were previously used due to their compatibility with a single line 488 nm excitation source. Here we show that an alternative dye combination, containing the energy transfer dye system phycoerythrin.cy5 along with phycoerythrin, provides more evenly matched signal intensities and decreased spectral overlap between the two fluorophores, while maintaining compatibility with a 488 nm excitation source. C1 NIH, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. Affymetrix, Santa Clara, CA 95051 USA. RP Collins, FS (reprint author), NIH, Natl Human Genome Res Inst, Bldg 49-3A14, Bethesda, MD 20892 USA. OI Sun, Bryan/0000-0002-0740-0125 NR 3 TC 21 Z9 23 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD AUG 15 PY 1998 VL 26 IS 16 BP 3865 EP 3866 DI 10.1093/nar/26.16.3865 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 110YB UT WOS:000075408200034 PM 9685507 ER PT J AU Teplyakov, A Obmolova, G Badet-Denisot, MA Badet, B Polikarpov, I AF Teplyakov, A Obmolova, G Badet-Denisot, MA Badet, B Polikarpov, I TI Involvement of the C terminus in intramolecular nitrogen channeling in glucosamine 6-phosphate synthase: evidence from a 1.6 angstrom crystal structure of the isomerase domain SO STRUCTURE WITH FOLDING & DESIGN LA English DT Article DE aldose/ketose isomerase; crystal structure; glucosamine-6P synthase; glutamine amidotransferase ID COLI GLUCOSAMINE-6-PHOSPHATE SYNTHASE; D-XYLOSE ISOMERASE; ESCHERICHIA-COLI; FRUCTOSE 6-PHOSPHATE; ACTIVE-SITE; MECHANISM; RESOLUTION; SUBSTRATE; BINDING; SYNTHETASE AB Background: Glucosamine 6-phosphate synthase (GlmS) catalyses the first step in hexosamine metabolism, converting fructose-6P (6 phosphate) into glucosamine-6P using glutamine as a nitrogen source. GlmS is a bienzyme complex consisting of two domains that catalyse glutamine hydrolysis and sugar-phosphate isomerisation, respectively. Knowledge of the three-dimensional structure of GlmS is essential for understanding the general principles of catalysis by ketol isomerases and the mechanism of nitrogen transfer in glutamine amidotransferases, Results: The crystal structure of the isomerase domain of the Escherichia coli GlmS with the reaction product, glucosamine-6P, has been determined at 1.57 Angstrom resolution. It is comprised of two topologically identical subdomains, each of which is dominated by a nucleotide-binding motif of a flavodoxin type. The catalytic site is assembled by dimerisation of the protein. Conclusions: The isomerase active site of GlmS seems to be the result of evolution through gene duplication and subsequent dimerisation. Isomerisation of fructose-6P is likely to involve the formation of a Schiff base with Lys603 of the enzyme, the ring-opening step catalysed by His504, and the proton transfer from C1 to C2 of the substrate effected by Glu488. The highly conserved C-terminal fragment of the chain may play a key role in substrate binding, catalysis and communication with the glutaminase domain. The corresponding sequence pattern DXPXXLAK[SC]VT tin single-letter aminoacid code, where X is any amino acid and letters in brackets indicate that either serine or cysteine may take this position) may be considered as a fingerprint of GlmS. C1 DESY, European Mol Biol Lab, Hamburg Outstn, D-22603 Hamburg, Germany. CNRS, Inst Chim Subst Nat, F-91198 Gif Sur Yvette, France. Lab Nacl Luz Sinchrotron, BR-13087410 Campinas, SP, Brazil. RP Teplyakov, A (reprint author), NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RI Polikarpov, Igor/D-2575-2012 NR 42 TC 69 Z9 72 U1 0 U2 9 PU CURRENT BIOLOGY LTD PI LONDON PA 34-42 CLEVELAND STREET, LONDON W1P 6LB, ENGLAND SN 0969-2126 J9 STRUCT FOLD DES JI Struct. Fold. Des. PD AUG 15 PY 1998 VL 6 IS 8 BP 1047 EP 1055 DI 10.1016/S0969-2126(98)00105-1 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 114FN UT WOS:000075598600010 PM 9739095 ER PT J AU Hasenkrug, KJ Brooks, DM Robertson, MN Srinivas, RV Chesebro, B AF Hasenkrug, KJ Brooks, DM Robertson, MN Srinivas, RV Chesebro, B TI Immunoprotective determinants in friend murine leukemia virus envelope protein SO VIROLOGY LA English DT Article ID FOCUS-INDUCING VIRUS; HOST GENETIC-CONTROL; FBL-3 TUMOR-CELLS; INDUCED ERYTHROLEUKEMIA; VACCINE DEVELOPMENT; RETROVIRAL DISEASE; PRIMARY INFECTION; HIV VACCINE; ENV GENE; RECOMBINANT AB Several immunological epitopes are known to be located within the Friend murine leukemia virus (F-MULV) envelope protein, but their relative contributions to protection from Friend virus-induced disease are not known. To determine how expression of various immunological determinants affected protection, mice were immunized with recombinant vaccinia viruses expressing different portions of the FMuLV envelope protein, and they were then challenged with a lethal dose of Friend virus complex. The disease parameters that were followed in the mice were early viremia, early splenomegaly, and late splenomegaly. Both the N-terminal and C-terminal portions of the F-MuLV gp70 were found to protect against late splenomegaly, the primary clinical sign associated with virus-induced erythroleukemia. However, neither region alone protected against early splenomegaly and early viremia, indicating poor immunological control over early virus replication and spread through the spleen and blood. In contrast, mice immunized with a vaccine expressing the entire F-MuLV envelope protein were protected against all three disease parameters. The results indicated that expression of multiple immunological determinants including both T-helper and B cell epitopes was necessary for full protection. (C) 1998 Academic Press. C1 NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Univ Washington, Med Ctr, Retrovirus Lab, Div Infect Dis,Dept Med, Seattle, WA 98195 USA. St Jude Childrens Res Hosp, Dept Infect Dis, Memphis, TN 38105 USA. RP Hasenkrug, KJ (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 44 TC 33 Z9 33 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 AUG 15 PY 1998 VL 248 IS 1 BP 66 EP 73 DI 10.1006/viro.1998.9264 PG 8 WC Virology SC Virology GA 113BC UT WOS:000075528600008 PM 9705256 ER PT J AU Moore-Hoon, ML Turner, RJ AF Moore-Hoon, ML Turner, RJ TI Molecular and topological characterization of the rat parotid Na+-K+-2Cl(-) cotransporter SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Article DE secretory isoform of Na+-K+-2Cl(-) cotransporter; exocrine fluid secretion; antipeptide antibody ID K-CL COTRANSPORTER; ACINAR-CELLS; FUNCTIONAL EXPRESSION; UP-REGULATION; LOCALIZATION; CLONING; PROTEIN AB Na+-K+-2Cl(-) cotransporters play a central role in driving salt and water movements across secretory and absorptive epithelia. We report the cloning of the rat parotid secretory Na+-K+-2Cl(-) cotransporter, rtNKCC1. The predicted amino acid sequence of this protein is highly homologous to a previously cloned NKCC1 from the shark rectal gland and to mammalian NKCC1s cloned from several cultured cell lines, confirming the presence of the NKCC1 isoform in a naturally occurring mammalian secretory epithelium. In contrast to previously published NKCC1 clones, our sequence also includes an apparently complete 2680 bp 3'-UTR. Hydropathy analyses of rtNKCC1 predicts that this protein consists of large hydrophilic N and C termini (approx. 30 kDa and 50 kDa, respectively) flanking a central hydrophobic transmembrane region consisting of ten to 12 membrane spanning domains, In addition, we report the results of confocal immunofluorescent microscopic studies using rat parotid acini and antibodies directed against specific regions of the predicted N- and C-terminal portions of rtNKCC1. These studies demonstrate that the epitopes recognized by these antibodies are exposed in permeabilized but not in unpermeabilized cells, indicating that the predicted N and C termini of rtNKCC1 are intracellular. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIDR, Membrane Biol Sect, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Moore-Hoon, ML (reprint author), NIDR, Membrane Biol Sect, Gene Therapy & Therapeut Branch, NIH, Bldg 10,Rm 1A06,10 Ctr Dr, Bethesda, MD 20892 USA. NR 19 TC 51 Z9 51 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD AUG 14 PY 1998 VL 1373 IS 1 BP 261 EP 269 DI 10.1016/S0005-2736(98)00112-6 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 114DQ UT WOS:000075594200026 PM 9733980 ER PT J AU Kitanaka, N Sora, I Kinsey, S Zeng, ZZ Uhl, GR AF Kitanaka, N Sora, I Kinsey, S Zeng, ZZ Uhl, GR TI No heroin or morphine 6 beta-glucuronide analgesia in mu-opioid receptor knockout mice SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE morphine; pain; opiate AB Recent reports suggest that heroin and its metabolite morphine 6 beta-glucuronide can produce analgesia independent of the morphine-preferring mu-opioid receptor. We have tested heroin and morphine 6 beta-glucuronide analgesia in wild-type, homozygous and heterozygous mu-opioid receptor knockout mice. Homozygotes display no heroin or morphine 6 beta-glucuronide analgesia. Heterozygous mice with one mu-opioid receptor gene copy reveal reduced heroin and morphine 6 beta-glucuronide analgesia. The mu-opioid receptor-dependence of heroin and morphine 6 beta-glucuronide fails to support a requirement for a heroin-specific opiate receptor subtype. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIDA, Mol Neurobiol Branch, Intramural Res Program, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Uhl, GR (reprint author), NIDA, Mol Neurobiol Branch, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 7 TC 39 Z9 39 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD AUG 14 PY 1998 VL 355 IS 1 BP R1 EP R3 DI 10.1016/S0014-2999(98)00516-0 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 113VT UT WOS:000075575100014 PM 9754945 ER PT J AU Margolis, L AF Margolis, L TI HIV: from molecular recognition to tissue pathogenesis SO FEBS LETTERS LA English DT Review DE human immunodeficiency virus type 1; molecular tropism; molecular recognition ID HUMAN LYMPHOID-TISSUE; THYMIC ORGAN-CULTURE; CHEMOKINE RECEPTORS; IN-VIVO; T-LYMPHOCYTES; INFECTION; CCR5; ENTRY; CELLS; MODEL AB Dramatic progress has been made recently in identifying both viral and cellular molecules responsible for binding and fusion of HIV-1 to target cells. In vivo, HIV-1 infection is transmitted by viruses that recognize chemokine receptor CCR5, while viruses isolated at later stages of HIV disease often recognize another chemokine receptor, CXCR4. It is still not understood how this molecular tropism of HIV-1 is translated into the virus' ability to compromise normal cell functions, which results in impairment of lymphoid tissue and causes AIDS. Here, we discuss how the new molecular findings might relate to HIV pathogenesis in cells and tissues. (C) 1998 Federation of European Biochemical Societies. C1 NICHHD, Lab Mol & Cellular Biophys, NIH, Bethesda, MD 20892 USA. RP Margolis, L (reprint author), NICHHD, Lab Mol & Cellular Biophys, NIH, Bldg 10,Room 10D14, Bethesda, MD 20892 USA. NR 46 TC 8 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD AUG 14 PY 1998 VL 433 IS 1-2 BP 5 EP 8 DI 10.1016/S0014-5793(98)00858-8 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 113WT UT WOS:000075577400002 PM 9738921 ER PT J AU Tsai, SC Adamik, R Hong, JX Moss, J Vaughan, M Kanoh, H Exton, JH AF Tsai, SC Adamik, R Hong, JX Moss, J Vaughan, M Kanoh, H Exton, JH TI Effects of arfaptin 1 on guanine nucleotide-dependent activation of phospholipase D and cholera toxin by ADP-ribosylation factor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EXCHANGE PROTEIN; BREFELDIN-A; BOVINE BRAIN; FACTOR ARF; GTP; GOLGI; PURIFICATION; STIMULATION; CONTAINS; DOMAINS AB Arfaptin 1, a similar to 39-kDa protein based on the deduced amino acid sequence, had been initially identified in a yeast two-hybrid screen using dominant active ARF3 (Q71L) as bait with an HL-60 cDNA library. It was suggested that arfaptin 1 may be involved in Golgi functions, since the FLAG-tagged protein was associated with Golgi membranes when expressed in COS-7 cells and could be bound to Golgi in vitro in an ADP-ribosylation factor (ARF)- and GTP gamma S-dependent, brefeldin A-inhibited fashion. Arfaptin 2, found in the same two-hybrid screen as arfaptin 1, is 60% identical in amino acid sequence and may or may not have an analogous function. We now report some effects of arfaptin 1 on ARF activation of phospholipase D and cholera toxin ADP-ribosyltransferase, Arfaptin 1 inhibited activation of both enzymes in a concentration-dependent manner and was without effect in the absence of ARF. Two ARF1 mutants that activated the toxin, one lacking 13 N-terminal amino acids and the other, in which 73 residues at the N terminus were replaced with the analogous sequence from ARL1, were not inhibited by arfaptin, consistent with the conclusion that arfaptin interaction requires the N terminus of ARF. This region has also been implicated in phospholipase D activation, but whether the two proteins interact with the same structural elements in ARF remains to be determined, Arfaptin inhibition of the action of ARF5 and ARF6 was less than that of ARF1 and ARF3; its effects were less on nanmyristoylated than myristoylated ARFs. Arfaptin effects on guanine nucleotide binding by ARFs were minimal whether or not a purified ARF guanine nucleotide-exchange protein was present. These findings indicate that arfaptin acts as an inhibitor of ARF actions in vitro, raising the possibility that it has a similar role in vivo. C1 NHLBI, NIH, Pulm Crit Care Med Branch, Bethesda, MD 20892 USA. Vanderbilt Univ, Sch Med, Howard Hughes Med Inst, Dept Mol Physiol & Biophys & Pharmacol, Nashville, TN 37232 USA. RP Tsai, SC (reprint author), NHLBI, NIH, Pulm Crit Care Med Branch, Rm 5N-307,Bldg 10,10 Ctr Dr,MSC 1434, Bethesda, MD 20892 USA. NR 21 TC 20 Z9 20 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 AUG 14 PY 1998 VL 273 IS 33 BP 20697 EP 20701 DI 10.1074/jbc.273.33.20697 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 110MZ UT WOS:000075386100004 PM 9694811 ER PT J AU Kelly, D Kim, SJ Rizzino, A AF Kelly, D Kim, SJ Rizzino, A TI Transcriptional activation of the type II transforming growth factor-beta receptor gene upon differentiation of embryonal carcinoma cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NEGATIVE REGULATORY ELEMENT; SERINE THREONINE KINASE; ENDODERM-LIKE CELLS; EARLY MOUSE EMBRYOS; RNA POLYMERASE-II; TGF-BETA; NF-Y; MICROSATELLITE INSTABILITY; GROWTH-FACTOR-BETA-2 GENE; EXPRESSION CLONING AB Previously, it has been shown that differentiation of embryonal carcinoma (EC) cells turns on the expression of functional transforming growth factor type-beta receptors, Here, we show that the type II receptor (T beta R-II) gene is activated at the transcriptional level when EC cells differentiate. We show that the differentiated cells, but not the parental EC cells, express transcripts for T beta R-II, In addition, the expression of T beta R-II promoter/ reporter gene constructs are elevated dramatically when EC cells differentiate and we identify at least two positive and two negative regulatory regions in the 5' flanking region of the T beta R-II gene. Moreover, we identify a cAMP response element/activating transcription factor site that acts as a positive cis-regulatory element in the T beta R-II promoter, and we demonstrate that the transcription factor ATF-1 binds to this site and strongly stimulates the expression of the T beta R-II promoter/reporter gene constructs when ATF-1 is overexpressed in EC-derived differentiated cells, Equally important, we identify a negative regulatory element in a 53-base pair region that had previously been shown to inhibit strongly the expression of T beta R-II promoter/reporter gene constructs, Specifically, we demonstrate that this region, which contains an inverted CCAAT box motif, binds the transcription factor complex NF-Y (also referred to as CBF) in vitro. Furthermore, expression of a dominant-negative NF-YA mutant protein, which prevents DNA binding by NF-Y, enhances TPR-II promoter expression. Together, these studies suggest that the transcription factors ATF-1 and NF-Y play important roles in the regulation of the T beta R-II gene. C1 Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Rizzino, A (reprint author), Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, 600 S 42nd St, Omaha, NE 68198 USA. FU NCI NIH HHS [CA 36727, CA 74771, T32 CA09476] NR 77 TC 42 Z9 42 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 AUG 14 PY 1998 VL 273 IS 33 BP 21115 EP 21124 DI 10.1074/jbc.273.33.21115 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 110MZ UT WOS:000075386100059 PM 9694866 ER PT J AU Srivastava, DK Vande Berg, BJ Prasad, R Molina, JT Beard, WA Tomkinson, AE Wilson, SH AF Srivastava, DK Vande Berg, BJ Prasad, R Molina, JT Beard, WA Tomkinson, AE Wilson, SH TI Mammalian abasic site base excision repair - Identification of the reaction sequence and rate-determining steps SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA-POLYMERASE-BETA; DEOXYRIBOSE-PHOSPHATE RESIDUES; BOVINE TESTIS; LIGASE-III; XRCC1; RECONSTITUTION; PATHWAY; GENE; ENDONUCLEASE; REPLICATION AB Base excision repair (BER) is one of the cellular defense mechanisms repairing damage to nucleoside 5'-monophosphate residues in genomic DNA. This repair pathway is initiated by spontaneous or enzymatic N-glycosidic bond cleavage creating an abasic or apurinic-apyrimidinic (AP) site in double-stranded DNA. Class II AP endonuclease, deoxyribonucleotide phosphate (dRP) lyase, DNA synthesis, and DNA ligase activities complete repair of the AP site. In mammalian cell nuclear extract, BER can be mediated by a macromolecular complex containing DNA polymerase beta (beta-pol) and DNA ligase I. These two enzymes are capable of contributing the latter three of the four BER enzymatic activities. In the present study, we found that AP site BER can be reconstituted in vitro using the following purified human proteins:AP endonuclease, beta-pol, and DNA ligase I. Examination of the individual enzymatic steps in BER allowed us to identify an ordered reaction pathway: subsequent to 5' "nicking" of the AP site-containing DNA strand by AP endonuclease, beta-pol performs DNA synthesis prior to removal of the 5'-dRP moiety in the gap. Removal of the (dRP flap is strictly required for DNA ligase I to seal the resulting nick, Additionally, the catalytic rate of the reconstituted BER system and the individual enzymatic activities was measured. The reconstituted BER system performs repair of AP site DNA at a rate that is slower than the respective rates of AP endonuclease, DNA synthesis, and ligation, suggesting that these steps are not rate-determining in the overall reconstituted BER system, Instead, the rate-limiting step in the reconstituted system was found to be removal of dRP tie. dRP lyase), catalyzed by the amino-terminal domain of beta-pol, This work is the first to measure the rate of BER in an in vitro reaction. The potential significance of the dRP-containing intermediate in the regulation of BER is discussed. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Texas, Med Branch, Dept Human Biol Chem & Genet, Galveston, TX 77555 USA. Univ Texas, Hlth Sci Ctr, Ctr Mol Med, Inst Biotechnol, San Antonio, TX 78245 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, 111 Alexander Dr,Bldg 101,Rm B246, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov NR 43 TC 277 Z9 281 U1 1 U2 6 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 AUG 14 PY 1998 VL 273 IS 33 BP 21203 EP 21209 DI 10.1074/jbc.273.33.21203 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 110MZ UT WOS:000075386100070 PM 9694877 ER PT J AU Ishaq, M Zhang, YM Natarajan, V AF Ishaq, M Zhang, YM Natarajan, V TI Activation-induced down-regulation of retinoid receptor RXR alpha expression in human T lymphocytes - Role of cell cycle regulation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ARBITRARILY PRIMED PCR; DIFFERENTIAL DISPLAY; MONOCLONAL-ANTIBODIES; INDUCED APOPTOSIS; GENE-EXPRESSION; MESSENGER-RNA; ACID; PROTEIN; INHIBITION; INTERLEUKIN-2 AB A 5.4-kilobase mRNA, the expression of which is downregulated after treatment of human peripheral blood mononuclear cells (PBMCs) with various T cell-activating agents, was isolated using an mRNA differential display method. Nucleotide sequence analysis identified the 5' end of this RNA as human retinoid receptor RXR alpha mRNA. Here, we report the nucleotide sequence of 3.6 kilobases of this RNA, which represents the 3' end of RXR alpha mRNA, the sequence of which has not been previously described. Activated PBMCs also expressed lower levels of RXR alpha protein, and a DNA binding assay showed that the activation-induced loss of RXRa mRNA and protein expression correlated with the loss of DNA binding activity of this protein. We present evidence that the transition from G(0)/G(1) to S phase of the cell cycle results in the down-regulation of RXR alpha expression and that cell cycle inhibitors, which block the cells in G(1) phase, prevent this down-regulation. The decrease in the levels of RXR alpha mRNA was found to be regulated at the posttranscriptional level and involved new protein synthesis. These observations indicate that the levels of RXR alpha expression in T lymphocytes are coupled to cell cycle progression, and there is tight regulatory control of RXR alpha expression during the transition from G(0)/G(1) to S phase of the cell cycle. C1 NCI, Frederick Canc Res & Dev Ctr, Mol Cell Biol Lab, SAIC Frederick, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Lab Mol Retrovirol, SAIC Frederick, Frederick, MD 21702 USA. RP Ishaq, M (reprint author), NCI, Frederick Canc Res & Dev Ctr, Mol Cell Biol Lab, SAIC Frederick, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-5600] NR 41 TC 15 Z9 15 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 AUG 14 PY 1998 VL 273 IS 33 BP 21210 EP 21216 DI 10.1074/jbc.273.33.21210 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 110MZ UT WOS:000075386100071 PM 9694878 ER PT J AU Yuan, Y Mead, D Schroeder, BG Zhu, YQ Barry, CE AF Yuan, Y Mead, D Schroeder, BG Zhu, YQ Barry, CE TI The biosynthesis of mycolic acids in Mycobacterium tuberculosis - Enzymatic methyl(ene) transfer to acyl carrier protein bound meromycolic acid in vitro SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL-FREE-EXTRACTS; FATTY-ACIDS; AURUM; WALL; IDENTIFICATION; CONDENSATION; SMEGMATIS; SYSTEM AB A closely related family of enzymes from Mycobacterium tuberculosis has been shown by heterologous expression to catalyze the modification of mycolic acids through the addition of a methyl (or methylene) group derived from S-adenosyl-L-methionine (SAM). Overproduction of all six of these enzymes in Escherichia coli and subsequent in vitro reactions with heat-inactivated acceptor fractions derived from Mycobacterium smegmatis in the presence of [methyl-H-3]SAM demonstrated that the immediate substrate to which methyl group addition occurs was a family of very long-chain fatty acids. Inhibitors of methyl transfer, such as S-adenosyl-L-homocysteine and sinefungin, were shown to inhibit this reaction but had no effect on whole cells of either M. smegmatis or M. tuberculosis. Purified mycolic acids from M. tuberculosis were pyrolyzed, and the resulting meroaldehyde was oxidized and methylated to produce full-length methyl meromycolates. These esters were shown to comigrate with a fraction of the acceptor from the in vitro reactions, suggesting that methyl group addition occurs up to the level of the meromycolate, Protease and other treatments destroyed the activity of the acceptor fraction, which was also found to be extremely sensitive to basic pH. Antibody to the acyl carrier protein AcpM, which has recently been shown to be the carrier of full-length meromycolate produced by a unique type II fatty acid synthase system, inhibited the cell-free methyl(en)ation of these acids. These results suggest that mycolate modification reactions occur parallel with the synthesis of the AcpM-bound meromycolate chain. C1 NIAID, Rocky Mt Labs, TB Res Stn, Lab Intracellular Parasites,NIH, Hamilton, MT 59840 USA. RP Barry, CE (reprint author), NIAID, Rocky Mt Labs, TB Res Stn, Lab Intracellular Parasites,NIH, 903 S 4th St, Hamilton, MT 59840 USA. RI Barry, III, Clifton/H-3839-2012 FU Intramural NIH HHS [Z01 AI000783-11] NR 31 TC 47 Z9 49 U1 0 U2 4 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 AUG 14 PY 1998 VL 273 IS 33 BP 21282 EP 21290 DI 10.1074/jbc.273.33.21282 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 110MZ UT WOS:000075386100081 PM 9694888 ER PT J AU Vinores, SA Chan, CC Vinores, MA Matteson, DM Chen, YS Klein, DA Shi, A Ozaki, H Campochiaro, PA AF Vinores, SA Chan, CC Vinores, MA Matteson, DM Chen, YS Klein, DA Shi, A Ozaki, H Campochiaro, PA TI Increased vascular endothelial growth factor (VEGF) and transforming growth factor beta (TGF(beta)) in experimental autoimmune uveoretinitis: upregulation of VEGF without neovascularization SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE vascular endothelial growth factor; transforming growth factor beta; experimental autoimmune uveoretinitis; retina; blood-retinal barrier ID PIGMENT EPITHELIAL-CELLS; BLOOD-RETINAL BARRIER; PROLIFERATIVE DIABETIC-RETINOPATHY; FACTOR MESSENGER-RNA; PERMEABILITY FACTOR; FACTOR EXPRESSION; ULTRASTRUCTURAL PATHOLOGY; EXPERIMENTAL UVEITIS; UP-REGULATION; TGF-BETA AB Experimental autoimmune uveoretinitis (EAU) was induced in Lewis rats and B10.A mice by immunization with S-antigen (S-Ag) to study the potential roles of vascular endothelial growth factor (VEGF) and the beta(1) and beta(2) isoforms of transforming growth factor (TGF(beta 1) staining for VEGF, TGF(beta 1) and TGF(beta 2)) during the progression of the disease. VEGF has been implicated as an angiogenic factor in ischemic retinopathies; however, Lewis rats developing EAU have high levels of VEGF in the retina, but no neovascularization. In the present study, immunohistochemical staining for VEGF, TGF(beta 1) and TGF(beta 2) was performed on the retinas of Lewis rats developing EAU or with oxygen-induced ischemic retinopathy. In rats immunized with S-antigen, a marked upregulation of VEGF was immunohistochemically visualized from the inner nuclear layer to the inner limiting membrane prior to blood-retinal barrier (BRB) failure and lymphocytic infiltration. VEGF is normally induced by hypoxia and its induction leads to neovascularization. Coincident with the increase in VEGF, there was increased immunoreactivity for TGF(beta 1) and TGF(beta 2) within the same layers of the retina. In contrast, rats with ischemic retinopathy and retinal neovascularization showed only a modest increase in VEGF immunoreactivity, which is largely confined to retinal ganglion cells and inner retinal vessels, and little or no increase in TGF(beta 1) or TGF(beta 2). In addition, in mice developing EAU, which does not have an abrupt onset as it does in rats and may involve neovascularization, a comparable upregulation of VEGF in the inner retina to that seen in rats developing EAU occurs with no increase in TGF(beta 1) or TGF(beta 2). Since TGF(beta) can inhibit endothelial cell proliferation, it is likely that an increase in TGF(beta) may prevent VEGF from exerting its endothelial growth activity in the rat EAU model, but VEGF may be operative in inducing BRB failure. These data suggest that there is a complex interaction among growth factors in the retina and that retinal neovascularization may require an imbalance between stimulatory and inhibitory factors. (C) 1998 Elsevier Science B.V. All rights reserved. C1 Johns Hopkins Hosp, Sch Med, Wilmer Ophthalmol Inst, Baltimore, MD 21287 USA. NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. Cathay Gen Hosp, Taipei, Taiwan. RP Vinores, SA (reprint author), Johns Hopkins Hosp, Sch Med, Wilmer Ophthalmol Inst, 825 Maumenee Bldg,600 N Wolfe St, Baltimore, MD 21287 USA. FU NEI NIH HHS [EY10017, EY05951] NR 59 TC 56 Z9 59 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD AUG 14 PY 1998 VL 89 IS 1-2 BP 43 EP 50 DI 10.1016/S0165-5728(98)00075-7 PG 8 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 113UH UT WOS:000075571000006 PM 9726824 ER PT J AU Calabresi, PA Tranquill, LR McFarland, HF Cowan, EP AF Calabresi, PA Tranquill, LR McFarland, HF Cowan, EP TI Cytokine gene expression in cells derived from CSF of multiple sclerosis patients SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE PCR; tumor necrosis factor; interferon; interleukin; MRI ID EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; RESONANCE-IMAGING LESIONS; MESSENGER-RNA EXPRESSION; FLUID MONONUCLEAR-CELLS; CENTRAL-NERVOUS-SYSTEM; NECROSIS-FACTOR-ALPHA; CEREBROSPINAL-FLUID; DISEASE-ACTIVITY; INTERFERON-BETA; T-LYMPHOCYTES AB Cytokines are produced by numerous cell types in the peripheral blood and central nervous system (CNS), and have been implicated in the immunopathogenesis of multiple sclerosis (MS). We examined the relationship between cytokine gene expression of cerebrospinal fluid (CSF) derived cells from MS patients and disease activity as measured by contrast enhanced MRI. There was a significant correlation between the number of CSF cells and the number of contrast enhancing MRI lesions. Cytokine gene expression of TNF-alpha, IFN-gamma, and IL-10 was routinely seen, but IL-4 expression was absent except in two clinically quiescent patients. Trends were observed toward decreased TNF-alpha expression, but increased IL-10 expression, after treatment with IFN-beta 1b. (C) 1998 Elsevier Science B.V. All rights reserved. C1 Brown Univ, Rhode Isl Hosp, Dept Neurol, Providence, RI 02903 USA. NINDS, Neuroimmunol Branch, Bethesda, MD 20892 USA. US FDA, Div Transfus Transmitted Dis, CBER, OBRR, Rockville, MD 20852 USA. RP Calabresi, PA (reprint author), Brown Univ, Rhode Isl Hosp, Dept Neurol, 110 Lockwood St,Suite 342, Providence, RI 02903 USA. NR 27 TC 45 Z9 45 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD AUG 14 PY 1998 VL 89 IS 1-2 BP 198 EP 205 DI 10.1016/S0165-5728(98)00139-8 PG 8 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 113UH UT WOS:000075571000025 PM 9726843 ER PT J AU Carballo, E Lai, WS Blackshear, PJ AF Carballo, E Lai, WS Blackshear, PJ TI Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin SO SCIENCE LA English DT Article ID FINGER TRANSCRIPTION FACTOR; MESSENGER-RNA DEGRADATION; TNF-ALPHA; NUCLEOTIDE-SEQUENCE; TRANSGENIC MICE; PROTEIN; GENE; EXPRESSION; ARTHRITIS; DISEASE AB Tumor necrosis factor-alpha (TNF-alpha) is a major mediator of both acute and chronic inflammatory responses in many diseases. Tristetraprolin (TTP), the prototype of a class of Cys-Cys-Cys-His (CCCH) zinc finger proteins, inhibited TNF-alpha production from macrophages by destabilizing its messenger RNA. This effect appeared to result from direct TTP binding to the AU-rich element of the TNF-alpha messenger RNA. TTP is a cytosolic protein in these cells, and its biosynthesis was induced by the same agents that stimulate TNF-alpha production. including TNF-alpha itself. These findings identify TTP as a component of a negative feedback Loop that interferes with TNF-alpha production by destabilizing its messenger RNA. This pathway represents a potential target for anti-TNF-alpha therapies. C1 NIEHS, Off Clin Res, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Signal Transduct, 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, Res Triangle Pk, NC 27709 USA. EM black009@niehs.nih.gov NR 36 TC 796 Z9 812 U1 5 U2 17 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD AUG 14 PY 1998 VL 281 IS 5379 BP 1001 EP 1005 DI 10.1126/science.281.5379.1001 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 110ZK UT WOS:000075412700051 PM 9703499 ER PT J AU Wurtz, RH AF Wurtz, RH TI Optic flow: A brain region devoted to optic flow analysis? SO CURRENT BIOLOGY LA English DT Article ID SUPERIOR TEMPORAL AREA; MACAQUE MONKEY; EYE-MOVEMENTS; MST NEURONS; EXPANSION CONTRACTION; ROTATION CELLS; VISUAL-CORTEX; DORSAL PART; MOTION; FIELD AB The visual motion - or optic flow - that results from an observer's own movement can indicate the direction of heading through the environment. Recent experiments have strengthened the argument that neurons in a specialized region of the cerebral cortex are critical for the analysis of this important class of visual stimuli. (C) Current Biology Publications ISSN 0960-9822. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Wurtz, RH (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 20 TC 17 Z9 17 U1 0 U2 4 PU CURRENT BIOLOGY LTD PI LONDON PA 34-42 CLEVELAND STREET, LONDON W1P 6LB, ENGLAND SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD AUG 13 PY 1998 VL 8 IS 16 BP R554 EP R556 DI 10.1016/S0960-9822(07)00359-4 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 108JE UT WOS:000075262100005 PM 9707391 ER PT J AU Baraldi, PG Cacciari, B de Las Infantas, MJP Romagnoli, R Spalluto, G Volpini, R Costanzi, S Vittori, S Cristalli, G Melman, N Park, KS Ji, XD Jacobson, KA AF Baraldi, PG Cacciari, B de Las Infantas, MJP Romagnoli, R Spalluto, G Volpini, R Costanzi, S Vittori, S Cristalli, G Melman, N Park, KS Ji, XD Jacobson, KA TI Synthesis and biological activity of a new series of N-6-arylcarbamoyl, 2-(Ar)alkynyl-N-6-arylcarbamoyl, and N-6-carboxamido derivatives of adenosine-5 '-N-ethyluronamide as A(1) and A(3) adenosine receptor agonists SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID RAT-BRAIN; 2-ALKYNYL DERIVATIVES; SELECTIVE AGONISTS; MOLECULAR-CLONING; ANTAGONISTS; POTENT; MEMBRANES; A1; N-6-BENZYLADENOSINE-5'-URONAMIDES; NOMENCLATURE AB A new series of 1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-beta-D-ribofuranuronamide-bearing N-arylureas or N-arylcarboxamido groups at the purine 6 position and N-arylureas combined with halogens Or alkynyl chains at the 2 position have been synthesized and tested for affinity at A(1) and A(2A) adenosine receptors in rat brain membranes and at cloned rat A(3) receptors expressed in CHO cells. The derivatives contained the 5' substituent found in the potent, nonselective agonist 1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-beta-D-ribofuranuronamide (NECA). While the carboxamido derivatives (9-13) showed affinity for A(1) receptors, the urea derivatives (30-45) showed different degrees of affinity and selectivity for the A(3) adenosine receptor subtype. In particular the derivative bearing a p-sulfonamidophenyl-urea at the 6 position, 31 showed a high affinity (K-i = 9 nM) and selectivity for the A(3) receptors compared to that of the reference compound 1-[6 -[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-beta-D-ribofuranuronamide (IB-MEGA). Furthermore, the importance of the stereochemistry in the interaction of these ligands at the rat A(3) adenosine receptors has been evaluated by introducing a chiral chain at the 6 position. The introduction of halogens or alkynyl chains at the purine 2 position of selected ureas did not give the expected enhancement of potency at A(2A) and/or A(3) receptors but rather showed a dramatic reduction of A(2A) affinity, resulting in compounds with good A(2A)/A(3) selectivity. For example, the 2-(3-hydroxy-3-phenyl-1-propyn-1-yl)-6-(4-methoxyphenylurea) derivative 61 showed the capability to bind simultaneously to A(1) and A(3) receptor subtypes, excluding the A2A receptor. Compound 31 was shown to be an agonist, 9-fold more potent than NECA, at A(3) receptors in rat RBL-2H3 mast cell membranes through stimulation of binding of [S-35]GTP-gamma-S. C1 Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. Univ Camerino, Dipartimento Sci Chim, I-62032 Camerino, Italy. NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Baraldi, PG (reprint author), Univ Ferrara, Dipartimento Sci Farmaceut, Via Fossato Mortara 17-19, I-44100 Ferrara, Italy. RI Jacobson, Kenneth/A-1530-2009; Costanzi, Stefano/G-8990-2013; PINEDA DE LAS INFANTAS Y VILLATORO, MARIA JOSE/L-7955-2014; Baraldi, Pier Giovanni/B-7933-2017; OI Jacobson, Kenneth/0000-0001-8104-1493; PINEDA DE LAS INFANTAS Y VILLATORO, MARIA JOSE/0000-0002-0617-6408; Costanzi, Stefano/0000-0003-3183-7332 NR 65 TC 66 Z9 66 U1 0 U2 2 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 AUG 13 PY 1998 VL 41 IS 17 BP 3174 EP 3185 DI 10.1021/jm980147p PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 111BY UT WOS:000075418500005 PM 9703463 ER PT J AU Li, AH Moro, S Melman, N Ji, XD Jacobson, KA AF Li, AH Moro, S Melman, N Ji, XD Jacobson, KA TI Structure-activity relationships and molecular modeling of 3,5-diacyl-2,4-dialkylpyridine derivatives as selective A(3) adenosine receptor antagonists SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MAST-CELLS; RAT-BRAIN; STIMULATION; ACTIVATION; CLONING AB The structure-activity relationships of 6-phenyl-1,4-dihydropyridine derivatives as selective antagonists at human A(3) adenosine receptors have been explored (Jiang et al. J. Med. Chem. 1997, 39, 4667-4675). In the present study, related pyridine derivatives have been synthesized and tested for affinity at adenosine receptors in radioligand binding assays. K-i values in the nanomolar range were observed for certain 3,5-diacyl-2,4-dialkyl-6-phenylpyridine derivatives in displacement of [I-125]AB-MECA (N-6-(4-amino-3-iodobenzyl)-5'-N-methylcarbamoyladenosine) at recombinant human A(3) adenosine receptors. Selectivity for As adenosine receptors was determined vs radioligand binding at rat brain A(1) and A(2A) receptors. Structure-activity relationships at various positions of the pyridine ring (the 3- and 5-acyl substituents and the 2- and 4-alkyl substituents) were probed. A 4-phenylethynyl group did not enhance A(3) selectivity of pyridine derivatives, as it did for the 4-substituted dihydropyridines. At the 2- and 4-positions ethyl was favored over methyl. Also, unlike the dihydropyridines, a thioester group at the 3-position was favored over an ester for affinity at As adenosine receptors, and a 5-position benzyl ester decreased affinity. Small cycloalkyl groups at the 6-position of 4-phenylethynyl-1,4-dihydropyridines were favorable for high affinity at human A(3) adenosine receptors, while in the pyridine series a 6-cyclopentyl group decreased affinity. 5-Ethyl 2,4-diethyl-3 -(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 38, was highly potent at human A(3) receptors, with a K-i value of 20 nM. A 4-propyl derivative, 39b, was selective and highly potent at both human and rat A(3) receptors, with K-i values of 18.9 and 113 nM, respectively. A 6-(3-chlorophenyl) derivative, 44, displayed a K-i value of 7.94 nM at human A(3) receptors and selectivity of 5200-fold. Molecular modeling, based on the steric and electrostatic alignment (SEAL) method, defined common pharmacophore elements for pyridine and dihydropyridine structures, e.g., the two ester groups and the 6-phenyl group. Moreover, a relationship between affinity and hydrophobicity was found for the pyridines. C1 NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, 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. EM kajacobs@helix.nih.gov RI Moro, Stefano/A-2979-2012; Jacobson, Kenneth/A-1530-2009 OI Moro, Stefano/0000-0002-7514-3802; Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031117-20, Z99 DK999999] NR 38 TC 100 Z9 100 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD AUG 13 PY 1998 VL 41 IS 17 BP 3186 EP 3201 DI 10.1021/jm980093j PG 16 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 111BY UT WOS:000075418500006 PM 9703464 ER PT J AU Neamati, N Hong, HX Owen, JM Sunder, S Winslow, HE Christensen, JL Zhao, H Burke, TR Milne, GWA Pommier, Y AF Neamati, N Hong, HX Owen, JM Sunder, S Winslow, HE Christensen, JL Zhao, H Burke, TR Milne, GWA Pommier, Y TI Salicylhydrazine-containing inhibitors of HIV-1 integrase: Implication for a selective chelation in the integrase active site SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID DRUG INFORMATION-SYSTEM; REVERSE-TRANSCRIPTASE; RIBONUCLEASE-H; N1-SUBSTITUTED-3-METHYL-5-PYRAZOLONES; HYDRAZONE; AGENTS AB In previous studies we identified N,N'-bis(salicylhydrazine) (1) as a lead compound against purified recombinant HIV-1 integrase. We have now expanded upon these earlier observations and tested 45 novel hydrazides. Among the compounds tested, 11 derivatives exhibited 50% inhibitory concentrations (IC50) of less than 3 mu M. A common feature for activity among these inhibitors is the hydroxyl group of the salicyl moiety. Although the active inhibitors must contain this hydroxyl group, other structural modifications can also influence potency. Removal of this hydroxyl group or replacement with an amino, bromo, fluoro, carboxylic acid, or ethyl ether totally abolished potency against integrase. Several asymmetric structures exhibited similar potency to the symmetric lead inhibitor 1. The superimposition of the lowest-energy conformations upon one another revealed three sites whose properties appear important for ligand binding. Site A is composed of the 2-hydroxyphenyl, the alpha-keto, and the hydrazine moieties in a planar conformation. We propose that this site could interact with HIV-1 integrase by chelation of the metal in the integrase active site as inhibition of HIV-1 integrase catalytic activity and DNA binding were strictly Mn2+-dependent. The hydrophobic sites B and C are probably responsible for complementarity of molecular shape between ligand and receptor. Our data indicate that only those compounds which possessed sites A, B, and C in a linear orientation were potent inhibitors of HIV-1 integrase. Although all the active inhibitors possessed considerable cytotoxicity and no apparent antiviral activity in CEM cells, the study presents useful information regarding ligand interaction with HIV-1 integrase protein. C1 NCI, Mol Pharmacol Lab, Div Basic Sci, Bethesda, MD 20892 USA. NCI, Med Chem Lab, Div Basic Sci, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Div Basic Sci, Bldg 37,Rm 5D02, Bethesda, MD 20892 USA. RI Burke, Terrence/N-2601-2014 NR 23 TC 80 Z9 81 U1 0 U2 3 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 AUG 13 PY 1998 VL 41 IS 17 BP 3202 EP 3209 DI 10.1021/jm9801760 PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 111BY UT WOS:000075418500007 PM 9703465 ER PT J AU Shin, JM Oh, WS AF Shin, JM Oh, WS TI Study of move set in cubic lattice model for protein folding SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID MONTE-CARLO SIMULATION; ENERGY LANDSCAPE; KINETICS; PATHWAYS; SEQUENCE; TRANSITION; COPOLYMERS; DYNAMICS; FUNNELS; CHAINS AB In cubic lattice model, we have devised a new move set that is fast and suitable for use in a protein folding study by Monte-Carlo simulations, where the number of moving monomers are more extended and flexible in pivot moves and crankshaft moves. In Monte Carlo simulations using 100 model proteins with 27-mers in a cubic lattice, this new move set shows much higher foldicity and faster mean first passage time than the most commonly used move set. From the results of lattice simulation at equilibrium conditions, it is found that the conformational space sampled by this new move set is almost the same as the one sampled with the commonly used move set. However, in the simulation at low temperature, the detailed kinetic folding paths of this new move set are shown to be different from that of the commonly used move set. C1 Hanhyo Inst Technol, Mol Design Lab, Yoosung Ku, Taejon 305390, South Korea. RP Shin, JM (reprint author), NIH, Mol Biol Lab, Bldg 37,Room 4B15, Bethesda, MD 20892 USA. EM jms@rose.hci.nih.gov NR 36 TC 5 Z9 6 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1089-5647 J9 J PHYS CHEM B JI J. Phys. Chem. B PD AUG 13 PY 1998 VL 102 IS 33 BP 6405 EP 6412 DI 10.1021/jp972648c PG 8 WC Chemistry, Physical SC Chemistry GA 112TP UT WOS:000075510500016 ER PT J AU Topham, MK Bunting, M Zimmerman, GA McIntyre, TM Blackshear, PJ Prescott, SM AF Topham, MK Bunting, M Zimmerman, GA McIntyre, TM Blackshear, PJ Prescott, SM TI Protein kinase C regulates the nuclear localization of diacylglycerol kinase-zeta SO NATURE LA English DT Article ID MOLECULAR-CLONING; SUBSTRATE MARCKS; CELL-CYCLE; MEMBRANE; FAMILY; PHOSPHORYLATION; EXPRESSION; LOCATION; ISOZYME; DOMAIN AB Diacylglycerol kinases (DGKs) terminate signalling from diacylglycerol by converting it to phosphatidic acid(1-8) Diacylglycerol regulates cell growth and differentiation, and its transient accumulation in the nucleus may be particularly important in this regulation(9,10) Here we show that a fraction of DGK-zeta is found in the nucleus, where it regulates the amount of nuclear diacylglycerol. Reducing nuclear diacylglycerol levels by conditional expression of DGK-zeta attenuates cell growth. The nuclear-localization signal of DGK-zeta is located in a region that is homologous to the phosphorylation-site domain of the MARCKS protein. This is, to our knowledge, the first evidence that this domain, which is a major target for protein kinase C, can localize a protein to the nucleus. Two isoforms of protein kinase C, but not others, regulate the localization of DGK-zeta. Our results define a cycle in which diacylglycerol activates protein kinase C, which then regulates the metabolism of diacylglycerol by alternating the intracellular location of DGK-zeta. This maybe a general mechanism to control mitogenic signals that depend on nuclear diacylglycerol. C1 Univ Utah, Huntman Canc Inst, Salt Lake City, UT 84112 USA. Univ Utah, Eccles Program Human Mol Biol & Genet, Salt Lake City, UT 84112 USA. Univ Utah, Dept Internal Med, Salt Lake City, UT 84112 USA. Natl Inst Environm Hlth, Res Triangle Pk, NC 27709 USA. RP Prescott, SM (reprint author), Univ Utah, Huntman Canc Inst, Salt Lake City, UT 84112 USA. NR 29 TC 211 Z9 213 U1 0 U2 3 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON, ENGLAND N1 9XW SN 0028-0836 J9 NATURE JI Nature PD AUG 13 PY 1998 VL 394 IS 6694 BP 697 EP 700 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 110MD UT WOS:000075384200049 PM 9716136 ER PT J AU Hrabie, JA Srinivasan, A George, C Keefer, LK AF Hrabie, JA Srinivasan, A George, C Keefer, LK TI Reaction of nitric oxide with the imine double bond of certain Schiff bases SO TETRAHEDRON LETTERS LA English DT Article DE nitrogen oxides; imines; fragmentation reactions; diazenes AB Reaction of nitric oxide with N-benzylidene-4-methoxyaniline produced 4-methoxybenzenediazonium nitrate and benzaldehyde. This may represent an example of the electrophilic reaction of NO with a double bond. (C) 1998 Elsevier Science Ltd. All rights reserved. C1 NCI, Chem Synth & Anal Lab, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, Chem Sect, Comparat Carcinogenesis Lab, FCRDC, Frederick, MD 21702 USA. USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. RP Hrabie, JA (reprint author), NCI, Chem Synth & Anal Lab, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 NR 14 TC 19 Z9 19 U1 0 U2 0 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 AUG 13 PY 1998 VL 39 IS 33 BP 5933 EP 5936 DI 10.1016/S0040-4039(98)01218-0 PG 4 WC Chemistry, Organic SC Chemistry GA 104XF UT WOS:000075041200015 ER PT J AU Melbye, M Cook, PM Hjalgrim, H Begtrup, K Simpson, GR Biggar, RJ Ebbesen, P Schulz, TF AF Melbye, M Cook, PM Hjalgrim, H Begtrup, K Simpson, GR Biggar, RJ Ebbesen, P Schulz, TF TI Risk factors for Kaposi's-sarcoma-associated herpesvirus (KSHV/HHV-8) seropositivity in a cohort of homosexual men, 1981-1996 SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID DNA-SEQUENCES; BISEXUAL MEN; INFECTION; AIDS; ANTIBODIES; SEROEPIDEMIOLOGY; TRANSMISSION; EPIDEMIOLOGY; ANTIGENS; KSHV AB A newly identified herpesvirus has been associated with Kaposi's sarcoma, We determined risk factors for Kaposi's-sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV-B) seropositivity and incidence of infection over time in a cohort of Danish homosexual men followed from 1981 to 1996. Antibodies to a latent nuclear (LANA) and a structural (orf65) antigen of KSHV/HHV-8 were measured by immunofluorescence and ELISA/WB respectively. Through linkage with the national AIDS registry, all cohort members diagnosed with AIDS as of September 1996 were identified and their hospital records were scrutinized to record all diagnoses of KS. Overall, 21.1% (52/246) of the men were KSHV/HHV-8-seropositive in 1981. Among the initially seronegative, the rate of KSHV/HHV-8 seroconversion was highest between 1981 and 1982 and declined steadily thereafter. In a multivariate analysis of the status at enrollment in 1981, KSHV/HHV-1 seropositivity was not associated with age but was independently associated both with number of receptive anal intercourses (OR = 2.83; p = 0.03) and with sex with US men (OR = 2.27; p < 0.05). In a multivariate analysis of follow-up data, risk of KSHV/HHV-8 seroconversion was independently associated with having visited homosexual communities in the United States, and current HIV-positive status. More than 5 years' homosexual experience was associated with an insignificantly increased risk (RR = 2.68). KS occurred only in HIV-positive men who were KSHV/HHV-8-positive at or prior to their KS diagnosis. In conclusion, KSHV/HHV-8 appears to be sexually transmitted, probably by receptive anal intercourse, and may have been introduced to Danish homosexual men via sex with US men. The epidemic of KSHV/HHV-8 is now declining. These findings are concordant with the view that KSHV/HHV-8 may have been actively spread simultaneously with and by the same activities that lead to the spread of HIV. Int. J. Cancer 77:543-548, 1998. (C) 1998 Wiley-Liss, Inc. C1 Statens Serum Inst, Dept Epidemiol Res, Danish Epidemiol Sci Ctr, DK-2300 Copenhagen, Denmark. Univ Liverpool, Dept Med Microbiol & Genitourinary Med, Liverpool L69 3BX, Merseyside, England. NCI, Viral Epidemiol Branch, Rockville, MD USA. Danish Canc Soc, Aarhus, Denmark. RP Melbye, M (reprint author), Statens Serum Inst, Dept Epidemiol Res, Danish Epidemiol Sci Ctr, 5 Artillerivej, DK-2300 Copenhagen, Denmark. EM mme@ssi.dk NR 29 TC 135 Z9 142 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 AUG 12 PY 1998 VL 77 IS 4 BP 543 EP 548 DI 10.1002/(SICI)1097-0215(19980812)77:4<543::AID-IJC12>3.0.CO;2-7 PG 6 WC Oncology SC Oncology GA 102PF UT WOS:000074932500012 PM 9679756 ER PT J AU Hsing, AW McLaughlin, JK Chow, WH Schuman, LM Chien, HTC Gridley, G Bielke, E Wacholder, S Blot, WJ AF Hsing, AW McLaughlin, JK Chow, WH Schuman, LM Chien, HTC Gridley, G Bielke, E Wacholder, S Blot, WJ TI Risk factors for colorectal cancer in a prospective study among US white men SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID IOWA WOMENS HEALTH; COLON-CANCER; ALCOHOL-CONSUMPTION; CIGARETTE-SMOKING; UNITED-STATES; FIBER INTAKE; MEAT; FAT; TOBACCO; ADENOMA AB The association of diet, smoking/drinking and occupation with subsequent risk of fatal colorectal cancer was investigated in a cohort of 17,633 white males aged 35 and older, who completed a mail questionnaire in 1966. During the subsequent 20 years of follow-up, 120 colon cancer and 25 rectal cancer deaths were identified. Due to small numbers, no significant dose-response trends were observed in the study, but risk of colon cancer was elevated among heavy cigarette smokers (greater than or equal to 30/day; RR = 2.3, 95% CI 0.9-5.7), heavy beer drinkers (greater than or equal to 14 times/month; RR = 1.9, 95% CI 1.0-3.8) and white-collar workers (RR = 1.7, 95% CI 1.0-3.0) or crafts workers within service and trade industries (RR = 2.6, 95% CI 1.1-5.8). In addition, an increased risk was seen for those who consumed red meat more than twice a day (RR = 1.8, 95% CI 0.8-4.4). Risk patterns for cancers of the colon and rectum combined were similar to those reported for cancer of the colon, but the estimates were somewhat dampened. Our findings support previous reports that a high intake of red meat and a sedentary life-style may increase the risk of colon cancer. Int. J. Cancer 77:549-553, 1998. (C) 1998 Wiley-Liss, Inc.dagger C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Int Epidemiol Inst, Rockville, MD USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. Westat Inc, Rockville, MD USA. Univ Bergen, Ctr Epidemiol Res, Bergen, Norway. RP Hsing, AW (reprint author), NCI, Div Canc Epidemiol & Genet, EPN 443,6130 Execut Blvd, Bethesda, MD 20892 USA. EM hsinga@epndce.nci.nih.gov NR 35 TC 138 Z9 140 U1 0 U2 6 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 AUG 12 PY 1998 VL 77 IS 4 BP 549 EP 553 DI 10.1002/(SICI)1097-0215(19980812)77:4<549::AID-IJC13>3.0.CO;2-1 PG 5 WC Oncology SC Oncology GA 102PF UT WOS:000074932500013 PM 9679757 ER PT J AU Kang, SH Won, K Chung, HW Jong, HS Song, YS Kim, SJ Bang, YJ Kim, NK AF Kang, SH Won, K Chung, HW Jong, HS Song, YS Kim, SJ Bang, YJ Kim, NK TI Genetic integrity of transforming growth factor beta (TGF-beta) receptors in cervical carcinoma cell lines: Loss of growth sensitivity but conserved transcriptional response to TGF-beta SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID II RECEPTOR; MICROSATELLITE INSTABILITY; CANCER CELLS; EPITHELIAL-CELLS; INHIBITION; EXPRESSION; RESISTANCE; TGF-BETA-1; MUTATIONS; PROTEINS AB Transforming growth factor beta (TGF-beta) exerts an inhibitory effect on the growth of most epithelial cell types, and the loss of responsiveness to this growth inhibition has been implicated in the development of a variety of human cancers. The genetic alteration of TGF-beta receptors is known to play a critical role in this escape from growth regulation. We asked whether there is a correlation between TGF-beta sensitivity and the genetic status of TGF-beta type I and type II receptors (RI and RII, respectively) in human cervical carcinoma cell lines. Among 8 cell lines examined, 3 (ME-180, C-33A and HeLaS3) showed resistance to TGF-beta and 3 (SiHa, CaSki and HeLa229) showed minimal response to the growth inhibitory effect of TGF-beta; the other cell lines (HeLa and HT-3) were sensitive. Northern blot analysis revealed that the RII mRNA was not expressed in 2 TGF-beta-resistant cell lines (ME-180 and C-33A) but was expressed in the other cell lines. Southern blot analysis of RI and RII revealed a homozygous deletion of the entire TGF-beta RII gene in the cell line ME-180. We then asked whether the other TGF-beta-resistant or refractory cell lines had microsatellite instability and/or poly-adenine tract mutations of RII. We also checked for point mutations in the individual exons of the entire RII using polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP). Although C-33A exhibited poly-adenine microsatellite instability, its RII gene showed no signs of mutation. The molecular integrity of the TGF-beta receptors in all cell lines, except ME-180 and C-33A, could be confirmed by examining the distinct transcriptional induction of plasminogen activator inhibitor-I (PAI-I), p21(WAFI/CIPI) and, in some cases, the accompanying downregulation of c-myc in response to TGF-beta. Our observations, taken together, indicate that inactivation of the RII contributes to the resistance to TGF-beta of some cervical carcinoma cell lines. Loss of or attenuated sensitivity to TGF-beta growth inhibition in other cells may be attributed to the disruption of distal components in the TGF-beta signal pathway, but not to the receptor system. Int. J. Cancer 77:620-625, 1998. (C) 1998 Wiley-Liss, Inc. C1 Seoul Natl Univ, Coll Med, Canc Res Ctr, Seoul, South Korea. Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul 151, South Korea. Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Bang, YJ (reprint author), Seoul Natl Univ Hosp, Dept Internal Med, 28 Yongon Dong Chongno Ku, Seoul 110799, South Korea. RI Song, Yong Sang/E-7824-2012; Bang, Yung Jue/J-2759-2012 NR 30 TC 38 Z9 41 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 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD AUG 12 PY 1998 VL 77 IS 4 BP 620 EP 625 DI 10.1002/(SICI)1097-0215(19980812)77:4<620::AID-IJC23>3.3.CO;2-5 PG 6 WC Oncology SC Oncology GA 102PF UT WOS:000074932500023 PM 9679767 ER PT J AU Kim, WH Nomizu, M Song, SY Tanaka, K Kuratomi, Y Kleinman, HK Yamada, Y AF Kim, WH Nomizu, M Song, SY Tanaka, K Kuratomi, Y Kleinman, HK Yamada, Y TI Laminin-alpha 1-chain sequence Leu-Gln-Val-Gln-Leu-Ser-Ile-Arg (LQVQLSIR) enhances murine melanoma cell metastases SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID LAMININ-A-CHAIN; BASEMENT-MEMBRANE; TUMOR-CELLS; MESSENGER-RNA; ADHESION; PEPTIDES; IDENTIFICATION; PENTAPEPTIDE; PROTEIN; DOMAIN AB We earlier screened overlapping synthetic peptides from the globular domain of the laminin alpha 1 chain to identify active sites for cell attachment. We report here that one of the active cell-adhesion peptides, AG-73 (Arg-Lys-Arg-Leu-Gln-Val-Gln-Leu-Ser-Ile-Arg-Thr; RKRLQVQLSIRT) causes B16-F10 murine melanoma cells to metastasize to the liver, a site not normally colonized by these cells. Increases in liver metastases and in lung colonization are observed in immune-deficient beige/nude/xid and in C57BI/6 mice with this peptide. This metastatic activity was observed with i.v. and with i.p. peptide injections, regardless of tumor cell or of peptide-injection times. In vitro, the AG-73 peptide enhances tumor cell adhesion, migration, invasion, and gelatinase production, and blocks laminin-1-mediated cell migration. AG-73 was found to significantly inhibit cell adhesion to a proteolytic laminin-1 fragment, E3, containing the AG-73 sequence. Cell attachment to AG-73, the E3 fragment, and laminin-1 involved cation-dependent receptors. We report that a laminin peptide has the novel and unexpected activity of causing B16F10 melanoma cells, a lung selected cell line, to metastasize to the liver. The minimal active sequence of AG-73, LQVQLSIR, could be one of the most important biologically active sites of laminin-1, especially in promotion of the malignant phenotype. Activation of the malignant phenotype by this peptide provides a significant new model for understanding metastatic mechanisms. Int. i. Cancer 77:632-639, 1998. (C) 1998 Wiley-Liss, Inc.dagger. C1 NIDR, NIH, Bethesda, MD 20892 USA. RP Kleinman, HK (reprint author), NIDR, NIH, Bldg 30,Room 433,30 Convent Dr MSC 4370, Bethesda, MD 20892 USA. EM kleinman@yoda.nidr.nih.gov NR 32 TC 46 Z9 47 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 AUG 12 PY 1998 VL 77 IS 4 BP 632 EP 639 DI 10.1002/(SICI)1097-0215(19980812)77:4<632::AID-IJC25>3.0.CO;2-6 PG 8 WC Oncology SC Oncology GA 102PF UT WOS:000074932500025 PM 9679769 ER PT J AU Ioannidis, JPA Cappelleri, JC Lau, J AF Ioannidis, JPA Cappelleri, JC Lau, J TI Comparing results from meta-analyses vs large trials - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID MYOCARDIAL-INFARCTION C1 NIH, Bethesda, MD 20892 USA. Pfizer Inc, Pfizer Cent Res, Groton, CT 06340 USA. Tufts Univ, New England Med Ctr Hosp, Boston, MA 02111 USA. RP Ioannidis, JPA (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. RI Ioannidis, John/G-9836-2011 NR 5 TC 0 Z9 0 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 12 PY 1998 VL 280 IS 6 BP 518 EP 519 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 108AY UT WOS:000075244900022 ER PT J AU Mofenson, LM AF Mofenson, LM TI Perinatal transmission of HIV in women receiving zidovudine - Abstract and commentary SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID HUMAN-IMMUNODEFICIENCY-VIRUS; REDUCTION; INFANT; TYPE-1 C1 NICHHD, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD 20892 USA. RP Mofenson, LM (reprint author), NICHHD, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD 20892 USA. NR 10 TC 2 Z9 2 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 12 PY 1998 VL 280 IS 6 BP 569 EP 570 DI 10.1001/jama.280.6.569 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 108AY UT WOS:000075244900039 PM 9707153 ER PT J AU Freedberg, DI Wang, YX Stahl, SJ Kaufman, JD Wingfield, PT Kiso, Y Torchia, DA AF Freedberg, DI Wang, YX Stahl, SJ Kaufman, JD Wingfield, PT Kiso, Y Torchia, DA TI Flexibility and function in HIV protease: Dynamics of the HIV-1 protease bound to the asymmetric inhibitor kynostatin 272 (KNI-272) SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID MODEL-FREE APPROACH; ROTATIONAL DIFFUSION ANISOTROPY; MAGNETIC-RESONANCE RELAXATION; HUMAN-IMMUNODEFICIENCY-VIRUS; N-15 NMR RELAXATION; BACKBONE DYNAMICS; MOLECULAR-DYNAMICS; SPECTROSCOPY; PROTEINS; MACROMOLECULES AB The HIV-1 protease is a 22 kDa homodimeric protein essential-for function of the AIDS virus, and protease inhibitors have been developed into effective HN drugs. In order to better understand HIV-1 protease-inhibitor interactions, we have investigated amide backbone dynamics by correlated H-1-N-15 NMR spectroscopy. To date, HIV-1 protease/inhibitor complexes Studied by NMR Spectroscopy have been limited to C-2 symmetric structures, consisting of the protease bound to a symmetric inhibitor. Herein we report studies of the dynamics of HIV-1 protease complexed to KNI-272, a potent (K-i ca. 5 pM), asymmetric inhibitor which lifts the chemical shift degeneracy of the protease monomers and allows us to ascertain if the individual protease monomers have significantly different backbone motions. Using isotope filtered/edited spectra of N-15/C-13 protease complexed with unlabeled KNI-272, together with distances derived from the protease/KNI-272 X-ray structure, we obtained monomer specific NMR signal assignments. We derived information about monomer dynamics from a Lipari-Szabo analysis of amide N-15 T-1, T-2,and NOE values. Modeling the complex as an axially symmetric:rotor yielded an average overall correlation time of 9.65 ns and an anisotropy, D-parallel to/D-perpendicular to, of 1.27. Over 90% of the backbone amide sites are highly ordered with the squared order parameter, averaged over all measured residues, being 0.85. High amplitude internal motions are observed in several loops in the protease; especially those in the elbows of the flaps, while millisecond to microsecond time scale motion is observed at the flap-tips. While these results are similar to those reported for complexes with symmetric inhibitors, we find differences in internal motions between several residues in the flap of one monomer and the corresponding residues on the other monomer. Residue Gly 149 has a significantly larger-order parameter than Gly 49; in addition, the motions on the chemical exchange time scale contribute to the relaxation of Gly 152 and Phe 153 but not to the relaxation of Gly 52 and Phe 53. These differences inflexibility correlate with differences in interactions made-by these residues with KNI-272, as seed in the crystal structure.; We also find that: the average of the order parameters measured for residues in monomer 1 is less than for monomer 2, a result that correlates with the observation that average (B) over dot factor for these residues is less in monomer 2 than in monomer 1. C1 Natl Inst Dent Res, Struct Mol Biol Unit, NIH, Bethesda, MD 20892 USA. National Institute Arthritis & Musculoskeletal &, Bethesda, MD 20892 USA. Kyoto Pharmaceut Univ, Yamashima Ku, Kyoto 607, Japan. RP Torchia, DA (reprint author), Natl Inst Dent Res, Struct Mol Biol Unit, NIH, Bethesda, MD 20892 USA. EM torchia@yoda.nidr.nih.gov NR 47 TC 40 Z9 40 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD AUG 12 PY 1998 VL 120 IS 31 BP 7916 EP 7923 DI 10.1021/ja981206r PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA 111CQ UT WOS:000075420100029 ER PT J AU Kitsiou, AN Srinivasan, G Quyyumi, AA Summers, RM Bacharach, SL Dilsizian, V AF Kitsiou, AN Srinivasan, G Quyyumi, AA Summers, RM Bacharach, SL Dilsizian, V TI Stress-induced reversible and mild-to-moderate irreversible thallium defects - Are they equally accurate for predicting recovery of regional left ventricular function after revascularization? SO CIRCULATION LA English DT Article DE coronary disease; scintigraphy; myocardium; ischemia; revascularization ID CORONARY-ARTERY DISEASE; MYOCARDIAL VIABILITY; VIABLE MYOCARDIUM; BYPASS SURGERY; BLOOD-FLOW; DOBUTAMINE ECHOCARDIOGRAPHY; HIBERNATING MYOCARDIUM; STUNNED MYOCARDIUM; EJECTION FRACTION; DYSFUNCTION AB Background-In patients with coronary artery disease, stress-redistribution-reinjection thallium scintigraphy provides important information regarding myocardial ischemia and viability. Although both reversible and mild-to-moderate irreversible thallium defects retain metabolically active, viable myocardium, we hypothesized that stress-induced reversible thallium defects may better differentiate reversible from irreversible regional left ventricular dysfunction after revascularization. Methods and Results-Twenty-four patients with chronic coronary artery disease underwent prerevascularization and postrevascularization exercise-redistribution-reinjection thallium single photon emission CT, gated MRI, and radionuclide angiography. After revascularization, mean left ventricular ejection fraction increased from 30 +/- 9% to 37 +/- 13% at rest (P < 0.001). Before revascularization, abnormal contraction at rest was observed in 56 of 110 reversible and 20 of 37 mild-to-moderate irreversible thallium defects (51% and 54%, respectively). After revascularization, regional contraction improved in 44 of 56 reversible compared with 6 of 20 mild-to-moderate irreversible thallium defects (79% and 30%, respectively; P < 0.001). The final thallium content (maximum tracer uptake on redistribution-reinjection images) was significantly higher in regions with reversible defects that improved than in those that did not improve after revascularization (86 +/- 16% versus 66 +/- 9%, P < 0.001). In contrast, final thallium content was similar in regions with mild-to-moderate irreversible defects that improved and in those that did not improve after revascularization (69 +/- 9% versus 65 +/- 10%, P = NS), Furthermore, when asynergic regions were grouped according to the final thallium content, at 60% threshold value, functional recovery was observed in 83% of regions with reversible defects compared with 33% of regions with mild-to-moderate irreversible defects (P < 0.001). Conclusions-These findings suggest that although both reversible and mild-to-moderate irreversible thallium defects after stress retain viable myocardium, the identification of reversible thallium defect on stress in an asynergic region more accurately predicts recovery of function after revascularization. Even at a similar mass of viable myocardial tissue las reflected by the final thallium content), the presence of inducible ischemia is associated with an increased likelihood of functional recovery. C1 NHLBI, Cardiol Branch, NIH, Ctr Clin, Bethesda, MD 20892 USA. NIH, Dept Nucl Med, Bethesda, MD 20892 USA. RP Dilsizian, V (reprint author), NHLBI, Cardiol Branch, NIH, Ctr Clin, 10 Ctr Dr,Bldg 10,Room 7B-15, Bethesda, MD 20892 USA. NR 38 TC 72 Z9 74 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 11 PY 1998 VL 98 IS 6 BP 501 EP 508 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 107WJ UT WOS:000075233700006 PM 9714106 ER PT J AU Summers, RM Andrasko-Bourgeois, J Feuerstein, IM Hill, SC Jones, EC Busse, MK Wise, B Bove, KE Rishforth, BA Tucker, E Spray, TL Hoeg, JM AF Summers, RM Andrasko-Bourgeois, J Feuerstein, IM Hill, SC Jones, EC Busse, MK Wise, B Bove, KE Rishforth, BA Tucker, E Spray, TL Hoeg, JM TI Evaluation of the aortic root by MRI - Insights from patients with homozygous familial hypercholesterolemia SO CIRCULATION LA English DT Article; Proceedings Paper CT 4th Annual Scientific Meeting of the International-Society-for-Magnetic-Resonance-in-Medicine CY APR 27-MAY 03, 1996 CL NEW YORK, NEW YORK SP Int Soc Magnet Resonance Med DE atherosclerosis; magnetic resonance imaging; vasculature; cholesterol; aorta ID CORONARY OSTIAL STENOSIS; ELECTRON-BEAM CT; ECHOCARDIOGRAPHIC ASSESSMENT; CALCIFIC ATHEROSCLEROSIS; COMPUTED-TOMOGRAPHY; DISEASE AB Background-In homozygous familial hypercholesterolemia (HFH), the aortic root is prone to develop atherosclerotic plaque at an early age. However, the aortic wall and plaque have not yet been assessed in this condition by MRI, We evaluated the aortic root by use of MRI in 17 HFH patients and 12 normal control subjects in a prospective, blinded, controlled study. Methods and Results-Morphological assessment of the aortic root was done with spin-echo and gradient-echo MRI scanning. Comparisons were made with a number of measures of disease severity, including cholesterol-year score, calcium score on electron-beam CT (EBCT), and size of Achilles tendon xanthomas, Atherosclerotic plaque, visible on fat-suppressed images but never on water-suppressed images, was present in 9 HFH patients (53%). Supravalvular aortic stenosis was present in 7 patients with HFH (41%). Maximum supravalvular aortic wall thickness was significantly greater and OD and lumen cross-sectional area (CSA) were smaller in patients than in control subjects (P = 0.006, 0.0005, and 0.06, respectively). Maximum wall thickness was associated with a greater calcium score on electron-beam CT (P = 0.02). Although the cumulative exposure of the aortic root to cholesterol (the cholesterol-year score) was significantly correlated with the Achilles tendon CSA and vascular calcification, this score did not correlate with the wall thickness or aortic CSA. Conclusions-This study not only demonstrates the utility of MRI for detecting and characterizing aortic root atherosclerotic plaque and supravalvular aortic stenosis in HFH patients but also suggests that the LDL receptor plays a direct or indirect role in aortic mural development and vascular growth. C1 NCI, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. NHLBI, Bethesda, MD 20892 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. RP Summers, RM (reprint author), NCI, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, Bldg 10,Room 1C660,10 Ctr Dr,MSC 1182, Bethesda, MD 20892 USA. EM rms@nih.gov NR 28 TC 56 Z9 58 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 11 PY 1998 VL 98 IS 6 BP 509 EP 518 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 107WJ UT WOS:000075233700007 PM 9714107 ER PT J AU Tomizawa, M Garfield, S Factor, V Xanthopoulos, KG AF Tomizawa, M Garfield, S Factor, V Xanthopoulos, KG TI Hepatocytes deficient in CCAAT/enhancer binding protein alpha (C/EBP alpha) exhibit both hepatocyte and biliary epithelial cell character SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE knockout mice; transcription factors; development; cell differentiation; A6; hepatoblasts ID TRANSCRIPTION FACTORS; LIVER DEVELOPMENT; MOUSE; DIFFERENTIATION; OVAL; EXPRESSION; LINEAGES; FETAL; MICE AB To further elucidate the role of CCAAT/Enhancer Binding Protein alpha (C/EBP alpha) in hepatocyte differentiation, we investigated fetal and newborn C/EBP alpha-deficient (C/EBP alpha -/-) mice using confocal microscopy and markers specific for hepatocyte (AFP) and biliary epithelial cell (A6) differentiation. Histologically, in fetal liver of C/EBP alpha -/- mice, pseudoglandular structures appeared starting at 16.5 days of gestation, In newborn livers, the diameters of these structures greatly increased. They were randomly distributed between portal and central veins and interfered with the establishment of normal hepatic plates. However, the portal bile ducts developed normally. The pseudoglandular structures were lined with small hepatocytes with round nuclei and were positive for both AFP and A6 antigens. These data show that C/EBP alpha -/- hepatocytes exhibit biliary epithelial cell characters and suggest an involvement of C/EBP alpha in the control of the switch in the differentiation of bi-potential hepatoblasts along the hepatocyte lineage, (C) 1998 Academic Press. C1 Natl Human Genome Res Inst, CGTB, NIH, Bethesda, MD 20892 USA. NCI, DBS, NIH, Bethesda, MD 20892 USA. RP Tomizawa, M (reprint author), Natl Human Genome Res Inst, CGTB, NIH, Bethesda, MD 20892 USA. NR 18 TC 32 Z9 32 U1 1 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 AUG 10 PY 1998 VL 249 IS 1 BP 1 EP 5 DI 10.1006/bbrc.1998.8999 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 110CR UT WOS:000075363000001 PM 9705820 ER PT J AU Zeng, FY Oka, JA Weigel, PH AF Zeng, FY Oka, JA Weigel, PH TI A specific antibody to the carbohydrate recognition domain of the asialoglycoprotein receptor RHL1 subunit does not react with RHL2/3 but blocks ligand binding SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID ISOLATED RAT HEPATOCYTES; MAJOR SUBUNIT; GALACTOSYL RECEPTORS; MICE LACKING; 2 SUBUNITS; LIVER; SURFACE; FORMS; HETEROOLIGOMERS; ENDOCYTOSIS AB The rat asialoglycoprotein receptor (ASGPR) is believed to be a hetero oligomer composed of three subunits, designated rat hepatic lectin 1, 2, and 3 (RHL1, 2, and 3). The carbohydrate recognition domains (CRDs) of RHL1 and RHL2/3 are 56% identical. We developed a polyclonal antibody that specifically recognizes the CRD of RHL1 but not RHL2/3. When purified ASGPRs were bound to ligand-Sepharose, the CRD of RHL1, but not RHL2 or RHLS, was resistant to digestion with subtilisin. Antibody against purified RHL1 CRD recognized only RHL1 in Western blot analysis of crude cell extracts or purified receptors without detectable cross-reaction to RHL2/3. Although it does not recognize the CRD of RHL2 or RHLS, this antibody specifically inhibited 80-90% of the cell surface or total cellular I-125-ASOR binding to isolated rat hepatocytes and >90% of ligand binding to purified rat ASGPRs. The antibody also immunoprecipitates active ASGPRs containing all three RHL subunits. The results indicate that homo-oligomeric RHL2/3 complexes, able to bind ASOR, do not form on hepatocytes by subunit rearrangement. (C) 1998 Academic Press. C1 Univ Oklahoma, Hlth Sci Ctr, Dept Biochem & Mol Biol, Oklahoma City, OK 73190 USA. RP Weigel, PH (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bldg 8A,Room BIA-09, Bethesda, MD 20892 USA. FU NIGMS NIH HHS [GM 49695] NR 23 TC 3 Z9 4 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 AUG 10 PY 1998 VL 249 IS 1 BP 236 EP 240 DI 10.1006/bbrc.1998.9120 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 110CR UT WOS:000075363000045 PM 9705864 ER PT J AU Marmorstein, AD Gan, YC Bonilha, VL Finnemann, SC Csaky, KG Rodriguez-Boulan, E AF Marmorstein, AD Gan, YC Bonilha, VL Finnemann, SC Csaky, KG Rodriguez-Boulan, E TI Apical polarity of N-CAM and EMMPRIN in retinal pigment epithelium resulting from suppression of basolateral signal recognition SO JOURNAL OF CELL BIOLOGY LA English DT Article DE adenovirus gene transfer; interphotoreceptor matrix; p75-; NTR; polarity; RET-PE2 ID HEPATOCYTE PLASMA-MEMBRANE; MOUSE INTERPHOTORECEPTOR MATRIX; CANINE KIDNEY-CELLS; MDCK CELLS; IMMUNOGLOBULIN SUPERFAMILY; PROTEIN RET-PE2; NEURAL RETINA; RAT; DOMAIN; NA+,K+-ATPASE AB Retinal pigment epithelial (RPE) cells apically polarize proteins that are basolateral in other epithelia. This reversal may be generated by the association of RPE with photoreceptors and the interphotoreceptor matrix, postnatal expansion of the RPE apical surface, and/or changes in RPE sorting machinery. We compared two proteins exhibiting reversed, apical polarities in RPE cells, neural cell adhesion molecule (N-CAM; 140-kD isoform) and extracellular matrix metalloproteinase inducer (EMMPRIN), with the cognate apical marker, p75-neurotrophin receptor (p75-NTR). N-CAM and p75-NTR were apically localized from birth to adulthood, contrasting with a basolateral to apical switch of EMMPRIN in developing postnatal rat RPE. Morphometric analysis demonstrated that this switch cannot be attributed to expansion of the apical surface of maturing RPE because the basolateral membrane expanded proportionally, maintaining a 3:1 apical/basolateral ratio. Kinetic analysis of polarized surface delivery in MDCK and RPE-J cells showed that EMMPRIN has a basolateral signal in its cytoplasmic tail recognized by both cell lines. In contrast, the basolateral signal of N-CAM is recognized by MDCK cells but not RPE-J cells. Deletion of N-CAM's basolateral signal did not prevent its apical localization in vivo. The data demonstrate that the apical polarity of EMMPRIN and N-CAM in mature RPE results from suppressed decoding of specific basolateral signals resulting in randomized delivery to the cell surface. C1 Cornell Univ Med Coll, Dept Ophthalmol, Margaret M Dyson Vis Res Inst, New York, NY 10021 USA. Cornell Univ Med Coll, Dept Cell Biol & Anat, New York, NY 10021 USA. NEI, Immunol Lab, Bethesda, MD 20892 USA. RP Rodriguez-Boulan, E (reprint author), Cornell Univ Med Coll, Dept Ophthalmol, Margaret M Dyson Vis Res Inst, 1300 York Ave, New York, NY 10021 USA. EM Boulan@mail.med.cornell.edu FU NEI NIH HHS [R01-EY08538, F32 EY06669, F32 EY006669, R01 EY008538] NR 60 TC 41 Z9 41 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD AUG 10 PY 1998 VL 142 IS 3 BP 697 EP 710 DI 10.1083/jcb.142.3.697 PG 14 WC Cell Biology SC Cell Biology GA 111AT UT WOS:000075415700008 PM 9700159 ER PT J AU Percy, E Singh, M Takahashi, T Takeuchi, Y Kirk, KL AF Percy, E Singh, M Takahashi, T Takeuchi, Y Kirk, KL TI Synthesis of E- and Z-alpha-fluorourocanic acids as potential inhibitors of urocanase SO JOURNAL OF FLUORINE CHEMISTRY LA English DT Article DE E- and Z-alpha-fluorourocanic acids; urocanase; inhibitor AB Reaction of 1-trityl-4-imidazole carboxaldehyde with triethyl 2-fluoro-2-phosphonoacetate produced an E/Z mixture of ethyl 2-fluoro-3-(1-triphenylmethylimidazol-4-yl]-2-propenoates (1a,b). [GRAPHICS] After separation of the geometric isomers, acid hydrolysis produced the corresponding urocanic acids (2a,b), Neither isomer was a substrate or inhibitor of urocanase. (C) 1998 Elsevier Science S.A. All rights reserved. C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Toyama Med & Pharmaceut Univ, Fac Pharmaceut Sci, Toyama 93001, Japan. RP Kirk, KL (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NR 9 TC 14 Z9 14 U1 1 U2 2 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 0022-1139 J9 J FLUORINE CHEM JI J. Fluor. Chem. PD AUG 10 PY 1998 VL 91 IS 1 BP 5 EP 7 DI 10.1016/S0022-1139(98)00196-1 PG 3 WC Chemistry, Inorganic & Nuclear; Chemistry, Organic SC Chemistry GA 112MA UT WOS:000075497400002 ER PT J AU Bicout, DJ Szabo, A AF Bicout, DJ Szabo, A TI Electron transfer reaction dynamics in non-Debye solvents SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID CONTROLLED INTRACHAIN REACTIONS; POLAR-SOLVENTS; TRANSFER KINETICS; SIMULATION; ACTIVATIONLESS; TRANSITION; POLYMERS; QUANTUM; REGIME AB The dynamics of electron transfer in a non-Debye solvent is described by multidimensional Markovian reaction-diffusion equation. To highlight differences with existing approaches in the simplest possible context, the irreversible outer-sphere reaction in a solvent with a biexponential energy-gap autocorrelation function, Delta(t), is studied in detail. In a Debye solvent, Delta(t)= exp(-t/tau(L)) and the rate can be rigorously expressed as an explicit functional of exp(-t/tau(L)) It has been suggested that the exact rate in a non-Debye solvent can be found by replacing exp(-t/tau(L)) With the appropriate (nonexponential) Delta(t). For a ''biexponential'' solvent, our approach is based on an anisotropic diffusion equation for motion on a harmonic surface in the presence of a two-dimensional delta function sink. Three approximations, which reduce the solution of this equation to effective one-dimensional ones, are considered and compared with exact Brownian dynamics simulation results. The crudest approximation replaces the non-Debye solvent with an effective Debye one with tau(eff)(-1)=(-d Delta/dt)(t=0). The second is obtained by invoking the Wilemski-Fixman-type closure approximation for the equivalent two-dimensional integral equation. This approximation turns out to be identical to the above mentioned ''substitution'' procedure. When the relaxation times of the two exponentials are sufficiently different, it is shown how the two-dimensional problem can be reduced to a one-dimensional one with a nonlocal sink function. This anisotropic relaxation time approximation is in excellent agreement with simulations when the relaxation times differ by at least a factor of three and the activation energy is greater than k(B)T. Finally, it is indicated how the influence of intramolecular vibrational modes (i,e., nonlocal sink functions) can be treated within the framework of this formalism. (C) 1998 American Institute of Physics. [S0021-9606(98)50930-0]. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bicout, DJ (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5,Room 136, Bethesda, MD 20892 USA. RI Szabo, Attila/H-3867-2012 NR 32 TC 76 Z9 76 U1 2 U2 7 PU AMER INST PHYSICS PI WOODBURY PA CIRCULATION FULFILLMENT DIV, 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2999 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD AUG 8 PY 1998 VL 109 IS 6 BP 2325 EP 2338 DI 10.1063/1.476800 PG 14 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 107XW UT WOS:000075237100035 ER PT J AU Wellems, TE Wootton, JC Fujioka, H Su, XZ Cooper, R Baruch, D Fidock, DA AF Wellems, TE Wootton, JC Fujioka, H Su, XZ Cooper, R Baruch, D Fidock, DA TI P-falciparum CG2, linked to chloroquine resistance, does not resemble Na+/H+ exchangers SO CELL LA English DT Article C1 NIAID, NIH, Bethesda, MD 20892 USA. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. RP Wellems, TE (reprint author), NIAID, NIH, Bethesda, MD 20892 USA. OI Fidock, David/0000-0001-6753-8938 NR 10 TC 21 Z9 21 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD AUG 7 PY 1998 VL 94 IS 3 BP 285 EP 286 DI 10.1016/S0092-8674(00)81471-3 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 109EN UT WOS:000075308400004 PM 9708730 ER PT J AU McMahon, SB Van Buskirk, HA Dugan, KA Copeland, TD Cole, MD AF McMahon, SB Van Buskirk, HA Dugan, KA Copeland, TD Cole, MD TI The novel ATM-related protein TRRAP is an essential cofactor for the c-Myc and E2F oncoproteins SO CELL LA English DT Article ID NEOPLASTIC TRANSFORMATION; ATAXIA-TELANGIECTASIA; ONCOGENIC ACTIVITY; REPRESSOR SIN3; GENE-PRODUCT; LINEAR-SPACE; KINASE; TRANSCRIPTION; APOPTOSIS; BINDING AB The c-Myc and E2F transcription factors are among the most potent regulators of cell cycle progression in higher eukaryotes. This report describes the isolation of a novel, highly conserved 434 kDa protein, designated TRRAP, which interacts specifically with the c-Myc N terminus and has homology to the ATM/PI3- kinase family. TRRAP also interacts specifically with the E2F-1 transactivation domain. Expression of transdominant mutants of the TRRAP protein or antisense RNA blocks c-Myc- and E1A-mediated oncogenic transformation. These data suggest that TRRAP is an essential cofactor for both the c-Myc and E1A/E2F oncogenic transcription factor pathways. C1 Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA. NCI, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Cole, MD (reprint author), Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA. NR 52 TC 411 Z9 421 U1 1 U2 18 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD AUG 7 PY 1998 VL 94 IS 3 BP 363 EP 374 DI 10.1016/S0092-8674(00)81479-8 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 109EN UT WOS:000075308400012 PM 9708738 ER PT J AU Pease, JE Wang, J Ponath, PD Murphy, PM AF Pease, JE Wang, J Ponath, PD Murphy, PM TI The N-terminal extracellular segments of the chemokine receptors CCR1 and CCR3 are determinants for MIP-1 alpha and eotaxin binding, respectively, but a second domain is essential for efficient receptor activation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN INTERLEUKIN-8 RECEPTOR; FUNCTIONAL EXPRESSION; MOLECULAR-CLONING; AMINO TERMINUS; HIV-1 ENTRY; LIGAND; CHEMOATTRACTANT; RANTES; CXC; SELECTIVITY AB CCR1 and CCR3 are seven-transmembrane domain G protein-coupled receptors specific for members of the CC chemokine subgroup of leukocyte chemoattractants, Both have been implicated in the inflammatory response, and CCR3, through its expression on eosinophils, basophils, and Th2 lymphocytes, may be especially important in allergic inflammation. CCR1 and CCR3 are 54% identical in amino acid sequence and share some ligands but not others. In particular, macrophage inflammatory protein la (MIP-la) is a ligand for CCR1 but not CCR3, and eotaxin is a ligand for CCR3 but not CCR1. To map ligand selectivity determinants and to guide rational antagonist design, we analyzed CCR1: CCR3 chimeric receptors, When expressed in mouse pre-B cells, chimeras in which the N-terminal extracellular segments were switched were both able to bind both MIP-1 alpha and eotaxin, but in each case, binding occurred via separate sites. Nevertheless, neither MIP-1 alpha nor eotaxin were effective agonists at either chimeric receptor in either calcium flux or chemotaxis assays. These data are consistent with a multi-site model for chemokine-chemokine receptor interaction in which one or more subsites determine chemokine selectivity, but others are needed for receptor activation. Agents that bind to the N-terminal segments of CCR1 and CCR3 may be useful in blocking receptor function. C1 Univ Sheffield, Krebs Inst, Sheffield S10 2TN, S Yorkshire, England. NIAID, Host Def Lab, Bethesda, MD 20892 USA. LeukoSite Inc, Cambridge, MA 02142 USA. RP Ponath, PD (reprint author), Univ London Imperial Coll Sci Technol & Med, Sch Med, Div Biomed Sci, Exhibit Rd, London SW7 2AZ, England. NR 44 TC 80 Z9 83 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 AUG 7 PY 1998 VL 273 IS 32 BP 19972 EP 19976 DI 10.1074/jbc.273.32.19972 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 109DF UT WOS:000075305400009 PM 9685332 ER PT J AU Zhang, Q Cox, D Tseng, CC Donaldson, JG Greenberg, S AF Zhang, Q Cox, D Tseng, CC Donaldson, JG Greenberg, S TI A requirement for ARF6 in Fc gamma receptor-mediated phagocytosis in macrophages SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ADP-RIBOSYLATION FACTOR; PERIPHERAL MEMBRANE-PROTEIN; BREFELDIN-A; GOLGI MEMBRANES; NUCLEOTIDE-EXCHANGE; GUANINE-NUCLEOTIDE; MOUSE MACROPHAGES; CELLS; APPARATUS; BINDING AB Phagocytosis requires extension of F-actin-rich pseudopods and is accompanied by membrane fusion events. Members of the ARF family of GTPases are essential for many aspects of membrane trafficking. To test a role for this family of proteins in Fc gamma receptor-mediated phagocytosis, we utilized the fungal metabolite brefeldin A (BFA). The addition of 100 mu M BFA to a subclone of RAW 264.7 macrophages disrupted the appearance and function of the Golgi apparatus as indicated by altered immunofluorescent distribution of P-COP and reduced efflux of BODIPY C-5-ceramide, a phospholipid that normally accumulates in the Gels apparatus. In contrast, BFA had no effect on phagocytosis of IgG-coated erythrocytes. These results suggested that activation of BFA-sensitive ARFs is not required for phagocytosis, ARF6 is unique among members of the ARF family in that its membrane association is unaffected by BFA. Expression of ARF6 mutants defective in either GTP hydrolysis (Q67L) or binding (T27N) inhibited phagocytosis of IgG-coated erythrocytes and attenuated the focal accumulation of F-actin beneath the test particles. These results indicate a requirement for ARF6 in Fc gamma receptor-mediated phagocytosis and suggest that ARF6 is an important mediator of cytoskeletal alterations after Fc gamma receptor activation. C1 Columbia Univ, Dept Med & Pharmacol, Coll Phys & Surg, New York, NY 10032 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Greenberg, S (reprint author), Columbia Univ, Dept Med & Pharmacol, Coll Phys & Surg, PH8C,630 W 168th St, New York, NY 10032 USA. EM greenberg@cuccfa.ccc.columbia.edu NR 35 TC 151 Z9 153 U1 3 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 AUG 7 PY 1998 VL 273 IS 32 BP 19977 EP 19981 DI 10.1074/jbc.273.32.19977 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 109DF UT WOS:000075305400010 PM 9685333 ER PT J AU Sattlegger, E Hinnebusch, AG Barthelmess, IB AF Sattlegger, E Hinnebusch, AG Barthelmess, IB TI cpc-3, the Neurospora crassa homologue of yeast GCN2, encodes a polypeptide with juxtaposed eIF2 alpha kinase and histidyl-tRNA synthetase-related domains required for general amino acid control SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSFER-RNA-SYNTHETASE; FACTOR-2-ALPHA EIF-2-ALPHA KINASE; ARGININE BIOSYNTHETIC ENZYMES; CROSS-PATHWAY REGULATION; PROTEIN-KINASE; INITIATION FACTOR-2-ALPHA; SACCHAROMYCES-CEREVISIAE; TRANSLATIONAL CONTROL; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI AB Based on characteristic amino acid sequences of kinases that phosphorylate the alpha subunit of eukaryotic translation initiation factor 2 (eIF2 alpha kinases), degenerate oligonucleotide primers were constructed and used to polymerase chain reaction-amplify from genomic DNA of Neurospora crassa a sequence encoding part of a putative protein kinase. With this sequence an open reading frame was identified encoding a predicted polypeptide with juxtaposed eIF2 alpha kinase and histidyl-tRNA synthetase-related domains. The 1646 amino acid sequence of this gene, called cpc-3, showed 35% positional identity over almost the entire sequence with GCN2 of yeast, which stimulates translation of the transcriptional activator of amino acid biosynthetic genes encoded by GCN4, Strains disrupted for cpc-3 were unable to induce increased transcription and derepression of amino acid biosynthetic enzymes in amino acid-deprived cells. The cpc-3 mutation did not affect the ability to up-regulate mRNA levels of cpc-1, encoding the GCN4 homologue and transcriptional activator of amino acid biosynthetic genes in N. crassa, but the mutation abolished the dramatic increase of CPC1 protein level in response to amino acid deprivation, These findings suggest that cpc-3 is the functional homologue of GCN2, being required for increased translation of cpc-1 mRNA in amino acid-starved cells. C1 NICHD, Lab Eukaryot Gene Regulat, NIH, Bethesda, MD 20892 USA. Leibniz Univ Hannover, Inst Appl Genet, D-30419 Hannover, Germany. RP NICHD, Lab Eukaryot Gene Regulat, NIH, Bldg 6A,Rm B1A-05, Bethesda, MD 20892 USA. EM esattlegger@aghmac1.nichd.nih.gov NR 86 TC 34 Z9 35 U1 4 U2 6 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 AUG 7 PY 1998 VL 273 IS 32 BP 20404 EP 20416 DI 10.1074/jbc.273.32.20404 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 109DF UT WOS:000075305400071 PM 9685394 ER PT J AU O'Bryan, JP Lambert, QT Der, CJ AF O'Bryan, JP Lambert, QT Der, CJ TI The Src homology 2 and phosphotyrosine binding domains of the ShcC adaptor protein function as inhibitors of mitogenic signaling by the epidermal growth factor receptor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SH2 DOMAIN; AUTOPHOSPHORYLATION SITES; TYROSINE PHOSPHATASE; PHOSPHORYLATION; ASSOCIATION; KINASE; TRANSDUCTION; ACTIVATION; PATHWAYS; ASSAYS AB Upon ligand activation, the epidermal growth factor receptor (EGFR) becomes tyrosine-phosphorylated, thereby recruiting intracellular signaling protei:ns such as Shc. EGFR binding of Shc proteins results in their tyrosine phosphorylation and subsequent activation of the Ras and Erk pathways. Shc interaction wi th activated receptor tyrosine kinases is mediated by two distinct phosphotyrosine interaction domains, an NH2-terminal phosphotyrosine binding (PTB) domain and a COOH-terminal Src homology 2 (SH2) domain. The relative importance of these two domains for EGFR binding was examined by determining if expression of the isolated SH2 or PTB domain of ShcC would inhibit EGFR signaling. The SH2 domain potently inhibited numerous aspects of EGFR signaling including activation of Erb2 and the Elk-1 transcription factor as well as EGFR-dependent transformation. Furthermore, the SH2 domain inhibited focus formation by the Neu oncoprotein, another EGFR family member. Surprisingly, inhibition of the EGFR by the SH2 domain did not involve stable association with the receptor. In contrast, the PTB domain associated quite well with the receptor yet had little effect on EGFR signaling. Although the EGFR cytoplasmic tail contains consensus binding sites for the PTB and SH2 domains of ShcC, and both domains of ShcC interact with the receptor in vitro, the SH2 domain is more potent for inhibiting receptor function in vivo. However, inhibition is not due to stable association with the receptor, suggesting that the SH2 domain is binding to a heretofore unknown protein(s) necessary for proper EGFR function. C1 Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. RP O'Bryan, JP (reprint author), NIEHS, NIH, POB 12233,Bldg Rm 101-F332,MD F3-06, Res Triangle Pk, NC 27709 USA. EM obryan@niehs.nih.gov FU NCI NIH HHS [CA76570, CA68733, CA42978] NR 43 TC 24 Z9 25 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 AUG 7 PY 1998 VL 273 IS 32 BP 20431 EP 20437 DI 10.1074/jbc.273.32.20431 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 109DF UT WOS:000075305400074 PM 9685397 ER PT J AU Dimitriadis, EK Prasad, R Vaske, MK Chen, L Tomkinson, AE Lewis, MS Wilson, SH AF Dimitriadis, EK Prasad, R Vaske, MK Chen, L Tomkinson, AE Lewis, MS Wilson, SH TI Thermodynamics of human DNA ligase I trimerization and association with DNA polymerase beta SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BASE EXCISION-REPAIR; DOMAIN; IDENTIFICATION; RESIDUES; BINDING; SITE AB The interaction between human DNA polymerase beta (pol beta) and DNA Ligase I, which appear to be responsible for the gap filling and nick ligation steps in short patch or simple base excision repair, has been examined by affinity chromatography and analytical ultracentrifugation. Domain mapping studies revealed that complex formation is mediated through the non-catalytic N-terminal domain of DNA ligase I and the N-terminal 8-kDa domain of pol beta that interacts with the DNA template and excises 5'-deoxyribose phosphate residue. Intact pol beta, a 39-kDa bi-domain enzyme, undergoes indefinite self-association, forming oligomers of many sizes. The binding sites for self-association reside within the C-terminal 31-kDa domain. DNA ligase I undergoes self-association to form a homotrimer, At temperatures over 18 degrees C, three pol beta monomers attached to the DNA ligase I trimer, forming a stable heterohexamer, In contrast, at lower temperatures (<18 degrees C), pol beta and DNA ligase I formed a stable 1:1 binary complex only. In agreement with the domain mapping studies, the 8-kDa domain of pol beta interacted with DNA ligase I, forming a stable 3:3 complex with DNA ligase I at all temperatures, whereas the 31-kDa domain of pol beta did not. Our results indicate that the association between pol beta and DNA ligase I involves both electrostatic binding and an entropy-driven process. Electrostatic binding dominates the interaction mediated by the 8-kDa domain of pol beta, whereas the entropy-driven aspect of interprotein binding appears to be contributed by the 31-kDa domain. C1 NIEHS, LSB, NIH, Res Triangle Pk, NC 27709 USA. NIH, Biomed Engn & Phys Sci Program, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, Inst Biotechnol, Dept Mol Med, San Antonio, TX 78245 USA. RP Wilson, SH (reprint author), NIEHS, LSB, NIH, POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. FU NIGMS NIH HHS [R01 GM047251, GM47251] NR 33 TC 50 Z9 51 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 AUG 7 PY 1998 VL 273 IS 32 BP 20540 EP 20550 DI 10.1074/jbc.273.32.20540 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 109DF UT WOS:000075305400088 PM 9685411 ER PT J AU Roth, JS Ford, H Tanaka, M Mitsuya, H Kelley, JA AF Roth, JS Ford, H Tanaka, M Mitsuya, H Kelley, JA TI Determination of 2 '-beta-fluoro-2 ',3 '-dideoxyadenosine, an experimental anti-AIDS drug, in human plasma by high-performance liquid chromatography SO JOURNAL OF CHROMATOGRAPHY B LA English DT Article DE 2 '-beta-fluoro-2 ',3 '-dideoxyadenosine ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIRETROVIRAL AGENT; LYMPHOTROPIC VIRUS; BIOLOGICAL-FLUIDS; HTLV-III; INACTIVATION; HIV; 2',3'-DIDEOXYINOSINE; URINE; 2',3'-DIDEOXYADENOSINE AB 2'-beta-Fluoro-2',3'-dideoxyadenosine (F-ddA, lodenosine) is an experimental anti-AIDS drug currently being evaluated in a Phase I clinical trial. A simple and specific HPLC method with UV detection, suitable for use in clinical studies, has been developed to determine both F-ddA and its deaminated catabolite, 2'-beta-fluoro-2',3'-dideoxyinosine (F-ddI) in human plasma. After inactivation of plasma HIV by 0.5% Triton X-100, the compounds of interest are isolated and concentrated using solid-phase extraction. Processed samples are separated by use of a pH 4.8 buffered methanol gradient on a reversed-phase phenyl column. The method has a linear range of 0.05-5 mu g/ml (0.2-20 mu M) and intra-assay precision is better than 8%, Analyte recovery is quantitative and plasma protein binding is minimal. In addition, drug and metabolite levels measured in Triton-treated human plasma remain stable for at least 5 months when samples are stored frozen without further treatment. Compound concentrations determined after samples are processed and then frozen for up to 1 month before analysis are also unchanged. Published by Elsevier Science BN. C1 NCI, Med Chem Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NCI, Med Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Roth, JS (reprint author), NCI, Med Chem Lab, Div Basic Sci, NIH, Bldg 37,Room 5C-02,37 Convent Dr,MSC-4255, Bethesda, MD 20892 USA. NR 34 TC 12 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-4347 J9 J CHROMATOGR B JI J. Chromatogr. B PD AUG 7 PY 1998 VL 712 IS 1-2 BP 199 EP 210 DI 10.1016/S0378-4347(98)00144-3 PG 12 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 100RW UT WOS:000074830000021 PM 9698243 ER PT J AU Booy, FP Roden, RBS Greenstone, HL Schiller, JT Trus, BL AF Booy, FP Roden, RBS Greenstone, HL Schiller, JT Trus, BL TI Two antibodies that neutralize papillomavirus by different mechanisms show distinct binding patterns at 13 angstrom resolution SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE papillomavirus; cryo-electron microscopy; neutralizing antibodies; 3D structure; image reconstruction ID HERPES-SIMPLEX VIRUS; MONOCLONAL-ANTIBODIES; CRYOELECTRON MICROSCOPY; MEDIATED NEUTRALIZATION; 3-DIMENSIONAL STRUCTURE; BOVINE PAPILLOMAVIRUS; FAB FRAGMENTS; RECEPTOR; ATTACHMENT; CAPSIDS AB Complexes between bovine papillomavirus type 1 (BPV1) and examples of two sets of neutralizing, monoclonal antibodies (mAb) to the major capsid protein (L1) were analyzed by low-dose cryo-electron microscopy and three-dimensional (3D) image reconstruction to 13 Angstrom resolution. mAb #9 is representative of a set of neutralizing antibodies that can inhibit viral binding to the cell surface, while mAb 5B6 is representative of a second set that efficiently neutralizes papillomaviruses without significantly inhibiting viral binding to the cell surface. The 3D reconstructions reveal that mAb #9 binds to L1 molecules of both pentavalent and hexavalent capsomeres. In contrast, 5B6 binds only to hexavalent capsomeres, reflecting the significant structural or environmental differences for the 5B6 epitope in the 12 pentavalent capsomeres. Epitope localization shows that mAb #9 binds monovalently to the tips of capsomeres whereas 5B6 binds both monovalently and bivalently to the sides of hexavalent capsomeres approximately two-thirds of the way down from the outer tips, very close to the putative stabilizing intercapsomere connections. The absence of mAb 5B6 from the pentavalent capsomeres and its inability to prevent viral binding to the cell surface suggest that receptor binding may occur at one or more of the 12 virion vertices. (C) 1998 Academic Press C1 NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. NIH, Computat Biosci & Engn Lab, Div Comp Res & Technol, Bethesda, MD 20892 USA. RP Trus, BL (reprint author), NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. NR 50 TC 49 Z9 52 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 AUG 7 PY 1998 VL 281 IS 1 BP 95 EP 106 DI 10.1006/jmbi.1998.1920 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 108FK UT WOS:000075255200008 PM 9680478 ER PT J AU Thibaudeau, C Kumar, A Bekiroglu, S Matsuda, A Marquez, VE Chattopadhyaya, J AF Thibaudeau, C Kumar, A Bekiroglu, S Matsuda, A Marquez, VE Chattopadhyaya, J TI NMR conformation of (-)-beta-D-aristeromycin and its 2 '-deoxy and 3 '-deoxy counterparts in aqueous solution SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID HIV AIDS VIRUS; PSEUDOROTATIONAL EQUILIBRIUM; PENTOFURANOSE MOIETY; COUPLING-CONSTANTS; CRYSTAL-STRUCTURE; SUBSTITUENT ELECTRONEGATIVITIES; CARBOCYCLIC THYMIDINE; REVERSE-TRANSCRIPTASE; H-1-NMR SPECTROSCOPY; MOLECULAR-STRUCTURE AB The solution conformations of aristeromycin (1), 2'-deoxyaristeromycin (2), and 3'-deoxyaristeromycin (3) have been determined from an integrated analysis of X-ray (for 1 only), NMR data (i.e., (3)J(HH) coupling constants), and ab initio calculations. One-dimensional NOE difference experiments showed that the adenin-9-yl ring in 1 and 2 is involved in a similar to 50% syn reversible arrow similar to 50% anti equilibrium around the C-glycosyl torsion angle, whereas an anti orientation (chi = -113 degrees) is found in the X-ray crystal structure of 1. The preferred conformation around the gamma torsion angle is gamma(t) both in solution for 1-3 and in the solid state (for 1 only). The plots of energy as a function of the phase angle of pseudorotation (Figure 2) for the structures optimized by ab initio calculations (HF/3-21G *) show that there are two major wells of low energy conformers for 1-3, supporting the two-state North-type reversible arrow South/West-type equilibrium of the constituent cyclopentane rings in 1-3. The ab initio calculations suggested that the South/West-type conformers are more stable than the North-type forms for 1 [Delta E (120 degrees < P < 240 degrees) - (330 degrees < P < 30 degrees) similar to 10 kcal/mol], for 2 [Delta E (210 degrees < P < 240 degrees) - (330 degrees < P < 60 degrees) similar to 4 kcal/mol] and for 3 [Delta E (P = 240 degrees) - (330 degrees < P < 0 degrees) similar to 6 kcal/mol]. Newly developed A and B sets of parameters correlating the H-C-C-H torsions to the endocyclic torsions based on the ab initio optimised structures of 1-3 have been subsequently used to interpret the time-averaged (3)J(HH) couplings using the program PSEUROT. The discrepancy found between the X-ray crystal structure (P = 89 degrees, Psi(m) = 41 degrees) of aristeromycin (1) and its structure calculated by NMR-PSEUROT conformational analysis (35 degrees < P [T-3(4) - T-0(4)] < 65 degrees, 35 degrees < Psi(m) < 45 degrees) reversible arrow (128 degrees < P [E-1] < 131 degrees, 34 degrees < Psi(m) < 36 degrees) based on observed (3)J(HH) couplings in aqueous solution, as well as the relatively high error in the NMR-PSEUROT analyses for 1-3 [Delta J(max) less than or equal to 1.6 Hz (i.e., maximal difference between experimental and PSEUROT-calculated 3JHH) and root mean square (rms) error less than or equal to 0.7 Hz] prompted us to reparametrize the Karplus equation implemented in the PSEUROT program by using torsion angles derived from solid-state geometries of conformationally constrained nucleosides and their corresponding experimental (3)J(HH). The precision of our reparametrized Karplus-type equation (rms error = 0.40 Hz) became comparable to that expected for the standard Haasnoot-Altona Karplus (0.48 Hz) equation. The results of the PSEUROT analyses performed with the standard Haasnoot-Altona Karplus equation are also very comparable in terms of geometry with those based on our reparametrized equation (eq 4). Both series of PSEUROT analyses suggest that the predominant conformation of the cyclopentane ring in 1-3 is defined by 128 degrees < P < 140 degrees for 1, 105 degrees < P < 116 degrees for 2, and 118 degrees < P < 127 degrees for 3, with the puckering amplitude in the range from 34 degrees to 40 degrees for 1-3. However, PSEUROT analyses based on our Karplus equation produced a smaller rms error by less than or equal to 0.14 Hz and Delta J(max) error by less than or equal to 0.5 Hz than those performed with the standard Haasnoot-Altona equation. This work therefore highlights two important points: (i) the solution- and the solid-state structures of aristeromycin (1) are indeed different, and (ii) the close similarity of geometries derived from Haashoot-Altona's equation or from our Karplus equation suggest that the solution structures for 1-3 are correctly defined. C1 Univ Uppsala, Ctr Biomed, Dept Bioorgan Chem, S-75123 Uppsala, Sweden. NCI, NIH, DCT, DPT,Lab Med Chem, Bethesda, MD 20892 USA. Hokkaido Univ, Fac Pharmaceut Sci, Sapporo, Hokkaido 060, Japan. RP Chattopadhyaya, J (reprint author), Univ Uppsala, Ctr Biomed, Dept Bioorgan Chem, Box 581, S-75123 Uppsala, Sweden. EM jyoti@bioorgchem.uu.se RI Matsuda, Akira/D-5477-2012 NR 70 TC 28 Z9 28 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD AUG 7 PY 1998 VL 63 IS 16 BP 5447 EP 5462 DI 10.1021/jo980364y PG 16 WC Chemistry, Organic SC Chemistry GA 110DM UT WOS:000075364900028 ER PT J AU Hohmann, AG Herkenham, M AF Hohmann, AG Herkenham, M TI Regulation of cannabinoid and mu opioid receptors in rat lumbar spinal cord following neonatal capsaicin treatment SO NEUROSCIENCE LETTERS LA English DT Article DE cannabinoid; mu opioid; C-fiber; capsaicin; autoradiography ID BRAIN; PAIN; LOCALIZATION; NEURONS; AGONIST AB In vitro receptor binding and quantitative autoradiography were used to determine whether cannabinoid receptors in rat lumbar spinal cord are localized to the central terminals of nociceptive primary afferents. Rats were treated as neonates with capsaicin to destroy sensory C-fibers. The densities of cannabinoid and mu opioid receptors in the spinal cord of the adult rats were compared with age-matched vehicle controls. Neonatal capsaicin produced a moderate but reliable suppression (16%) of [H-3]CP55,940 binding to cannabinoid receptors, By contrast, the binding of [H-3][D-Ala(2)-MePhe(4),Gly-ol(5)]enkephalin (DAMGO) to mu receptors was depleted by approximately 60% in near adjacent sections. These data suggest that only a subpopulation of cannabinoid receptors is situated on the central terminals of primary efferent C-fibers. The present data provide anatomical evidence for a dissociation between cannabinoid and mu opioid modulation of sensory transmission at the level of the primary afferent inputs to the spinal cord. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved. C1 NIMH, Funct Neuroanat Sect, Bethesda, MD 20892 USA. RP Hohmann, AG (reprint author), NIMH, Funct Neuroanat Sect, Bldg 36,Room 2D15, Bethesda, MD 20892 USA. OI Herkenham, Miles/0000-0003-2228-4238 NR 19 TC 74 Z9 76 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD AUG 7 PY 1998 VL 252 IS 1 BP 13 EP 16 DI 10.1016/S0304-3940(98)00534-5 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 113GV UT WOS:000075543100004 PM 9756347 ER PT J AU Pfeffer, MA Domanski, M Rosenberg, Y Verter, J Geller, N Albert, P Hsia, J Braunwald, E AF Pfeffer, MA Domanski, M Rosenberg, Y Verter, J Geller, N Albert, P Hsia, J Braunwald, E TI Prevention of Events with Angiotensin-Converting Enzyme Inhibition - (The PEACE Study Design) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article; Proceedings Paper CT Symposium on New Insights into the Pathogenesis and Management of Coronary Artery Disease at XIXth Congress of European-Society-of-Cardiology CY AUG 24-28, 1997 CL STOCKHOLM, SWEDEN SP European Soc Cardiol ID LEFT-VENTRICULAR DYSFUNCTION; MYOCARDIAL-INFARCTION; CLINICAL-TRIALS AB The Prevention of Events with Angiotensin-Converting Enzyme Inhibition (PEACE) trial is an 8,100 patient, randomized, double-blind, placebo-controlled trial designed to determine the usefulness of angiotensin-converting enzyme (ACE) inhibitors in treating coronary patients with preserved left ventricular ejection fraction. The hypothesis being tested in this trial is that patients with coronary disease and election fraction greater than or equal to 40% who are treated with ACE inhibitors will experience a reduction in the incidence of cardiovascular death, nonfatal myocardial infarction, or a revascularization procedure compared with patients treated with conventional therapy. The design of the PEACE trial is described herein. (C) 1998 by Excerpta Medico, Inc. C1 Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. NHLBI, Bethesda, MD USA. George Washington Univ, Ctr Biostat, Rockville, MD USA. RP Pfeffer, MA (reprint author), Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. NR 13 TC 44 Z9 46 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 AUG 6 PY 1998 VL 82 IS 3A SI SI BP 25H EP 30H PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111JL UT WOS:000075433500006 PM 9719019 ER PT J AU Zwahlen, C Gardner, KH Sarma, SP Horita, DA Byrd, RA Kay, LE AF Zwahlen, C Gardner, KH Sarma, SP Horita, DA Byrd, RA Kay, LE TI An NMR experiment for measuring methyl-methyl NOEs in C-13-labeled proteins with high resolution SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID LINEAR PREDICTION; LARGER PROTEINS; SPECTROSCOPY; ENHANCEMENT; ASSIGNMENT; PROGRAM; SPECTRA; SIGNALS; PULSES; PHASE AB A three-dimensional NMR experiment is presented for correlating NOEs between methyl groups in protonated, N-15,C-13-labeled or methyl protonated, highly deuterated N-15,C-13-labeled proteins. The high resolution of this experiment facilitates the assignment of NOEs between methyls that can be poorly resolved in other; three- and four-dimensional experiments and extends the utility of solution-based NMR structural studies to proteins in the 40 kDa molecular weight regime. Applications to methyl protonated, highly deuterated samples of the 370 residue maltose binding protein (122 methyl groups) and the dimer of the 124 residue amino terminal domain of human STAT-4 (59 methyls) are presented. The method is also well suited for studies of fully protonated proteins, as demonstrated with an application involving the 160 residue phosphotyrosine binding domain from Drosophila Numb. Distance restraints obtained from the present experiment are particularly useful in the generation of global protein folds since many methyls are located in hydrophobic protein cores and inter-methyl restraints therefore link elements of secondary structure that are often distant in the primary sequence. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Macromol NMR Sect, Frederick, MD 21702 USA. Univ Toronto, Prot Engn Network Ctr Excellence, Toronto, ON M5S 1A8, Canada. Univ Toronto, Dept Med & Mol Genet, Toronto, ON M5S 1A8, Canada. Univ Toronto, Dept Chem & Biochem, Toronto, ON M5S 1A8, Canada. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. RP Byrd, RA (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Macromol NMR Sect, Frederick, MD 21702 USA. RI Byrd, R. Andrew/F-8042-2015; Gardner, Kevin/K-7802-2012; OI Byrd, R. Andrew/0000-0003-3625-4232; Gardner, Kevin/0000-0002-8671-2556; Horita, David/0000-0002-9563-107X NR 36 TC 69 Z9 69 U1 1 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD AUG 5 PY 1998 VL 120 IS 30 BP 7617 EP 7625 DI 10.1021/ja981205z PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA 109WB UT WOS:000075346200027 ER PT J AU Dorgan, JF AF Dorgan, JF TI Physical activity and breast cancer: Is there a link? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID REPRODUCTIVE FACTORS; MENSTRUAL-CYCLE; EXERCISE; MENARCHE; WOMEN; RISK; AGE; FAT C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Dorgan, JF (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Execut Plaza N,Rm 443, Bethesda, MD 20892 USA. NR 25 TC 10 Z9 10 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 AUG 5 PY 1998 VL 90 IS 15 BP 1116 EP 1117 DI 10.1093/jnci/90.15.1116 PG 2 WC Oncology SC Oncology GA 106XQ UT WOS:000075176900001 PM 9701355 ER PT J AU Lakhani, SR Jacquemier, J Sloane, JP Gusterson, BA Anderson, TJ van de Vijver, MJ Farid, LM Venter, D Antoniou, A Storfer-Isser, A Smyth, E Steel, CM Haites, N Scott, RJ Goldgar, D Neuhausen, S Daly, PA Ormiston, W McManus, R Scherneck, S Ponder, BAJ Ford, D Peto, J Stoppa-Lyonnet, D Bignon, YJ Struewing, JP Spurr, NK Bishop, DT Klijn, JGM Devilee, P Cornelisse, CJ Lasset, C Lenoir, G Barkardottir, RB Egilsson, V Hamann, U Chang-Claude, J Sobol, H Weber, B Stratton, MR Easton, DF AF Lakhani, SR Jacquemier, J Sloane, JP Gusterson, BA Anderson, TJ van de Vijver, MJ Farid, LM Venter, D Antoniou, A Storfer-Isser, A Smyth, E Steel, CM Haites, N Scott, RJ Goldgar, D Neuhausen, S Daly, PA Ormiston, W McManus, R Scherneck, S Ponder, BAJ Ford, D Peto, J Stoppa-Lyonnet, D Bignon, YJ Struewing, JP Spurr, NK Bishop, DT Klijn, JGM Devilee, P Cornelisse, CJ Lasset, C Lenoir, G Barkardottir, RB Egilsson, V Hamann, U Chang-Claude, J Sobol, H Weber, B Stratton, MR Easton, DF TI Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SUSCEPTIBILITY GENE; MEDULLARY CARCINOMA; IDENTIFICATION; LOCALIZATION; FAMILIES; LINKAGE; GROWTH AB Background: We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors. Methods: Specimens of tumor tissue (5-mu m-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells; cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data mere combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided. Results: Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P<.0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e,, control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P<.0001), and a lower mitotic count (P = .003) than control cancers. Conclusions: Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in individuals with a family history of the disease and may ultimately aid in the clinical management of patients. C1 Inst Canc Res, Haddow Labs, Sect Canc Genet, Sutton SM2 5NG, Surrey, England. Inst Canc Res, Haddow Labs, Epidemiol Sect, Sutton SM2 5NG, Surrey, England. Inst Canc Res, Haddow Labs, Sect Cell Biol & Expt Pathol, Sutton SM2 5NG, Surrey, England. UCL, Sch Med, Dept Histopathol, London W1N 8AA, England. Inst J Paoli I Calmettes, Dept Oncol Genet, F-13009 Marseille, France. Inst J Paoli I Calmettes, Lab Anat & Cytol Pathol, INSERM CRI 9703, F-13009 Marseille, France. Univ Liverpool, Dept Pathol, Liverpool L69 3BX, Merseyside, England. Univ Edinburgh, Sch Med, Dept Pathol, Edinburgh, Midlothian, Scotland. Antoni Van Leeuwenhoek Huis, Netherlands Canc Inst, Amsterdam, Netherlands. Univ Penn, Med Ctr, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. Peter MacCallum Canc Inst, Dept Pathol, Melbourne, Vic 3000, Australia. Univ Melbourne, Dept Pathol, Parkville, Vic 3052, Australia. Dept Pure Math & Math Stat, Stat Lab, Cambridge CB2 1SB, England. Univ Cambridge, Inst Publ Hlth, Canc Res Campaign, Genet Epidemiol Grp,Dept Community Med, Cambridge, England. Western Gen Hosp, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. Univ St Andrews, Sch Biol & Med Sci, St Andrews, Fife, Scotland. Univ Aberdeen, Dept Med & Therapeut, Aberdeen, Scotland. Kantonsspital, Dept Forsch, CH-4031 Basel, Switzerland. Int Agcy Res Canc, F-69372 Lyon, France. Univ Utah, Dept Med Informat, Salt Lake City, UT 84112 USA. Trinity Coll Dublin, Sch Med, Dept Med, Dublin, Ireland. Max Delbruck Ctr Mol Med, Berlin, Germany. Addenbrookes Hosp, CRC, Human Canc Genet Res Grp, Cambridge, England. Inst Curie, Unite Genet Oncol, Paris, France. Ctr Jean Perrin, Oncol Mol Lab, Clermont Ferrand, France. NCI, Div Canc Epidemiol & Genet, Genet Epidemiol Branch, Bethesda, MD 20892 USA. Imperial Canc Res Fund, Leeds, W Yorkshire, England. St James Univ Hosp, Imperial Canc Res Fund, Genet Epidemiol Lab, Leeds LS9 7TF, W Yorkshire, England. Dr Daniel Den Hoed Canc Ctr, NL-3008 AE Rotterdam, Netherlands. Leiden Univ, Dept Genet & Pathol, NL-2300 RA Leiden, Netherlands. Ctr Leon Berard, F-69373 Lyon, France. Univ Hosp Iceland, Cell Biol Lab, Reykjavik, Iceland. Deutsch Krebsforschungszentrum, Div Epidemiol & Mol Genome Anal, D-6900 Heidelberg, Germany. Univ Penn, Ctr Canc, Philadelphia, PA 19104 USA. RP Stratton, MR (reprint author), Inst Canc Res, Haddow Labs, Sect Canc Genet, 15 Cotswold Rd, Sutton SM2 5NG, Surrey, England. EM mikes@icr.ac.uk RI Struewing, Jeffery/C-3221-2008; gusterson, barry/D-3752-2009; Struewing, Jeffery/I-7502-2013; OI Struewing, Jeffery/0000-0002-4848-3334; McManus, Ross/0000-0002-0529-9617; Bishop, Tim/0000-0002-8752-8785 FU NCI NIH HHS [CA61231] NR 31 TC 437 Z9 443 U1 1 U2 18 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD AUG 5 PY 1998 VL 90 IS 15 BP 1138 EP 1145 DI 10.1093/jnci/90.15.1138 PG 8 WC Oncology SC Oncology GA 106XQ UT WOS:000075176900008 PM 9701363 ER PT J AU Chittum, HS Lane, WS Carlson, BA Roller, PP Lung, FD Lee, BJ Hatfield, DL AF Chittum, HS Lane, WS Carlson, BA Roller, PP Lung, FD Lee, BJ Hatfield, DL TI Rabbit beta-globin is extended beyond its UGA stop codon by multiple suppressions and translational reading gaps SO BIOCHEMISTRY LA English DT Article ID TRANSFER-RNA; PROTEIN; TRYPTOPHAN; SEQUENCES; YEAST; HOP AB Translational reading gaps occur when genetic information encoded in mRNA is not translated during the normal course of protein synthesis. This phenomenon has been observed thus far only in prokaryotes and is a mechanism for extending the reading frame by circumventing the normal stop codon. Reading frames of proteins may also be extended by suppression of the stop codon mediated by a suppressor tRNA. The rabbit beta-globin read-through protein, the only known, naturally occurring read-through protein in eukaryotes, was sequenced by ion trap mass spectrometry to determine how the reading frame is extended. Seven different proteolytic peptide fragments decoded by the same sequence that spans the UGA stop codon of rabbit beta-globin mRNA were detected. Three of these peptides contain translational reading gaps of one to three amino acids that correspond to the UGA stop codon site and/or one or two of the immediate downstream codons. To our knowledge, this is the first reported example of the occurrence of reading gaps in protein synthesis in eukaryotes. This event is unique in that it is associated with bypasses involving staggered lengths of untranslated information. Four of the seven peptides contain serine, tryptophan, cysteine, and arginine decoded by UGA and thus arise by suppression. Serine is donated by selenocysteine tRNA, and it, like the other tRNAs, has previously been shown to suppress UGA in vitro in mammals, but not in vivo. C1 NCI, Lab Basic Res, NIH, Bethesda, MD 20892 USA. NCI, Med Chem Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Harvard Microchem Facil, Cambridge, MA 02138 USA. Seoul Natl Univ, Mol Genet Lab, Inst Mol Biol & Genet, Seoul 151742, South Korea. RP Hatfield, DL (reprint author), NCI, Lab Basic Res, NIH, Bldg 37,Rm 2D09, Bethesda, MD 20892 USA. NR 30 TC 167 Z9 168 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 4 PY 1998 VL 37 IS 31 BP 10866 EP 10870 DI 10.1021/bi981042r PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 110TT UT WOS:000075397000002 PM 9692979 ER PT J AU Perera, L Darden, TA Pederson, LG AF Perera, L Darden, TA Pederson, LG TI Trans-cis isomerization of proline 22 in bovine prothrombin fragment 1: A surprising result of structural characterization SO BIOCHEMISTRY LA English DT Article ID GAMMA-CARBOXYGLUTAMIC ACID; MOLECULAR-DYNAMICS SIMULATION; ANTICOAGULATION PROTEIN-C; COAGULATION-FACTOR-IX; MESH EWALD METHOD; MEMBRANE-BINDING; GLA DOMAIN; STAPHYLOCOCCAL NUCLEASE; PHOSPHOLIPID-VESICLES; RESIDUES AB The calcium ion-mediated interaction of bovine prothrombin (BF1) with negatively charged phospholipid membranes is assumed to be largely via the Gla domain of BF1 with the fold of the cia domain essential for binding. It has been reported that Pro22 undergoes classical trans to cis isomerization in the presence of calcium ions with the cis conformation of Pro22 of BF1 responsible for membrane binding [Evans, T.C., Jr., and Nelsestuen, G. L. (1996) Biochemistry 35, 8210-8215]. However, Pro22 was found to be in the trans conformation in the crystal structure of BF1. In the present work, we have used molecular dynamics simulations to investigate the relative importance of the two conformations of Pro22 to the structural and dynamical properties of BF1. The initial trans conformation of Pro22 in BF1 was slowly converted to cis-Pro22 using constrained dynamics. The second-generation AMBER force field in conjunction with the particle mesh Ewald method to accommodate long-range interaction was employed in the trajectory calculations. Comparison of the BF1(trans-Pro22) and BF1(cis-Pro22) equilibrated structures reveals surprisingly that the overall structural changes associated with the trans-cis isomerization is minimal and only minor modifications to the hydrogen bond network and the network of N-terminus Alal take place. The calculated electrostatic potential energy surfaces of the two protein structures also appear to be very similar, indicating the near equality of the local interaction site environments in the protein prior to lipid binding. C1 Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Pederson, LG (reprint author), Univ N Carolina, Dept Chem, CB 3290, Chapel Hill, NC 27599 USA. RI perera, Lalith/B-6879-2012; Pedersen, Lee/E-3405-2013 OI perera, Lalith/0000-0003-0823-1631; Pedersen, Lee/0000-0003-1262-9861 FU NHLBI NIH HHS [HL-06350] NR 43 TC 14 Z9 14 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 4 PY 1998 VL 37 IS 31 BP 10920 EP 10927 DI 10.1021/bi980263u PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 110TT UT WOS:000075397000007 PM 9692984 ER PT J AU Ciotti, M Cho, JW George, J Owens, IS AF Ciotti, M Cho, JW George, J Owens, IS TI Required buried alpha-helical structure in the bilirubin UDP-glucuronosyltransferase, UCT1A1, contains nonreplaceable phenylalanine SO BIOCHEMISTRY LA English DT Article ID NAJJAR TYPE-I; UGT1 GENE-COMPLEX; SUBSTRATE-SPECIFICITY; COS-1 CELLS; CLONING; EXPRESSION; PATIENT; PHENOL; LOCUS; CDNAS AB A conserved hydrophobic region in the bilirubin-type UDP-glucuronosyltransferase isozyme was first uncovered as a consequence of a deleterious mutation in the UGT1A1 (HUG-Br1) isozyme of a Crigler-Najjar (CN) Type I patient. According to analysis by the RAOARGOS computer program, this hydrophobic region in UGT1A1 is located between residues 159-177 and defines a buried helix centered over position 169-172 with a positive factor of 1.22. Further analysis showed that the planar phenol-type UGT1A6 (HLUG P1) isoform, unlike the steroid-type UGT2B7 (UDPGTh2) isozyme, has a similar conserved hydrophobic region and that the positive factor for its buried helix is 1.14 compared to the threshold of 1.13 for such a structure. The analysis detected the typical membrane-insertion-signal sequence and a membrane-anchoring domain in each isoform. The different amino acid sequence patterns between positions 168-172 for the three types of isoforms and the deleterious mutations in this microregion (MRA) of UGT1A1 in CN-I patients are evidence of a critical and discriminating role for MRA. With the recombinant UGT1A1 enzyme and its mutants, P167G, F170del, F170L, F170I F170V, F170A, F170Y, F170E, F171L, F171I, F171V, F171A, F171Y, or L175Q, expressed in COS-1 cells, bilirubin glucuronidating activity at both pH 6.4 and 7.6 demonstrated that Phe-170 is not replaceable, whereas Phe-171 can be replaced by Leu without any loss of activity. The less hydrophobic buried helix in the phenolic-type UGT1A6 has a Tyr/Leu at position 170/171; this isoform glucuronidated bilirubin at 1/10 the level of that by UGT1A1 with a Km (bilirubin) of 25 mu M compared to that for UGT1A1 of 5.0 mu M. C1 NICHHD, Human Genet Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Owens, IS (reprint author), NICHHD, Human Genet Branch, NIH, Bldg 10,Room 9S-242, Bethesda, MD 20892 USA. NR 31 TC 24 Z9 24 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 4 PY 1998 VL 37 IS 31 BP 11018 EP 11025 DI 10.1021/bi980747q PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 110TT UT WOS:000075397000019 PM 9692996 ER PT J AU Chen, CH Ting, CT Lin, SJ Hsu, TL Ho, SJ Chou, P Chang, MS O'Connor, F Spurgeon, H Lakatta, E Yin, FCP AF Chen, CH Ting, CT Lin, SJ Hsu, TL Ho, SJ Chou, P Chang, MS O'Connor, F Spurgeon, H Lakatta, E Yin, FCP TI Which arterial and cardiac parameters best predict left ventricular mass? SO CIRCULATION LA English DT Article DE hypertrophy; cardiac load; arterial system; vascular load; blood pressure ID AGE-RELATED-CHANGES; BLOOD-PRESSURE; HYPERTENSIVE ADULTS; BODY-SIZE; DETERMINANTS; POPULATION; LOAD; SEX; DISTENSIBILITY; HYPERTROPHY AB Background-Many cardiovascular and noncardiovascular parameters are thought to be determinants of left ventricular mass (LVM). Complicated interactions necessitate the simultaneous measurement and consideration of each to determine their individual and collective impact on LVM. We undertook such a comprehensive study. Methods and Results-Tne influence of anthropometry, cardiac size and contractility, arterial structure and function, as well as indices of lifestyle, physical activity, and dietary salt intake on LVM (by two-dimensionally guided M-mode echocardiography) was analyzed in 1315 Chinese subjects who were either normotensive or had untreated hypertension. Effects of many cardiac and arterial factors were assessed. In univariate analysis, almost all measured noncardiovascular, cardiac, and arterial variables were significantly correlated with LVM. In multivariate linear regression analyses, when age, sex, body habitus, fasting serum C-peptide level, dietary salt, physical activity, and lifestyle were accounted for, the optimum multivariate linear regression main effects model had an adjusted model r(2) of 0.740, with 98% of the model variance accounted for by the 5 independent determinants of LVM: stroke volume (49.6%), systolic blood pressure (30.7%), contractility (14.7%), body mass index (1.8%), and aortic root diameter (1.6%). Other proposed arterial indices were significant independent determinants of LVM only when blood pressure was removed from the model and, even then, these indices not only resulted in less powerful prediction but also accounted for only a very small percentage of the total variance of LVM. Conclusions-In a large population, we (1) confirmed that age, body habitus, and some indexes of arterial structure and function are independent determinants of LVM; (2) found aortic diameter to be an independent structural determinant of LVM; (3) demonstrated that the effects of the derived measures of arterial function were small and provided no better predictive power than blood pressure alone; and (4) showed that when the best measures of cardiac and vascular load were included, the single most potent predictor was an index of left ventricular size. C1 Vet Gen Hosp, Div Cardiol, Taipei, Taiwan. Vet Gen Hosp, Div Cardiol, Taichung, Taiwan. Natl Yang Ming Univ, Inst Publ Hlth, Taipei, Taiwan. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD USA. RP Yin, FCP (reprint author), Washington Univ, Dept Biomed Engn, Campus Box 1097,1 Brookings Dr, St Louis, MO 63130 USA. FU NIA NIH HHS [N01-AG-1-2118] NR 45 TC 77 Z9 77 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 4 PY 1998 VL 98 IS 5 BP 422 EP 428 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 106PP UT WOS:000075138300007 PM 9714092 ER PT J AU Goldgur, Y Dyda, F Hickman, AB Jenkins, TM Craigie, R Davies, DR AF Goldgur, Y Dyda, F Hickman, AB Jenkins, TM Craigie, R Davies, DR TI Three new structures of the core domain of HIV-1 integrase: An active site that binds magnesium SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CATALYTIC DOMAIN; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; TYPE-1 INTEGRASE; DNA; RESIDUES; PROTEIN; IDENTIFICATION; ENDONUCLEASE AB HIV-1 integrase is an essential enzyme in the life cycle of the virus, responsible for catalyzing the insertion of the viral genome into the host cell chromosome; it provides an attractive target for antiviral drug design. The previously reported crystal structure of the HIV-1 integrase core domain revealed that this domain belongs to the superfamily of polynucleotidyltransferases. However, the position of the conserved catalytic carboxylic acids differed from those observed in other enzymes of the class, and attempts to crystallize in the presence of the cofactor, Mg2+, were unsuccessful. We report here three additional crystal structures of the core domain of HIV-1 integrase mutants, crystallized in the presence and absence of cacodylate, as well as complexed with Mg2+. These three crystal forms, containing between them seven independent core domain structures, demonstrate the unambiguous extension of the previously disordered helix alpha 4 toward the amino terminus from residue M154 and show that the catalytic E152 points in the general direction of the two catalytic aspartates, D64 and D116, In the vicinity of the active site, the structure of the protein in the absence of cacodylate exhibits significant deviations from the previously reported structures. These differences can be attributed to the modification of C65 and C130 by cacodylate, which was an essential component of the original crystallization mixture. We also demonstrate that in the absence of cacodylate this protein will bind to Mg2+, and could provide a satisfactory platform for binding of inhibitors. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Davies, DR (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 27 TC 289 Z9 299 U1 1 U2 12 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 AUG 4 PY 1998 VL 95 IS 16 BP 9150 EP 9154 DI 10.1073/pnas.95.16.9150 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 108BR UT WOS:000075246600019 PM 9689049 ER PT J AU Hochstenbach, F Klis, FM van den Ende, H van Donselaar, E Peters, PJ Klausner, RD AF Hochstenbach, F Klis, FM van den Ende, H van Donselaar, E Peters, PJ Klausner, RD TI Identification of a putative alpha-glucan synthase essential for cell wall construction and morphogenesis in fission yeast SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID COLI GLYCOGEN-SYNTHASE; SCHIZOSACCHAROMYCES-POMBE; S-POMBE; PROTEIN; SEQUENCE; SITE; CLASSIFICATION; GENOME AB The cell wall protects fungi against lysis and determines their cell shape. Alpha-glucan is a major carbohydrate component of the fungal cell wall, but its function is unknown and its synthase has remained elusive, Here, we describe a fission yeast gene, ags1(+), which encodes a putative alpha-glucan synthase, In contrast to the structure of other carbohydrate polymer synthases, the predicted Ags1 protein consists of two probable catalytic domains for alpha-glucan assembly, namely an intracellular domain for alpha-glucan synthesis and an extracellular domain speculated to cross-link or remodel alpha-glucan. In addition, the predicted Ags1 protein contains a multipass transmembrane domain that might contribute to transport of alpha-glucan across the membrane. Loss of Ags1p function in a temperature-sensitive mutant results in cell lysis, whereas mutant cells grown at the semipermissive temperature contain decreased levels of cell wall alpha-glucan and fail to maintain rod shapes, causing rounding of the cells, These findings demonstrate that alpha-glucan is essential for fission yeast morphogenesis. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. Univ Amsterdam, Inst Mol Cell Biol, Bioctr Amsterdam, NL-1098 SM Amsterdam, Netherlands. Univ Utrecht, Fac Med, Dept Cell Biol, NL-3584 CX Utrecht, Netherlands. Univ Utrecht, Inst Biomembranes, NL-3584 CX Utrecht, Netherlands. RP Hochstenbach, F (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RI Hochstenbach, Frans/B-5232-2008; Klis, Frans/B-9085-2008 OI Klis, Frans/0000-0003-0079-9492 NR 30 TC 96 Z9 100 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 4 PY 1998 VL 95 IS 16 BP 9161 EP 9166 DI 10.1073/pnas.95.16.9161 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 108BR UT WOS:000075246600021 PM 9689051 ER PT J AU Guo, QB Xie, JW Dang, CV Liu, ET Bishop, JM AF Guo, QB Xie, JW Dang, CV Liu, ET Bishop, JM TI Identification of a large Myc-binding protein that contains RCC1-like repeats SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HELIX ZIPPER PROTEIN; N-MYC; C-MYC; TRANSCRIPTIONAL ACTIVATION; NEOPLASTIC TRANSFORMATION; EMBRYONIC LETHALITY; MOUSE EMBRYO; DNA-BINDING; EXPRESSION; CELLS AB The protooncogene MYC plays an important role in the regulation of cellular proliferation, differentiation, and apoptosis and has been implicated in a variety of human tumors. MYC and the closely related MYCN encode highly conserved nuclear phosphoproteins (Myc and NMyc) that apparently function as transcription factors in the cell, We have identified a large and highly conserved nuclear protein that interacts directly with the transcriptional activating domain of Myc (designated "protein associated with Mgc" or Pam). Pam contains an extended amino acid sequence with similarities to a protein known as regulator of chromosome condensation (RCC1), which mag play a role in the function of chromatin, The gene encoding Pam (PAM) is expressed in all of the human tissue examined, but expression is exceptionally abundant in brain and thymus, Pam binds specifically to Myc, but not NMyc. The region in MSc required for binding to Pam includes a domain that is essential for the function of Myc and that is frequently mutated in Burkitt's lymphomas. PAM is located within a 300-kb region on chromosome 13q22. C1 NCI, Sect Cellular & Mol Oncogenesis, Div Clin Sci, Bethesda, MD 20892 USA. Univ Calif San Francisco, George Williams Hooper Fdn, San Francisco, CA 94143 USA. Univ Calif San Francisco, Canc Res Inst, San Francisco, CA 94143 USA. Johns Hopkins Univ, Sch Med, Dept Med, Div Hematol, Baltimore, MD 21205 USA. RP Guo, QB (reprint author), NCI, Sect Cellular & Mol Oncogenesis, Div Clin Sci, Bldg 10,Room 6C-209,9000 Rockville Pike, Bethesda, MD 20892 USA. EM guoq@pop.nci.nih.gov RI Liu, Edison/C-4141-2008 FU NCI NIH HHS [CA44338, CA57341, R01 CA057341] NR 35 TC 94 Z9 96 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 AUG 4 PY 1998 VL 95 IS 16 BP 9172 EP 9177 DI 10.1073/pnas.95.16.9172 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 108BR UT WOS:000075246600023 PM 9689053 ER PT J AU Cutler, RE Stephens, RM Saracino, MR Morrison, DK AF Cutler, RE Stephens, RM Saracino, MR Morrison, DK TI Autoregulation of the Raf-1 serine/threonine kinase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE signal transduction ID DISTINCT BINDING DOMAINS; COMPLETE CODING SEQUENCE; CYSTEINE-RICH REGION; MAP KINASE; HA-RAS; V-RAF; ACTIVATION; C-RAF-1; ONCOGENE; PHOSPHORYLATION AB The Raf-1 serine/threonine kinase is a key protein involved in the transmission of many growth and developmental signals. Im this report, we sinew that antoinhibition mediated by the noncatalytic, N-terminal regulatory region of Raf-1 is an important mechanism regulating Raf-1 function, The inhibition of the regulatory region occurs, at lease in part, through binding interactions involving the cysteine-rich domain. Events that disrupt this autoinhibition, such as mutation of the cysteine-rich domain or a mutation mimicking an activating phosphorylation event (Y340D), alleviate the repression of the regulatory region and increase Raf-1 activity. Based on the striking similarites ibt tween the autoregulation of the serine/threonine kinases protein kinase C, Byr2, and Raf-1, we propose that relief of autorepression and activation at the plasma membrane is an evolutionarily conserved mechanism of kinase regulation. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Mol Basis Carcinogenesis Lab, Frederick, MD 21702 USA. RP Morrison, DK (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Mol Basis Carcinogenesis Lab, Frederick, MD 21702 USA. NR 44 TC 80 Z9 81 U1 3 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 4 PY 1998 VL 95 IS 16 BP 9214 EP 9219 DI 10.1073/pnas.95.16.9214 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 108BR UT WOS:000075246600030 PM 9689060 ER PT J AU Lee, KS Grenfell, TZ Yarm, FR Erikson, RL AF Lee, KS Grenfell, TZ Yarm, FR Erikson, RL TI Mutation of the polo-box disrupts localization and mitotic functions of the mammalian polo kinase Plk SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PROTEIN-KINASE; SERINE/THREONINE KINASE; ANIMAL-CELLS; DROSOPHILA POLO; GENE; IDENTIFICATION; SACCHAROMYCES; CYTOKINESIS; CLONING; SPINDLE AB Members of the polo subfamily of protein kinases play pivotal roles in cell proliferation. In addition to the kinase domain, polo kinases have a strikingly conserved sequence in the noncatalytic domain, termed the polo-box. The function of the polo-box is currently undefined. The mammalian polo-like kinase Plk is a functional homologue of Saccharomyces cerevisiae Cdc5, Here, we show that Plk localizes at the spindle poles and cytokinetic neck filaments. Without impairing kinase activity, a conservative mutation in the polo-box disrupts the capacity of Plk to complement the defect associated with a cdc5-1 temperature-sensitive mutation and to localize to these subcellular structures. Our data provide evidence that the polo-box plays a critical role in Plk function, likely by directing its subcellular localization. C1 Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. RP Lee, KS (reprint author), NCI, Lab Metab, NIH, 9000 Rockville Pike,Bldg 37,Room 3D25, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA42580] NR 32 TC 174 Z9 176 U1 1 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 4 PY 1998 VL 95 IS 16 BP 9301 EP 9306 DI 10.1073/pnas.95.16.9301 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 108BR UT WOS:000075246600045 PM 9689075 ER PT J AU Weinstein, M Yang, X Li, CL Xu, XL Gotay, J Deng, CX AF Weinstein, M Yang, X Li, CL Xu, XL Gotay, J Deng, CX TI Failure of egg cylinder elongation and mesoderm induction in mouse embryos lacking the tumor suppressor smad2 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE transforming growth factor beta; smad4; gastrulation; extraembryonic membranes ID TGF-BETA SUPERFAMILY; MAD-RELATED PROTEIN; SIGNALING PATHWAYS; RECEPTOR; GENE; DIFFERENTIATION; GASTRULATION; REQUIREMENT; EXPRESSION; SUGGESTS AB smad genes constitute a family of nine members whose products serve as intracellular mediators of transforming growth factor beta signals. SMAD2, which is a tumor suppressor involved in colorectal and lung cancer, has been shown to induce dorsal mesoderm in Xenopus laevis in response to transforming growth factor beta and activins. The smad2 gene is expressed ubiquitously during murine embryogenesis and in many adult mouse tissues, Animals that lacked smad2 died before 8.5 days of development (E8.5). E6.5 homozygous mutants were smaller than controls, lacked the extraembryonic portion of the egg cylinder, and appeased strikingly similar to E6.5 smad4 mutants. This similarity was no longer evident at E7.5, however, because the smad2 mutants contained embryonic ectoderm within their interiors, Molecular analysis showed that smad2 mutant embryos did not undergo gastrulation or make mesoderm. The results demonstrate that smad2 is required for egg cylinder elongation, gastrulation, and mesoderm induction. C1 NIDDKD, Biochem & Metab Lab, NIH, Bethesda, MD 20892 USA. RP Deng, CX (reprint author), NIDDKD, Biochem & Metab Lab, NIH, 10-9N105,10 Ctr Dr, Bethesda, MD 20892 USA. RI deng, chuxia/N-6713-2016 NR 39 TC 219 Z9 228 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 4 PY 1998 VL 95 IS 16 BP 9378 EP 9383 DI 10.1073/pnas.95.16.9378 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 108BR UT WOS:000075246600058 PM 9689088 ER PT J AU Makalowski, W Boguski, MS AF Makalowski, W Boguski, MS TI Evolutionary parameters of the transcribed mammalian genome: An analysis of 2,820 orthologous rodent and human sequences SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NONSYNONYMOUS SUBSTITUTIONS; RATES; NUCLEOTIDE; GENES; DATABASE; MOUSE; MAP AB We have rigorously defined 2,820 orthologous mRNA and protein sequence pairs from rats, mice, and humans. Evolutionary rate analyses indicate that mammalian genes are evolving 17-30% more slowly than previous textbook values. Data are presented on the average properties of mRNA and protein sequences, on variations in sequence conservation in coding and noncoding regions, and on the absolute and relative frequencies of repetitive elements and splice sites in untranslated regions of mRNAs, Our data set contains 1,880 unique human/rodent sequence pairs that represent about 2-4% of all mammalian genes. Of the 1,880 human orthologs, 70% are present on a new gene map of the human genome, thus providing a valuable resource for cross-referencing human and rodent genomes. In addition to comparative mapping, these results have practical applications in the interpretation of noncoding sequence conservation between syntenic regions of human and mouse genomic sequence, and in the design and calibration of gene expression arrays. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Boguski, MS (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bldg 38A,Rm 8N805,8600 Rockville Pike, Bethesda, MD 20894 USA. EM makalow@ncbi.nlm.nih.gov; boguski@ncbi.nlm.nih.gov RI Makalowski, Wojciech/I-2843-2016 NR 41 TC 310 Z9 319 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 4 PY 1998 VL 95 IS 16 BP 9407 EP 9412 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 108BR UT WOS:000075246600063 PM 9689093 ER PT J AU Robertson, GP Furnari, FB Miele, ME Glendening, MJ Welch, DR Fountain, JW Lugo, TG Huang, HJS Cavenee, WK AF Robertson, GP Furnari, FB Miele, ME Glendening, MJ Welch, DR Fountain, JW Lugo, TG Huang, HJS Cavenee, WK TI In vitro loss of heterozygosity targets the PTEN/MMAC1 gene in melanoma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN PROSTATE-CANCER; MALIGNANT-MELANOMA; HUMAN CHROMOSOME-11; TUMOR-SUPPRESSOR; WILMS-TUMOR; RETINOBLASTOMA; PROGRESSION; EXPRESSION; FRAGMENTS; GLIOMAS AB Gross genetic lesions of chromosome 10 occur in 30-50% of sporadic human melanomas. To test the functional significance of this observation, we have developed an in vitro loss of heterozygosity approach in which a wild-type chromosome 10 was transferred into melanoma cells, where there was selection for its breakage and regional deletion to relieve its growth suppressive effects. The overlap of these events was at hand 10q23, the site of the recently isolated PTEN/MMAC1 tumor suppressor gene, suggesting it as a potential target. Although the gene was expressed in the parental cells, both of its chromosomal alleles contained truncating mutations. In vitro loss of heterozygosity resulted in loss of the chromosomally introduced wild-type PTEN/MMAC1, and ectopic expression of the gene caused cell growth suppression. Thus, this approach identified PTEN/MMAC1 as a target in malignant melanoma and may provide an alter native means to localizing tumor suppressor genes. C1 Univ Calif San Diego, Ludwig Inst Canc Res, San Diego Branch, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. Univ Calif San Diego, Ctr Mol Genet, La Jolla, CA 92093 USA. Univ Calif San Diego, Ctr Canc, La Jolla, CA 92093 USA. Univ Delaware, Dept Med Technol, Newark, DE 19716 USA. Univ So Calif, Inst Med Genet, Los Angeles, CA 90033 USA. Penn State Univ, Jake Gittlen Canc Res Inst, Hershey, PA 17033 USA. NCI, Canc Diag Program, Rockville, MD 20892 USA. RP Robertson, GP (reprint author), Univ Calif San Diego, Ludwig Inst Canc Res, San Diego Branch, CMME-3080,9500 Gilman Dr, La Jolla, CA 92093 USA. EM gprobertson@ucsd.edu RI Welch, Danny/B-7310-2009; OI Welch, Danny/0000-0002-1951-4947; Robertson, Gavin P./0000-0003-0152-2997 FU CIT NIH HHS [CCT0197]; NCI NIH HHS [CA62168, CA66021] NR 39 TC 80 Z9 81 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 AUG 4 PY 1998 VL 95 IS 16 BP 9418 EP 9423 DI 10.1073/pnas.95.16.9418 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 108BR UT WOS:000075246600065 PM 9689095 ER PT J AU Yuan, Y Crane, DD Simpson, RM Zhu, YQ Hickey, MJ Sherman, DR Barry, CE AF Yuan, Y Crane, DD Simpson, RM Zhu, YQ Hickey, MJ Sherman, DR Barry, CE TI The 16-kDa alpha-crystallin (Acr) protein of Mycobacterium tuberculosis is required for growth in macrophages SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CYCLOPROPANATED MYCOLIC ACIDS; HEAT-SHOCK PROTEINS; IN-VITRO; ANTIGEN; IDENTIFICATION; BIOSYNTHESIS; CHAPERONE; DISEASE; LEPRAE; FAMILY AB Although the 16-kDa alpha-crystallin homologue of Mycobacterium tuberculosis (MTB) is the dominant protein produced by stationary phase cultures in vitro, it is undetectable in logarithmically growing cultures. BS growing bacilli at defined oxygen concentrations, acr transcription was shown to be strongly induced by mildly hypoxic conditions. Atr expression also was found to be induced during the course of in vitro infection of macrophages. The acr gene was replaced with a hygromycin resistance cassette by allelic exchange in hITB H37Rv. The resulting Delta acr::hpt strain was shown to be equivalent to wild-type H37Rv in in vitro growth rate and infectivity but was significantly impaired for growth in both mouse bone marrow derived macrophages and THP-1 cells. Lm addition to its proposed role in maintenance of long-term viability during latent, asymptomatic infections, these results establish a role for the Acr protein in replication during initial MTB infection. C1 NIAID, Rocky Mt Labs, TB Res Unit, Hamilton, MT 59840 USA. PathoGenesis Corp, Lab TB & Res Biol, Seattle, WA 98119 USA. NIAID, Immunogenet Lab, Rockville, MD 20852 USA. RP Barry, CE (reprint author), NIAID, Rocky Mt Labs, TB Res Unit, Hamilton, MT 59840 USA. EM clifton_barry@nih.gov RI Barry, III, Clifton/H-3839-2012 FU Intramural NIH HHS [Z01 AI000783-11] NR 35 TC 206 Z9 232 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 4 PY 1998 VL 95 IS 16 BP 9578 EP 9583 DI 10.1073/pnas.95.16.9578 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 108BR UT WOS:000075246600093 PM 9689123 ER PT J AU Bos, MP Kuroki, M Krop-Watorek, A Hogan, D Belland, RJ AF Bos, MP Kuroki, M Krop-Watorek, A Hogan, D Belland, RJ TI CD66 receptor specificity exhibited by neisserial Opa variants controlled by protein determinants in CD66 N-domains SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ANTIGEN GENE FAMILY; GOLGI VESICLE MEMBRANES; CARCINOEMBRYONIC ANTIGEN; EPITHELIAL-CELLS; OPACITY PROTEINS; MUTANT DEFICIENT; ESCHERICHIA-COLI; GONORRHOEAE; CEA; GONOCOCCI AB Neisseria gonorrhoeae strain MS11 is able to express 11 different opacity (Opa) proteins on its outer surface. A number of these Opa proteins have been shown to function as adhesins through binding of CD66 receptors present on human cells. CD66 antigens, or carcinoembryonic antigen family members, constitute a family of glycoproteins belonging to the immunoglobulin superfamily. Opa variants recognize this class of receptors in a differential manner such that certain Opa variants recognize up to four different CD66 receptors (CD66a, -c, -d, and -e), whereas others recognize only two (CD66a and -e) or none. Ve explored the basis for this receptor tropism in the present study. Our data show that glycoforms of CD66e and deglycosylated CD66e are recognized by gonococci in an Opa-specific manner. Binding by Opa variants of recombinant N-terminal domains of CD66 receptors expressed in Escherichia coli reflected the adherence specificities of Opa variants to HeLa cells expressing native CD66 molecules. These data indicate that recognition of CD66 receptors by Opa variants is mediated by the protein backbone of the CD66 N-domains. Furthermore, by using chimeric constructs between different CD66 N-domains me identified distinct binding regions on the CD66e N-domain for specific groups of Opa variants, suggesting that the differential recognition of CD66 receptors by Opa variants is dictated by the presence of specific binding regions on the N-domain of the receptor. C1 NIAID, Rocky Mt Labs, Lab Microbial Struct & Funct, NIH, Hamilton, MT 59840 USA. Fukuoka Univ, Sch Med, Dept Biochem 1, Fukuoka 81401, Japan. Polish Acad Sci, Inst Immunol & Expt Therapy, Dept Immunochem, PL-53114 Wroclaw, Poland. RP Bos, MP (reprint author), NIAID, Rocky Mt Labs, Lab Microbial Struct & Funct, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 38 TC 40 Z9 43 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 AUG 4 PY 1998 VL 95 IS 16 BP 9584 EP 9589 DI 10.1073/pnas.95.16.9584 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 108BR UT WOS:000075246600094 PM 9689124 ER PT J AU Schnermann, J Chou, CL Ma, TH Traynor, T Knepper, MA Verkman, AS AF Schnermann, J Chou, CL Ma, TH Traynor, T Knepper, MA Verkman, AS TI Defective proximal tubular fluid reabsorption in transgenic aquaporin-1 null mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE water transport; AQP1; urinary concentrating mechanism; kidney; micropuncture ID CHIP28 WATER CHANNELS; RENAL TUBULES; RECONSTITUTION; PERMEABILITY; LOCALIZATION; TRANSPORTER; EXPRESSION; LIPOSOMES; PROTEIN; NEPHRON AB To investigate the role of aquaporin-l (AQP1) water channels in proximal tubule function, in vitro proximal tubule microperfusion and in vivo micropuncture measurements were done on AQP1 knockout mice. The knock-out mice were generated by targeted gene disruption and found previously to be unable to concentrate their urine in response to water deprivation, Unanesthetized knockout mice consumed 2.8-fold more fluid than wild-type mice and had lower urine osmolality (505 +/- 40 vs. 1081 +/- 68 milliosmolar). Transepithelial osmotic water permeability (Pf) in isolated microperfused S2 segments of proximal tubule from AQP1 knockout [-/-] mice was 0.033 +/- 0.005 cm/s (SE, it = 6 mice, 37 degrees C), much lower than that of 0.15 +/- 0.03 cm/s (n = 8) in tubules from wild-type [ +/+] mice (P < 0.01). In the presence of isosmolar luminal perfusate and bath solutions, spontaneous fluid absorption rates (nl/min/mm tubule length) were 0.31 +/- 0.12 (-/-, it = 5) and 0.64 +/- 0.15 (+/+, n = 8), As determined by free-flow micropuncture, the ratios of tubular fluid-to-plasma concentrations of an impermeant marker TF/P in end proximal tubule fluid were 1.36 +/- 0.05 (-/-, rt 8 mice [53 tubules]) and 1.95 +/- 0.09 (+/+, n = 7 mice [40 tubules]) (P < 0.001), corresponding to 26 +/- 3% [-/-] and 48 +/- 2% [+/+] absorption of the filtered fluid load, In collections of distal tubule fluid, TF/P mere 2.8 +/- 0.3 [-/-] and 4.4 +/- 0.5 [+/+], corresponding to 62 +/- 4% [-/-] and 76 +/- 3% [+/+] absorption (P < 0.02), These data indicate that AQP1 deletion in mice results in decreased transepithelial proximal tubule water permeability and defective fluid absorption. Thus, the high water permeability in proximal tubule of wild-type mice is primarily transcellular, mediated by AQP1 mater channels, and required for efficient near-isosmolar fluid absorption. C1 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. Univ Michigan, Sch Med, Dept Physiol, Ann Arbor, MI 48109 USA. NIH, Kidney & Electrolyte Metab Lab, Bethesda, MD 20892 USA. RP Schnermann, J (reprint author), Univ Calif San Francisco, Cardiovasc Res Inst, Dept Med, San Francisco, CA 94143 USA. FU NHLBI NIH HHS [R01 HL059198]; NIDDK NIH HHS [DK35124, DK37448, DK40042, R01 DK035124, R37 DK035124] NR 28 TC 315 Z9 322 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 AUG 4 PY 1998 VL 95 IS 16 BP 9660 EP 9664 DI 10.1073/pnas.95.16.9660 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 108BR UT WOS:000075246600107 PM 9689137 ER PT J AU Bhattacharyya, A Malar, EJP Subramanian, S AF Bhattacharyya, A Malar, EJP Subramanian, S TI AM1 studies of photochemical reactions occurring from the S-1 and the T-1 states of some cyclopropyl ketones SO THEOCHEM-JOURNAL OF MOLECULAR STRUCTURE LA English DT Article DE photochemical reaction; alpha-cleavage; transition state; cyclopropyl ketone ID INTERNAL-ROTATION; PHOTOISOMERIZATION; ACETALDEHYDE; FORMALDEHYDE AB AMI studies of photochemical reaction mechanisms are carried out for three cyclopropyl ketones, namely methyl cyclopropyl ketone, 1-cyclopropyl-2-propanone and 1-cyclopropyl-3-butanone. Transition states for the feasible reactions have been verified by carrying out normal coordinate analysis and the activation barriers for the reactions have been calculated. The cyclopropane fission reaction is found to be more favourable energetically in comparison to the alpha-cleavage reactions for methyl cyclopropyl ketone. However, for 1-cyclopropyl-2-propanone and 1-cyclopropyl-3-butanone, the alpha-cleavage reaction is preferred over other competing reactions. (C) 1998 Elsevier Science B.V. All rights reserved. C1 Indian Inst Technol, Reg Sophisticated Instrumentat Ctr, Madras 600036, Tamil Nadu, India. Univ Madras, Dept Phys Chem, Madras 600025, Tamil Nadu, India. NIH, Radiat Biol Branch, Bethesda, MD 20892 USA. RP Bhattacharyya, A (reprint author), Indian Inst Technol, Reg Sophisticated Instrumentat Ctr, Madras 600036, Tamil Nadu, India. NR 39 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-1280 J9 THEOCHEM-J MOL STRUC JI Theochem-J. Mol. Struct. PD AUG 4 PY 1998 VL 434 BP 101 EP 119 DI 10.1016/S0166-1280(98)00062-1 PG 19 WC Chemistry, Physical SC Chemistry GA ZY382 UT WOS:000074615700012 ER PT J AU Liang, LP Kaufman, S AF Liang, LP Kaufman, S TI The regulation of dopamine release from striatum slices by tetrahydrobiopterin and L-arginine-derived nitric oxide SO BRAIN RESEARCH LA English DT Article DE tetrahydrobiopterin; L-arginine; dopamine release; NO; NO synthase; oxygen free radical ID LIVER PHENYLALANINE-HYDROXYLASE; ENDOTHELIAL-CELLS; SEPIAPTERIN REDUCTASE; RAT STRIATUM; GLUTAMATE; OXIDATION; MACROPHAGES; BIOPTERIN; 6R-L-ERYTHRO-TETRAHYDROBIOPTERIN; 6R-TETRAHYDROBIOPTERIN AB The regulation of dopamine release by 6(R)-tetrahydrobiopterin (BH4) and L-arginine-derived nitric oxide was examined by using a method of superfusion of rat striatum slices in vitro. L-Arginine, which can produce nitric oxide (NO) through the action of NO synthase, induces a concentration-dependent increase of [H-3] dopamine release in the superfusate of striatum slices. Pretreatment with inhibitors of NO synthase or with inhibitors of BH4 synthesis diminishes the increase of [H-3] dopamine release mediated by arginine. This increase is almost completely restored following repletion of intracellular BH4 levels by incubation of the slices with 7,8-dihydrobiopterin. Adding exogenous BH4 directly to the superfusion fluid leads to a massive increase in [H-3] dopamine release which can be inhibited 75% by superoxide dismutase and catalase, but is not inhibited by NG-nitro-arginine, a NO synthase inhibitor, or alpha-methyl-p-tyrosine, a tyrosine hydroxylase inhibitor. The increase of intracellular BH4 concentration by dihydrobiopterin administration causes a small increase of dopamine release which can be partially diminished by NG-nitro-arginine or alpha-methyl-p-tyrosine. It is suggested that the increase of dopamine release stimulated by an enhancement of intracellular BH4 is dependent on its cofactor activity with NO synthase and tyrosine hydroxylase. This study has also demonstrated that BH4 is a regulator of NO-mediated dopamine release in the striatum. Published by Elsevier Science B.V. C1 NIMH, Neurochem Lab, Bethesda, MD 20892 USA. RP Kaufman, S (reprint author), NIMH, Neurochem Lab, 36 Convent Dr,MSC 4096,Bldg 36 Rm 3D-30, Bethesda, MD 20892 USA. EM kaufman@codon.nih.gov NR 41 TC 30 Z9 30 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 AUG 3 PY 1998 VL 800 IS 2 BP 181 EP 186 DI 10.1016/S0006-8993(98)00452-1 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 107YP UT WOS:000075238800001 PM 9685635 ER PT J AU Scepek, S Coorssen, JR Lindau, M AF Scepek, S Coorssen, JR Lindau, M TI Fusion pore expansion in horse eosinophils is modulated by Ca2+ and protein kinase C via distinct mechanisms SO EMBO JOURNAL LA English DT Article DE capacitance; exocytosis; membrane fusion; patch-clamp; staurosporine ID ADRENAL CHROMAFFIN CELLS; GTP-GAMMA-S; RESOLVED CAPACITANCE MEASUREMENTS; MAST-CELLS; SECRETORY VESICLE; HUMAN-NEUTROPHILS; HUMAN PLATELETS; PHORBOL ESTER; SINGLE CELLS; EXOCYTOSIS AB Using the patch-clamp technique, we studied the role of protein phosphorylation and dephosphorylation on the exocytotic fusion of secretory granules with the plasma membrane in horse eosinophils. Phorbol 12-myristate 13-acetate (PMA) had no effect on the amplitude and dynamics of degranulation, indicating that the formation of fusion pores is insensitive to activation of protein kinase C (PKC). Fusion pore expansion, however, was accelerated similar to 2-fold by PMA, and this effect was abolished by staurosporine, Elevating intracellular Ca2+ to 1.5 mu M also resulted in a a-fold acceleration of pore expansion; this effect was not prevented by staurosporine, indicating that intracellular Ca2+ and activation of PKC accelerate fusion pore expansion via distinct mechanisms. However, fusion pores can expand fully even when PKC is inhibited. In contrast, the phosphatase inhibitor alpha-naphthylphosphate inhibits exocytotic fusion and slows fusion pore expansion, These results demonstrate that, subsequent to its formation, fusion pore expansion is under control of proteins subject to functional changes based on their phosphorylation states. C1 Cornell Univ, Sch Appl & Engn Phys, Ithaca, NY 14853 USA. Max Planck Inst Med Res, Dept Mol Cell Res, D-69120 Heidelberg, Germany. NICHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Lindau, M (reprint author), Cornell Univ, Sch Appl & Engn Phys, 217 Clark Hall, Ithaca, NY 14853 USA. NR 44 TC 91 Z9 92 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD AUG 3 PY 1998 VL 17 IS 15 BP 4340 EP 4345 DI 10.1093/emboj/17.15.4340 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 111DT UT WOS:000075422600013 PM 9687502 ER PT J AU Krosl, G He, G Lefrancois, M Charron, F Romeo, PH Jolicoeur, P Kirsch, IR Nemer, M Hoang, T AF Krosl, G He, G Lefrancois, M Charron, F Romeo, PH Jolicoeur, P Kirsch, IR Nemer, M Hoang, T TI Transcription factor SCL is required for c-kit expression and c-kit function in hemopoietic cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE SCL; TAL1; c-kit; apoptosis; Steel factor ID LOOP-HELIX PROTEIN; ACUTE LYMPHOBLASTIC-LEUKEMIA; COLONY-STIMULATING FACTOR; BONE-MARROW CELLS; TRANSGENIC MICE; ERYTHROID-DIFFERENTIATION; HEMATOPOIETIC-CELLS; SUPPRESSES APOPTOSIS; FACTOR GATA-1; GENE-PRODUCT AB In normal hemopoietic cells that are dependent on specific growth factors for cell survival, the expression of the basic helix-loop-helix transcription factor SCL/Tal1 correlates with that of c-Kit, the receptor for Steel factor (SF) or stem cell factor. To address the possibility that SCL may function upstream of c-kit, we sought to modulate endogenous SCL function in the CD34(+) hemopoietic cell line TF-1, which requires SF, granulocyte/macrophage colony-stimulating factor, or interleukin 3 for survival. Ectopic expression of an antisense SCL cDNA (as-SCL) or a dominant negative SCL (dn-SCL) in these cells impaired SCL DNA binding activity, and prevented the suppression of apoptosis by SF only, indicating that SCL is required for c-Kit-dependent cell survival. Consistent with the lack of response to SF, the level of c-kit mRNA and c-Kit protein was significantly and specifically reduced in as-SCL- or dn-SCL-expressing cells. c-kit mRNA, c-kit promoter activity, and the response to SF were rescued by SCL overexpression in the antisense or dn-SCL transfectants. Furthermore, ectopic c-kit expression in as-SCL transfectants is sufficient to restore cell survival in response to SF. Finally, enforced SCL in the pro-B cell line Ba/F3, which is both SCL and c-kit negative is sufficient to induce c-Kit and SF responsiveness. Together, these results indicate that c-kit, a gene that is essential for the survival of primitive hemopoietic cells, is a downstream target of the transcription factor SCL. C1 Clin Res Inst Montreal, Montreal, PQ H2W 1R7, Canada. Univ Montreal, Dept Pharmacol, Montreal, PQ H3C 3J7, Canada. Univ Montreal, Dept Biochem, Montreal, PQ H3C 3J7, Canada. Univ Montreal, Dept Immunol Microbiol, Montreal, PQ H3C 3J7, Canada. Univ Montreal, Program Mol Biol, Montreal, PQ H3C 3J7, Canada. NCI, Naval Med Ctr, Bethesda, MD 20892 USA. McGill Univ, Dept Med, Montreal, PQ H3A 2A7, Canada. Hop Henri Mondor, INSERM U91, F-94010 Creteil, France. RP Hoang, T (reprint author), Clin Res Inst Montreal, 110 Pine Ave W, Montreal, PQ H2W 1R7, Canada. OI Charron, Frederic/0000-0003-3483-8672 NR 67 TC 56 Z9 57 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 AUG 3 PY 1998 VL 188 IS 3 BP 439 EP 450 DI 10.1084/jem.188.3.439 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 109BA UT WOS:000075300300003 PM 9687522 ER PT J AU Balajee, AS May, A Bohr, VA AF Balajee, AS May, A Bohr, VA TI Fine structural analysis of DNA repair in mammalian cells SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article; Proceedings Paper CT 4th International Symposium on Chromosomal Aberrations CY AUG 26-29, 1998 CL UNIV ESSEN, ESSEN, GERMANY HO UNIV ESSEN DE nuclear matrix; transcription-coupled repair; nucleotide excision repair; chromatin organization ID MATRIX ASSOCIATED DNA; NUCLEAR MATRIX; ULTRAVIOLET-LIGHT; DAMAGED DNA; PROTEIN; SITES; CHROMATIN; GENES AB Nucleotide excision repair (NER) of ultraviolet (UV) light induced photo lesions is heterogeneous in the genomic DNA. We have investigated the mechanistic basis for this repair heterogeneity by analyzing NER activity in higher order chromatin of repair proficient hamster cells, Immunological labeling of repair and transcription sites indicates that NER initiates at the nuclear matrix in close association with transcription. The repair gradually extends into the loop DNA regions in a time dependent fashion. Repair analysis indicates that the DNA damaged by UV irradiation is recruited to the nuclear matrix soon after UV exposure. Consistent with this finding, immunofluorescence and western blotting analyses indicate the enrichment of many NER proteins (XPA, RPA, PCNA, the P62 and p89 sub-units of the basal transcription factor, TFIIH) in the nuclear matrix of UV treated cells. These results strengthen the notion that the nuclear matrix is an important site for the assembly of an efficient repair complex. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIA, Mol Genet Lab, NIH, Baltimore, MD 21224 USA. RP Balajee, AS (reprint author), NIA, Mol Genet Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 18 TC 30 Z9 32 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD AUG 3 PY 1998 VL 404 IS 1-2 SI SI BP 3 EP 11 DI 10.1016/S0027-5107(98)00088-8 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 113JE UT WOS:000075546700002 PM 9729238 ER PT J AU Herrmann, LM Caughey, B AF Herrmann, LM Caughey, B TI The importance of the disulfide bond in prion protein conversion SO NEUROREPORT LA English DT Article DE conversion; disulfide; prion; PrP; reduction; scrapie; TSE ID CELL-FREE CONVERSION; SCRAPIE PRION; PRP; MPRP(23-231); PURIFICATION; POLYPEPTIDE; INHIBITION AB THE conversion of normal, protease sensitive prion protein (PrP-sen) to the abnormal protease-resistant form (PrP-res) is of central importance in the pathogenesis of scrapie and other transmissible spongiform encephalopathies. In the present study, the effects of reduction of the disulfide bond on the PrP-sen to PrP-res conversion in a cell-free system were examined. The addition of the disulfide reducing agent dithiothreitol inhibited the cell-free conversion reaction with an IC,, of 2-2.5 mM. Separate pretreatment of either PrP-sen or PrP-res with dithiothreitol and an alkylating agent also inhibited the conversion reaction. Results of this study show that preservation of the disulfide bond is important in the conversion of PrP-sen to PrP-res. NeuroReport 9: 2457-2461 (C) 1998 Rapid Science Ltd. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. RP Caughey, B (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. NR 26 TC 64 Z9 66 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD AUG 3 PY 1998 VL 9 IS 11 BP 2457 EP 2461 DI 10.1097/00001756-199808030-00006 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 110YE UT WOS:000075408500007 PM 9721914 ER PT J AU Caudle, RM Finegold, AA Mannes, AJ Tobias, MD Kenshalo, DR Iadarola, MJ AF Caudle, RM Finegold, AA Mannes, AJ Tobias, MD Kenshalo, DR Iadarola, MJ TI Spinal kappa(1) and kappa(2) opioid binding sites in rats, guinea pigs, monkeys and humans SO NEUROREPORT LA English DT Article DE allodynia; analgesia; hyperalgesia; kappa opioid receptors; spinal cord ID RECEPTORS; HIPPOCAMPUS; DYNORPHIN; CELLS AB SEVERAL lines of work demonstrate that there are two subtypes of kappa opioid receptors. Intrathecally administered agonists for the kappa(1) subtype are not effective in treating pain, whereas agonists for the kappa(2) receptor are anti-hyperalgesic and anti-allodynic. The question addressed here was whether the ratio of spinal kappa(1) to kappa(2) receptors was conserved across species. Thus, binding experiments were performed on spinal cord membranes from rats, guinea pigs, monkeys and humans. We found that kappa(2) receptors were approximately ten times more abundant than kappa(1) receptors in all species tested. This suggests that the anti-hyperalgesic and anti-allodynic properties of kappa(2) agonists may also be conserved. Therefore, selective K-2 agonists may be effective in treating chronic pain in humans. NeuroReport port 9:2523-2525 (C) 1998 Rapid Science Ltd. C1 National Institute Dental Research, Pain & Neurosensory Mech Branch, NIH, Bethesda, MD 20892 USA. Hosp Univ Penn, Dept Anesthesiol, Philadelphia, PA 19104 USA. RP Caudle, RM (reprint author), National Institute Dental Research, Pain & Neurosensory Mech Branch, NIH, 49 Convent Dr,MSC 4410, Bethesda, MD 20892 USA. NR 12 TC 22 Z9 22 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD AUG 3 PY 1998 VL 9 IS 11 BP 2523 EP 2525 DI 10.1097/00001756-199808030-00018 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 110YE UT WOS:000075408500019 PM 9721926 ER PT J AU Hattori, A Luo, YQ Umegaki, H Munoz, J Roth, GS AF Hattori, A Luo, YQ Umegaki, H Munoz, J Roth, GS TI Intrastriatal injection of dopamine results in DNA damage and apoptosis in rats SO NEUROREPORT LA English DT Article DE apoptosis; DNA fragmentation; dopamine neurotoxicity; striatum; neurodegeneration; terminal deoxynucleotidyl transferase ID CELL-DEATH; PARKINSONS-DISEASE; SUBSTANTIA-NIGRA; STRIATUM; NEURONS; METHAMPHETAMINE; MICRODIALYSIS; ISCHEMIA; SYSTEM AB OVERFLOW Of the neurotransmitter dopamine (DA) in striatum is implicated in the neurodegenerative processes in ischemia, hypoxia and local exposure to high concentrations of excitatory amino acids. However, how DA causes neurotoxicity is not understood. We report that intrastriatal injection of DA (0.5-1 mu mol/mu l) in Wistar rats produces a robust increase in apoptotic cell death as determined by both a terminal deoxynucleotidyl transferase catalyzed dUTP-biotin nick labeling (TUNEL) and Klenow polymerase catalyzed [P-32]dCTP labeled DNA ladder. Cells in which apoptosis was induced by DA are characterized by condensed chromatin, DNA fragmentation, shrinkage and irregular shapes. The apoptotic cell death induced by DA is not due to the effect of hyperosmolar solution since intrastriatal injection of identical concentrations of NaCl on opposite sides of the same rat brains shows little TUNEL-positive labeling. The number of apoptotic cells is proportional to the amount of DA and length of exposure period. With DA concentrations from 0 to 1 mu mol/mu l, the maximal toxic effect appears at a concentration of 1 mu mol/mu l after 24 h exposure. Demonstration of DA-induced apoptosis in vivo may provide a potential molecular mechanism for DA neurotoxicity. (C) 1998 Rapid Science Ltd. C1 NIA, Mol Physiol & Genet Sect, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Luo, YQ (reprint author), NIA, Mol Physiol & Genet Sect, Gerontol Res Ctr, NIH, 4E02,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 23 TC 38 Z9 41 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD AUG 3 PY 1998 VL 9 IS 11 BP 2569 EP 2572 DI 10.1097/00001756-199808030-00026 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 110YE UT WOS:000075408500027 PM 9721934 ER PT J AU Freeman, JH Scharenberg, AM Olds, JL Schreurs, BG AF Freeman, JH Scharenberg, AM Olds, JL Schreurs, BG TI Classical conditioning increases membrane-bound protein kinase C in rabbit cerebellum SO NEUROREPORT LA English DT Article DE cerebellum; classical conditioning; eyeblink; learning; nictitating membrane; phorbol ester; protein kinase C; Purkinje cell; rabbit ID LONG-TERM DEPRESSION; MEMORY TRACE; LESIONS; HIPPOCAMPUS; ACTIVATION; CURRENTS; NUCLEI; CORTEX; RATS; PKC AB WE examined membrane-bound protein kinase C (PKC) in the cerebellum of rabbits given paired presentations of a tone conditioned stimulus (CS) that co-terminated with a periocular electrical stimulation unconditioned stimulus (US) or unpaired presentations of the CS and US or restraint in the experimental context. PKC activation was measured by quantitative film autoradiography of [H-3]phorbol 12,13-dibutyrate ([H-3]PBt2) binding in the molecular and granule cells layers of lobule HVI, anterior vermis and Crus I, and in the dentate/interpositus nuclei. There was a statistically significant increase in [H-3]PBt2 binding within the molecular layer of lobule HVI in rabbits given paired training relative to controls. The results indicate PKC activation in lobule HVI may be important in acquisition of conditioned eyeblink responses. (C) 1998 Rapid Science Ltd. C1 NINDS, Behav Neurosci Unit, Lab Adapt Syst, NIH, Bethesda, MD 20892 USA. Univ Iowa, Dept Psychol, Iowa City, IA 52242 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Dept Expt Pathol, Boston, MA 02115 USA. George Mason Univ, Krasnow Inst Adv Studies, Fairfax, VA 22030 USA. RP Schreurs, BG (reprint author), NINDS, Behav Neurosci Unit, Lab Adapt Syst, NIH, Bldg 36,Room B205, Bethesda, MD 20892 USA. RI Olds, James/D-2867-2011; OI Schreurs, Bernard/0000-0002-5776-0807 NR 25 TC 13 Z9 13 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD AUG 3 PY 1998 VL 9 IS 11 BP 2669 EP 2673 DI 10.1097/00001756-199808030-00045 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 110YE UT WOS:000075408500046 PM 9721953 ER PT J AU Litvan, I AF Litvan, I TI Progressive supranuclear palsy revisited SO ACTA NEUROLOGICA SCANDINAVICA LA English DT Review DE progressive supranuclear palsy; diagnosis; anatomy; pathology; therapy; epidemiology; genetic diversity ID STEELE-RICHARDSON-OLSZEWSKI; POSITRON EMISSION TOMOGRAPHY; FRONTAL-LOBE DYSFUNCTION; E EPSILON-4 ALLELE; TAU-POSITIVE GLIA; PARKINSONS-DISEASE; STRIATONIGRAL DEGENERATION; ALZHEIMERS-DISEASE; NATURAL-HISTORY; NEUROFIBRILLARY DEGENERATION AB Current understanding on the historic, epidemiologic, genetic, clinical, neuropathologic, neurochemical, diagnostic and therapeutic aspects of progressive supranuclear palsy (PSP) are revisited. In addition, new research directions are described. C1 NINDS, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. Henry M Jackson Fdn, Def & Vet Head Injury Program, Neuropharmacol Unit, Bethesda, MD USA. RP Litvan, I (reprint author), NINDS, Med Neurol Branch, NIH, Fed Bldg,Room 714, Bethesda, MD 20892 USA. OI Litvan, Irene/0000-0002-3485-3445 NR 143 TC 27 Z9 28 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 AUG PY 1998 VL 98 IS 2 BP 73 EP 84 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA 106LN UT WOS:000075131200001 PM 9724003 ER PT J AU Graham, K Wilsnack, R Dawson, D Vogeltanz, N AF Graham, K Wilsnack, R Dawson, D Vogeltanz, N TI Should alcohol consumption measures be adjusted for gender differences? SO ADDICTION LA English DT Article; Proceedings Paper CT 22nd Annual Epidemiology Symposium of the Kettill-Bruun-Society CY JUN 03-07, 1996 CL EDINBURGH, SCOTLAND SP Kettil Bruun Soc ID BREAST-CANCER; DEHYDROGENASE ACTIVITY; ETHANOL-METABOLISM; LARYNGEAL-CANCER; COLLEGE-STUDENTS; BODY-COMPOSITION; MENSTRUAL-CYCLE; WOMEN; DRINKING; INTOXICATION AB Because of biological differences between men and women, the same quantity of alcohol consumed over the same time period produces higher blood alcohol levels (BALs) in women than in men. Some alcohol researchers have proposed that quantity and volume measures of alcohol consumption (e.g. usual number of drinks per drinking day and overall amount of alcohol consumed) should be adjusted to reflect these biological differences. To date, no standard adjustment for biological gender differences has been adopted. In this paper, we review the literature on biological and behavioral differences related to alcohol consumption and effects and discuss the implications of these differences in terms of adjusting alcohol consumption measures. Our review suggests that adjusting measures of alcohol consumption to compensate for biological sex differences is most appropriate for research or policy applications involving the short and long-term physiological effects of alcohol in contexts where gender differences in how alcohol is consumed can be assumed to be minimal. In other circumstances, non-biological gender differences relating to alcohol use, such as pace of drinking, may moderate the relationship between alcohol consumption and biological gender differences, making an adjustment less defensible. We also identify areas where more Knowledge is needed not only to address the issue of adjusting alcohol measures for gender differences but also to understand better the relationship between alcohol consumption and effects. C1 Addict Res Fdn, London, ON N6G 4X8, Canada. Univ N Dakota, Sch Med, Dept Neurosci, Grand Forks, ND 58202 USA. NIAAA, Rockville, MD 20852 USA. Univ N Dakota, Dept Psychol, Grand Forks, ND 58202 USA. RP Graham, K (reprint author), Addict Res Fdn, 100 Collip Circle,Suite 200, London, ON N6G 4X8, Canada. EM kgraham@julian.uwo.ca NR 85 TC 89 Z9 91 U1 3 U2 4 PU CARFAX PUBL CO PI ABINGDON PA PO BOX 25, ABINGDON, OXFORDSHIRE, ENGLAND OX14 3UE SN 0965-2140 J9 ADDICTION JI Addiction PD AUG PY 1998 VL 93 IS 8 BP 1137 EP 1147 DI 10.1046/j.1360-0443.1998.93811372.x PG 11 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 105NQ UT WOS:000075080100002 PM 9813895 ER PT J AU Purohit, V AF Purohit, V TI Moderate alcohol consumption and estrogen levels in postmenopausal women: A review SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Review ID BONE-MINERAL DENSITY; BREAST-CANCER; CARDIOVASCULAR-DISEASE; URINE ESTROGENS; RISK; ESTRADIOL; THERAPY; INGESTION; HORMONES; ETHANOL AB This report reviews the literature to evaluate association between moderate alcohol consumption and estrogen levels in healthy postmenopausal women. Of the eight studies available in literature on postmenopausal women who were not on estrogen therapy, two analyzed urine samples and six analyzed blood samples for estrogen levels. Of the two urine sample studies, only one reported positive association (p < 0.05) between alcohol consumption and estrogen (estrone and estradiol) levels that increased by 16 to 20%. Of the six blood sample studies, only two- one in American women and one in European women-reported significant increases (p < 0.05) in estradiol levels in response to alcohol consumption. In the American women study, estradiol levels increased only with wine and not with beer or whiskey. In the European women study, estradiol levels increased in Danish and Portuguese women, but not in Spanish women. Thus, further studies are required to establish correlation between moderate alcohol consumption and estrogen levels in postmenopausal women. Of the two studies on postmenopausal women who were on estrogen replacement therapy, one administered estradiol through transdermal patch (0.15 mg) and one orally (1 mg/day). In both studies, blood estradiol levels were measured after administering a single dose of ethanol orally (0.7-0.75 g/kg of body weight). Estradiol levels were increased by 22 and 300% in the transdermal patch and oral studies, respectively. These results suggest that alcohol consumption may increase blood estradiol levels in postmenopausal women who are an estrogen replacement therapy, and this may increase the risk of breast cancer. C1 NIAAA, Biomed Res Branch, Div Basic Res, NIH, Bethesda, MD 20892 USA. RP Purohit, V (reprint author), NIAAA, Biomed Res Branch, Div Basic Res, NIH, 6000 Execut Blvd,Suite 402, Bethesda, MD 20892 USA. NR 22 TC 79 Z9 80 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG PY 1998 VL 22 IS 5 BP 994 EP 997 DI 10.1111/j.1530-0277.1998.tb03694.x PG 4 WC Substance Abuse SC Substance Abuse GA 112BW UT WOS:000075475100005 PM 9726268 ER PT J AU Eckardt, MJ File, SE Gessa, GL Grant, KA Guerri, C Hoffman, PL Kalant, H Koob, GF Li, TK Tabakoff, B AF Eckardt, MJ File, SE Gessa, GL Grant, KA Guerri, C Hoffman, PL Kalant, H Koob, GF Li, TK Tabakoff, B TI Effects of moderate alcohol consumption on the central nervous system SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Review DE moderate; ethanol; brain; behavior; biology ID CEREBELLAR GRANULE CELLS; ELEVATED-PLUS-MAZE; PROTEIN-KINASE-C; BRAIN GROWTH SPURT; VOLUNTARY ETHANOL INTAKE; FEMALE SOCIAL DRINKERS; FIRST-PASS-METABOLISM; D-ASPARTATE RECEPTORS; NICOTINIC ACETYLCHOLINE-RECEPTORS; CONDITIONED PLACE PREFERENCE AB The concept of moderate consumption of ethanol (beverage alcohol) has evolved over time from considering this level of intake to he nonintoxicating and noninjurious, to encompassing levels defined as "statistically" normal in particular populations, and the public health-driven concepts that define moderate drinking as the level corresponding to the lowest overall rate of morbidity or mortality in a population. The various approaches to defining moderate consumption of ethanol provide for a range of intakes that can result in blood ethanol concentrations ranging from 5 to 6 mg/dl, to levels of over 90 mg/dl (i.e., similar to 20 mM). This review summarizes available information regarding the effects of moderate consumption of ethanol on the adult and the developing nervous systems. The metabolism of ethanol in the human is reviewed to allow for proper appreciation of the important variables that interact to influence the level of exposure of the brain to ethanol once ethanol is orally consumed. At the neurochemical level, the moderate consumption of ethanol selectively affects the function of GABA, glutamatergic, serotonergic, dopaminergic, cholinergic, and opioid neuronal systems. Ethanol can affect these systems directly, and/or the interactions between and among these systems become important in the expression of ethanol's actions. The behavioral consequences of ethanol's actions on brain neurochemistry, and the neurochemical effects themselves, are very much dose- and time-related, and the collage of ethanol's actions can change significantly even on the rising and falling phases of the blood ethanol curve. The behavioral effects of moderate ethanol intake can encompass events that the human or other animal can perceive as reinforcing through either positive (e.g., pleasurable, activating) or negative (e.g., anxiolysis, stress reduction) reinforcement mechanisms. Genetic factors and gender play an important role in the metabolism and behavioral actions of ethanol, and doses of ethanol producing pleasurable feelings, activation, and reduction of anxiety in some humans/animals can have aversive, sedative, or no effect in others. Research on the cognitive effects of acute and chronic moderate intake of ethanol is reviewed, and although a number of studies have noted a measurable diminution in neuropsychologic parameters in habitual consumers of moderate amounts of ethanol, others have not found such changes. Recent studies have also noted some positive effects of moderate ethanol consumption on cognitive performance in the aging human. The moderate consumption of ethanol by pregnant women can have significant consequences on the developing nervous system of the fetus. Consumption of ethanol during pregnancy at levels considered to be in the moderate range can generate fetal alcohol effects (behavioral, cognitive anomalies) in the offspring. A number of factors-including gestational period, the periodicity of the mother's drinking, genetic factors, etc.-play important roles in determining the effect of ethanol on the developing central nervous system. A series of recommendations for future research endeavors, at all levels, is included with this review as part of the assessment of the effects of moderate ethanol consumption on the central nervous system. C1 Univ Colorado, Sch Med, Dept Pharmacol, Denver, CO 80262 USA. NIAAA, Off Sci Affairs, Bethesda, MD 20205 USA. Univ London, Guys Hosp, Psychopharmacol Res Unit, Div Pharmacol, London, England. Univ Cagliari, Dipartimento Neurosci, Cagliari, Italy. Wake Forest Univ, Bowman Gray Sch Med, Dept Physiol & Pharmacol, Winston Salem, NC 27103 USA. Inst Invest Citological Caja Ahorros Valencia, Valencia, Spain. Univ Colorado, Sch Med, Dept Pharmacol, Denver, CO 80202 USA. Univ Toronto, Dept Pharmacol, Toronto, ON, Canada. Scripps Res Inst, Dept Neuropharmacol, La Jolla, CA 92037 USA. Indiana Univ, Sch Med, Indianapolis, IN 46202 USA. RP Tabakoff, B (reprint author), Univ Colorado, Sch Med, Dept Pharmacol, Campus Box C236,4200 E 9th Ave, Denver, CO 80262 USA. RI Guerri, Consuelo/B-5181-2014; koob, george/P-8791-2016 NR 440 TC 371 Z9 376 U1 17 U2 115 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG PY 1998 VL 22 IS 5 BP 998 EP 1040 DI 10.1111/j.1530-0277.1998.tb03695.x PG 43 WC Substance Abuse SC Substance Abuse GA 112BW UT WOS:000075475100006 PM 9726269 ER PT J AU Kannel, WB Wilson, PWF D'Agostino, RB Cobb, J AF Kannel, WB Wilson, PWF D'Agostino, RB Cobb, J TI Sudden coronary death in women SO AMERICAN HEART JOURNAL LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; CARDIAC DEATH; RISK; MINNESOTA AB Objectives The objective of this study was to examine prospectively the incidence, predisposing cardiovascular conditions, and risk factors for sudden death in women compared with men. Methods and Results The study design was a prospective general population examination of a cohort of 2873 women for development of sudden coronary death in relation to antecedent overt coronary heart disease (CHD), cardiac failure, and risk factors for coronary heart disease. Participants were women aged 30 to 62 years participating in the Framingham Study, receiving routine biennial examinations for risk factors and cardiovascular conditions. Among women monitored over a period of 38 years, there were 750 initial coronary events, of which 94 (12%) were sudden cardiac deaths. Of the 292 CHD fatalities in women, 32% were sudden cardiac deaths and 37% of the women had a history of prior CHD. Sudden death incidence in women lagged behind that in men by >10 years. However, above age 75 years, 17% of all CHD events in women were sudden deaths. Sudden death risk in women with CHD was half as high as in men if they had CHD. In both sexes, a myocardial infarction conferred twice the risk of angina. Cardiac failure escalated sudden death risk of women 5-fold but was only one fourth that of men with failure or CHD. Ventricular ectopy increased sudden death risk only in women without prior overt CHD. Except for diabetes, CHD risk factors imposed a lower sudden death risk in women than men. However, even in women, sudden death risk increased over a 17-fold range in relation to their burden of CHD risk factors. Conclusions Sudden death is a prominent feature of CHD io women as well as men, particularly in advanced age A higher fraction of sudden deaths in women than men is unexpected occurring in the absence of prior overt CHD. It is subject to the same risk factors and as predictable in women as in men. However, at any level of multivariate risk, women are less vulnerable to sudden death than men. C1 Boston Univ, Sch Med, Evans Mem Res Fdn,Dept Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. Boston Univ, Dept Math, Boston, MA USA. Framingham Heart Dis Epidemiol Study, Div Epidemiol, NHLBI, Framingham, MA USA. RP Kannel, WB (reprint author), Boston Univ, Sch Med, Evans Mem Res Fdn,Dept Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. FU NHLBI NIH HHS [N01-HC-38038] NR 15 TC 208 Z9 215 U1 0 U2 0 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD AUG PY 1998 VL 136 IS 2 BP 205 EP 212 DI 10.1053/hj.1998.v136.90226 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 107PB UT WOS:000075216700005 PM 9704680 ER PT J AU Gardin, JM Arnold, AM Bild, DE Smith, VE Lima, JAC Klopfenstein, HS Kitzman, DW AF Gardin, JM Arnold, AM Bild, DE Smith, VE Lima, JAC Klopfenstein, HS Kitzman, DW TI Left ventricular diastolic filling in the elderly: The Cardiovascular Health Study SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ISOLATED SYSTOLIC HYPERTENSION; CONGESTIVE HEART-FAILURE; ECHOCARDIOGRAPHIC ASSESSMENT; DISEASE; INDEXES; MILD; MASS; AGE AB Changes in left ventricular (LV) diastolic function (e.g.., as measured by transmitral flow velocity) are known to occur with aging. In addition, impaired LV diastolic function plays an important role in such cardiovascular disorders common in the elderly as hypertension, ischemic heart disease, and congestive heart failure (CHF). Participants in the Cardiovascular Health Study, a multicenter study of community-dwelling men (n = 2,239) and women (n = 2,962) greater than or equal to 65 years of age, underwent an extensive baseline evaluation, including echocardiography. Early diastolic LV Doppler (transmitral) peak filling velocity decreased, and peak late diastolic (atrial) velocity increased with age in multivariate analyses tall p <0.001). Early and late diastolic peak filling velocities were both significantly higher in women than in men, even after adjustment for body surface area (or height and weight). In multivariate models in the entire cohort and a healthy subgroup (n = 703), gender, age, heart rate, and blood pressure (BP) were most strongly related to early and late diastolic transmitral peak velocities. Early and late diastolic peak velocities both increased with increases in systolic BP and decreased with increases in diastolic BP (p <0.001). Doppler transmitral velocities were compared among health status subgroups. In multiple regression models adjusted for other covariates, and in analysis of variance models examining differences across subgroups adjusted only for age, the subgroup with CHF had the highest early diastolic peak velocities. All clinical disease subgroups had higher late diastolic peak velocities than the healthy subgroup, with the subgroups with either CHF or hypertension having the highest age-adjusted means. The subgroup with hypertension had the lowest ratio of early-to-late diastolic peak velocity, and men with CHF had the highest ratio. These findings are consistent with previous reports that hypertensive subjects exhibit an abnormal relaxation pattern, whereas patients with CHF develop a pattern suggestive of an increased early diastolic left atrial-LV pressure gradient. (C)1998 by Excerpta Medica, Inc. C1 Univ Calif Irvine, Dept Med, Div Cardiol, Irvine, CA 92717 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Albany Med Coll, Div Cardiol, Albany, NY 12208 USA. Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Dept Epidemiol, Baltimore, MD 21205 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Med, Div Cardiol, Winston Salem, NC 27103 USA. RP Gardin, JM (reprint author), CHS Coordinating Ctr, Century Sq,1501 4th Ave,Suite 2105, Seattle, WA 98101 USA. FU NHLBI NIH HHS [N01-HC-85079, N01-HC-85080, N01-HC-85081] NR 30 TC 85 Z9 88 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 AUG 1 PY 1998 VL 82 IS 3 BP 345 EP 351 DI 10.1016/S0002-9149(98)00339-7 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 107EK UT WOS:000075193900016 PM 9708665 ER PT J AU Cappuccio, FP Elliott, P Follmann, D Cutler, JA AF Cappuccio, FP Elliott, P Follmann, D Cutler, JA TI Authors' response to "Comments on a meta-analysis of the relation between dietary calcium intake and blood pressure" SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material ID METAANALYSIS; POTASSIUM; ALCOHOL; SODIUM C1 Univ London St Georges Hosp, Sch Med, Dept Med, London SW17 0RE, England. Imperial Coll Sch Med, Dept Epidemiol & Publ Hlth, London, England. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Cappuccio, FP (reprint author), Univ London St Georges Hosp, Sch Med, Dept Med, London SW17 0RE, England. RI Cappuccio, Francesco/D-3028-2009 NR 12 TC 4 Z9 4 U1 0 U2 0 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 1 PY 1998 VL 148 IS 3 BP 232 EP 233 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 105PZ UT WOS:000075083900003 ER PT J AU Klebanoff, MA Levine, RJ Clemens, JD DerSimonian, R Wilkins, DG AF Klebanoff, MA Levine, RJ Clemens, JD DerSimonian, R Wilkins, DG TI Serum cotinine concentration and self-reported smoking during pregnancy SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cotinine; pregnancy; smoking ID BIRTH-WEIGHT; VALIDITY AB Although during pregnancy there is a better correlation between maternal serum cotinine concentration and adverse outcome than between self-reported smoking and such an outcome, few studies of pregnancy have measured cotinine concentration to determine how much a woman smokes. This study assessed the accuracy of self-reported smoking during pregnancy by performing serum cotinine assays on 448 women registered in the Collaborative Perinatal Project (1959-1966). Based on the assumption that a serum cotinine concentration of >10 ng/ml represented active smoking, 94.9% of women who denied smoking and 87.0% of women who stated that they smoked (kappa = 0.83) reported their status accurately. Among smokers, the correlation coefficient between cotinine concentration and number of cigarettes smoked per day was 0.44, Serum cotinine concentration correlated more strongly than self-reported smoking with infant birth weight (r = 0.246 vs. 0.200). In conclusion, this study showed that pregnant women accurately reported whether they smoked, but cotinine concentration was a better measure than self-report of the actual tobacco dose received. Am J Epidemiol 1998;148:259-62. C1 NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. Univ Utah, Ctr Human Toxicol, Salt Lake City, UT 84112 USA. RP Klebanoff, MA (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, NIH, 6100 Bldg,Room 7B03, Bethesda, MD 20892 USA. FU NICHD NIH HHS [N01-HD-7-3262] NR 14 TC 175 Z9 177 U1 1 U2 3 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 1 PY 1998 VL 148 IS 3 BP 259 EP 262 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 105PZ UT WOS:000075083900007 PM 9690362 ER PT J AU Dasso, M Pu, RT AF Dasso, M Pu, RT TI Nuclear transport: Run by Ran? SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID PROTEIN IMPORT; PATHWAY C1 NICHHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. RP Dasso, M (reprint author), NICHHD, Mol Embryol Lab, NIH, Bldg 18T,Room 106, Bethesda, MD 20892 USA. OI Dasso, Mary/0000-0002-5410-1371 NR 36 TC 16 Z9 16 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD AUG PY 1998 VL 63 IS 2 BP 311 EP 316 DI 10.1086/301990 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 110CB UT WOS:000075360800004 PM 9683621 ER PT J AU Puck, JM AF Puck, JM TI The timing of twinning: More insights from x inactivation SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Editorial Material ID PATTERNS; CARRIER C1 Natl Human Genome Res Inst, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Puck, JM (reprint author), Natl Human Genome Res Inst, Genet & Mol Biol Branch, NIH, Bldg 49,Room 3A14,49 Convent Dr, Bethesda, MD 20892 USA. NR 12 TC 20 Z9 21 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD AUG PY 1998 VL 63 IS 2 BP 327 EP 328 DI 10.1086/301988 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 110CB UT WOS:000075360800007 PM 9683619 ER PT J AU Juo, SHH Bredie, SJH Kiemeney, LA Demacker, PNM Stalenhoef, AFH AF Juo, SHH Bredie, SJH Kiemeney, LA Demacker, PNM Stalenhoef, AFH TI A common genetic mechanism determines plasma apolipoprotein B levels and dense LDL subfraction distribution in familial combined hyperlipidemia SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID LIPOPROTEIN SUBCLASS PATTERNS; INHERITED SUSCEPTIBILITY; SEGREGATION ANALYSIS; HYPERTRIGLYCERIDEMIA; ATHEROSCLEROSIS; TRIGLYCERIDE; DISEASE; MODEL; HYPERAPOBETALIPOPROTEINEMIA; HETEROGENEITY AB Familial combined hyperlipidemia (FCH) is a common lipid disorder characterized by elevations of plasma cholesterol and/or triglyceride in first-degree relatives. A predominance of small, dense LDL particles and elevated apolipoprotein B (apoB) levels is commonly found in members of FCH families. Many studies have investigated the genetic mechanisms determining individuals' lipid levels, in FCH families. Previously, we demonstrated a major gene effect on LDL particle size and codominant Mendelian inheritance involved in determination of apoB levels in a sample of 40 well-defined FCH families. An elevation of apoB levels is associated metabolically with a predominance of small, dense LDL particles in FCH. To establish whether a common gene regulates both traits, we conducted a bivariate genetic analysis to test the hypothesis of a common genetic mechanism. In this study, we found that 66% of the total phenotypic correlation is due to shared genetic components. Further bivariate segregation analysis suggested that both traits share a common major gene plus individual polygenic components. This common major gene explains 37% of the variance of adjusted LDL particle size and 23% of the variance of adjusted apoB levels. Our study suggests that a major gene that has pleiotropic effects on LDL particle size and apoB levels may be the gene underlying FCH in the families we studied. C1 NIH, Natl Human Genome Res Inst, Baltimore, MD USA. Rockefeller Univ, Lab Stat Genet, New York, NY 10021 USA. Univ Nijmegen, Dept Med, Div Gen Internal Med, Nijmegen, Netherlands. Univ Nijmegen, Dept Epidemiol & Urol, Nijmegen, Netherlands. RP Stalenhoef, AFH (reprint author), Univ Nijmegen Hosp, Dept Med, Div Gen Internal Med, POB 9101, NL-6500 HB Nijmegen, Netherlands. EM A.Stalenhorf@aig.azn.nl RI Juo, Suh-Hang/A-1765-2010; Juo, Suh-Hang/C-9545-2009; Kiemeney, Lambertus/D-3357-2009; Stalenhoef, A.F.H./H-8094-2014; Bredie, Sebastian/L-4226-2015 OI Kiemeney, Lambertus/0000-0002-2368-1326; Bredie, Sebastian/0000-0002-6973-7540 NR 35 TC 17 Z9 17 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD AUG PY 1998 VL 63 IS 2 BP 586 EP 594 DI 10.1086/301962 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 110CB UT WOS:000075360800035 PM 9683593 ER PT J AU Nelson, KB Grether, JK AF Nelson, KB Grether, JK TI Potentially asphyxiating conditions and spastic cerebral palsy in infants of normal birth weight SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE birth asphyxia; tight nuchal cord; maternal infection; Apgar scores; neonatal seizures; cerebral palsy ID NUCHAL CORD; RISK; ANTECEDENTS AB OBJECTIVE: Our purpose was to examine the association of cerebral palsy with conditions that can interrupt oxygen supply to the fetus as a primary pathogenetic event. STUDY DESIGN: A population-based case-control study was performed in four California counties, 1983 through 1985, comparing birth records of 46 children with disabling spastic cerebral palsy without recognized prenatal brain lesions and 378 randomly selected control children weighing greater than or equal to 2500 g at birth and surviving to age 3 years. RESULTS: Eight of 46 children with otherwise unexplained spastic cerebral palsy, all eight with quadriplegic cerebral palsy, and 15 of 378 controls had births complicated by tight nuchal cord (odds ratio for quadriplegia 18, 95% confidence interval 6.2 to 48). Other potentially asphyxiating conditions were uncommon and none was associated with spastic diplegia or hemiplegia. Level of care, oxytocin for augmentation of labor, and surgical delivery did not alter the association of potentially asphyxiating conditions with spastic quadriplegia. Intrapartum indicators of fetal stress, including meconium in amniotic fluid and fetal monitoring abnormalities, were common and did not distinguish children with quadriplegia who had potentially asphyxiating conditions from controls with such conditions. CONCLUSION: Potentially asphyxiating conditions, chiefly tight nuchal cord, were associated with an appreciable proportion of unexplained spastic quadriplegia but not with diplegia or hemiplegia. Intrapartum abnormalities were common both in children with cerebral palsy and controls and did not distinguish between them. C1 Calif Dept Hlth Serv, Calif Birth Defects Monitoring Program, Oakland, CA 94608 USA. NINDS, Neuroepidemiol Branch, Bethesda, MD 20892 USA. RP Grether, JK (reprint author), Calif Dept Hlth Serv, Calif Birth Defects Monitoring Program, 1900 Powell St,Suite 1050, Oakland, CA 94608 USA. FU NCI NIH HHS [263-95-CO255] NR 23 TC 176 Z9 181 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 AUG PY 1998 VL 179 IS 2 BP 507 EP 513 DI 10.1016/S0002-9378(98)70387-4 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 115MF UT WOS:000075668300048 PM 9731861 ER PT J AU Whitcup, SM Vistica, BP Milam, AH Nussenblatt, RB Gery, I AF Whitcup, SM Vistica, BP Milam, AH Nussenblatt, RB Gery, I TI Recoverin-associated retinopathy: A clinically and immunologically distinctive disease SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID CANCER-ASSOCIATED RETINOPATHY; RETINAL S-ANTIGEN; CELLULAR IMMUNE RESPONSIVENESS; PARA-NEOPLASTIC SYNDROME; CALCIUM-BINDING PROTEIN; PHOTORECEPTOR DEGENERATION; UVEITIS PATIENTS; AUTOIMMUNE BASIS; LUNG-CARCINOMA; LEWIS RATS AB PURPOSE: To compare the immune response to retinal antigens in a patient with a clinical condition resembling cancer-associated retinopathy with the immune responses of patients with other retinal degenerations or uveitis. METHODS: Cellular and humoral immune responses to retinal S-antigen and recoverin were determined in one patient with disease resembling cancer-associated retinopathy, three patients with other retinal degenerations, and eight patients with uveitis. RESULTS: A cellular immune response against recoverin was found only in the patient with the condition resembling cancer-associated retinopathy. Elevated levels of antibody against recoverin were found in this patient and in one of the three patients with a retinal degeneration, but in none of the eight patients with uveitis. In contrast, moderate lymphocyte responses to retinal S-antigen were found in most of the patients studied, and this response did not distinguish among the patient groups. Levels of serum antibodies against retinal S-antigen were also similar in all patients tested. Serum from the patient with disease resembling cancer-associated retinopathy produced strong immunostaining of the rods, cones, outer plexiform layer, and some cone bipolar cells, but serum from the patients with uveitis or other retinal degenerations did not show specific reactivity with the retina. CONCLUSIONS: We propose that this immunologically and clinically distinctive condition be termed recoverin-associated retinopathy, and we suggest that a cellular immune response against recoverin may be a distinguishing feature of the disorder. (Am J Ophthalmol 1998;126:230-237. (C) 1998 by Elsevier Science Inc. Al rights reserved.). C1 NEI, NIH, Bethesda, MD 20892 USA. Univ Washington, Dept Ophthalmol, Seattle, WA 98195 USA. RP Whitcup, SM (reprint author), NEI, NIH, 10 Ctr Dr,Bldg 10,Rm 105221, Bethesda, MD 20892 USA. FU NEI NIH HHS [EY0-1730, EY0-1311] NR 30 TC 73 Z9 76 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD AUG PY 1998 VL 126 IS 2 BP 230 EP 237 DI 10.1016/S0002-9394(98)00149-4 PG 8 WC Ophthalmology SC Ophthalmology GA 111CJ UT WOS:000075419500009 PM 9727517 ER PT J AU Liu, XB Rojas, E Ambudkar, IS AF Liu, XB Rojas, E Ambudkar, IS TI Regulation of K-Ca current by store-operated Ca2+ influx depends on internal Ca2+ release in HSG cells SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE calcium-activated potassium channel; store-operated calcium influx; salivary gland cells; muscarinic receptor ID CAPACITATIVE CALCIUM-ENTRY; SALIVARY ACINAR-CELLS; PATCH-CLAMP; ACTIVATION; PATHWAYS; LINE; OSCILLATIONS; MECHANISMS; DEPLETION; SECRETION AB This study examines the Ca2+ influx-dependent regulation of the Ca2+-activated K+ channel (K-Ca) in human submandibular gland (HSG) cells. Carbachol (CCh) induced sustained increases in the K-Ca current and cytosolic Ca2+ concentration ([Ca2+](i)), which were prevented by loading cells with 1,2-bis-(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). Removal of extracellular Ca2+ and addition of La3+ or Gd3+, but not Zn2+, inhibited the increases in K-Ca current and [Ca2+](i). Ca2+ influx during refill (i.e., addition of Ca2+ to cells treated with CCh and then atropine in Ca2+-free medium) failed to evoke increases in the K-Ca current but achieved internal Ca2+ store refill. When refill was prevented by thapsigargin, Ca2+ readdition induced rapid activation of K-Ca. These data provide further evidence that intracellular Ca2+ accumulation provides tight buffering of [Ca2+](i) at the site of Ca2+ influx (H. Mogami, K. Nakano, A. V. Tepikin, and O. H. Petersen. Cell 88: 49-55, 1997). We suggest that the Ca2+ influx-dependent regulation of the sustained K-Ca current in CCh-stimulated HSG cells is mediated by the uptake of Ca2+ into the internal Ca2+ store and release via the inositol 1,4,5-trisphosphate-sensitive channel. C1 NIDR, Secretory Physiol Sect, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Lab Cell Biol & Biochem, NIH, Bethesda, MD 20892 USA. RP Ambudkar, IS (reprint author), NIDR, Secretory Physiol Sect, Gene Therapy & Therapeut Branch, NIH, Bldg 10,Rm 1N-113, Bethesda, MD 20892 USA. NR 36 TC 29 Z9 29 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD AUG PY 1998 VL 275 IS 2 BP C571 EP C580 PG 10 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 106WQ UT WOS:000075174400027 PM 9688612 ER PT J AU Mullin, JM Kampherstein, JA Laughlin, KV Clarkin, CEK Miller, RD Szallasi, Z Kachar, B Soler, AP Rosson, D AF Mullin, JM Kampherstein, JA Laughlin, KV Clarkin, CEK Miller, RD Szallasi, Z Kachar, B Soler, AP Rosson, D TI Overexpression of protein kinase C-delta increases tight junction permeability in LLC-PK1 epithelia SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE phorbol ester; paracellular; transepithelial; resistance; cytoskeleton; mannitol; freeze fracture; dextran ID EPIDERMAL GROWTH-FACTOR; HIGH-AFFINITY RECEPTOR; TYROSINE PHOSPHORYLATION; PHORBOL ESTER; TRANSEPITHELIAL PERMEABILITY; PARACELLULAR PATHWAYS; TUMOR PROMOTERS; CELLS; ALPHA; EXPRESSION AB The Ca2+-independent delta-isoform of protein kinase C (PKC-delta) was overexpressed in LLC-PK1 epithelia and placed under control of a tetracycline-responsive expression system. In the absence of tetracycline, the exogenous PKC-delta is expressed. Western immunoblots show that the overexpressed PKC-delta is found in the cytosolic, membrane-associated, and Triton-insoluble fractions. Overexpression of PKC-delta produced subconfluent and confluent epithelial morphologies similar to that observed on exposure of wild-type cells to the phorbol ester 12-O-tetradecanoylphorbol-13-acetate. Transepithelial electrical resistance (R-T) in cell sheets overexpressing PKC-delta was only 20% of that in cell sheets incubated in the presence of tetracycline, in which the amount of PKC-delta and R-T were similar to those in LLC-PK1 parental cell sheets. Overexpression of PKC-delta also elicited a significant increase in transepithelial Aux of D-[C-14]mannitol and a radiolabeled 2 x 10(6)-molecular-weight dextran, suggesting with the R-T decrease that overexpression increased paracellular, tight junctional permeability. Electron microscopy showed that PKC-delta overexpression results in a multilayered cell sheet, the tight junctions of which are almost uniformly permeable to ruthenium red. Freeze-fracture electron microscopy indicates that overexpression of PKC-delta results in a more disorganized arrangement of tight junctional strands. As with LLC-PK1 cell sheets treated with 12-O-tetradecanoylphorbol-13-acetate, the reduced R-T, increased D-mannitol flux, and tight junctional leakiness to ruthenium red that are seen with PKC-delta overexpression suggest the involvement of PKC-delta id regulation of tight junctional permeability. C1 Lankenau Med Res Ctr, Wynnewood, PA 19096 USA. Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD 20814 USA. NIDCD, Cell Biol Lab, NIH, Rockville, MD 20850 USA. RP Mullin, JM (reprint author), Lankenau Med Res Ctr, 100 Lancaster Ave, Wynnewood, PA 19096 USA. FU NCI NIH HHS [CA-67113, CA-48121] NR 70 TC 61 Z9 61 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD AUG PY 1998 VL 275 IS 2 BP C544 EP C554 PG 11 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 106WQ UT WOS:000075174400024 PM 9688609 ER PT J AU Murphy, EJ AF Murphy, EJ TI L-FABP and I-FABP expression increase NBD-stearate uptake and cytoplasmic diffusion in L cells SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE fatty acid uptake; fatty acid cytoplasmic diffusion; liver fatty acid binding protein; intestinal fatty acid binding protein; fluorescence recovery after photobleaching ID ACID-BINDING-PROTEIN; RAT-LIVER; NILE RED; FATTY; FIBROBLASTS; ESTERIFICATION; TRANSPORT; MEMBRANES AB The effects of intestinal and liver fatty acid binding protein (I- and L-FABP, respectively) expression on single-cell fatty acid uptake, internalization, and cytoplasmic diffusion were determined in transfected L cell fibroblasts. These parameters were measured using the nonesterifiable fluorescent fatty acid probe 12-N-methyl-(7-nitrobenz-2-oxa-1,3-diazol)aminostearate (NBD-stearate) and fluorescence digital imaging. In single-cell fluorescence imaging experiments, L-FABP-expressing cells, but not I-FABP-expressing cells, increased NBD-stearate uptake 1.7-fold compared with control cells. Both I- and L-FABP increased the cytoplasmic diffusion rate of the internalized NBD-stearate 2.6- and 1.9-fold, respectively, compared with control cells. However, increased NBD-stearate lateral membrane mobility was observed only in L-FABP-expressing cells. After incubation of the cells with 4 mu M NBD-stearate at 37 degrees C for 30 min, fluorescence deconvolution imaging indicated that NBD-stearate was localized primarily into lipid droplets in all cell lines. The differential effect of these proteins on fatty acid uptake and intracellular trafficking in single cells illustrates a possible difference in the physiological function of I- and L-FABP in intact cells. C1 Texas A&M Univ, Dept Physiol & Pharmacol, College Stn, TX 77843 USA. RP Murphy, EJ (reprint author), NIA, Neurosci Lab, NIH, Bldg 10,Rm 6C-103,900 Rockville Pike, Bethesda, MD 20892 USA. NR 27 TC 66 Z9 68 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD AUG PY 1998 VL 275 IS 2 BP G244 EP G249 PG 6 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 108WT UT WOS:000075289300010 PM 9688651 ER PT J AU Murphy, EJ AF Murphy, EJ TI Sterol carrier protein-2 expression increases NBD-stearate uptake and cytoplasmic diffusion in L cells SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE fluorescence microscopy; fluorescence recovery after photobleaching ID LIPID-TRANSFER PROTEIN; ACID-BINDING PROTEINS; FATTY-ACID; RAT-LIVER; NILE RED; CHOLESTEROL; SEQUENCE; ESTERIFICATION; LOCALIZATION; HEPATOCYTES AB The effects of sterol carrier protein-2 (SCP-2) expression on fatty acid uptake and cytoplasmic diffusion were determined using L cell fibroblasts transfected with cDNA encoding either the 15- or 13.2-kDa form of SCP-2. Cis-parinarate and 12-N-methyl-(7-nitrobenz-2-oxa-1,3-diazol)aminostearate (NBD-stearate) were used as nonesterifiable fluorescent fatty acid probes. NBD-stearate and cis-parinarate uptake was rapid and saturable. In 15-kDa SCP-2-expressing cells, the extent of NBD-stearate and cis-parinarate uptake was increased 1.4- and 1.2-fold, respectively, compared with control. In the 13.2-kDa SCP-2-expressing cells, the extent of NBD-stearate and cis-parinarate uptake was increased 1.3- and 1.1-fold, respectively, compared with control cells. NBD-stearate cytoplasmic diffusion was increased 1.5-fold in 15-kDa SCP-2-expressing cells, but not in 13.2-kDa SCP-2-expressing cells, compared with control cells. After incubation with NBD-stearate for 30 min at 37 degrees C, fluorescence imaging indicated that NBD-stearate was localized primarily in lipid droplets in all cell lines. These results suggest that SCP-2 may be involved not only in fatty acid uptake but also in intracellular fatty acid trafficking. C1 Texas A&M Univ, Dept Physiol & Pharmacol, College Stn, TX 77843 USA. RP Murphy, EJ (reprint author), NIA, Neurosci Lab, NIH, Bldg 10,Rm 6C-103,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 32 TC 28 Z9 28 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD AUG PY 1998 VL 275 IS 2 BP G237 EP G243 PG 7 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 108WT UT WOS:000075289300009 PM 9688650 ER PT J AU Christensen, BM Marples, D Jensen, UB Frokiaer, J Sheikh-Hamad, D Knepper, M Nielsen, S AF Christensen, BM Marples, D Jensen, UB Frokiaer, J Sheikh-Hamad, D Knepper, M Nielsen, S TI Acute effects of vasopressin V(2)-receptor antagonist on kidney AQP2 expression and subcellular distribution SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE aquaporin-2; collecting duct; nephrogenic diabetes insipidus; vasopressin antagonist ID WATER CHANNEL EXPRESSION; INDUCED DOWN-REGULATION; RAT-KIDNEY; COLLECTING DUCT; AQUAPORIN FAMILY; PLASMA-MEMBRANE; PERMEABILITY; PHOSPHORYLATION; PROTEINS; RECEPTOR AB The acute effect of treatment with the vasopressin V(2)-receptor antagonist OPC-31260 (OPC) on aquaporin-2 (AQP2) distribution and expression in rat kidney was examined. Immunofluorescence and semi-quantitative immunoelectron microscopy revealed that 15 and 30 min of OPC treatment resulted in significant reduction in apical plasma membrane labeling of AQP2, with a concomitant increase in labeling of vesicles and multivesicular bodies. In parallel, OPC treatment induced a large increase in urine output [0.6 +/- 0.2 vs. 8.3 +/- 1.0 ml/h (n = 4)]. Northern blotting using a (32)P-labeled AQP2 cDNA probe and a digoxigenin-labeled AQP2 RNA probe revealed a band of similar to 1.6 kb corresponding to the predicted size of AQP2 mRNA. In control experiments, thirsting increased, whereas water loading decreased AQP2 mRNA levels. Treatment of rats with OPC caused a significant reduction in AQP2 mRNA within 30 min (52 +/- 21%, n = 8, P < 0.025) and 60 min (56 +/- 7%, n = 4, P < 0.001) of treatment compared with intravenous saline-injected controls. Thus a very rapid reduction in AQP2 mRNA was observed in response to vasopressin-receptor antagonist treatment. The reduction in AQP2 mRNA persisted after 24 h (40 +/- 17%, n = 5, P < 0.05) of OPC treatment. There was a parallel increase in diuresis and reduction in urine osmolality. In conclusion, V(2)-receptor blockade produced a rapid internalization of AQP2 parallel with a rapid increase in urine output. Furthermore, OPC treatment caused a rapid and significant reduction in AQP2 mRNA expression, demonstrating that for rapid regulation of AQP2 expression, modulation of AQP2 mRNA levels is regulated via vasopressin-receptor signaling pathways. C1 Aarhus Univ, Dept Cell Biol, Inst Anat, DK-8000 Aarhus, Denmark. Aarhus Univ Hosp, Dept Clin Physiol, DK-8000 Aarhus, Denmark. Univ Aarhus, Inst Expt Clin Res, DK-8000 Aarhus, Denmark. Univ Aarhus, Inst Human Genet, DK-8000 Aarhus, Denmark. Univ Leeds, Dept Physiol, Leeds LS2 9JT, W Yorkshire, England. Baylor Coll Med, Dept Med, Nephrol Sect, Houston, TX 77030 USA. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Nielsen, S (reprint author), Aarhus Univ, Dept Cell Biol, Inst Anat, DK-8000 Aarhus, Denmark. NR 48 TC 38 Z9 38 U1 2 U2 2 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 AUG PY 1998 VL 275 IS 2 BP F285 EP F297 PG 13 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 108DA UT WOS:000075249700015 PM 9691020 ER PT J AU Hyman, DJ Ho, KSI Dunn, JK Simons-Morton, D AF Hyman, DJ Ho, KSI Dunn, JK Simons-Morton, D TI Dietary intervention for cholesterol reduction in public clinic patients SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article DE cholesterol; diet therapy; low-income; minority groups; dietary fats; diet; low-fat; telephone; mail; intervention studies ID TELEPHONE; PROGRAM; TRIAL AB Objectives: To test the feasibility and effectiveness of a diet intervention (consisting of interactive mailings, computer-generated phone calls, and classes) in hypercholesterolemic low-income public clinic patients. Methods: Clinic patients with serum cholesterol >200 mg/dl, referred by their primary care physician were randomized to a 6-month special intervention (SI) or usual care (UC). The intervention included mailings, computer phone calls, and four 1-hour classes. Serum total cholesterol (TC) was measured before and after intervention, and participation was monitored. Results: One hundred sixty-five of the 212 patients referred (77.8%) agreed to participate. A medical records review revealed 123 (74.5%) met eligibility criteria. Eligible subjects had a mean age of 56.7 years, 80.0% were African American, 74.8% were female, 33.6% were married, and 89.4% had a high school or lower education. Subjects were randomized with 80.5% (99) completing follow-up cholesterol measures. SI subjects were encouraged to use all three components, with 84.6% (55 of 65) actively participating in at least one component. Seventy-two percent (47 of 65) returned at: least one mailing, 49.1% (28 of 57) of those with touch-tone phones accessed the computer system, and 43.1% (28 of 65) attended classes. The TC in SI decreased from 273.2 mg/dl to 265.0 mg/dl (P = 0.05) and in UC 272.4 mg/dl to 267.6 mg/dl (P = 0.32). The net reduction in SI compared with UC was 3.4 mg/dl (P = 0.58). Conclusions: (1) Low-income public clinic patients will participate in diet interventions, (2) computer-generated interactive phone calls are feasible in this population, and (3) clinically meaningful decreases in serum cholesterol are difficult to achieve with interventions of practical intensity. C1 Baylor Coll Med, Dept Med, Houston, TX 77030 USA. NHLBI, Bethesda, MD 20892 USA. RP Hyman, DJ (reprint author), Ben Taub Gen Hosp, 1504 Taub Loop, Houston, TX 77030 USA. NR 27 TC 30 Z9 30 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD AUG PY 1998 VL 15 IS 2 BP 139 EP 145 DI 10.1016/S0749-3797(98)00038-5 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 107VN UT WOS:000075231800008 PM 9713670 ER PT J AU Heinz, A Higley, JD Gorey, JG Saunders, RC Jones, DW Hommer, D Zajicek, K Suomi, SJ Lesch, KP Weinberger, DR Linnoila, M AF Heinz, A Higley, JD Gorey, JG Saunders, RC Jones, DW Hommer, D Zajicek, K Suomi, SJ Lesch, KP Weinberger, DR Linnoila, M TI In vivo association between alcohol intoxication, aggression, and serotonin transporter availability in nonhuman primates SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID CEREBROSPINAL-FLUID MONOAMINE; 5-HYDROXYINDOLEACETIC ACID CONCENTRATIONS; DIMINISHED SOCIAL COMPETENCE; I-123 BETA-CIT; RHESUS-MONKEYS; IN-VIVO; PREFERRING P; METABOLITES; DOPAMINE; PERSONALITY AB Studies on brain serotonin metabolism in human and nonhuman primates have indicated that dysfunction of serotonin transmission may play a role in the biological vulnerability to dependence on alcohol. Among young men, low sensitivity to alcohol intoxication predicts subsequent alcohol abuse and dependence. Method: The authors used single photon emission computed tomography and the radioligand [(I)123] beta-CIT ([(I)123]methyI 3 beta-(4-iodophenyl) tropane-2-carboxylate) to measure the availability of serotonin transporters in 11 male rhesus monkeys, and the monkeys were genotyped for a functional polymorphism of the serotonin transporter gene. The 11 monkeys had experienced parental separation after birth; their behavior and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in CSF had been assessed regularly. Results: In the 5-year-old monkeys, there was a significant negative correlation between beta-GIT binding to serotonin transporters in the brainstem and 5-HIAA concentrations in CSF. Animals with greater beta-CIT binding and low CSF 5-HIAA concentrations displayed greater aggressiveness and were less sensitive to alcohol-induced intoxication. The genetic constitution of the serotonin transporter promoter gene did not significantly contribute to the availability of brainstem serotonin transporters as measured by beta-CIT binding. Conclusions: In adult nonhuman primates who underwent early developmental stress, variables indicating a low serotonin turnover rate were associated with behavior patterns similar to those predisposing to early-onset alcoholism among humans. C1 St Elizabeths Hosp, Clin Brain Disorders Branch, NIMH, Ctr Neurosci, Washington, DC USA. NIAAA, Bethesda, MD USA. Univ Wurzburg, Dept Psychiat, D-8700 Wurzburg, Germany. RP Heinz, A (reprint author), Ruhr Univ Bochum, St Josef Hosp, Dept Neurol, Gudrunstr 56, D-44791 Bochum, Germany. EM jonesheinz@aol.com RI Lesch, Klaus-Peter/J-4906-2013 OI Lesch, Klaus-Peter/0000-0001-8348-153X NR 41 TC 117 Z9 117 U1 5 U2 10 PU AMER PSYCHIATRIC ASSOCIATION PI WASHINGTON PA 1400 K ST NW, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 1998 VL 155 IS 8 BP 1023 EP 1028 PG 6 WC Psychiatry SC Psychiatry GA 106JG UT WOS:000075125700006 PM 9699688 ER PT J AU Nopoulos, PC Giedd, JN Andreasen, NC Rapoport, JL AF Nopoulos, PC Giedd, JN Andreasen, NC Rapoport, JL TI Frequency and severity of enlarged cavum septi pellucidi in childhood-onset schizophrenia SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT VI International Congress of Schizophrenia Research CY APR 12-16, 1997 CL COLORDO SPRINGS, COLORADO ID CORPUS-CALLOSUM; BRAIN-DEVELOPMENT; ABNORMALITIES; PHENOMENOLOGY; PREVALENCE; MORPHOLOGY; CHILDREN; DISORDER; PARENT AB Objective: Patients with schizophrenia have been reported to have a higher frequency of enlarged cavum septi pellucidi (CSP) in comparison with normal subjects. Neurodevelopmental models of schizophrenia suggest that the more severe the brain dysgenesis, the earlier the onset of psychotic symptoms. Study of patients with childhood-onset schizophrenia allows the opportunity to test this hypothesis. Method: Two groups of subjects were evaluated: healthy volunteers (N=95, mean age=11.7 years) and patients with childhood-onset schizophrenia (N=24, mean age=14.6 years). Magnetic resonance images of l-mm resampled contiguous brain slices were rated blind to diagnosis. The size of the CSP was recorded as the number of consecutive slices in which the CSP was present. Abnormal enlargement was defined as a CSP greater than 6 mm in length. Results: The frequency of an enlarged CSP was significantly higher in the patient group: 12.5% (three of 24 subjects) versus 1.1% tone of 95 subjects). Also, two of the three patients with an enlarged CSP had complete nonfusion of the septal leaflets, a more severe anomaly than was found in the one comparison subject with an enlarged CSP and typically more severe than anomalies seen in groups with adult-onset schizophrenia. Conclusions: These findings suggest that patients with extremely early-onset (childhood) forms of schizophrenia may have more severe developmental brain anomalies than those with adult onset. C1 Univ Iowa Hosp & Clin, Mental Hlth Clin Res Ctr, Iowa City, IA 52242 USA. NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Nopoulos, PC (reprint author), Univ Iowa Hosp & Clin, Mental Hlth Clin Res Ctr, 2887 JPP,200 Hawkins Dr, Iowa City, IA 52242 USA. RI Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 FU NIMH NIH HHS [MH-31593, MHCRC-43271, MH-40856] NR 56 TC 49 Z9 49 U1 1 U2 2 PU AMER PSYCHIATRIC ASSOCIATION PI WASHINGTON PA 1400 K ST NW, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 1998 VL 155 IS 8 BP 1074 EP 1079 PG 6 WC Psychiatry SC Psychiatry GA 106JG UT WOS:000075125700014 PM 9699696 ER PT J AU Asbahr, FR Negrao, AB Gentil, V Zanetta, DMT da Paz, JA Marques-Dias, MJ Kiss, MH AF Asbahr, FR Negrao, AB Gentil, V Zanetta, DMT da Paz, JA Marques-Dias, MJ Kiss, MH TI Obsessive-compulsive and related symptoms in children and adolescents with rheumatic fever with and without chorea: A prospective 6-month study SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID SYDENHAMS CHOREA AB Objective: The incidence and course of neuropsychiatric symptoms were determined in pediatric patients with rheumatic fever. Method: The Leyton Obsessional Inventory and National Institute of Mental Health Global Obsessive-Compulsive Scale were used to evaluate children and adolescents who had rheumatic fever with Sydenham's chorea (N=30) or without chorea (N=20), They were assessed three times over 6 months from the onset of rheumatic fever. Psychiatric diagnoses were also determined, Results: Obsessive-compulsive symptoms abruptly appeared and peaked during the 2 months after the onset of rheumatic fever in 21 patients with chorea (70.0%) and were absent in all patients without chorea. Obsessive-compulsive disorder (OCD) was diagnosed in five patients with chorea (16.7%). Conclusions: The association between Sydenham's chorea and OCD supports suggestions that similar mechanisms involving the basal ganglia underlie both disorders. Obsessive-compulsive symptoms occurred at the beginning of rheumatic fever, so early psychopathological assessments are essential. C1 Univ Sao Paulo, Sch Med, Hosp Clin,Dept Psychiat, Dept Pediat & Discipline Med Informat, Sao Paulo, Brazil. NIMH, Clin Neuroendocrinol Branch, Bethesda, MD 20892 USA. RP Asbahr, FR (reprint author), FMUSP, Dept Psiquiatria, Rua Dr Ovdio Pires Campos S-N,Caixa Postal 8091, BR-05403010 Sao Paulo, Brazil. RI Zanetta, Dirce/G-4950-2013; Negrao, Andre Brooking/C-9526-2014; Asbahr, Fernando/G-8469-2015 OI Negrao, Andre Brooking/0000-0002-8133-6723; NR 11 TC 65 Z9 67 U1 0 U2 4 PU AMER PSYCHIATRIC ASSOCIATION PI WASHINGTON PA 1400 K ST NW, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 1998 VL 155 IS 8 BP 1122 EP 1124 PG 3 WC Psychiatry SC Psychiatry GA 106JG UT WOS:000075125700026 PM 9699708 ER PT J AU Fishman, AP Fishman, MC Freeman, BA Gimbrone, MA Rabinovitch, M Robinson, D Gail, DB AF Fishman, AP Fishman, MC Freeman, BA Gimbrone, MA Rabinovitch, M Robinson, D Gail, DB TI Mechanisms of proliferative and obliterative vascular diseases - Insights from the pulmonary and systemic circulations SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material C1 NHLBI, Lung Biol & Dis Program, Div Lung Dis, Rockledge Ctr 2, Bethesda, MD 20892 USA. NHLBI, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. Harvard Univ, Cardiovasc Res Ctr, Boston, MA 02115 USA. Harvard Univ, Div Vasc Res, Boston, MA 02115 USA. Univ Penn, Dept Rehabil Med, Philadelphia, PA 19104 USA. Univ Alabama, Dept Anesthesiol, Birmingham, AL USA. Univ Toronto, Div Cardiovasc Res, Toronto, ON, Canada. RP Gail, DB (reprint author), NHLBI, Lung Biol & Dis Program, Div Lung Dis, Rockledge Ctr 2, Suite 10018,6701 Rockledge Dr,MSC 7952, Bethesda, MD 20892 USA. NR 0 TC 19 Z9 20 U1 0 U2 0 PU AMER LUNG ASSOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD AUG PY 1998 VL 158 IS 2 BP 670 EP 674 PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 110NR UT WOS:000075387700045 PM 9700149 ER PT J AU Travis, WD Rush, W Flieder, DB Falk, R Fleming, MV Gal, AA Koss, MN AF Travis, WD Rush, W Flieder, DB Falk, R Fleming, MV Gal, AA Koss, MN TI Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE carcinoid; atypical carcinoid; small cell carcinoma; large cell neuroendocrine carcinoma; mitoses ID SMOOTH-MUSCLE TUMORS; MITOTIC INDEX; LUNG; CLASSIFICATION; NEOPLASMS; FEATURES; MITOSES; CANCER; CELLS; TRACT AB Neuroendocrine tumors of the lung embrace a spectrum from low-grade typical carcinoid (TC), intermediate-grade atypical carcinoid (AC), and high-grade categories of large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SCLC) We studied 200 neuroendocrine lung tumors to critically evaluate the Arrigoni histologic criteria for AC using statistical analysis to delimit more rigorously an intermediate survival for AC between TC and the high-grade tumors of LCNEC and SCLC. Histologic features that might predict prognosis were used for Kaplan-Meier and Cox proportional hazards survival analysis, and an optimal mitotic range fur AC was calculated. The optimal mitotic range for AC was 2 to 10 mitoses per 2 mm(2) of viable tumor (10 high-power fields). Based on this finding, we collapsed mitoses into three categories (< 2; 2-10; greater than or equal to 11) and performed Cox multivariate analysis for all 200 neuroendocrine tumors. Mitotic counts were the only independent predictor of prognosis. Based on this analysis, we propose that AC be defined as a tumor with neuroendocrine morphology, mitotic counts between 2-10 per 2 mm of viable tumor (10 high-power fields), or coagulative necrosis. Using these criteria, the 200 neuroendocrine tumors were classified as 51 TC, 62 AC, 37 LCNEC, and 50 SCLC. The 5- and 10-year survival was 87% and 87% for TC, 56% and 35% for AC, 27% and 9% for LCNEC, and 9% and 5% for SCLC, respectively. After stratification for stage, survival for AC was significantly worse than for TC (p < 0.001); for LCNEC and SCLC it was significantly worse than for AC, but the survival for LCNEC was no different than that for SCLC. C1 Armed Forces Inst Pathol, Dept Pulm & Med Pathol, Washington, DC 20306 USA. NCI, Environm Epidemiol Branch, NIH, Rockville, MD USA. Emory Univ, Dept Pathol, Atlanta, GA 30322 USA. RP Travis, WD (reprint author), Armed Forces Inst Pathol, Dept Pulm & Med Pathol, Bldg 54,Room Moo3B,6825 NW 16th St, Washington, DC 20306 USA. NR 35 TC 435 Z9 454 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD AUG PY 1998 VL 22 IS 8 BP 934 EP 944 DI 10.1097/00000478-199808000-00003 PG 11 WC Pathology; Surgery SC Pathology; Surgery GA 108CK UT WOS:000075248300003 PM 9706973 ER PT J AU Proschan, MA Presnell, B AF Proschan, MA Presnell, B TI Expect the unexpected from conditional expectation SO AMERICAN STATISTICIAN LA English DT Article DE conditional distributions; paradoxes; probability AB Conditioning arguments are often used in statistics. Unfortunately, many of them are incorrect. We show that seemingly logical reasoning can lead to erroneous conclusions because of lack of rigor in dealing with conditional distributions and expectations. C1 NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. Australian Natl Univ, Ctr Math & Applicat, Canberra, ACT, Australia. Univ Florida, Dept Stat, Gainesville, FL 32611 USA. RP Proschan, MA (reprint author), NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. NR 13 TC 10 Z9 10 U1 0 U2 3 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 1429 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0003-1305 J9 AM STAT JI Am. Stat. PD AUG PY 1998 VL 52 IS 3 BP 248 EP 252 DI 10.2307/2685937 PG 5 WC Statistics & Probability SC Mathematics GA 109FQ UT WOS:000075311300013 ER PT J AU Farley, J Loup, D Nelson, M Miller, MJ Taylor, R Gray, K AF Farley, J Loup, D Nelson, M Miller, MJ Taylor, R Gray, K TI Transferrin in normal and neoplastic endocervical tissues - Distribution and receptor expression SO ANALYTICAL AND QUANTITATIVE CYTOLOGY AND HISTOLOGY LA English DT Article DE transferrin; transferrin receptors; cervix neoplasms ID HUMAN PAPILLOMAVIRUS DNA; RAS GENE-MUTATIONS; UTERINE CERVIX; CELL-PROLIFERATION; BREAST-CANCER; LACTOFERRIN; ADENOCARCINOMA; TRANSFORMATION; INFECTION; PROTEIN AB OBJECTIVE: Our recent studies showed that lactoferrin seems to be down-regulated in endocervical adenocarcinomas. We extended those studies to examine the expression of transferrin (Tf) and its receptor (TfR) in endocervical carcinogenesis and any relationship to the expression of lactoferrin, steroid receptors and the proliferative index. STUDY DESIGN: A retrospective study was performed using sections prepared from paraffin-embedded, formalin-fixed surgical specimens of normal endocervix, endocervical adenocarcinoma and cervical adenocarcinoma in situ. Standard immunohistochemical techniques were used to localize Tf and ifs receptor in the normal and malignant endocervix. Ln situ detection of mRNA for Tf and the TfR was also performed. The relative intensity of: the immunoreaction was estimated using digital computer image analysis. Statistical significance was tested by Student's t test. RESULTS: No differences in the relative staining intensity for Tf and TfR proteins were noted between normal and neoplastic glands. However, quantitation revealed that a greater number of malignant glands stained positive for TfR than observed in the normal endocervix. Expression of Tf and TfR did not correlate with the expression of steroid receptors and lactoferrin or with the rate of proliferation. CONCLUSION: We have demonstrated the expression of Tf and its receptor by both normal and malignant endocervical glands. The increased number of malignant endocervical glands expressing TfR may indicate a special requirement for Tf and the iron that if carries. Our data provide evidence for the existence of a Tf, TfR autocrine or paracrine circuit involved in the regulation of normal and abnormal endocervical physiology. C1 NCI, Dept Cell & Canc Biol, NIH, Rockville, MD 20850 USA. Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. Natl Naval Med Ctr, Dept Obstet & Gynecol, Bethesda, MD USA. Walter Reed Army Med Ctr, Dept Obstet & Gynecol, Washington, DC 20307 USA. RP Farley, J (reprint author), NCI, Dept Cell & Canc Biol, NIH, 9610 Med Ctr Dr,Suite 300, Rockville, MD 20850 USA. NR 36 TC 0 Z9 0 U1 0 U2 0 PU SCI PRINTERS & PUBL INC PI ST LOUIS PA P.O. DRAWER 12425 8342 OLIVE BLVD, ST LOUIS, MO 63132 USA SN 0884-6812 J9 ANAL QUANT CYTOL JI Anal. Quant. Cytol. Histol. PD AUG PY 1998 VL 20 IS 4 BP 238 EP 249 PG 12 WC Cell Biology SC Cell Biology GA 111CC UT WOS:000075418900002 PM 9739406 ER PT J AU Hsu, IC Shih, WK Kong, DH Xu, JF AF Hsu, IC Shih, WK Kong, DH Xu, JF TI Freeing the target DNA for amplifying mismatch cleaved products SO ANALYTICAL BIOCHEMISTRY LA English DT Article ID REPAIR ENZYMES; GLYCOSYLASE; MUTATIONS; MISPAIRS; SEQUENCE; GENE C1 Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Hsu, IC (reprint author), Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. NR 16 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 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD AUG 1 PY 1998 VL 261 IS 2 BP 219 EP 222 DI 10.1006/abio.1998.2622 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 117KK UT WOS:000075780300011 PM 9716425 ER PT J AU Friedman, L Proschan, M AF Friedman, L Proschan, M TI P-value interpretation and alpha allocation in clinical trials SO ANNALS OF EPIDEMIOLOGY LA English DT Editorial Material C1 NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. RP Friedman, L (reprint author), NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. NR 3 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD AUG PY 1998 VL 8 IS 6 BP 349 EP 350 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 102JA UT WOS:000074919900001 PM 9708869 ER PT J AU Howard, G Bergman, R Wagenknecht, LE Haffner, SM Savage, PJ Saad, MF Laws, A D'Agostino, RB AF Howard, G Bergman, R Wagenknecht, LE Haffner, SM Savage, PJ Saad, MF Laws, A D'Agostino, RB CA Insulin Resistance Atherosclerosis Study Inves TI Ability of alternative indices of insulin sensitivity to predict cardiovascular risk: Comparison with the "minimal model" SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE insulin resistance; cardiovascular disease; measurement; risk factors; cohort study ID MEDIATED GLUCOSE DISPOSAL; RESISTANCE ATHEROSCLEROSIS; DIABETES-MELLITUS; TOLERANCE TEST; HEART-DISEASE; HYPERTENSION; THICKNESS; CLAMP AB INTRODUCTION: Although recognition of insulin sensitivity as a risk factor for cardiovascular disease is growing, a deeper understanding of its role is impeded by the cost and complexity of currently available measures. This report evaluates previously described alternative indices of insulin sensitivity with the goal of identifying a reliable, but logistically simpler, alternative. METHODS: Data from 1460 participants in the Insulin Resistance,Atherosclerosis Study (IRAS) were used to assess the proportion of the relationship between a recognized measure of insulin sensitivity (Bergman's S-1) and cardiovascular risk factors that is contained in each of nine alternative measures. RESULTS: A number of the alternative indices contained a substantial proportion of the information available in Bergman's S-1. The Galvin's index and the homeostasis model were most promising. However, there remained a significant amount of the information in Bergman's S-1 that was not contained in any of the alternative indices. DISCUSSION: There are simpler alternative indices of insulin sensitivity for use in epidemiological studies, but each alternative is associated with some loss of information. It may he possible that this loss can be overcome with an increased sample size; however, using the alternative indices may also confound the assessment of insulin sensitivity with other underlying factors (i.e., hyperinsulinemia). The alternative indices are not recommended for the clinical assessment of insulin sensitivity for an individual patient or subject. Published by Elsevier Science Inc. C1 Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27157 USA. Univ So Calif, Dept Physiol & Pharmacol, Los Angeles, CA USA. Univ So Calif, Dept Med, Los Angeles, CA USA. Univ Texas, Dept Med, San Antonio, TX 78285 USA. NHLBI, Bethesda, MD 20892 USA. Stanford Med Sch, Palo Alto, CA USA. RP Howard, G (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, 300 S Hawthorne Rd, Winston Salem, NC 27157 USA. RI Dagostino Jr, Ralph/C-4060-2017 OI Dagostino Jr, Ralph/0000-0002-3550-8395 FU NHLBI NIH HHS [HL47887, HL47889, HL47890] NR 36 TC 74 Z9 75 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD AUG PY 1998 VL 8 IS 6 BP 358 EP 369 DI 10.1016/S1047-2797(98)00002-7 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 102JA UT WOS:000074919900003 PM 9708871 ER PT J AU Fraenkel, L Zhang, YQ Chaisson, CE Evans, SR Wilson, PWF Felson, DT AF Fraenkel, L Zhang, YQ Chaisson, CE Evans, SR Wilson, PWF Felson, DT TI The Association of Estrogen Replacement Therapy and the Raynaud Phenomenon in Postmenopausal Women SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID MENSTRUAL-CYCLE; HEALTHY WOMEN; DIAGNOSIS; PROGESTERONE; POPULATION; ESTRADIOL AB Background: Hormonal factors may play an important role in the pathophysiology of the Raynaud phenomenon. Experimental studies have shown an increased vasoconstrictor response to estrogen, a response that can be prevented by the addition of progesterone. Objective: To measure the association between estrogen replacement therapy (alone and with progesterone) and the Raynaud phenomenon. Design: Cross-sectional study. Setting: Framingham Offspring Study. Participants: 497 postmenopausal women. Measurements: Prevalence of the Raynaud phenomenon according to hormone use. Covariates measured included age, body mass index, smoking, alcohol consumption, and p-blocker use. Results: Forty-nine women were classified as having the Raynaud phenomenon (9.9%). The prevalence of this phenomenon was 8.4% among women who did not receive estrogen, 19.1% among women receiving estrogen alone, and 9.8% among women receiving estrogen plus progesterone. The adjusted odds ratio for the Raynaud phenomenon was 2.5 (95% CI, 1.2 to 5.3) for unopposed estrogen and 0.9 (CI, 0.3 to 2.6) for estrogen plus progesterone, with nonusers as the reference group. Conclusions: Unopposed estrogen therapy was associated with the Raynaud phenomenon in postmenopausal women. This association was not present in women who were receiving combined hormone therapy. C1 Boston Univ, Ctr Arthritis, Boston, MA 02118 USA. Boston Univ, Med Ctr, Boston, MA USA. NHLBI, Bethesda, MD USA. RP Fraenkel, L (reprint author), Boston Univ, Ctr Arthritis, A203,715 Albany St, Boston, MA 02118 USA. FU NHLBI NIH HHS [N01-HC-38038]; NIA NIH HHS [AG09300]; NIAMS NIH HHS [AR20613] NR 20 TC 31 Z9 31 U1 0 U2 1 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD AUG 1 PY 1998 VL 129 IS 3 BP 208 EP 211 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 104UA UT WOS:000075032700006 PM 9696729 ER PT J AU Campo, E Gaulard, P Zucca, E Jaffe, ES Harris, NL Diebold, J Schlegelberger, B Feller, AC Delsol, C Gisselbrecht, C Montserrat, E AF Campo, E Gaulard, P Zucca, E Jaffe, ES Harris, NL Diebold, J Schlegelberger, B Feller, AC Delsol, C Gisselbrecht, C Montserrat, E CA European Task Force Lymphomas TI Report of the European task force on lymphomas: Workshop on peripheral T-cell lymphomas SO ANNALS OF ONCOLOGY LA English DT Editorial Material DE extranodal lymphomas; non-Hodgkin's lymphomas; peripheral T-cell lymphomas ID MONOCLONAL-ANTIBODY ALK1; NON-HODGKINS-LYMPHOMA; B-CELL; ANGIOIMMUNOBLASTIC LYMPHADENOPATHY; AMERICAN CLASSIFICATION; CYTOGENETIC FINDINGS; INTERFERON-GAMMA; ORGANIZATION; EXPRESSION; NEOPLASMS C1 Univ Barcelona, Hosp Clin Barcelona, Pathol Lab, Hematopathol Sect, E-08036 Barcelona, Spain. Univ Barcelona, Hosp Clin Barcelona, Dept Hematol, E-08036 Barcelona, Spain. CHU Henri Mondor, Pathol Lab, F-94010 Creteil, France. San Giovanni Hosp, Div Oncol, Bellinzona, Switzerland. NCI, Pathol Lab, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Pathol Lab, Boston, MA 02114 USA. Hotel Dieu, Pathol Lab, Paris, France. Univ Kiel, Dept Human Genet, Kiel, Germany. Univ Lubeck, D-2400 Lubeck, Germany. Hop Purpan, Pathol Lab, Toulouse, France. Hop St Louis, Inst Hematol, Paris, France. RP Campo, E (reprint author), Univ Barcelona, Hosp Clin Barcelona, Pathol Lab, Hematopathol Sect, Villarroel 170, E-08036 Barcelona, Spain. EM campo@medicina.ub.es RI Feller, Alfred/E-3853-2010; OI Campo, elias/0000-0001-9850-9793 NR 32 TC 24 Z9 24 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD AUG PY 1998 VL 9 IS 8 BP 835 EP 843 DI 10.1023/A:1008439620513 PG 9 WC Oncology SC Oncology GA 125ZD UT WOS:000076266900013 PM 9789605 ER PT J AU Alexander, HR Fraker, DL Norton, JA Bartlett, DL Tio, L Benjamin, SB Doppman, JL Goebel, SU Serrano, J Gibril, F Jensen, RT AF Alexander, HR Fraker, DL Norton, JA Bartlett, DL Tio, L Benjamin, SB Doppman, JL Goebel, SU Serrano, J Gibril, F Jensen, RT TI Prospective study of somatostatin receptor scintigraphy and its effect on operative outcome in patients with Zolinger-Ellison syndrome SO ANNALS OF SURGERY LA English DT Article ID MULTIPLE ENDOCRINE NEOPLASIA; ISLET CELL TUMORS; ENDOSCOPIC ULTRASONOGRAPHY; DUODENAL GASTRINOMAS; PREOPERATIVE LOCALIZATION; MANAGEMENT; RESECTION; INSULINOMAS; ABILITY AB Objective To determine the relative abilities of somatostatin receptor scintigraphy (SRS) and conventional imaging studies (computed tomography, magnetic resonance imaging, ultrasound, angiography) to localize gastrinomas before surgery in patients with Zollinger-Ellison syndrome (ZES) subsequently found at surgery, and to determine the effect of SRS on the disease-free rate. Summary Background Data Recent studies demonstrate that SRS is the most sensitive imaging modality for localizing neuroendocrine tumors such as gastrinomas. Because of conflicting results in small series, it is unclear in ZES whether SRS will alter the disease-free rate, which gastrinomas are not detected, what factors contribute to failure to detect a gastrinoma, or whether the SRS result should be used to determine operability in patients without hepatic metastases, as recently recommended by some investigators. Methods Thirty-five consecutive patients with ZES undergoing 37 exploratory laparotomies for possible cure were prospectively studied. All had SRS and conventional imaging studies before surgery. Imaging results were determined by an independent investigator depending on surgical findings. All patients underwent an identical surgical protocol (palpation after an extensive Kocher maneuver, ultrasound during surgery, duodenal transillumination, and 3 cm duodenotomy) and postoperative assessment of disease status (fasting gastrin, secretin test imaging within 2 weeks, at 3 to 6 months, and yearly), as used in pre-SRS studies previously. Results Gastrinomas were detected in all patients at each surgery. Seventy-four gastrinomas were found: 22 duodenal, 8 pancreatic, 3 primaries in other sites, and 41 lymph node metastases. The relative detection order on a per-patient or per-lesion basis was SRS > angiography, magnetic response imaging, computed tomography > ultrasound. On a per-lesion basis, SRS had greater sensitivity than all conventional studies combined. SRS missed one third of all lesions found at surgery. SRS detected 30% of gastrinomas less than or equal to 1.1 cm, 64% of those 1.1 to 2 cm, and 96% of those >2 cm and missed primarily small duodenal tumors. Tumor size correlated closely with SRS rate of detection. SRS did not increase the disease-free rate immediately after surgery or at 2 years mean follow-up. Conclusions SRS is the most sensitive preoperative imaging study for extrahepatic gastrinomas in patients with ZES and should replace conventional imaging studies as the preoperative study of choice. Negative results of SRS for localizing extrahepatic gastrinomas should not be used to decide operability, because a surgical procedure will detect 33% more gastrinomas, especially in the duodenum and in periduodenal lymph nodes, or more extensive surgery will be needed to improve post-operative disease-free rate in ZES. C1 NIDDK, DDB, NIH, Bethesda, MD 20892 USA. NCI, Surg Metab Sect, Surg Branch, NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA. Georgetown Univ, Med Ctr, Div Gastroenterol, Washington, DC 20007 USA. NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Jensen, RT (reprint author), NIDDK, DDB, NIH, Bldg 10,Rm 9C-103,10 Ctr Dr MSC 1804, Bethesda, MD 20892 USA. NR 58 TC 111 Z9 116 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD AUG PY 1998 VL 228 IS 2 BP 228 EP 238 DI 10.1097/00000658-199808000-00013 PG 11 WC Surgery SC Surgery GA 108ZY UT WOS:000075297600013 PM 9712569 ER PT J AU Theodos, CM Griffiths, JK D'Onfro, J Fairfield, A Tzipori, S AF Theodos, CM Griffiths, JK D'Onfro, J Fairfield, A Tzipori, S TI Efficacy of nitazoxanide against Cryptosporidium parvum in cell culture and in animal models SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID IN-VITRO; MONOLAYERS; COLOSTRUM AB Nitazoxanide (NTZ), a drug currently being tested in human clinical trials for efficacy against chronic cryptosporidiosis,,vas assessed in cell culture and in two animal models. The inhibitory activity of NTZ was compared with that of paromomycin (PRM), a drug that is partially effective against Cryptosporidium parvum, A concentration of 10 mu g of NTZ/ml (32 mu M) consistently reduced parasite growth in cell culture by more than 90% with little evidence of drug-associated cytotoxicity, in contrast to an 80% reduction produced by PRM at 2,000 mu g/ml (3.2 mM), In contrast to its efficacy in vitro, NTZ at either 100 or 200 mg/kg of body weight/day for 10 days was ineffective at reducing the parasite burden in C, parvum-infected, anti-gamma-interferon-conditioned SCID mice. Combined treatment with NTZ and PRM was no more effective than treatment with PRM alone, Finally, NTZ was partially effective at reducing the parasite burden in a gnotobiotic piglet diarrhea model when given orally for 11 days at 250 mg/kg/day but not at 125 mg/kg/day, However, the higher dose of NTZ induced a drug-related diarrhea in piglets that might have influenced its therapeutic efficacy, As we have previously reported, PRM was effective at markedly reducing the parasite burden in piglets at a dosage of 500 mg/kg/day, Our results indicate that of all of the models tested, the piglet diarrhea model most closely mimics the partial response to NTZ treatment reported to occur in patients with chronic cryptosporidiosis. C1 Tufts Univ, Sch Vet Med, Div Infect Dis, N Grafton, MA 01536 USA. Tufts Univ, Sch Med, Dept Family Med & Community Hlth, Boston, MA 02111 USA. Tufts Univ, Sch Med, Dept Med, Boston, MA 02111 USA. NIAID, Opportunist Infect Res Branch, Div Aids, NIH, Bethesda, MD USA. RP Tzipori, S (reprint author), Tufts Univ, Sch Vet Med, Div Infect Dis, 200 Westboro Rd,Bldg 20, N Grafton, MA 01536 USA. EM stzipori@infonet.tufts.edu FU NIAID NIH HHS [N0-AI-25143] NR 20 TC 98 Z9 103 U1 2 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD AUG PY 1998 VL 42 IS 8 BP 1959 EP 1965 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 106LV UT WOS:000075131800014 PM 9687390 ER PT J AU Schwartz, GN Liu, YQ Tisdale, J Walshe, K Fowler, D Gress, R Bergan, RC AF Schwartz, GN Liu, YQ Tisdale, J Walshe, K Fowler, D Gress, R Bergan, RC TI Growth inhibition of chronic myelogenous leukemia cells by ODN-1, an aptameric inhibitor of p210(bcr-abl) tyrosine kinase activity SO ANTISENSE & NUCLEIC ACID DRUG DEVELOPMENT LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; AUTOLOGOUS BONE-MARROW; PROSTATE-CANCER CELLS; FOCAL ADHESION KINASE; LONG-TERM CULTURE; ANTISENSE OLIGODEOXYNUCLEOTIDES; PHILADELPHIA-CHROMOSOME; HEMATOPOIETIC-CELLS; BLAST CRISIS; ABL AB p210(bcr-abl)-Related tyrosine kinase activity has been shown to cause chronic myelogenous leukemia (CML), a disease of bone marrow stem cells, Having previously demonstrated that the aptameric oligonucleotide, ODN-1, could inhibit p210(bcr-abl) kinase activity, the current study sought to determine if ODN-1 could selectively inhibit the growth of CML cells relative to that of normal bone marrow. ODN-1, when introduced by electroporation into peripheral blood mononuclear cells (PBMC) from patients with CML, decreased the number of committed progenitors (CML CFU-GM) by an average of 67% +/- 19% (mean +/- SEM, range 28-98%), Treatment of CML PBMC with ODN-1 was also shown to decrease the number of more primitive cobblestone area-forming cells (CAFC) by 35%-87%, In contrast, there was little suppressive effect by the combination of electroporation and ODN-1 on either CFU-GM or CAFC numbers from normal donor bone marrow. These studies suggest that inhibition of p210(bcr-abl) protein-tyrosine kinase (PTK) activity by ODN-1 is associated with some degree of selective growth inhibition of p210(bcr-abl)-transformed cells. p210(bcr-abl) kinase inhibitory agents may be useful for the ex vivo purging of bone marrow or peripheral blood progenitor/stem cells in the setting of autologous transplantation for CML. C1 NCI, Med Branch, NIH, Bethesda, MD 20892 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Bergan, RC (reprint author), NIH, 9000 Rockville Pike, Bethesda, MD 20897 USA. NR 41 TC 9 Z9 9 U1 1 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1087-2906 J9 ANTISENSE NUCLEIC A JI Antisense Nucleic Acid Drug Dev. PD AUG PY 1998 VL 8 IS 4 BP 329 EP 339 DI 10.1089/oli.1.1998.8.329 PG 11 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 116KL UT WOS:000075723600008 PM 9743470 ER PT J AU Masters, E Granter, S Duray, P Cordes, P AF Masters, E Granter, S Duray, P Cordes, P TI Physician-diagnosed erythema migrans and erythema migrans-like rashes following lone star tick bites SO ARCHIVES OF DERMATOLOGY LA English DT Article; Proceedings Paper CT 6th International Conference on Lyme Borreliosis CY JUN 19-22, 1994 CL BOLOGNA, ITALY ID BORRELIA-BURGDORFERI; LYME-DISEASE; UNITED-STATES; AMBLYOMMA-AMERICANUM; NORTH-CAROLINA; MISSOURI; IXODIDAE; ILLNESS; ACARI AB Objective: To differentiate cases of physician-diagnosed erythema migrans and erythema migrans-like rashes associated with Lone Star tick (Amblyomma americanum) bites. Design: Retrospective case series. Setting: Private primary care clinic in rural Missouri. Patients: Seventeen patients with physician-diagnosed erythema migrans following a definite Lone Star tick bite at the rash site. Interventions: A biopsy was performed on all rash sites. All patients were treated with oral antibiotics. Main Outcome Measures: Rash appearance, size, body location, multiple lesions, incubation time, associated symptoms, seasonal occurrence, histopathological features, tick stage and sex, patient age and sex, treatment response, growth in BSK II culture media, and serologic evaluation. Results: Rashes associated with Lone Star ticks were similar to erythema migrans vectored by other Ixodes ticks. Differences were noted in Lyme disease serology results, especially flagellin-based enzyme immunoassays, and failure to yield spirochetes in BSK II cultures. Lyme serology results were often negative, but were also frequently inconsistent viith results of controls without Lyme disease. Conclusions: Lone Star ticks are associated with rashes that are similar, if not identical, to erythema migrans associated with borrelial infection. The recent isolation and cultivation of Borrelia burgdorferi from ticks (including 1 Lone Star tick) from the farm of a patient included in this report has raised the possibility that Lone Star ticks are "bridge vectors" for human borrelial infection. Although further investigation is needed, these rashes may be secondary to spirochetal infection. C1 Reg Primary Care, Cape Girardeau, MO 63703 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. NIH, Bethesda, MD 20892 USA. SE Missouri Hosp, Cape Girardeau, MO USA. RP Masters, E (reprint author), Reg Primary Care, 69 Doctors Pk, Cape Girardeau, MO 63703 USA. NR 34 TC 68 Z9 69 U1 1 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD AUG PY 1998 VL 134 IS 8 BP 955 EP 960 DI 10.1001/archderm.134.8.955 PG 6 WC Dermatology SC Dermatology GA 110ZY UT WOS:000075413900006 PM 9722725 ER PT J AU Brady, RO AF Brady, RO TI Therapy for the sphingolipidoses SO ARCHIVES OF NEUROLOGY LA English DT Article AB Sphingolipidoses are human metabolic storage disorders characterized by the accumulation of harmful quantities of glycosphingolipids and phosphosphingolipids. These lipids have in common a hydrophobic portion of their structure called ceramide. In glycosphingolipids, various oligosaccharides are linked to ceramide through glycosidic bonds. An example is glucocerebroside, composed of ceramide and 1 molecule of glucose. Large quantities of glucocerebroside accumulate in tissues in patients with Gaucher disease. Higher oligosaccharide homologues contain additional neutral and acidic oligosaccharides. Among these are gangliosides that have 1 or more molecules of N-acetylneuraminic acid. A ganglioside called G(M2) accumulates in Tay-Sachs disease. Sphingomyelin is a phosphosphingolipid that accumulates in patients with Niemann-Pick disease. C1 NIH, Bethesda, MD 20892 USA. RP Brady, RO (reprint author), NIH, Bldg 10 Room 3D04,10 Ctr Dr,MSC 1260, Bethesda, MD 20892 USA. NR 10 TC 13 Z9 13 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD AUG PY 1998 VL 55 IS 8 BP 1055 EP 1056 DI 10.1001/archneur.55.8.1055 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 107WU UT WOS:000075234600002 PM 9708954 ER PT J AU Kompoliti, K Goetz, CG Litvan, I Jellinger, K Verny, M AF Kompoliti, K Goetz, CG Litvan, I Jellinger, K Verny, M TI Pharmacological therapy in progressive supranuclear palsy SO ARCHIVES OF NEUROLOGY LA English DT Article ID RICHARDSON-OLSZEWSKI SYNDROME; ELECTROCONVULSIVE-THERAPY; CLINICAL-CRITERIA; PHYSOSTIGMINE; MOVEMENT; AGONIST; TRIAL; TOXIN AB Background: To our knowledge, previous reports on drug treatment in progressive supranuclear palsy have not evaluated autopsy-confirmed cases. Objective: To evaluate pharmacological treatment responses from detailed clinical records in patients with autopsy-confirmed progressive supranuclear palsy. Subjects and Methods: We reviewed medical records for clinical presentation and pharmacological response in 12 patients with autopsy-confirmed progressive supranuclear palsy diagnosed using the National Institute of Neurological Disorders and Stroke pathologic criteria. For each drug class, exposure, global positive response, and specific positive response (parkinsonism, other movement disorders, or gaze dysfunction) were recorded. Results: Drug classes examined were dopaminergics (all patients), tricyclics (3 patients), methysergide maleate (3 patients), 5-hydroxytryptophan (2 patients), and anticholinergics and selective serotonin inhibitors (1 patient). Positive clinical response was detected in 7 of the patients receiving dopaminergic drugs and in 1 patient each receiving tricyclics, methysergide, and 5-hydroxytryptophan, respectively. None of the patients responded markedly however, and there was no persistent beneficial effect. Use of dopaminergic drugs most frequently improved parkinsonian features, but disabling adverse effects included orthostatic hypotension (6 patients), hallucinations and delusions (3 patients), gastrointestinal complaints (3 patients), and dizziness (1 patient). Only 1 patient developed dyskinesia. Conclusion: Use of antiparkinsonian medications and other neurotransmitter replacement therapies was largely ineffective and caused frequent adverse effects in this series of patients with autopsy-confirmed with progressive supranuclear palsy. C1 Rush Presbyterian St Lukes Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. NINDS, Neuroepidemiol Branch, NIH, Bethesda, MD 20892 USA. Lainz Hosp, Ludwig Boltzmann Inst Clin Neurobiol, A-1130 Vienna, Austria. Hop Charles Foix, Paris, France. RP Kompoliti, K (reprint author), Rush Presbyterian St Lukes Med Ctr, Dept Neurol Sci, 1725 W Harrison St,Suite 1106, Chicago, IL 60612 USA. EM kkompoli@rpslmc.edu OI Litvan, Irene/0000-0002-3485-3445 NR 31 TC 49 Z9 51 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD AUG PY 1998 VL 55 IS 8 BP 1099 EP 1102 DI 10.1001/archneur.55.8.1099 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 107WU UT WOS:000075234600008 PM 9708960 ER PT J AU Park, DW Folk, JC Whitcup, SM Polk, TD Kansupada, K Fountain, C Brown, J Nussenblatt, RB AF Park, DW Folk, JC Whitcup, SM Polk, TD Kansupada, K Fountain, C Brown, J Nussenblatt, RB TI Phakic patients with cystoid macular edema, retinal periphlebitis, and vitreous inflammation SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID PARS PLANITIS; ASSOCIATION AB Objective: To characterize a group of phakic patients with idiopathic intermediate uveitis as defined by vitritis, cystoid macular edema, and retinal periphlebitis. Design: Cross-sectional study. Participants: Nineteen phakic patients (35 eyes) with vitreous inflammation, cystoid macular edema, and/or retinal periphlebitis of unknown cause. Intervention: None. Main Outcome Measures: Best-corrected final visual acuities, standardized clinical examinations, photographic and fluorescein angiographic evaluations, and class I and II HLA analysis on all 19 patients. Results: Fifteen of the 19 patients were women. The mean age was 38 years, the mean follow-up was 104 months, and the mean duration of symptoms was 154 months. All 35 affected eyes had significant vitritis; 21 eyes (60%) had cystoid macular edema, 21 eyes (60%) had retinal periphlebitis, The median initial visual acuity was 20/30. The median final visual acuity was 20/20 with 32 (91%) of 35 eyes having 20/40 or better visual acuity at the final visit. No patient developed "snow-banks" or evidence of systemic disease, including multiple sclerosis or sarcoidosis, during the follow-up period. There were no statistically significant HLA associations in these patients compared with controls from another study from Iowa, but the Iowa phakic patients with cystoid macular edema did differ from the Iowa patients with pars-planitis at loci HLA-B8, HLA-B51, and HLA-DR2. Conclusions: We describe a disease entity of idiopathic intermediate uveitis that affects primarily young to middle-aged women and usually causes bilateral vitritis, cystoid macular edema, and retinal periphlebitis, Most patients retained good vision over a prolonged follow-up period. Multiple sequential examinations and HLA associations suggest that these conditions are distinct from other syndromes of intermediate uveitis, particularly parsplanitis. C1 Univ Iowa Hosp & Clin, Dept Ophthalmol & Visual Sci, Iowa City, IA 52242 USA. NEI, Bethesda, MD 20892 USA. RP Park, DW (reprint author), Retinal Consultants Arizona, 2720 N 20th St,Suite 225, Phoenix, AZ 85006 USA. NR 7 TC 3 Z9 4 U1 0 U2 0 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 AUG PY 1998 VL 116 IS 8 BP 1025 EP 1029 PG 5 WC Ophthalmology SC Ophthalmology GA 110ZP UT WOS:000075413100005 PM 9715682 ER PT J AU Hirsch, R Lin, JP Scott, WW Ma, LD Pillemer, SR Kastner, DL Jacobsson, LTH Bloch, DA Knowler, WC Bennett, PH Bale, SJ AF Hirsch, R Lin, JP Scott, WW Ma, LD Pillemer, SR Kastner, DL Jacobsson, LTH Bloch, DA Knowler, WC Bennett, PH Bale, SJ TI Rheumatoid arthritis in the Pima Indians - The intersection of epidemiologic, demographic, and genealogic data SO ARTHRITIS AND RHEUMATISM LA English DT Article ID SUSCEPTIBILITY GENE; RECESSIVE MODE; HLA COMPONENT; ASSOCIATION; EPITOPE; INHERITANCE; COMMUNITY; CRITERIA; ALLELES; ARIZONA AB Objective. To describe the clinical features and familial distribution of rheumatoid arthritis (RA) in the Pima Indians. Methods. From 1965 through 1990, all cases of RA as defined by the American College of Rheumatology (formerly, the American Rheumatism Association) 1987 criteria or all eases of seropositive, erosive disease as defined by the Rome criteria were identified in individuals who were age 20 years and older and were of 50% or more Pima/Tohouo-O'odham heritage. Radiographs were reviewed by 2 musculoskeletal radiologists who were blinded to case status. Kinship coefficients were used to evaluate familial aggregation. Results. Eighty-eight RA cases were identified from this population-based sample. Over 66% of the cases had seropositive disease, over 60% had erosive disease, and over 40% had subcutaneous nodules. Of the 88 RA cases, 40 were members of families with more than 1 RA case. The remainder were simplex cases. Conclusion, In this population, clinical markers of severe RA were present in a majority of cases. The presence of familial aggregation for RA in the Pinna Indians suggests underlying genetic factors in disease pathogenesis. C1 NIAMSD, Bethesda, MD 20892 USA. Johns Hopkins Sch Med, Baltimore, MD USA. Univ Lund, Malmo, Sweden. Stanford Univ, Stanford, CA 94305 USA. NIDDKD, Phoenix, AZ 85016 USA. RP Hirsch, R (reprint author), Natl Arthrit & Muscoloskeletal & Skin Dis Informa, 1 AMS Circle, Bethesda, MD 20892 USA. FU NIAMS NIH HHS [AR-43584] NR 27 TC 20 Z9 20 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD AUG PY 1998 VL 41 IS 8 BP 1464 EP 1469 DI 10.1002/1529-0131(199808)41:8<1464::AID-ART17>3.0.CO;2-X PG 6 WC Rheumatology SC Rheumatology GA 108ZT UT WOS:000075297100016 PM 9704646 ER PT J AU Klippel, JH AF Klippel, JH TI Indications for, and use of, cytotoxic agents in SLE SO BAILLIERES CLINICAL RHEUMATOLOGY LA English DT Article DE immune suppression; cyclophosphamide; azathioprine; methotrexate ID SYSTEMIC LUPUS-ERYTHEMATOSUS; DOSE INTRAVENOUS CYCLOPHOSPHAMIDE; PULSE CYCLOPHOSPHAMIDE; MEMBRANOUS NEPHROPATHY; CONTROLLED TRIAL; IMMUNOSUPPRESSIVE THERAPY; RHEUMATOID-ARTHRITIS; CYCLOSPORINE-A; NEPHRITIS; METHOTREXATE AB Over the past decade, cytotoxic drugs have came to assume an increasingly important role in the management of systemic lupus erythematosus. Intravenous cyclophosphamide has become the standard treatment for lupus affecting major organs, in particular lupus nephritis. Cytotoxics with less potential for adverse side effects such as azathioprine and methotrexate are widely used in the management of non-major organ lupus and as an adjunct to reduce corticosteroid requirements. Recent clinical experience in lupus with newer cytotoxic drugs such as cyclosporin A, adenosine analogues, and mycophenolate mofetil appear promising and may offer improvements in lupus management in the future. C1 NIAMSD, Clin Invest Sect, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. RP Klippel, JH (reprint author), NIAMSD, Clin Invest Sect, Arthrit & Rheumatism Branch, NIH, Bldg 10,Room 9S205, Bethesda, MD 20892 USA. NR 54 TC 13 Z9 13 U1 0 U2 1 PU BAILLIERE TINDALL PI LONDON PA 24-28 OVAL RD, LONDON, ENGLAND NW1 7DX SN 0950-3579 J9 BAILLIERE CLIN RHEUM JI Baillieres Clin. Rheumatol. PD AUG PY 1998 VL 12 IS 3 BP 511 EP 527 DI 10.1016/S0950-3579(98)80033-2 PG 17 WC Rheumatology SC Rheumatology GA 132MD UT WOS:000076633100009 PM 9890110 ER PT J AU Regier, DA AF Regier, DA TI Mental health parity under managed care - Results to date and implications SO BEHAVIORAL HEALTHCARE TOMORROW LA English DT Article C1 NIMH, Rockville, MD 20857 USA. RP Regier, DA (reprint author), NIMH, Rockville, MD 20857 USA. NR 11 TC 0 Z9 0 U1 0 U2 0 PU CENTRALINK PUBLICATIONS PI TIBURON PA 1110 MAR WEST ST STE E, TIBURON, CA 94920-1879 USA SN 1063-8490 J9 BEHAV HEALTHC TOM JI Behav. Healthcare Tomorrow PD AUG PY 1998 VL 7 IS 4 BP 29 EP + PG 4 WC Psychology, Clinical; Health Policy & Services SC Psychology; Health Care Sciences & Services GA 105DC UT WOS:000075056600006 PM 10182150 ER PT J AU Thornton, JA Malkova, L Murray, EA AF Thornton, JA Malkova, L Murray, EA TI Rhinal cortex ablations fail to disrupt reinforcer devaluation effects in rhesus monkeys (Macaca mulatta) SO BEHAVIORAL NEUROSCIENCE LA English DT Article ID MACAQUE MONKEYS; AMYGDALA; STIMULUS; RECOGNITION; MEMORY; FASCICULARIS; CONNECTIONS; MECHANISMS; CORTICES; LESIONS AB Studies have shown that excitotoxic lesions of the amygdala attenuate reinforcer devaluation effects in monkeys and rats. Because the rhinal (i.e., entorhinal and perirhinal) cortex has prominent reciprocal connections with the amygdala and has been suggested to store knowledge about objects, it is possible that it too composes part of the critical circuitry subserving learning about objects and their associated reinforcement value. To test this possibility, rhesus monkeys with rhinal cortex removals as well as unoperated controls were tested using a reinforcer devaluation procedure. Monkeys with rhinal cortex removals and controls: unlike those with amygdala lesions, tended to avoid displacing objects overlying a devalued food. These results indicate that the rhinal cortex is not a critical part of the neural circuitry mediating the effects of reinforcer devaluation. C1 NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. RP Murray, EA (reprint author), NIMH, Neuropsychol Lab, Bldg 49,Room 1B80,49 Convent Dr, Bethesda, MD 20892 USA. EM eam@ln.nimh.nih.gov OI Murray, Elisabeth/0000-0003-1450-1642 NR 32 TC 24 Z9 24 U1 0 U2 0 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7044 J9 BEHAV NEUROSCI JI Behav. Neurosci. PD AUG PY 1998 VL 112 IS 4 BP 1020 EP 1025 DI 10.1037/0735-7044.112.4.1020 PG 6 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 114NL UT WOS:000075615500026 PM 9733208 ER PT J AU Chase, D Feng, Y Hanshew, B Winkles, JA Longo, DL Ferris, DK AF Chase, D Feng, Y Hanshew, B Winkles, JA Longo, DL Ferris, DK TI Expression and phosphorylation of fibroblast-growth-factor-inducible kinase (Fnk) during cell-cycle progression SO BIOCHEMICAL JOURNAL LA English DT Article ID SACCHAROMYCES-CEREVISIAE CDC5; POLO-LIKE KINASE; PROTEIN-KINASE; SERINE/THREONINE KINASE; DROSOPHILA POLO; MESSENGER-RNA; GENE; PLK; IDENTIFICATION; CLONING AB Fnk is a member of the polo family of cell-cycle-regulated serine/threonine kinases. We report here that it is present in serum-starved quiescent cells and that mitogenic stimulation of quiescent cells with calf serum results in the modification of a significant fraction of the Fnk pool. This modification results in a slower migrating form when analysed by SDS/PAGE. The modification is transient and by 9 h after stimulation all of the Fnk is again present as the faster migrating form. We also show that the Fnk protein increases in abundance as cells progress from G(I) to mitosis and is post-translationally modified as cells enter and exit mitosis. The Fnk modification is again manifested as a slower migrating species by SDS/PAGE and is due to phosphorylation of the protein. The mitotic-specific phosphorylation of Fnk correlates with an increase in its kinase activity, and this activity is dramatically reduced by phosphatase treatment of mitotic Fnk immunoprecipitates. During the later stages of mitosis, Fnk is dephosphorylated such that, by the time the cells enter G(I), it is all present as the dephosphorylated form. These results suggest that Fnk has two functions, one during the entry of cells into the cell cycle and a second during mitosis of cycling cells. C1 NCI, Frederick Canc Res Facil, SAIC, Frederick, MD 21702 USA. NCI, Frederick Canc Res Facil, NIA, Frederick, MD 21702 USA. Amer Red Cross, Jerome H Holland Lab, Rockville, MD 20855 USA. NIA, Baltimore, MD 21224 USA. RP Ferris, DK (reprint author), NCI, Frederick Canc Res Facil, SAIC, Frederick, MD 21702 USA. FU NCI NIH HHS [N01CO56000]; NHLBI NIH HHS [HL-54710] NR 32 TC 41 Z9 44 U1 0 U2 0 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON, ENGLAND W1N 3AJ SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD AUG 1 PY 1998 VL 333 BP 655 EP 660 PN 3 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 110NJ UT WOS:000075387000024 PM 9677325 ER PT J AU Ankrom, MA Patterson, JA d'Avis, PY Vetter, UK Blackman, MR Sponseller, PD Tayback, M Robey, PG Shapiro, JR Fedarko, NS AF Ankrom, MA Patterson, JA d'Avis, PY Vetter, UK Blackman, MR Sponseller, PD Tayback, M Robey, PG Shapiro, JR Fedarko, NS TI Age-related changes in human oestrogen receptor alpha function and levels in osteoblasts SO BIOCHEMICAL JOURNAL LA English DT Article ID STEROID-HORMONE RECEPTORS; HUMAN ESTROGEN-RECEPTOR; NUCLEAR-BINDING; PITUITARY-GLAND; MESSENGER-RNA; SKIN COLLAGEN; FEMALE RATS; ER-BETA; BONE; ESTRADIOL AB Oestrogen receptors (ERs) are present in human osteoblasts and mediate anti-resorptive effects on bone. Human osteoblast-like cells derived from different aged healthy female donors not on hormone replacement therapy were utilized under well-defined conditions in vitro to investigate ER function and levels, Treatment with 0.1 nM oestradiol-17 beta of cell strains derived from eight young women (less than 50 years of age) increased hydroxyproline levels significantly [an average (2.2 +/- 0.1 S.E.M.)-fold increase], whereas cells derived from nine older women (more than 50 years of age) were not significantly affected. Similarly, cell strains, derived from younger women, transfected with a consensus oestrogen-responsive element linked to chloramphenicol acetyltransferase exhibited a greater response to oestrogen than strains derived from older women, When basal ER alpha levels were measured by enzyme immunoassay and normalized on a per cell basis, osteoblast-like strains derived from younger women (n = 24) had a mean value of 2.54 +/- 0.16 fmol of ER alpha per 10(6) cells. In contrast, strains derived from older women (n = 20) had a mean value of 5.44 +/- 0.48 fmol of ER alpha per 10(6) cells. An age-related increase in ER alpha number was also observed in human skin-derived fibroblasts and directly in dermal biopsies from women not on hormone replacement therapy. The results demonstrate ligand concentration-dependent ER alpha induction and indicate a loss of receptor regulation and diminution of ligand-receptor signal transduction with increasing donor age. C1 Johns Hopkins Univ, Sch Med, Dept Med, Div Geriatr & Gerontol, Baltimore, MD 21224 USA. Allgemeines Krankenhaus Heidberg, D-22413 Hamburg, Germany. Johns Hopkins Univ, Sch Med, Dept Med, Div Endocrinol & Metab, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Orthopaed, Baltimore, MD 21224 USA. NIDR, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. RP Fedarko, NS (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Div Geriatr & Gerontol, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 USA. EM ndarko@welchlink.welch.jhu.edu RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU NIAMS NIH HHS [AR 42358] NR 67 TC 42 Z9 44 U1 0 U2 2 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON, ENGLAND W1N 3AJ SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD AUG 1 PY 1998 VL 333 BP 787 EP 794 PN 3 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 110NJ UT WOS:000075387000040 PM 9677341 ER PT J AU Tirumalai, PS Bhamre, S Upadhya, SC Boyd, MR Ravindranath, V AF Tirumalai, PS Bhamre, S Upadhya, SC Boyd, MR Ravindranath, V TI Expression of multiple forms of cytochrome P450 and associated mono-oxygenase activities in rat brain regions SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE cytochrome P450; mono oxygenase; brain; drug metabolism; cytochrome P4502B1; cytochrome P4502E1 ID FUNCTION OXIDASE SYSTEM; MESSENGER-RNAS; P-450; QUANTITATION; REDUCTASE; INDUCTION; MONOOXYGENASE; INDUCIBILITY; LOCALIZATION; ENZYME AB Cytochrome P450 (P450) content and P450-mediated mono-oxygenase activities were measured in microsomes prepared from various regions of rat brain. The regional P450 content in brain varied between 0.1 and 0.15 nmol/mg of protein, with the brainstem and cerebellum showing the highest levels. NADPH cytochrome c reductase activity was highest in the cortex followed by cerebellum and brainstem as compared with the whole brain. Mono-oxygenase activities also varied among the various brain regions. Southern blot analysis of the cDNA synthesized from the poly(A)RNA isolated from rat: brain regions and hybridized with cDNA to rat liver P4502B or P4502E1 revealed the presence of a transcript in untreated rat brain that had a molecular mass similar to that of the corresponding transcript from rat liver. Immunoblot analyses using antisera to purified rat liver P4502E1, P450(2B1/2B2), and a phenobarbital-inducible form of rat brain P450 revealed the presence of corresponding immunoreactive protein bands in all the brain regions examined. The present study demonstrated the diversity in the distribution of P450 and associated mono-oxygenase activities in brain and thus may reflect the differential capability of various regions of the brain to detoxify or bioactivate diverse xenobiotics. BIOCHEM PHARMACOL 56;3:371-375, 1998. (C) 1998 Elsevier Science Inc. C1 Natl Inst Mental Hlth & Neurosci, Dept Neurochem, Bangalore 560029, Karnataka, India. NCI, Lab Drug Discovery Res & Dev, DTP, DCTDC,FCRDC, Frederick, MD 21702 USA. RP Ravindranath, V (reprint author), Natl Inst Mental Hlth & Neurosci, Dept Neurochem, Hosur Rd, Bangalore 560029, Karnataka, India. EM vijaravi@nimhans.ren.nic.in NR 35 TC 23 Z9 23 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD AUG 1 PY 1998 VL 56 IS 3 BP 371 EP 375 DI 10.1016/S0006-2952(98)00036-7 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 104KG UT WOS:000075013000015 PM 9744575 ER PT J AU Mitchell, DC Gawrisch, K Litman, BJ Salem, N AF Mitchell, DC Gawrisch, K Litman, BJ Salem, N TI Why is docosahexaenoic acid essential for nervous system function? SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT 665th Meeting of the Royal-Irish-Academy-Lecture on Peptide Metabolism in Cytoplasm of Brain Cells CY MAR 31-APR 02, 1998 CL UNIV SOUTHAMPTON, HANTS, ENGLAND SP Royal Irish Acad Lecture HO UNIV SOUTHAMPTON ID POLYUNSATURATED FATTY-ACIDS; HIGHER-ORDER ANALYSIS; ACYL-CHAIN; RAT-BRAIN; ANISOTROPY DECAY; BILAYER LIPIDS; INFANTS; CHOLESTEROL; EQUILIBRIUM; PHOSPHATIDYLCHOLINES C1 NIAAA, Lab Membrane Biochem & Biophys, DICBR, NIH, Rockville, MD 20852 USA. RP Salem, N (reprint author), NIAAA, Lab Membrane Biochem & Biophys, DICBR, NIH, 12420 Parklawn Dr,Room 158, Rockville, MD 20852 USA. NR 42 TC 60 Z9 70 U1 2 U2 5 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON, ENGLAND W1N 3AJ SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD AUG PY 1998 VL 26 IS 3 BP 365 EP 370 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 115XX UT WOS:000075692600015 PM 9765880 ER PT J AU Hendler, RW Shrager, RI AF Hendler, RW Shrager, RI TI O-2-binding to fully reduced cytochrome aa(3) reexamined using SVD analysis of simulated and real data SO BIOCHEMISTRY AND MOLECULAR BIOLOGY INTERNATIONAL LA English DT Article DE electron transfer; heme proteins; rapid kinetics ID C-OXIDASE; REDUCTION; KINETICS; BINDING; O-2 AB Using new time-resolved multichannel experimental and simulated data, analyzed by SVD, it is concluded that the second order binding rate constant for O-2-binding to fully reduced mammalian cytochrome aa(3) is approximately five times higher than the currently accepted value of similar to 1.5 x 10(8) M-1 s(-1). C1 NHLBI, Cell Biol Lab, Bethesda, MD 20892 USA. NIH, Phys Sci Lab, Div Comp Res & Technol, Bethesda, MD 20892 USA. RP Hendler, RW (reprint author), NHLBI, Cell Biol Lab, Bethesda, MD 20892 USA. NR 6 TC 2 Z9 2 U1 0 U2 0 PU ACADEMIC PRESS AUST PI MARRICKVILLE PA LOCKED BAG 16, MARRICKVILLE, NSW 2204, AUSTRALIA SN 1039-9712 J9 BIOCHEM MOL BIOL INT JI Biochem. Mol. Biol. Int. PD AUG PY 1998 VL 45 IS 5 BP 1031 EP 1045 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 112MB UT WOS:000075497500020 PM 9739468 ER PT J AU Post, RM Weiss, SRB AF Post, RM Weiss, SRB TI Sensitization and kindling phenomena in mood, anxiety, and obsessive-compulsive disorders: The role of serotonergic mechanisms in illness progression SO BIOLOGICAL PSYCHIATRY LA English DT Article; Proceedings Paper CT Neuroscience Discussion Forum on a Decade of Serotonin Research CY NOV 16-18, 1997 CL AMELIA ISLAND, FLORIDA SP Soc Biol Psychiat, Eli Lilly & Co DE kindling; sensitization; serotonin; affective disorders; lithium; anticonvulsants ID TRANSCRANIAL MAGNETIC STIMULATION; POSTTRAUMATIC-STRESS-DISORDER; THYROTROPIN-RELEASING-HORMONE; RECURRENT AFFECTIVE-DISORDER; DORSAL RAPHE NUCLEUS; MESSENGER-RNA; NEURO-ENDOCRINE; COCAINE SENSITIZATION; RESISTANT DEPRESSION; SPONTANEOUS SEIZURES AB A number of untreated or inadequately treated psychiatric illnesses often demonstrate syndrome progression manifested by either increasing frequency, severity, or spontaneity of episodes. Behavioral sensitization to psychomotor stimulants (and its cross sensitization to stress) and electrophysiological kindling provide two very different models for conceptualizing physiological and behavioral abnormalities that progress in severity in response to the same inducing stimulation over time. These models are highly indirect, and the behaviors induced and specific pharmacologic interventions do not directly parallel those in many of these psychiatric syndromes. Nonetheless, these preclinical models help us conceptualize potential mechanisms involved in syndrome progression based on experience-dependent modifications of the genome at the level of transcriptional regulation, In both preclinical models, agents that are effective in the earlier developmental phase of sensitization or kindling are not necessarily effective in amelioration of The full-blown syndromes, and vice versa. Thus these models also suggest a variety of intervention principles that can be directly rested in the clinic, such as differential efficacy elf treatment as a function of stage of evolution of the given syndrome. Although serotonergic mechanisms do not appear central to the basic phenomena of sensitization and kindling, they appear capable of modulating their development and severity. As such, it becomes of considerable importance To assess whether serotonergic mechanisms that have been implicated in acute treatment of mood and anxiety syndromes are also involved in the longitudinal course and prevention of syndrome progression or occurrence, Identification of the more precise molecular mechanisms involved might provide a target for new therapeutic approaches to these recurrent and potentially disabling major psychiatric illnesses, Published 1998 by Society of Biological Psychiatry. C1 NIMH, Biol Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP Post, RM (reprint author), NIMH, Biol Psychiat Branch, NIH, Bldg 10,Room 3N212,10 Ctr Dr MSC 1272, Bethesda, MD 20892 USA. NR 132 TC 125 Z9 127 U1 3 U2 7 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 AUG 1 PY 1998 VL 44 IS 3 BP 193 EP 206 DI 10.1016/S0006-3223(98)00144-9 PG 14 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 104KF UT WOS:000075012900007 PM 9693391 ER PT J AU Hamosh, M Salem, N AF Hamosh, M Salem, N TI Long-chain polyunsaturated fatty acids SO BIOLOGY OF THE NEONATE LA English DT Review DE docosahexaenoic acid; arachidonic acid; visual, cognitive function; long-chain polyunsaturated fatty acid supplementation; premature, term infants ID ALPHA-LINOLENATE DIET; BIRTH-WEIGHT INFANTS; FULL-TERM INFANTS; VISUAL-ACUITY DEVELOPMENT; MATURE HUMAN-MILK; 1ST YEAR GROWTH; DOCOSAHEXAENOIC ACID; PRETERM INFANTS; BREAST-MILK; ARACHIDONIC-ACID AB Long-chain polyunsaturated fatty acids (LC-PUFA) are essential for normal development, Fetal accretion of LC-PUFA occurs during the last trimester of gestation; therefore, premature infants are born with minimal LC-PUFA reserves. Recent studies indicate that the newborn can synthesize LC-PUFA from essential fatty acid precursors; however, the extent of de novo synthesis remains to be established. Postnatally, human mill; provides LC-PUFA to the newborn. Maternal LC-PUFA reserves depend upon diet and can be improved by supplementation of docosahexaenoic acid and arachidonic acid during pregnancy and lactation. This in turn affects fetal LC-PUFA accretion and postnatal provision through mother's milk. Supplementation of formula-fed preterm or full-term infants with docosahexaenoic acid and arachidonic acid leads to plasma and red blood cell LC-PUFA levels similar to those of breast-fed infants. The higher blood and presumably tissue levels of LC-PUFA following supplementation lead, however, to only temporary functional benefits. C1 Georgetown Univ, Med Ctr, Dept Pediat, Washington, DC 20007 USA. NIAAA, Lab Membrane Biochem & Biophys, Rockville, MD 20852 USA. RP Hamosh, M (reprint author), Georgetown Univ, Med Ctr, Dept Pediat, 3800 Reservoir Rd NW, Washington, DC 20007 USA. EM hamoshp@medlib.georgetown.edu NR 119 TC 65 Z9 67 U1 6 U2 7 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0006-3126 J9 BIOL NEONATE JI Biol. Neonate PD AUG PY 1998 VL 74 IS 2 BP 106 EP 120 DI 10.1159/000014017 PG 15 WC Pediatrics SC Pediatrics GA 105JT UT WOS:000075070500005 PM 9691153 ER PT J AU Keizer, J Smith, GD Ponce-Dawson, S Pearson, JE AF Keizer, J Smith, GD Ponce-Dawson, S Pearson, JE TI Saltatory propagation of Ca2+ waves by Ca2+ sparks SO BIOPHYSICAL JOURNAL LA English DT Article ID RYANODINE RECEPTOR ADAPTATION; RAT-HEART CELLS; CALCIUM SPARKS; RELEASE; MUSCLE; OSCILLATIONS; DIFFUSION; BUFFERS AB Punctate releases of Ca2+, called Ca2+ sparks, originate at the regular array of t-tubules in cardiac myocytes and skeletal muscle. During Ca2+ overload sparks serve as sites for the initiation and propagation of Ca2+ waves in myocytes. Computer simulations of spark-mediated waves are performed with model release sites that reproduce the adaptive Ca2+ release observed for the ryanodine receptor. The speed of these waves is proportional to the diffusion constant of Ca2+, D, rather than root D, as is true for reaction-diffusion equations in a continuous excitable medium. A simplified "fire-diffuse-fire" model that mimics the properties of Ca2+-induced Ca2+ release (CICR) from isolated sites is used to explain this saltatory mode of wave propagation. Saltatory and continuous wave propagation can be differentiated by the temperature and Ca2+ buffer dependence of wave speed. C1 Univ Calif Davis, Inst Theoret Dynam, Davis, CA 95616 USA. Univ Calif Davis, Sect Neurobiol Physiol & Behav, Davis, CA 95616 USA. NIDDKD, Math Res Branch, NIH, Bethesda, MD 20814 USA. Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Fis, RA-1428 Buenos Aires, DF, Argentina. Univ Buenos Aires, Fac Ciencias Exactas & Nat, IAFE, RA-1428 Buenos Aires, DF, Argentina. Univ Calif Los Alamos Natl Lab, XCM, Los Alamos, NM 87545 USA. RP Keizer, J (reprint author), Univ Calif Davis, Inst Theoret Dynam, 2201 Acad Surge Bldg,1 Shields Ave, Davis, CA 95616 USA. OI Ponce Dawson, Silvina/0000-0001-6550-4267 FU NCRR NIH HHS [R01 RR10081] NR 25 TC 129 Z9 132 U1 0 U2 5 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD AUG PY 1998 VL 75 IS 2 BP 595 EP 600 PG 6 WC Biophysics SC Biophysics GA 107KB UT WOS:000075206000003 PM 9675162 ER PT J AU Mitchell, DC Litman, BJ AF Mitchell, DC Litman, BJ TI Effect of cholesterol on molecular order and dynamics in highly polyunsaturated phospholipid bilayers SO BIOPHYSICAL JOURNAL LA English DT Article ID TIME-RESOLVED FLUORESCENCE; NUCLEAR-MAGNETIC-RESONANCE; CHAIN PHOSPHATIDYLCHOLINE VESICLES; ACYL-CHAIN; ORIENTATIONAL ORDER; ANISOTROPY DECAY; HETEROACID PHOSPHATIDYLCHOLINES; ROTATIONAL DIFFUSION; MEMBRANES; UNSATURATION AB The effect of cholesterol on phospholipid acyl chain packing in bilayers consisting of highly unsaturated acyl chains in the liquid crystalline phase was examined for a series of symmetrically and asymmetrically substituted phosphatidylcholines (PCs). The time-resolved fluorescence emission and decay of fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene (DPH) was used to characterize equilibrium and dynamic structural properties of bilayers containing 30 mot % cholesterol. The bilayers were composed of symmetrically substituted PCs with acyl chains of 14:0, 18:1n9, 20:4n6, or 22:6n3, containing 0, 1, 4, or 6 double bonds, respectively, and mixed-chain PCs with a saturated 16:0 sn-l chain and 1, 4, or 6 double bonds in the sn-2 chain. DPH excited-state lifetime was fit to a Lorentzian lifetime distribution, the center of which was increased 1-2 ns by 30 mol % cholesterol relative to the cholesterol-free bilayers. Lifetime distributions were dramatically narrowed by the addition of cholesterol in all bilayers except the two consisting of dipolyunsaturated PCs, DPH anisotropy decay was interpreted in terms of the Brownian rotational diffusion model. The effect of cholesterol on both the perpendicular diffusion coefficient D-perpendicular to and the orientational distribution function f(theta) varied with acyl chain unsaturation. In all bilayers, except the two dipolyunsaturated PCs, 30 mol % cholesterol dramatically slowed DPH rotational motion and restricted DPH orientational freedom. The effect of cholesterol was especially diminished in di-22:6n3 PC, suggesting that this phospholipid may be particularly effective at promoting lateral domains, which are cholesterol-rich and unsaturation-rich, respectively, The results are discussed in terms of a model for lipid packing in membranes containing cholesterol and PCs with highly unsaturated acyl chains. C1 NIAAA, Lab Membrane Biophys & Biochem, Sect Fluorescence Studies, NIH, Rockville, MD 20852 USA. RP Mitchell, DC (reprint author), NIAAA, Lab Membrane Biophys & Biochem, Sect Fluorescence Studies, NIH, Pk Bldg,Room 158,12420 Parklawn Dr, Rockville, MD 20852 USA. EM dmitchell@niaaa.nih.gov NR 53 TC 103 Z9 103 U1 2 U2 10 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD AUG PY 1998 VL 75 IS 2 BP 896 EP 908 PG 13 WC Biophysics SC Biophysics GA 107KB UT WOS:000075206000031 PM 9675190 ER PT J AU Zeng, G AF Zeng, G TI Sticky-end PCR: New method for subcloning SO BIOTECHNIQUES LA English DT Article ID POLYMERASE CHAIN-REACTION; PRODUCTS C1 Georgetown Univ, Med Ctr, Washington, DC 20007 USA. RP Zeng, G (reprint author), NCI, Surg Branch, NIH, Room 4B50,Bldg 10, Bethesda, MD 20892 USA. NR 4 TC 97 Z9 99 U1 1 U2 8 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD AUG PY 1998 VL 25 IS 2 BP 206 EP 208 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 109BU UT WOS:000075302000005 PM 9714877 ER PT J AU Katz, BZ Krylov, D Aota, SI Olive, M Vinson, C Yamada, KM AF Katz, BZ Krylov, D Aota, SI Olive, M Vinson, C Yamada, KM TI Green fluorescent protein labeling of cytoskeletal structures - Novel targeting approach based on leucine zippers SO BIOTECHNIQUES LA English DT Article ID MUTANTS; GFP AB Green fluorescent protein (GFP) is a valuable marker for intracellular protein localization. However, the fusion of GFP with structural proteins can alter their properties, resulting in a loss of fusion protein localization, decreased GFP fluorescence or both. We describe a novel targeting approach based on noncovalent heterodimerization of GFP and cytoplasmic structural proteins. The formation of structural protein/GFP complexes was mediated by modified leucine zipper protein spacers designed to form high-affinity heterodimers. The complexes localized accurately to specific sites within cells, providing selective fluorescence labeling of subcellular structures such as microfilaments or focal contacts. C1 NIDR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Katz, BZ (reprint author), NIDR, 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 17 Z9 17 U1 0 U2 3 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD AUG PY 1998 VL 25 IS 2 BP 298 EP + PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 109BU UT WOS:000075302000020 PM 9714891 ER PT J AU Pinkoski, MJ Hobman, M Heibein, JA Tomaselli, K Li, F Seth, P Froelich, CJ Bleackley, RC AF Pinkoski, MJ Hobman, M Heibein, JA Tomaselli, K Li, F Seth, P Froelich, CJ Bleackley, RC TI Entry and trafficking of granzyme B in target cells during granzyme B-perforin-mediated apoptosis SO BLOOD LA English DT Article ID BINDING PROTEIN RAB4; DNA FRAGMENTATION; CYTOTOXIC LYMPHOCYTES; ENDOCYTIC PATHWAY; SERINE PROTEASES; RAPID INDUCTION; NATURAL-KILLER; IN-VIVO; ACTIVATION; DEATH AB In the widely accepted model of granule-mediated killing by cytotoxic lymphocytes, granzyme B entry into the target cell is facilitated by the pore forming molecule, perforin. Using indirect immunofluorescence and also direct visualization of fluorescein isothiocyanate (FITC)-conjugated granzyme B, we demonstrate internalization in the absence of perforin. Induction of the lytic pathway, however, required a second signal that was provided by perforin or adenovirus (Ad2). The combination of agents also resulted ire a dramatic relocalization of the granzyme, Microinjection of granzyme B directly into the cytoplasm of target cells resulted in apoptosis without the necessity of a second stimulus. This suggested that the key event is the presence of granzyme B in the cytoplasm, and that when the enzyme is internalized by a target cell, it trafficks to an intracellular compartment and accumulates until release is stimulated by the addition of perforin. We found that the proteinase passed through rab5-positive vesicles and then accumulated within a novel compartment. On the basis of these results, we propose a new model for granzyme-perforin-induced target cell lysis in which granzyme B is subjected to trafficking events in the target cell that control and contribute to cell death. (C) 1998 by The American Society of Hematology. C1 Univ Alberta, Dept Biochem, Edmonton, AB T6G 2H7, Canada. IDUN PHarmaceut, La Jolla, CA USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. Northwestern Univ, Evanston Hosp, Dept Med, Evanston, IL 60201 USA. RP Bleackley, RC (reprint author), Univ Alberta, Dept Biochem, 4-63 Med Sci Bldg, Edmonton, AB T6G 2H7, Canada. EM Chris.Bleackley@UAlberta.Ca NR 51 TC 151 Z9 159 U1 0 U2 3 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 1998 VL 92 IS 3 BP 1044 EP 1054 PG 11 WC Hematology SC Hematology GA 104UY UT WOS:000075035300038 PM 9680374 ER PT J AU Gerloff, C Richard, J Hadley, J Schulman, AE Honda, M Hallett, M AF Gerloff, C Richard, J Hadley, J Schulman, AE Honda, M Hallett, M TI Functional coupling and regional activation of human cortical motor areas during simple, internally paced and externally paced finger movements SO BRAIN LA English DT Review DE motor cortex; supplementary motor area; finger movements; EEG; motor control ID POSITRON EMISSION TOMOGRAPHY; CEREBRAL BLOOD-FLOW; SUPPLEMENTARY SENSORIMOTOR AREA; EVENT-RELATED DESYNCHRONIZATION; PRECEDING VOLUNTARY MOVEMENT; INTERNATIONAL 10-20 SYSTEM; BIMANUAL VISUOMOTOR TASK; PARKINSONS-DISEASE; NEURONAL-ACTIVITY; HAND MOVEMENTS AB We studied the activation and interaction of cortical motor regions during simple, internally paced and externally paced right-hand finger extensions in healthy volunteers. We recorded EEGs from 28 scalp electrodes and analysed task-related coherence, task-related power and movement-related cortical potentials. Task-related coherence reflects inter-regional functional coupling of oscillatory neuronal activity, task-related power reflects regional oscillatory activity of neuronal assemblies and movement-related cortical potentials reflect summated potentials of apical dendrites of pyramidal cells, A combination of these three analytical techniques allows comprehensive evaluation of different aspects of information processing in neuronal assemblies, For both externally and internally paced finger extensions, movement-related regional activation was predominant over the contralateral premotor and primary sensorimotor cortex, and functional coupling occurred between the primary sensorimotor cortex of both hemispheres and between the primary sensorimotor cortex and the mesial premotor areas, probably including the supplementary motor area. The main difference between the different types of movement pacing was enhanced functional coupling of central motor areas during internally paced finger extensions, particularly inter-hemispherically between the left and right primary sensorimotor cortexes and between the contralateral primary sensorimotor cortex and the mesial premotor areas, Internally paced finger extensions were also associated with additional regional (premovement) activation over the mesial premotor areas, The maximal task-related coherence differences between internally and externally paced finger extensions occurred in the frequency range of 20-22 Hz rather than in the range of maximal task-related power differences (9-11 Hz). This suggests that important aspects of information processing in the human motor system could be based on networklike oscillatory cortical activity and might be modulated on at least two levels, which to some extent can operate independently from each other: (i) regional activation (task-related power) and (ii) inter-regional functional coupling. We propose that internal pacing of movement poses higher demands on the motor system than external pacing, and that the motor system responds not only by increasing regional activation of the mesial premotor system, including the supplementary motor area, but also by enhancing information flow between lateral and mesial premotor and sensorimotor areas of both hemispheres, even if the movements are simple and unimanual. C1 NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Gerloff, C (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10,Room 5N226,10 Ctr Dr,MSC-1428, Bethesda, MD 20892 USA. NR 126 TC 275 Z9 279 U1 1 U2 17 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD AUG PY 1998 VL 121 BP 1513 EP 1531 DI 10.1093/brain/121.8.1513 PN 8 PG 19 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 111BM UT WOS:000075417500012 PM 9712013 ER PT J AU Lee, HY Whiteside, MB Herkenham, M AF Lee, HY Whiteside, MB Herkenham, M TI Area postrema removal abolishes stimulatory effects of intravenous interleukin-1 beta on hypothalamic-pituitary-adrenal axis activity and c-fos mRNA in the hypothalamic paraventricular nucleus SO BRAIN RESEARCH BULLETIN LA English DT Article DE cytokine; blood-brain barrier; corticotropin-releasing hormone; corticosterone; nucleus of the solitary tract; circumventricular organ; norepinephrine; in situ hybridization; histochemistry ID CORTICOTROPIN-RELEASING-FACTOR; RECEPTOR MESSENGER-RNA; RAT-BRAIN; NERVOUS-SYSTEM; ADRENAL-GLAND; VAGUS NERVE; NEURONS; ACTIVATION; PATHWAYS; LOCALIZATION AB This study examined the role of the area postrema (AP) in transducing peripheral immune signals, represented by intravenous (i.v.) interleukin-1 beta (IL-1), into neuroendocrine responses. The AP, a circumventricular organ with a leaky blood-brain barrier, lies adjacent to the nucleus of the solitary tract (NTS) in the medulla, The AP was removed by aspiration, and 2 weeks later, AP-lesioned or sham-lesioned rats were injected i.v. with 0.5 mu g/kg IL-1 or sterile saline. After 30 min, brains were removed and analyzed for c-fos mRNA levels in various structures implicated in the hypothalamic-pituitary-adrenal axis response to peripheral cytokine challenge, The sham-lesioned animals responded to IL-1 with large elevations in adrenocorticotropic hormone (ACTH) and corticosterone levels in the plasma and c-fos mRNA levels in cells of the AP, NTS, central nucleus of the amygdala, bed nucleus of the stria terminalis, hypothalamic paraventricular nucleus (PVN), and meninges. Prior AP removal abolished the IL-1-induced increases in ACTH and corticosterone in the plasma and c-fos mRNA levels in the NTS and PVN, However, AP removal had no effect on IL-1-induced increases in c-fos mRNA levels in the other areas examined. The selective AP lesion effects suggest that the AP and adjacent NTS play a pivotal role in transducing a circulating IL-1 signal into hypothalamic-pituitary-adrenal axis activation by a pathway that may be comprised of known anatomical links between the AP, NTS, and corticotropin-releasing hormone neurons of the PVN, Published 1998 Elsevier Science Inc. C1 NIMH, Funct Neuroanat Sect, Bethesda, MD 20892 USA. RP Herkenham, M (reprint author), NIMH, Funct Neuroanat Sect, Bldg 36,Rm 2D-15, Bethesda, MD 20892 USA. OI Herkenham, Miles/0000-0003-2228-4238 NR 63 TC 42 Z9 43 U1 0 U2 3 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 AUG PY 1998 VL 46 IS 6 BP 495 EP 503 DI 10.1016/S0361-9230(98)00045-8 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 116FV UT WOS:000075714400005 PM 9744286 ER PT J AU Bradshaw, TD Schultz, RJ Paull, KD Kelland, L Wilson, A Garner, C Fiebig, HH Wrigley, S Stevens, MFG AF Bradshaw, TD Schultz, RJ Paull, KD Kelland, L Wilson, A Garner, C Fiebig, HH Wrigley, S Stevens, MFG TI Influence of 2-(4-aminophenyl)benzothiazoles on growth of human ovarian carcinoma cells in vitro and in vivo SO BRITISH JOURNAL OF CANCER LA English DT Article DE ovarian carcinoma; 2-(4-aminophenyl)benzothiazole; COMPARE analysis; 5-(4-dimethylaminophenylazo)quinoline ID BENZOTHIAZOLES; LINES AB 2-(4-Aminophenyl)benzothiazole molecules substituted in the 3 position of the phenyl ring with a halogen atom or methyl moiety compromise a group of compounds that potently inhibit specific human ovarian carcinoma cell lines. GI(50) values fall within the nM range. Inhibition is highly selective - whereas the GI(50) value in IGROV1 cells consistently lies at < 10 nM, SK-OV-3 presents GI(50) values > 10 mu M. Biphasic dose-response relationships were observed in sensitive cell lines after 48-h drug exposure. COMPARE analyses revealed the very similar profiles of anti-tumour activity of 3-substituted benzothiazoles and 5-(4-dimethylaminophenylazo)quinoline, with Pearson correlation coefficients > 0.65. Anti-tumour activity extended to preliminary in vivo tests. The growth of OVCAR-3 cells in polyvinylidene fluoride (PVDF) hollow fibres implanted in the peritoneal cavity of mice was inhibited by more than 50% after intraperitoneal (i.p.) administration of 2-(4-amino-3-methylphenyl)benzothiazole (10 mg kg(-1)), 2-(4-amino-3-chlorophenyl)benzothiazole (100 mg kg(-1)) or 2-(4-amino-3-bromophenyl)benzothiazole (150 mg kg(-1)). The growth of OVCAR-3 tumours in subcutaneously (s.c.) implanted hollow fibres was retarded by more than 50% after treatment with 2-(4-amino-3-methylphenyl)benzothiazole (6.7 and 10 mg kg(-1)). In addition, the growth of s.c. OVCAR-3 xenografts was delayed after exposure to DF 203. However, the relationship between drug concentration and growth inhibition was inverse. C1 Univ Nottingham, Dept Pharmaceut Sci, Canc Res Labs, Nottingham NG7 2RD, England. NCI, Bethesda, MD 20902 USA. Inst Canc Res, CRC, Ctr Canc Therapeut, Sutton SM2 5NG, Surrey, England. Derby City Gen Hosp, Dept Oncol, Derby DE22 3NE, England. Univ Freiburg, Inst Expt Oncol, D-79110 Freiburg, Germany. RP Bradshaw, TD (reprint author), Univ Nottingham, Dept Pharmaceut Sci, Canc Res Labs, Univ Pk, Nottingham NG7 2RD, England. NR 14 TC 62 Z9 64 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 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD AUG PY 1998 VL 78 IS 4 BP 421 EP 429 DI 10.1038/bjc.1998.510 PG 9 WC Oncology SC Oncology GA 110CN UT WOS:000075362700001 PM 9716022 ER PT J AU Ridge, SA Sludden, J Brown, O Robertson, L Wei, XX Sapone, A Fernandez-Salguero, PM Gonzalez, FJ Vreken, P van Kuilenburg, ABP van Gennip, AH McLeod, HL AF Ridge, SA Sludden, J Brown, O Robertson, L Wei, XX Sapone, A Fernandez-Salguero, PM Gonzalez, FJ Vreken, P van Kuilenburg, ABP van Gennip, AH McLeod, HL TI Dihydropyrimidine dehydrogenase pharmacogenetics in Caucasian subjects SO BRITISH JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE drug metabolism; dihydropyrimidine dehydrogenase; pharmacogenetics; polymorphism ID 5-FLUOROURACIL TOXICITY; POPULATION CHARACTERISTICS; CANCER-PATIENTS; MOLECULAR-BASIS; DEFICIENCY; CHEMOTHERAPY; ENZYME AB Aims Dihydropyrimidine dehydrogenase (DPD) catalyses the reduction of pyrimidines, including the anticancer agent 5-fluorouracil (5FU). Impaired 5FU degradation, through low DPD activity, has led to severe, life-threatening or fatal toxicity after administration of 5FU. Complete DPD deficiency is associated with the inherited metabolic disease thymine uraciluria. Several mutations in the gene encoding DPD have recently been identified, but the phenotype-genotype concordance of these alterations in the general population has not been reported. Methods Mononuclear cells were isolated from whole blood and DPD activity was determined after ex vivo incubation with C-14-5FU followed by h.p.l.c. analysis of 5FU metabolites. Analysis of mutations in the DPD gene at an exon splice site, codons 534, 543, and 732, and a deletion at base 1897 (Delta C1897) were performed in 30 subjects with the lowest and 30 subjects with the highest enzyme activity using PCR-RFLP. Results DPD activity was measured in 226 Caucasian subjects and was highly variable (range 19.1-401.4 pmol min(-1) mg(-1) protein). Mutations were frequently observed at codons 543 (allele frequency 28%), 732 (allele frequency 5.8%), and 534 (allele frequency 0.8%), but were not associated with low DPD activity. There were no splice site or Delta C1897 mutations found in this population. Conclusions The five mutations analysed in this study are insufficient for identification of patients at risk for 5FU toxicity or thymine uraciluria. Both the splice site mutation and Delta C1897 are relatively rare in the general Caucasian population. Therefore, identification of further molecular alterations is required to facilitate the use of DPD analysis in genetic diagnosis and cancer therapeutics. C1 Univ Aberdeen, Inst Med Sci, Dept Med & Therapeut, Aberdeen, Scotland. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. Univ Amsterdam, Acad Med Hosp, Emma Childrens Hosp, Amsterdam, Netherlands. Univ Amsterdam, Dept Clin Chem, NL-1105 AZ Amsterdam, Netherlands. RP McLeod, HL (reprint author), Univ Aberdeen, Inst Med Sci, Dept Med & Therapeut, Aberdeen, Scotland. RI Sapone, Andrea/E-6704-2013; OI Sapone, Andrea/0000-0001-8496-6977; Fernandez-Salguero, Pedro M./0000-0003-2839-5027 FU Wellcome Trust NR 19 TC 95 Z9 109 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0306-5251 J9 BRIT J CLIN PHARMACO JI Br. J. Clin. Pharmacol. PD AUG PY 1998 VL 46 IS 2 BP 151 EP 156 DI 10.1046/j.1365-2125.1998.00751.x PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 109BP UT WOS:000075301600010 PM 9723824 ER PT J AU Vitiello, B AF Vitiello, B TI Pediatric psychopharmacology and the interaction between drugs and the developing brain SO CANADIAN JOURNAL OF PSYCHIATRY-REVUE CANADIENNE DE PSYCHIATRIE LA English DT Review DE psychopharmacology; brain; development ID AUTISTIC-CHILDREN; NURSING RATS; IN-UTERO; DYSKINESIAS; PREGNANCY; RECEPTOR; WOMEN AB With increasing frequency, psychotropic medications are being prescribed to young children, often for long periods of time. The interaction between psychotropics and the developing brain has not been systematically investigated in humans, Data collected from animals suggest that developing neurotransmitter systems can be exquisitely sensitive to early inhibition or stimulation by pharmacological agents, which can lend to permanent changes in adult life. Most of these data are collected from rodents, and their extrapolation to humans is difficult. More relevant models could be developed, for instance using primates. In humans, the focus of research has traditionally been on the possible teratogenic effects of prenatal drug exposure. Recently introduced quantitative imaging techniques can offer new approaches to studying the effects of psychotropics on the developing brain. This research has clear implications for the safety and efficacy of psychopharmacologic drug use in children. C1 NIMH, Child & Adolescent Treatment & Prevent Intervent, Rockville, MD 20857 USA. RP Vitiello, B (reprint author), NIMH, Child & Adolescent Treatment & Prevent Intervent, Room 10C-09 5600 Fishers Lane, Rockville, MD 20857 USA. EM bvitiell@nih.gov NR 21 TC 43 Z9 43 U1 2 U2 2 PU CANADIAN PSYCHIATRIC ASSOC PI OTTAWA PA 260-441 MACLAREN ST, OTTAWA, ONTARIO K2H 2P3, CANADA SN 0706-7437 J9 CAN J PSYCHIAT JI Can. J. Psychiat.-Rev. Can. Psychiat. PD AUG PY 1998 VL 43 IS 6 BP 582 EP 584 PG 3 WC Psychiatry SC Psychiatry GA 112ZD UT WOS:000075524000004 PM 9729684 ER PT J AU Jensen, PS AF Jensen, PS TI Ethical and pragmatic issues in the use of psychotropic agents in young children SO CANADIAN JOURNAL OF PSYCHIATRY-REVUE CANADIENNE DE PSYCHIATRIE LA English DT Review DE pediatric psychopharmacology; ethical issues; safety; efficacy; child psychopathology ID PSYCHOPHARMACOLOGY AB Objective: To provide an overview of the knowledge base concerning the prescribing of psychotropic agents in young children with mental disorders and related mental health problems. Method: Relevant information is reviewed concerning the knowledge base available to inform pediatric psychopharmacology prescribing practices. Results: Very few psychoactive medications have been adequately tested for safety and efficacy in young children, despite relatively high rates of prescribing. Conclusion: Behavioural and psychotherapeutic strategies are often the wisest first therapeutic intervention for this age group. Psychotropic medications may be required, but should be used cautiously in young children, while additional studies are being conducted. C1 NIMH, Dev Psychopathol Res Branch, Child & Adolescent Res, Rockville, MD 20857 USA. RP Jensen, PS (reprint author), NIMH, Dev Psychopathol Res Branch, Child & Adolescent Res, Room 18C-17,5600 Fishers Lane, Rockville, MD 20857 USA. OI Jensen, Peter/0000-0003-2387-0650 NR 13 TC 16 Z9 16 U1 0 U2 1 PU CANADIAN PSYCHIATRIC ASSOC PI OTTAWA PA 260-441 MACLAREN ST, OTTAWA, ONTARIO K2H 2P3, CANADA SN 0706-7437 J9 CAN J PSYCHIAT JI Can. J. Psychiat.-Rev. Can. Psychiat. PD AUG PY 1998 VL 43 IS 6 BP 585 EP 588 PG 4 WC Psychiatry SC Psychiatry GA 112ZD UT WOS:000075524000005 PM 9729685 ER PT J AU Nicolson, R Bhalerao, S Sloman, L AF Nicolson, R Bhalerao, S Sloman, L TI 47,XYY karyotypes and pervasive developmental disorders SO CANADIAN JOURNAL OF PSYCHIATRY-REVUE CANADIENNE DE PSYCHIATRIE LA English DT Article DE pervasive developmental disorders; sex chromosomes; XYY karyotype ID SEX-CHROMOSOME ABNORMALITIES; HEAD CIRCUMFERENCE; INFANTILE-AUTISM; Y-CHROMOSOME; XYY SYNDROME; CHILDHOOD; CHILDREN AB Objective: The presence of a 47,XYY karyotype in boys with pervasive developmental disorders (PDDs) has rarely been described in the past. Herein, 2 boys with PDDs and a supernumerary Y chromosome are presented. Methods: The case histories of the 2 patients are described along with the results of associated testing. The literature on psychosocial development as well as brain morphology and physiology in males with 47,XYY karyotypes is reviewed. Results: Both boys had presentations typical of PDDs, one with autistic disorder and the other with PDD not otherwise specified Conclusions: The finding that, in a clinic for children with developmental disorders, 2 of 40 male referrals had 47,XYY karyotypes suggests that the rate of this sex chromosome anomaly may be increased in PDDs. An extra Y chromosome may be related to abnormal brain development, which may, in turn, predispose vulnerable males to PDDs. C1 Univ Toronto, Dept Psychiat, Toronto, ON, Canada. RP Nicolson, R (reprint author), NIMH, Child Psychiat Branch, Bldg 10,Room 3N202,10 Ctr Dr MSC 1600, Bethesda, MD 20892 USA. RI Nicolson, Robert/E-4797-2011 NR 40 TC 30 Z9 30 U1 1 U2 2 PU CANADIAN PSYCHIATRIC ASSOC PI OTTAWA PA 260-441 MACLAREN ST, OTTAWA, ONTARIO K2H 2P3, CANADA SN 0706-7437 J9 CAN J PSYCHIAT JI Can. J. Psychiat.-Rev. Can. Psychiat. PD AUG PY 1998 VL 43 IS 6 BP 619 EP 622 PG 4 WC Psychiatry SC Psychiatry GA 112ZD UT WOS:000075524000010 PM 9729690 ER PT J AU Friedenreich, CM Thune, I Brinton, LA Albanes, D AF Friedenreich, CM Thune, I Brinton, LA Albanes, D TI Epidemiologic issues related to the association between physical activity and breast cancer SO CANCER LA English DT Article; Proceedings Paper CT National Action Plan on Breast Cancers Workshop on Physical Activity and Breast Cancer CY NOV 13-14, 1997 CL ALBUQUERQUE, NEW MEXICO DE breast neoplasms; physical activity; epidemiologic methods; review ID BODY-FAT DISTRIBUTION; MENSTRUAL-CYCLE; REPRODUCTIVE FACTORS; AMERICAN WOMEN; UNITED-STATES; WEIGHT CHANGE; RISK-FACTORS; EXERCISE; AGE; DETERMINANTS AB A workshop on physical activity and breast cancer was held in November 1997 to review previous epidemiologic research on this topic and to identify new areas for research. This article is the first of three summaries of the workshop's activities. The material reviewed included 21 studies that reported a measure of physical activity in relation to breast cancer outcomes and were published by December 1997. They were identified in a computerized literature search and a "by-hand" review of journals. The study designs, populations, data collection methods, and results were examined and the strengths and limitations of the studies identified. The strengths and limitations are discussed herein, as are recommendations for future research. Fifteen of the 21 studies suggested that physical activity reduces the risk of breast cancer, whereas four studies found no association and two studies found an increased risk of breast cancer associated with physical activity. Specific subgroups of the population may experience a greater decrease in breast cancer with increased levels of physical activity. These include women who are lean, parous, and premenopausal. Some examination of confounding and effect modification was undertaken. Hypothesized biologic mechanisms for this putative association include an effect of physical activity on endogenous hormones, energy balance, and the immune system. The overall evidence supports a reduction in breast cancer risk with increased physical activity. However, numerous questions remain regarding this putative association. These include the underlying biologic model and the parameters of physical activity that are associated with risk, such as the types of activity (occupational, recreational, and household), the components of activity (frequency, intensity, and duration), the time periods in life that are associated with risk reduction, and the important confounders and effect modifiers of this association. Use of intermediate endpoints for breast cancer may be useful in such investigations. Cancer 1998;83:600-10. (C) 1998 American Cancer Society. C1 Alberta Canc Board, Div Epidemiol Prevent & Screening, Calgary, AB T2N 4N2, Canada. Univ Tromso, Inst Community Med, Dept Epidemiol & Med Stat, Tromso, Norway. NCI, Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NCI, Canc Prevent Studies Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Friedenreich, CM (reprint author), Alberta Canc Board, Div Epidemiol Prevent & Screening, 1331 29 St NW, Calgary, AB T2N 4N2, Canada. RI Albanes, Demetrius/B-9749-2015; Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 65 TC 66 Z9 68 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 0008-543X J9 CANCER JI Cancer PD AUG 1 PY 1998 VL 83 IS 3 SU S BP 600 EP 610 DI 10.1002/(SICI)1097-0142(19980801)83:3+<600::AID-CNCR2>3.0.CO;2-B PG 11 WC Oncology SC Oncology GA 105GN UT WOS:000075064500001 PM 9690523 ER PT J AU Ainsworth, BE Sternfeld, B Slattery, ML Daguise, V Zahm, SH AF Ainsworth, BE Sternfeld, B Slattery, ML Daguise, V Zahm, SH TI Physical activity and breast cancer - Evaluation of physical activity assessment methods SO CANCER LA English DT Article; Proceedings Paper CT National Action Plan on Breast Cancers Workshop on Physical Activity and Breast Cancer CY NOV 13-14, 1997 CL ALBUQUERQUE, NEW MEXICO DE physical activity; breast cancer; questionnaires; women; exercise ID RISK; EXERCISE; WOMEN; DISEASE; RECALL AB Studies of the association between physical activity and breast cancer have yielded inconsistent findings. These findings may be related to a true null association or an inability to measure physical activity with enough precision to measure a protective relation. The authors reviewed and critiqued physical activity measurement methods used in published studies of the association between physical activity and breast cancer. The authors examined the quality of physical activity measures in 20 published studies. A summary score was created to rank the quality of the activity score. Studies with higher scores had a more precise measure of physical activity Physical activity measurement methods were different in each study. Activity was measured by job classification, occupational tasks, participation in competitive athletics, and recreational and leisure-time pursuits. The recall period for physical activity ranged from a lifetime to the past year. Comparison of quality scores showed no associations between the precision of activity measures and the study results. Future studies of physical activity and breast cancer should utilize standardized methods to measure physical activity. Researchers should be encouraged to choose a measure based on hypotheses regarding physical activity and breast cancer mechanisms. Studies also should extend to subgroups of women with differences in other breast cancer risk factors, such as body mass, menopausal status, and hormone replacement status. Cancer 1998;83:611-20, (C) 1998 American Cancer Society. C1 Univ S Carolina, Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. Univ S Carolina, Sch Publ Hlth, Dept Exercise Sci, Columbia, SC 29208 USA. Kaiser Permanente Med Care Program, Div Res, Oakland, CA 94611 USA. Univ Utah, Sch Med, Salt Lake City, UT USA. NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Ainsworth, BE (reprint author), Univ S Carolina, Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. RI Zahm, Shelia/B-5025-2015 NR 43 TC 64 Z9 66 U1 2 U2 6 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER JI Cancer PD AUG 1 PY 1998 VL 83 IS 3 SU S BP 611 EP 620 DI 10.1002/(SICI)1097-0142(19980801)83:3+<611::AID-CNCR3>3.0.CO;2-A PG 10 WC Oncology SC Oncology GA 105GN UT WOS:000075064500002 PM 9690524 ER PT J AU Ron, E Preston, DL Kishikawa, M Kobuke, T Iseki, M Tokuoka, S Tokunaga, M Mabuchi, K AF Ron, E Preston, DL Kishikawa, M Kobuke, T Iseki, M Tokuoka, S Tokunaga, M Mabuchi, K TI Skin tumor risk among atomic-bomb survivors in Japan SO CANCER CAUSES & CONTROL LA English DT Article DE atomic-bomb survivors; basal cell carcinoma; Japan; radiation dose; radiation effects; squamous cell carcinoma ID BASAL-CELL CARCINOMA; CANCER INCIDENCE; RADIATION; HEAD; NECK AB Objectives: Elevated risks of skin cancer following high doses of ionizing radiation have long been known, Recent reports on atomic-bomb survivors indicate that nonmelanoma skin cancer can be induced at low to medium doses, We studied atomic-bomb survivors to determine the effects of radiation on specific histologic types of skin cancer and to describe the dose-response relationship. Methods: Cases of melanoma, nonmelanoma skin cancers, and Bowen's disease were ascertained between 1958 and 1987 for the 80,000 cohort members through the population-based Hiroshima and Nagasaki (Japan) tumor registries augmented by searches of other records. Results: An excess of basal cell carcinoma (n = 80), with some suggestion of a non-linear dose-response, was observed. The excess risk decreased markedly as age at exposure increased, and there was no evidence for an interaction between ionizing and ultraviolet radiation. No dose-response was found for squamous cell carcinoma (n = 69), The excess relative risk point-estimates were large, but statistically nonsignificant for both melanoma (n = 10) and Bowen's disease (n = 26). Conclusions: The basal layer of the epidermis appears to be quite sensitive to radiation carcinogenesis, particularly at a young age, The suprabasal layer seems to be more resistant, as shown by the lack of an association for squamous cell carcinomas. C1 Radiat Effects Res Fdn, Dept Stat, Minami Ku, Hiroshima 7320815, Japan. NCI, Radiat Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Radiat Effects Res Fdn, Dept Epidemiol, Minami Ku, Hiroshima 7320815, Japan. Aichi Prefectural Colony, Aichi Human Serv Ctr, Inst Dev Res, Dept Morphol, Aichi, Japan. Nagasaki Univ, Inst Trop Med, Nagasaki 852, Japan. Welf Assoc Onomichi Gen Hosp, Res Lab, Onomichi, Japan. Kagoshima Univ, Sch Med, Dept Publ Hlth, Ctr Shron Viral Dis, Kagoshima 890, Japan. Kagoshima Univ, Sch Med, Div Persistent Oncogen Viruses, Ctr Shron Viral Dis, Kagoshima 890, Japan. RP Preston, DL (reprint author), Radiat Effects Res Fdn, Dept Stat, Minami Ku, 5-2 Hijiyama Pk, Hiroshima 7320815, Japan. FU NCPDCID CDC HHS [NCI-4893-8-001] NR 31 TC 88 Z9 92 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD AUG PY 1998 VL 9 IS 4 BP 393 EP 401 DI 10.1023/A:1008867617415 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 127AT UT WOS:000076328100006 PM 9794171 ER PT J AU Sturgeon, SR Brock, JW Potischman, N Needham, LL Rothman, N Brinton, LA Hoover, RN AF Sturgeon, SR Brock, JW Potischman, N Needham, LL Rothman, N Brinton, LA Hoover, RN TI Serum concentrations of organochlorine compounds and endometrial cancer risk (United States) SO CANCER CAUSES & CONTROL LA English DT Article DE endometrial cancer; DDT; PCB; organochlorines; United States; women ID POLYCHLORINATED-BIPHENYLS PCBS; BREAST-CANCER; CIGARETTE-SMOKING; WOMEN; PESTICIDES; RESIDUES; UTERUS AB Objectives: Endogenous and exogenous estrogens are important in the development of endometrial cancer. Several organochlorine compounds, such as o,p'-DDT, have estrogenic properties. The objective of this case-control analysis was to examine serum concentrations of organochlorine compounds and risk of endometrial cancer. Methods: Analyses were based on a sample of 90 endometrial cancer cases and 90 individually matched community controls from a multicenter case-control study in five geographic regions of the United States. Information on potential confounders, including menstrual and reproductive factors, cigarette smoking, diet, and weight, was obtained by interview. Results: The adjusted relative risk of endometrial cancer in the highest quartile of exposure compared with women in the lowest quartile was 0.7 (95 percent confidence interval [CI] = 0.2-2.0) for p,p'-DDE, and 0.9 for total polychlorinated biphenyls (PCBs) (CI = 0.4-2.5). Conclusions: These findings do not support the hypothesis that organochlorine compounds are linked to the development of endometrial cancer. C1 NCI, Div Canc Epidemiol & Genet, Hormonal Studies Sect, Environm Epidemiol Branch, Bethesda, MD 20852 USA. Ctr Dis Control, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA. RP Sturgeon, SR (reprint author), NCI, Div Canc Epidemiol & Genet, Hormonal Studies Sect, Environm Epidemiol Branch, Execut Plaza N,Room 443, Bethesda, MD 20852 USA. RI Needham, Larry/E-4930-2011; Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 30 TC 30 Z9 35 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD AUG PY 1998 VL 9 IS 4 BP 417 EP 424 DI 10.1023/A:1008823802393 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 127AT UT WOS:000076328100009 PM 9794174 ER PT J AU Conley, BA Kaplan, RS Arbuck, SG AF Conley, BA Kaplan, RS Arbuck, SG TI National Cancer Institute Clinical Trials Program in colorectal cancer SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article; Proceedings Paper CT 13th Bristol-Myers-Squibb Nagoya International Cancer Treatment Symposium CY OCT 17-18, 1997 CL NAGOYA, JAPAN SP Bristol-Myers Squibb DE colon cancer; chemotherapy; adjuvant therapy; clinical trials ID ADJUVANT THERAPY; CARCINOMA AB Colorectal cancer will be diagnosed in approximately 150,000 patients in the USA this year. Chemotherapy has recently been shown to improve survival when given as adjuvant therapy to surgery in patients with stage IU colorectal cancer. Demonstration of this benefit required large, randomized controlled trials. Either 5-fluorouracil (5-FU) and leucovorin for 6 months or 5-FU and levamisole for 12 months are currently considered standard adjuvant treatment for stage In colorectal cancer. However, current adjuvant trials are comparing continuous infusion and intravenous bolus 5-FU regimens and oral uracil/Ftorafur with intravenous 5-FU and leucovorin, as well as studying the timing of chemotherapy in the adjuvant setting. Subsequent adjuvant trials will examine newer regimens with activity in advanced colorectal cancer, as well as the efficacy of monoclonal antibodies. Other trials will study which type of surgery is optimal and whether adjuvant therapy is helpful in stage II colon cancer. Trials in metastatic disease will focus on combinations of newer agents which may improve survival in this patient group. Studies in rectal cancer will focus on determining which agents are optimal in combination with radiation therapy in the adjuvant setting. Molecular characteristics of tumor cells are being defined, which may guide therapy in the future. Careful, logically designed clinical trials will hope fully provide more efficacious therapy for this common cancer. C1 NCI, Clin Invest Branch, Canc Therapy Evaluat Program, NIH, Rockville, MD 20852 USA. NCI, Invest Drug Branch, Canc Therapy Evaluat Program, NIH, Rockville, MD USA. RP Conley, BA (reprint author), NCI, Clin Invest Branch, Canc Therapy Evaluat Program, NIH, 741 Execut Plaza N,6130 Execut Blvd, Rockville, MD 20852 USA. NR 15 TC 10 Z9 10 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 AUG PY 1998 VL 42 SU S BP S75 EP S79 PG 5 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 120EN UT WOS:000075942100011 PM 9750034 ER PT J AU Sausville, EA Lush, RD Headlee, D Smith, AC Figg, WD Arbuck, SG Senderowicz, AM Fuse, E Tanii, H Kuwabara, T Kobayashi, S AF Sausville, EA Lush, RD Headlee, D Smith, AC Figg, WD Arbuck, SG Senderowicz, AM Fuse, E Tanii, H Kuwabara, T Kobayashi, S TI Clinical pharmacology of UCN-01: initial observations and comparison to preclinical models SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article; Proceedings Paper CT 13th Bristol-Myers-Squibb Nagoya International Cancer Treatment Symposium CY OCT 17-18, 1997 CL NAGOYA, JAPAN SP Bristol-Myers Squibb DE staurosporine, 7-hydroxy; protein kinase antagonist; alpha(1)-acidic glycoprotein ID PROTEIN-KINASE-C; ANTITUMOR-ACTIVITY; INHIBITOR; 7-HYDROXYSTAUROSPORINE; CELLS AB UCN-01 (7-hydroxystaurosporine; NSC 638850) is a protein kinase antagonist selected for clinical trial based in part on evidence of efficacy in a preclinical renal carcinoma xenograft model. Schedule studies and in vitro studies suggested that a 72-h continuous infusion would be appropriate. In rats and dogs, maximum tolerated doses produced peak plasma concentrations of approximately 0.2-0.3 mu M. However, concentrations 10-fold greater are well tolerated in humans, and the compound has a markedly prolonged T-1/2. Specific binding to human alpha(1)-acidic glycoprotein has been demonstrated. These findings reinforce the need to consider actual clinical pharmacology data in "real time" with phase I studies. C1 NCI, DTP, Clin Trials Unit, Med Branch,Div Clin Sci, Bethesda, MD 20892 USA. NCI, Dev Therapeut Dept, Med Branch, Div Clin Sci, Bethesda, MD 20892 USA. NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Bethesda, MD 20892 USA. NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. Kyowa Hakko Kogyo Co Ltd, Pharmaceut Res Inst, Drug Dev Res Labs, Shizuoka, Japan. RP Sausville, EA (reprint author), NCI, Dev Therapeut Program, Execut Plaza N,Suite 843,6130 Execut Blvd, Rockville, MD 20852 USA. EM sausville@dtpax2.ncifcrf.gov RI Figg Sr, William/M-2411-2016 NR 13 TC 69 Z9 70 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 AUG PY 1998 VL 42 SU S BP S54 EP S59 DI 10.1007/s002800051080 PG 6 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 120EN UT WOS:000075942100007 PM 9750030 ER PT J AU Ji, BT Devesa, SS Chow, WH Jin, F Gao, YT AF Ji, BT Devesa, SS Chow, WH Jin, F Gao, YT TI Colorectal cancer incidence trends by subsite in urban Shanghai, 1972-1994 SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID COLON-CANCER; PHYSICAL-ACTIVITY; UNITED-STATES; TIME TRENDS; RISK; CHINA; JAPAN; EPIDEMIOLOGY; AUSTRALIA; MORTALITY AB Epidemiological characteristics of colorectal cancer may differ by particular anatomical subsite, suggesting that the subsite-specific colorectal cancers may represent different disease entities. This study explored the time trends over a 23-year period in colorectal cancer incidence at various subsites by sex and age group. Data on the incidence of colorectal cancer were obtained from a population-based cancer registry in Shanghai, People's Republic of China. Between 1972 and 1994, 30,693 patients with colorectal cancer were registered at the Shanghai Cancer Registry. The overall age-adjusted colorectal cancer incidence rates increased > 50%, or 2% per year from 1972-1977 to 1990-1994, from 14 to 22 per 100,000 among men and from 12 to 19 per 100,000 among women. The increases in rates were considerably more rapid for colon cancer, with rates approximately doubling, than they were for rectal cancer. Proximal colon cancer was more common than distal colon cancer over the whole study period, whereas rates for both cancers rose with similar annual percentage changes (>5% per year) and across virtually all age groups. The estimated annual increases rose from 2% at ages 35-44 years to 7% at ages 75-84 years for proximal colon cancer, but they were more uniform for distal colon cancer (5-6% per year). Age-adjusted and age-specific rectal cancer rates changed little. The male:female age-adjusted rate ratio for colorectal cancer was 1.19 in 1990-1994, The ratios increased over time and varied by subsites, with ratios increasing from the proximal colon to the distal colon and to the rectum, Furthermore, men had higher rates than women for distal colon and rectal cancers at ages 55 and older, whereas women had higher rates than men at younger ages for these two cancers. Male:female rate ratios for proximal colon cancer did not vary substantially with age. The findings from this study indicate that subsite-specific incidence rates of colorectal cancer differ by sex and age and in their time trends. Cancers arising in the proximal colon, distal colon, and rectum may have somewhat different disease etiologies. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20952 USA. Shanghai Canc Inst, Dept Epidemiol, Shanghai 100032, Peoples R China. RP Ji, BT (reprint author), NCI, 6130 Execut Blvd,EPN 415, Rockville, MD 20852 USA. NR 28 TC 89 Z9 96 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 AUG PY 1998 VL 7 IS 8 BP 661 EP 666 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 108UJ UT WOS:000075283700004 PM 9718217 ER PT J AU Seetharam, S Nodzenski, E Beckett, MA Heimann, R Cha, A Margulies, I Pastan, I Kufe, DW Weichselbaum, RR AF Seetharam, S Nodzenski, E Beckett, MA Heimann, R Cha, A Margulies, I Pastan, I Kufe, DW Weichselbaum, RR TI Modulation of apoptotic response of a radiation-resistant human carcinoma by Pseudomonas exotoxin-chimeric protein SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-ALPHA; MEDIATED APOPTOSIS; CARBOXYL-TERMINUS; DNA FRAGMENTATION; DIPHTHERIA-TOXIN; FACTOR RECEPTOR; BLADDER-CANCER; CELLS; CERAMIDE; CYTOTOXICITY AB Strategies to sensitize human tumors that are resistant to apoptosis have been clinically unsuccessful. We demonstrate that a structurally modified chimeric Pseudomonas exotoxin, PE Delta 53L/TGF-alpha/KDEL, with binding specificity for the epidermal growth factor receptor, markedly enhances sensitivity of human xenografts to radiation killing. Exposure to PE Delta 53L/TGF-alpha/KDEL decreases the apoptotic threshold through protein synthesis inhibition and simultaneous production of ceramide in tumor cells that lack functional p53 protein. In contrast, no increase in local or systemic toxicity was observed with the chimeric toxin and radiation. We conclude that biochemical targeting of the chimeric toxin and physical targeting of ionizing radiation may increase the therapeutic ratio in the treatment of human cancers with alterations of p53 expression. This strategy offers a high therapeutic potential for Pseudomonas exotoxin A chimeric proteins and irradiation. C1 Univ Chicago Hosp, Dept Radiat & Cellular Oncol, Chicago, IL 60637 USA. NCI, Mol Biol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Canc Pharmacol, Boston, MA 02115 USA. RP Weichselbaum, RR (reprint author), Univ Chicago Hosp, Dept Radiat & Cellular Oncol, Chicago, IL 60637 USA. EM rrw@rover.uchicago.edu FU NCI NIH HHS [CA-42596, CA-55241] NR 31 TC 4 Z9 4 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 AUG 1 PY 1998 VL 58 IS 15 BP 3215 EP 3220 PG 6 WC Oncology SC Oncology GA 105ZD UT WOS:000075104500005 PM 9699644 ER PT J AU Fuse, E Tanii, H Kurata, N Kobayashi, H Shimada, Y Tamura, T Sasaki, Y Tanigawara, Y Lush, RD Headlee, D Figg, WD Arbuck, SG Senderowicz, AM Sausville, EA Akinaga, S Kuwahara, A Kobasashi, S AF Fuse, E Tanii, H Kurata, N Kobayashi, H Shimada, Y Tamura, T Sasaki, Y Tanigawara, Y Lush, RD Headlee, D Figg, WD Arbuck, SG Senderowicz, AM Sausville, EA Akinaga, S Kuwahara, A Kobasashi, S TI Unpredicted clinical pharmacology of UCN-01 caused by specific binding to human alpha(1)-acid glycoprotein SO CANCER RESEARCH LA English DT Article ID PROTEIN-KINASE-C; HUMAN ALPHA-1-ACID GLYCOPROTEIN; SELECTIVE INHIBITOR; ANTITUMOR-ACTIVITY; PHARMACOKINETICS; DISPOSITION; SERUM AB The pharmacokinetics of UCN-01 after administration as a 72- or 3-h infusion to cancer patients in initial Phase I trials displayed distinctive features that could not have been predicted from preclinical data. The distribution volumes (0.0796-0.158 liters/kg) and the systemic clearance (0.0407-0.252 ml/h/kg) were extremely low, in contrast to large distribution volume and rapid systemic clearance in experimental animals. The elimination half-lives (253-1660 h) were unusually long. In vitro protein binding experiments demonstrated that UCN-01 mas strongly bound to human alpha(1)-acid glycoprotein. The results suggest that unusual pharmacokinetics of UCN-01 in humans could be due, at least in part, to its specifically high binding to alpha(1)-acid glycoprotein. C1 Kyowa Hakko Kogyo Co Ltd, Drug Dev Res Labs, Pharmaceut Res Inst, Nagaizumi, Shizuoka 411, Japan. Natl Canc Ctr Hosp, Dept Med Oncol, Tokyo 104, Japan. Natl Canc Ctr Hosp, Div Hematol & Oncol, Kashiwa, Chiba 277, Japan. Kobe Univ, Sch Med, Dept Hosp Pharm, Kobe, Hyogo 650, Japan. NCI, Div Clin Sci, Bethesda, MD 20892 USA. Div Canc Treatment & Diag, Rockville, MD 20852 USA. RP Kuwahara, A (reprint author), Kyowa Hakko Kogyo Co Ltd, Drug Dev Res Labs, Pharmaceut Res Inst, 1188 Shimotogari, Nagaizumi, Shizuoka 411, Japan. RI Figg Sr, William/M-2411-2016 NR 21 TC 171 Z9 174 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 AUG 1 PY 1998 VL 58 IS 15 BP 3248 EP 3253 PG 6 WC Oncology SC Oncology GA 105ZD UT WOS:000075104500011 PM 9699650 ER PT J AU McCormick, DL Rao, KVN Dooley, L Steele, VE Lubet, RA Kelloff, GJ Bosland, MC AF McCormick, DL Rao, KVN Dooley, L Steele, VE Lubet, RA Kelloff, GJ Bosland, MC TI Influence of N-methyl-N-nitrosourea, testosterone, and N-(4-hydroxyphenyl)-all-trans-retinamide on prostate cancer induction in Wistar-unilever rats SO CANCER RESEARCH LA English DT Article ID SEMINAL-VESICLE; SEQUENTIAL TREATMENT; CYPROTERONE-ACETATE; CARCINOMA; MICE; N-(4-HYDROXYPHENYL)RETINAMIDE; HISTOGENESIS; 7,12-DIMETHYLBENZ(A)ANTHRACENE; 3,2'-DIMETHYL-4-AMINOBIPHENYL; ADENOCARCINOMAS AB The influence of chemical carcinogen, hormonal stimulation, and chronic dietary administration of the synthetic retinoid, N-(4-hydroxyphenyl)-all-trans-retinamide (4-HPR), on the induction of prostate cancer in male Wistar-Unilever rats was determined. Three different tumor induction regimens were used: (a) a single i.v. dose of 50 mg of N-methyl-N-nitrosourea (MNU) per kg body weight, followed by chronic androgen stimulation via s.c. implantation of two silastic capsules containing 40 mg testosterone each; (b) a single i.v, dose of 50 mg of MNU per kg body weight (no testosterone treatment); and (c) chronic androgen stimulation with implanted testosterone capsules (no MNU treatment). In a fourth series of animals, the incidence of spontaneous prostate tumors was determined in groups of rats receiving neither carcinogen nor hormone stimulation. Within each series, parallel groups of animals were fed a control (vehicle-supplemented) diet or control diet supplemented with 4-HPR beginning 1 day after carcinogen administration; retinoid administration was continuous until termination of the study at 450 days. The incidence of accessory sex gland cancer in rats treated sequentially with MNU + testosterone was >60%, in comparison with cancer incidences of <20% in rats receiving MNU only and <5% in rats treated with testosterone only. No spontaneous accessory sex gland tumors were observed in rats receiving no carcinogen and no testosterone, Tumor induction in the accessory sex glands by MNU + testosterone was relatively specific for the prostate: the incidence of carcinoma of the dorsolateral/anterior prostate was more than 5-fold greater than the incidence of cancer present only in the seminal vesicle. 4-HPR conferred no protection against cancer induction in the prostate by any regimen of MNU and/or testosterone, These results demonstrate the importance of both carcinogen exposure and hormone stimulation on the induction of neoplasia in the prostate of Wistar-Unilever rats. C1 IIT, Res Inst, Dept Life Sci, Chicago, IL 60616 USA. NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. NYU, Med Ctr, Nelson Inst Environm Med, Tuxedo Pk, NY 10987 USA. NYU, Med Ctr, Dept Urol, Tuxedo Pk, NY 10987 USA. RP McCormick, DL (reprint author), IIT, Res Inst, Dept Life Sci, 10 W 35 St, Chicago, IL 60616 USA. FU NCI NIH HHS [N01-CN-85097-08] NR 27 TC 51 Z9 51 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 1 PY 1998 VL 58 IS 15 BP 3282 EP 3288 PG 7 WC Oncology SC Oncology GA 105ZD UT WOS:000075104500017 PM 9699656 ER PT J AU Poruchynsky, MS Wang, EE Rudin, CM Blagosklonny, MV Fojo, T AF Poruchynsky, MS Wang, EE Rudin, CM Blagosklonny, MV Fojo, T TI Bcl-x(L) is phosphorylated in malignant cells following microtubule disruption SO CANCER RESEARCH LA English DT Article ID TAXOL-INDUCED APOPTOSIS; BCL-2 PROTEIN; DEATH; MITOCHONDRIA; EXPRESSION; MECHANISM; C-RAF-1; KINASE; RAF-1 AB The oncogenic protein Bcl-2 functions as a potent inhibitor of programmed cell death. This survival activity has been shown in some settings to be influenced by the Bcl-2 phosphorylation state. It has been demonstrated that treatment with microtubule-targeted agents results in phosphorylation of both Raf-1 kinase and Bcl-2, The Bcl-2-related family member Bcl-x(L) also exhibits a death suppressive activity, but its potential for phosphorylation following exposure to drugs that interact with microtubules has not been evaluated. Several tumor cell lines with low or undetectable levels of Bcl-2 protein expression were found to express Bcl-x(L), A more slowly migrating Bcl-x(L) band was observed on immunoblots after cells were treated with microtubule-targeted agents. The appearance of this band was responsive to dose and was absent when the cell lysates were treated with lambda protein phosphatase. Using a Bcl-x(L)-specific monoclonal antibody, the phosphorylated form of Bcl-x(L) was immunoprecipitated from cells treated with paclitaxel and metabolically labeled with P-32-labeled inorganic orthophosphate, Herein, we report that Bcl-x(L) is phosphorylated in malignant cells after incubation with agents that target tubulin, including paclitaxel, vincristine, vinblastine, colchicine, and nocodazole. Moreover, paclitaxel-resistant ovarian carcinoma cell lines that have mutations in tubulin failed to exhibit phosphorylation of Bcl-x(L) after paclitaxel exposure, but they did demonstrate Bcl-x(L) phosphorylation in the presence of other tubulin-targeting agents. As observed for Bcl-2, phosphorylation of Bcl-x(L) was accompanied by phosphorylation of Raf-1, Interestingly, phosphorylation of these three proteins failed to occur or was much less pronounced when cells grown at high density were challenged with drug. Also, reduced Raf-1 expression, observed after treatment of cells with geldanamycin prior to and during incubation with the microtubule-active drugs, correlated with diminished Bcl-x(L) phosphorylation, Taken together, these results suggest that Bcl-x(L), like Bcl-2, is phosphorylated by agents that disrupt microtubule architecture, By analogy with Bcl-2, this phosphorylation may play a critical role in modulating Bcl-x(L) function and may be an important determinant of microtubule-directed chemotherapeutic efficacy in human tumors. C1 NCI, Div Clin Sci, Med Branch, NIH, Bethesda, MD 20892 USA. Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA. RP Poruchynsky, MS (reprint author), NCI, Div Clin Sci, Med Branch, NIH, Bldg 10,Room 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 38 TC 149 Z9 151 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 1 PY 1998 VL 58 IS 15 BP 3331 EP 3338 PG 8 WC Oncology SC Oncology GA 105ZD UT WOS:000075104500024 PM 9699663 ER PT J AU Dunn, SE Ehrlich, M Sharp, NJH Reiss, K Solomon, G Hawkins, R Baserga, R Barrett, CJ AF Dunn, SE Ehrlich, M Sharp, NJH Reiss, K Solomon, G Hawkins, R Baserga, R Barrett, CJ TI A dominant negative mutant of the insulin-like growth factor-I receptor inhibits the adhesion, invasion, and metastasis of breast cancer SO CANCER RESEARCH LA English DT Article ID GENE-EXPRESSION; ANTISENSE RNA; TUMOR-CELLS; LYMPH NODES; NUDE-MICE; IGF-II; CARCINOMA; TRANSFORMATION; TAMOXIFEN; VIVO AB The 5-year survival rate for women with metastatic breast cancer is only 25-30%; thus, the need to improve treatment is apparent. Overexpression of insulin-like growth factor-I receptor (IGF-IR) correlates with poor prognosis and local recurrence. In this study, we addressed whether functional impairment of IGF-IR affects adhesion, invasion, and metastasis of breast cancer, Impairment of IGF-IR function was achieved by transfecting a dominant negative form of the receptor, termed 486stop, into MDA-MB-435 metastatic breast cancer cells, The protein product of 486stop is secreted extracellularly, resulting in a bystander effect. Cellular adhesion to laminin and collagen was inhibited 94 and 88%, respectively. Furthermore, 486stop inhibited insulin-like growth factor-I-stimulated invasion through collagen IV by 75%. The dominant negative receptor was secreted, as evidenced by the observation that MDA-MB-435 and MDA-MB-231 cells were prevented from binding to laminin by 90% when treated with conditioned medium (CM) from 486stop-transfected cells, CM also inhibited the invasion of MDA-MB-231 cells across collagen IV by 80%, Finally, CM made MDA-MB-231 cells 30% more sensitive to Taxol(R)-induced cell death. Growth in soft agar was suppressed by 486stop, but growth in monolayer was unaffected. When injected into the mammary fat pad, 486stop did not significantly suppress growth of the primary tumor, but metastasis to the lungs, livers, lymph nodes, and lymph vessels was significantly decreased compared to the vector control. In conclusion, inhibition of IGF-IR resulted in suppression of adhesion, invasion, and metastasis, providing a mechanistic rationale for targeting IGF-IR in the treatment of metastatic breast cancer. C1 NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. Thomas Jefferson Univ, Jefferson Med Coll, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. N Carolina State Univ, Coll Vet Med, Raleigh, NC 27606 USA. RP Barrett, CJ (reprint author), NIEHS, Mol Carcinogenesis Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM Barrett@niehs.nih.gov FU NCI NIH HHS [P0ICA56309] NR 43 TC 228 Z9 235 U1 1 U2 10 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 AUG 1 PY 1998 VL 58 IS 15 BP 3353 EP 3361 PG 9 WC Oncology SC Oncology GA 105ZD UT WOS:000075104500027 PM 9699666 ER PT J AU Fenton, RG Hixon, JA Wright, PW Brooks, AD Sayers, TJ AF Fenton, RG Hixon, JA Wright, PW Brooks, AD Sayers, TJ TI Inhibition of Fas (CD95) expression and Fas-mediated apoptosis by oncogenic Ras SO CANCER RESEARCH LA English DT Article ID INDUCED CELL-DEATH; NF-KAPPA-B; ANTI-FAS; RECEPTOR SUPERFAMILY; PLASMA-MEMBRANE; APO-1 CD95; ACTIVATION; PROTEIN; LIGAND; FAS/APO-1 AB The ras oncogene plays an important role in the multistep progression to cancer by activation of signal transduction pathways that contribute to aberrant growth regulation. Although many of these effects are cell autonomous, the ras oncogene also regulates the expression of genes that alter host/tumor interactions. We now extend the mechanisms through which ras promotes tumor survival by demonstrating that oncogenic Ras inhibits expression of the fas gene and renders Ras-transformed cells resistant to Fas-induced apoptosis. A panel of Ras-transformed clones exhibited a marked inhibition in fas mRNA and Fas cell surface expression as compared with untransformed parental cell lines. Fas expression was induced by culture in the presence of IFN-gamma + tumor necrosis factor or; however, the maximal level attained in Ras transformants was similar to 10-fold below the level of untransformed cells. Whereas untransformed cells were sensitive to apoptotic death induced by cross-linking surface Fas (especially after cytokine treatment), pas-transformed cells were very resistant to Fas-induced death even under the most stringent assay conditions. To demonstrate that this resistance was mediated by oncogenic Ras and not secondary genetic events, pools of Ras-transformed cells were generated using a highly efficient retroviral transduction technique. Transformed pools were assayed 6 days after infection and demonstrated a marked decrease in fas gene expression and Fas-mediated apoptosis, Oncogenic pas did not promote general resistance to apoptosis, because ectopic expression of a fas cDNA in Ras-transformed cells restored sensitivity to Fas-induced apoptosis. These data indicate that oncogenic Ras inhibits basal levels of expression of the fas gene, and although cytokine signal transduction pathways are functional in these cells, the level of surface Fas expression remains below the threshold required for induction of apoptosis, These data identify a mechanism by which Ras-transformed cells may escape from host-mediated immune destruction. C1 NCI, Dept Expt Transplantat & Immunol, Div Clin Sci, Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA. Sci Applicat Int Corp, Intramural Res Support Program, Frederick, MD 21702 USA. RP Fenton, RG (reprint author), Univ Maryland, Sch Med, Greenebaum Canc Ctr, 655 W Baltimore St, Baltimore, MD 21201 USA. RI Sayers, Thomas/G-4859-2015 NR 54 TC 60 Z9 64 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 AUG 1 PY 1998 VL 58 IS 15 BP 3391 EP 3400 PG 10 WC Oncology SC Oncology GA 105ZD UT WOS:000075104500032 PM 9699671 ER PT J AU Tang, CK Goldstein, DJ Payne, J Czubayko, F Alimandi, M Wang, LM Pierce, JH Lippman, ME AF Tang, CK Goldstein, DJ Payne, J Czubayko, F Alimandi, M Wang, LM Pierce, JH Lippman, ME TI ErbB-4 ribozymes abolish neuregulin-induced mitogenesis SO CANCER RESEARCH LA English DT Article ID FACTOR RECEPTOR FAMILY; EGF RECEPTOR; BREAST-CANCER; CARCINOMA-CELLS; GENE-PRODUCT; HEREGULIN; LIGAND; HETERODIMERIZATION; EXPRESSION; MEMBER AB The epidermal growth factor-like receptor tyrosine kinase (ErbB) family is frequently overexpressed in a variety of human carcinomas, including breast cancer. To assist in characterizing the role of ErbB-4 in breast cancer, we generated three specific hammerhead ribozymes targeted to the ErbB-4 mRNA, These ribozymes, Rz6, Rz21, and Rz29, efficiently catalyzed the specific cleavage of ErbB-4 message in a cell-free system. We demonstrated that the neuregulin-induced mitogenic effect was abolished in ribozyme Rz29- and Rz6-transfected 32D/ErbB-4 cells, Inhibition of mitogenesis was characterized by ribozyme-mediated down-regulation of ErbB-4 expression. In addition, we provide the first evidence that different threshold levels of ErbB-4 expression and activation correlate with different responses to nenregulin stimulation, High levels of ErbB-4 expression, phosphorylation, and homodimerization are necessary for neuregulin-stimulated, interleukin 3-independent cell proliferation in the 32D/E4 cells, In the case of RzZ9-transfected 32D/E4 cells, low levels of ErbB-4 expression allowed neuregulin-induced phosphorylation but were insufficient to couple the activated receptor to cellular signaling. Furthermore, expression of the functional ErbB-4 ribozyme in T47D human breast carcinoma cells led to a down-regulation of endogenous ErbB-4 expression and a reduction of anchorage-independent colony formation. These studies support the use of ErbB-4 ribozymes to define the role of ErbB-4 receptors in human cancers. C1 Georgetown Univ, Med Ctr, Dept Biochem, Lombardi Canc Ctr, Washington, DC 20007 USA. NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. RP Tang, CK (reprint author), Georgetown Univ, Med Ctr, Dept Biochem, Lombardi Canc Ctr, Res Bldg E512,3970 Reservoir Rd NW, Washington, DC 20007 USA. EM Tangc@gunet.georgetown.edu FU NCI NIH HHS [R29 CA-63044, IP50-CA58185-04, IP30-CA-51008] NR 40 TC 21 Z9 21 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 AUG 1 PY 1998 VL 58 IS 15 BP 3415 EP 3422 PG 8 WC Oncology SC Oncology GA 105ZD UT WOS:000075104500035 PM 9699674 ER PT J AU Hirsch, J Koos, M Kovac, P AF Hirsch, J Koos, M Kovac, P TI Improved synthesis of an aldobiouronic acid related to hardwood xylans, and preparation of a derivative thereof suitable for linking to proteins SO CARBOHYDRATE RESEARCH LA English DT Article DE aldobiouronic acid; stereoselective alpha-glycosylation; xylopyranosides; disaccharides; neoglycoconjugate AB Treatment of 1,3,4-tri-O-acetyl-alpha-D-xylopyranose with methyl 2,3-di-O-benzyl-1-chloro-1-deoxy-4-O-methyl-alpha, beta-D-glucopyranuronate in the presence of silver trifluoromethanesulfonate was highly stereoselective to give the alpha-linked aldobiouronic acid derivative (4) in 86% yield, after hydrogenolysis of the crude product of the coupling and chromatography. Compound 4 was acetylated and the fully protected substance was converted to the corresponding glycosyl chloride. Reaction of the latter with p-nitrophenol under phase-transfer catalysis afforded, after deacetylation, p-nitrophenyl 2-O-(methyl 4-O-methyl-alpha-D-glucopyranosyluronate)-beta-D-xylopyranoside. (C) 1998 Elsevier Science Ltd. All rights reserved. C1 NIDDK, NIH, Bethesda, MD 20892 USA. Slovak Acad Sci, Inst Chem, SK-84238 Bratislava, Slovakia. RP Kovac, P (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. NR 14 TC 17 Z9 17 U1 3 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 J9 CARBOHYD RES JI Carbohydr. Res. PD AUG PY 1998 VL 310 IS 1-2 BP 145 EP 149 DI 10.1016/S0008-6215(98)00161-X PG 5 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 128ZW UT WOS:000076439100019 PM 9794078 ER PT J AU Lubet, RA Steele, VE DeCoster, R Bowden, C You, M Juliana, MM Eto, I Kelloff, GJ Grubbs, CJ AF Lubet, RA Steele, VE DeCoster, R Bowden, C You, M Juliana, MM Eto, I Kelloff, GJ Grubbs, CJ TI Chemopreventive effects of the aromatase inhibitor vorozole (R 83842) in the methylnitrosourea-induced mammary cancer model SO CARCINOGENESIS LA English DT Article ID ADVANCED BREAST-CANCER; GROWTH-FACTOR-I; POSTMENOPAUSAL PATIENTS; TAMOXIFEN; TUMORS; RATS; BIOSYNTHESIS; EXPRESSION; CARCINOGEN; INDUCTION AB The chemopreventive activity of the highly specific non-steroidal aromatase inhibitor, vorozole, was examined in the methylnitrosourea (MNU)-induced rat model of mammary carcinogenesis, Various doses of vorozole (0.08-1.25 mg/kg body wt/day) were administered daily (by gavage) to female Sprague-Dawley rats starting at 43 days of age. Seven days later, the rats were given a single i,v, dose of MNU (50 mg/kg body wt). Rats were continually treated with vorozole until the end of the experiment (120 days post-MNU), Vorozole caused a dose dependent inhibition of mammary cancer multiplicity. The highest dose of vorozole (1.25 mg/kg body wt/day) decreased cancer multiplicity by similar to 90 %, and simultaneously decreased cancer incidence from 100 to 44 %, The next two highest doses of vorozole (0.63 and 0.31 mg/kg body wt/day) inhibited MNU-induced mammary cancer multiplicity by 70-80 %, Even the two lowest doses of vorozole (0.16 and 0.08 mg/kg body wt/day) decreased cancer multiplicity similar to 50%. Serum level determinations were performed on a variety of endpoints at either 4 or 24 h following the last dose of vorozole, Insulin-like growth factor (IGF)-1 levels were slightly, but significantly, increased by vorozole treatment. Vorozole induced striking increases in serum testosterone levels at 4 h at all the dose levels employed. Testosterone levels were significantly elevated over controls at 24 h in rats given the lower doses of vorozole (0.08-0.31 mg/kg body wt/day), but were significantly lower than in rats administered the higher doses of vorozole (0.63 or 1.25 mg/kg body wt/day). This result presumably reflects the limited half-life of vorozole in rats. In a second series of experiments, the effects of limited duration of dosing with vorozole (2.5 mg/kg body wt/day) or intermittent dosing with vorozole were determined. Treatment of rats with vorozole for limited time periods, from 3 days post-MNU administration until 30 or 60 days post-MNU treatment, resulted in significant delays in the time to appearance of palpable cancers. However, these limited treatments did not greatly affect the overall incidence or multiplicity of mammary cancers when compared with the MNU controls at the end of the study (150 days post-MNU), Finally, the effects of intermittent dosing with vorozole (2.5 mg/kg body wt/day) were examined. Rats were administered cycles of vorozole daily for a period of 3 weeks followed by treatment with the vorozole vehicle for the next 3 weeks (total of four cycles). Although this intermittent treatment did inhibit the appearance of new tumors during each of the periods that vorozole was administered, it did not cause regression of palpable cancers. C1 NCI, DCP, EPN 201, Bethesda, MD 20892 USA. Med Coll Ohio, Toledo, OH 43699 USA. Univ Florida, Gainesville, FL 32611 USA. Univ Alabama, Birmingham, AL 35294 USA. RP Lubet, RA (reprint author), NCI, DCP, EPN 201, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM lubetr@dcpcepn.nci.nih.gov FU NCI NIH HHS [CA28103, N01-CN-95156-03] NR 35 TC 31 Z9 31 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 1998 VL 19 IS 8 BP 1345 EP 1351 DI 10.1093/carcin/19.8.1345 PG 7 WC Oncology SC Oncology GA 111TW UT WOS:000075454900004 PM 9744527 ER PT J AU Whyatt, RM Bell, DA Jedrychowski, W Santella, RM Garte, SJ Cosma, G Manchester, DK Young, TL Cooper, TB Ottman, R Perera, FP AF Whyatt, RM Bell, DA Jedrychowski, W Santella, RM Garte, SJ Cosma, G Manchester, DK Young, TL Cooper, TB Ottman, R Perera, FP TI Polycyclic aromatic hydrocarbon-DNA adducts in human placenta and modulation by CYP1A1 induction and genotype SO CARCINOGENESIS LA English DT Article ID LUNG-CANCER PATIENTS; GLUTATHIONE S-TRANSFERASES; CIGARETTE-SMOKE EXPOSURE; MATERNAL SMOKING; CYTOCHROME-P450IA1 GENE; HYDROXYLASE-ACTIVITY; TOBACCO SMOKING; METABOLISM; EXPRESSION; TISSUES AB This study investigated the relationship in human placenta between polycyclic aromatic hydrocabon (PAH)-DNA adduct levels and two biomarkers of cytochrome P4501A1 (CYP1A1): gene induction evidenced by CYP1A1 mRNA, and a genetic polymorphism, the CYP1A1 MspI RFLP. CYP1A1 codes for an inducible enzyme system that catalyzes the bioactivation of PAHs, Prior research found a high correlation in human lung tissue between CYP1A1 activity and DNA damage from PAHs. The CYP1A1 MspI RFLP has been linked in some studies to risk of lung cancer. The relationships in human placenta between DNA damage, CYP1A1 activity and genotype have not been well characterized and may be relevant to risks from transplacental PAH exposure, The study cohort consisted of 70 newborns from Krakow, Poland, a city with elevated air pollution, and 90 newborns from nearby Limanowa, an area with lower air pollution but greater indoor coal use. Contrary to results seen previously in lung tissue, CYP1A1 mRNA was not significantly correlated with PAH-DNA adduct levels in the placenta, Smoking (self-reported maternal and infant plasma cotinine) was significantly associated with CYP1A1 mRNA levels (P < 0.01), but not with PAH-DNA adduct levels. Placental PAH-DNA adduct levels were significantly higher in infants with the CYP1A1 MspI restriction site compared with infants without the restriction site (P < 0.01), implicating a genetic factor in inter-individual variation in DNA damage in human placenta, Further studies are needed to determine the relevance of this finding to risk of transplacental carcinogenesis. C1 Columbia Univ, Sch Publ Hlth, Div Environm Hlth Sci, New York, NY 10032 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Jagiellonian Univ, Coll Med, Krakow, Poland. NYU, Med Ctr, Nelson Inst Environm Med, New York, NY 10016 USA. NYU, Med Ctr, Kaplan Comprehens Canc Ctr, New York, NY 10016 USA. Colorado State Univ, Ft Collins, CO 80523 USA. Childrens Hosp, Dept Genet, Denver, CO 80218 USA. New York State Psychiat Inst, New York, NY 10032 USA. RP Perera, FP (reprint author), Columbia Univ, Sch Publ Hlth, Div Environm Hlth Sci, 60 Haven Ave B-1, New York, NY 10032 USA. RI Ottman, Ruth/O-2371-2013 FU NCI NIH HHS [5RO1CA-39174, 5RO1CA-35809]; NIEHS NIH HHS [1-PO1-ESO5294] NR 50 TC 81 Z9 84 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 1998 VL 19 IS 8 BP 1389 EP 1392 DI 10.1093/carcin/19.8.1389 PG 4 WC Oncology SC Oncology GA 111TW UT WOS:000075454900011 PM 9744534 ER PT J AU Smith, MK Trempus, CS Gilmour, SK AF Smith, MK Trempus, CS Gilmour, SK TI Co-operation between follicular ornithine decarboxylase and v-Ha-ras induces spontaneous papillomas and malignant conversion in transgenic skin SO CARCINOGENESIS LA English DT Article ID MOUSE SKIN; TUMOR PROMOTION; ALPHA-DIFLUOROMETHYLORNITHINE; MULTISTAGE CARCINOGENESIS; EPIDERMAL HYPERPLASIA; RETINOIC ACID; STEM-CELLS; MICE; OVEREXPRESSION; HYPERKERATOSIS AB Ornithine decarboxylase (ODC) is aberrantly regulated in tumor cells and results in high basal levels of ODC and polyamines in many epithelial tumors. To determine if elevated ODC/polyamine levels can co-operate with a mutant Ha-ras gene in mouse skin tumorigenesis, double transgenic mice were generated by breeding K6/ODC transgenic mice with TG,AC v-Ha-ras transgenic mice. A K6 keratin promoter drives the ODC transgene in K6/ODC transgenic mice, which results in elevated ODC/polyamine levels directed to the outer root sheath cells of hair follicles, TG,AC transgenic mice carry a v-aa-ras transgene while still retaining two normal c-aa-ras alleles, Transgenic mice that possess only the K6/ODC or the v-Ha-ras transgene did not develop tumors unless treated with either a carcinogen or a tumor promoter, respectively. However, a high percentage of double transgenic mice possessing both the K6/ODC and v-Ha-ras transgenes developed spontaneous tumors. All tumors were well-differentiated keratoacanthomas, some of which progressed to carcinomas within 2 months. The development and the maintenance of these ODC/ras tumors was ODC-dependent since a-difluoromethylornithine (DFMO), a specific ODC inhibitor, prevented the formation and caused the regression of these tumors. These findings indicate that ODC overexpression and an activated Ha-ras are sufficient to produce a high rate of malignant transformation in an animal model. The ODC/ras double transgenic mouse provides a simple in vivo model without the use of chemical carcinogens or tumor promoters in which to test downstream effecters that play a key role in mediating the development of epithelial tumors resulting from the co-operation between ODC and v-Ha-ras. C1 Lankenau Med Res Ctr, Wynnewood, PA 19096 USA. NIEHS, Lab Environm Carcinogenesis & Mutagenesis, Res Triangle Pk, NC 27709 USA. RP Gilmour, SK (reprint author), Lankenau Med Res Ctr, 100 Lancaster Ave, Wynnewood, PA 19096 USA. EM gilmours@mlhs.org NR 42 TC 69 Z9 70 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 1998 VL 19 IS 8 BP 1409 EP 1415 DI 10.1093/carcin/19.8.1409 PG 7 WC Oncology SC Oncology GA 111TW UT WOS:000075454900014 PM 9744537 ER PT J AU Walker, NJ Miller, BD Kohn, MC Lucier, GW Tritscher, AM AF Walker, NJ Miller, BD Kohn, MC Lucier, GW Tritscher, AM TI Differences in kinetics of induction and reversibility of TCDD-induced changes in cell proliferation and CYP1A1 expression in female Sprague-Dawley rat liver SO CARCINOGENESIS LA English DT Article ID GROWTH-FACTOR RECEPTOR; DOSE-RESPONSE RELATIONSHIPS; TUMOR PROMOTION; GENE-EXPRESSION; CHRONIC EXPOSURE; CANCER RISK; 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN; HEPATOCARCINOGENESIS; INCREASES; MODEL AB 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent tumor promoter in two-stage initiation-promotion models and induces cell proliferation and development of enzyme-altered hepatic foci, It is believed that increased cell proliferation is a necessary step in carcinogenesis, Therefore, the analysis of the effect of TCDD on cell proliferation in rat liver may aid in the understanding of the mechanism of hepatocarcinogenesis induced by TCDD, The aim of this study was to investigate the time course and reversibility of cell proliferation in non-initiated and diethylnitrosamine-initiated female rats exposed biweekly to a daily averaged dose of 125 ng TCDD/kg/day for up to 60 weeks. In addition we evaluated the suitability of different dose metrics for the evaluation of TCDD-induced changes in cell proliferation and CYP1A1 enzyme induction. Cell proliferation was measured as the incorporation of 5-bromo-2' -deoxyuridine (BrdU) into hepatocytes undergoing replicative DNA synthesis. Mean BrdU labeling indices in TCDD-treated animals were not increased over controls after 14 weeks exposure, but were increased 8- and 2-fold after 30 and 60 weeks) treatment respectively, despite similar liver levels of TCDD at all these times (23-30 p.p.b.). In comparison, CYP1A1 activity, as measured by ethoxyresorufin deethylase activity, was significantly induced at all times points analyzed. Sixteen weeks following cessation of TCDD treatment, labeling indices were still significantly elevated over controls, but after 30 weeks of withdrawal, labeling indices were no different from controls, indicating that TCDD-induced changes in cell proliferation were reversible. Dosimetric analysis indicated that rat liver tissue burden was suitable for prediction of CYP1A1 expression but not cell proliferation and that the area under the curve was unsuitable for prediction of both TCDD-induced changes in CYP1A1 expression and cell proliferation. C1 NIEHS, Lab Computat Biol & Risk Anal, Res Triangle Pk, NC 27709 USA. RP Walker, NJ (reprint author), NIEHS, Lab Computat Biol & Risk Anal, POB 12233,111 Alexander Dr,MD D4-01, Res Triangle Pk, NC 27709 USA. RI Walker, Nigel/D-6583-2012 OI Walker, Nigel/0000-0002-9111-6855 NR 41 TC 16 Z9 16 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 1998 VL 19 IS 8 BP 1427 EP 1435 DI 10.1093/carcin/19.8.1427 PG 9 WC Oncology SC Oncology GA 111TW UT WOS:000075454900016 PM 9744539 ER PT J AU Watson, DE Reichert, W Di Giulio, RT AF Watson, DE Reichert, W Di Giulio, RT TI Induction of hepatic CYP1A in channel catfish increases binding of 2-aminoanthracene to DNA in vitro and in vivo SO CARCINOGENESIS LA English DT Article ID FLAVIN-CONTAINING MONOOXYGENASE; PROSTAGLANDIN-H SYNTHASE; P-32 POSTLABELING ASSAY; AROMATIC-AMINES; ADDUCTS; ACTIVATION; RAT; ENHANCEMENT; CELLS; CDNA AB Data are presented from in vitro and in vivo studies that indicate cytochrome P4501A (CYP1A) in channel catfish (Ictalurus punctatus) hepatic tissue activates 2-aminoanthracene (AA) to a reactive metabolite that binds to DNA, Channel catfish were injected i.p. with vehicle or 10 mg/kg beta-naphthoflavone (beta NF) on two consecutive days. Two days after the final injection of vehicle or beta NF, vehicle or [H-3]AA was injected i.p. at 10 mg/kg, creating four different treatments: vehicle only, beta NF only, [H-3]AA only, and beta NF/[H-3]AA, Hepatic tissue was examined for CYP1A-associated ethoxyresorufin-O-de-ethylase (EROD) activity, and for DNA adducts at 1, 2, 4 and 7 days following administration of vehicle or [H-3]AA. Hepatic EROD activity in beta NF-treated fish was 17-fold higher at day 0 and remained significantly greater than untreated animals for the 7-day experiment. Hepatic DNA adducts, as measured by tritium-associated DNA, ranged from 4.8 to 8.6 pmol/mg DNA in vehicle-pretreated fish injected with [H-3]AA, but ranged from 12.6 to 22.7 pmol/mg DNA in beta NF-pretreated fish injected with [H-3]AA, Thus, pretreatment with beta NF significantly increased binding of [H-3]AA to hepatic DNA in vivo at all four times. Analysis by P-32-post-labeling and thin layer chromatography of hepatic DNA from channel catfish treated with AA revealed two major and several minor spots, which are indicative of DNA adduct formation. Hepatic microsomes from beta NF-pretreated fish were more effective at catalysing the binding of [H-3]AA to DNA in vitro than were microsomes from non-treated fish, In addition, binding was decreased by the CYP1A inhibitor 3,3',4,4'-tetrachlorobiphenyl. Collectively, these data demonstrate that CYP1A is involved in the activation of AA in channel catfish. C1 Duke Univ, Ecotoxicol Lab, Nicholas Sch Environm, Durham, NC 27708 USA. NOAA, Natl Marine Fisheries Serv, NW Fisheries Sci Ctr, Environm Conservat Div, Seattle, WA 98112 USA. RP Di Giulio, RT (reprint author), NIEHS, Mail Drop F1-08,POB 12233, Res Triangle Pk, NC 27709 USA. FU NIEHS NIH HHS [T32ES07031-15S1] NR 45 TC 5 Z9 6 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 1998 VL 19 IS 8 BP 1495 EP 1501 DI 10.1093/carcin/19.8.1495 PG 7 WC Oncology SC Oncology GA 111TW UT WOS:000075454900025 PM 9744548 ER PT J AU Arif, JM Gairola, CG Glauert, HP Kelloff, GJ Lubet, RA Gupta, RC AF Arif, JM Gairola, CG Glauert, HP Kelloff, GJ Lubet, RA Gupta, RC TI Inhibition of cigarette smoke-related lipophilic DNA adducts in rat tissues by dietary oltipraz SO CARCINOGENESIS LA English DT Article ID 5-(2-PYRAZINYL)-4-METHYL-1,2-DITHIOL-3-THIONE OLTIPRAZ; INDUCTION; LIVER AB The present study investigated the effects of dietary oltipraz on cigarette smoke-related lipophilic DNA adduct formation. Female Sprague-Dawley rats were exposed daily to sidestream cigarette smoke in a whole-body exposure chamber 6 h/day for 4 consecutive weeks. One group of rats was maintained on control diet while another group received the same diet supplemented with either a low (167 p.p.m.) or high (500 p.p.m.) dose of oltipraz, starting 1 week prior to initiation of smoke exposure until the end of the experiment. Analysis of lipophilic DNA adducts by the nuclease pi-mediated P-32-post-labeling showed up to five smoke-related adducts, Adduct no. 5 predominated in both the lung and the heart while adduct nos 3 and 2 predominated in the trachea and bladder, respectively, Quantitative analysis revealed that the total adduct level was the highest in lungs (270 +/- 68 adducts/10(10) nucleotides), followed by trachea (196 +/- 48 adducts/10(10) nucleotides), heart (141 +/- 22 adducts/10(10) nucleotides) and bladder (85 +/-. 16 adducts/10(10) nucleotides). High dose oltipraz treatment reduced the adduct levels in lungs and bladder by >60%, while the reduction in lungs in the low-dose group was similar to 35%, In trachea, the effect of low and high dietary oltipraz on smoke DNA adduction was equivocal, while smoke-related DNA adducts in the heart were minimally inhibited by high-dose oltipraz, In a repeat experiment that employed a 3-fold lower dose of cigarette smoke, oltipraz (500 p.p.m.) was found to inhibit the formation of DNA adducts in rat lungs and trachea by 80 and 65%, respectively. These data clearly demonstrate a high efficacy of oltipraz in inhibiting the formation of cigarette smoke-induced DNA adducts in the target tissues. C1 Univ Kentucky, Dept Prevent Med & Environm Hlth, Lexington, KY 40536 USA. Univ Kentucky, Tobacco & Hlth Res Inst, Lexington, KY 40536 USA. Univ Kentucky, Dept Nutr & Food Sci, Lexington, KY 40536 USA. NCI, Dept Chemoprevent Invest Branch, Bethesda, MD 20892 USA. RP Gupta, RC (reprint author), Univ Kentucky, Dept Prevent Med & Environm Hlth, 345 Hlth Sci Res Bldg, Lexington, KY 40536 USA. FU NCI NIH HHS [CN-45591] NR 20 TC 14 Z9 14 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 1998 VL 19 IS 8 BP 1515 EP 1517 DI 10.1093/carcin/19.8.1515 PG 3 WC Oncology SC Oncology GA 111TW UT WOS:000075454900028 PM 9744551 ER PT J AU Griffiths, EJ Ocampo, CJ Savage, JS Rutter, GA Hansford, RG Stern, MD Silverman, HS AF Griffiths, EJ Ocampo, CJ Savage, JS Rutter, GA Hansford, RG Stern, MD Silverman, HS TI Mitochondrial calcium transporting pathways during hypoxia and reoxygenation in single rat cardiomyocytes SO CARDIOVASCULAR RESEARCH LA English DT Article DE rat; mitochondria; cardiomyocytes; calcium; hypoxia; ruthenium red; clonazepam; sodium-calcium exchange ID ISOLATED HEART-MITOCHONDRIA; CYTOSOLIC FREE CALCIUM; RUTHENIUM RED; CARDIAC MYOCYTES; 2,3-BUTANEDIONE MONOXIME; METABOLIC INHIBITION; CONTRACTILE FUNCTION; REPERFUSION INJURY; ISCHEMIC-INJURY; FREE CA2+ AB Objective: Mitochondrial [Ca2+]([Ca2+](m)) rises in parallel with cytosolic [Ca2+]([Ca2+](c)) following ATP-depletion rigor contracture induced by hypoxia in isolated cardiomyocytes. We investigated the pathways involved in the hypoxia induced changes in [Ca2+](m) by using known inhibitors of mitochondrial Ca2+ transport, namely ruthenium red, an inhibitor of the Ca2+ uniporter (the normal influx route) and clonazepam, an inhibitor of Na+/Ca2+ exchange, (the normal efflux route). Methods: [Ca2+](m) was determined from indo-1/am loaded rat myocytes where the cytosolic fluorescence signal had been quenched by superfusion with Mn2+. [Ca2+](c) was measured by loading myocytes with indo-1 pentapotassium salt during the isolation procedure. Cells were placed in a specially developed chamber for induction of hypoxia and reoxygenated 40 min after rigor development. Results: 50% of control cells hypercontracted upon reoxygenation; this correlated with a [Ca2+](m) or [Ca2+](c) higher than approximately 350 nM at the end of rigor. Clonazepam completely abolished the rigor-induced rise in [Ca2+](m) but not [Ca2+](c). On reoxygenation [Ca2+](m) increased over the first 5 min and remained elevated whereas [Ca2+](c) fell. In the presence of ruthenium red a dramatic increase in [Ca2+](m) occurred 5-10 min after rigor development (the indo-1 fluorescence signal was saturated); [Ca2+](c) also increased but to a lesser extent. On reoxygenation, [Ca2+](m) fell rapidly even though cells hypercontracted and [Ca2+](c) remained elevated. Conclusions: During hypoxia following rigor development Ca2+ uptake into mitochondria occurs largely via the Na+ /Ca2+ exchanger rather than the Ca2+ uniporter whereas on reoxygenation the transporters resume their normal directionality. (C) 1998 Elsevier Science B.V. All rights reserved. C1 Univ Bristol, Bristol Royal Infirm, Bristol Heart Inst, Dept Cardiac Surg, Bristol BS2 8HW, Avon, England. Johns Hopkins Univ Hosp, Div Cardiol, Baltimore, MD 21205 USA. Univ Bristol, Dept Biochem, Bristol BS8 1TD, Avon, England. NIH, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. RP Griffiths, EJ (reprint author), Univ Bristol, Bristol Royal Infirm, Bristol Heart Inst, Dept Cardiac Surg, Level 7, Bristol BS2 8HW, Avon, England. EM elinor.griffiths@bristol.ac.uk NR 57 TC 79 Z9 89 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD AUG PY 1998 VL 39 IS 2 BP 423 EP 433 DI 10.1016/S0008-6363(98)00104-7 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 105ZE UT WOS:000075104600019 PM 9798527 ER PT J AU Rosenberg, HF AF Rosenberg, HF TI The eosinophil ribonucleases SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE eosinophils; host defence; primates; rodents; evolution ID RESPIRATORY SYNCYTIAL VIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; GRANULE CATIONIC PROTEINS; LEUKEMIC MYELOID CELLS; AMINO-ACID SEQUENCE; MAJOR BASIC-PROTEIN; DOUBLE-STRANDED-RNA; MOLECULAR-CLONING; GENE FAMILY; PANCREATIC-TYPE AB The eosinophil ribonucleases, eosinophil-derived neurotoxin (EDN/RNase 2) and eosinophil cationic protein (ECP/RNase 3) are two closely related proteins with intriguing functional and evolutionary properties. While both EDN and ECP maintain the structural and catalytic residues typical of the RNase A superfamily, the role of ribonuclease activity in the physiologic function of these proteins remains unclear. The biochemistry and physiology of EDN, ECP and the recently discovered ribonuclease k6 (RNase 6) will be reviewed in this chapter. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Rosenberg, HF (reprint author), NIAID, Host Def Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 95 TC 62 Z9 64 U1 0 U2 1 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 AUG PY 1998 VL 54 IS 8 BP 795 EP 803 DI 10.1007/s000180050208 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 116CQ UT WOS:000075706400005 PM 9760988 ER PT J AU Bergmann-Leitner, ES Kantor, JA Shupert, WL Schlom, J Abrams, SI AF Bergmann-Leitner, ES Kantor, JA Shupert, WL Schlom, J Abrams, SI TI Identification of a human CD8(+) T lymphocyte neo-epitope created by a ras codon 12 mutation which is restricted by the HLA-A2 allele SO CELLULAR IMMUNOLOGY LA English DT Article DE CD8(+) cytotoxic T lymphocytes; ras oncogenes; tumor immunity; neo-epitopes; HLA-A2 restriction ID TUMOR-ASSOCIATED GLYCOPROTEIN-72; MUTANT P21 RAS; K-RAS; CARCINOEMBRYONIC ANTIGEN; CARCINOMA PATIENTS; CELL RESPONSES; IN-VIVO; INFILTRATING LYMPHOCYTES; OVERLAPPING EPITOPES; COLORECTAL-CARCINOMA AB Point mutations in the ras proto-oncogenes, notably at codon 12, are found in a high frequency of human malignancies and, thus, may be appropriate targets for the induction of tumor-specific T cell responses in cancer immunotherapy. In this study, we examined the mutant ras protein sequence reflecting the substitution of Gly to Val at position 12 as a putative point-mutated determinant for potential induction of an HLA-A2-reactive, CD8(+) cytotoxic T lymphocyte (CTL) response. We identified the ras 4-12(Val12) sequence as a minimal 9-mer peptide, which displayed specific binding to HLA-A2 by T2 bioassays. Peptide binding to HLA-A2 on T2 cells was weak and required coincaubation with exogenous beta(2)-microglobulin to facilitate and enhance complex formation. In contrast, the wild-type ras 4-12(Gly12) peptide failed to bind to HLA-A2 even in the presence of beta(2)-microglobulin, consistent with the hypothesis that the point mutation creates a C-terminus anchor residue. A CD8(+) CTL line against the ras 4-12(Val12) peptide was derived in vitro from a normal HLA-A2(+) donor using a model culture system consisting of T2 cells as antigen presenting cells pulsed with exogenous mutant ras peptide and beta(2)-microglobulin plus cytokines (interleukin-2 and 12). Functional characterization of the CD8(+) CTL line revealed: (1) peptide-specific and HLA-A2-restricted cytotoxicity against a panel of peptide-pulsed targets; (2) no specific lysis using the normal ras peptide sequence; (3) half-maximal lysis with exogenous peptide of similar to 0.3 mu M; (4) lysis of HLA-A2(+) B cell lines infected with a recombinant vaccinia virus construct encoding the point-mutated human K-ras gene; and (5) specific lysis of the HLA-A2(+) SW480 colon carcinoma cell line expressing the naturally occurring K-ras Val12 mutation. Maximal lysis of SW480 cells occurred following interferon (IFN)-gamma pretreatment, which correlated with enhanced HLA-A2 and ICAM-1 (CD54) expression. Specificity of lysis was revealed by the absence of lysis against a HLA-A2(+) melanoma cell line (+/-IFN-gamma), which lacked the mutant Val12 mutation, and the inability of an irrelevant CD8(+) CTL line to lyse SW480 (+/-IFN-gamma) unless the appropriate exogenous peptide was added. These findings demonstrated that tumor cells may endogenously process and express mutant ras epitopes, such as the 4-12(Val12) sequence, albeit in limiting amounts that may be potentiated by IFN-gamma treatment. These data support the biological relevance of this sequence and, thus, may have important implications for the generation of ras oncogene-specific CTL responses in clinical situations. C1 NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, NIH, Bldg 10,Room 8B07,10 Ctr Dr, Bethesda, MD 20892 USA. EM js141c@nih.gov RI Bergmann-Leitner, Elke/B-3548-2011 OI Bergmann-Leitner, Elke/0000-0002-8571-8956 NR 69 TC 21 Z9 23 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0008-8749 J9 CELL IMMUNOL JI Cell. Immunol. PD AUG 1 PY 1998 VL 187 IS 2 BP 103 EP 116 DI 10.1006/cimm.1998.1325 PG 14 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 117NG UT WOS:000075787500004 PM 9732698 ER PT J AU Mao, Y Moore, RJ Wagnon, KB Pierce, JT Debban, KH Smith, CS Dill, JA Fuciarelli, AF AF Mao, Y Moore, RJ Wagnon, KB Pierce, JT Debban, KH Smith, CS Dill, JA Fuciarelli, AF TI Analysis of alpha(2u)-globulin in rat urine and kidneys by liquid chromatography-electrospray ionization mass spectrometry SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID RENAL-CELL PROLIFERATION; TERT-BUTYL ETHER; ALPHA-2U-GLOBULIN NEPHROPATHY; UNLEADED GASOLINE; NONCOVALENT INTERACTIONS; FISCHER-344 RATS; RISK ASSESSMENT; PROTEIN; DECALIN; BINDING AB A quantitative method was developed for determination of alpha(2u)-globulin in urine and kidney samples collected from male rats using liquid chromatography-electrospray ionization mass spectrometry (LC-ESI/MS). Samples prepared from urine and kidney homogenates using size exclusion filters were subject to reversed-phase liquid chromatography and the effluent passed into an electrospray ionization source. Quantitative analysis using external standard calibration was based upon selected ion monitoring of protonated molecular ions by the mass spectrometer. Linear calibration curves were developed over the range of similar to 4.6-370 mu g of alpha(2u)-globulin/mu l for spiked urine standards and over the range of similar to 4.6-550 mu g of alpha(2u)-globulin/mu L for spiked kidney standards. The precision (relative standard deviation) for repeated injection (using urine samples) and intra-assay precision (using both urine and kidney samples) were within +/-10.4% and +/-13.2%, respectively. Using spiked urine standards, inter-assay precision, intra-assay accuracy, and inter-assay accuracy were within +/-20%, +/-20%, and +/-15%, respectively. Using spiked kidney standards, intra-assay accuracy was within +/-15%. The limits of detection (LOD) for the determination of alpha(2u)-globulin in urine and kidney samples were similar to 0.41 pg/nL (1.0 fmol injected) and 25 pg/nL (similar to 13 fmol injected), respectively. The limits of quantitation (LOQ) for determination of alpha(2u)-globulin in urine and kidney samples were calculated as 1.4 pg/nL (3.7 fmol injected) and 83 pg/nL (45 fmol injected), respectively. Applicability of the LC-ESI/MS method was demonstrated by determination of alpha(2u)-globulin in both urine and kidney samples collected from male Fischer 344/N rats dosed intravenously with cis-Decalin at concentrations of 0, 2.5, 5.0, 10, and 20 mg/kg. A dose-dependent relationship was found between the amount of cis-Decalin administered and alpha(2u)-globulin accumulation in kidney samples, whereas no significant change in the urinary levels of alpha(2u)-globulin occurred. These observations are consistent with excessive accumulation of alpha(2u)-globulin occurring in protein droplets in renal proximal tubule epithelial cells as a result of decreased catabolic activity due to formation of ligand-protein complexs with Decalin and its metabolite(s). This report demonstrates that LC-ESI/MS may be routinely applied for quantitative analysis of alpha(2u)-globulin in rat urine and kidney samples to address alpha(2u)-globulin accumulation and its role in the development of nephrotoxicity associated with chemical exposures. C1 Battelle Preclin Drug Dev NW Operat, Toxicokinet & Bioanalyt Chem Tech Ctr, Richland, WA 99352 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Fuciarelli, AF (reprint author), Battelle Preclin Drug Dev NW Operat, Toxicokinet & Bioanalyt Chem Tech Ctr, Richland, WA 99352 USA. NR 48 TC 10 Z9 10 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD AUG PY 1998 VL 11 IS 8 BP 953 EP 961 DI 10.1021/tx9800405 PG 9 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 112EW UT WOS:000075482000014 PM 9705758 ER PT J AU Keefer, LK AF Keefer, LK TI Nitric oxide-releasing compounds: From basic research to promising drugs SO CHEMTECH LA English DT Article ID CONTROLLED BIOLOGICAL RELEASE; IN-VITRO; COMPLEXES; AGENTS; DONOR; NUCLEOPHILES; INHIBITION; VIVO; NO; PROLIFERATION AB By attaching the anionic [N(O)NO](-) functional group to various carrier molecules, new biomedical research tools that spontaneously generate bioactive NO at physiological pH have been made possible. C1 NCI, Frederick Canc Res & Dev Ctr, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. RP Keefer, LK (reprint author), NCI, Frederick Canc Res & Dev Ctr, Comparat Carcinogenesis Lab, Bldg 538, Frederick, MD 21702 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 NR 39 TC 55 Z9 56 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0009-2703 J9 CHEMTECH JI Chemtech PD AUG PY 1998 VL 28 IS 8 BP 30 EP 35 PG 6 WC Chemistry, Applied SC Chemistry GA 109FF UT WOS:000075310000009 ER PT J AU Meduri, GU Chrousos, GP AF Meduri, GU Chrousos, GP TI Duration of glucocorticoid treatment and outcome in sepsis - Is the right drug used the wrong way? SO CHEST LA English DT Editorial Material ID RESPIRATORY-DISTRESS SYNDROME; RECEPTOR-BINDING AFFINITY; HIGH-DOSE CORTICOSTEROIDS; ACUTE LUNG DAMAGE; SEPTIC SHOCK; KAPPA-B; INFLAMMATORY RESPONSE; PULMONARY FIBROSIS; ARDS; MORTALITY C1 Univ Tennessee, Div Pulm & Crit Care Med, Memphis, TN 38163 USA. Vet Affairs Med Ctr, Memphis, TN USA. NICHHD, Sect Pediat Endocrinol, NIH, Bethesda, MD 20892 USA. RP Meduri, GU (reprint author), Univ Tennessee, Div Pulm & Crit Care Med, Memphis, TN 38163 USA. NR 52 TC 36 Z9 40 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD AUG PY 1998 VL 114 IS 2 BP 355 EP 360 DI 10.1378/chest.114.2.355-a PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 110ER UT WOS:000075367700004 PM 9726712 ER PT J AU Movsas, B Teruya-Feldstein, J Smith, J Glatstein, E Epstein, AH AF Movsas, B Teruya-Feldstein, J Smith, J Glatstein, E Epstein, AH TI Primary cardiac sarcoma - A novel treatment approach SO CHEST LA English DT Article DE cardiac sarcoma; hyperfractionation; radiosensitization; radiotherapy AB Primary cardiac sarcomas carry a dismal prognosis with no known curative therapy using standard treatment approaches. By its very location, the possibility of a radical complete resection-the underlying principle in the management of any soft-tissue sarcoma-is precluded. While literally in a continuous "blood bath," cardiac sarcomas are associated with a very high rate of hematogenous metastases. This report describes the management of a case in a 51-year-old white man with a high-grade unresectable cardiac sarcoma who was treated with hyperfractionated (twice daily) radiotherapy to a total dose of 7,050 eGy along with a radiosensitizer, (5'-iodode-oxyuridipne. The patient currently is disease-free and functioning well more than 5 years following this novel treatment approach. C1 Fox Chase Canc Ctr, Dept Radiat Oncol, Philadelphia, PA 19111 USA. Hosp Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Dept Radiat Oncol, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Radiol & Nucl Med, Bethesda, MD 20814 USA. RP Movsas, B (reprint author), Fox Chase Canc Ctr, Dept Radiat Oncol, 7701 Burholme Ave, Philadelphia, PA 19111 USA. NR 6 TC 16 Z9 18 U1 0 U2 1 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD AUG PY 1998 VL 114 IS 2 BP 648 EP 652 DI 10.1378/chest.114.2.648 PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 110ER UT WOS:000075367700056 PM 9726764 ER PT J AU Lamb, ME Sternberg, KJ Esplin, PW AF Lamb, ME Sternberg, KJ Esplin, PW TI Conducting investigative interviews of alleged sexual abuse victims SO CHILD ABUSE & NEGLECT LA English DT Article ID UTTERANCE TYPES; SUGGESTIBILITY; STATEMENTS; WITNESSES; VALIDITY; CHILDREN AB Objectives: There were two aims: First, to describe the factors that influence children's competence and second, to discuss ways in which investigative interviewers can maximize the quality and quantity of information they obtain from alleged witnesses and victims. Method: No new research is described in this paper. Rather, the authors provide a focused review of the relevant literature designed to be maximally useful for practitioners. Conclusions: Children are often the only available sources of information about possible abusive experiences. Research has shown that children can, in fact, be remarkably competent informants, although the quality and quantity of the information they provide is greatly influenced by the ways in which they are interviewed. This article describes ways in which investigative interviewers can maximize the amount and quality of information they elicit from alleged victims. (C) 1998 Elsevier Science Ltd. C1 NICHHD, Sect Social & Emot Dev, Bethesda, MD 20814 USA. RP Lamb, ME (reprint author), NICHHD, Sect Social & Emot Dev, 9190 Rockville Pike, Bethesda, MD 20814 USA. NR 41 TC 60 Z9 61 U1 1 U2 5 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 AUG PY 1998 VL 22 IS 8 BP 813 EP 823 DI 10.1016/S0145-2134(98)00056-8 PG 11 WC Family Studies; Psychology, Social; Social Work SC Family Studies; Psychology; Social Work GA 101YU UT WOS:000074896900007 PM 9717618 ER PT J CA NICHD Early Child Care Res Network TI Early child care and self-control, compliance, and problem behavior at twenty-four and thirty-six months SO CHILD DEVELOPMENT LA English DT Article ID INFANT DAY-CARE; NATIONAL LONGITUDINAL SURVEY; MATERNAL EMPLOYMENT; FAMILY-INTERACTION; SOCIAL-DEVELOPMENT; HOME CARE; QUALITY; MOTHER; COMPETENCE; TEMPERAMENT AB To evaluate child-care effects on young children's self-control, compliance, and problem behavior, children enrolled in the NICHD Study of Early Child Care were tested and observed in the laboratory and in child care at 24 and 36 months, and mothers and caregivers completed questionnaires. Indicators of child-care quantity, quality, stability, type, and age of entry, along with measures of family background, mothering, and child characteristics obtained through the first 3 years of Life were used to predict 2 and 3 year child functioning. Results revealed (1) mothering to be a stronger and more consistent predictor of child outcomes than child care; (2) Little evidence that early, extensive, and continuous care was related to problematic child behavior, in contrast to results from earlier work; (3) that among the child-care predictors, child-care quality was the most consistent predictor of child functioning, although limited variance could be explained by any (or all) child-care variables; and (4) that virtually none of the anticipated interactions among child-care factors or between them and family or child measures proved significant. C1 NICHD, Publ Informat & Commun Branch, Bethesda, MD 20892 USA. RP NICHD, Publ Informat & Commun Branch, Bldg 31,2A32,31 Ctr Dr,MSC 2425, Bethesda, MD 20892 USA. NR 72 TC 0 Z9 0 U1 2 U2 14 PU BLACKWELL PUBLISHERS PI MALDEN PA 350 MAIN STREET, STE 6, MALDEN, MA 02148 USA SN 0009-3920 J9 CHILD DEV JI Child Dev. PD AUG PY 1998 VL 69 IS 4 BP 1145 EP 1170 PG 26 WC Psychology, Educational; Psychology, Developmental SC Psychology GA 122KG UT WOS:000076070300018 ER PT J AU Kroll, MH Chesler, R AF Kroll, MH Chesler, R TI The nonlinearity seen for LDL-cholesterol with lyophilized material is a matrix effect SO CLINICAL CHEMISTRY LA English DT Letter C1 Johns Hopkins Univ, Sch Med, Dept Pathol, Div Clin Chem, Baltimore, MD 21287 USA. NIH, Dept Clin Pathol, Clin Chem Serv, Ctr Clin, Bethesda, MD 20892 USA. RP Kroll, MH (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Div Clin Chem, 600 N Wolfe St,Meyer B-125, Baltimore, MD 21287 USA. NR 6 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 AUG PY 1998 VL 44 IS 8 BP 1770 EP 1771 PG 2 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 107QW UT WOS:000075221600035 PM 9702977 ER PT J AU Satoh, T Brown, LM Blattner, WA Maloney, EM Kurman, CC Nelson, DL Fuchs, D Wachter, H Tollerud, DJ AF Satoh, T Brown, LM Blattner, WA Maloney, EM Kurman, CC Nelson, DL Fuchs, D Wachter, H Tollerud, DJ TI Serum neopterin, beta(2)-microglobulin, soluble interleukin-2 receptors, and immunoglobulin levels in healthy adolescents SO CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY LA English DT Article DE neopterin; beta(2)-microglobulin; soluble interleukin-2 receptors; age; race; gender ID T-CELL SUBSETS; CLINICAL-APPLICATION; HIV-1 INFECTION; MARKERS; ACTIVATION; BETA-2-MICROGLOBULIN; TRANSPLANTATION; PROGNOSIS; DISEASES; INVITRO AB Serum biomarkers, such as neopterin, beta(2)-microglobulin (B2M), and soluble interleukin-a receptors (sIL-2R), are elevated in viral infections, including HIV-1 infection, and in inflammatory conditions, autoimmune disease, and malignancies. For many of these conditions, serum levels correlate with disease activity. Application of these biomarkers in adolescents is limited by a lack of information on the range and determinants of variability (age, sex, race) for serum levels of these important molecules in this age group. To address this question, we analyzed serum samples from a well-characterized heterogeneous population of 111 healthy adolescents. White children had significantly higher serum levels of sIL-2R and IgM and lower levels of IgG: (P less than or equal to 0.001) than black children. Boys had higher sIL-2R and B2M levels (P < 0.005) and lower IgM levels (P < 0.05) than girls. No significant age effect on B2M or neopterin level was observed over the age range of 12-19 years included in this analysis. However, stratification by race showed that serum sIL-2R level was significantly associated with age among whites, but not among blacks. Values of these biomarkers in this population are compared with age-stratified values in the previously analyzed 20- to 69-year-old population from whose households the adolescent subjects were recruited. (C) 1998 Academic Press. C1 Univ Pittsburgh, Grad Sch Publ Hlth, Dept Environm & Occupat Hlth, Pittsburgh, PA 15260 USA. Allegheny Univ Hlth Sci, Sch Publ Hlth, Ctr Environm & Occupat Hlth, Philadelphia, PA 19102 USA. NCI, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. NCI, Metab Branch, Bethesda, MD 20892 USA. Univ Innsbruck, Inst Med Chem & Biochem, A-6020 Innsbruck, Austria. RP Allegheny Univ Hlth Sci, Sch Publ Hlth, Ctr Environm & Occupat Hlth, 1505 Race St,Mail Stop 660,Bellet Bldg,11th Floor, Philadelphia, PA 19102 USA. NR 40 TC 12 Z9 12 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-1229 J9 CLIN IMMUNOL IMMUNOP JI Clin. Immunol. Immunopathol. PD AUG PY 1998 VL 88 IS 2 BP 176 EP 182 DI 10.1006/clin.1998.4568 PG 7 WC Immunology; Pathology SC Immunology; Pathology GA 116UM UT WOS:000075743400007 PM 9714695 ER PT J AU Hospenthal, DR Bennett, JE AF Hospenthal, DR Bennett, JE TI Flucytosine monotherapy for cryptococcosis SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID AMPHOTERICIN-B; 5-FLUOROCYTOSINE; MENINGITIS; NEOFORMANS; EXPERIENCE; MYCOSES AB Flucytosine (5-FC) monotherapy for cryptococcosis is not advocated because drug resistance emerges during therapy. Reported documentation of this widely accepted belief is surprisingly scarce. Therefore, we reviewed our experience with 5-FC monotherapy for 27 patients treated between 1968 and 1973. Patients were selected on the basis of criteria associated with good prognosis. In this group, 5-FC monotherapy resulted in cure in eight cases and improvement in two. Overall, response was seen in 10 (43%) of 23 evaluable patients. Therapy failed for 13 patients, including 5 who relapsed, 2 who had partial responses, and 6 without response. Resistance was noted to have developed in isolates from six (50%) of 12 patients for whom therapy failed. Although the 57% failure rate associated with 5-FC alone precludes its use as monotherapy, our study did show that this treatment was well tolerated and that failure was not invariably associated with development of resistance. C1 NIAID, Clin Mycol Sect, LCI, NIH, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Infect Dis Serv, Washington, DC 20307 USA. RP Hospenthal, DR (reprint author), NIAID, Clin Mycol Sect, LCI, NIH, Bldg 10,Room 11C304,10 Ctr Dr MSC1882, Bethesda, MD 20892 USA. NR 24 TC 28 Z9 29 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG PY 1998 VL 27 IS 2 BP 260 EP 264 DI 10.1086/514669 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 108VB UT WOS:000075285400005 PM 9709874 ER PT J AU Bolla, KI Gray, S Resnick, SM Galante, R Kawas, C AF Bolla, KI Gray, S Resnick, SM Galante, R Kawas, C TI Category and letter fluency in highly educated older adults SO CLINICAL NEUROPSYCHOLOGIST LA English DT Article ID VERBAL FLUENCY; ALZHEIMER-TYPE; DEMENTIA AB Performance on letter and category fluency was studied in a group of 478 healthy, highly intelligent and educated, older adults (aged 55 to 94 years). The aim of the study was to determine and contrast the effects of age, sex, and intelligence (estimated by the NAART) on letter (FAS) and category (fruits, animal, vegetables) verbal fluency performance. Significant effects were found for age and NAART error score on all fluency scores. However, these effects were small in magnitude. The NAART was found to be a better predictor of verbal fluency scores than education. The relative sensitivity of letter and category fluency to age was not significantly different. Sex was related to performance for the categories of fruits and vegetables, with women outperforming men. Separate mean values for fluency measures are provided for different ages, NAART error scores, educational level, and sex. C1 Johns Hopkins Univ, Bayview Med Ctr, Dept Neurol, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Baltimore, MD USA. NIA, Lab Personal & Cognit, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Bolla, KI (reprint author), Johns Hopkins Univ, Bayview Med Ctr, Dept Neurol, Baltimore, MD 21224 USA. NR 22 TC 31 Z9 31 U1 0 U2 2 PU SWETS ZEITLINGER PUBLISHERS PI LISSE PA P O BOX 825, 2160 SZ LISSE, NETHERLANDS SN 0920-1637 J9 CLIN NEUROPSYCHOL JI Clin. Neuropsychol. PD AUG PY 1998 VL 12 IS 3 BP 330 EP 338 DI 10.1076/clin.12.3.330.1986 PG 9 WC Psychology, Clinical; Clinical Neurology; Psychology SC Psychology; Neurosciences & Neurology GA 153UR UT WOS:000077851600005 ER PT J AU Wiggins, JS AF Wiggins, JS TI Clinical versus statistical prediction: A theoretical analysis and a review of the evidence SO CONTEMPORARY PSYCHOLOGY LA English DT Book Review C1 NIA, Bethesda, MD 20892 USA. Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. RP Wiggins, JS (reprint author), NIA, Bethesda, MD 20892 USA. NR 8 TC 0 Z9 0 U1 0 U2 2 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0010-7549 J9 CONTEMP PSYCHOL JI Comtemp. Psychol. PD AUG PY 1998 VL 43 IS 8 BP 548 EP 549 PG 2 WC Psychology, Multidisciplinary SC Psychology GA 106NZ UT WOS:000075136900009 ER PT J AU Reel, JR Hild-Petito, S Blye, RP AF Reel, JR Hild-Petito, S Blye, RP TI Antiovulatory and postcoital antifertility activity of the antiprogestin CDB-2914 when administered as single, multiple, or continuous doses to rats SO CONTRACEPTION LA English DT Article; Proceedings Paper CT 29th Annual Meeting of the Society-for-the-Study-of-Reproduction CY JUL 27-30, 1996 CL UNIV WESTERN ONTARIO, LONDON, CANADA SP Soc Study Reprod HO UNIV WESTERN ONTARIO DE antagonist; contraception; endometrium; anti-implantation ID EARLY LUTEAL-PHASE; PROGESTERONE ANTAGONIST RU-486; ANTI-IMPLANTATION ACTIVITY; ENDOMETRIAL MATURATION; MIFEPRISTONE RU-486; RECEPTOR-BINDING; MENSTRUAL-CYCLE; RHESUS-MONKEY; RU486; CONTRACEPTION AB The present studies in rats were undertaken to investigate the potential of a new antiprogestin, CDB-2914, for use as an emergency postcoital contraceptive for women. When given orally at noon on the day of proestrus, both CDB-2914 and mifepristone displayed dose-dependent antiovulatory activity; however, CDB-2914 was about eight times more potent than mifepristone. Both antiprogestins were considerably less potent in blocking ovulation when injected subcutaneously. To evaluate antifertility activity during continuous low dose administration, rats were dosed orally with 0.5 mg of either CDB-2914 or mifepris tone daily, commencing on the day of estrus and continuing for 24 days. Females were cohabited with proven fertile males on day 8 of treatment and were removed 1-3 days later after confirmed mating. The pregnancy rate was significantly reduced (p <0.05) only in the CDB-2914-treated females; however, the mean number of normal implantation sites per pregnant rat was significantly reduced (p <0.05) by mifepristone as compared with the vehicle control group. CDB-2914 was also found to prevent pregnancy when administered orally after mating from days 0-3 during tubal egg transport, or from days 4-6 during the pre- and peri-implantation periods. To determine the day of maximal sensitivity to CDB-2914, a single 2-mg dose per rat was given orally on days 0, 1, 2, 3, 4 or 5 postmating. This dose of CDB-2914 was without effect on pregnancy at days 0, 1, 2, or 3 postmating. In contrast, 2 mg CDB-2914 per rat was highly effective in blocking pregnancy when given on either day 4 or 5 postmating. Collectively, these data demonstrate that CDB-2914 is an orally active postcoital antifertility agent that is more potent than mifepristone in the rat. Hence, CDB-2914 may prove to be an effective emergency postcoital contraceptive in women. (C) 1998 Elsevier Science Inc. All rights reserved. C1 BIOQUAL Inc, Rockville, MD 20852 USA. NICHHD, Populat Res Ctr, Contracept & Reprod Hlth Branch, NIH, Rockville, MD USA. RP Reel, JR (reprint author), BIOQUAL Inc, 9600 Med Ctr Dr, Rockville, MD 20852 USA. FU NICHD NIH HHS [N01-HD-6-3259] NR 36 TC 25 Z9 25 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0010-7824 J9 CONTRACEPTION JI Contraception PD AUG PY 1998 VL 58 IS 2 BP 129 EP 136 DI 10.1016/S0010-7824(98)00067-5 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 119UW UT WOS:000075917100009 PM 9773268 ER PT J AU Gail, MH You, WC Chang, YS Zhang, L Blot, WJ Brown, LM Groves, FD Heinrich, JP Hu, J Jin, ML Li, JY Liu, WD Ma, JL Mark, SD Rabkin, CS Fraumeni, JF Xu, GW AF Gail, MH You, WC Chang, YS Zhang, L Blot, WJ Brown, LM Groves, FD Heinrich, JP Hu, J Jin, ML Li, JY Liu, WD Ma, JL Mark, SD Rabkin, CS Fraumeni, JF Xu, GW TI Factorial trial of three interventions to reduce the progression of precancerous gastric lesions in shandong, China: Design issues and initial data SO CONTROLLED CLINICAL TRIALS LA English DT Article DE stomach neoplasms; Helicobacter pylori; ascorbic acid; vitamin C; vitamin E; selenium; garlic; precancerous lesions; factorial intervention studies ID HELICOBACTER-PYLORI INFECTION; HIGH-RISK; CARDIOVASCULAR-DISEASE; CLINICAL-TRIALS; STOMACH-CANCER; BETA-CAROTENE; SUPPLEMENTATION; POPULATION; CARCINOMA; ASSOCIATION AB In the fall of 1995, 3411 subjects in 13 rural villages in Linqu County, Shandong Province, China, began participating in a blinded, randomized 2(3) factorial trial to determine whether interventions can reduce the prevalence of dysplasia and other precancerous gastric lesions. One intervention is treatment for infection by Helicobacter pylori with amoxicillin and omeprazole. A second is dietary supplementation with capsules containing vitamin C, vitamin E, and selenium. A third is dietary supplementation with capsules containing steam-distilled garlic oil and Kyolic aged garlic extract. Investigators will evaluate histopathologic endpoints after gastroscopies with biopsies from seven standard sites in 1999. Initial data from pill counts and sampled blood levels of vitamin E, vitamin C, and S-allylcysteine indicate excellent compliance. Subjects have tolerated all interventions well, although 3.1% of those assigned to amoxicillin and omeprazole developed rashes, compared to 0.3% to those in the control group. Preliminary breath tests demonstrate substantial reductions in gastric urease activity, an indication of infection by Helicobacter pylori, among those assigned to amoxicillin and omeprazole. (C) Elsevier Science Inc. 1998. C1 NCI, Biostat Branch, Div Canc Epidmiol & Genet, Bethesda, MD 20892 USA. Beijing Inst Canc Res, Beijing, Peoples R China. RP Gail, MH (reprint author), NCI, Biostat Branch, Div Canc Epidmiol & Genet, 6130 Execut Plaza N,EPN431, Bethesda, MD 20892 USA. NR 40 TC 48 Z9 52 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD AUG PY 1998 VL 19 IS 4 BP 352 EP 369 DI 10.1016/S0197-2456(98)00016-6 PG 18 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA ZZ971 UT WOS:000074787800004 PM 9683311 ER PT J AU Feldman, HA Proschan, MA Murray, DM Goff, DC Stylianou, M Dulberg, E McGovern, PG Chan, WY Mann, NC Bittner, V AF Feldman, HA Proschan, MA Murray, DM Goff, DC Stylianou, M Dulberg, E McGovern, PG Chan, WY Mann, NC Bittner, V TI Statistical design of REACT (Rapid Early Action for Coronary Treatment), a multisite community trial with continual data collection SO CONTROLLED CLINICAL TRIALS LA English DT Article DE community trial design; community intervention; multisite trials; surveillance studies; two-stage analytic methods; random coefficients analysis; power analysis; emergency medicine; health promotion ID CLUSTER RANDOMIZATION; MYOCARDIAL-INFARCTION; THROMBOLYTIC THERAPY; INTERVENTION TRIALS; PREVENTION; ISSUES AB Unusual problems in statistical design were faced by Rapid Early Action for Coronary Treatment (REACT), a multisite trial testing a community intervention to reduce the delay between onset of symptoms of acute myocardial infarction (MI) and patients' arrival at a hospital emergency department. Ln 20 pair-matched U.S. communities, hospital staff members recorded delay time throughout a 4-month baseline period and the subsequent 18-month intervention period, during which one randomly selected community of each pair received a campaign of public and professional education. To exploit the continual nature of its data-collection protocol, REACT estimated the trend of delay time separately in each community by Linear regression, adjusting for age, sex, and history of MI, and compared the ten adjusted slopes from intervention communities with those from control communities by a paired I-test. Power calculations based on the analytical model showed that with K = 600-800 cases per community, REACT would have 80% power to demonstrate a differential reduction of 30 min in mean delay time between intervention and control communities, as well as effects on a variety of secondary outcomes. Sensitivity analysis confirmed that the number of communities' was optimal within constraints of funding and that the detectable effect depended weakly on the effectiveness of matching but strongly on K, helping the investigators set operational priorities. The methodologic strategy developed for REACT should prove useful in the design of similar trials in the future. (C) Elsevier Science Inc. 1998. C1 New England Res Inst, Watertown, MA 02172 USA. NHLBI, Bethesda, MD 20892 USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. Univ Texas, Sch Publ Hlth, Houston, TX USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. King Cty Dept Emergency Med Serv, Seattle, WA USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. Univ Alabama, Sch Med, Birmingham, AL USA. RP Feldman, HA (reprint author), New England Res Inst, 9 Galen St, Watertown, MA 02172 USA. FU NHLBI NIH HHS [HL-53149, HL-53155, HL-53142] NR 28 TC 25 Z9 25 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD AUG PY 1998 VL 19 IS 4 BP 391 EP 403 DI 10.1016/S0197-2456(98)00014-2 PG 13 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA ZZ971 UT WOS:000074787800006 PM 9683313 ER PT J AU Charukamnoetkanok, P Fukushima, A Whitcup, SM Gery, I Egwuagu, CE AF Charukamnoetkanok, P Fukushima, A Whitcup, SM Gery, I Egwuagu, CE TI Expression of ocular autoantigens in the mouse thymus SO CURRENT EYE RESEARCH LA English DT Article DE immunotolerance; ocular-specific autoantigens; RT-PCR; thymic expression of antigens; mouse ID ALPHA-A-CRYSTALLIN; EXPERIMENTAL AUTOIMMUNE UVEORETINITIS; RETINOID-BINDING PROTEIN; EVOLUTIONARY RELATIONSHIPS; S-ANTIGEN; GENE; PINEALITIS; SELECTION; TISSUES; OPSIN AB Purpose. The occurrence of eye diseases of autoimmune nature. as well as experimental models of the:ie diseases, has been attributed to the sequestration of ocular antigens from the immune system, that prevents the development of tolerance against these antigens. Here, we tested this assertion by examining whether transcripts of certain ocular antigens are constitutively expressed in the thymus, the site of central tolerance induction. Method. RNA was isolated from the eyes and thymi of two mouse strains and analyzed for the expression of genes encoding four retinal and three lens proteins by reverse transcribed-polymernse chain reaction, Southern blot and DNA sequence analyses. Results. We detected gene transcripts of S-Antigen (S-Ag), interphotoreceptor retinoid-binding protein, opsin, recoverin, lens major intrinsic protein (MIP) alpha A-, alpha A(-ins)- and gamma-crystallins in the thymi of BALB/c and FVB/N mouse strains. DNA sequence analysis of the thymic MIP and S-Ag transcripts confirmed their identity to the lens and retinal proteins, respectively. Conclusions. Our results reveal that transcripts of several ocular-specific proteins are expressed in the thymus and suggest that the commonly held view that ocular-specific antigens are sequestered from the immune system should be modified. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. RP Egwuagu, CE (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Room 10N116, Bethesda, MD 20892 USA. EM emeka@helix.nih.gov NR 30 TC 19 Z9 19 U1 0 U2 0 PU AEOLUS PRESS PI BUREN PA PO BOX 740, 4116 ZJ BUREN, NETHERLANDS SN 0271-3683 J9 CURR EYE RES JI Curr. Eye Res. PD AUG PY 1998 VL 17 IS 8 BP 788 EP 792 DI 10.1076/ceyr.17.8.788.5153 PG 5 WC Ophthalmology SC Ophthalmology GA 105BW UT WOS:000075053300005 PM 9723993 ER PT J AU Newman, AH Agoston, GE AF Newman, AH Agoston, GE TI Novel benztropine [3 alpha-(diphenylmethoxy)tropane] analogs as probes for the dopamine transporter SO CURRENT MEDICINAL CHEMISTRY LA English DT Review ID COCAINE RECEPTOR; UPTAKE INHIBITORS; LIGAND-BINDING; RHESUS-MONKEYS; HIGH-AFFINITY; SITES; ANTAGONISTS; DEPENDENCE; GBR-12909; DISCOVERY AB The design, synthesis and pharmacological evaluation of novel dopamine transporter ligands, based on Benztropine [3 alpha-(diphenylmethoxy) tropane], has been a focus of our research efforts toward the development of novel cocaine-abuse pharmacotherapeutics. Structure-activity relationships at the dopamine transporter, for this series of compounds, have been derived and compared to those of cocaine and GBR 12909. These studies suggest that structurally diverse dopamine uptake inhibitors may access different binding domains on the dopamine transporter. The distinctive behavioral profile displayed in this series of compounds, as compared to cocaine and other dopamine uptake inhibitors, is of particular interest and is proposed to be relevant to the pharmacodynamic and pharmacokinetic properties of this class of tropane-based molecules. C1 NIDA, Psychol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Newman, AH (reprint author), NIDA, Psychol Sect, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 55 TC 15 Z9 15 U1 1 U2 1 PU BENTHAM SCIENCE PUBL BV PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 0929-8673 J9 CURR MED CHEM JI Curr. Med. Chem. PD AUG PY 1998 VL 5 IS 4 BP 305 EP 319 PG 15 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 106YW UT WOS:000075179900004 PM 9668197 ER PT J AU Kwon-Chung, KJ AF Kwon-Chung, KJ TI Gene disruption to evaluate the role of fungal candidate virulence genes SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID PH-REGULATED GENE; CRYPTOCOCCUS-NEOFORMANS; SACCHAROMYCES-CEREVISIAE; MAMMALIAN-CELLS; LACCASE GENE; ALBICANS; PROTEIN; YEAST; GROWTH; MORPHOGENESIS AB Gene disruption is a powerful genetic tool that can define pathogenic or virulence factors. In the past two years gene disruption approaches have been used to identify fungal virulence genes. The capsule genes, an a subunit of G protein and certain kinases of Cryptococcus neoformans have clearly been demonstrated to be associated with pathogenicity. In Candida albicans at least four genes involved in hyphal formation have been disrupted and tested for virulence. In other fungi, such as Histoplasma capsulatum, however, more efficient gene disruption methods need to be developed before such approaches can be regularly used for identifying virulence genes. C1 NIAID, Mol Microbiol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Kwon-Chung, KJ (reprint author), NIAID, Mol Microbiol Sect, Clin Invest Lab, NIH, Bldg 10,11C304, Bethesda, MD 20892 USA. EM June_Kwon-Chung@nih.gov NR 59 TC 17 Z9 17 U1 1 U2 2 PU CURRENT BIOLOGY LTD PI LONDON PA 34-42 CLEVELAND STREET, LONDON W1P 6LB, ENGLAND SN 1369-5274 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD AUG PY 1998 VL 1 IS 4 BP 381 EP 389 DI 10.1016/S1369-5274(98)80053-2 PG 9 WC Microbiology SC Microbiology GA 117DL UT WOS:000075765300002 PM 10066511 ER PT J AU Yuan, XQ Eisen, AM McBain, CJ Gallo, V AF Yuan, XQ Eisen, AM McBain, CJ Gallo, V TI A role for glutamate and its receptors in the regulation of oligodendrocyte development in cerebellar tissue slices SO DEVELOPMENT LA English DT Article DE glutamate receptors; O-2A cells; glia; voltage-dependent K+ channels; tetraethylammonium; cyclic nucleotide phosphodiesterase ID 2',3'-CYCLIC NUCLEOTIDE 3'-PHOSPHODIESTERASE; CENTRAL-NERVOUS-SYSTEM; GLIAL PROGENITOR-CELL; RAT OPTIC-NERVE; PRECURSOR CELLS; CHANNEL EXPRESSION; MACROGLIAL CELLS; GROWTH-FACTORS; K+ CHANNELS; NG2 ANTIGEN AB We tested the hypothesis that the neurotransmitter glutamate would influence glial proliferation and differentiation in a cytoarchitecturally intact system. Postnatal day 6 cerebellar slices were maintained in organotypic culture and treated with glutamate receptor agonists or antagonists. After dissociation, cells were stained with antibodies for different oligodendrocyte developmentally regulated antigens, Treatment of the slices with the glutamate receptor agonists kainate or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid significantly decreased the percentage of LB1(+), NG2(+) and O4(+) cells, and their bromodeoxyuridine labeling index. The non-N-methyl-D-aspartate glutamate receptor antagonist 6,7-dinitroquinoxaline-2,3-dione increased the percentage and bromodeoxyuridine labeling of LB1(+), NG2(+) and O4(+) cells. In intact slices, RNA levels of the oligodendrocyte gene for 2',3'-cydic nucleotide 3'-phosphodiesterase were decreased by kainate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and increased by 6,7-dinitroquinoxaline-2,3-dione. The percentage of astrocytes was not modified by kainate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid or 6,7-dinitroquinoxaline-2,3-dione, Treatment with the N-methyl-D-aspartate receptor antagonist 2-amino-5-phosphonopentanoic acid did not alter the percentage of O4(+) cells, nor their proliferation. Incubation with the gamma-aminobutyric acid receptor antagonist bicuculline did not modify the percentage of LB1(+), A2B5(+) and O4(+) cells. In purified cerebellar oligodendrocyte progenitor cells, glutamate receptor agonists blocked Kf currents, and inhibited cell proliferation and lineage progression. The K+ channel blocker tetraethylammonium also inhibited oligodendrocyte progenitor cell proliferation. These findings indicate that in rat cerebellar tissue slices: (i) glutamate specifically modulates oligodendrocyte but not astrocyte development through selective activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and (ii) cell depolarization and blockage of voltage-dependent K+ channels is likely to be the triggering mechanism. C1 NICHD, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. RP Gallo, V (reprint author), NICHD, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. EM vgallo@helix.nih.gov RI Messier, Claude/A-2322-2008 OI Messier, Claude/0000-0002-4791-1763 NR 78 TC 148 Z9 149 U1 0 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE, CAMBS, ENGLAND CB4 4DL SN 0950-1991 J9 DEVELOPMENT JI Development PD AUG PY 1998 VL 125 IS 15 BP 2901 EP 2914 PG 14 WC Developmental Biology SC Developmental Biology GA 111RW UT WOS:000075452200014 PM 9655812 ER PT J AU Kobayashi, M Toyama, R Takeda, H Dawid, IB Kawakami, K AF Kobayashi, M Toyama, R Takeda, H Dawid, IB Kawakami, K TI Overexpression of the forebrain-specific homeobox gene six3 induces rostral forebrain enlargement in zebrafish SO DEVELOPMENT LA English DT Article DE sine oculis; six3; homeobox; rostral forebrain; zebrafish; optic stalk; eye; brain ID HOMEODOMAIN-ENCODING GENE; SINE OCULIS GENE; EYES ABSENT GENE; GOOSECOID EXPRESSION; EMBRYONIC ZEBRAFISH; REDUCES EXPRESSION; MOUSE FOREBRAIN; NERVOUS-SYSTEM; MESSENGER-RNAS; VISUAL-SYSTEM AB The Drosophila homeobox gene sine oculis is expressed in the rostral region of the embryo in early development and is essential for eye and brain formation. Its murine homolog, Six3, is expressed in the anterior neural plate and eye anlage, and may have crucial functions in eye and brain development. In this study, we describe the cloning and expression of zebrafish six3, the apparent ortholog of the mouse Six3 gene. Zebrafish six3 transcripts are first seen in hypoblast cells in early gastrula embryos and are found in the anterior axial mesendoderm through gastrulation, six3 expression in the head ectoderm begins at late gastrula, Throughout the segmentation period, six3 is expressed in the rostral region of the prospective forebrain. Overexpression of six3 in zebrafish embryos induced enlargement of the rostral forebrain, enhanced expression of pax2 in the optic stalk and led to a general disorganization of the brain. Disruption of either the Six domain or the homeodomain abolish these effects, implying that these domains are essential for six3 gene function. Our results suggest that the vertebrate Six3 genes are involved in the formation of the rostral forebrain. C1 Jichi Med Sch, Dept Biol, Minami Kawachi, Tochigi 3290498, Japan. NICHHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. RP Kobayashi, M (reprint author), Univ Tsukuba, Inst Basic Med Sci, Tsukuba, Ibaraki 3058575, Japan. RI Kobayashi, Makoto/B-2537-2008 NR 55 TC 153 Z9 153 U1 0 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE, CAMBS, ENGLAND CB4 4DL SN 0950-1991 J9 DEVELOPMENT JI Development PD AUG PY 1998 VL 125 IS 15 BP 2973 EP 2982 PG 10 WC Developmental Biology SC Developmental Biology GA 111RW UT WOS:000075452200021 PM 9655819 ER PT J AU Josephson, R Muller, T Pickel, J Okabe, S Reynolds, K Turner, PA Zimmer, A McKay, RDG AF Josephson, R Muller, T Pickel, J Okabe, S Reynolds, K Turner, PA Zimmer, A McKay, RDG TI POU transcription factors control expression of CNS stem cell-specific genes SO DEVELOPMENT LA English DT Article DE neuroepithelium; precursor cell; nestin intermediate; filament; brain fatty acid binding protein; mouse ID CENTRAL-NERVOUS-SYSTEM; FIBROBLAST GROWTH-FACTOR; LIPID-BINDING PROTEIN; HIPPOCAMPAL-NEURONS; RETINOIC ACID; FACTOR BRN-2; FACTOR SCIP; DOMAIN; BRAIN; DIFFERENTIATION AB Multipotential stem cells throughout the developing central nervous system have common properties. Among these is expression of the intermediate filament protein nestin and the brain fatty acid binding protein (B-FABP), To determine if common mechanisms control transcription in CNS stem cells, the regulatory elements of these two genes were mapped in transgenic mice. A 257 basepair enhancer of the rat nestin gene is sufficient for expression throughout the embryonic neuroepithelium. This enhancer contains two sites bound by the class III POU proteins Brn-1, Brn-2, Brn-4, and Tst-1, Only one of the two POU sites is required for CNS expression. An adjacent hormone response element is necessary for expression in the dorsal midbrain and forebrain, The regulatory sites of the B-FABP gene are strikingly similar to those of the nestin gene. A hybrid POU/Pbx binding site is recognized in vitro by Pbx-1, Brn-1 and Brn-2, This site is essential for expression in most of the CNS. In addition, a hormone response element is necessary for forebrain expression, Both the nestin and B-FABP genes therefore depend on POU binding sites for general CNS expression, with hormone response elements additionally required for activity in the anterior CNS. These data indicate that regulation by POU proteins and hormone receptors is a general mechanism for CNS stem cell-specific transcription. C1 NINDS, Mol Biol Lab, Bethesda, MD 20892 USA. NIMH, Dev Biol Unit, Bethesda, MD 20892 USA. RP NINDS, Mol Biol Lab, 36 Convent Dr, Bethesda, MD 20892 USA. EM mckay@codon.nih.gov RI Zimmer, Andreas/B-8357-2009 NR 66 TC 112 Z9 119 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD AUG PY 1998 VL 125 IS 16 BP 3087 EP 3100 PG 14 WC Developmental Biology SC Developmental Biology GA 116XA UT WOS:000075749300008 PM 9671582 ER PT J AU Harris, MI Klein, R Cowie, CC Rowland, M Byrd-Holt, DD AF Harris, MI Klein, R Cowie, CC Rowland, M Byrd-Holt, DD TI Is the risk of diabetic retinopathy greater in non-Hispanic blacks and Mexican Americans than in non-Hispanic whites with type 2 diabetes? A US population study SO DIABETES CARE LA English DT Article ID NIDDM; PREVALENCE; INDIANS AB OBJECTIVE - To compare the risk for diabetic retinopathy in non-Hispanic white, non-Hispanic black, and Mexican-American adults with type 2 diabetes in the U.S, population. RESEARCH DESIGN AND METHODS - Representative population-based samples of people aged greater than or equal to 40 years in each of the three racial/ethnic groups were studied in the 1988-1994 Third National Health and Nutrition Examination Survey (NHANES III). Diagnosed diabetes was ascertained by medical history interview and undiagnosed diabetes by measurement of fasting plasma glucose. A fundus photograph of a single eye was taken with a nonmydriatic camera, and a standardized protocol was used to grade diabetic retinopathy. Information on risk factors for retinopathy was obtained by interview and standard laboratory procedures. RESULTS - Prevalence of any lesions of diabetic retinopathy in people with diagnosed diabetes was 46% higher in non-Hispanic blacks and 84% higher in Mexican Americans, compared with non-Hispanic whites. Blacks and Mexican Americans also had higher rates of moderate and severe retinopathy and higher levels of many putative risk factors for retinopathy. Blacks had lower retinopathy prevalence among those with undiagnosed diabetes. In logistic regression, retinopathy in people with diagnosed diabetes was associated only with measures of diabetes severity (duration of diabetes, HbA(1c) level, treatment with insulin and oral agents) and systolic blood pressure. After adjustment for these factors, the risk of retinopathy in Mexican Americans was twice that of non-Hispanic whites, but non-Hispanic blacks were not at higher risk for retinopathy. These risks were similar when people with undiagnosed diabetes were included in the logistic regression models. CONCLUSIONS - The prevalence and severity of diabetic retinopathy is greater in non-Hispanic blacks and Mexican Americans with type 2 diabetes in the U.S. population than in non-Hispanic whites. For blacks, this can be attributed to their higher levels of risk factors for retinopathy, but the excess risk in Mexican Americans is unexplained. C1 NIDDK, NIH, Bethesda, MD 20892 USA. Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. Univ Wisconsin, Dept Ophthalmol, Madison, WI USA. RP Harris, MI (reprint author), NIDDK, NIH, Natcher Bldg,Room 5AN24,45 Ctr Dr, Bethesda, MD 20892 USA. EM harrism@ep.niddk.nih.gov NR 23 TC 207 Z9 214 U1 1 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD AUG PY 1998 VL 21 IS 8 BP 1230 EP 1235 DI 10.2337/diacare.21.8.1230 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 106YA UT WOS:000075177900005 PM 9702425 ER PT J AU Pettitt, DJ Knowler, WC AF Pettitt, DJ Knowler, WC TI Long-term effects of the intrauterine environment, birth weight, and breast-feeding in Pima Indians SO DIABETES CARE LA English DT Article; Proceedings Paper CT 4th International Workshop-Conference on Gestational Diabetes Mellitus CY MAR 14-16, 1997 CL CHICAGO, ILLINOIS SP Amer Diabetes Assoc, Council Diabetes Pregnancy ID GLUCOSE-TOLERANCE; DIABETES-MELLITUS; THRIFTY PHENOTYPE; PREGNANCY; MOTHERS; OBESITY; WOMEN; RATS AB The objectives of this study were to evaluate the long-term effect of the diabetic pregnancy on Pima Indian offspring and to see how the prevalence of diabetes during pregnancy is influenced by early life events, such as birth weight and type of infant feeding, that are known to influence the prevalence of diabetes in nonpregnant Pima adults. A modified 75-g oral glucose tolerance test was administered to women during each pregnancy These women and, from the age of 5 years, their children were followed biennially with a standardized examination that includes measurement of height and weight and a standard 75-g oral glucose tolerance test administered in the morning after an overnight fast. We found that diabetes during pregnancy is a major risk factor for diabetes and hyperglycemia in the offspring. Diabetes in the next generation is less common among breast-fed children (6.9 and 30.1% among offspring of nondiabetic and diabetic women, respectively) than among bottle-fed children (11.9 and 43.6%, respectively). The prevalence of diabetes during pregnancy is influenced by conditions. such as birth weight, known to influence the prevalence of diabetes in this population in general. The highest rates of diabetes during pregnancy at 25-34 years of age (25%) were found among women with a birth weight below 2.5 kg. The infant of the woman with diabetes during pregnancy is at risk of becoming obese and of developing type 2 diabetes at a young age. The prevalence of diabetes in women of childbearing age is influenced by factors occurring early in life (i.e.,birth weight and type of infant feeding). Whether or not the long-term. adverse outcomes, including diabetic pregnancies in the next generation, can be lessened or prevented by meticulous control of diabetes during pregnancy, careful attention to intrauterine growth, or more general infant breast-feeding remains unknown. C1 NIDDKD, Diabet & Arthrit Epidemiol Sect, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ USA. RP Pettitt, DJ (reprint author), Sansum Med Res Fdn, 2219 Bath St, Santa Barbara, CA 93105 USA. NR 29 TC 139 Z9 143 U1 0 U2 5 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD AUG PY 1998 VL 21 SU 2 BP B138 EP B141 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 107PQ UT WOS:000075218200024 PM 9704241 ER PT J AU Seissler, J de Sonnaville, JJJ Morgenthaler, NG Steinbrenner, H Glawe, D Khoo-Morgenthaler, UY Lan, MS Notkins, AL Heine, RJ Scherbaum, WA AF Seissler, J de Sonnaville, JJJ Morgenthaler, NG Steinbrenner, H Glawe, D Khoo-Morgenthaler, UY Lan, MS Notkins, AL Heine, RJ Scherbaum, WA TI Immunological heterogeneity in Type I diabetes: presence of distinct autoantibody patterns in patients with acute onset and slowly progressive disease SO DIABETOLOGIA LA English DT Article DE Type I diabetes; slowly progressive Type I diabetes; autoantibodies; protein tyrosine phosphatase; glutamic acid decarboxylase; islet cell antibodies ID GLUTAMIC-ACID DECARBOXYLASE; PROTEIN-TYROSINE-PHOSPHATASE; ISLET-CELL ANTIBODIES; FIRST-DEGREE RELATIVES; IDDM; MELLITUS; INSULIN; ANTIGENS; IA-2; IDENTIFICATION AB Type I diabetes mellitus may represent a heterogeneous disorder with a distinct pathogenesis in patients with young and adult onset of the disease. To investigate whether serological markers directed to different autoantigens have the potential to distinguish acute onset from slowly progressive Type I diabetes we analysed antibodies to tyrosine phosphatases IA-2/ICA512 (IA-2A) and IA-2 beta/phogrin (IA2 beta A), antibodies to GAD65 (GADA) and cytoplasmic islet cell antibodies (ICA) in a non-selected group of diabetic patients clinically classified as having Type I or Type II diabetes at diagnosis. Both IA-2A and IA-2 beta A were found to be positively associated with onset before the age of 20 years and the presentation of classical features of Type I diabetes. In Type I diabetes 56 % (112/200) of patients were positive for IA-2A and 38 % (76/200) for IA-2 beta A. In contrast, only 1 of 785 (0.1 %) patients with Type II diabetes had IA-2A and all of them were negative for IA-2 beta A (p < 0.001). Among the patients with Type II diabetes 7.6 % (n = 60) were ICA positive and 2.8 % (n = 22) had GADA suggesting the presence of slowly progressive Type I diabetes. GADA were found in 8 of 60 (13.3 %) ICA positive subjects which was lower than the percentage detected in patients with acute onset of diabetes (115/157 73.2 %) (p < 0.001). Blocking of double antibody positive sera showed that only 3 of 8 (37.5 %) patients with slowly progressive diabetes had ICA restricted to GAD or IA-2 whereas ICA were completely inhibited in 12 of 20 (60.0 %) patients with Type I diabetes. Among 193 patients with Type II diabetes available for follow-up, 35 % of ICA positives, 58 % of GADA positives and 60 % of those positive for both markers required insulin by 3 years. However. using strict criteria for the switch to insulin treatment the corresponding sensitivity of each marker was only low (9 %, 10 % and 5 %). We show that clinical subtypes of Type I diabetes are associated with distinct humoral autoimmunity. IA-2A and GADA were associated with classical features of Type I diabetes whereas GADA and an uncharacterized ICA subspecificity indicate slowly progressive disease. C1 Univ Dusseldorf, Diabet Res Inst, D-40225 Dusseldorf, Germany. Univ Amsterdam, Dept Endocrinol, NL-1012 WX Amsterdam, Netherlands. NIH, Oral Med Lab, Bethesda, MD 20892 USA. RP Seissler, J (reprint author), Univ Dusseldorf, Diabet Res Inst, Hennekamp 65, D-40225 Dusseldorf, Germany. NR 33 TC 105 Z9 124 U1 0 U2 4 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 1998 VL 41 IS 8 BP 891 EP 897 DI 10.1007/s001250051004 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 108RB UT WOS:000075278300003 PM 9726590 ER PT J AU Dabelea, D Hanson, RL Bennett, PH Roumain, J Knowler, WC Pettitt, DJ AF Dabelea, D Hanson, RL Bennett, PH Roumain, J Knowler, WC Pettitt, DJ TI Increasing prevalence of type II diabetes in American Indian children SO DIABETOLOGIA LA English DT Article DE prevalence; epidemic; children; Type II diabetes; obesity; diabetic pregnancy ID PIMA-INDIANS; MELLITUS; OBESITY; ONSET; MINNESOTA; AGE AB Until recently, Type II diabetes was considered rare in children. The disease is, however, increasing among children in populations with high rates of Type II diabetes in adults. The prevalence of Type II diabetes was determined in 5274 Pima Indian children between 1967 and 1996 in three 10-year time periods, for age groups 5-9, 10-14 and 15-19 years. Diabetes was diagnosed using World Health Organisation criteria, based on an oral glucose tolerance test. The prevalence of diabetes increased over time in children aged 10 years and over: in boys from 0% in 1967-1976 to 1.4% in 1987-1996 in the 10-14 year old age group, and from 2.43% to 3.78% for age group 15-19 and in girls from 0.72% in 1967-1976 to 2.88% in 1987-1996 in the 10-14 year old age group, and from 2.73% to 5.31% for age group 15-19 years. Along with the increase in the prevalence of Type II diabetes (p < 0.0001), there was an increase in weight (calculated as percentage of relative weight, p < 0.0001), and in frequency of exposure to diabetes in utero (p < 0.0001). The increasing weight and increasing frequency of exposure to diabetes in utero accounted for most of the increase in diabetes prevalence in Pima Indian children over the past 30 years. Type II diabetes is now a common disease in American Indian children aged 10 or more years and has increased dramatically over time, along with increasing weight. A vicious cycle related to an increase in the frequency of exposure to diabetes in utero appears to be an important feature of this epidemic. C1 NIDDKD, Diabet & Arthrit Epidemiol Sect, NIH, Phoenix, AZ 85014 USA. RP Dabelea, D (reprint author), NIDDKD, Diabet & Arthrit Epidemiol Sect, NIH, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 NR 42 TC 217 Z9 228 U1 2 U2 6 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 1998 VL 41 IS 8 BP 904 EP 910 DI 10.1007/s001250051006 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 108RB UT WOS:000075278300005 PM 9726592 ER PT J AU Dabclea, D Hanson, RL Bennett, PH Roumain, J Imperatore, G Pettitt, DJ Knowler, WC AF Dabclea, D Hanson, RL Bennett, PH Roumain, J Imperatore, G Pettitt, DJ Knowler, WC TI Birth weight and serum insulin concentrations in non-diabetic Pima Indian children SO DIABETOLOGIA LA English DT Meeting Abstract C1 NIDDK, NIH, Phoenix, AZ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 1998 VL 41 SU 1 MA 167 BP A44 EP A44 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 109ZG UT WOS:000075353800171 ER PT J AU Fagot-Campagna, A Knowler, W Narayan, V Saaddine, J Goldschmid, M Beckles, G Gregg, E Howard, B AF Fagot-Campagna, A Knowler, W Narayan, V Saaddine, J Goldschmid, M Beckles, G Gregg, E Howard, B TI HDL subfractions and incidence of type 2 diabetes: Opposite effects in men and women. SO DIABETOLOGIA LA English DT Meeting Abstract C1 Ctr Dis Control, DDT, Atlanta, GA 30333 USA. NIDDK, NIH, Phoenix, AZ USA. Medlant Res Inst, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 1998 VL 41 SU 1 MA 467 BP A120 EP A120 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 109ZG UT WOS:000075353800470 ER PT J AU Fenselau, S Schrezenmeier, J Baier, L AF Fenselau, S Schrezenmeier, J Baier, L TI Impact of a I-FABP gene polymorphism on insulin resistance in young men with postprandial hypertriglyceridaemia SO DIABETOLOGIA LA English DT Meeting Abstract C1 NIDDK, NIH, Phoenix, AZ USA. Fed Res Ctr, Inst Biochem & Physiol Nutr, Kiel, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 1998 VL 41 SU 1 MA 1345 BP A348 EP A348 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 109ZG UT WOS:000075353801347 ER PT J AU Shirakawa, T Nagaoka, T Manganiello, VC Gao, G Kobayashi, K Fujita-Yamaguchi, Y AF Shirakawa, T Nagaoka, T Manganiello, VC Gao, G Kobayashi, K Fujita-Yamaguchi, Y TI Cyclic nucleotide phosphodiesterase 3 inhibitors: Determination of PDE3A or 3B isoform-specificity SO DIABETOLOGIA LA English DT Meeting Abstract C1 City Hope Natl Med Ctr, Beckman Res Inst, Dept Mol Biol, Duarte, CA 91010 USA. Kanazawa Univ, Sch Med, Dept Internal Med 1, Kanazawa, Ishikawa 920, Japan. NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 1998 VL 41 SU 1 MA 668 BP A171 EP A171 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 109ZG UT WOS:000075353800672 ER PT J AU Soomers, AJ Tack, CJ AF Soomers, AJ Tack, CJ TI Extreme metformin-induced lactic acidosis successfully treated with bicarbonate haemodialysis SO DIABETOLOGIA LA English DT Meeting Abstract C1 Med Ctr Alkmaar, Alkmaar, Netherlands. NIH, Clin Neurosci Branch, Bethesda, MD 20892 USA. RI Tack, Cees/A-2368-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 1998 VL 41 SU 1 MA 901 BP A233 EP A233 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 109ZG UT WOS:000075353800905 ER PT J AU Weyer, C Tataranni, PA Snitker, S Danforth, E Ravussin, E AF Weyer, C Tataranni, PA Snitker, S Danforth, E Ravussin, E TI Improvement in insulin action and increase in fat oxidation following treatment with CL 316.243, a selective beta(3)-adrenoceptor agonist in humans. SO DIABETOLOGIA LA English DT Meeting Abstract C1 NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD AUG PY 1998 VL 41 SU 1 MA 235 BP A61 EP A61 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 109ZG UT WOS:000075353800238 ER PT J AU Abati, A McKee, G AF Abati, A McKee, G TI Grading of breast carcinoma in fine-needle aspiration cytology SO DIAGNOSTIC CYTOPATHOLOGY LA English DT Letter C1 NIH, Cytopathol Sect, Bethesda, MD 20892 USA. Royal Cty Hosp, Guildford, Surrey, England. RP Abati, A (reprint author), NIH, Cytopathol Sect, Bldg 10, Bethesda, MD 20892 USA. NR 10 TC 3 Z9 3 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 8755-1039 J9 DIAGN CYTOPATHOL JI Diagn. Cytopathol. PD AUG PY 1998 VL 19 IS 2 BP 153 EP 154 DI 10.1002/(SICI)1097-0339(199808)19:2<153::AID-DC20>3.0.CO;2-D PG 2 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 106XT UT WOS:000075177100020 PM 9702499 ER PT J AU Hoofnagle, JH AF Hoofnagle, JH TI Therapy of viral hepatitis SO DIGESTION LA English DT Article; Proceedings Paper CT World Congresses of Gastroenterology CY SEP 06-11, 1998 CL VIENNA, AUSTRIA DE hepatitis B virus; hepatitis C virus; hepatitis D virus; cirrhosis; alpha-interferon; nucleoside analogues; genotypes; randomized controlled trials ID RANDOMIZED CONTROLLED TRIAL; NON-B-HEPATITIS; PLACEBO-CONTROLLED TRIAL; RECOMBINANT INTERFERON-ALFA; HUMAN ALPHA-INTERFERON; TERM FOLLOW-UP; CHRONIC NON-A; HUMAN-IMMUNODEFICIENCY-VIRUS; D DELTA HEPATITIS; LONG-TERM AB Worldwide viral hepatitis is the most common cause of jaundice, chronic liver disease cirrhosis and hepatocellular carcinoma. While important advances have been made in prevention of viral hepatitis, therapy of this disease remains unsatisfactory. There are no specific therapies of proven benefit for acute hepatitis, although use of alpha-interferon during the acute phase of hepatitis C may result in a decrease in the rate of chronicity. For chronic viral hepatitis, alpha-interferon has been widely used, but is expensive, poorly tolerated and limited in effectiveness. New antiviral agents and use of combinations of antivirals are now being evaluated and promise to provide a therapy that is effective in the majority of patients. The currently recommended therapy of chronic hepatitis B is a 4- to 6-month course of alpha-interferon in doses of 5-10 million units three times a week; a regimen that results in sustained clearance of hepatitis B virus (HBV) DNA and hepatitis B e antigen (HBeAg) from serum in approximately one-third and a loss of hepatitis B surface antigen (HBsAg) in one-tenth of patients. Long-term follow-up of patients who respond to interferon treatment with clearance of HBeAg indicate that the majority ultimately clear HBsAg as well and have continued remission in the liver disease, although low levels of HBV DNA can commonly be detected in liver tissue. Better therapies of hepatitis B are needed. Recently, several oral 'second-generation' nucleoside analogues have been developed that have potent activity against HBV. The best studied is lamivudine (3-thiacytidine) which results in marked inhibition of HBV DNA levels and improvement in serum aminotransferases and hepatic histology in the majority of patients. When stopped, however, most patients relapse and the shortcomings of long-term therapy have been the development of viral resistance in up to one-quarter of patients within a year and a higher percentage with mon prolonged therapy. Future approaches of therapy of promise for hepatitis B are combinations of lamivudine with interferon and other antiviral nucleoside analogues. The currently recommended therapy of chronic hepatitis C is a 12- to 18-month course of alpha interferon in doses of 3 million units three times a week: a regimen that results in sustained clearance of hepatitis C virus (HCV) RNA in approximately 20% of patients. Sustained responses have been associated with marked improvements in hepatic histology and long-term studies indicate that the majority of patients remain free of virus in serum and liver, suggesting a 'cure' of infection. Responses to interferon correlate to some degree with clinical and virological features, including young age, absence of hepatic fibrosis, low levels of HCV RNA in serum and HCV genotypes 2 and 3. Most recently, combinations of alpha interferon and ribavirin, an oral nucleoside analogue, have been evaluated and shown to increase the sustained response rate to 30-40%. Better therapies are still needed, as the majority of patients with hepatitis C do not have a sustained response to therapy. Extensive research on the molecular structure of HCV indicates several potential means of inhibition of viral replication, including use of protease and helicase inhibitions. What is most needed to advance the field of therapeutics in hepatitis C is development of animal models and cell culture systems with which to study this important viral cause of liver disease. C1 NIDDK, Liver Dis Sect, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Hoofnagle, JH (reprint author), NIDDK, Liver Dis Sect, Digest Dis Branch, NIH, Bldg 31,Room 9A23, Bethesda, MD 20892 USA. EM Hoofnaglej@hq.niddk.nih.gov NR 136 TC 99 Z9 104 U1 0 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0012-2823 J9 DIGESTION JI Digestion PD AUG PY 1998 VL 59 IS 5 BP 563 EP 578 DI 10.1159/000007532 PG 16 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 111YL UT WOS:000075466400012 PM 9705540 ER PT J AU Yan, L Otterness, DM Kozak, CA Weinshilboum, RM AF Yan, L Otterness, DM Kozak, CA Weinshilboum, RM TI Mouse nicotinamide n-methyltransferase gene: Molecular cloning, structural characterization, and chromosomal localization SO DNA AND CELL BIOLOGY LA English DT Article ID COMPLETE NUCLEOTIDE-SEQUENCE; DNA; TRANSCRIPTION; PHARMACOGENETICS; EXPRESSION; EVENTS; VIRUS AB Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation of nicotinamide and structurally related compounds. There are large strain-dependent variations in the expression of NNMT activity in mouse liver during growth and development, raising the possibility of developmental regulation of the gene. Therefore, we set out to clone and structurally characterize the mouse NNMT gene, Nnmt, The gene spanned approximately 16 kb and consisted of three exons, 348 bp, 208 bp, and 487 bp in length, with an initial 1228-bp intron and a second intron that was approximately 14 kb in length. The locations of the splice junctions within the gene were highly conserved compared with those in genes for structurally related methyltransferase enzymes. The Nnmt gene contained no canonical TATA box sequences, but an "initiator" (Inr) sequence was located at the site of transcription initiation as determined by 5' rapid amplification of cDNAs ends. A promoter was located within the initial 750 bp of the 5' flanking region of the gene according to studies of the expression of a reporter gene in HepG2 cells. 5'-Flanking region sequences for mouse strains with high and low hepatic NNMT activity differed with regard to a series of nucleotide substitutions, insertions, and deletions, with the most striking difference being a 12-bp insertion/deletion. The Nnmt gene mapped to mouse chromosome 9 in an area of conserved synteny to human chromosome 11q, consistent with the localization of the human NNMT gene to 11q23, Cloning and structural characterization of the mouse Nnmt gene will make it possible to study molecular genetic mechanisms involved in the expression of this important methyltransferase. C1 Mayo Clin & Mayo Fdn, Mayo Med Sch, Dept Pharmacol, Rochester, MN 55905 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Weinshilboum, RM (reprint author), Mayo Clin & Mayo Fdn, Mayo Med Sch, Dept Pharmacol, Rochester, MN 55905 USA. FU NIGMS NIH HHS [R01 GM28157, R01 GM35720] NR 30 TC 5 Z9 7 U1 0 U2 2 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1044-5498 J9 DNA CELL BIOL JI DNA Cell Biol. PD AUG PY 1998 VL 17 IS 8 BP 659 EP 667 DI 10.1089/dna.1998.17.659 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity GA 113EZ UT WOS:000075538600002 PM 9726248 ER PT J AU Zhou, YY Lakatta, EG Xiao, RP AF Zhou, YY Lakatta, EG Xiao, RP TI Age-associated alterations in calcium current and its modulation in cardiac myocytes SO DRUGS & AGING LA English DT Review ID RAT VENTRICULAR MYOCYTES; FAILING HUMAN-HEART; BETA-ADRENERGIC MODULATION; TACHYCARDIA-INDUCED CARDIOMYOPATHY; SPONTANEOUSLY HYPERTENSIVE RAT; CAMP-DEPENDENT PHOSPHORYLATION; ACTION-POTENTIAL PROLONGATION; RECEPTOR DOWN-REGULATION; SMOOTH-MUSCLE CELLS; EXCITATION-CONTRACTION AB The calcium current is one of the most important components in cardiac excitation-contraction coupling. During aging, the magnitude of L-type Ca++ channel current (I-Ca,I-L) is significantly increased in parallel with the enlargement of cardiac myocytes, resulting in unaltered I-Ca,I-L density. Since the inactivation of I-Ca,I-L is slowed and the action potential duration is prolonged, the net Ca++ influx during each action potential is likely to be increased in senescent hearts relative to young ones. This augmentation of Ca++ influx may be important for the preserved cardiac function of the older heart in the basal state. However, it increases the risk of Ca++ overload and Ca++-dependent arrhythmias in the senescent heart. During stress, the response of I-Ca,I-L to beta-adrenergic receptor stimulation is markedly reduced, which may be an important cause of the age-related decrease in cardiac reserve function. These age-dependent changes in I-Ca,I-L and its modulations are similar to those observed in the enlarged myocytes of the hypertrophied and failing heart. C1 NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Xiao, RP (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 113 TC 17 Z9 18 U1 1 U2 4 PU ADIS INTERNATIONAL LTD PI AUCKLAND PA 41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 10, NEW ZEALAND SN 1170-229X J9 DRUG AGING JI Drugs Aging PD AUG PY 1998 VL 13 IS 2 BP 159 EP 171 DI 10.2165/00002512-199813020-00007 PG 13 WC Geriatrics & Gerontology; Pharmacology & Pharmacy SC Geriatrics & Gerontology; Pharmacology & Pharmacy GA 112ZY UT WOS:000075525900008 PM 9739504 ER PT J AU Ziemann, U Tergau, F Wischer, S Hildebrandt, J Paulus, W AF Ziemann, U Tergau, F Wischer, S Hildebrandt, J Paulus, W TI Pharmacological control of facilitatory I-wave interaction in the human motor cortex. A paired transcranial magnetic stimulation study SO ELECTROMYOGRAPHY AND MOTOR CONTROL-ELECTROENCEPHALOGRAPHY AND CLINICAL NEUROPHYSIOLOGY LA English DT Article; Proceedings Paper CT 14th Meeting of the IFCN CY AUG 24-29, 1997 CL FLORENCE, ITALY SP IFCN DE paired transcranial magnetic stimulation; human motor cortex; I-waves; motor evoked potential; antiepileptic drugs; gamma-aminobutyric acid (GABA) ID AMYOTROPHIC-LATERAL-SCLEROSIS; GABA-MEDIATED INHIBITION; CHANDELIER CELL AXONS; HUMAN CEREBRAL-CORTEX; ELECTRICAL-STIMULATION; EVOKED-POTENTIALS; CORTICOSPINAL VOLLEYS; CORTICAL EXCITABILITY; CORTICOCORTICAL INHIBITION; INTRACORTICAL INHIBITION AB A novel paired transcranial magnetic stimulation (TMS) paradigm with a suprathreshold first and a subthreshold second stimulus was used in healthy volunteers to investigate the acute effects of a single oral dose of various CNS-active drugs on short-interval motor evoked potential (MEP) facilitation. MEPs were recorded from the relaxed abductor digiti muscle. Three peaks of MEP facilitation were consistently observed at interstimulus intervals of 1.1-1.5 ms, 2.3-2.7 ms, and 3.9-4.5 ms. The size of these MEP peaks was transiently suppressed by drugs which enhance gamma-aminobutyric acid (GABA) function in the neocortex (lorazepam, vigabatrin, phenobarbital, ethanol), while the GABA-B receptor agonist baclofen, anti-glutamate drugs (gabapentin, memantine), and sodium channel blockers (carbamazepine, lamotrigine) had no effect. The interstimulus intervals effective for the production of the MEP peaks remained unaffected by all drugs. The MEP peaks are thought to be due to a facilitatory interaction of I-(indirect) waves in the motor cortex. Therefore, the present results indicate that the production of I-waves is primarily controlled by GABA related neuronal circuits. The potential relevance of this nan-invasive paired TMS protocol for the investigation of I-waves in patients with neurological disease will be discussed. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Gottingen, Dept Clin Neurophysiol, D-37075 Gottingen, Germany. RP Ziemann, U (reprint author), NINDS, Human Cort Physiol Unit, NIH, Bldg 10,Room 5N242,10 Ctr Dr, Bethesda, MD 20982 USA. EM ziemann@codon.nih.gov RI Paulus, Walter/A-3544-2009 OI Paulus, Walter/0000-0001-5549-8377 NR 67 TC 107 Z9 108 U1 1 U2 4 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0924-980X J9 ELECTROMYOGR MOTOR C JI Electromyogr. Mot. Control-Electroencephalogr. Clin. Neurophysiol. PD AUG PY 1998 VL 109 IS 4 BP 321 EP 330 DI 10.1016/S0924-980X(98)00023-X PG 10 WC Engineering, Biomedical; Neurosciences SC Engineering; Neurosciences & Neurology GA 116LA UT WOS:000075725100007 PM 9751295 ER PT J AU Tajima, T Fujieda, K Nakae, J Mikami, A Cutler, GB AF Tajima, T Fujieda, K Nakae, J Mikami, A Cutler, GB TI Mutations of the CYP21 gene in nonclassical steroid 21-hydroxylase deficiency in Japan SO ENDOCRINE JOURNAL LA English DT Article DE congenital adrenal hyperplasia; nonclassical 21-hydroxylase deficiency; polymerase-chain-reaction; point mutation; neonatal mass screening ID CONGENITAL ADRENAL-HYPERPLASIA; GENOTYPE; PHENOTYPE; PATIENT; ALLELE AB To determine whether nonclassical steroid 21-hydroxylase deficiency in Japan has the same molecular basis as in western countries, we have characterized the mutations of the CYP21 gene in 7 Japanese patients with nonclassical (NC) steroid 21-hydroxylase deficiency. In the Japanese NC cases the P30L was present in one allele in 5 of the 7 patients and on both alleles in one patient. By contrast, the V281L mutation, which was present in about 60% of NC cases in western countries, was not identified in any patient. Among our 7 cases, 4 were detected through neonatal mass screening by a mild increase in serum 17-hydroxyprogesterone (without any symptoms of CAH) at birth, but the 2 cases who were diagnosed as adults were born before nationwide neonatal screening was instituted, so that the Japanese neonatal screening program does detect some cases of NC steroid 21-hydroxylase deficiency. We suggest that P30L mutation is more frequent in Japanese NC CAH than V281L and that the frequency of the mutations causing NC steroid 21-hydroxylase deficiency in Japan might be different from that in western countries. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Hokkaido Univ, Sch Med, Dept Pediat, Sapporo, Hokkaido 060, Japan. Publ Hlth Sapporo City Inst, Sapporo, Hokkaido 003, Japan. RP Tajima, T (reprint author), NICHHD, Dev Endocrinol Branch, NIH, Bldg 10 Rm 10N262,10 Ctr Dr MSC 1862, Bethesda, MD 20892 USA. RI Toshihiro, Tajima/A-5720-2012 NR 23 TC 14 Z9 20 U1 0 U2 0 PU JAPAN ENDOCRINE SOCIETY PI TOKYO PA C/O DEPT VETERINARY PHYSIOL, VET MED SCI, UNIV TOKYO, 1-1-1 YAYOI, BUNKYO-KU, TOKYO, 113, JAPAN SN 0918-8959 J9 ENDOCR J JI Endocr. J. PD AUG PY 1998 VL 45 IS 4 BP 493 EP 497 DI 10.1507/endocrj.45.493 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 118KC UT WOS:000075836300008 PM 9881898 ER PT J AU Miller, AC Blakely, WF Livengood, D Whittaker, T Xu, JQ Ejnik, JW Hamilton, MM Parlette, E St John, T Gerstenberg, HM Hsu, H AF Miller, AC Blakely, WF Livengood, D Whittaker, T Xu, JQ Ejnik, JW Hamilton, MM Parlette, E St John, T Gerstenberg, HM Hsu, H TI Transformation of human osteoblast cells to the tumorigenic phenotype by depleted uranium uranyl chloride SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE alpha radiation; depleted uranium; osteoblast; transformation ID SISTER CHROMATID EXCHANGES; HUMAN OSTEOSARCOMA CELLS; MOUSE EMBRYO CELLS; GENOMIC INSTABILITY; IONIZING-RADIATION; ALPHA-PARTICLES; DAMAGE; CARCINOGENESIS; RETINOBLASTOMA; ACTIVATION AB Depleted uranium (DU) is a dense heavy metal used primarily in military applications. Although the heath effects of occupational uranium exposure are well known, limited data exist regarding the long-term health effects of internalized DU in humans. We established an in vitro cellular model to study DU exposure. Microdosimetric assessment, determined using a Monte Carlo computer simulation based on measured intracellular and extracellular uranium levels, showed that few (0.0014%) cell nuclei were hit by alpha particles. We report the ability of DU-uranyl chloride to transform immortalized human osteoblastic cells (HOS) to the tumorigenic phenotype. DU-uranyl chioride-transformants are characterized by anchorage-independent growth, tumor formation in nude mice, expression of high levels of the k-ras oncogene, reduced production of the ph tumor-suppressor protein, and elevated levels of sister chromatid exchanges per cell. DU-uranyl chloride treatment resulted in a 9.6 (+/- 2.8)-fold increase in transformation frequency compared to untreated cells. In comparison, nickel sulfate resulted in a 7.1 (+/- 2.1)-fold increase in transformation frequency. This is the first report showing that a DU compound caused human cell transformation to the neoplastic phenotype. Although additional studies are needed to determine if protracted DU exposure produces tumors in vivo, the implication from these in vitro results is that the risk of cancer induction from internalized DU exposure may be comparable to other biologically reactive and carcinogenic heavy-metal compounds (e.g., nickel). C1 Armed Forces Radiobiol Res Inst, Appl Cellular Radiobiol Dept, Bethesda, MD 20889 USA. Armed Forces Radiobiol Res Inst, Dept Radiat Sci, Bethesda, MD 20889 USA. NCI, Div Canc Treatment, Mol Pharmacol Branch, NIH, Bethesda, MD 20892 USA. RP Miller, AC (reprint author), Armed Forces Radiobiol Res Inst, Appl Cellular Radiobiol Dept, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. NR 40 TC 99 Z9 111 U1 0 U2 4 PU US DEPT HEALTH HUMAN SERVICES PUBLIC HEALTH SERVICE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SERVICES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD AUG PY 1998 VL 106 IS 8 BP 465 EP 471 DI 10.1289/ehp.98106465 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 120CC UT WOS:000075936100019 PM 9681973 ER PT J AU Loffredo, CA Silbergeld, EK Parascandola, M AF Loffredo, CA Silbergeld, EK Parascandola, M TI The environmental genome project: Suggestions and concerns SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Letter C1 Univ Maryland, Sch Med, Program Human Hlth & Environm, Baltimore, MD 21201 USA. NIH, Hist Off, Bethesda, MD 20892 USA. RP Loffredo, CA (reprint author), Univ Maryland, Sch Med, Program Human Hlth & Environm, Baltimore, MD 21201 USA. NR 3 TC 3 Z9 4 U1 0 U2 1 PU US DEPT HEALTH HUMAN SERVICES PUBLIC HEALTH SERVICE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SERVICES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD AUG PY 1998 VL 106 IS 8 BP A368 EP A368 DI 10.2307/3434161 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 120CC UT WOS:000075936100002 PM 9867455 ER PT J AU Wilson, S AF Wilson, S TI The environmental genome project: Suggestions and concerns - Reply SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Letter C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Wilson, S (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 0 TC 2 Z9 2 U1 0 U2 1 PU US DEPT HEALTH HUMAN SERVICES PUBLIC HEALTH SERVICE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SERVICES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD AUG PY 1998 VL 106 IS 8 BP A368 EP A369 DI 10.2307/3434162 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 120CC UT WOS:000075936100003 ER PT J AU Gulson, BL Cameron, MA Smith, AJ Mizon, KJ Korsch, MJ Vimpani, G McMichael, AJ Pisaniello, D Jameson, CW Mahaffey, KR AF Gulson, BL Cameron, MA Smith, AJ Mizon, KJ Korsch, MJ Vimpani, G McMichael, AJ Pisaniello, D Jameson, CW Mahaffey, KR TI Blood lead urine lead relationships in adults and children SO ENVIRONMENTAL RESEARCH LA English DT Article ID SMELTER WORKERS; NERVOUS-SYSTEM; ISOTOPE; KIDNEY; SERUM; BONE AB To determine the potential for using urine instead of blood as an indicator of lead exposure, especially in infants, lead concentrations and high-precision lead isotopic measurements have been compared in venous blood and "spot" urine (n > 260 from 182 different subjects) collected within the same 24-h period. Physiological conditions for the children and most of the adults were considered to be in a steady-state between body stores and lead in the environment. In the case of some adults, conditions were initially not steady-state because exposure conditions changed (for example, subjects moved to a country with lead of different isotopic composition.) There was a high correlation (r(2) = 0.98) between the blood and urine measurements of the isotope ratios but about 10% of measurements were outliers-the blood and urine measurements were further apart than was consistent with the measurement error that was generally obtained. The discrepancy was usually found to be associated with the urine measurement and was attributed to contamination during sampling. Weekly urine and monthly blood monitoring of an adult male over a 24-month period showed excellent correlations, although the standard deviations were about an order of magnitude higher than the precision measured for replicate analyses of a single blood or urine sample. "Spot" urine analyses for two male subjects gave excellent agreement with 24-h urine samples. Standard deviations of the spot analyses were of similar order to those in the 24-month monitored subject. In cases where female adults from Eastern Europe migrated to Australia, there was generally a more rapid exchange of skeletal lead with Australian environmental lead in urine compared with blood. These data do not support a differential partitioning of endogenous lead into the plasma. At this stage, isotopic measurements of urine can be used as a proxy for isotopic measurements in blood. However, lead concentrations in blood and in urine are only weakly related. Concentrations of lead in urine cannot serve to predict concentrations of lead in blood, particularly at the lower range of exposures, for example, at blood lead concentrations less than 10 mu g/dl. (C) 1995 Academic Press. C1 Macquarie Univ, Grad Sch Environm, Sydney, NSW 2109, Australia. CSIRO, EM, N Ryde, NSW 2113, Australia. Hunter Area Hlth Serv, Wallsend, NSW 2287, Australia. Univ Adelaide, Dept Community Med, Adelaide, SA 5000, Australia. NIEHS, Res Triangle Pk, NC 27709 USA. US EPA, Cincinnati, OH 45268 USA. RP Gulson, BL (reprint author), Macquarie Univ, Grad Sch Environm, Sydney, NSW 2109, Australia. RI Cameron, Murray/C-9970-2009 OI Cameron, Murray/0000-0002-4874-0927 FU NIEHS NIH HHS [N01-ES-05292] NR 21 TC 25 Z9 25 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 J9 ENVIRON RES JI Environ. Res. PD AUG PY 1998 VL 78 IS 2 BP 152 EP 160 DI 10.1006/enrs.1997.3810 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 113EV UT WOS:000075538200011 PM 9719619 ER PT J AU Markley, JL Bax, A Arata, Y Hilbers, CW Kaptein, R Sykes, BD Wright, PE Wuthrich, K AF Markley, JL Bax, A Arata, Y Hilbers, CW Kaptein, R Sykes, BD Wright, PE Wuthrich, K TI Recommendations for the presentation of NMR structures of proteins and nucleic acids - IUPAC-IUBMB-IUPAB inter-union task group on the standardization of data bases of protein and nucleic acid structures determined by NMR spectroscopy SO EUROPEAN JOURNAL OF BIOCHEMISTRY LA English DT Article ID COUPLING-CONSTANTS; MAGNETIC-RESONANCE; 3-DIMENSIONAL STRUCTURES; FILE; CRYSTALLOGRAPHY; CONFORMATION; CONSTRAINTS; PROGRAMS; QUALITY; C-13 AB The recommendations presented here are designed to support easier communication of NMR data and NMR structures of proteins and nucleic acids through unified nomenclature and reporting standards. Much of this document pertains to the reporting of data in journal articles; however, in the interest of the future development of structural biology, it is desirable that the bulk of the reported information be stored in computer-accessible form and be freely accessible to the scientific community in standardized formats for data exchange. These recommendations stem from an IUPAC-IUBMB-IUPAB inter-union venture with the direct involvement of ICSU and CODATA. The Task Group has reviewed previous formal recommendations and has extended them in the light of more recent developments in the field of biomolecular NMR spectroscopy. Drafts of the recommendations presented here have been examined critically by more than 50 specialists in the field and have gone through two rounds of extensive modification to incorporate suggestions and criticisms. C1 ETH Honggerberg, Inst Mol Biol & Biophys, CH-8093 Zurich, Switzerland. Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Water Res Inst, Tsukuba, Ibaraki, Japan. Univ Nijmegen, Biophys Chem Lab, Nijmegen, Netherlands. Univ Utrecht, Dept Chem, NL-3508 TC Utrecht, Netherlands. Univ Alberta, Dept Biochem, Edmonton, AB, Canada. Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. RP Wuthrich, K (reprint author), ETH Honggerberg, Inst Mol Biol & Biophys, CH-8093 Zurich, Switzerland. NR 63 TC 65 Z9 65 U1 0 U2 15 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0014-2956 J9 EUR J BIOCHEM JI Eur. J. Biochem. PD AUG PY 1998 VL 256 IS 1 BP 1 EP 15 DI 10.1046/j.1432-1327.1998.2560001.x PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 112NN UT WOS:000075500800001 PM 9746340 ER PT J AU Strickler, HD Schiffman, MH Shah, KV Rabkin, CS Schiller, JT Wacholder, S Clayman, B Viscidi, RP AF Strickler, HD Schiffman, MH Shah, KV Rabkin, CS Schiller, JT Wacholder, S Clayman, B Viscidi, RP TI A survey of human papillomavirus 16 antibodies in patients with epithelial cancers SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Article DE antibodies; cancer; carcinoma; HPV 16; human papillomavirus; virus-like particles; VLP ID POLYMERASE CHAIN-REACTION; VIRUS-LIKE PARTICLES; CERVICAL INTRAEPITHELIAL NEOPLASIA; SQUAMOUS-CELL CARCINOMAS; IN-SITU; INSITU HYBRIDIZATION; INVASIVE-CARCINOMA; TYPE-16 INFECTION; SERUM ANTIBODIES; PENILE CANCER AB Human papillomavirus (HPV), particularly HPV 16, is linked to the development of cervical cancer. However, the role of HPV 16 in a number of extra-cervical epithelial tumours is controversial, To assess exposure to HPV 16 in patients with different cancers, we conducted a large serosurvey of 905 patients with 21 types of tumours and measured IgG to HPV 16 virus-like particles (VLPs) using a well characterized enzyme linked immunosorbent assay (ELISA), Patients with cervical cancer were considered 'positive controls', as about half were expected to be specifically HPV 16-related. A non-cancer study group consisting of 48 patients with endocrine disorders leg diabetes) was also tested. HPV 16 antibody prevalence was highest in patients with cancers of the cervix (52% +/- 7%), vulva (27% +/- 9%), vagina (27% +/- 13%) and penis (63% +/- 16%), Seroprevalence was much lower in the non-cancer group (4% +/- 3%) and all other cancer patients: uterus (9% +/- 4%); ovary (4% +/- 3%); testis (5% +/- 4%); prostate (6% +/- 4%); squamous carcinoma (6% +/- 3%) and adenocarcinoma (4% +/- 3%) of the lung; rectum (2% +/- 2%); pancreas (8% +/- 4%); colon (2% +/- 2%); stomach (0%); oesophagus (8% +/- 4%); buccal cavity (12% +/- 5%); breast (10% +/- 4%); non-melanomatous (9% +/- 6%) and melanomatous (6% +/- 3%) skin tumours; bladder (8% +/- 4%); and kidney (2% +/- 2%), The results confirm the strong relation of HPV with several lower anogenital tract tumours, but, at least in this population, fail to identify additional epithelial tumours associated with high seroprevalence of HPV 16 VLP antibodies, (C) 1998 Lippincott Williams & Wilkins. C1 NCI, NIH, Rockville, MD 20852 USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. RP Strickler, HD (reprint author), NCI, NIH, 6130 Execut Blvd,Room 434, Rockville, MD 20852 USA. NR 52 TC 50 Z9 52 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0959-8278 J9 EUR J CANCER PREV JI Eur. J. Cancer Prev. PD AUG PY 1998 VL 7 IS 4 BP 305 EP 313 DI 10.1097/00008469-199808000-00006 PG 9 WC Oncology SC Oncology GA 129QC UT WOS:000076473600006 PM 9806119 ER PT J AU O'Connell, BC Redman, RS Zheng, CY AF O'Connell, BC Redman, RS Zheng, CY TI In vitro use of adenoviral vectors: Effects on salivary gland structure SO EUROPEAN JOURNAL OF MORPHOLOGY LA English DT Article; Proceedings Paper CT 2nd Symposium on Salivary Glands Dedicated to Niels Steensen (Niccolo Stenone) CY MAY 23-25, 1997 CL CAGLIARI, ITALY DE adenovirus; gene expression; gene transfer; saliva; salivary glands ID MEDIATED GENE-TRANSFER; RECOMBINANT ADENOVIRUS; TRANSGENE EXPRESSION; PREVENTS FORMATION; MOUSE-LIVER; IN-VIVO; RAT; DELIVERY; CELLS; IMMUNOSUPPRESSION AB Recently there has been considerable progress in the development of in vivo gene transfer technology. By this means new genetic information may be introduced directly to cells, while the cells remain in their natural milieu. The ability to express exogenous proteins makes it possible to explore the functions of native or altered proteins and thereby develop new insights into cell function and dysfunction. We have demonstrated that the major salivary glands are efficiently infected by recombinant adenovirus vectors. These vectors are capable of expressing transgenes in both acinar and ductal cell types. Recently, we have developed vectors that contain cell-specific promoters so that proteins may be expressed in selected subpopulations of salivary cells. Early generations of adenoviral vectors elicited potent immune responses in vivo. However, modified vectors and adjunctive measures have improved the safety of gene transfer to salivary glands. Future studies will aim to increase the duration of adenovirus-based gene expression and to produce vector systems that are not toxic to the host. C1 NIDR, GTTB, Gene Transfer Unit, NIH, Bethesda, MD 20892 USA. VA Med Ctr, Oral Pathol Res Lab, Washington, DC USA. RP O'Connell, BC (reprint author), NIDR, GTTB, Gene Transfer Unit, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. OI O'Connell, Brian/0000-0003-4529-7664 NR 26 TC 1 Z9 1 U1 0 U2 0 PU SWETS ZEITLINGER PUBLISHERS PI LISSE PA P O BOX 825, 2160 SZ LISSE, NETHERLANDS SN 0924-3860 J9 EUR J MORPHOL JI Eur. J. Morphol. PD AUG PY 1998 VL 36 SU S BP 55 EP 60 PG 6 WC Anatomy & Morphology SC Anatomy & Morphology GA 133CU UT WOS:000076669500012 PM 9825894 ER PT J AU Delporte, C Baum, BJ AF Delporte, C Baum, BJ TI Preclinical and biological studies using recombinant adenoviruses encoding aquaporins 1 and 5 SO EUROPEAN JOURNAL OF MORPHOLOGY LA English DT Article; Proceedings Paper CT 2nd Symposium on Salivary Glands Dedicated to Niels Steensen (Niccolo Stenone) CY MAY 23-25, 1997 CL CAGLIARI, ITALY DE adenoviruses; aquaporins; epithelial cells; gene transfer ID WATER CHANNELS; EPITHELIAL-CELLS; SALIVARY-GLANDS; GENE-EXPRESSION; PROTEIN; CDNA AB In this report, we have reviewed several of our recent studies using replication-deficient recombinant adenoviruses encoding either aquaporin 1 or 5. The aquaporins are a relatively recently described family of water channels that mediate osmotically-driven transmembrane water permeability. Recombinant adenoviruses are highly efficient gene transfer vectors and readily result in significant levels of transgene expression. These aggregate studies provide examples of how such "tools" can be used in a novel way to address problems of both clinical and biological significance. C1 NIDR, GTTB, NIH, Bethesda, MD 20892 USA. RP Baum, BJ (reprint author), NIDR, GTTB, NIH, 9000 Rockville Pike,10 Ctr Dr,MSC 1190,Bldg 10,Ro, Bethesda, MD 20892 USA. RI Delporte, Christine/A-5733-2012 NR 17 TC 0 Z9 0 U1 0 U2 0 PU SWETS ZEITLINGER PUBLISHERS PI LISSE PA P O BOX 825, 2160 SZ LISSE, NETHERLANDS SN 0924-3860 J9 EUR J MORPHOL JI Eur. J. Morphol. PD AUG PY 1998 VL 36 SU S BP 118 EP 122 PG 5 WC Anatomy & Morphology SC Anatomy & Morphology GA 133CU UT WOS:000076669500023 PM 9825905 ER PT J AU Moore-Hoon, ML Turner, RJ AF Moore-Hoon, ML Turner, RJ TI Molecular characterization of the cation-chloride cotransporter family SO EUROPEAN JOURNAL OF MORPHOLOGY LA English DT Article; Proceedings Paper CT 2nd Symposium on Salivary Glands Dedicated to Niels Steensen (Niccolo Stenone) CY MAY 23-25, 1997 CL CAGLIARI, ITALY DE epithelial salt transport; fluid transport; Na-K-2Cl cotransport ID K-CL COTRANSPORTER; HYPOKALEMIC ALKALOSIS; BARTTERS-SYNDROME; MUTATIONS; RAT AB Na-K-2Cl cotransporters, Na-Cl cotransporters and K-Cl cotransporters have recently been shown to constitute a new gene family of membrane transport proteins. At least five distinct members of this family of cation-chloride cotransporters have been found in vertebrates and several as yet functionally uncharacterized sequences have been identified in insects, worms and yeast. The relationships among the various known members of this gene family is briefly reviewed along with our current knowledge about the topological structure of these proteins in the plasma membrane. C1 NIDR, Membrane Biol Sect, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Turner, RJ (reprint author), NIDR, Membrane Biol Sect, Gene Therapy & Therapeut Branch, NIH, Bldg 10,Rm 1A06,10 Ctr Dr MSC 1190, Bethesda, MD 20892 USA. NR 10 TC 6 Z9 6 U1 0 U2 0 PU SWETS ZEITLINGER PUBLISHERS PI LISSE PA P O BOX 825, 2160 SZ LISSE, NETHERLANDS SN 0924-3860 J9 EUR J MORPHOL JI Eur. J. Morphol. PD AUG PY 1998 VL 36 SU S BP 137 EP 141 PG 5 WC Anatomy & Morphology SC Anatomy & Morphology GA 133CU UT WOS:000076669500027 PM 9825909 ER PT J AU Evans, RL Turner, RJ AF Evans, RL Turner, RJ TI New insights into the upregulation and function of the salivary Na+-K+-2Cl(-) cotransporter SO EUROPEAN JOURNAL OF MORPHOLOGY LA English DT Article; Proceedings Paper CT 2nd Symposium on Salivary Glands Dedicated to Niels Steensen (Niccolo Stenone) CY MAY 23-25, 1997 CL CAGLIARI, ITALY DE fluid secretion; Na+-K+-2C1(-); cotransporter; NH4+ transport; salivary glands; stimulus-secretion coupling ID PAROTID ACINAR-CELLS; UP-REGULATION; CL; CYTOCHROME-P450; TRANSPORT; ACID AB In many exocrine epithelia, the Na+-K+-2Cl(-) cotransporter is the main provider of cellular chloride entry during transepithelial salt and water secretion. Because of its accessibility and hormonal responsiveness, the salivary gland has recently emerged as a convenient preparation in which to study the regulation and characteristics of this transport protein. In this review, we summarize recent findings from our laboratory which demonstrate that muscarinic, alpha(1)-adrenergic and peptidergic stimulation of rat parotid acinar cells induce a dramatic (up to twenty-fold) upregulation of Na+-K+-2Cl(-) cotransporter activity. Our results indicate that this effect is dependent on the rise in intracellular calcium concentration ([Ca2+](i)) that accompanies stimulation, and is not a consequence of the KCl loss and the concomitant cell shrinkage associated with fluid secretion. In addition, we show that the effect of muscarinic stimulation on the cotransporter can be blocked by inhibitors of phospholipase A(2,) by a general inhibitor of arachidonic acid metabolism, and by specific inhibitors of the cytochrome P450 pathway. These data argue strongly for the involvement of a product of the cytochrome P450 pathway of arachidonic acid metabolism in upregulation of the salivary Na+-K+-2Cl(-) cotransporter. C1 NIDR, Membrane Biol Sect, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Evans, RL (reprint author), Univ Rochester, Sch Med & Dent, Dept Dent Res, 601 Elmwood Ave,Box 611, Rochester, NY 14642 USA. EM evans@pharmacol.rochester.edu NR 14 TC 8 Z9 8 U1 0 U2 0 PU SWETS ZEITLINGER PUBLISHERS PI LISSE PA P O BOX 825, 2160 SZ LISSE, NETHERLANDS SN 0924-3860 J9 EUR J MORPHOL JI Eur. J. Morphol. PD AUG PY 1998 VL 36 SU S BP 142 EP 146 PG 5 WC Anatomy & Morphology SC Anatomy & Morphology GA 133CU UT WOS:000076669500028 PM 9825910 ER PT J AU Bird, GSJ Louzao, MC Ribeiro, CMP Putney, JW AF Bird, GSJ Louzao, MC Ribeiro, CMP Putney, JW TI Calcium signalling in exocrine glands SO EUROPEAN JOURNAL OF MORPHOLOGY LA English DT Article; Proceedings Paper CT 2nd Symposium on Salivary Glands Dedicated to Niels Steensen (Niccolo Stenone) CY MAY 23-25, 1997 CL CAGLIARI, ITALY DE calcium signalling; capacitative calcium entry; exocrine glands; G-proteins; thapsigargin ID INOSITOL TRISPHOSPHATE; CA2+ INFLUX; ENTRY; THAPSIGARGIN; INACTIVATION; ACTIVATION; MESSENGER; FEEDBACK; CELLS AB In exocrine gland cells, stimulation of a variety of surface receptors initiates a Ca2+ signalling system through activation of a polyphosphoinositide-specific phospholipase C. One product of phospholipase C activity, inositol 1,4,5-trisphosphate ((1,4,5)IP3), signals the release of intracellular Ca2+. Release of intracellular Ca2+ is followed by entry of Ca2+ into the cell across the plasma membrane. The mechanism by which Ca2+ entry is regulated is not well understood, although it is clear that (1,4,5)IP3 plays an important role. One hypothesis suggests that Ca2+ entry is triggered by the depletion of intracellular Ca(2+)stores by (1,4,5)IP3, a process termed 'capacitative calcium entry'. The purpose of these studies is to gain understanding into the processes controlling capacitative calcium entry in exocrine gland cells. C1 NIEHS, Calcium Regulat Sect, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Bird, GSJ (reprint author), NIEHS, Calcium Regulat Sect, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Ribeiro, Carla Maria/A-6955-2009 NR 17 TC 6 Z9 6 U1 0 U2 0 PU SWETS ZEITLINGER PUBLISHERS PI LISSE PA P O BOX 825, 2160 SZ LISSE, NETHERLANDS SN 0924-3860 J9 EUR J MORPHOL JI Eur. J. Morphol. PD AUG PY 1998 VL 36 SU S BP 153 EP 156 PG 4 WC Anatomy & Morphology SC Anatomy & Morphology GA 133CU UT WOS:000076669500030 PM 9825912 ER PT J AU Maric, D Maric, I Smith, SV Serafini, R Hu, Q Barker, JL AF Maric, D Maric, I Smith, SV Serafini, R Hu, Q Barker, JL TI Potentiometric study of resting potential, contributing K+ channels and the onset of Na+ channel excitability in embryonic rat cortical cells SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE central nervous system; development; flow cytometry; oxonol ID SENSITIVE SODIUM-CHANNELS; ION CHANNELS; NEURONAL DIFFERENTIATION; GLUTAMATE RECEPTORS; GROWTH-REGULATION; CYCLE DEPENDENCE; SPINAL-CORD; LYMPHOCYTES; EMBRYOGENESIS; POTASSIUM AB Resting membrane potential (RMP), K+ channel contribution to RMP and the development of excitability were investigated in the entire population of acutely dissociated embryonic (E) rat cortical cells over E11-22 using a voltage-sensitive fluorescent indicator dye and flow cytometry. During the period of intense proliferation (E11-13), two cell subpopulations with distinct estimated RMPs were recorded: one polarized at similar to -70 mV and the other relatively less-polarized at similar to -40 mV. Ca-o(2+) was critical in sustaining the RMP of the majority of less-polarized cells, while the well-polarized cells were characterized by membrane potentials exhibiting a similar to Nernstian relationship between RMP and [K+](o). Analysis of these two subpopulations revealed that > 80% of less-polarized cells were proliferative, while > 90% of well-polarized cells were postmitotic. Throughout embryonic development, the disappearance of Ca-o(2+)-sensitive, less-polarized cells correlated with the disappearance of the proliferating population, while the appearance of the K-o(+)-sensitive, well-polarized population correlated with the appearance of terminally postmitotic neurons, immune-identified as BrdU(-), tetanus toxin(+) cells. Differentiating neurons were estimated to contain increased K-i(+) relative to less-polarized cells, coinciding with the developmental expression of Cs+/Ba2+-sensitive and Ca2+-dependent K+ channels. Both K+ channels contributed to the RMP of well-polarized cells, which became more negative toward the end of neurogenesis. Depolarizing effects of veratridine, first observed at E11, progressively changed from Ca-o(2+)-dependent and tetrodotoxin-insensitive to Na-o(+)-dependent and tetrodotoxin-sensitive response by E18. The results reveal a dynamic development of RMP, contributing K+ channels and voltage-dependent Na+ channels in the developing cortex as it transforms from proliferative to primarily differentiating tissue. C1 Natl Inst Neurol Disorders & Stroke, NIH, Neurophysiol Lab, Bethesda, MD 20892 USA. RP Maric, D (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, Neurophysiol Lab, Bethesda, MD 20892 USA. NR 53 TC 22 Z9 22 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD AUG PY 1998 VL 10 IS 8 BP 2532 EP 2546 DI 10.1046/j.1460-9568.1998.00284.x PG 15 WC Neurosciences SC Neurosciences & Neurology GA 111VM UT WOS:000075459200006 PM 9767384 ER PT J AU Carmona, GN Schindler, CW Shoaib, M Jufer, R Cone, EJ Goldberg, SR Greig, NH Yu, QS Gorelick, DA AF Carmona, GN Schindler, CW Shoaib, M Jufer, R Cone, EJ Goldberg, SR Greig, NH Yu, QS Gorelick, DA TI Attenuation of cocaine-induced locomotor activity by butyrylcholinesterase SO EXPERIMENTAL AND CLINICAL PSYCHOPHARMACOLOGY LA English DT Article ID HUMAN-PLASMA; RATS; CHOLINESTERASE; METABOLITES; TOXICITY AB A primary enzyme for the metabolism of cocaine is butyrylcholinesterase (BChE). To determine whether the systemic administration of BChE can increase the metabolism of cocaine sufficiently to alter a behavioral effect, rats were tested in a locomotor activity chamber after receiving 17 mg of cocaine per kg intraperitoneally. In rats pretreated intravenously with 5,000 TCT of horse serum-derived BChE, the locomotor activity effect was significantly attenuated. BChE pretreatment increased plasma BChE levels approximately 400-fold. When added to rat plasma, this amount of BChE reduced the cocaine half-life from over 5 hr to less than 5 min. BChE altered the cocaine metabolic pattern such that the relatively nontoxic metabolite ecgonine methyl ester was produced, rather than benzoylecgonine. These results suggest that systemic administration of BChE can increase the metabolism of cocaine sufficiently to alter a behavioral effect of cocaine and thus should be investigated as a potential treatment for cocaine abuse. C1 NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. NIA, Gerontol Res Ctr, NIH, Bethesda, MD 20892 USA. RP Carmona, GN (reprint author), NIDA, Intramural Res Program, NIH, POB 5180, Baltimore, MD 21224 USA. EM gcarmona@intra.nida.nih.gov NR 21 TC 29 Z9 29 U1 0 U2 1 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1064-1297 J9 EXP CLIN PSYCHOPHARM JI Exp. Clin. Psychopharmacol. PD AUG PY 1998 VL 6 IS 3 BP 274 EP 279 PG 6 WC Psychology, Biological; Psychology, Clinical; Pharmacology & Pharmacy; Psychiatry SC Psychology; Pharmacology & Pharmacy; Psychiatry GA 111DW UT WOS:000075422900005 PM 9725111 ER PT J AU Wise, SP Moody, SL Blomstrom, KJ Mitz, AR AF Wise, SP Moody, SL Blomstrom, KJ Mitz, AR TI Changes in motor cortical activity during visuomotor adaptation SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE visually guided movement; skill; motor cortex; motor learning ID POSITRON EMISSION TOMOGRAPHY; CONDITIONAL OCULOMOTOR ASSOCIATIONS; TRANSCRANIAL MAGNETIC STIMULATION; STIMULUS-RESPONSE COMPATIBILITY; SUPPLEMENTARY EYE FIELD; NEURONAL-ACTIVITY; FUNCTIONAL-ANATOMY; PREMOTOR CORTICES; PARIETAL CORTEX; CEREBRAL-CORTEX AB We examined neuronal activity in three motor cortical areas while a rhesus monkey adapted to novel visuomotor transforms. The monkey moved a joystick that controlled a cursor on a video screen. Each trial began with the joystick centered. Next, the cursor appeared in one of eight positions, arranged in a circle around a target stimulus at the center of the screen. To receive reinforcement, the monkey moved the joystick so that the cursor contacted the target continuously for Is. The video monitor provided continuous visual feedback of both cursor and target position. With those elements of the task constant, we modified the transform between joystick movement and that of the cursor at the beginning of a block of trials. Neuronal activity was studied as the monkey adapted to these novel joystick-cursor transforms. Some novel tasks included spatial transforms such as single-axis inversions, asymmetric double-axis inversions and angular deviations (also known as rotations). Other tasks involved changes in the spatiotemporal pattern and magnitude of joystick movement. As the monkey adapted to various visuomotor tasks, 209 task-related neurons (selected for stable background activity) showed significant changes in their task-related activity: 88 neurons in the primary motor cortex (M1), 32 in the supplementary motor cortex (M2), and 89 in the caudal part of the dorsal premotor cortex (PMdc). Slightly more than half of the sample in each area showed significant changes in the magnitude of activity modulation during adaptation, with the number of increases approximately equaling the number of decreases. These data support the prediction that changes in task-related neuronal activity can be observed in M1 during motor adaptation, but fail to support the hypothesis that M1 and PMdc differ in this regard. When viewed in population averages, motor cortex continued to change its activity for at least dozens of trials after performance reached a plateau. This slow, apparently continuing change in the pattern and magnitude of task-related activity may reflect the initial phases of consolidating the motor memory for preparing and executing visuomotor skills. C1 NIMH, Sect Neurophysiol, Lab Syst Neurosci, NIH, Poolesville, MD 20837 USA. RP Wise, SP (reprint author), NIMH, Sect Neurophysiol, Lab Syst Neurosci, NIH, POB 608, Poolesville, MD 20837 USA. NR 61 TC 119 Z9 119 U1 0 U2 7 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0014-4819 J9 EXP BRAIN RES JI Exp. Brain Res. PD AUG PY 1998 VL 121 IS 3 BP 285 EP 299 DI 10.1007/s002210050462 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 114GT UT WOS:000075601300008 PM 9746135 ER PT J AU Boissy, RE Sakai, C Zhao, HQ Kobayashi, T Hearing, VJ AF Boissy, RE Sakai, C Zhao, HQ Kobayashi, T Hearing, VJ TI Human tyrosinase related protein-1 (TRP-1) does not function as a DHICA oxidase activity in contrast to murine TRP-1 SO EXPERIMENTAL DERMATOLOGY LA English DT Article DE melanocyte; pigmentation ID BROWN LOCUS PROTEIN; OCULOCUTANEOUS ALBINISM; MELANIN BIOSYNTHESIS; MAMMALIAN TYROSINASE; HUMAN HOMOLOG; CELL-LINE; B-LOCUS; MOUSE; GENE; MELANOCYTES AB Tyrosinase related protein-1 is a melanocyte specific protein and a member of the tyrosinase gene family which also includes tyrosinase and TRP-2 (DOPAchrome tautomerase). In murine melanocytes, TRP-1 functions as a 5,6-dihydroxyindole-2-carboxylic acid [DHICA] oxidase during the biosynthetic conversion of tyrosine to eumelanin and mutations affecting TRP-1 result in the synthesis of brown rather than black pelage coloration. In this study, we examined the putative DHICA oxidase activity of TRP-1 in human melanocytes using several approaches. We first utilized a line of cultured melanocytes established from a patient with a form of oculocutaneous albinism completely lacking expression of TRP-1 (OCA3). This line of melanocytes endogenously exhibited the same amount of DHICA oxidase activity as control melanocytes expressing TRP-1. In other experiments, cultured human fibroblasts were transfected with a cDNA for TRP-1, in either the sense or antisense direction, or with the retroviral vector alone. TRP-1 expression was induced in fibroblasts transfected with the TRP-1 cDNA in the sense direction only. Although TRP-1 was expressed by sense-transfected cells, there was no significant DHICA oxidase activity above controls. These results demonstrate that human TRP-1 does not use DHICA as a substrate for oxidation. C1 Univ Cincinnati, Coll Med, Dept Dermatol, Cincinnati, OH 45267 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Boissy, RE (reprint author), Univ Cincinnati, Coll Med, Dept Dermatol, 231 Bethesda Ave,Mail Locat 0592, Cincinnati, OH 45267 USA. EM boissyre@email.uc.edu FU NIAMS NIH HHS [AR43368] NR 46 TC 57 Z9 58 U1 0 U2 1 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 AUG PY 1998 VL 7 IS 4 BP 198 EP 204 DI 10.1111/j.1600-0625.1998.tb00324.x PG 7 WC Dermatology SC Dermatology GA 119YH UT WOS:000075925900013 PM 9758418 ER PT J AU Kador, PF Inoue, J Secchi, EF Lizak, MJ Rodriguez, L Mori, K Greentree, W Blessing, K Lackner, PA Sato, S AF Kador, PF Inoue, J Secchi, EF Lizak, MJ Rodriguez, L Mori, K Greentree, W Blessing, K Lackner, PA Sato, S TI Effect of sorbitol dehydrogenase inhibition on sugar cataract formation in galactose-fed and diabetic rats SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE cataract; sorbitol dehydrogenase; aldose reductase; inhibitors; galactosemia; diabetes ID ALDOSE REDUCTASE; FED DOGS; LENS; COMPLICATIONS; PURIFICATION AB Several recent studies with the sorbitol dehydro gen a se inhibitors 4-[4-(N,N-dimethylsulfamoyl)piperazino]-2-methylpyrimidine, SDH-1, and its active metabolite 4-[4-(N, N-dimethylsulfamoyl)piperazino]-2-hydroxymethylpyrimidine, SDH-2, suggest that inhibition of sorbitol dehydrogenase may be beneficial in delaying the onset of diabetic complications due to their ability to ameliorate redox changes associated with polyol metabolism. To compare the relative importance of sorbitol dehydrogenase versus aldose reductase inhibition on sugar cataract formation, cataract formation was monitored in 50% galactose-fed and diabetic rats treated with/without the sorbitol dehydrogenase inhibitors SDH-1 or SDH-2 or the aldose reductase inhibitors AL 1576 or Ponalrestat, For these studies, diabetes was induced in young 50 g rats with streptozotocin while galactosemia was produced by feeding a diet containing 50% galactose. Inhibitors were administered in the diet with the diet containing 0.06% (w/w) of the sorbitol dehydrogenase inhibitors or Ponalrestat, and 0.0125% (w/w) of AL 1576. Cataract formation was monitored by hand-held slit lamp and polyol levels were measured by gas chromatography. Sugar cataract formation was accelerated in diabetic rats treated with sorbitol dehydrogenase inhibitors while no difference in cataract formation was observed in galactose-fed rats treated with/without SDH inhibitors. Cataract formation was inhibited in both diabetic and galactosemic rats by either Ponalrestat or AL 1576. These results support the concept that sugar cataract formation is initiated by the aldose reductase catalysed intracellular accumulation of polyols and that these sugar cataracts can be prevented through inhibition of aldose reductase. (C) 1998 Academic Press. C1 NEI, Lab Ocular Therapeut, NIH, Bethesda, MD 20892 USA. Senju Pharmaceut Co Inc, Creat Ctr, Kobe, Hyogo, Japan. RP Kador, PF (reprint author), NEI, Lab Ocular Therapeut, NIH, 10 Ctr Dr,MSC 1850,Bldg 10,Room 10B11, Bethesda, MD 20892 USA. NR 21 TC 34 Z9 38 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 AUG PY 1998 VL 67 IS 2 BP 203 EP 208 DI 10.1006/exer.1998.0502 PG 6 WC Ophthalmology SC Ophthalmology GA 119PF UT WOS:000075904600008 PM 9733586 ER PT J AU Nakamura, E Lane, MA Roth, GS Ingram, DK AF Nakamura, E Lane, MA Roth, GS Ingram, DK TI A strategy for identifying biomarkers of aging: Further evaluation of hematology and blood chemistry data from a calorie restriction study in rhesus monkeys SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE nutrition; development; albumin; creatinine; alkaline phosphatase; calcium; lymphocyte ID MACAQUES MACACA-NEMESTRINA; DIETARY RESTRICTION; PIGTAILED MACAQUES; BIOLOGICAL AGE; LYMPHOCYTE SUBSETS; NONHUMAN-PRIMATES; SERUM-ALBUMIN; HEALTH-STATUS; LIFE-SPAN; MULATTA AB We examined a dataset derived from a battery of hematology and blood chemistry tests to identify candidate biomarkers of aging in a sample of 33 male rhesus monkeys (Macaca mulatta) ranging in age from 4-27 years. About half this sample comprised an experimental: group subjected to 30% calorie restriction for six to seven years compared to the control group fed the same nutritionally fortified diet to approximate ad lib levels. Variables that met the following criteria were selected: (1) longitudinal change within the cohorts of control monkeys, (2) cross-sectional correlation with age across the adult lifespan in the control group; (3) stability of individual differences within all groups; and (4) no obvious redundancy with other selected variables, Five variables emerged from this step-wise selection, including the percentage lymphocytes, and serum levels of alkaline phosphatase, albumin, creatinine, and calcium. These variables were then submitted to a principal component analysis, which yielded a single component accounting for about 58% of the total variance. Based on this marked degree of covariance, these candidate biomarkers of aging could he combined into a biological age score (BAS) for the control and experimental groups. When chronological age was regressed onto BAS, the slopes of the control and experimental groups could be compared. Although a trend toward a slower aging rate in calorie-restricted monkeys was apparent, this analysis did not detect a statistically significant difference in the rate of aging between these groups estimated by this index. Despite this result, a logical strategy was confirmed for expanding the search for candidate biomarkers of aging to apply to this and to other studies assessing interventions that purport to affect the rate of aging in long-lived species. Published by Elsevier Science Inc. C1 NIA, Mol Physiol & Genet Sect, Nathan W Shock Labs, Gerontol Res Ctr,NIH, Baltimore, MD 21224 USA. Kyoto Univ, Fac Integrated Human Studies, Div Nat Environm Sci, Kyoto 606, Japan. RP Ingram, DK (reprint author), NIA, Mol Physiol & Genet Sect, Nathan W Shock Labs, Gerontol Res Ctr,NIH, Johns Hopkins Bayview Campus,4940 Eastern Ave, Baltimore, MD 21224 USA. NR 74 TC 33 Z9 33 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD AUG PY 1998 VL 33 IS 5 BP 421 EP 443 DI 10.1016/S0531-5565(97)00134-4 PG 23 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 105EU UT WOS:000075060400005 PM 9762521 ER PT J AU Shefer, VI Talan, MI AF Shefer, VI Talan, MI TI The effect of exercise training in cold on shivering and nonshivering thermogenesis in adult and aged C57BL/6J mice SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE body temperature; cold tolerance; heat production; rodents; thermoregulation; anesthesia; myorelaxation ID BROWN ADIPOSE-TISSUE; HEAT-PRODUCTION; RATS; EXPOSURE; NOREPINEPHRINE; ACCLIMATION; TOLERANCE AB To understand the mechanisms of improvement of cold-induced heat production in aged mice following exercise training, the relative contributions of shivering and nonshivering thermogenesis to cold-induced metabolic responses were assessed in adult and aged C57BL/6J male mice, which inhabited sedentarily at room temperature, or were subjected either to a regimen of moderate intensity exercise training at 6 degrees C, or to sedentary repeated exposures to the same temperature. The main findings were that (1) aged mice had greater cold-induced nonshivering thermogenesis, but lower shivering than adult mice; (2) exercise training in a cold environment enhanced cold-induced nonshivering thermogenesis in adult mice, but suppressed it in aged animals, (3) exercise training in a cold environment increased shivering thermogenesis in both age groups, but this increase was much greater in aged mice; (4) the increase of cold-induced shivering thermogenesis was mainly responsible for increased cold tolerance in aged mice after exercise training in a cold environment. (C) 1998 Elsevier Science Inc. C1 NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. NIA, Behav Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Talan, MI (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 27 TC 2 Z9 2 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD AUG PY 1998 VL 33 IS 5 BP 467 EP 476 DI 10.1016/S0531-5565(98)00009-6 PG 10 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 105EU UT WOS:000075060400008 PM 9762524 ER PT J AU Bhalla, KN Kreitman, RJ Hall, P Frankel, A AF Bhalla, KN Kreitman, RJ Hall, P Frankel, A TI Diphtheria toxin fused to GM-CSF in combination Ara-C exerts synergistic toxicity to human AML (HL60) cells. SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 Emory Univ, Sch Med, Div Hematol, Atlanta, GA USA. NIH, Bethesda, MD USA. Med Univ S Carolina, Charleston, SC USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD AUG PY 1998 VL 26 IS 8 MA 50 BP 696 EP 696 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 118GT UT WOS:000075830600052 ER PT J AU Warren, MK Zujewski, J Hakim, F Gress, RE Schwartz, GN AF Warren, MK Zujewski, J Hakim, F Gress, RE Schwartz, GN TI Reduced numbers of megakaryocyte and primitive progenitors in marrow after mobilization with cyclophosphamide plus G-CSF. SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 NCI, Med Branch, Bethesda, MD 20892 USA. Poiet Technol Inc, Gaithersburg, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD AUG PY 1998 VL 26 IS 8 MA 81 BP 706 EP 706 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 118GT UT WOS:000075830600083 ER PT J AU Krosl, G He, G Lefrancois, M Charron, F Romeo, PH Jolicoeur, P Kirsch, IR Nemer, M Hoang, T AF Krosl, G He, G Lefrancois, M Charron, F Romeo, PH Jolicoeur, P Kirsch, IR Nemer, M Hoang, T TI Transcription factor SCL is required for C-Kit expression and C-Kit function in hemopoietic cells. SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 Clin Res Inst Montreal, Montreal, PQ H2W 1R7, Canada. Hop Henri Mondor, INSERM, U91, F-94010 Creteil, France. Naval Med Ctr, Natl Canc Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD AUG PY 1998 VL 26 IS 8 MA 217 BP 741 EP 741 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 118GT UT WOS:000075830600219 ER PT J AU Frankel, A Eaves, C Hall, P Kreitman, R Lilly, M Beran, M Freedman, M Emanuel, P Tagge, E Berger, M Willman, C Hogge, D AF Frankel, A Eaves, C Hall, P Kreitman, R Lilly, M Beran, M Freedman, M Emanuel, P Tagge, E Berger, M Willman, C Hogge, D TI Diphtheria toxin fused to human GM-CSF is toxic to primary malignant progenitors from patients with AML, JMML and CMML. SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 BC Canc Agcy, Terry Fox Lab, Vancouver, BC, Canada. NIH, Bethesda, MD USA. Univ Washington, Seattle, WA USA. Md Anderson Canc Ctr, Houston, TX USA. Hosp Sick Children, Toronto, ON, Canada. Univ Alabama, Birmingham, AL USA. Med Univ S Carolina, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD AUG PY 1998 VL 26 IS 8 MA 229 BP 745 EP 745 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 118GT UT WOS:000075830600231 ER PT J AU Fukazawa, M Gress, RE Schwartz, GN AF Fukazawa, M Gress, RE Schwartz, GN TI Early effects of IGF-II on extracellular acidification rates and cell cycle kinetics of megakaryoblastic CMK cells. SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 NCI, Med Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD AUG PY 1998 VL 26 IS 8 MA 316 BP 770 EP 770 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 118GT UT WOS:000075830600318 ER PT J AU Nolta, JA Arakawa-Hoyt, J Dao, MA Barsky, L Puck, J Weinberg, KI AF Nolta, JA Arakawa-Hoyt, J Dao, MA Barsky, L Puck, J Weinberg, KI TI IL-2 responsive human T lymphocytes develop in BNX mice from X-SCID CD34+ progenitors transduced with a normal gamma c gene. SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 Childrens Hosp Los Angeles, Div Res Immunol BMT, Los Angeles, CA 90027 USA. NCHGR, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD AUG PY 1998 VL 26 IS 8 MA 452 BP 806 EP 806 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 118GT UT WOS:000075830600454 ER PT J AU Jenkins, NA Copeland, NG AF Jenkins, NA Copeland, NG TI Myeloid leukemia: Disease genes and mouse models. SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 NCI, Mammalian Genet Lab, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD AUG PY 1998 VL 26 IS 8 MA 483 BP 816 EP 816 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 118GT UT WOS:000075830600485 ER PT J AU Bayewitch, ML Avidor-Reiss, T Levy, R Pfeuffer, T Nevo, I Simonds, WF Vogel, Z AF Bayewitch, ML Avidor-Reiss, T Levy, R Pfeuffer, T Nevo, I Simonds, WF Vogel, Z TI Inhibition of adenylyl cyclase isoforms V and VI by various G(beta gamma) subunits SO FASEB JOURNAL LA English DT Article DE G(beta gamma); signal transduction; inhibition; plasmid ID BETA-GAMMA-SUBUNITS; EXPRESSION; CLONING; ACTIVATION; CELLS; SPECIFICITY; MODULATION; RECEPTORS; CHANNELS; PROTEINS AB An intriguing development in the G-protein signaling field has been the finding that not only the G(alpha) subunit, but also G(beta gamma) subunits, affect a number of downstream target molecules. One of the downstream targets of G(beta gamma) is adenylyl cyclase, and it has been demonstrated that a number of isoforms of adenylyl cyclase can be either inhibited or stimulated by G(beta gamma) subunits. Until now, adenylyl cyclase type I has been the only isoform reported to be inhibited by free G(beta gamma). Here we show by transient cotransfection into COS-7 cells of either adenylyl cyclase V or VI, together with G gamma(gamma 2) and various G(beta) subunits, that these two adenylyl cyclase isozymes are markedly inhibited by G(beta gamma). In addition, we show that G(beta 1) and G(beta 5) subunits differ in their activity. G(beta 1) transfected alone markedly inhibited adenylyl cylcase V and VI (probably by recruiting endogenous G(gamma) subunits). On the other hand, G(beta 5) produced less inhibition of these isozymes, and its activity was enhanced by the addition of G(gamma 2). These results demonstrate that adenylyl cyclase types V and VI are inhibited by G(beta gamma) dimers and that G(beta 1) and G(beta 5) Subunits differ in their capacity to regulate these adenylyl cyclase isozymes. C1 Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. Univ Dusseldorf, Dept Physiol Chem 2, D-40225 Dusseldorf, Germany. NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Vogel, Z (reprint author), Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. EM bnvogel@weizmann.weizmann.ac.il FU NIDA NIH HHS [DA-06265] NR 41 TC 67 Z9 68 U1 0 U2 0 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 AUG PY 1998 VL 12 IS 11 BP 1019 EP 1025 PG 7 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 110GR UT WOS:000075372600012 PM 9707174 ER PT J AU Chen, Z Notohamiprodjo, M Guan, XY Paietta, E Blackwell, S Stout, K Turner, A Richkind, K Trent, JM Lamb, A Sandberg, AA AF Chen, Z Notohamiprodjo, M Guan, XY Paietta, E Blackwell, S Stout, K Turner, A Richkind, K Trent, JM Lamb, A Sandberg, AA TI Gain of 9p in the pathogenesis of polycythemia vera SO GENES CHROMOSOMES & CANCER LA English DT Article ID GENE; DISORDERS AB Polycythemia vera (PV) is a clonal stem cell disorder characterized by excessive erythrocyte production, resulting in absolute erythrocytosis. No specific structural chromosomal abnormalities have been reported in PV to date. We have observed two cases of PV with an extra i(9)(p10) as the sole anomaly, and FISH analysis using a 9p-specitic chromosome microdissection probe showed that two other PV patients previously identified as having an add( 18p) and an add(lp) as the primary changes actually carried a der(18)t(9; 18)(p 12;p 11.2) and a der( l)t(1;9)(p 12;p 12), respectively. The same FISH assay was employed to evaluate domain signals on interphase cells of 15 more cases of PV with normal karyotypes and five normal controls. Two patients were observed with a significant increase in the percentage of cells with three domain signals. Our results strongly indicate that an additional i(9)(p 10) is a new and recurrent primary chromosome anomaly in PV, and, in consideration of trisomy 9 being one of the most common anomalies in PV, amplification of a gene or genes on 9p, but not on 9q, may play a crucial role in the pathogenesis of PV. (C) 1998 Wiley-Liss, Inc. C1 Genzyme Genet, Santa Fe, NM 87505 USA. NIH, Natl Ctr Human Genome Res, Bethesda, MD 20892 USA. Montefiore Med Ctr, Bronx, NY 10467 USA. RP Sandberg, AA (reprint author), Genzyme Genet, 2000 Vivigen Way, Santa Fe, NM 87505 USA. RI Guan, Xin-Yuan/A-3639-2009 OI Guan, Xin-Yuan/0000-0002-4485-6017 NR 15 TC 24 Z9 26 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 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD AUG PY 1998 VL 22 IS 4 BP 321 EP 324 DI 10.1002/(SICI)1098-2264(199808)22:4<321::AID-GCC8>3.0.CO;2-X PG 4 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA ZX625 UT WOS:000074537100008 PM 9669670 ER PT J AU Slade, RW Moritz, C Hoelzel, AR Burton, HR AF Slade, RW Moritz, C Hoelzel, AR Burton, HR TI Molecular population genetics of the southern elephant seal Mirounga leonina SO GENETICS LA English DT Article ID HUMAN MITOCHONDRIAL-DNA; CHINOOK SALMON POPULATIONS; MALE MATING SUCCESS; NUCLEOTIDE SUBSTITUTIONS; STATISTICAL TESTS; RESTRICTION DATA; EVOLUTION; SEQUENCES; POLYMORPHISM; PERSPECTIVES AB Southern elephant seals breed on sub-Antarctic islands and have a circumpolar distribution. We assayed mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) variation in the three main populations in the south Atlantic, south Indian, and south Pacific oceans, and a smaller continental population in South America. Population structure of mtDNA was strong and not consistent with isolation by distance. The nDNA loci, although less informative, were consistent with the mtDNA results. Geographic structure appears to be dominated by historical processes, not contemporary gene flow. Uncorrected levels of nucleotide diversity for mtDNA control region I (2.86%) and nDNA (0.09%) were similar to those in humans and mice. Mutation rates for control region I (75 x 10(-9) substitutions per site per year) and nDNA (1.23 x 10(-9)) were similar to those in other mammals. Female effective population size and total effective population size were roughly equal at similar to 4 x 10(4), indicating a twofold greater rate of drift for mtDNA. Effective breeding sex ratio of four to five females per male was estimated from nucleotide diversity and mutation rates for mtDNA and nDNA, and was much less than behavioral observations would suggest. There was no evidence for selection at any of the assayed loci. C1 Univ Queensland, Dept Zool, Brisbane, Qld 4072, Australia. Univ Queensland, Ctr Cellular & Mol Biol, Brisbane, Qld 4072, Australia. Australian Antarctic Div, Kingston, Tas 7002, Australia. NCI, Frederick, MD 21702 USA. RP Slade, RW (reprint author), Royal Brisbane Hosp, Queensland Inst Med Res, Brisbane, Qld 4029, Australia. EM roberts@qimr.edu.au RI Moritz, Craig/A-7755-2012 NR 81 TC 73 Z9 77 U1 2 U2 17 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD AUG PY 1998 VL 149 IS 4 BP 1945 EP 1957 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 107VR UT WOS:000075232100026 PM 9691049 ER PT J AU Pruitt, KD AF Pruitt, KD TI WebWise: Guide to the University of Oklahoma's Advanced Center for Genome Technology web site SO GENOME RESEARCH LA English DT Article C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Pruitt, KD (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1054-9803 J9 GENOME RES JI Genome Res. PD AUG PY 1998 VL 8 IS 8 BP 763 EP 767 PG 5 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 115PT UT WOS:000075674400003 PM 9724322 ER PT J AU Galperin, MY Walker, DR Koonin, EV AF Galperin, MY Walker, DR Koonin, EV TI Analogous enzymes: Independent inventions in enzyme evolution SO GENOME RESEARCH LA English DT Article ID COMPLETE GENOME SEQUENCE; PURINE NUCLEOSIDE PHOSPHORYLASE; ESCHERICHIA-COLI; FRUCTOSE-1,6-BISPHOSPHATE ALDOLASE; STRUCTURAL CLASSIFICATION; PROTEIN SEQUENCES; BACTERIAL GENOMES; CRYSTAL-STRUCTURE; ACTIVE-SITE; DATABASE AB It is known that the same reaction may be catalyzed by structurally unrelated enzymes. We performed a systematic search for such analogous (as opposed to homologous) enzymes by evaluating sequence conservation among enzymes with the same enzyme classification (EC) number using sensitive, iterative sequence database search methods. Enzymes without detectable sequence similarity to each other were found for 105 EC numbers (a total of 243 distinct proteins). In 34 cases, independent evolutionary origin of the suspected analogous enzymes was corroborated by showing that they possess different structural folds. Analogous enzymes were found in each class of enzymes, but their overall distribution on the map of biochemical pathways is patchy, suggesting multiple events of gene transfer and selective loss in evolution, rather than acquisition of entire pathways catalyzed by a set of unrelated enzymes. Recruitment of enzymes that catalyze a similar but distinct reaction seems to be a major scenario for the evolution of analogous enzymes, which should be taken into account for functional annotation of genomes. For many analogous enzymes, the bacterial form of the enzyme is different from the eukaryotic one; such enzymes may be promising targets for the development of new antibacterial drugs. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RI Galperin, Michael/B-5859-2013 OI Galperin, Michael/0000-0002-2265-5572 NR 69 TC 153 Z9 156 U1 3 U2 6 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1054-9803 J9 GENOME RES JI Genome Res. PD AUG PY 1998 VL 8 IS 8 BP 779 EP 790 PG 12 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 115PT UT WOS:000075674400005 PM 9724324 ER PT J AU Wei, XX Elizondo, G Sapone, A McLeod, HL Raunio, H Fernandez-Salguero, P Gonzalez, FJ AF Wei, XX Elizondo, G Sapone, A McLeod, HL Raunio, H Fernandez-Salguero, P Gonzalez, FJ TI Characterization of the human dihydropyrimidine dehydrogenase gene SO GENOMICS LA English DT Article ID 5-FLUOROURACIL TOXICITY; MOLECULAR-BASIS; DEFICIENCY; DRUG; CHEMOTHERAPY; THYMINE; IDENTIFICATION; POLYMORPHISM; DEGRADATION; SORIVUDINE AB Dihydropyrimidine dehydrogenase (DPD) catabolizes endogenous pyrimidines and pyrimidine-based antimetabolite drugs. A deficiency in human DPD is associated with congenital thymine-uraciluria in pediatric patients and severe 5-fluorouracil toxicity in cancer patients. The dihydropyrimidine dehydrogenase gene (DPYD) was isolated, and its physical map and exon-intron organization were determined by analysis of P1, PAC, BAG, and YAC clones. The DPYD gene was found to contain 23 exons ranging in size from 69 bp (exon 15) to 961 bp (exon 23), A physical map derived from a YAC clone indicated that DPYD is at least 950 kb in length with 3 kb of coding sequence and an average intron size of about 43 kb, The previously reported 5' donor splice site mutation present in pediatric thymine-uraciluria and cancer patients can now be assigned to exon 14. All 23 exons were sequenced from a series of human DNA samples, and three point mutations were identified in three racial groups as G1601A (exon 13, Ser534Asn), A1627G (exon 13, Ile543Val), and G2194A (exon 18, Val732Ile). These studies, which have established that the DPYD gene is unusually large, lay a framework for uncovering new mutations that are responsible for thymine-uraciluria and toxicity to fluoropyrimidine drugs. (C) 1998 Academic Press C1 NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. Univ Aberdeen, Dept Med & Therapeut, Aberdeen AB9 2ZD, Scotland. Univ Oulu, Dept Pharmacol & Toxicol, Oulu, Finland. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, NIH, Bldg 37,Room 3E-24, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov RI Sapone, Andrea/E-6704-2013; OI Sapone, Andrea/0000-0001-8496-6977; Fernandez-Salguero, Pedro M./0000-0003-2839-5027 NR 39 TC 108 Z9 115 U1 0 U2 4 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 AUG 1 PY 1998 VL 51 IS 3 BP 391 EP 400 DI 10.1006/geno.1998.5379 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 115PN UT WOS:000075674000009 PM 9721209 ER PT J AU Kadar, N AF Kadar, N TI Quasi-randomized trials - Reply SO GYNAECOLOGICAL ENDOSCOPY LA English DT Letter ID ACTIVE MANAGEMENT; LABOR C1 Englewood Hosp & Med Ctr, Englewood, CO USA. NICHHD, Bethesda, MD 20892 USA. RP Kadar, N (reprint author), Englewood Hosp & Med Ctr, Englewood, CO USA. NR 2 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0962-1091 J9 GYNAECOL ENDOSC JI Gynaecol. Endosc. PD AUG PY 1998 VL 7 IS 4 BP 219 EP 220 DI 10.1046/j.1365-2508.1998.00183.x PG 2 WC Obstetrics & Gynecology; Surgery SC Obstetrics & Gynecology; Surgery GA 142BB UT WOS:000077179100009 ER PT J AU Glanz, K Patterson, RE Kristal, AR Feng, ZD Linnan, L Heimendinger, J Hebert, JR AF Glanz, K Patterson, RE Kristal, AR Feng, ZD Linnan, L Heimendinger, J Hebert, JR TI Impact of work site health promotion on stages of dietary change: The working well trial SO HEALTH EDUCATION & BEHAVIOR LA English DT Article ID SMOKING CESSATION; BEHAVIOR-CHANGE; PSYCHOSOCIAL DETERMINANTS; VEGETABLE CONSUMPTION; FAT REDUCTION; INTERVENTION; LIKELIHOOD; PREDICTORS; MODELS; FRUIT AB The stages of change construct has been applied to healthful dietary behavior in cross-sectional studies. This report examines associations of stages of change with diet prospectively and addresses whether (1) baseline stage of change predicts participation, (2) forward changes in stage movement were greater in treatment work sites, and (3) change in stage was associated with adoption of healthful diets, using data from a cohort of 11,237 employees. Findings indicate that persons in later stages of change reported higher participation levels. Employees from intervention work sites who were in preaction stages at baseline were much more likely to shift into action and maintenance stages than controls. Changes in dietary stage of change were associated with decreases in fat intake and increases in fiber, fruit and vegetable intake. Net change in diet due to the intervention was modest. Stage of change appears to be useful for understanding mediators of health promotion intervention effectiveness. C1 Univ Hawaii, Canc Res Ctr Hawaii, Prevent & Control Program, Honolulu, HI 96813 USA. Fred Hutchinson Canc Res Ctr, Canc Prevent Res Program, Seattle, WA USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Brown Univ, Miriam Hosp, Providence, RI USA. AMC Canc Res Ctr, Denver, CO USA. NCI, Bethesda, MD 20892 USA. Univ Massachusetts, Sch Med, Div Prevent Med & Behav Med, Worcester, MA USA. Univ Massachusetts, Sch Med, Canc Prevent & Control Canc Ctr, Worcester, MA USA. RP Glanz, K (reprint author), Univ Hawaii, Canc Res Ctr Hawaii, Prevent & Control Program, 1236 Lauhala St,Suite 406, Honolulu, HI 96813 USA. OI Kristal, Alan/0000-0002-7329-1617 FU NCI NIH HHS [U01 CA51671, U01 CA51686, U01 CA51687] NR 45 TC 50 Z9 50 U1 2 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1090-1981 J9 HEALTH EDUC BEHAV JI Health Educ. Behav. PD AUG PY 1998 VL 25 IS 4 BP 448 EP 463 DI 10.1177/109019819802500404 PG 16 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 102PP UT WOS:000074933300004 PM 9690103 ER PT J AU Nagy, P Kiss, A Schnur, J Thorgeirsson, SS AF Nagy, P Kiss, A Schnur, J Thorgeirsson, SS TI Dexamethasone inhibits the proliferation of hepatocytes and oval cells but not bile duct cells in rat liver SO HEPATOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; BILIARY EPITHELIAL-CELLS; LEAD NITRATE; GROWTH-FACTORS; MESSENGER-RNA; PARTIAL-HEPATECTOMY; ETHYLENE DIBROMIDE; PRIMARY CULTURES; NITRIC-OXIDE; INTERLEUKIN-6 AB Recent advances have implicated the importance of tumor necrosis factor (TNF) and interleukin 6 (IL-6) in the regulation of liver growth, Therefore, we studied how dexamethasone, a well-known inhibitor of these cytokines, influences the proliferation of different hepatic cell populations. As we expected, dexamethasone pretreatment suppressed the expression of both TNF and IL-6 after partial hepatectomy and significantly reduced the proliferative response of the hepatocytes. Furthermore, the proliferative response of hepatocytes could be rescued by IL-6 administration. Dexamethasone also severely diminished the induction and expansion of oval cells induced by the 2-acetylaminofluorene/partial hepatectomy (AAF/PH) protocol but did not have any effect on the proliferation of the bile duct cells stimulated by bile duct ligation. The differential inhibition of these two morphologically very similar cell types may be used to characterize divergent regulatory mechanisms responsible for the proliferative response of oval cells and adult bile epithelial cells. C1 Semmelweis Univ Med, Inst Pathol 1, H-1085 Budapest, Hungary. NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Nagy, P (reprint author), Semmelweis Univ Med, Inst Pathol 1, Ulloi Ut 26, H-1085 Budapest, Hungary. NR 36 TC 71 Z9 74 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD AUG PY 1998 VL 28 IS 2 BP 423 EP 429 DI 10.1002/hep.510280220 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 105UM UT WOS:000075092000020 PM 9696007 ER PT J AU Jensen, MR Factor, VM Thorgeirsson, SS AF Jensen, MR Factor, VM Thorgeirsson, SS TI Regulation of cyclin G1 during murine hepatic regeneration following dipin-induced DNA damage SO HEPATOLOGY LA English DT Article ID CELL-CYCLE; MESSENGER-RNA; LIVER-REGENERATION; GROWTH ARREST; G GENE; PROTEIN; P53; EXPRESSION; KINASE; MOUSE AB Cyclin G1 has been linked to both positive and negative growth regulation. The expression of cyclin G1 is induced by transforming growth factor beta(1) and p53, as well as by multiple mitogenic stimuli in mammalian cells in culture. However, the physiological role of cyclin G1 remains unclear. To examine the cell-cycle regulation of cyclin G1 in vivo, two models of coordinated cell proliferation induced by partial hepatectomy (PH) in the presence or absence of DNA damage were used. To introduce DNA damage, mice were treated with the alkylating drug, 1,4-bis[N,N'-di(ethylene)-phosphamide]piperazine (Dipin) 2 hours before PH. Cell-cycle progression was monitored by 5-bromo-2-deoxyuridine (BrdU) incorporation into the DNA, the frequency of mitoses, the expression of cell-cycle control genes, and by flow cytometry. Dipin treatment resulted in cell-cycle arrest at the G2/M boundary without affecting G0/G1 and G1/S transitions. While the hepatocytes progressively entered G2 phase arrest, the cyclin G1 mRNA and protein levels increased more than five- and eightfold, respectively. Cyclin G1 had a nuclear localization in all interphase cells with clear absence from nucleoli. In contrast, during mitosis, cyclin G1 was undetectable by immunohistochemistry. Taken together, our data provide evidence for a putative role of cyclin G1 in G2/M checkpoint control. C1 NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Thorgeirsson, SS (reprint author), NCI, Expt Carcinogenesis Lab, NIH, Bldg 37,Room 3C28,37 Convent Dr MSC4255, Bethesda, MD 20892 USA. RI Jensen, Michael/E-9677-2011 NR 50 TC 25 Z9 26 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD AUG PY 1998 VL 28 IS 2 BP 537 EP 546 DI 10.1002/hep.510280235 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 105UM UT WOS:000075092000035 PM 9696022 ER PT J AU Kidd, KK Morar, B Castiglione, CM Zhao, HY Pakstis, AJ Speed, WC Bonne-Tamir, B Lu, RB Goldman, D Lee, CY Nam, YS Grandy, DK Jenkins, T Kidd, JR AF Kidd, KK Morar, B Castiglione, CM Zhao, HY Pakstis, AJ Speed, WC Bonne-Tamir, B Lu, RB Goldman, D Lee, CY Nam, YS Grandy, DK Jenkins, T Kidd, JR TI A global survey of haplotype frequencies and linkage disequilibrium at the DRD2 locus SO HUMAN GENETICS LA English DT Article ID DOPAMINE-D2 RECEPTOR GENE; D2-DOPAMINE RECEPTOR; CLADISTIC-ANALYSIS; DNA POLYMORPHISMS; MODERN HUMANS; D2; SCHIZOPHRENIA; REGION; ASSOCIATION; POPULATION AB A four-site haplotype system at the dopamine D2 receptor locus (DRD2) has been studied in a global sample of 28 distinct populations. The haplotype system spans about 25 kb, encompassing the coding region of the gene. The four individual markers include three TaqI restriction site polymorphisms (RSPs) - TaqI "A", "B", and "D" sites - and one dinucleotide short tandem repeat polymorphism (STRP). All four of the marker systems are polymorphic in all regions of the world and in most individual populations. The haplotype system shows the highest average heterozygosity in Africa, a slightly lower average heterozygosity in Europe, and the lowest average heterozygosities in East Asia and the Americas. Across all populations, 20 of the 48 possible haplotypes reached a frequency of at least 5% in at least one population sample. However, no single population had more than six haplotypes reaching that frequency. In general, African populations had more haplotypes present in each population and more haplotypes occurring at a frequency of at least 5% in that population. Permutation tests for significance of overall disequilibrium tall sites considered simultaneously) were highly significant (P < 0.001) in all 28 populations. Except for three African samples, the pairwise disequilibrium between the outermost RSP markers, TaqI "B" and "A", was highly significant with D' values greater than 0.8; in two of those exceptions the RSP marker was not polymorphic. Except for those same two African populations, the 16-repeat allele at the STRP also showed highly significant disequilibrium with the TaqI "B" site in all populations, with D' values usually greater than 0.7. Only four haplotypes account for more than 70% of all chromosomes in virtually all non-African populations, and two of those haplotypes account for more than 70% of all chromosomes in most East Asian and Amerindian populations. A new measure of the amount of overall disequilibrium shows least disequilibrium in African populations, somewhat more in European populations, and the greatest amount in East Asian and Amerindian populations. This pattern seems best explained by random genetic drift with low levels of recombination, a low mutation rate at the STRP, and essentially no recurrent mutation at the RSP sites, all in conjunction with an "Out of Africa" model for recent human evolution. C1 Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA. Yale Univ, Sch Med, Dept Epidemiol, New Haven, CT 06520 USA. SAIMR, Dept Human Genet, Johannesburg, South Africa. Univ Witwatersrand, Johannesburg, South Africa. Tel Aviv Univ, Sackler Sch Med, Dept Human Genet, IL-69978 Tel Aviv, Israel. Natl Def Med Ctr, Tri Serv Gen Hosp, Dept Psychiat, Taipei, Taiwan. NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. Hallym Univ, Inst Environm & Life Sci, Lab Stat Genet, Chuncheon 200702, South Korea. Korea Univ, Dept Legal Med, Seoul 136701, South Korea. Oregon Hlth Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97201 USA. RP Kidd, KK (reprint author), Yale Univ, Sch Med, Dept Genet, 333 Cedar St, New Haven, CT 06520 USA. EM kidd@biomed.med.yale.edu RI Lee, Chaeyoung/C-7929-2012; Morar, Bharti/O-8697-2014; Goldman, David/F-9772-2010 OI Lee, Chaeyoung/0000-0002-2940-1778; Goldman, David/0000-0002-1724-5405 FU NIAAA NIH HHS [AA09379]; NIMH NIH HHS [MH30929, MH39239] NR 61 TC 158 Z9 160 U1 2 U2 5 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD AUG PY 1998 VL 103 IS 2 BP 211 EP 227 DI 10.1007/s004390050809 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA 121VP UT WOS:000076035600017 PM 9760208 ER PT J AU Singh, JP Larson, MG Tsuji, H Evans, JC O'Donnell, CJ Levy, D AF Singh, JP Larson, MG Tsuji, H Evans, JC O'Donnell, CJ Levy, D TI Reduced heart rate variability and new-onset hypertension - Insights into pathogenesis of hypertension: The Framingham Heart Study SO HYPERTENSION LA English DT Article DE heart rate; hypertension, essential; Framingham Heart Study; autonomic nervous system; pathogenesis ID SPECTRAL-ANALYSIS; MORTALITY; DISEASE; WOMEN; RISK AB Heart rate variability (HRV) is a useful noninvasive tool to assess cardiac autonomic function. The purpose of this study was to (1) compare measures of HRV between hypertensive and normotensive subjects and (2) examine the role of HRV as a predictor of new-onset hypertension. The first 2 hours of ambulatory ECG recordings obtained from 931 men and 1111 women attending a routine examination at the Framingham Heart Study were processed for HRV. Three time-domain and 5 frequency-domain variables were studied: standard deviation of normal RR intervals (SDNN), percentage of differences between adjacent normal RR intervals exceeding 50 milliseconds, square root of the mean of squared differences between adjacent normal RR intervals, total power (0.01 to 0.40 Hz), high frequency power (HF, 0.15 to 0.40 Hz), low frequency power (LF, 0.04 to 0.15 Hz), very low frequency power (0.01 to 0.04 Hz), and LF/HF ratio. On cross-sectional analysis, HRV was significantly lower in hypertensive men and women. Among 633 men and 801 women who were normotensive at baseline (systolic blood pressure <140 mm Hg and diastolic blood pressure <90 mm Hg and not receiving antihypertensive treatment), 119 men and 125 women were newly hypertensive at follow-up 4 years later. After adjustment for factors associated with hypertension, multiple logistic regression analysis revealed that LF was associated with incident hypertension in men (odds ratio per SD decrement [OR], 1.38; 95% confidence interval [CI], 1.04 to 1.83) but not in women (OR, 1.12; 95% CI, 0.86 to 1.46). SDNN, HF, and LF/HF were not associated with hypertension in either sex. HRV is reduced in men and women with systemic hypertension. Among normotensive men, lower HRV was associated with greater risk for developing hypertension. These findings are consistent with the hypothesis that autonomic dysregulation is present in the early stage of hypertension. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. Boston Univ, Sch Med, Div Epidemiol & Prevent Med, Boston, MA USA. Beth Israel Hosp, Div Cardiol, Boston, MA 02215 USA. Beth Israel Hosp, Div Clin Epidemiol, Boston, MA 02215 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Cardiac Unit, Boston, MA USA. Kansai Med Univ, Osaka, Japan. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, 5 Thurber St, Framingham, MA 01702 USA. EM dan@fram.nhlbi.nih.gov FU NHLBI NIH HHS [N01-HC-38038] NR 29 TC 234 Z9 259 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD AUG PY 1998 VL 32 IS 2 BP 293 EP 297 PG 5 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 112RV UT WOS:000075508700016 PM 9719057 ER PT J AU Pagano, PJ Chanock, SJ Siwik, DA Colucci, WS Clark, JK AF Pagano, PJ Chanock, SJ Siwik, DA Colucci, WS Clark, JK TI Angiotensin II induces p67(phox) mRNA expression and NADPH oxidase superoxide generation in rabbit aortic adventitial fibroblasts SO HYPERTENSION LA English DT Article DE rabbits; angiotensin II; superoxide; free radicals; reactive oxygen species; NADPH oxidoreductases ID SMOOTH-MUSCLE CELLS; HYPERTENSIVE RATS; RESPIRATORY BURST; FREE-RADICALS; COMPONENT; RECEPTOR; MEMBRANE; CLONING; PROTEIN; SYSTEM AB Superoxide radical (O-2(-)) is ubiquitously critical to the bioactivity of endothelial nitric oxide. In angiotens-independent hypertension, vascular O-2(-) levels rise and impede endothelium/nitric oxide-dependent vascular relaxation. We have reported that the major O-2(-) source in the rabbit aorta is adventitial fibroblast phagocyte-like NADPH oxidase and shown that angiotensin (Ang) II treatment of adventitial fibroblasts causes a concentration-dependent increase in particulate NADPH-dependent O-2(-) From cultured rabbit aortic adventitial fibroblasts treated or not treated with Ang II, we prepared particulate fractions and measured lucigenin-enhanced chemiluminescence. Because [Sar(1),Thr(8)]-Ang II, a generalized antagonist of Ang II and plausible inhibitor of the conversion of Ang II, reversed Ang LI (10 nmol/L)-induced NADH- and NADPH-dependent O-2(-) to basal levels, we tested the effect of the inhibitor of aminopeptidase N, amastatin (10 mu mol/L), and found no effect on Ang II-stimulated O-2(-). Ang(1-7), Ang III, and Ang IV also were not effective in stimulating O-2(-) levels at concentrations similar to those of Ang II, Kinetic analysis showed a rise in NADPH oxidase O-2(-) production in response to Ang II, which peaks at 3 hours and returns to basal levels by 16 hours, p67(phox), a cytosolic factor, appears to be affected at both the level of transcription and protein synthesis because actinomycin and cycloheximide individually inhibited the observed effect. A partial sequence of p67(phox) was recovered by reverse transcriptase from mRNA harvested from cultured rabbit aortic adventitial fibroblasts. Furthermore, the p67(phox) mRNA transcript in aortic fibroblasts is induced by Ang II before the peak of NADPH oxidase by Northern analysis and ribonuclease protection assays. These data suggest that Ang II stimulates NAD(P)H oxidase O-2(-) generation in fibroblasts of aortic adventitia via transcriptional activation of p67(phox). These data also provide preliminary evidence for the regulation of factors of the NADPH oxidase and potentially provide a novel means by which to abrogate the development of O-2(-)-dependent hypertension. C1 Boston Med Ctr, Vasc Biol Lab, Boston, MA USA. Boston Med Ctr, Myocardial Biol Lab, Boston, MA USA. NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Pagano, PJ (reprint author), Henry Ford Hosp, Div Nephrol & Hypertens, Room 7044,E&R Bldg,2799 W Grand Blvd, Detroit, MI 48202 USA. FU NHLBI NIH HHS [R29 HL55425-02] NR 37 TC 175 Z9 184 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD AUG PY 1998 VL 32 IS 2 BP 331 EP 337 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 112RV UT WOS:000075508700022 PM 9719063 ER PT J AU Bornstein, SR Torpy, DJ AF Bornstein, SR Torpy, DJ TI Leptin and the renin-angiotensin-aldosterone system SO HYPERTENSION LA English DT Letter C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP Bornstein, SR (reprint author), NICHHD, NIH, Bethesda, MD 20892 USA. NR 6 TC 11 Z9 11 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD AUG PY 1998 VL 32 IS 2 BP 376 EP 376 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 112RV UT WOS:000075508700030 PM 9719071 ER PT J AU Smith, MF Jaszczak, RJ AF Smith, MF Jaszczak, RJ TI A rotating parallel hole collimator for high resolution imaging of medium energy radionuclides SO IEEE TRANSACTIONS ON NUCLEAR SCIENCE LA English DT Article; Proceedings Paper CT 1997 Medical Imaging Conference CY NOV 13-15, 1997 CL ALBUQUERQUE, NEW MEXICO ID PATIENT-SPECIFIC DOSIMETRY; ULTRA-HIGH-RESOLUTION; PHASE-I; COMPUTED-TOMOGRAPHY; PINHOLE SPECT; GAMMA-CAMERA; I-131; THERAPY; RADIOIMMUNOTHERAPY; IMPLEMENTATION AB A rotating parallel hole collimator has been designed and built for high resolution gamma camera imaging of medium energy radionuclides. This cast lead collimator has 2.0 mm thick septa and was designed for imaging 50-100 mCi I-131 radiolabeled monoclonal antibodies being administered intratumorally for brain tumor therapy. Projection data from different collimator rotation positions are summed to create a composite projection dataset with more dense spatial sampling than projection data at a single position. Measured single photon emission computed tomography (SPECT) resolution with I-131 was 5.5-7.5 mm full-width at half-maximum (FWHM) for a 13 cm radius of rotation compared with 9.9- 13.9 mm with a conventional medium energy collimator. SPECT resolution for the rotating collimator was only slightly worse with I-131 than with Tc-99m, indicating good attenuation by the septa. Sensitivity was 56 counts/sec/mCi with a tight region of interest (ROI) around the projection of an I-131 line source 12 cm from the collimator surface and 64 counts/sec/mCi with a tight ROI around the projection of an 11 cm diameter I-131 disk source 10 cm from the collimator surface. SPECT studies of 3.7 cm and 6.2 cm diameter shell-core tumor phantoms filled with I-131 were made. The lower activity core and higher activity shell were well resolved in a SPECT study using the rotating hole collimator. SPECT shell to core activity concentration ratios were more accurate with the rotating collimator than with a medium energy collimator. These results show the potential of this rotating collimator for high resolution human tumor studies with I-131 tracers. C1 Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. Duke Univ, Dept Biomed Engn, Durham, NC 27708 USA. RP Smith, MF (reprint author), NIH, Dept Nucl Med, Ctr Clin, Bldg 10,Room 1C401, Bethesda, MD 20892 USA. NR 45 TC 16 Z9 16 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 0018-9499 J9 IEEE T NUCL SCI JI IEEE Trans. Nucl. Sci. PD AUG PY 1998 VL 45 IS 4 BP 2102 EP 2112 DI 10.1109/23.708311 PN 2 PG 11 WC Engineering, Electrical & Electronic; Nuclear Science & Technology SC Engineering; Nuclear Science & Technology GA 110VJ UT WOS:000075401600006 ER PT J AU Wang, JTL Shapiro, BA Shasha, D Zhang, KZ Currey, KM AF Wang, JTL Shapiro, BA Shasha, D Zhang, KZ Currey, KM TI An algorithm for finding the largest approximately common substructures of two trees SO IEEE TRANSACTIONS ON PATTERN ANALYSIS AND MACHINE INTELLIGENCE LA English DT Article DE computational biology; dynamic programming; pattern matching; pattern recognition; trees ID RNA SECONDARY STRUCTURES; DISTANCE AB Ordered, labeled trees are trees in which each node has a label and the left-to-right order of its children (if it has any) is fixed. Such trees have many applications in vision, pattern recognition, molecular biology and natural language processing. We consider a substructure of an ordered labeled tree T to be a connected subgraph of T. Given two ordered labeled trees T-1 and T-2 and an integer d, the largest approximately common substructure problem is to find a substructure U-1 of T-2 and a substructure U-2 of T-2 such that U-1 is within edit distance d of U-2 and where there does not exist any other substructure V-1 of T-1 and V-2 of T-2 such that V-1 and V-2 satisfy the distance constraint and the sum of the sizes of V-1 and V-2 is greater than the sum of the sizes of U-1 and U-2 We present a dynamic programming algorithm to solve this problem, which runs as fast as the fastest known algorithm for computing the edit distance of two trees when the distance allowed in the common substructures is a constant independent of the input trees. To demonstrate the utility of our algorithm, we discuss its application to discovering motifs in multiple RNA secondary structures (which are ordered labeled trees). C1 New Jersey Inst Technol, Dept Comp & Informat Sci, Newark, NJ 07102 USA. NCI, Image Proc Sect, Lab Expt & Computat Biol, Div Basic Sci,NIH, Frederick, MD 21702 USA. NYU, Courant Inst Math Sci, New York, NY 10012 USA. Univ Western Ontario, Dept Comp Sci, London, ON N6A 5B7, Canada. Univ Maryland, Med Ctr, Dept Pediat, Baltimore, MD 21201 USA. RP Wang, JTL (reprint author), New Jersey Inst Technol, Dept Comp & Informat Sci, Univ Hts, Newark, NJ 07102 USA. NR 28 TC 46 Z9 49 U1 0 U2 2 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1314 USA SN 0162-8828 J9 IEEE T PATTERN ANAL JI IEEE Trans. Pattern Anal. Mach. Intell. PD AUG PY 1998 VL 20 IS 8 BP 889 EP 895 DI 10.1109/34.709622 PG 7 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic SC Computer Science; Engineering GA 110GT UT WOS:000075372700014 ER PT J AU Weng, NP Hathcock, KS Hodes, RJ AF Weng, NP Hathcock, KS Hodes, RJ TI Regulation of telomere length and telomerase in T and B cells: A mechanism for maintaining replicative potential SO IMMUNITY LA English DT Review ID LYMPHOCYTE DEVELOPMENT; HEMATOPOIETIC-CELLS; SHORTENED TELOMERES; MOUSE TELOMERASE; ANTIGEN RECEPTOR; HIV-1 INFECTION; RNA COMPONENT; ACTIVATION; PROTEIN; EXPRESSION C1 National Institutes Health, National Institute Aging, Baltimore, MD 21228 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Hodes, RJ (reprint author), National Institutes Health, National Institute Aging, Baltimore, MD 21228 USA. NR 59 TC 115 Z9 119 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD AUG PY 1998 VL 9 IS 2 BP 151 EP 157 DI 10.1016/S1074-7613(00)80597-X PG 7 WC Immunology SC Immunology GA 114LE UT WOS:000075610300001 PM 9729035 ER PT J AU Sant'Angelo, DB Lucas, B Waterbury, PG Cohen, B Brabb, T Goverman, J Germain, RN Janeway, CA AF Sant'Angelo, DB Lucas, B Waterbury, PG Cohen, B Brabb, T Goverman, J Germain, RN Janeway, CA TI A molecular map of T cell development SO IMMUNITY LA English DT Article ID CHAIN GENE REARRANGEMENT; POSITIVE SELECTION; MATURATION PATHWAY; INTERMEDIATE STEPS; THYMOCYTES; DIFFERENTIATION; RECOMBINATION; COMMITMENT; LINEAGES; THYMUS AB Using a sensitive molecular marker for positive selection, the appearance of a particular functional TCR alpha chain sequence in cells from mice bearing a transgenic beta chain, we address several aspects of intrathymic T cell development. First, by examining specific TCR prior to and after maturation, we demonstrate how a restricted TCR repertoire is positively selected from a highly diverse immature TCR repertoire. Second, since this molecular marker is enriched in cells progressing toward the CD4 lineage and depleted in cells progressing toward the CD8 lineage, a map of the developmental pathway of alpha beta thymocytes can be inferred. Third, the first cells that show clear signs of positive intrathymic selection are identified. C1 Yale Univ, Howard Hughes Med Inst, Sch Med, Immunol Sect, New Haven, CT 06520 USA. National Institute Allergy & Infectious Diseases, Immunol Lab, NIH, Bethesda, MD 20892 USA. Univ Washington, Sch Med, Dept Mol Biotechnol, Seattle, WA 98195 USA. RP Lucas, B (reprint author), Yale Univ, Howard Hughes Med Inst, Sch Med, Immunol Sect, New Haven, CT 06520 USA. EM derek.santangelo@yale.edu FU NIAID NIH HHS [AI-14579]; NINDS NIH HHS [NS35126-02] NR 33 TC 72 Z9 73 U1 1 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD AUG PY 1998 VL 9 IS 2 BP 179 EP 186 DI 10.1016/S1074-7613(00)80600-7 PG 8 WC Immunology SC Immunology GA 114LE UT WOS:000075610300004 PM 9729038 ER PT J AU Naramura, M Hu, RJ Gu, H AF Naramura, M Hu, RJ Gu, H TI Mice with a fluorescent marker for interleukin 2 gene activation SO IMMUNITY LA English DT Article ID CD4(+) T-CELLS; TRANSGENIC MICE; EXPRESSION; RESPONSES; HETEROGENEITY; LYMPHOCYTES; T-HELPER-1; PATHWAY; NUCLEAR; ALPHA AB Production of interleukin (IL)-2 by T lymphocytes is one of the earliest events during immune response. A mutant mouse strain was generated by replacing the IL-2 gene with a cDNA encoding green fluorescent protein (GFP). In this model, GFP fluorescence is readily detectable upon T cell activation and is mostly coexpressed with IL-2 at the single cell level. Thus, individual activated T cells can express the IL-2 gene biallelically. Upon stimulation through the T cell antigen receptor, CD4(+) cells separate into distinct GFP(+) and GFP(-) populations, both of which are capable of differentiating into either Th1 or Th2 effecters. These mice allow noninvasive detection of IL-2 production by single cells and analysis of the subsequent differentiative fate of these cells as an immune response develops. C1 National Institute Allergy & Infectious Diseases, Immunol Lab, NIH, Rockville, MD 20852 USA. RP Gu, H (reprint author), National Institute Allergy & Infectious Diseases, Immunol Lab, NIH, Rockville, MD 20852 USA. EM hgu@pop.niaid.nih.gov OI Naramura, Mayumi/0000-0003-3658-0767 NR 37 TC 82 Z9 82 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD AUG PY 1998 VL 9 IS 2 BP 209 EP 216 DI 10.1016/S1074-7613(00)80603-2 PG 8 WC Immunology SC Immunology GA 114LE UT WOS:000075610300007 PM 9729041 ER PT J AU Zhang, WG Trible, RP Samelson, LE AF Zhang, WG Trible, RP Samelson, LE TI LAT palmitoylation: Its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation SO IMMUNITY LA English DT Article ID SIGNAL-TRANSDUCTION; ANTIGEN RECEPTOR; G-PROTEINS; KINASE; LOCALIZATION; DOMAINS; CAVEOLAE; MYRISTYLATION; PALMITYLATION; ACYLATION AB The linker molecule LAT is a critical substrate of the tyrosine kinases activated upon TCR engagement. Phosphorylated LAT binds Grb2, PLC-gamma 1, and other signaling molecules. We demonstrate that human LAT is palmitoylated and that palmitoylated LAT predominantly localizes into glycolipid-enriched microdomains (GEMs). Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. LAT palmitoylation is necessary for its tyrosine phosphorylation. After T cell activation, most tyrosine-phosphorylated LAT molecules and a fraction of PLC-gamma 1 and other signaling molecules are present in GEMs. LAT is central to T cell activation and is a novel linker molecule shown to require targeting to membrane microdomains for signaling. C1 National Institute Child Health & Human Dev, Cell Biol & Metab Branch, Sect Lymphocyte Signaling, NIH, Bethesda, MD 20892 USA. RP Samelson, LE (reprint author), National Institute Child Health & Human Dev, Cell Biol & Metab Branch, Sect Lymphocyte Signaling, NIH, Bethesda, MD 20892 USA. NR 39 TC 684 Z9 697 U1 3 U2 18 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD AUG PY 1998 VL 9 IS 2 BP 239 EP 246 DI 10.1016/S1074-7613(00)80606-8 PG 8 WC Immunology SC Immunology GA 114LE UT WOS:000075610300010 PM 9729044 ER PT J AU Wagelie-Steffen, AL Hartmann, K Vliagoftis, H Metcalfe, DD AF Wagelie-Steffen, AL Hartmann, K Vliagoftis, H Metcalfe, DD TI Fas ligand (FasL, CD95L, APO-1L) expression in murine mast cells SO IMMUNOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; MEDIATED CYTOTOXICITY; INDUCED APOPTOSIS; T-CELLS; DIFFERENTIAL EXPRESSION; GLD MICE; LYMPHOCYTES; ACTIVATION; DEATH; GENE AB Fas ligand (FasL, CD95L, Apo-1L), a type II membrane protein belonging to the tumour necrosis factor family, induces apoptosis in Fas-bearing cells. As murine mast cells have been shown to express Fas antigen, we hypothesized that mast cells might also express Fast. To explore this possibility, we first demonstrated Fast mRNA in mast cells by reverse transcription-polymerase chain reaction and Fast protein by immunoblot analysis. Fast protein was shown to be exclusively located within the cell by flow cytometry. Ln agreement with this observation, bone marrow cultured mast cells were unable to kill Jurkat T cells. Our results demonstrate that Fast is expressed in murine mast cells and suggest that this murine mast cell Fast is not lytic, owing to the intracellular localization. C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Metcalfe, DD (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C205,10 Ctr Dr MSC 1881, Bethesda, MD 20892 USA. RI Vliagoftis, Harissios/C-6480-2013; Hartmann, Karin/N-4865-2015 OI Hartmann, Karin/0000-0002-4595-8226 NR 43 TC 17 Z9 17 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD AUG PY 1998 VL 94 IS 4 BP 569 EP 574 PG 6 WC Immunology SC Immunology GA 108VJ UT WOS:000075286200016 PM 9767446 ER PT J AU Liu, MF Zeng, J Robey, FA AF Liu, MF Zeng, J Robey, FA TI Specific interaction of conformational polypeptides derived from HIV gp120 with human T lymphocyte CD4 receptor SO IMMUNOLOGY LETTERS LA English DT Article DE gp120-CD4 interaction; synthetic C4 peptide; peptomer; peptomer-CD4 binding ID IMMUNODEFICIENCY-VIRUS TYPE-1; SYNTHETIC PEPTIDE POLYMERS; AUTOMATED SYNTHESIS; PROTEIN; ENVELOPE; BINDING; GLYCOPROTEIN; CELLS AB Specifically cross-linked peptides (peptomers) have been prepared from the repeating sequences of the C4 domains of glycoproteins 120 present in different isolates of human immunodeficiency virus (HIV). In order to investigate if the HIV C4 peptomers could function as gp120 protein, we have used a novel protein-binding assay to examine if and which components of the peptomers could interact with CD4 receptor in vitro. Here, we demonstrate that all the polymeric components of the HIV-1 C4 peptomer could bind to recombinant soluble CD4 protein. A similar result was also obtained with HIV-2 C4 peptomer except that the binding occured only in those of constituents having molecular weights higher than that of trimer. Remarkably, the CD4-binding was demonstrated to be specific to the HIV C4 peptomers as it did not occur with control peptomers such as Poly V3 MN and Poly NINA whose peptide sequences bore no homology to those of the HIV C4 peptomers. Furthermore, consistent with previous findings, no interaction of HIV-1 C4 monomeric peptide (419-436) with CD4 was detected under the same conditions. Since it is known that the HIV C4 peptomers have much higher contents of a-helical conformation than those of their monomeric peptides, we conclude that the secondary structure is a pivotal determinant for the successful CD4-binding by the peptomers. Our finding reveals a more defined molecular nature of the gp120-CD4 interaction and may be important for designing HIV vaccines and therapeutics which target the first step in the virus infection. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIDR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Liu, MF (reprint author), Inst Pasteur, CIBP, 1 Rue Calmette, F-59019 Lille, France. NR 20 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2478 J9 IMMUNOL LETT JI Immunol. Lett. PD AUG PY 1998 VL 63 IS 1 BP 27 EP 32 DI 10.1016/S0165-2478(98)00051-0 PG 6 WC Immunology SC Immunology GA 108UU UT WOS:000075284600004 PM 9719435 ER PT J AU Chen, EH Gadina, M Galon, J Chen, M O'Shea, JJ AF Chen, EH Gadina, M Galon, J Chen, M O'Shea, JJ TI Not just another meeting: the coming of age of JAKs and STATs SO IMMUNOLOGY TODAY LA English DT Article AB The discovery of JAKs and STATs provided long-awaited clues to the mechanism of cytokine signal trnasduction. A recent meeting* reviewed the current state of JAK/STAT biology and discussed new advances that offer novel insights into cytokine signaling. C1 NIAMSD, Lymphocyte Cell Biol Sect, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. RP Chen, EH (reprint author), NIAMSD, Lymphocyte Cell Biol Sect, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. EM osheajo@arb.niams.nih.gov NR 16 TC 13 Z9 16 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0167-5699 J9 IMMUNOL TODAY JI Immunol. Today PD AUG PY 1998 VL 19 IS 8 BP 338 EP 341 DI 10.1016/S0167-5699(98)01295-X PG 4 WC Immunology SC Immunology GA 107MQ UT WOS:000075213400001 PM 9709499 ER PT J AU Yang, YL Liu, ZH Tolosa, E Yang, JW Li, LS AF Yang, YL Liu, ZH Tolosa, E Yang, JW Li, LS TI Triptolide induces apoptotic death of T lymphocyte SO IMMUNOPHARMACOLOGY LA English DT Article DE apoptosis; triptolide; caspase; T cell hybridoma ID TRIPTERYGIUM-WILFORDII HOOK; INTERLEUKIN-1-BETA CONVERTING-ENZYME; FAS-MEDIATED APOPTOSIS; CHINESE HERBAL REMEDY; RHEUMATOID-ARTHRITIS; ANTIGEN RECEPTOR; CELL HYBRIDOMAS; CYTOCHROME-C; ACTIVATION; EXTRACT AB Extract of Tripterygium wilfordii Hook. f (TWHf) has immunosuppressive activity and has been used as anti-inflammatory agent in traditional Chinese medicine for centuries. Recent studies have demonstrated that triptolide is the major active component in the extract that inhibits antigen or mitogen-induced T cell proliferation. In attempting to investigate its effect on activation of T lymphocytes, we found triptolide induces apoptotic death of T cell hybridomas and peripheral T cells but not that of thymocytes. The triptolide-induced apoptosis is accompanied by increase of DEVD-cleavable caspases activity and degradation of caspase substrate poly (ADP-ribose) polymerase (PARP). A specific inhibitor of caspases, zVAD-FMK, prevents triptolide-induced PARP degradation and DNA fragmentation but not growth arrest. Furthermore, enforced expression of Bcl-2 inhibited triptolide-induced degradation of PARP and apoptosis. These results indicate that triptolide induces T cell apoptosis through activating caspases, and suggest the growth arrest and apoptotic effect of triptolide may contribute to the immunosuppressive activity of TWHf extract. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NCI, Lab Immune Cell Biol, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Nanjing Univ, Sch Med, Res Inst Nephrol, Jinling Hosp, Nanjing 210002, Peoples R China. RP Yang, YL (reprint author), NCI, NIH, Bldg 10,Room 1B-40,9000 Rockville Pike, Bethesda, MD 20879 USA. EM yiliyang@box-y.nih.gov NR 40 TC 110 Z9 141 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0162-3109 J9 IMMUNOPHARMACOLOGY JI Immunopharmacology PD AUG PY 1998 VL 40 IS 2 BP 139 EP 149 DI 10.1016/S0162-3109(98)00036-8 PG 11 WC Immunology; Pharmacology & Pharmacy SC Immunology; Pharmacology & Pharmacy GA 132HD UT WOS:000076623500005 PM 9826028 ER PT J AU Paranjape, RS Gadkari, DA Lubaki, M Quinn, TC Bollinger, RC AF Paranjape, RS Gadkari, DA Lubaki, M Quinn, TC Bollinger, RC TI Cross-reactive HIV-1-specific CTL in recent seroconverters from Pune, India SO INDIAN JOURNAL OF MEDICAL RESEARCH LA English DT Article DE cytolytic T lymphocyte (CTL); immunotype; limiting dilution analysis (LDA); precursor frequency; subtype C ID VIRUS TYPE-1 INFECTION; TOXIC LYMPHOCYTES-T; RESPONSES; HIV-1; VACCINES; VIREMIA; ASSAY; CELLS AB In the light of the diversity of HIV, matching the genotype of candidate HIV vaccines with the transmitted genotype may be required. Alternatively, matching the immunotype of HIV vaccines and transmitted subtypes may be the best option. Since studies of cross-subtype HIV-1 immunity are limited, subtype B specific cytolytic T lymphocyte (CTL) responses were measured in subtype C infected individuals. HIV-1 subtype B-specific CTLs, plasma viral load and absolute CD4 and CD8 lymphocyte numbers were measured in six HIV-1 subtype C infected individuals within a year of seroconversion, HIV-1 subtype B env, gag and nef-specific CTL precursor frequencies were measured by limiting dilution analysis. Three of the six subjects had demonstrable CTL directed at more than one HIV-1 subtype B antigens. One individual demonstrated CTL directed against all three HIV-1 subtype B antigens, while two individuals did not demonstrate CTL against HIV-2 subtype B antigens. The frequencies of CTL precursor were not associated with plasma viral load or absolute CD4 cell counts in peripheral blood. These findings suggest that some individuals recently infected with subtype C HIV-1 generate cross-reactive CTL that are directed against HIV-1 subtype B. C1 Natl AIDS Res Inst, Pune 411026, Maharashtra, India. Johns Hopkins Univ, Baltimore, MD USA. NIAID, NIH, Bethesda, MD 20892 USA. Natl Inst Virol, Pune, Maharashtra, India. RP Paranjape, RS (reprint author), Natl AIDS Res Inst, Plot 73 G Block MIDC,POB 1895, Pune 411026, Maharashtra, India. FU FIC NIH HHS [D43 TW0000] NR 20 TC 11 Z9 13 U1 0 U2 0 PU INDIAN COUNCIL MEDICAL RES PI NEW DELHI PA PO BOX 4508 ANSARI NAGAR, NEW DELHI 110029, INDIA SN 0971-5916 J9 INDIAN J MED RES JI Indian J. Med. Res. PD AUG PY 1998 VL 108 BP 35 EP 41 PG 7 WC Immunology; Medicine, General & Internal; Medicine, Research & Experimental SC Immunology; General & Internal Medicine; Research & Experimental Medicine GA 122XJ UT WOS:000076096500001 PM 9785676 ER PT J AU James, SL Cheever, AW Caspar, P Wynn, TA AF James, SL Cheever, AW Caspar, P Wynn, TA TI Inducible nitric oxide synthase-deficient mice develop enhanced type 1 cytokine-associated cellular and humoral immune responses after vaccination with attenuated Schistosoma mansoni cercariae but display partially reduced resistance SO INFECTION AND IMMUNITY LA English DT Article ID TUMOR-NECROSIS-FACTOR; PERITONEAL-MACROPHAGES; IRRADIATED CERCARIAE; PARASITE DEATH; FACTOR-ALPHA; IFN-GAMMA; EXPRESSION; CELLS; PATHWAY; IL-12 AB High levels of nitric oxide (NO) are produced by inducible nitric oxide synthase (iNOS) in response to activating signals from Th1-associated cytokines and play an important role in cytotoxicity and cytostasis against many pathogenic microorganisms. In addition to its direct effector function, NO serves as a potent immunoregulatory factor, NO produced by gamma interferon-activated macrophages immobilizes and kills Schistosoma mansoni larvae, and several studies have indicated a role for this pathway in protective immunity against this parasite. The potential regulatory influence of NO in immunity to S. mansoni is less well understood. In this study, we have used iNOS-deficient mice to determine the role of NO in mice vaccinated with irradiated cercariae of S, mansoni. We show by enzyme-linked immunosorbent assay and reverse transcriptase PCR analysis that vaccinated iNOS-deficient mice develop exacerbated type 1 cytokine responses in the lungs, the site where resistance to infection is primarily manifested. In addition, parasite-specific immunoglobulin G2a (IgG2a) and IgG2b antibody responses were significantly increased in vaccinated iNOS-deficient animals and total IgE antibody levels in serum were decreased relative to those in wild-type controls. Surprisingly, since resistance in this vaccine model is largely Th1 dependent and since Th1-related cellular and humoral immune responses were found to be exacerbated in vaccinated iNOS-deficient mice, vaccine-elicited protective immunity against challenge infection was found to be reduced, These findings demonstrate that iNOS plays a paradoxical role in immunity to S, mansoni, both in the effector mechanism of resistance and in the down regulation of the type 1 cytokine response, which is ultimately required for NO production. C1 NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Inst Biomed Res, Rockville, MD USA. RP Wynn, TA (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bldg 4,Room 126,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tw12b@nih.gov RI Wynn, Thomas/C-2797-2011 NR 47 TC 49 Z9 52 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD AUG PY 1998 VL 66 IS 8 BP 3510 EP 3518 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 103TJ UT WOS:000074973700004 PM 9673227 ER PT J AU Vos, Q Ortaldo, JR Conan-Cibotti, M Vos, MD Young, HA Anderson, SK Witherspoon, K Prager, I Snapper, CM Mond, JJ AF Vos, Q Ortaldo, JR Conan-Cibotti, M Vos, MD Young, HA Anderson, SK Witherspoon, K Prager, I Snapper, CM Mond, JJ TI Phenotypic and functional characterization of a panel of cytotoxic murine NK cell clones that are heterogeneous in their enhancement of Ig secretion in vitro SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE B cell; cytotoxicity; granzyme; Ig secretion; NK cell; Tl-2 response ID NATURAL-KILLER-CELLS; LARGE GRANULAR LYMPHOCYTES; MONOCLONAL-ANTIBODIES; INTERFERON-GAMMA; IFN-GAMMA; T-CELLS; B-CELLS; LEISHMANIA-MAJOR; SERINE-PROTEASE; MICE AB NK cells not only function as cytotoxic effector cells, but also have immunoregulatory roles including the enhancement of Ig secretion. To have a stable and uniform population of NK cells to study their role in Ig secretion, we generated murine NK clones. Thus, culture of splenocytes from mice that were homozygous for a mutation in the p53 tumor suppressor gene (p53-KO) with IL-2 and poly(IC) resulted in a long-term NK line, from which four stable clones were derived. This approach also yielded a long-term NK line from splenocytes of normal C57BL/6 mice. Identification of the clones as members of the NK lineage was based on large granular morphology, expression of NK-TR and absence of TCR gene rearrangement. Flow cytometry revealed that all clones expressed IL-2R alpha and beta, chains and B220, but no CD3, NK1.1, DX5 or Ly-49, RT-PCR analysis showed heterogeneity in NK1.1 gene expression, and demonstrated expression of perforin and several granzymes in all clones. Three out of four clones lysed YAC-1, but not P815 target cells, corresponding to a pattern of NK specificity. All NK clones enhanced Ig secretion in an in vitro model for T cell-independent type 2 antigens, albeit to varying degrees. We found no correlation between the degree of helper activity of the NK clones and the revel of their cytotoxic activity on YAC-1 targets. Thus, we established murine NK clones, and show that they mediate both cytotoxicity and enhancement of Ig secretion. C1 Uniformed Serv Univ Hlth Sci, Dept Med, Bethesda, MD 20814 USA. Uniformed Serv Univ Hlth Sci, Dept Pathol, Bethesda, MD 20814 USA. NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Expt Immunol Lab, Frederick, MD 21702 USA. NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. NCI, Div Clin Sci, Dept Cell & Canc Biol, Rockville, MD 20850 USA. RP Vos, Q (reprint author), Uniformed Serv Univ Hlth Sci, Dept Med, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. RI Anderson, Stephen/B-1727-2012 OI Anderson, Stephen/0000-0002-7856-4266 FU NIAID NIH HHS [AI 32560, AI 33411] NR 63 TC 10 Z9 14 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD AUG PY 1998 VL 10 IS 8 BP 1093 EP 1101 DI 10.1093/intimm/10.8.1093 PG 9 WC Immunology SC Immunology GA 111GY UT WOS:000075430000009 PM 9723695 ER PT J AU Murata, T Husain, SR Mohri, H Puri, RK AF Murata, T Husain, SR Mohri, H Puri, RK TI Two different IL-13 receptor chains are expressed in normal human skin fibroblasts, and IL-4 and IL-13 mediate signal transduction through a common pathway SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE activation; IL-13 receptor structure; insulin response substrate (IRS); Janus (JAK) kinase; phosphorylation; signal transduction and activator of transcription (STAT) ID HUMAN INTERLEUKIN-4 RECEPTOR; CARCINOMA CELL-LINES; GAMMA-CHAIN; JANUS KINASE; ALPHA CHAIN; B-CELLS; GROWTH; PHOSPHORYLATION; PROLIFERATION; SIMILARITIES AB IL-13 and IL-4, pleiotropic immune regulatory cytokines, have been shown to mediate similar prominent effects in human fibroblast cell lines, However, molecular mechanisms for their redundant effects are not known. Here, we have investigated the structure of IL-13 receptors (IL-13R) and molecular mechanisms of signal transduction through IL-13 and IL-4 receptors in non-transformed normal skin fibroblast cell lines. We demonstrate that high-affinity IL-13R is expressed in normal skin fibroblast cell lines. Upon [I-125]IL-13 cross-linking, a similar to 60-70 kDa band was observed in sk559 and sk574 fibroblast cell lines. By RT-PCR analysis, mRNA for IL-13R alpha, IL-13R alpha' and IL-4R beta chains were expressed; however, the lL-2R gamma chain, shown to participate and modulate IL-4 and IL-13 binding, was not expressed in any of the cell lines examined, The Janus kinase (JAK)2 and Tyk2 were phosphorylated in response to IL-4 or IL-13 in sk559 and sk574 cell lines, JAK1 was also phosphorylated in one of two cell lines while JAK3 was present but not phosphorylated in any of the cell lines studied, A signal transduction and activator of transcription (STAT)6 was also activated in response to both IL. An insulin receptor substrate (IRS)-1 was constitutively phosphorylated and its phosphorylation level was augmented in response to both IL, These results suggest that the mechanism of signal transduction through IL-13 and IL-4 receptors in human fibroblast cell lines is similar, and this may, at least in part, be responsible for the redundant effects of these two cytokines, In addition, JAK2 tyrosine kinase instead of JAK3 appears to play a major role in IL-4- and IL-13-induced signal transduction in human fibroblasts. C1 US FDA, Ctr Biol Evaluat & Res, Lab Mol Tumor Biol, Div Cellular & Gene Therapy, Bethesda, MD 20892 USA. Yokohama City Univ, Sch Med, Dept Internal Med 1, Yokohama, Kanagawa 236, Japan. RP Puri, RK (reprint author), US FDA, Ctr Biol Evaluat & Res, Lab Mol Tumor Biol, Div Cellular & Gene Therapy, NIH Bldg 29B,Room 2NN10,29 Lincoln Dr MSC 4555, Bethesda, MD 20892 USA. NR 32 TC 72 Z9 75 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 AUG PY 1998 VL 10 IS 8 BP 1103 EP 1110 DI 10.1093/intimm/10.8.1103 PG 8 WC Immunology SC Immunology GA 111GY UT WOS:000075430000010 PM 9723696 ER PT J AU Baas, D Fressinaud, C Vitkovic, L Sarlieve, LL AF Baas, D Fressinaud, C Vitkovic, L Sarlieve, LL TI Glutamine synthetase expression and activity are regulated by 3,5,3 '-triodo-L-thyronine and hydrocortisone in rat oligodendrocyte cultures SO INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE LA English DT Article DE oligodendrocyte cultures; thyroid hormone; hydrocortisone; glutamine synthetase; mRNA; activity; protein ID CENTRAL-NERVOUS-SYSTEM; FIBROBLAST GROWTH-FACTORS; MOUSE-BRAIN; THYROID-HORMONE; GENE-EXPRESSION; IN-VITRO; CELLS; PROTEIN; TRIIODOTHYRONINE; PROLIFERATION AB Glutamine synthetase plays a central role in the detoxification of brain ammonia. Previously, we demonstrated that in vitro glutamine synthetase is expressed by all macroglial cell types and is developmentally regulated in oligodendrocyte lineage. Furthermore, glutamine synthetase is increased in secondary cultures of oligodendrocytes following a 72 h treatment with 30 nM 3,5,3'-triodo-L-thyronine [Baas, D., Bourbeau, D., Sarlieve, L. L., Ittel, M. E., Dussault, J. H. and Puymirat, J., Oligodendrocyte maturation and progenitor cell proliferation are independently regulated by thyroid hormone. Glia, 1997, 19, 324-332]. Hydrocortisone also increases glutamine synthetase activity after 72 h [Fressinaud, C., Weinrauder, H., Delaunoy, J. P., Tholey, G., Labourdette, G. and Sarlieve, L. L., Glutamine synthetase expression in rat oligodendrocytes in culture: regulation by hormones and growth factors. J. Cell. Physiol., 1991, 149, 459-468]; however, it is still unknown whether these increases in glutamine synthetase expression in oliorodendrocytes after 3,5,3'-triodo-L-thyronine and hydrocortisone application are dose- and time-dependent. To further investigate this issue, we measured glutamine synthetase levels by Northern analysis, immunostaining and determination of glutamine synthetase activity after 3,5,3'-triodo-L-thyronine or hydrocortisone stimulation. We find that in rat oligodendrocyte secondary cultures, 3,5,3'-triodo-L-thyronine and hydrocortisone cause a dose- and time-dependent increase in glutamine synthetase mRNA, protein and activity. However. these hormones do not exert an additive or synergistic effect. Because purines, pyrimidines, and certain amino acids necessary for the synthesis of myelin components. are, in part, provided by the glutamine synthetase pathway, 3,5,3'-triodo-L-thyronine effect on myelination development and maturation could be mediated in part, through the glutamine synthetase gene regulation. (C) 1998 ISDN. Published by Elsevier Science Ltd. C1 CNRS, UPR 416, F-67084 Strasbourg, France. CHU Angers, Serv Neurol B, Angers, France. NIMH, Div Basic & Clin Neurosci Res, NIH, Rockville, MD 20857 USA. RP Sarlieve, LL (reprint author), CNRS, UPR 416, 5 Rue Blaise Pascal, F-67084 Strasbourg, France. RI Fressinaud, Catherine/K-4393-2015 NR 43 TC 9 Z9 9 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0736-5748 J9 INT J DEV NEUROSCI JI Int. J. Dev. Neurosci. PD AUG PY 1998 VL 16 IS 5 BP 333 EP 340 DI 10.1016/S0736-5748(98)00040-9 PG 8 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 139HU UT WOS:000077023100003 PM 9829169 ER PT J AU Ma, JL You, WC Gail, MH Zhang, L Blot, WJ Chang, YS Jiang, J Liu, WD Hu, YR Brown, LM Xu, GW Fraumeni, JF AF Ma, JL You, WC Gail, MH Zhang, L Blot, WJ Chang, YS Jiang, J Liu, WD Hu, YR Brown, LM Xu, GW Fraumeni, JF TI Helicobacter pylori infection and mode of transmission in a population at high risk of stomach cancer SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Helicobacter pylori; children; transmission; stomach cancer ID PRECANCEROUS GASTRIC-LESIONS; CAMPYLOBACTER-PYLORI; SOCIOECONOMIC-STATUS; LIVING-CONDITIONS; CHILDHOOD; CHILDREN; SEROPREVALENCE; EPIDEMIOLOGY; ANTIBODIES; PREVALENCE AB Background Helicobacter pylori (H. pylori) is a recognized cause of chronic gastritis and peptic ulcer disease, and is strongly suspected to play a role in the aetiology of stomach cancer but little is known about the mode of transmission. Aim To determine the prevalence of H. pylori infection in children and investigate potential modes of transmission in rural China. Subjects and setting We examined 98 children aged 3-12 years and 289 adults aged 35-64 years in a village in Linqu County, China, which has one of the highest rates of stomach cancer in the world. Method H. pylori infection was determined by C-13-urea breath test in children and by an enzyme-linked immunosorbent assay in adults. Results Among 98 tested children, 68 (69%) were H. pylori positive, but the prevalence rates varied as a function of age, rising from about 50% at ages 3-4 to 85% at ages 9-10 before falling to 67% at ages 11-12. Boys had a higher infection rate than girls (77.8% versus 59.1%, P <0.05). Among 289 adults, 195 (68%) were H. pylori positive, with a somewhat higher rate of positivity in younger compared to older age groups. The prevalence of H. pylori infection clustered within families. In families with at least one infected parent, 85% of children were H, pylori positive, while in families with both parents uninfected, only 22% of children were H. pylori positive (odds ratio [OR] = 30.4, 95% CI : 4.0-232). Conclusions These findings demonstrate the acquisition of H. pylori infection during early childhood in a population at high risk of stomach cancer, in a manner consistent with a person-to-person mode of transmission between parents and children. C1 NCI, Bethesda, MD 20892 USA. Weifang Blood Ctr, Shandong 261041, Peoples R China. Beijing Med Univ, Beijing Inst Canc Res, Beijing 100034, Peoples R China. Beijing Med Univ, Sch Oncol, Beijing 100034, Peoples R China. Int Epidemiol Inst, Rockville, MD 20850 USA. Beijing Union Med Coll Hosp, Beijing 100730, Peoples R China. Linqu Publ Hlth Bur, Shandong 262600, Peoples R China. Westat Inc, Rockville, MD 20850 USA. RP You, WC (reprint author), NCI, EPN Room 431, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CP-95660, N01-CP-15620, N01-CP-05631] NR 41 TC 52 Z9 57 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD AUG PY 1998 VL 27 IS 4 BP 570 EP 573 DI 10.1093/ije/27.4.570 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 120QM UT WOS:000075967900004 PM 9758108 ER PT J AU Li, QD Ding, L Bever, CT AF Li, QD Ding, L Bever, CT TI Interferon-gamma induces cathepsin B expression in a human macrophage-like cell line by increasing both transcription and mRNA stability SO INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE LA English DT Article DE phorbol ester; IFN-gamma; cathepsin B; THP-1 cells; transcriptional regulation; mRNA stability; tumor metastasis ID MESSENGER-RNA STABILITY; THP-1 CELLS; INSITU HYBRIDIZATION; GENE-EXPRESSION; HUMAN MONOCYTES; HUMAN PROSTATE; BREAST-CANCER; LOCALIZATION; ANGIOGENESIS; PROGRESSION AB We have demonstrated previously that treatment of the phorbol ester PMA-primed THP-1 human macrophagelike cells with interferon-gamma (IFN-gamma) in vitro induced time and dose-dependent increases in steady-state levels of cathepsin B (CB) mRNA. The present study was undertaken to investigate the mechanism of that increase. In vitro nuclear transcription (nuclear run-off) assays of CB gene expression were performed with purified nuclei from IFN-gamma-treated or untreated THP-1 cells. These assays showed transcription to be increased approximately three-fold by IFN-gamma in the PMA-primed THP-1 cells. Studies with alpha-amanitin indicated that the half-life of CB mRNA is prolonged after PMA and IFN-gamma treatment, by more than 90%. Therefore, the elevated CB mRNA level results from a combination of IFN-gamma-induced increase in the transcription rate of the CB gene and stabilization of the corresponding transcripts. The IFN-gamma-mediated increase in CB gene transcription and steady-state mRNA level was blocked by alpha-amanitin or cycloheximide, suggesting the involvement of RNA polymerase II and the requirement of de novo protein synthesis. C1 Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Pharmacol & Expt Therapeut, Baltimore, MD 21201 USA. Univ Maryland, Sch Dent, Dept Microbiol, Baltimore, MD 21201 USA. Baltimore VA Med Ctr, Med Res Serv, Baltimore, MD 21201 USA. NIDDKD, Biochem Pharmacol Lab, Bethesda, MD 20892 USA. RP Li, QD (reprint author), NCI, Med Ovarian Canc Sect, Dept Dev Therapeut, Med Branch,Div Clin Sci,NIH, Bldg 10,Room 13N248,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 47 TC 11 Z9 11 U1 0 U2 0 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1107-3756 J9 INT J MOL MED JI Int. J. Mol. Med. PD AUG PY 1998 VL 2 IS 2 BP 181 EP 186 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 117EA UT WOS:000075766600008 ER PT J AU Park, WS Pham, T Wang, CY Pack, S Mueller, E Mueller, J Vortmeyer, A Zhuang, ZP Fogt, F AF Park, WS Pham, T Wang, CY Pack, S Mueller, E Mueller, J Vortmeyer, A Zhuang, ZP Fogt, F TI Loss of heterozygosity and microsatellite instability in nonneoplastic mucosa from patients with chronic ulcerative colitis SO INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE LA English DT Article DE ulcerative colitis; microsatellite instability; loss of heterozygosity ID INFLAMMATORY BOWEL-DISEASE; SIMPLE REPETITIVE DNA; MISMATCH REPAIR; PANCREATIC ADENOCARCINOMA; COLORECTAL-CARCINOMA; REPLICATION FIDELITY; RAS MUTATIONS; CANCER; DYSPLASIA; REQUIREMENT AB Microsatellite instability and allelic deletions of tumor suppressor genes have been observed frequently in tumors. Molecular pathogenesis of the development of dysplasia and carcinoma in ulcerative colitis is still unclear. In order to detect microsatellite alterations in ulcerative colitis, we analyzed loss of heterozygosity (LOH) and microsatellite instability (MI) on chromosomes 3, 6, 7, 12, and tumor suppressor gene loci, including p53, APC, and p16, of chronically inflamed, non-dysplastic epithelium after microdissection. Twelve of 13 (92%) cases showed LOH and/or MI at one or more loci. LOH at chromosome 3 and MI at chromosome 12 were observed in 50% and 62%, respectively. However, LOH at p53 and p16 was detected in only one case each. These results suggest that chronic inflammation may initiate microsatellite alteration, which subsequently transform ulcerative colitis to dysplasia or cancer. This finding provides information for the evaluation and treatment of patients with ulcerative colitis. C1 Hosp Univ Penn, Presbyterian Med Ctr, Dept Pathol, Philadelphia, PA 19104 USA. NIH, Dept Pathol, Bethesda, MD 20892 USA. Tech Univ, Dept Pathol, Muenchen, Germany. RP Fogt, F (reprint author), Hosp Univ Penn, Presbyterian Med Ctr, Dept Pathol, 39th & Market St, Philadelphia, PA 19104 USA. RI Pack, Svetlana/C-2020-2014 NR 28 TC 38 Z9 39 U1 0 U2 0 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1107-3756 J9 INT J MOL MED JI Int. J. Mol. Med. PD AUG PY 1998 VL 2 IS 2 BP 221 EP 224 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 117EA UT WOS:000075766600014 ER PT J AU Lipinski, LJ Ross, HL Zajc, B Sayer, JM Jerina, DM Dipple, A AF Lipinski, LJ Ross, HL Zajc, B Sayer, JM Jerina, DM Dipple, A TI Effect of single benzo[alpha]pyrene diol epoxide-deoxyguanosine adducts on the action of DNA polymerases in vitro SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE benzo[alpha]pyrene; DNA polymerase; DNA adduct; diol epoxide; translesion synthesis ID BENZOPYRENE 7,8-DIOL-9,10-EPOXIDES; OPTICAL ENANTIOMERS; MUTATIONS; DEOXYADENOSINE; CARCINOGEN; MUTAGENESIS; TEMPLATES; POSITION; ACID AB Neither Sequenase 2.0 nor Klenow fragment were able to extend 12-mer primers using the eight templates (16-mers) derived by placing each of the four isomeric benzo[a]pyrene diol epoxide-deoxyguanosine adducts at the 13th nucleotide from the 3'-end of two different sequence contexts. Using an Il-mer primer to get a running start did not overcome the adduct induced block of primer extension except for the Klenow fragment and one of the two sequence contexts, indicating primer extension is dependent on both the polymerase and sequence context. In this case, purine nucleoside triphosphates (dATP>dGTP) were incorporated opposite each of the four adducts. C1 NCI, Frederick Canc Res & Dev Ctr, Chem Carcinogenesis Lab, ABL Basic Res Program, Frederick, MD 21702 USA. NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Dipple, A (reprint author), NCI, Frederick Canc Res & Dev Ctr, Chem Carcinogenesis Lab, ABL Basic Res Program, POB B, Frederick, MD 21702 USA. NR 30 TC 26 Z9 26 U1 0 U2 1 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD AUG PY 1998 VL 13 IS 2 BP 269 EP 273 PG 5 WC Oncology SC Oncology GA 101LR UT WOS:000074870900010 PM 9664121 ER PT J AU Shrayer, DP Bogaars, H Hearing, VJ Wolf, SF Wanebo, HJ AF Shrayer, DP Bogaars, H Hearing, VJ Wolf, SF Wanebo, HJ TI A new mouse model of experimental melanoma for vaccine and lymphokine therapy SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE melanoma; polyvalent antigen; monovalent antigen; immunization; polyclonal antibody ID FORMALINIZED EXTRACELLULAR ANTIGENS; PURIFIED GM2 GANGLIOSIDE; AUTOREACTIVE T-CELLS; MURINE MELANOMA; TUMOR REJECTION; ADJUVANT IMMUNOTHERAPY; MONOCLONAL-ANTIBODIES; PROTEOGLYCAN ANTIGEN; PULMONARY METASTASIS; PLATELET-AGGREGATION AB The annual incidence of malignant melanoma is estimated at 10-12 per 100,000 inhabitants in countries of central Europe and the United States, and alarmingly there has been a dramatic upward trend in that estimate. The B16 murine melanoma in a rapidly growing metastatic tumor of spontaneous origin, as are human malignant melanomas. Melanoma cells produce specific antigens which are uniquely different from normal cellular antigens, and the expression of such antigens is the cornerstone for preparation of anti-melanoma vaccines. One major problem in evaluating the effectiveness of vaccination and other biologic therapies is the variability of experimental tumor models. A new metastatic model of experimental melanoma which was developed in our laboratory imitates the major clinical stages of malignant metastatic melanoma: stage I, primary (local) tumor growth and bone marrow invasion; stage II, regional lymph node involvement; and stage III, metastasis to distant organs, such as the lungs. This model has been used successfully for screening vaccines constructed in our laboratory. Immunization with formalinized vaccines (of extracellular antigens, intact melanoma cells, or B700 antigen) or irradiated vaccines (of intact melanoma cells) partially inhibit primary melanoma tumor growth, reduce metastasis to regional lymph nodes and lungs, and significantly increase mean survival time. These anti-tumor effects were improved when polyvalent and monovalent vaccines were combined with IL-2 therapy. We also compared the immunogenic activity of vaccines made from B16 melanoma cells transfected with genes encoding murine IL-2 or GM-CSF, and effects on tumor bearing mice were compared with or without therapy using the corresponding lymphokines. In sum, comparison of antibody production, growth of primary melanoma tumors, number of surviving mice, mean survival time, and percent of mice with lung metastases, showed that the best course of immunotherapy involves vaccination of mice with irradiated B16 melanoma cells transfected to secrete GM-CSF, coupled with GM-CSF therapy. C1 Brown Univ, Roger Williams Med Ctr, Dept Surg, Surg Oncol Res Lab, Providence, RI 02908 USA. Genet Inst, Cambridge, MA 02140 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Shrayer, DP (reprint author), Brown Univ, Roger Williams Med Ctr, Dept Surg, Surg Oncol Res Lab, 825 Chalkstone Ave, Providence, RI 02908 USA. NR 96 TC 8 Z9 8 U1 0 U2 1 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD AUG PY 1998 VL 13 IS 2 BP 361 EP 374 PG 14 WC Oncology SC Oncology GA 101LR UT WOS:000074870900023 PM 9664134 ER PT J AU Choi, YH Zhang, LJ Lee, WH Park, KY AF Choi, YH Zhang, LJ Lee, WH Park, KY TI Genistein-induced G2/M arrest is associated with the inhibition of cyclin B1 and the induction of p21 in human breast carcinoma cells SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE genistein; breast carcinoma cells; cyclin B1; p21 ID DEPENDENT KINASES; LEUKEMIA-CELLS; NIH-3T3 CELLS; IN-VITRO; CANCER; GROWTH; TUMOR; SUPPRESSION; PROGRESSION; APOPTOSIS AB Genistein is an isoflavone known to inhibit both tyrosine protein kinase and DNA topoisomerase II. We have investigated the mechanism of genistein-induced growth inhibition in MCF-7 and MDA-MB-231 breast carcinoma cell lines. DNA flow cytometric analysis indicated that genistein induced a G2/M arrest in both cell lines. Therefore, we examined the effect of genistein on cell cycle-related proteins. Western blot analysis using whole cell lysates from MCF-7 and MDA-MB-231 treated with genistein demonstrated that genistein treatment did not change the steady-state level of cdks, cyclin A, D-type cyclins and cyclin E protein, but inhibited expression of cyclin B1 protein in a time-dependent manner. The reduction in the protein level of cyclin BZ correlated with a decrease in the level of cyclin B1 mRNA. Genistein induced expression of p21, and the increased levels of p21 were associated with increased binding of p21 with cdc2 and cdk2. These observations suggest that genistein induces a G2/M arrest in human breast cancer cells, the mechanism of which is in part due to inhibition of kinase activities of cdc2 and cdk2, and decrease in cyclin B1 expression. C1 Pusan Natl Univ, Dept Food Sci & Nutr, Pusan Canc Res Ctr, Keumjung Ku, Pusan 609735, South Korea. Pusan Natl Univ, Dept Biol, Pusan Canc Res Ctr, Pusan 609735, South Korea. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Park, KY (reprint author), Pusan Natl Univ, Dept Food Sci & Nutr, Pusan Canc Res Ctr, Keumjung Ku, 30 Jang Jundong, Pusan 609735, South Korea. NR 34 TC 90 Z9 94 U1 0 U2 1 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD AUG PY 1998 VL 13 IS 2 BP 391 EP 396 PG 6 WC Oncology SC Oncology GA 101LR UT WOS:000074870900027 PM 9664138 ER PT J AU Rodriguez, IR Mazuruk, K Jaworski, C Iwata, F Moreira, EF Kaiser-Kupfer, MI AF Rodriguez, IR Mazuruk, K Jaworski, C Iwata, F Moreira, EF Kaiser-Kupfer, MI TI Novel mutations in the XLRS1 gene may be caused by early Okazaki fragment sequence replacement SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID RETINOSCHISIS AB PURPOSE. TO determine whether two families diagnosed with X-linked retinoschisis contained mutations in the XLRS1 gene. METHODS. DNA from the patients was obtained from blood lymphocytes using commercially available kits. Single-strand conformation assay was performed in an electrophoresis apparatus using 10% acrylamide TBE gels at 10 degrees C. The gels were stained with SYB green II and were scanned in a phosphoimager. DNA was sequenced using an automated fluorescence sequencer. RESULTS. A deletion that eliminates exon 2 was found in one family. An abnormal sequence replacement in exon 4 was found in the other family. Both mutations have severe effects in the coding region by inserting premature stop codons. CONCLUSIONS. Bath of the families have mutations in the XLRS1 gene. One of these mutations points to a novel mechanism. The mutation is caused by a replacement of 17 bp of a normal sequence with 20 bp of a sequence originating from two different places in the antisense strand. This suggests that early Okazaki fragments were incorporated into the sense strand of exon 4, replacing the normal sequence. C1 NEI, NIH, Bethesda, MD 20892 USA. RP Rodriguez, IR (reprint author), NEI, NIH, 6 Ctr Dr MSC 2740,Bldg 6,Room 304, Bethesda, MD 20892 USA. NR 6 TC 16 Z9 17 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 AUG PY 1998 VL 39 IS 9 BP 1736 EP 1739 PG 4 WC Ophthalmology SC Ophthalmology GA 106DE UT WOS:000075113800026 PM 9699564 ER PT J AU Tasaki, I AF Tasaki, I TI Repetitive mechanical responses of the amphibian skin to adrenergic stimulation SO JAPANESE JOURNAL OF PHYSIOLOGY LA English DT Article DE frog skin glands; epinephrine; repetitive mechanical changes ID VOLUME; CELLS AB Mechanical responses of the amphibian nerve-skin preparation to adrenergic stimulation were investigated by recording pressure changes at the skin surface with a piezoelectric sensor. When a dilute epinephrine (or norepinephrine) solution was applied to the inner skin surface, repetitive mechanical responses, representing quick swelling of the skin repeating at more or less regular intervals of about 1 min, were frequently observed. In about 10% of the preparations, the skin was found to undergo repetitive quick shrinkage (instead of swelling) under practically indistinguishable experimental conditions. Rapid volume changes occurring in the cytoplasmic gel of the gland cells are considered to be at the base of these repetitive mechanical responses. C1 NIMH, NIH, Bethesda, MD 20892 USA. RP Tasaki, I (reprint author), NIMH, NIH, Rm 3e-25 Bldg,13, Bethesda, MD 20892 USA. NR 11 TC 3 Z9 3 U1 0 U2 0 PU CENTER ACADEMIC PUBL JAPAN PI TOKYO PA 4-16 YAYOI 2-CHOME, BUNKYO-KU, TOKYO, 113, JAPAN SN 0021-521X J9 JPN J PHYSIOL JI Jpn. J. Physiol. PD AUG PY 1998 VL 48 IS 4 BP 297 EP 300 DI 10.2170/jjphysiol.48.297 PG 4 WC Physiology SC Physiology GA 125TE UT WOS:000076252500009 PM 9757146 ER PT J AU Kendziora, KT O'Leary, SG AF Kendziora, KT O'Leary, SG TI Appraisals of child behavior by mothers of problem and nonproblem toddlers SO JOURNAL OF ABNORMAL CHILD PSYCHOLOGY LA English DT Article; Proceedings Paper CT Annual Convention of the Association-for-the-Advancement-of-Behavior-Therapy CY NOV, 1996 CL NEW YORK, NEW YORK SP Assoc Advancement Behav Therapy DE appraisal; bias; tracking; toddlers; child behavior ID PARENTS; ABUSE AB Mothers of problem and nonproblem toddlers rated videotapes of their own and unfamiliar children's behavior. They classified the behaviors as positive, negative, or neutral, and evaluated the intensity of the positive or negative behaviors. Ratings did not differ by problem status; however, all mothers classified their own children's behavior as less negative than did an independent observer. Mothers also evaluated all children's negative behavior as less aversive than did the observer. Finally, mothers "mistakenly" classified less of their own children's behavior as negative and more as positive when compared to their biases in classifying unfamiliar children's behavior. C1 NIMH, Sect Dev Psychopathol, Bethesda, MD 20892 USA. SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. RP Kendziora, KT (reprint author), NIMH, Sect Dev Psychopathol, Bldg 15K,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 22 TC 11 Z9 11 U1 0 U2 0 PU PLENUM PUBL CORP PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0091-0627 J9 J ABNORM CHILD PSYCH JI J. Abnorm. Child Psychol. PD AUG PY 1998 VL 26 IS 4 BP 247 EP 255 DI 10.1023/A:1022650316551 PG 9 WC Psychology, Clinical; Psychology, Developmental SC Psychology GA 106EW UT WOS:000075117800002 PM 9700517 ER PT J AU Klimes-Dougan, B AF Klimes-Dougan, B TI Screening for suicidal ideation in children and adolescents: methodological considerations SO JOURNAL OF ADOLESCENCE LA English DT Article ID MULTIPLE SOURCES; AFFECTIVELY ILL; RISK-FACTORS; PARENTS; INTERVIEW; BEHAVIOR AB The prevalence of suicidal ideation and attempts varies considerably depending on (a) who the reporters are for youth suicidality, (b) the degree of retrospection required, and (c) the type of measure used to assess suicidality. The purpose of this study is to examine some of the methodological issues that should be considered when administering suicidal screening measures to children and adolescents. The risk group was comprised of offspring of depressed mothers (26 mothers with Bipolar Disorder, 42 mothers with Major Depressive Disorder). The comparison group was comprised of offspring of mothers without past or current psychiatric diagnosis (30 mothers). Two siblings from each family were recruited for participation (n=192). Screening for youth suicidality was based on (a) structured diagnostic interviews with youth (yielding interval and lifetime reports), (b) youth self-reports, and (c) maternal reports. Assessments were made when the younger siblings were approximately 6, 9, and 14 years of age and older siblings were approximately 6, 9, 13, and 18 years of age. Mothers reported a lower prevalence of youth suicidal content than did youth. Discrepancies between mother and child report were more common in the risk group. When lifetime retrospection of suicidal content was assessed, fewer youth reported suicidal thoughts or actions than when suicidal content was assessed approximately every 3 years. Also, the prevalence of self-reported suicidal content was somewhat higher (7 to 13%) than when assessing suicidality within the context of an interview. Child and maternal characteristics were found to correspond to patterns of consistent and discrepant reporting. (C) 1998 The Association for Professionals in Services for Adolescents. C1 NIMH, Sect Dev Psychopathol, Bethesda, MD 20892 USA. RP Klimes-Dougan, B (reprint author), NIMH, Sect Dev Psychopathol, Bldg 15-K,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 30 TC 43 Z9 45 U1 0 U2 1 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0140-1971 J9 J ADOLESCENCE JI J. Adolesc. PD AUG PY 1998 VL 21 IS 4 BP 435 EP 444 DI 10.1006/jado.1998.0166 PG 10 WC Psychology, Developmental SC Psychology GA 119QC UT WOS:000075906900009 PM 9757408 ER PT J AU Hagberg, JM Goldberg, AP Lakatta, L O'Connor, FC Becker, LC Lakatta, EG Fleg, JL AF Hagberg, JM Goldberg, AP Lakatta, L O'Connor, FC Becker, LC Lakatta, EG Fleg, JL TI Expanded blood volumes contribute to the increased cardiovascular performance of endurance-trained older men SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE plasma volume; red cell volume; total blood volume; body composition; stroke volume; cardiac output ID AEROBIC CAPACITY; SEDENTARY MEN; EXERCISE; YOUNG; RESPONSES AB To determine whether expanded intravascular volumes contribute to the older athlete's higher exercise stroke volume and maximal oxygen consumption ((V) over dot O-2max), we measured peak upright cycle ergometry cardiac volumes (Tc-99m ventriculography) and plasma (I-125-labeled albumin) and red cell (NaCr51) volumes in 7 endurance-trained and 12 age-matched lean sedentary men. The athletes had similar to 40% higher (V) over dot O-2max values than did the sedentary men and larger relative plasma (46 vs. 38 ml/kg), red cell (30 vs. 26 ml/kg), and total blood volumes (76 vs. 64 ml/kg) (all P < 0.05). Athletes had larger peak cycle ergometer exercise stroke volume indexes (75 vs. 57 ml/m(2), P < 0.05) and 17% larger end-diastolic volume indexes. In the total group, (V) over dot O-2max, correlated with plasma, red cell, and total blood volumes (r = 0.61-0.70, P < 0.01). Peak exercise stroke volume was correlated directly with the blood volume variables (r = 0.59-0.67, P < 0.01). Multiple regression analyses showed that fat-free mass and plasma or total blood volume, but not red cell volume, were independent determinants of (V) over dot O-2max, and peak exercise stroke volume. Plasma and total blood volumes correlated with the stroke volume and end-diastolic volume changes from rest to peak exercise. This suggests that expanded intravascular volumes, particularly plasma and total blood volumes, contribute to the higher peak exercise left ventricular end-diastolic volume, stroke volume, and cardiac output and hence the higher (V) over dot O-2max in master athletes by eliciting both chronic volume overload and increased utilization of the Frank-Starling effect during exercise. C1 Univ Maryland, Dept Kinesiol, College Pk, MD 20742 USA. Univ Maryland, Ctr Aging, College Pk, MD 20742 USA. Univ Maryland, Sch Med, Geriatr Serv, Dept Med,Div Gerontol, Baltimore, MD 21201 USA. Baltimore Vet Adm Med Ctr, Ctr Geriatr Res Educ & Clin, Baltimore, MD 21201 USA. NIA, Cardiovasc Sci Lab, Ctr Gerontol Res, Baltimore, MD 21224 USA. Johns Hopkins Med Inst, Div Cardiol, Baltimore, MD 21222 USA. RP Hagberg, JM (reprint author), Univ Maryland, Dept Kinesiol, College Pk, MD 20742 USA. FU NCRR NIH HHS [M01-RR-02719]; NIA NIH HHS [P01-AG-04402, R01-AG-07660] NR 28 TC 40 Z9 40 U1 0 U2 2 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 AUG PY 1998 VL 85 IS 2 BP 484 EP 489 PG 6 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 114CV UT WOS:000075592300017 PM 9688724 ER PT J AU Matten, SR Schneider, TD Ringquist, S Brusilow, WSA AF Matten, SR Schneider, TD Ringquist, S Brusilow, WSA TI Identification of an intragenic ribosome binding site that affects expression of the uncB gene of the Escherichia coli proton-translocating ATPase (unc) operon SO JOURNAL OF BACTERIOLOGY LA English DT Article ID MESSENGER-RNA; TRANSLATIONAL INITIATION; SUBUNIT-A; H+-ATPASE; SYNTHASE; OVERPRODUCTION; DEGRADATION; CLEAVAGES; SEQUENCE; FUSIONS AB The uncB gene codes for the a subunit of the F-o proton channel sector of the Escherichia coli F-1 F-o ATPase, Control of expression of uncB appears to be exerted at some step after translational initiation. Sequence analysis by the perceptron matrices (G. D. Stormo, T. D. Schneider, L, Gold, and A, Ehrenfeucht, Nucleic Acids Res. 10:2997-3011, 1982) identified a potential ribosome binding site within the uncB reading frame preceding a five-codon reading frame which is shifted one base relative to the uncB reading frame. Elimination of this binding site by mutagenesis resulted in a four- to fivefold increase in expression of an uncB'-'lacZ fusion gene containing most of uncB. Primer extension inhibition (toeprint) analysis to measure ribosome binding demonstrated that ribosomes could form an initiation complex at this alternative start site. Two fusions of lacZ to the alternative reading frame demonstrated that this site is recognized by ribosomes in vivo, The results suggest that expression of uncB is reduced by translational frameshifting and/or a translational false start at this site within the uncB reading frame. C1 Wayne State Univ, Sch Med, Dept Biochem & Mol Biol, Detroit, MI 48201 USA. NCI, Lab Computat & Expt Biol, Frederick, MD 21702 USA. Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA. RP Brusilow, WSA (reprint author), Wayne State Univ, Sch Med, Dept Biochem & Mol Biol, Scott Hall,540 E Canfield Ave, Detroit, MI 48201 USA. EM wbrusilow@med.wayne.edu OI Schneider, Thomas/0000-0002-9841-1531 NR 29 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 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD AUG PY 1998 VL 180 IS 15 BP 3940 EP 3945 PG 6 WC Microbiology SC Microbiology GA 105YY UT WOS:000075104000028 PM 9683492 ER PT J AU Sheng, ZH Westenbroek, RE Catterall, WA AF Sheng, ZH Westenbroek, RE Catterall, WA TI Physical link and functional coupling of presynaptic calcium channels and the synaptic vesicle docking/fusion machinery SO JOURNAL OF BIOENERGETICS AND BIOMEMBRANES LA English DT Article DE presynaptic calcium channels; synaptic vesicle; fusion; synprint ID PROTEIN-PROTEIN INTERACTIONS; N-TYPE; TRANSMITTER RELEASE; NEUROTRANSMITTER RELEASE; CA2+ CHANNELS; SYNAPTOTAGMIN-I; ACTIVE ZONES; IMMUNOCHEMICAL IDENTIFICATION; DIFFERENTIAL PHOSPHORYLATION; SUBCELLULAR-DISTRIBUTION AB N- and P/Q-type calcium channels are localized in high density in presynaptic nerve terminals and are crucial elements in neuronal excitation-secretion coupling. In addition to mediating Ca2+ entry to initiate transmitter release, they are thought to interact directly with proteins of the synaptic vesicle docking/fusion machinery. As outlined in the preceding article, these calcium channels can be purified from brain as a complex with SNARE proteins which are involved in exocytosis. In addition, N-type and P/Q-type calcium channels are co-localized with syntaxin in high-density clusters in nerve terminals. Here we review the role of the synaptic protein interaction (synprint) sites in the intracellular loop II-III (LII-III) of both alpha(1B) and alpha(1A) subunits of N-type and P/Q-type calcium channels, which bind to syntaxin, SNAP-25, and synaptotagmin. Calcium has a biphasic effect on the interactions of N-type calcium channels with SNARE complexes, stimulating optimal binding in the range of 10-20 mu M. PKC or CaM KII phosphorylation of the N-type synprint peptide inhibits interactions with native brain SNARE complexes containing syntaxin and SNAP-25. Introduction of the synprint peptides into presynaptic superior cervical ganglion neurons reversibly inhibits EPSPs from synchronous transmitter release by 42%. At physiological Ca2+ concentrations, synprint peptides cause an approximate 25% reduction in transmitter release of injected frog neuromuscular junction in cultures, consistent with detachment of 70% of the docked vesicles from calcium channels based on a theoretical model. Together, these studies suggest that presynaptic calcium channels not only provide the calcium signal required by the exocytotic machinery, but also contain structural elements that are integral to vesicle docking, priming, and fusion processes. C1 NINCDS, Synap Funct Unit, NIH, Bethesda, MD 20892 USA. Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA. RP Sheng, ZH (reprint author), NINCDS, Synap Funct Unit, NIH, Bldg 36,Rm 5A23, Bethesda, MD 20892 USA. NR 80 TC 100 Z9 102 U1 2 U2 6 PU PLENUM PUBL CORP PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0145-479X J9 J BIOENERG BIOMEMBR JI J. Bioenerg. Biomembr. PD AUG PY 1998 VL 30 IS 4 BP 335 EP 345 DI 10.1023/A:1021985521748 PG 11 WC Biophysics; Cell Biology SC Biophysics; Cell Biology GA 120ZW UT WOS:000075988600004 PM 9758330 ER PT J AU Fletcher, CF Copeland, NG Jenkins, NA AF Fletcher, CF Copeland, NG Jenkins, NA TI Genetic analysis of voltage-dependent calcium channels SO JOURNAL OF BIOENERGETICS AND BIOMEMBRANES LA English DT Article DE voltage-dependent calcium channels; calcium release channels; mutations; disease loci; paroxysmal disorders; triplet repeats ID HYPOKALEMIC PERIODIC PARALYSIS; RYANODINE-RECEPTOR GENE; CENTRAL CORE DISEASE; INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; MALIGNANT-HYPERTHERMIA SUSCEPTIBILITY; FAMILIAL HEMIPLEGIC MIGRAINE; CA2+ RELEASE CHANNEL; MUTANT MICE LACKING; SKELETAL-MUSCLE; CAENORHABDITIS-ELEGANS AB Molecular cloning of calcium channel subunit genes has identified an unexpectedly large number of genes and splicing variants, and a central problem of calcium channel biology is to now understand the functional significance of this genetic complexity. While electrophyisological. pharmacological, and molecular cloning techniques are providing one level of understanding, a complete understanding will require many additional kinds of studies, including genetic studies done in intact animals. In this regard, an intriguing variety of episodic diseases have recently been identified that result from defects in calcium channel genes. A study of these diseases illustrates the kind of insights into calcium channel function that can be expected from this method of inquiry. C1 NCI, Mammalian Genet Lab, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Fletcher, CF (reprint author), NCI, Mammalian Genet Lab, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NR 88 TC 10 Z9 11 U1 0 U2 0 PU PLENUM PUBL CORP PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0145-479X J9 J BIOENERG BIOMEMBR JI J. Bioenerg. Biomembr. PD AUG PY 1998 VL 30 IS 4 BP 387 EP 398 DI 10.1023/A:1021993723565 PG 12 WC Biophysics; Cell Biology SC Biophysics; Cell Biology GA 120ZW UT WOS:000075988600008 PM 9758334 ER PT J AU Duncan, WC Johnson, KA Wehr, TA AF Duncan, WC Johnson, KA Wehr, TA TI Decreased sensitivity to light of the photic entrainment pathway during chronic clorgyline and lithium treatments SO JOURNAL OF BIOLOGICAL RHYTHMS LA English DT Article; Proceedings Paper CT 6th Meeting of the Society-for-Research-on-Biological-Rhythms CY MAY 06-10, 1998 CL AMELIA ISL PLANTATION, FL SP Soc Res Biol Rhythms DE circadian rhythm; antidepressant; depression; light; MAOI; lithium; serotonin; melatonin; activity-rest cycle; photoreceptor ID MONOAMINE-OXIDASE INHIBITORS; MAMMALIAN CIRCADIAN-RHYTHMS; SEASONAL AFFECTIVE-DISORDER; RETINALLY DEGENERATE MICE; CENTRAL NERVOUS-SYSTEM; LONG-TERM TREATMENT; BRIGHT-LIGHT; SYRIAN-HAMSTERS; ANTIDEPRESSANT TREATMENTS; ANTI-DEPRESSANTS AB Certain antidepressant drugs (ADs) cause disturbances in sleep that could result from their capacity to alter the timing of circadian rhythms. Effects on the timing of rhythms could be due to the drugs' known capacity to alter the frequency of the intrinsic rhythm of the circadian pacemaker, or to a capacity to modify the pacemaker's response to external stimuli that serve as time cues (Zeitgebers) that regulate the timing (phase) of its rhythm. To examine the possibility that ADs alter the sensitivity of the system that mediates the phase-shifting effects of Light, hamsters were treated chronically with the MAOI, clorgyline, and lithium. Each hamster was then exposed to a single 5-min light pulse (intensity range = 0.00137 to 137 mu W/cm(2)) at circadian phases known to elicit phase advances (CT18) and phase delays (CT13.5) in the daily onset of wheel running. The half-saturation constant (sigma), photic sensitivity (1/sigma), and maximum phase-shifting response to light were estimated from the best-fit stimulus response curves. In addition, threshold sensitivity, the light intensity required to produce a threshold phase-shifting response, was determined. Clorgyline decreased the magnitude of light-induced phase advances at each of the light intensities tested. Clorgyline also decreased the magnitude of Light-induced phase delays at low light intensities, but increased the magnitude of phase delays at higher light intensities. Clorgyline decreased the sensitivity of the photic phase-shifting system, as indicated both by the threshold sensitivities at CT13.5 and CT18 and by 1/sigma at CT13.5. Lithium decreased the threshold sensitivity at CT18, and 1/sigma at CT13.5. Lithium decreased the magnitude of phase delays, but not phase advances. Clorgyline's effects on the photic entrainment pathway may be mediated by its effects on serotonin, which has been shown to modulate the pacemaker's response to morning and evening light, and by tolerance to this effect of serotonin. The fact that both clorgyline and lithium decrease the photic sensitivity of the entrainment pathway suggests that other psychoactive drugs might also share this property. It is possible that the decreased sensitivity to light of the entrainment pathway affects the clinical response to these and other psychoactive medications. C1 NIMH, Sect Biol Rhythms, Bethesda, MD 20892 USA. RP Duncan, WC (reprint author), NIMH, Sect Biol Rhythms, Bethesda, MD 20892 USA. NR 86 TC 11 Z9 13 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0748-7304 J9 J BIOL RHYTHM JI J. Biol. Rhythms PD AUG PY 1998 VL 13 IS 4 BP 330 EP 346 DI 10.1177/074873098129000165 PG 17 WC Biology; Physiology SC Life Sciences & Biomedicine - Other Topics; Physiology GA 105XF UT WOS:000075100100008 PM 9711508 ER PT J AU McCutchen, CW AF McCutchen, CW TI A theoretical formulation for boundary friction in articular cartilage - Discussion SO JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME LA English DT Editorial Material C1 NIDDKD, NIH, Bethesda, MD 20892 USA. RP McCutchen, CW (reprint author), NIDDKD, NIH, Bethesda, MD 20892 USA. NR 7 TC 0 Z9 1 U1 0 U2 0 PU ASME-AMER SOC MECHANICAL ENG PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 0148-0731 J9 J BIOMECH ENG-T ASME JI J. Biomech. Eng.-Trans. ASME PD AUG PY 1998 VL 120 IS 4 BP 547 EP 547 DI 10.1115/1.2798029 PG 1 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA 117AC UT WOS:000075756700018 PM 10412430 ER PT J AU Le, SY Chen, JH Pattabiraman, N Maizel, JV AF Le, SY Chen, JH Pattabiraman, N Maizel, JV TI Ion-RNA interactions in the RNA pseudoknot of a ribosomal frameshifting site: Molecular modeling studies SO JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS LA English DT Article ID HAMMERHEAD RIBOZYME; MESSENGER-RNA; DNA DUPLEX; VIRUS; DYNAMICS; IDENTIFICATION; SIMULATION; MECHANISM; CLEAVAGE AB The three-dimensional (3-D) structure of a RNA pseudoknot that causes the efficient ribosomal frameshifting in the gag-pro region of mouse mammary tumor virus (MMTV) has been determined recently by nuclear magnetic resonance (NMR) studies (9). But since the structure refinement in the studies did not use metal ions and waters, it is not clear how metal ions participate in the stabilization of the pseudoknot, and what kind of ion-RNA interactions dominate in the tertiary contacts for the RNA pseudoknotting. Based on the reported structure data of the pseudoknot VPK of MMTV (9), we gradually refined the structure by restrained molecular dynamics (MD) using NMR distance restraints (17). Restrained MD simulation of the RNA pseudoknot was performed with sodium ions and water molecules. Our results are in good agreement with known NMR data and delineate the importance of the metal ion coordination in the stability of the pseudoknot. In the non-coaxially stacking pseudoknot, stem 1 (S1), stem 2 (S2), and the intervening A14 involves unconventional stacking of base pairs coordinated by Na+ and/or bridging water molecules. A6 and G7 of loop L1 make a perfect base stacking in the major groove and are further stabilized by coordinated Na+ ions and water molecules. The first 4-nucleotide (nt) ACUC of loop L2 form a sharp turn and the following 4-nt AAAA cross the minor groove of S1 and are steadied by interactions with the nucleotides of S1, bridging water molecules and coordinated Na+ ions. Our studies suggest that the metal ion plays a crucial role in the RNA pseudoknotting of VPK. In the stacking interior of S1 and S2, the Na+ ion is positioned in the major groove and interacts directly with the carbonyl group O-6 of G28 and carbonyl group O-4 of U13 in the wobble base pair U13:G28. The ion-RNA interactions in MMTV VPK not only stabilize the RNA pseudoknot but also modify the electrostatic properties of the nucleotides at the critical parts of the pseudoknot VPK. C1 NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, DBS,NIH, Frederick, MD 21701 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick Biomed Supercomp Ctr, SAIC, Frederick, MD 21702 USA. RP Le, SY (reprint author), NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, DBS,NIH, Frederick, MD 21701 USA. EM shuyun@orleans.ncifcrf.gov NR 34 TC 8 Z9 8 U1 1 U2 1 PU ADENINE PRESS INC PI GUILDERLAND PA PO BOX 355/340, GUILDERLAND, NY 12084 USA SN 0739-1102 J9 J BIOMOL STRUCT DYN JI J. Biomol. Struct. Dyn. PD AUG PY 1998 VL 16 IS 1 BP 1 EP 11 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 116HJ UT WOS:000075718400001 PM 9745889 ER PT J AU Song, J Khachikian, Z Radhakrishna, H Donaldson, JG AF Song, J Khachikian, Z Radhakrishna, H Donaldson, JG TI Localization of endogenous ARF6 to sites of cortical actin rearrangement and involvement of ARF6 in cell spreading SO JOURNAL OF CELL SCIENCE LA English DT Article DE GTP binding protein; ADP-ribosylation factor; actin cytoskeleton; cell spreading ID ADP-RIBOSYLATION FACTOR; NUCLEOTIDE-EXCHANGE PROTEIN; PHOSPHOLIPASE-D; GOLGI MEMBRANES; BREFELDIN-A; ENDOPLASMIC-RETICULUM; MAMMALIAN-CELLS; PLASMA-MEMBRANE; CHOLERA-TOXIN; KINASE-C AB To study the function of the endogenous ARF6 GTP binding protein in cells, we generated an antibody which specifically recognizes ARF6, and not the other ARF proteins. Using this antibody, ARF6 was detected in all mouse organs tested and in a variety of cultured cell lines including RBL, MDCK, NRK, BHK, COS, and HeLa cells. In NRK cells, by immunofluorescence, ARF6 Localized to the plasma membrane, especially at regions exhibiting membrane ruffling, and was also concentrated in a fine punctate distribution in the juxtanuclear region. This pattern of localization of the endogenous protein was similar to the localization of ARF6 when overexpressed in NRK, or HeLa, cells. Treatments which perturb cortical actin in NRK cells, such as replating of cells after trypsinization or treatment with phorbol ester, resulted in the recruitment of endogenous ARF6 to the regions of cortical actin rearrangement. ARF6 activation and subsequent membrane recycling was required for cell spreading activity since expression of the dominant-negative, GTP-binding defective mutant of ARF6, T27N, previously shown to inhibit ARF6-regulated membrane recycling, inhibited cell attachment and spreading in HeLa cells. Furthermore, phorbol ester treatment enhanced the cell spreading activities in NRK cells, and in HeLa cells, but was not observed in cells expressing T27N, Taken together, these observations support a role for endogenous ARF6 in modeling the plasma membrane and cortical actin cytoskeleton. C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Donaldson, JG (reprint author), NHLBI, Cell Biol Lab, NIH, Bld 3,Room B1-22, Bethesda, MD 20892 USA. EM jdonalds@helix.nih.gov NR 41 TC 137 Z9 137 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE, CAMBS, ENGLAND CB4 4DL SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD AUG PY 1998 VL 111 BP 2257 EP 2267 PN 15 PG 11 WC Cell Biology SC Cell Biology GA 111KR UT WOS:000075436700019 PM 9664047 ER PT J AU Mincione, G Piccirelli, A Lazzereschi, D Salomon, DS Colletta, G AF Mincione, G Piccirelli, A Lazzereschi, D Salomon, DS Colletta, G TI Heregulin-dependent autocrine loop regulates growth of K-ras but not erbB-2 transformed rat thyroid epithelial cells SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID MURINE SARCOMA-VIRUS; FACTOR-ALPHA; EXPRESSION; RECEPTOR; CARCINOMAS; GENE; OVEREXPRESSION; COEXPRESSION; FAMILY; RNA AB The ECF-like family of proteins, such as epidermal growth factor (ECF), transforming growth factor alpha (TGF alpha), amphiregulin (AR), betacellulin (BTC), cripto-1 (CR-1), and heregulin (HRC), plays an important role in the pathogenesis of several human carcinomas as autocrine growth factors. Differentiation and proliferation of rat thyroid cells in culture (FRTL-5 cells) are regulated by thyrotropin (TSH); withdrawal of TSH from culture medium produces growth arrest, whereas its addition to quiescent cells stimulates cell entry into S phase. Instead, transformed thyroid cell lines as FRTL-5H2 cell line, overexpressing erbB-2, Kimol cells, transformed by the wild-type K-ras and A6 clone, transformed by a temperature sensitive K-ras mutant, can grow without addition of TSH to the culture medium. In order to identify whether ECF-like growth factors and corresponding receptors (erbB-2, erbB-3, and erbB-4) could be involved in the autonomous growth of these transformed rat thyroid epithelial cells, Northern blot for mRNA analysis and Western blot for protein expression were performed. In contrast to normal control FRTL-5 cells, both K-ras and erbB-2-transformed cells expressed elevated levels of erbB-2 receptor. Moreover, both K-ras transformed cells, Kimol and A6 cells, but no FRTL-5H2 cells, were found able to express also high levels of erbB-4 receptor and HRG/NDF ligand. Treatment of K-ras transformed thyroid cells with neutralizing antibody against HRG/NDF reduced by 50% cell proliferation. These data indicate that unlike the erbB-2 overexpressing FRTL-5 cells, in K-ras rat thyroid epithelial cells, the growth factor heregulin signals through the heterodimer erbB-2/erbB-4 receptors in an autocrine fashion. (C) 1998 Wiley-Liss, Inc. C1 Univ G DAnnunzio, Fac Med & Chirurg, Cattedra Patol Gen, Dipartimento Oncol & Neurosci, I-66013 Chieti, Italy. Univ Rome La Sapienza, Dipartimento Med Sperimentale & Patol, Rome, Italy. NCI, Tumor Growth Factor Sect, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. RP Colletta, G (reprint author), Univ G DAnnunzio, Fac Med & Chirurg, Cattedra Patol Gen, Dipartimento Oncol & Neurosci, Via Vestini 1, I-66013 Chieti, Italy. NR 42 TC 11 Z9 11 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 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD AUG PY 1998 VL 176 IS 2 BP 383 EP 391 DI 10.1002/(SICI)1097-4652(199808)176:2<383::AID-JCP17>3.0.CO;2-4 PG 9 WC Cell Biology; Physiology SC Cell Biology; Physiology GA ZV411 UT WOS:000074301900017 PM 9648926 ER PT J AU Li, SH Huang, FL Feng, QP Liu, J Fan, SX McKenna, TM AF Li, SH Huang, FL Feng, QP Liu, J Fan, SX McKenna, TM TI Overexpression of protein kinase C alpha enhances lipopolysaccharide-induced nitric oxide formation in vascular smooth muscle cells SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID NF-KAPPA-B; L-ARGININE TRANSPORT; PHORBOL ESTERS; ENDOTHELIAL-CELLS; SYNTHASE ACTIVITY; MESSENGER-RNA; NO SYNTHASE; EXPRESSION; INDUCTION; RAT AB Our previous studies showed that lipopolysaccharide (LPS)-induced nitric oxide (NO) synthesis in cardiovascular tissues is attenuated by protein kinase C (PKC) inhibitors. In the current study, we identify a specific PKC isotype involved in the LPS signal transduction pathway that leads to NO formation in rat vascular smooth muscle cells (VSMC). VSMC were transfected with a mammalian expression vector containing a full length PKC alpha cDNA insert, and a stable transfectant overexpressing PKC alpha was obtained as evidenced by increased expression of PKC alpha mRNA and protein. In response to 100 ng/ml LPS stimulation, the PKC alpha transfectants showed a 1.8-fold increase in PKC activity at 30 min and a twofold increase in NO production over 24 hr compared with cells transfected with control plasmids. The LPS-stimulated increase in NO synthesis in PKC alpha transfectants was blocked by the specific PKC alpha inhibitor Ga 6976. After 6 hr LPS treatment, PKC alpha-transfected and control cells showed equivalent increases in mRNA and protein for the inducible NO synthase. NO synthase activity of the cell extracts assayed in the presence of excess substrate and cofactors was not significantly different between PKC alpha-transfected and control cells after LPS stimulation. However, mRNA levels for GTP cyclohydrolase I, a key enzyme in (GR)-tetrahydro-L-biopterin synthesis, and cationic amino acid transporter-2, involved in L-arginine transport, was enhanced in cells overexpressing PKC alpha compared with control cells. These results suggest that PKC alpha plays an important role in LPS-induced NO formation and that a significant portion of this effect may be by means of enhanced substrate availability to the inducible nitric oxide synthase enzyme. (C) 1998 Wiley-Liss, Inc. C1 NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. USN, Res Inst, Resuscitat Med Program, Bethesda, MD USA. Univ Western Ontario, Dept Pharmacol & Toxicol, London, ON, Canada. RP Li, SH (reprint author), John P Robarts Res Inst, Vasc Biol Grp, 100 Perth Dr, London, ON N6A 5K8, Canada. EM shli@rri.on.ca NR 49 TC 20 Z9 24 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 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD AUG PY 1998 VL 176 IS 2 BP 402 EP 411 DI 10.1002/(SICI)1097-4652(199808)176:2<402::AID-JCP19>3.0.CO;2-4 PG 10 WC Cell Biology; Physiology SC Cell Biology; Physiology GA ZV411 UT WOS:000074301900019 PM 9648928 ER PT J AU Rosen, AC Newby, RF Sauer, CM Lacey, T Hammeke, TA Lubinsky, MS AF Rosen, AC Newby, RF Sauer, CM Lacey, T Hammeke, TA Lubinsky, MS TI A further report on a case of Floating-Harbor Syndrome in a mother and daughter SO JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY LA English DT Article ID EARLY OTITIS-MEDIA; SHORT-TERM-MEMORY; LANGUAGE; AGE; DISABILITIES; SPEECH AB We present the most extensive neuropsychological and language assessment yet reported of patients diagnosed with Floating-Harbor Syndrome (FHS), a rare genetic condition characterized by dysmorphid figures, short stature, and speech-onset delay. This is also the second reported occurrence of both a mother and daughter with FHS. Whereas the child demonstrated gross deficits in verbal expression, speech and language problems were largely ameliorated in the mother. Neuropsychological assessment also revealed a strikingly similar pattern of cognitive problems additional to language dysfunction, including difficulties with attention, mathematical, and visuospatial abilities. A mood disorder continued to be quite disabling for the mother. C1 Med Coll Wisconsin, Milwaukee, WI 53226 USA. Childrens Hosp Wisconsin, Milwaukee, WI 53201 USA. RP Rosen, AC (reprint author), NIA, Neurosci Lab, NIH, Bldg 10,Rm 6C414,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 23 TC 14 Z9 15 U1 0 U2 1 PU SWETS ZEITLINGER PUBLISHERS PI LISSE PA P O BOX 825, 2160 SZ LISSE, NETHERLANDS SN 1380-3395 J9 J CLIN EXP NEUROPSYC JI J. Clin. Exp. Neuropsychol. PD AUG PY 1998 VL 20 IS 4 BP 483 EP 495 DI 10.1076/jcen.20.4.483.1472 PG 13 WC Psychology, Clinical; Clinical Neurology; Psychology SC Psychology; Neurosciences & Neurology GA 153JY UT WOS:000077831000006 PM 9892052 ER PT J AU Stratakis, CA Kirschner, LS Taymans, SE Tomlinson, IPM Marsh, DJ Torpy, DJ Giatzakis, C Eccles, DM Theaker, J Houlston, RS Blouin, JL Antonarakis, SE Basson, CT Eng, C Carney, JA AF Stratakis, CA Kirschner, LS Taymans, SE Tomlinson, IPM Marsh, DJ Torpy, DJ Giatzakis, C Eccles, DM Theaker, J Houlston, RS Blouin, JL Antonarakis, SE Basson, CT Eng, C Carney, JA TI Carney complex, Peutz-Jeghers syndrome, Cowden disease, and Bannayan-Zonana syndrome share cutaneous and endocrine manifestations, but not genetic loci SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID SPOTTY SKIN PIGMENTATION; DOMINANT INHERITANCE; GERMLINE MUTATIONS; LINKAGE ANALYSIS; CARDIAC MYXOMAS; CELL TUMORS; FOLLOW-UP; CANCER; OVERACTIVITY; NEOPLASIA AB Carney complex (CC), Peutz-Jeghers syndrome (PJS), Cowden disease (CD), and Bannayan-Zonana syndrome (BZS) share clinical features, such as mucocutaneous lentigines and multiple tumors (thyroid, breast, ovarian, and testicular neoplasms), and autosomal dominant inheritance. A genetic locus has been identified for CC on chromosome 2 (2p16), and the genes for PJS, CD, and BZS were recently identified; genetic heterogeneity appears likely in both CC and PJS. The genes for PJS and CD/BZS, STK11/LKB1 and PTEN, respectively, may act as tumor suppressors, because loss of heterozygosity (LOH) of the PJS and CD/BZS loci has been demonstrated in tumors excised from patients with these disorders. We studied 2 families with CC in whom the disease could not be shown to segregate with polymorphic markers from the 2p16 locus. Their members presented with lesions frequently seen in PJS and the other lentiginosis syndromes. We also tested 16 tumors and cell lines established from patients with CC for LOH involving the PJS and CD/BZS loci. DNA was extracted from peripheral blood, tumor cell lines, and tissues and subjected to PCR amplification with primers from microsatellite sequences flanking the STK11/LKB1 and PTEN genes on 19p13 and 10q23, respectively, and a putative PJS locus on 19q13. All loci were excluded as candidates in both families with LOD scores less than -2 and/or by haplotype analysis. LOR for these loci was not present in any of the tumors that were histologically identical to those seen in PJS. The overall rate of LOH for the PJS and CD/BZS loci in tumors from patients with CC was less than 10%. We conclude that despite substantial clinical overlap among CC, PJS, CD, and BZS, LOH for the STK11 and PTEN loci is an infrequent event in CC-related tumors. Linkage analysis excluded the PJS and CD/BZS loci on chromosomes 19 (19p13 and 19913) and 10 (10q23) from harboring the gene defect(s) responsible for the phenotype in these 2 families. C1 NICHHD, Unit Genet & Endocrinol, Sect Pediat Endocrinol, Dev Endocrinol Branch,NIH, Bethesda, MD 20892 USA. Cornell Univ, Med Ctr, New York Hosp, Dept Med,Cardiol Div, New York, NY 10021 USA. Cornell Univ, Med Ctr, New York Hosp, Dept Cell Biol & Anat, New York, NY 10021 USA. Mayo Clin, Emeritus Staff, Rochester, MN 55905 USA. Dana Farber Canc Inst, Charles A Dana Human Canc Genet Unit, Richard & Susan Smith Labs, Boston, MA 02115 USA. Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Clin Med, Tumor Genet Grp, Oxford OX3 7HN, England. Inst Canc Res, Sutton SM2 5NG, Surrey, England. Univ Cambridge, Canc Res Campaign, Human Canc Genet Res Grp, Cambridge CB2 2QQ, England. Princess Anne Hosp, Wessex Clin Genet Serv, Southampton SO16 5YA, Hants, England. Univ Geneva, Sch Med, Dept Genet, Div Med Genet, CH-1211 Geneva, Switzerland. RP Stratakis, CA (reprint author), NICHHD, Unit Genet & Endocrinol, Sect Pediat Endocrinol, Dev Endocrinol Branch,NIH, Bldg 10,Room 10N262,10 Ctr Dr,MSC1862, Bethesda, MD 20892 USA. EM stratakc@cc1.nichd.nih.gov RI Marsh, Deborah/I-1491-2014; Antonarakis, Stylianos/N-8866-2014; OI Marsh, Deborah/0000-0001-5899-4931; Antonarakis, Stylianos/0000-0001-8907-5823; Eng, Charis/0000-0002-3693-5145; Houlston, Richard/0000-0002-5268-0242 NR 38 TC 35 Z9 35 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 AUG PY 1998 VL 83 IS 8 BP 2972 EP 2976 DI 10.1210/jc.83.8.2972 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 108KL UT WOS:000075265300060 PM 9709978 ER PT J AU Baier, LJ Dobberfuhl, AM Pratley, RE Hanson, RL Bogardus, C AF Baier, LJ Dobberfuhl, AM Pratley, RE Hanson, RL Bogardus, C TI Variations in the vitamin D-binding protein (Gc locus) are associated with oral glucose tolerance in nondiabetic Pima Indians SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID NORMAL INSULIN-SECRETION; PERFUSED RAT PANCREAS; D DEFICIENCY AB Electrophoretic variants of the vitamin D-binding protein (DBP) have been associated with type 2 diabetes as well as with metabolic characteristics that predispose to type 2 diabetes in several populations. The Ge gene that encodes DBP maps to chromosome 4q12, a region that has recently been found to be potentially linked to plasma glucose and insulin concentrations in Pima Indians. Therefore, the gene that encodes DBP was analyzed as a candidate gene for our linkage findings in the Pima Indians. Sequence analysis of the coding exons identified two previously described missense polymorphisms at codons 416 and 420, which are the genetic basis for the three common electrophoretic variants of DBP (Gc1f, Gc1s, and Gc2). These variants in DBP were associated with differences in oral glucose tolerance in nondiabetic Pima Indians. C1 NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. RP Baier, LJ (reprint author), NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, NIH, 4212 N 16Th St, Phoenix, AZ 85016 USA. EM lbaier@phx.niddk.nih.gov RI Dobberfuhl, Angela/C-9450-2012; Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 NR 19 TC 35 Z9 37 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 1998 VL 83 IS 8 BP 2993 EP 2996 DI 10.1210/jc.83.8.2993 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 108KL UT WOS:000075265300063 PM 9709981 ER PT J AU Ioannidis, JPA Lau, J AF Ioannidis, JPA Lau, J TI Uncontrolled pearls, controlled evidence, meta-analysis and the individual patient SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE randomized controlled trials; meta-analysis; clinical epidemiology; subgroup analyses; observational studies ID TRIALS AB Medicine has been dominated by uncontrolled data, often of unproven validity and insufficient to answer clinically important questions pertaining to individual patients. Controlled clinical trials, when de signed and conducted rigorously, offer advantages over uncontrolled data, but they cannot be done for everything and often cater to the interests of sponsors rather than medical knowledge. With such sparse evidence, clinical research is doomed to look at main effects across populations rather than diversity of effects among individuals. By accumulating data from a large number of studies, meta-analysis provides a unique opportunity to address individual and study-level heterogeneity. Diversity may be due to biases or may be real. Both sources must be scrutinized and meta-analysis may find a prime role in dissecting these components of diversity. Concurrent progress in basic sciences revolutionizing our predictive power for disease outcomes will heighten the importance of considering individual heterogeneity. (C) 1998 Elsevier Science Inc. C1 Tufts Univ, Sch Med, New England Med Ctr Hosp, Div Clin Care Res, Boston, MA 02111 USA. RP Ioannidis, JPA (reprint author), NIAID, Therapeut Res Program, DAIDS, NIH, Solar 2C31, Bethesda, MD 20892 USA. RI Ioannidis, John/G-9836-2011 NR 9 TC 17 Z9 18 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD AUG PY 1998 VL 51 IS 8 BP 709 EP 711 DI 10.1016/S0895-4356(98)00042-0 PG 3 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 104KD UT WOS:000075012700011 PM 9743320 ER PT J AU Asico, LD Ladines, C Fuchs, S Accili, D Carey, RM Semeraro, C Pocchiari, F Felder, RA Eisner, GM Jose, PA AF Asico, LD Ladines, C Fuchs, S Accili, D Carey, RM Semeraro, C Pocchiari, F Felder, RA Eisner, GM Jose, PA TI Disruption of the dopamine D-3 receptor gene produces renin-dependent hypertension SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE dopamine receptor; D-3 receptor gene; renin; catecholamines ID GLUTAMYL-L-DOPA; ANGIOTENSIN-II; BLOOD-PRESSURE; RAT; MICE; ACTIVATION; INHIBITION; RELEASE; TUBULE; CELLS AB Since dopamine receptors are important in the regulation of renal and cardiovascular function, we studied the cardiovascular consequences of the disruption of the D-3 receptor, a member of the family of D-2-like receptors, expressed in renal proximal tubules and juxtaglomerular cells. Systolic and diastolic blood pressures were higher (similar to 20 mmHg) in heterozygous and homozygous than in wild-type mice. An acute saline load increased urine flow rate and sodium excretion to a similar extent in wild-type and heterozygous mice but the increase was attenuated in homozygous mice. Renal renin activity was much greater in homozygous than in wild-type mice; values for heterozygous mice were intermediate, Blockade of angiotensin II subtype-1 receptors decreased systolic blood pressure for a longer duration in mutant than in wild-type mice. Thus, disruption of the D3 receptor increases renal renin production and produces renal sodium retention and renin-dependent hypertension. C1 Georgetown Univ, Med Ctr, Dept Pediat, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Dept Med, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Dept Physiol & Biophys, Washington, DC 20007 USA. Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel. NICHHD, Dev Endocrinol Branch, Bethesda, MD 20892 USA. Zambon Grp SpA, I-20091 Bresso, MI, Italy. Univ Virginia, Hlth Sci Ctr, Dept Med, Charlottesville, VA 22908 USA. Univ Virginia, Hlth Sci Ctr, Dept Pathol, Charlottesville, VA 22908 USA. RP Jose, PA (reprint author), Georgetown Univ, Med Ctr, Dept Pediat, 3800 Reservoir Rd NW, Washington, DC 20007 USA. EM josep@gunet.georgetown.edu FU NHLBI NIH HHS [HL58536]; NIDDK NIH HHS [DK39308] NR 39 TC 115 Z9 118 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD AUG 1 PY 1998 VL 102 IS 3 BP 493 EP 498 DI 10.1172/JCI3685 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 109ND UT WOS:000075327900004 PM 9691085 ER PT J AU Sunday, ME Yoder, BA Cuttitta, F Haley, KJ Emanuel, RL AF Sunday, ME Yoder, BA Cuttitta, F Haley, KJ Emanuel, RL TI Bombesin-like peptide mediates lung injury in a baboon model of bronchopulmonary dysplasia SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE radioimmunoassay; monoclonal antibody; oxygenation index; histopathology; proliferating cell nuclear antigen ID GASTRIN-RELEASING PEPTIDE; HYALINE-MEMBRANE DISEASE; PULMONARY NEUROENDOCRINE CELLS; RESPIRATORY-DISTRESS SYNDROME; FETAL LUNG; GENE-EXPRESSION; MATURATION INUTERO; PRETERM RABBIT; GROWTH; INFANTS AB The etiology of bronchopulmonary dysplasia (BPD), a chronic lung disease of infants surviving respiratory distress syndrome, remains fundamentally enigmatic. BPD is decreasing in severity but continues to be a major problem in pediatric medicine, being especially prevalent among very premature infants. Increased numbers of pulmonary neuroendocrine cells containing bombesin-like peptide (BLP) have been reported to occur in human infants with BPD. We tested the hypothesis that BLP mediates BPD using the hyperoxic baboon model. Urine BLP levels increased soon after birth only in 100% O-2-treated 140-d animals which developed BPD, correlating closely with severity of subsequent chronic lung disease. Similar elevations in urine BLP were observed in the 125-d baboon "interrupted gestation" model of BPD. Postnatal administration of anti-BLP antibody attenuated clinical and pathological evidence of chronic lung disease in the hyperoxic baboon model. Urine BLP could be a biological predictor of infants at risk for BPD, and blocking BLP postnatally could be useful for BPD prevention. C1 Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Wilford Hall USAF Med Ctr, Dept Pediat, Lackland AFB, TX 78236 USA. SW Fdn Biomed Res, San Antonio, TX 78228 USA. NCI, NIH, Rockville, MD 20850 USA. Childrens Hosp, Dept Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Div Pulm Crit Care, Boston, MA 02115 USA. RP Sunday, ME (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. FU NHLBI NIH HHS [HL-52636, U10-HL52638] NR 48 TC 47 Z9 49 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD AUG 1 PY 1998 VL 102 IS 3 BP 584 EP 594 DI 10.1172/JCI2329 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 109ND UT WOS:000075327900014 PM 9691095 ER PT J AU Higgins, JA Ezzell, J Hinnebusch, BJ Shipley, M Henchal, EA Ibrahim, MS AF Higgins, JA Ezzell, J Hinnebusch, BJ Shipley, M Henchal, EA Ibrahim, MS TI 5 ' nuclease PCR assay to detect Yersinia pestis SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID POLYMERASE CHAIN-REACTION; PLAGUE; IDENTIFICATION; PROBE; FLEAS AB The 5' nuclease PCR assay uses a fluorescently labeled oligonucleotide probe (TaqMan) to rapidly detect and quantitate DNA templates in clinical samples. We developed a 5' nuclease PCR assay targeting the plasminogen activator gene (pla) of Yersinia pestis. The assay is species specific, with a detection threshold of 2.1 x 10(5) copies of the pla target or 1.6 pg of total cell DNA. The assay detected Y. pestis in experimentally infected Xenopsylla cheopis fleas and in experimentally infected monkey blood and oropharyngeal swabs. The TaqMan assay is simple to perform and rapid and shows promise as a future field-adaptable technique. C1 USA, Med Res Inst Infect Dis, Diagnost Syst Div, Ft Detrick, MD 21702 USA. NIAID, Rocky Mt Labs, Microbial Struct & Funct Lab, Hamilton, MT 59840 USA. RP Ibrahim, MS (reprint author), USA, Med Res Inst Infect Dis, Diagnost Syst Div, 1425 Porter St, Ft Detrick, MD 21702 USA. EM sibrahim@detrick.army.mil NR 21 TC 70 Z9 76 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD AUG PY 1998 VL 36 IS 8 BP 2284 EP 2288 PG 5 WC Microbiology SC Microbiology GA ZZ359 UT WOS:000074721500023 PM 9666006 ER PT J AU Fisher, B Bryant, J Wolmark, N Mamounas, E Brown, A Fisher, ER Wickerham, DL Begovic, M DeCillis, A Robidoux, A Margolese, RG Cruz, AB Hoehn, JL Lees, AW Dimitrov, NV Bear, HD AF Fisher, B Bryant, J Wolmark, N Mamounas, E Brown, A Fisher, ER Wickerham, DL Begovic, M DeCillis, A Robidoux, A Margolese, RG Cruz, AB Hoehn, JL Lees, AW Dimitrov, NV Bear, HD TI Effect of preoperative chemotherapy on the outcome of women with operable breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PRIMARY TUMOR REMOVAL; GROWTH-STIMULATING FACTOR; RANDOMIZED TRIAL; KINETICS; THERAPY; SURGERY; MICE AB Purpose: To determine, in women with primary operable breast cancer, if preoperative doxorubicin (Adriamycin) and cyclophasphamide (Cytoxan: AC) therapy yields a better outcome than postoperative AC therapy if a relationship exists between outcome and tumor response to preoperative chemotherapy, and if such therapy results in the performance of more lumpectomies. Patients and Methods: Women (1,523) enrolled onto National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 were randomly assigned to preoperative or postoperative AC therapy. Clinical tumor response to preoperative therapy was graded as complete (cCR), partial (cPR), or no response (cNR). Tumors with a cCR were further categorized as either pathologic complete response (pCR) or invasive cells (pINV). Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were estimated through 5 years and compared between treatment groups. In the preoperative arm, proportional-hazards models were used to investigate the relationship between outcome and tumor response. Results: There was no significant difference in DFS, DDFS, or survival (P = .99, .70, and .83, respectively) among patients in either group. More patients treated preoperatively than postoperatively underwent lumpectomy and radiation therapy (67.8% v 59.8%, respectively). Rates of ipsilateral breast tumor recurrence (IBTR) after lumpectomy were similar in both groups (7.9% and 5.8%, respectively; P = .23). Outcome was better in women whose tumors showed a pCR than in those with a pINV, cPR, or cNR (relapse-free survival [RFS] rates, 85.7%, 76.9%, 68.1%, and 63.9%, respectively; P < .0001), even when baseline prognostic variables were controlled. When prognostic models were compared for each treatment group, the preoperative model, which included breast tumor response as a variable, discriminated outcome among patients to about the same degree as the postoperative model. Conclusion: Preoperative chemotherapy is as effective as postoperative chemotherapy, permits more lumpectomies, is appropriate for the treatment of, certain patients with stages I and II disease, and can be used to study breast cancer biology. Tumor response to preoperative chemotherapy correlates with outcome and could be a surrogate for evaluating the effect of chemotherapy on micrometastases; however, knowledge of such a response provided little prognostic information beyond that which resulted from postoperative therapy. J Clin Oncol 16: 2672-2685. (C) 1998 by American Society of Clinical Oncology. C1 Natl Surg Adjuvant Breast & Bowel Project, Operat Ctr, Pittsburgh, PA USA. Natl Surg Adjuvant Breast & Bowel Project, Ctr Biostat, Pittsburgh, PA USA. RP Fisher, B (reprint author), Allegheny Univ Hlth Sci, Sci Directors Off, 4 Allegheny Ctr,Suite 602, Pittsburgh, PA 15212 USA. FU NCI NIH HHS [NCI-U10-CA-12027, NCI-U10-CA-37377, NCI-U10-CA-39086] NR 20 TC 1280 Z9 1352 U1 5 U2 34 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG PY 1998 VL 16 IS 8 BP 2672 EP 2685 PG 14 WC Oncology SC Oncology GA 107NT UT WOS:000075215900013 PM 9704717 ER PT J AU Curti, BD Ochoa, AC Powers, GC Kopp, WC Alvord, WG Janik, JE Gause, BL Dunn, B Kopreski, MS Fenton, R Zea, A Dansky-Ullmann, C Strobl, S Harvey, L Nelson, E Sznol, M Longo, DL AF Curti, BD Ochoa, AC Powers, GC Kopp, WC Alvord, WG Janik, JE Gause, BL Dunn, B Kopreski, MS Fenton, R Zea, A Dansky-Ullmann, C Strobl, S Harvey, L Nelson, E Sznol, M Longo, DL TI Phase I trial of anti-CD3-stimulated CD4(+) T cells infusional interleukin-2, and cyclophosphamide in patients with advanced cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID TUMOR-INFILTRATING LYMPHOCYTES; SIGNAL-TRANSDUCTION MOLECULES; HUMAN-IMMUNODEFICIENCY-VIRUS; MONOCLONAL-ANTIBODY; METASTATIC MELANOMA; AUTOLOGOUS TUMOR; KILLER-CELLS; IMMUNOTHERAPY; CARCINOMA; CD4+ AB Purpose: We performed a phase I trial to determine whether in vivo expansion of activated CD4(+) T cells was possible in cancer patients. (111)Indium labeling was used to observe trafficking patterns of the infused stimulated CD4(+) T cells. The influence of cyclophosphamide (CTX) dosing on immunologic outcome was also examined. Patients and Methods: patients with advanced solid tumors or non-Hodgkin's lymphoma received CTX at 300 or 1,000 mg/m(2) intravenously (IV). Leukapheresis was performed to harvest peripheral-blood mononuclear cells (PBMCs) either just before the CTX dose, or when the patient was either entering or recovering from the leukocyte nadir induced by CTX. An enriched population of CD4(+) T cells was obtained by negative selection. The CD4(+) T cells were activated ex vivo with anti-CD3, cultured with interleukin-2 (IL-2) for 4 days, and adoptively transferred. After adoptive transfer, patients received IL-2 (9.0 x 10(6) IU/m(2)/d) by continuous infusion for 7 days. Results: The absolute number of CD4(+), CD4(+)/DR+, and CD4(+)/CD45RO(+) T cells increased in a statistically significant fashion in all cohorts after the first course of therapy. The degree of CD4 expansion was much greater than CD8 expansion, which resulted in a CD4:CD8 ratio that increased in 26 of 31 patients. The greatest in vivo CD4 expansion occurred when cells were harvested as patients entered the CTX-induced nadir. One complete response (CR), two partial responses (PRs), and eight minor responses were observed. Trafficking of (111)Indium-labeled CD4 cells to subcutaneous melanoma deposits was also documented, Conclusion: CD4(+) T cells can be expanded in vivo in cancer patients, which results in increased CD4:CD8 ratios. The timing of pheresis in relation to CTX administration influences the degree of CD4 expansion. Tumor responses with this regimen were observed in a variety of tumors, including melanoma and non-Hodgkin's lymphoma; a high percentage of patients had at least some tumor regression from the regimen that produced the greatest CD4(+) T-cell expansion. C1 NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment, Bethesda, MD 20892 USA. NCI, Data Management Serv, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. SAIC Inc, Clin Serv Program, Frederick, MD USA. NIA, Geriatr Res Ctr, Baltimore, MD 21224 USA. Louisiana State Univ, Stanley Scott Canc Ctr, New Orleans, LA USA. Biomira USA, Cranbury, NJ USA. RP Curti, BD (reprint author), Penn State Geisinger Hlth Syst, Dept Med, HO46,POB 850, Hershey, PA 17033 USA. EM bcurti@psghs.edu NR 26 TC 41 Z9 42 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 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG PY 1998 VL 16 IS 8 BP 2752 EP 2760 PG 9 WC Oncology SC Oncology GA 107NT UT WOS:000075215900024 PM 9704728 ER PT J AU Albandar, JM Kingman, A Lamster, IB AF Albandar, JM Kingman, A Lamster, IB TI Crevicular fluid level of beta-glucuronidase in relation to clinical periodontal parameters and putative periodontal pathogens in early-onset periodontitis SO JOURNAL OF CLINICAL PERIODONTOLOGY LA English DT Article DE adolescents; periodontal diseases : diagnosis; periodontal diseases : early-onset; periodontitis : immunology; neutrophils ID LOCALIZED JUVENILE PERIODONTITIS; ADULT PERIODONTITIS; SUBGINGIVAL PLAQUE; ENZYME-ACTIVITY; ATTACHMENT LOSS; ADOLESCENTS; DISEASE; MULTICENTER; LESIONS; CARIES AB Analysis of beta-glucuronidase (beta G) in the gingival crevicular fluid (GCF) provides an indication of neutrophil influx into the crevicular environment. The aim of this study was to test the hypotheses that: (1) beta G is significantly elevated in individuals with early-onset periodontitis (EOP) and that beta G activity correlates with disease severity; and (2) beta G level may reflect the local bacterial challenge in the gingival crevice. The study subjects consisted of a sub-sample of individuals examined in the National Survey of Oral Health of United States Children, which was undertaken during the 1986/87 school year. A total of 249 individuals were selected based on presence or absence of clinical attachment loss at baseline. The individuals were examined a second time 6 years later and the clinical attachment loss was assessed, and subgingival plaque and GCF were collected. The subjects were classified into 3 types of EOP and a control group. beta G activity in the GCF and the levels of 7 putative micro-organisms in the pocket were assessed. The generalized EOP group had the highest beta G activity, followed by the localized and incidental EOP groups, and the controls, respectively. There was a significant increase in beta G activity with the increase in probing depth, Also, sites with bleeding on probing had a significantly higher beta G activity than sites without bleeding. However, the effect of gingival inflammation on beta G activity was more evident in the generalized and localized EOP groups. Sites harboring high levels of one or more of the micro-organisms tended to have high beta G activity. There were moderate differences between the organisms with respect to their effect on beta G activity, but sites with high numbers of Porphyromonas gingivalis, Prevotella intermedia, or Treponema denticola also had the highest beta G activity. The present findings suggest that beta G activity in GCF from patients with EOP can be of value in the early identification of individuals at higher risk of developing EOP. The findings also suggest that host mechanisms leading to higher beta G activity in EOP represent systemic responses and are only partly related to the presence of local factors at the site-level. C1 NIDR, Bethesda, MD 20892 USA. Columbia Univ, Sch Dent & Oral Surg, Div Periodont, New York, NY 10027 USA. RP Albandar, JM (reprint author), Univ Bergen, Fac Dent, Sect Periodontol, Arstadveien 17, N-5009 Bergen, Norway. OI Albandar, Jasim M./0000-0001-7801-3811 NR 27 TC 13 Z9 14 U1 0 U2 1 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0303-6979 J9 J CLIN PERIODONTOL JI J. Clin. Periodontol. PD AUG PY 1998 VL 25 IS 8 BP 630 EP 639 DI 10.1111/j.1600-051X.1998.tb02499.x PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 105EG UT WOS:000075059300005 PM 9722267 ER PT J AU Preston, KL Silverman, K Higgins, ST Brooner, RK Montoya, I Schuster, CR Cone, EJ AF Preston, KL Silverman, K Higgins, ST Brooner, RK Montoya, I Schuster, CR Cone, EJ TI Cocaine use early in treatment predicts outcome in a behavioral treatment program SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article; Proceedings Paper CT Annual Scientific Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics CY MAR, 1996 CL LAKE BUENA VISTA, FLORIDA SP Amer Soc Clin Pharmacol & Therapeut ID METHADONE; DEPENDENCE; ABSTINENCE; OPIATE AB In this evaluation of baseline drug use as a predictor of treatment outcome, cocaine use during a 5-week baseline was compared in methadone maintenance patients who had <5 (n = 10) versus greater than or equal to 5 (n = 9) weeks of abstinence during an experimental cocaine abstinence reinforcement treatment. Cocaine use was evaluated at the Ist and last visit and the Ist and last week of baseline and as a mean across the 5-week baseline treatment; response was calculated as a mean across 12 weeks of experimental treatment. Those who had successful outcomes (abstainers) used significantly less cocaine in the 5-week baseline than those with less successful outcomes (nonabstainers). Differences in cocaine use were-not evident in the Ist baseline visit or week,but the abstainers used significantly less cocaine in the last visit and week of baseline compared with the nonabstainers. Cocaine use during baseline provided critical predictors of response to the experimental treatment. C1 NIDA, Intramural Res Program, Baltimore, MD 21224 USA. Univ Vermont, Dept Psychiat, Burlington, VT 05405 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. RP Preston, KL (reprint author), NIDA, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Preston, Kenzie/J-5830-2013; OI Preston, Kenzie/0000-0003-0603-2479; Silverman, Kenneth/0000-0003-2724-1413 NR 16 TC 67 Z9 67 U1 1 U2 1 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD AUG PY 1998 VL 66 IS 4 BP 691 EP 696 DI 10.1037/0022-006X.66.4.691 PG 6 WC Psychology, Clinical SC Psychology GA 110MM UT WOS:000075385000014 PM 9735588 ER PT J AU Fukae, M Tanabe, T Uchida, T Lee, SK Ryu, OH Murakami, C Wakida, K Simmer, JP Yamada, Y Bartlett, JD AF Fukae, M Tanabe, T Uchida, T Lee, SK Ryu, OH Murakami, C Wakida, K Simmer, JP Yamada, Y Bartlett, JD TI Enamelysin (Matrix metalloproteinase-20): Localization in the developing tooth and effects of pH and calcium on amelogenin hydrolysis SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE matrix metalloproteinase; dental enamel; dentin; ameloblast; odontoblast; Tomes' process ID BOVINE ENAMEL; GEL ELECTROPHORESIS; PORCINE ENAMEL; COLLAGENASE; PROTEINS; RAT; IDENTIFICATION; INHIBITORS; CLEAVAGE; DENTIN AB The formation of dental Enamel is a precisely regulated and dynamic developmental process. The forming enamel starts as a soft, protein-rich tissue and ends as a hard tissue that is over 95% mineral by weight. intact amelogenin and its proteolytic cleavage products are the most abundant proteins present within the developing enamel. Proteinases are also present within the enamel matrix and are thought to help regulate enamel development and to expedite the removal of proteins prior to enamel maturation. Recently, a novel matrix metalloproteinase named enamelysin was cloned from the porcine enamel organ. Enamelysin transcripts have previously been observed in the enamel organ and dental papillae of the developing tooth. Here, we show that the sources of the enamelysin transcripts are the ameloblasts of the enamel organ and the odontoblasts of the dental papilla. Furthermore, we show that enamelysin is present within the forming enamel and that it is transported in secretory vesicles prior to its secretion from the ameloblasts. We also characterize the ability of recombinant enamelysin (rMMP-20) to degrade amelogenin under conditions of various pHs and calcium ion concentrations. Enamelysin displayed the greatest activity at neutral pH (7.2) and high calcium ion concentration (10 mM). During the initial stages of enamel formation, the enamel matrix maintains a neutral pH of between 7.0 and 7.4. Thus, enamelysin may play a role in enamel and dentin formation by cleaving proteins that are also present during these initial developmental stages. C1 Forsyth Dent Ctr, Dept Biomineralizat, Boston, MA 02115 USA. Tsurumi Univ, Sch Dent Med, Dept Biochem, Tsurumi Ku, Yokohama, Kanagawa 230, Japan. Hiroshima Univ, Sch Dent, Dept Oral Anat, Hiroshima 734, Japan. NIDR, Craniofacial Dev Biol & Regenerat Branch, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, Dept Pediat Dent, San Antonio, TX 78284 USA. RP Forsyth Dent Ctr, Dept Biomineralizat, Boston, MA 02115 USA. FU NIDCR NIH HHS [DE 12098, R29 DE012098] NR 40 TC 82 Z9 86 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 EI 1544-0591 J9 J DENT RES JI J. Dent. Res. PD AUG PY 1998 VL 77 IS 8 BP 1580 EP 1588 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 111QG UT WOS:000075448700005 PM 9719031 ER PT J AU Grzesik, WJ Ivanov, B Robey, FA Southerland, J Yamauchi, M AF Grzesik, WJ Ivanov, B Robey, FA Southerland, J Yamauchi, M TI Synthetic integrin-binding peptides promote adhesion and proliferation of human periodontal ligament cells in vitro SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE RGD; oligopeptides; integrins; collagens; periodontium ID GUIDED TISSUE REGENERATION; BONE SIALOPROTEIN; CITRIC-ACID; FIBRONECTIN; GROWTH; ATTACHMENT; APOPTOSIS; INVITRO; MATRIX; ALPHA(V)BETA(3) AB Periodontal ligament (PDL) cells have been shown to express several integrins (alpha(v), alpha(5), beta(1), beta(3)) that use RGD (arginine-glycine-aspartic Acid)-dependent mechanisms for the recognition and binding of their Ligands. The objective of this study was to evaluate the effects of certain integrin-binding cyclic and Linear synthetic RGD-containing peptides on PDL cells' adhesion, proliferation, and de novo protein synthesis in vitro. Fifth passages of normal human PDL cells established from teeth extracted from patients (ages 12 to 14) for orthodontic reasons were used for all experiments. Synthetic peptides containing the EPRGDNYR sequence in two different spatial conformations (linear and cyclic) were covalently attached to bovine serum albumin (BSA). Type I collagen, EPRGDNYR-BSA conjugates; 1:1 mixtures of type I collagen and conjugates, as well as BSA (a negative control) were coated on bacteriological plastic and evaluated for their attachment-promoting activities. In addition, the effects of these substrates on cell proliferation were evaluated by [H-3]thymidine incorporation by the PDL cells. For attachment and spreading, the cyclic forms of EPRGDNYR-BSA conjugate and type I collagen were most potent, followed by linear EPRGDNYR;BSA conjugate. The effects of all collagen/conjugate mixtures were equivalent to that of type I collagen except for the collagen/linear EPRGDNYR-BSA mixture, which was less potent. nle cyclic EPRGDNYR-BSA conjugate was the most effective substrate to stimulate cell proliferation, and it-vas followed in potency by the Linear peptide-BSA conjugate. Collagen alone did not stimulate [H-3]thymidine incorporation above the control level. Mixtures of collagen with all of the conjugates showed stimulatory effects similar to that of the cyclic peptide-BSA conjugate. No significant differences in de novo protein synthesis were detected. These results suggest that the synthetic RGD-containing, peptides attached to a carrier are potent ligands for the human PDL cells, and that they could provide a basis for the development of new strategies aimed at the regeneration of the periodontium. C1 Univ N Carolina, Sch Dent, Dent Res Ctr, Dept Periodont, Chapel Hill, NC 27599 USA. NIDR, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. RP Grzesik, WJ (reprint author), Univ N Carolina, Sch Dent, Dent Res Ctr, Dept Periodont, Chapel Hill, NC 27599 USA. FU NIDCR NIH HHS [DE 10489] NR 32 TC 23 Z9 24 U1 0 U2 0 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 AUG PY 1998 VL 77 IS 8 BP 1606 EP 1612 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 111QG UT WOS:000075448700008 PM 9719034 ER PT J AU Summers, RM AF Summers, RM TI Image Gallery: A tool for rapid endobronchial lesion detection and display using virtual bronchoscopy SO JOURNAL OF DIGITAL IMAGING LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-for-Computer-Applications-in-Radiology CY JUN 04-07, 1998 CL BALTIMORE, MARYLAND SP Soc Comp Applicat Radiol (SCAR), Amer Coll Radiol (ACR) C1 NIH, Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Summers, RM (reprint author), NIH, Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, Bldg 10,Room 1C660,10 Ctr Dr,Msc 1182, Bethesda, MD 20892 USA. NR 7 TC 12 Z9 12 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0897-1889 J9 J DIGIT IMAGING JI J. Digit. Imaging PD AUG PY 1998 VL 11 IS 3 SU 1 BP 53 EP 55 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 111NH UT WOS:000075443600015 PM 9735433 ER PT J AU Ostchega, Y Long, LR Goh, GH Hirsch, R Ma, LD Scott, WW Johnson, W Thoma, GR AF Ostchega, Y Long, LR Goh, GH Hirsch, R Ma, LD Scott, WW Johnson, W Thoma, GR TI Establishing the level of digitization for wrist and hand radiographs for the third National Health and Nutrition Examination Survey SO JOURNAL OF DIGITAL IMAGING LA English DT Article DE NHANES III; radiograph; hand; digital resolution ID RHEUMATOID-ARTHRITIS AB In the third National Health and Nutrition Examination Survey (NHANES III) conducted by the National Center for Health Statistics, Centers for Disease Control and Prevention, radiographs of the hands and knees were taken of participants 60 years and older as part of the study of arthritis and musculoskeletal conditions. The purpose of the study was to decide the digitizing resolution to be used for these radiographs. A set of wrist and hand radiographs (N = 49) was graded by two radiologists for degree of bone erosions and served as a "gold standard." The radiographs were then digitized at three resolution levels; low-resolution 150 mu m (2001 x 1634 x 12 bit matrix); intermediate-resolution 100 mu m (3000 x 2400 x 12 bit matrix); and high-resolution 50 mu m (4900 x 3000 x 12 bit matrix). A comparison of the digital images versus the gold standard reading was made at the three resolutions by two radiologists. Kappa statistics suggested fair (K > .4) to excellent (K > .75) agreement between the gold standard and the images at all levels. Intraclass correlation coefficient suggested high agreement between readers (ICC > .5), with minimal individual reader effect. Variance component estimates showed that the major contribution (78-83%) to scoring came from variability in the images themselves, not from the readers. The 100 mu m resolution was selected over the 150 and 50 mu m on the basis of practical considerations such as storage requirements, display time, and easier manipulation of the digital images by the readers. Copyright (C) 1998 by W.B. Saunders Company. C1 Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Div Hlth Examinat Stat, Hyattsville, MD 20782 USA. Century Comp Inc, Laurel, MD USA. Natl Lib Med, Bethesda, MD USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Off Res Methodol, Hyattsville, MD 20782 USA. RP Ostchega, Y (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Div Hlth Examinat Stat, Room 900,6525 Belcrest Rd, Hyattsville, MD 20782 USA. NR 11 TC 4 Z9 4 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 0897-1889 J9 J DIGIT IMAGING JI J. Digit. Imaging PD AUG PY 1998 VL 11 IS 3 BP 116 EP 120 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 110MP UT WOS:000075385200002 PM 9718501 ER PT J AU Pinn, VW AF Pinn, VW TI Reaping the fruits of research: Promoting health equity for all SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Editorial Material C1 NIH, Off Res Womens Hlth, Bethesda, MD 20892 USA. RP Pinn, VW (reprint author), NIH, Off Res Womens Hlth, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 4 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1049-2089 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD AUG PY 1998 VL 9 IS 3 BP 213 EP 216 PG 4 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 105YH UT WOS:000075102600001 PM 10073203 ER PT J AU Fernandez-Rodriguez, CM Prada, IR Prieto, J Montuenga, LM Elssasser, T Quiroga, J Moreiras, M Andrade, A Cuttitta, F AF Fernandez-Rodriguez, CM Prada, IR Prieto, J Montuenga, LM Elssasser, T Quiroga, J Moreiras, M Andrade, A Cuttitta, F TI Circulating adrenomedullin in cirrhosis: relationship to hyperdynamic circulation SO JOURNAL OF HEPATOLOGY LA English DT Article DE adrenomedullin; cirrhosis; peripheral vasodilation ID NITRIC-OXIDE SYNTHASE; PORTAL-HYPERTENSIVE RATS; NECROSIS-FACTOR-ALPHA; SMOOTH-MUSCLE CELLS; SODIUM RETENTION; ARTERIAL VASODILATION; HEPATORENAL-SYNDROME; HYPOTENSIVE PEPTIDE; REFRACTORY ASCITES; LIVER-CIRRHOSIS AB Background/Aims: Peripheral arterial vasodilation may be the key factor in the sodium and mater retention of cirrhosis. The mechanism responsible for this vasodilation remains to be fully elucidated. Adrenomedullin is a novel peptide, highly expressed in cardiovascular tissues, with potent and long-lasting vasodilating activity, Methods: The possible implication of adrenomedullin in the hemodynamic changes of cirrhosis has been investigated. We measured the plasma concentration of adrenomedullin in 20 cirrhotic patients and 11 healthy subjects. In addition, systemic, portal and renal hemodynamics, hormonal factors and renal function parameters were evaluated in the same patients. Results: Circulating adrenomedullin was significantly higher in the group of patients with cirrhosis (72.1; 46-100 vs 21.6; 11-34 fmol/dl, respectively; p<0.02) and was directly correlated with the Pugh score (r: 0.6; p: 0.01), inversely correlated with the creatinine clearance (r: -0.6; p<0.01) and tended to inversely correlate with systemic vascular resistance index (r: -0.46; p: 0.07). There were no portal-peripheral differences in adrenomedullin levels. Transjugular intrahepatic portosystemic shunt insertion did not induce changes in the peripheral concentration of adrenomedullin, but baseline values of this hormone predicted the degree of hyperdynamic circulation after TIPS. Conclusions: Circulating adrenomedullin is increased in cirrhosis. These levels increase with the severity of the disease, especially in patients with hepatorenal syndrome. This peptide may contribute to vasodilation of cirrhosis. C1 Univ Navarra, Univ Navarra Clin, Dept Med, E-31080 Pamplona, Spain. Hosp Xeral, Serv Gastroenterol, Vigo, Spain. Hosp Xeral Vigo, Serv Nephrol, Vigo, Spain. Hosp Xeral Vigo, Lab Hormones, Vigo, Spain. NCI, DCS, NIH, Rockville, MD USA. Univ Navarra, Dept Histol & Pathol, E-31080 Pamplona, Spain. ARS, USDA, Beltsville, MD USA. RP Prieto, J (reprint author), Univ Navarra Clin, Dept Internal Med, Pio 12 S-N, Pamplona 31080, Spain. OI Prieto, Jesus/0000-0002-1091-9593 NR 49 TC 36 Z9 37 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD AUG PY 1998 VL 29 IS 2 BP 250 EP 256 DI 10.1016/S0168-8278(98)80010-X PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 105QA UT WOS:000075084000010 PM 9722206 ER PT J AU Hansal, SA Morris, DI Sechler, JMG Love, PE Rosenberg, AS AF Hansal, SA Morris, DI Sechler, JMG Love, PE Rosenberg, AS TI Cutting edge: Induction of antigen-specific hyporesponsiveness by transplantation of hemopoietic cells containing an MHC class I transgene regulated by a lymphocyte-specific promoter SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GRAFT-REJECTION; VETO CELLS; T-CELLS; TOLERANCE; EXPRESSION; CHIMERISM; MARROW; MICE; SKIN; CD2 AB We explored a novel approach to tolerance induction by the transplantation of bone marrow (BM) cells (BMCs) that themselves do not express a foreign histocompatibility Ag, but which give rise to mature lymphocytes that do so. Lines of transgenic (FVB) mice were generated that contained an MHC class I D-d cDNA regulated by a CD2 promoter. Because the CD2 promoter is lymphocyte-specific and activated relatively late in lymphocyte ontogeny, D-d is expressed on most mature lymphocytes in the periphery but only on developing B cells in the BM of transgenic mice. Transgenic BMCs are tolerogenic and reproducibly engraft in nontransgenic mice using a conditioning regimen that is nonpermissive for the engraftment of conventional (MHC promoter) D-d-transgenic BMCs, Engrafted BMCs generate transgene-expressing lymphocytes and confer a state of Ag-specific hyporesponsiveness on the host that is primarily attributable to a peripheral mechanism. The strategies by which tolerance can be optimized in this system are discussed. C1 US FDA, Ctr Biol Evaluat & Res, Immunol Lab, Div Hematol Prod, Bethesda, MD 20892 USA. NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Rosenberg, AS (reprint author), US FDA, Ctr Biol Evaluat & Res, Immunol Lab, Div Hematol Prod, 29A,2B-12,8800 Rockville Pike, Bethesda, MD 20892 USA. NR 25 TC 6 Z9 6 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 1998 VL 161 IS 3 BP 1063 EP 1068 PG 6 WC Immunology SC Immunology GA 102VA UT WOS:000074944900001 PM 9686561 ER PT J AU Lesma, E Moss, J Brewer, HB Bortell, R Greiner, D Mordes, J Rossini, AA AF Lesma, E Moss, J Brewer, HB Bortell, R Greiner, D Mordes, J Rossini, AA TI Characterization of high density lipoprotein-bound and soluble RT6 released following administration of anti-RT6.1 monoclonal antibody SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PRONE BB RATS; LYMPHOCYTE ALLOANTIGEN RT6.1; DIFFERENTIATION MARKER RT6; ADP-RIBOSYLATION; MAST-CELLS; ACTIVATION; GENE; LOCALIZATION; EXPRESSION; PROTEINS AB RT6 is a rat lymphocyte glycosylphosphatidylinositol (GPT)-anchored alloantigen with nicotinamide adenine dinucleotide (NAD) glycohydrolase (NADase) and auto-ADP-ribosyltransferase activities. RT6 may have immunoregulatory properties based in part on the observation that injection of diabetes-resistant (DR)-BB rats with depleting doses of anti-RT6.1 mAb induced autoimmune diabetes and thyroiditis. We now report that injection of DR-BE rats with anti-RT6.1 mAb increased plasma NADase activity, which localized, by fluid phase liquid chromatography fractionation, to the high density lipoprotein (HDL) fraction. Following ultracentrifugation in high salt, however, RT6 was found in the nonlipoprotein fraction, where it existed, under nondenaturing conditions, as a 200-kDa complex and, by SDS-PAGE, as a 30- to 36-kDa species, Thy-1, another GPI-linked protein, and proteins that reacted with anti-GPI-oligosaccharide Abs also translocated from HDL to the nonlipoprotein fraction under similar conditions, Injection of anti-RT6.1 mAb into thymectomized DR and diabetes-prone-BE rats increased soluble RT6 to levels comparable to those observed in euthymic DR-BB rats, suggesting that HDL-bound RT6 is not derived from peripheral lymphocytes. In agreement, NADase activity in the plasma of eviscerated DR-BE rats did not increase following injection of anti-RT6 mAb, These data suggest that HDL is a carrier of plasma RT6 and other GPT-linked proteins, with equilibrium between the lipoprotein and nonlipoprotein fractions being salt dependent. Since GPI-linked proteins in HDL can transfer to cells in a functionally active form, the presence of RT6 in HDL is consistent with it having a role in signaling in nonlymphoid cells. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. Univ Massachusetts, Med Ctr, Diabetes Div, Worcester, MA 01605 USA. RP Moss, J (reprint author), NHLBI, Pulm Crit Care Med Branch, NIH, 10 Ctr Dr,MSC 1590,Bldg 10,Room 6D03, Bethesda, MD 20892 USA. EM mossj@fido.nhlbi.nih.gov FU NIDDK NIH HHS [DK41235, DK25306, DK36024] NR 39 TC 5 Z9 5 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 1998 VL 161 IS 3 BP 1212 EP 1219 PG 8 WC Immunology SC Immunology GA 102VA UT WOS:000074944900021 PM 9686581 ER PT J AU Rajagopalan, S Long, EO AF Rajagopalan, S Long, EO TI Zinc bound to the killer cell-inhibitory receptor modulates the negative signal in human NK cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HLA-C; GROWTH-HORMONE; DIRECT BINDING; COMPLEX; RECOGNITION; MOLECULES; CLONES; LYSIS; DIMERIZATION; SPECIFICITY AB The lysis of target cells by human NK cells is inhibited by several kinds of receptors with varying specificities for the MHC class I molecules of target cells. The requirements for complete inhibition of NK cytotoxicity appear to be complex and not well defined. The HLA-C-specific members of the killer cell-inhibitory receptor (KIR) family, carrying two Ig domains (KIR2D), are unusual among Ig superfamily members in their ability to bind zinc. A role for the zinc-binding site in KIR-mediated inhibition was demonstrated in this study using a functional reconstitution system in NK cells. Replacement of six histidines by alanine residues in putative zinc binding sites of a KIR2D ablated zinc binding and markedly impaired its inhibitory function, but left intact its ability to bind HLA-C and to transduce a positive signal through an immunoreceptor tyrosine-based activation motif grafted onto its cytoplasmic tail, Thus, zinc modulates specifically the negative signal transmitted by this KIR molecule. Mutation of an exposed amino-terminal zinc-binding motif alone was sufficient to impair the inhibitory function of KIR, The data suggest that complete inhibition of HLA-C-specific NK cells requires a zinc-dependent protein-protein interaction via the amino-terminal end of KIR2D. C1 NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Long, EO (reprint author), NIAID, Immunogenet Lab, NIH, Twinbrook 2,12441 Parklawn Dr, Rockville, MD 20852 USA. RI Long, Eric/G-5475-2011 OI Long, Eric/0000-0002-7793-3728 NR 37 TC 35 Z9 35 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 1998 VL 161 IS 3 BP 1299 EP 1305 PG 7 WC Immunology SC Immunology GA 102VA UT WOS:000074944900031 PM 9686591 ER PT J AU Muller, JR Giese, T Henry, DL Mushinski, JF Marcu, KB AF Muller, JR Giese, T Henry, DL Mushinski, JF Marcu, KB TI Generation of switch hybrid DNA between Ig heavy chain-mu and downstream switch regions in B lymphocytes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IMMUNOGLOBULIN; RECOMBINATION; TRANSCRIPTS; EXPRESSION; INTERLEUKIN-4; INDUCTION; FAMILY; CELLS; RNA AB Ig heavy chain isotype switching in B lymphocytes is known to be preceded by transcription of a portion of the particular heavy chain gene segment that is targeted for recombination. Here, we describe an active role for these transcripts in the switch recombination process. Using an in vitro assay that exposes an artificial switch-mu (S mu) minisubstrate to switch region transcripts in the presence of nuclear extracts from switching cells, we demonstrate that free 3' ends of the S mu sequence are extended onto switch region transcripts by reverse transcription. The activity was induced in splenic B lymphocytes upon activation with LPS or CD40 ligand, This in vitro process is thought to be relevant to in vivo class switching for two reasons: 1) although only one-third of the S mu minisubstrate actually contains S mu sequence, all crossovers between snitch regions occurred in the S mu portion; and 2) treatment of B lymphocytes with IL-4, which enriches for switching to S gamma 1, increases the ratio of S mu-S gamma 1 to S mu-S gamma 3 hybrids by 16% after LPS treatment and by 37% after CD40 ligand activation, implicating this S mu-primed reverse transcription of switch region transcripts as a novel mechanism of regulating the specificity of isotype switching. Further evidence for an active role of switch region transcripts was obtained by expressing S alpha RNA in trans in the Bcl(1)B(1) B lymphoma line. Endogenous S mu-S alpha switch circles were detected in Bcl(1)B(1) cells expressing exogenous S alpha RNA but not in mock-transfected cells. C1 SUNY Stony Brook, Dept Biochem & Cell Biol, Stony Brook, NY 11794 USA. NCI, Genet Lab, NIH, Bethesda, MD 20892 USA. RP Marcu, KB (reprint author), SUNY Stony Brook, Dept Biochem & Cell Biol, Life Sci Bldg,Room 324, Stony Brook, NY 11794 USA. FU NIGMS NIH HHS [GM26939] NR 29 TC 11 Z9 11 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 1998 VL 161 IS 3 BP 1354 EP 1362 PG 9 WC Immunology SC Immunology GA 102VA UT WOS:000074944900038 PM 9686598 ER PT J AU Rabkin, CS Schulz, TF Whitby, D Lennette, ET Magpantay, LI Chatlynne, L Biggar, RJ AF Rabkin, CS Schulz, TF Whitby, D Lennette, ET Magpantay, LI Chatlynne, L Biggar, RJ CA HHV-8 Interlaboratory Collaborat Grp TI Interassay correlation of human herpesvirus 8 serologic tests SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 4th Conference on Retroviruses and Opportunistic Infections CY JAN 22-31, 1997 CL WASHINGTON, D.C. ID SARCOMA-ASSOCIATED HERPESVIRUS; KAPOSIS-SARCOMA; DNA-SEQUENCES; ANTIBODIES; INFECTION; KSHV; PREVALENCE; SEMEN; AIDS AB To standardize human herpesvirus 8 (HHV-8) antibody assays for application to asymptomatic infection, a blinded comparison was done of seven immunofluorescence assays and ELISAs. Five experienced laboratories tested a serum panel from 143 subjects in 4 diagnostic groups. Except for a minor capsid protein ELISA, the other six tests detected HHV-8 antibodies most frequently in classic (80%-100%) and AIDS-related (67%-91%) Kaposi's sarcoma, followed by human immunodeficiency virus-seropositive patients (27%-60%), and least frequently in healthy blood donors (0-29%). However, these six assays frequently disagreed on individual sera, particularly for blood donor samples. Current HHV-8 antibody tests have uncertain accuracy in asymptomatic HHV-8 infection and may require correlation with viral protein or nucleic acid detection. Antibody assays are useful for epidemiologic investigations, but the absolute prevalence of HHV-8 infection in the United States cannot yet be determined. C1 NCI, Viral Epidemiol Branch, Rockville, MD 20852 USA. Adv Biotechnol Inc, Columbia, MD USA. Univ Liverpool, Dept Med Microbiol & Genitourinary Med, Liverpool L69 3BX, Merseyside, England. Inst Canc Res, Virol Lab, London SW3 6JB, England. Virolab Inc, Berkeley, CA USA. Univ Calif Los Angeles, Ctr AIDS Res & Educ, Los Angeles, CA USA. RP Rabkin, CS (reprint author), NCI, Viral Epidemiol Branch, 6130 Execut Blvd,EPN-434, Rockville, MD 20852 USA. NR 18 TC 141 Z9 146 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD AUG PY 1998 VL 178 IS 2 BP 304 EP 309 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 103JA UT WOS:000075153000003 PM 9697708 ER PT J AU Kimura, H Wang, Y Pesnicak, L Cohen, JI Hooks, JJ Straus, SE Williams, RK AF Kimura, H Wang, Y Pesnicak, L Cohen, JI Hooks, JJ Straus, SE Williams, RK TI Recombinant varicella-zoster virus glycoproteins E and I: Immunologic responses and clearance of virus in a guinea pig model of chronic uveitis SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 22nd International Herpesvirus Workshop CY AUG 02-08, 1997 CL SAN DIEGO, CALIFORNIA ID OUTER RETINAL NECROSIS; IMMUNE-RESPONSES; GAMMA-INTERFERON; FACTOR-ALPHA; TYPE-1; EXPRESSION; INFECTION; PROTECTION; INTERLEUKIN-6; SECRETION AB Guinea pigs immunized with recombinant varicella-zoster virus (VZV) glycoproteins E (gE) and I(gI)developed antigen-specific antibodies in the sera, vitreous, and conjunctival washes. Sera from immunized animals neutralized both cell-free and cell-associated VZV, and peripheral blood lymphocytes proliferated in vitro in response to recombinant gE and gI and to antigens from VZV-infected cells. Immunized guinea pigs were inoculated intravitreally with VZV, which induces chronic uveitis. VZV DNA was more rapidly cleared and infectious VZV was isolated less frequently from the retinas of animals immunized with gE and gI compared with that in controls receiving adjuvant alone. Nonetheless, cellular infiltrates in the vitreous, retina, and choroid were prevalent 21 days after VZV inoculation in both the adjuvant-alone- and gE-gI-immunized animals. Immunization with VZV gE and gI induced potent humoral and cellular responses that accelerated the clearance of VZV DNA and may neutralize virus within the eye. C1 NEI, Immunol Lab, Bethesda, MD 20892 USA. NIAID, Med Virol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Williams, RK (reprint author), NIAID, Med Virol Sect, Clin Invest Lab, NIH, Bldg 10,Room 11N228,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Kimura, Hiroshi/I-2246-2012 NR 32 TC 27 Z9 27 U1 2 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG PY 1998 VL 178 IS 2 BP 310 EP 317 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 103JA UT WOS:000075153000004 PM 9697709 ER PT J AU Ioannidis, JPA Collier, AC Cooper, DA Corey, L Fiddian, AP Gazzard, BG Griffiths, PD Contopoulos-Ioannidis, DG Lau, J Pavia, AT Saag, MS Spruance, SL Youle, MS AF Ioannidis, JPA Collier, AC Cooper, DA Corey, L Fiddian, AP Gazzard, BG Griffiths, PD Contopoulos-Ioannidis, DG Lau, J Pavia, AT Saag, MS Spruance, SL Youle, MS TI Clinical efficacy of high-dose acyclovir in patients with human immunodeficiency virus infection: A meta-analysis of randomized individual patient data SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 5th Conference on Retroviruses and Opportunistic Infections CY FEB 01-05, 1998 CL CHICAGO, ILLINOIS ID MULTICENTER AIDS COHORT; HIV-1 INFECTION; DOUBLE-BLIND; ANTIHERPES DRUGS; KAPOSIS-SARCOMA; ZIDOVUDINE; SURVIVAL; DISEASE; PHARMACOKINETICS; PROGRESSION AB A meta-analysis of 8 randomized trials (1792 patients, 2947 patient-years of follow-up) showed that acyclovir (greater than or equal to 3200 mg/day) offered a significant survival benefit (P = .006 by log-rank test) in human immunodeficiency virus (HIV) infection. The treatment effect did not vary significantly in patient subgroups of different CD4 cell counts, hemoglobin levels, age, race, and sex, and with or without AIDS diagnosis. Acyclovir treatment (hazard ratio, 0.78; 95% confidence interval [CI], 0.65-0.93), higher CD4 cell count (P < .001), higher hemoglobin level (P < .001), and younger age (P < .001) reduced the hazard of mortality. Acyclovir decreased herpes simplex virus infections (odds ratio [OR], 0.28; 95% CI, 0.21-0.37) and varicella-zoster virus infections (OR, 0.29; 95% CI, 0.13-0.63) but not cytomegalovirus disease or mortality from lymphoma or Kaposi's sarcoma. A survival advantage was seen specifically in studies with high incidence of clinical herpesvirus infections (greater than or equal to 25% per year). Given the wide confidence intervals, the small effect in low-risk patients, and recent changes in HIV therapeutics, the results should be interpreted cautiously, but the metaanalysis supports the importance of pathogenetic interactions between herpesviruses and HIV. C1 NIAID, HIV Res Branch, NIH, Bethesda, MD 20892 USA. Univ Washington, Dept Med, Seattle, WA USA. Univ New S Wales, Natl Ctr HIV Epidemiol & Clin Res, Sydney, NSW, Australia. St Vincents Hosp, HIV Med Unit, Sydney, NSW 2010, Australia. Chelsea & Westminster Hosp, London, England. Royal Free Hosp, Sch Med, London, England. Glaxo Wellcome Inc, Int Med Affairs, Viral Dis, London, England. Childrens Natl Med Ctr, Washington, DC 20010 USA. George Washington Univ, Sch Med, Washington, DC USA. Tufts Univ, New England Med Ctr Hosp, Div Clin Care Res, Boston, MA 02111 USA. Tufts Univ, Sch Med, Boston, MA 02111 USA. Univ Utah, Sch Hlth Sci, Dept Med, Salt Lake City, UT USA. Univ Utah, Sch Hlth Sci, Dept Pediat, Salt Lake City, UT USA. Univ Alabama, Sch Med, Dept Med, Birmingham, AL USA. RP Ioannidis, JPA (reprint author), NIAID, HIV Res Branch, NIH, Solar Bldg,Room 2C31,6003 Execut Blvd, Bethesda, MD 20892 USA. EM ji24m@nih.gov RI Ioannidis, John/G-9836-2011 FU CIT NIH HHS [ACTG 010, ACTG 063] NR 54 TC 70 Z9 72 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG PY 1998 VL 178 IS 2 BP 349 EP 359 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 103JA UT WOS:000075153000009 PM 9697714 ER PT J AU Perno, CF Newcomb, FM Davis, DA Aquaro, S Humphrey, RW Calio, R Yarchoan, R AF Perno, CF Newcomb, FM Davis, DA Aquaro, S Humphrey, RW Calio, R Yarchoan, R TI Relative potency of protease inhibitors in monocytes/macrophages acutely and chronically infected with human immunodeficiency virus SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 5th Conference on Retroviruses and Opportunistic Infections CY FEB 01-05, 1998 CL CHICAGO, ILLINOIS ID IN-VITRO ACTIVITY; HIV-1 PROTEASE; ANTIVIRAL ACTIVITY; TYPE-1 PROTEASE; MONONUCLEAR PHAGOCYTES; MONOCYTES MACROPHAGES; OXIDATIVE STRESS; REPLICATION; LYMPHOCYTES; CELLS AB The activity of three human immunodeficiency virus (HIV) protease inhibitors was investigated in human primary monocytes/macrophages (M/M) chronically infected by HIV-1. Saquinavir, KNI-272, and ritonavir inhibited the replication of HIV-1 in vitro, with EC(50)s of similar to 0.5-3.3 mu M. However, only partial inhibition was achievable, even at the highest concentrations tested. Also, the activity of these drugs in chronically infected M/M was similar to 7- to 26-fold lower than in acutely infected M/M and similar to 2- to 10-fold lower than in chronically infected H9 lymphocytes, When protease inhibitors were removed from cultures of chronically infected M/M, production of virus rapidly returned to the levels found in untreated MIM. Therefore, relatively high concentrations of protease inhibitors are required to suppress HIV-1 production in chronically infected macrophages, and such cells may be a vulnerable point for the escape of virus in patients taking these drugs. C1 NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. Univ Roma Tor Vergata, Dept Expt Med & Biochem Sci, Rome, Italy. RP Yarchoan, R (reprint author), Bldg 10,Rm 12N226,10 Ctr Dr,MSC 1906, Bethesda, MD 20892 USA. RI perno, carlo federico/O-1544-2016 NR 71 TC 106 Z9 110 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG PY 1998 VL 178 IS 2 BP 413 EP 422 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 103JA UT WOS:000075153000016 PM 9697721 ER PT J AU Rodrigues, RG Yan, SZ Walsh, TJ Roberts, DD AF Rodrigues, RG Yan, SZ Walsh, TJ Roberts, DD TI Hemoglobin differentially induces binding of Candida, Trichosporon, and Saccharomyces species to fibronectin SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID EXTRACELLULAR-MATRIX; ALBICANS; ADHERENCE; RECEPTOR; PROTEIN; ADHESIN; SYSTEMS; LIGAND; DOMAIN; FACE AB Fibronectin (FN) is an abundant host protein that is specifically recognized by several pathogenic yeasts, Binding of FN in solution to Candida, Trichosporon, and Saccharomyces species is increased 20- to 110-fold by growth in medium containing hemoglobin, but specific adhesion to immobilized FN is increased only in Candida albicans, Candida tropicalis, Candida krusei, and Candida glabrata. Hemoglobin induces both specific and nonspecific binding of soluble FN, Nonspecific binding accounts for all of the enhancement in Trichosporon beigelii and Saccharomyces cerevisiae, but the Candida species possess a saturable, high-affinity binding site for FN that is induced by hemoglobin. Induction of displaceable soluble FN binding correlates with the ability of hemoglobin to regulate adhesion to immobilized FN, since hemoglobin does not induce adhesion of S. cerevisiae or T. beigelii to immobilized FN, Regulation by hemoglobin of FN binding to Candida species may therefore be an important factor in the pathogenesis in these yeast infections. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Pediat Branch, NIH, Bethesda, MD 20892 USA. RP Roberts, DD (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Room 2A33,10 Ctr Dr MSC 1500, Bethesda, MD 20892 USA. EM droberts@helix.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 NR 29 TC 3 Z9 3 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG PY 1998 VL 178 IS 2 BP 497 EP 502 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 103JA UT WOS:000075153000027 PM 9697732 ER PT J AU McIntosh, K FitzGerald, G Pitt, J Bremer, JW Hillyer, GV Landesman, S Rosenblatt, H Lew, JF Davenny, K Moye, J AF McIntosh, K FitzGerald, G Pitt, J Bremer, JW Hillyer, GV Landesman, S Rosenblatt, H Lew, JF Davenny, K Moye, J CA Women Infants Transmission Study TI A comparison of peripheral blood coculture versus 18- or 24-month serology in the diagnosis of human immunodeficiency virus infection in the offspring of infected mothers SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 35th Annual Meeting of the Infectious-Diseases-Society-of-America CY SEP 07-16, 1997 CL SAN FRANCISCO, CALIFORNIA SP Infect Dis Soc Amer ID CLINICAL-TRIALS; CHILDREN BORN; TRANSMISSION; TYPE-1; HIV AB The Women and Infants Transmission Study (WITS) has established virologic definitions of human immunodeficiency virus (HIV)-infected and uninfected children that have been widely used but never formally compared with serologic definitions of infection, Data from the offspring of HIV-infected women in the WITS with frequent HIV cultures during the first year of life and with HIV serology at 18 and/or 24 months of age were analyzed. Seventy-seven infants were HIV-infected and 430 uninfected by both virologic and serologic criteria. Thirteen were virologically infected (greater than or equal to 2 positive cultures) but either seronegative or serologically indeterminate. All but 1 of these had clinical HIV disease at the time of analysis. In this pediatric cohort, children defined as infected by virologic criteria often (13/90) had negative or indeterminate serology despite symptoms of HIV disease. Results suggest that serology at 18-24 months has high specificity but poor sensitivity. It should not be considered the reference standard in identifying HIV infection in perinatally exposed children. C1 Childrens Hosp, Dept Pediat, Div Infect Dis, Boston, MA 02115 USA. New England Res Inst, Watertown, MA USA. Columbia Univ Coll Phys & Surg, Dept Pediat, Div Infect Dis, New York, NY 10032 USA. Brookdale Univ Hosp & Med Ctr, Div Infect Dis, Brooklyn, NY USA. Rush Presbyterian St Lukes Med Ctr, Clin Retrovirol Lab, Chicago, IL 60612 USA. Univ Puerto Rico, Dept Microbiol, San Juan, PR 00936 USA. Texas Childrens Hosp, Dept Pediat, Houston, TX 77030 USA. NIAID, Div Aids, Bethesda, MD 20892 USA. Natl Inst Drug Abuse, Div Clin Res, Bethesda, MD USA. NICHHD, Pediat Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD 20892 USA. RP McIntosh, K (reprint author), Childrens Hosp, Dept Pediat, Div Infect Dis, 300 Longwood Ave, Boston, MA 02115 USA. OI moye, john/0000-0001-9976-8586 FU NIAID NIH HHS [AI-34856, AI-34842, AI-34858] NR 14 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG PY 1998 VL 178 IS 2 BP 560 EP 563 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 103JA UT WOS:000075153000039 PM 9697744 ER PT J AU Roilides, E Sein, T Schaufele, R Chanock, SJ Walsh, TJ AF Roilides, E Sein, T Schaufele, R Chanock, SJ Walsh, TJ TI Increased serum concentrations of interleukin-10 in patients with hepatosplenic candidiasis SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID TUMOR-NECROSIS-FACTOR; ALBICANS; MICE AB Hepatosplenic candidiasis (HSC) becomes clinically overt in cancer patients upon recovery from neutropenia, HSC may be a consequence of a Th1-Th2 imbalance, characterized by increased serum levels of one or more cytokines. Serum levels of two immunosuppressive cytokines, markers of the Th2 pathway, interleukin (IL)-4 and IL-10 were measured by ELISA in 10 patients with HSC (22 samples) and compared with 19 healthy blood donors, 13 patients with cancer but no infection (23 samples), and 11 patients with cancer and various bacterial infections (17 samples). IL-4 was undetectable in all controls and patients. By contrast, levels of IL-10 were increased in HSC patients compared with levels in healthy donors and cancer patients without infection (P < .001) or with bacterial infections (P < .01). These findings indicate that IL-10 but not IL-4 is increased in patients with HSC and suggest that IL-10 plays a role in the pathogenesis of this infection. C1 NCI, Pediat Oncol Branch, Immunocompromised Host Sect, NIH, Bethesda, MD 20892 USA. Aristotelian Univ Thessaloniki, Pediat Dept 3, Thessaloniki, Greece. RP Walsh, TJ (reprint author), NCI, Pediat Oncol Branch, Immunocompromised Host Sect, NIH, Bldg 10,Room 13N240, Bethesda, MD 20892 USA. NR 14 TC 31 Z9 32 U1 1 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG PY 1998 VL 178 IS 2 BP 589 EP 592 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 103JA UT WOS:000075153000046 PM 9697751 ER PT J AU Lambert, JS Mofenson, LM Moye, J AF Lambert, JS Mofenson, LM Moye, J TI Clinical trials of HIVIG - Reply SO JOURNAL OF INFECTIOUS DISEASES LA English DT Letter ID IMMUNODEFICIENCY-VIRUS TYPE-1; ZIDOVUDINE TREATMENT; TRANSMISSION; INFANT C1 Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. NICHHD, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD 20892 USA. RP Lambert, JS (reprint author), Univ Maryland, Inst Human Virol, 725 W Lombard St,N548, Baltimore, MD 21201 USA. NR 12 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG PY 1998 VL 178 IS 2 BP 598 EP 599 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 103JA UT WOS:000075153000051 ER PT J AU Roessler, E Muenke, M AF Roessler, E Muenke, M TI Holoprosencephaly: A paradigm for the complex genetics of brain development SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Article; Proceedings Paper CT 35th Annual Symposium of the SSIEM CY 1997 CL GOTHENBURG, SWEDEN SP Swedish Cancer Fdn, Frognal Trust, Orphan Fdn, Orphan Europe, Milupa, Scientif Hospital Supplies, Genzyme Therapeut ID LEMLI-OPITZ-SYNDROME; SONIC-HEDGEHOG GENE; DEFECTIVE CHOLESTEROL-BIOSYNTHESIS; TERMINAL CLEAVAGE PRODUCT; CELL CARCINOMA SYNDROME; KINESIN-RELATED PROTEIN; CRITICAL REGION; SIGNALING PATHWAY; NEURAL-TUBE; VERTEBRATE DEVELOPMENT AB Holoprosencephaly (HPE) is the most common major developmental defect of the forebrain in humans. Clinical expression is variable, ranging from a small brain with a single cerebral ventricle and cyclopia to clinically unaffected carriers in familial HPE. Significant aetiological heterogeneity exists in HPE and includes both genetic and environmental causes. Recently, defects in the cell signalling pathway involving the Sonic Hedgehog (SHH) gene, as well as defects in the cholesterol biosynthesis, have been shown to cause HPE in humans. These discoveries and current genetic approaches serve as a paradigm for studying normal and abnormal brain morphogenesis. C1 Natl Human Genome Res Inst, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Penn, Childrens Hosp Philadelphia, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. Univ Penn, Childrens Hosp Philadelphia, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. Univ Penn, Childrens Hosp Philadelphia, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. RP Muenke, M (reprint author), Natl Human Genome Res Inst, Med Genet Branch, NIH, 10 Ctr Dr,10 C 101, Bethesda, MD 20892 USA. FU NICHD NIH HHS [HD28732, 5T32HD07107, HD29862] NR 127 TC 112 Z9 113 U1 0 U2 8 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0141-8955 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD AUG PY 1998 VL 21 IS 5 BP 481 EP 497 DI 10.1023/A:1005406719292 PG 17 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 111TL UT WOS:000075453600004 PM 9728329 ER PT J AU Dong, WM Simeonova, PP Gallucci, R Matheson, J Fannin, R Montuschi, P Flood, L Luster, MI AF Dong, WM Simeonova, PP Gallucci, R Matheson, J Fannin, R Montuschi, P Flood, L Luster, MI TI Cytokine expression in hepatocytes: Role of oxidant stress SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Article ID TUMOR-NECROSIS-FACTOR; FACTOR KAPPA-B; FACTOR-ALPHA; INDUCED HEPATOTOXICITY; GENE-EXPRESSION; ALCOHOLIC HEPATITIS; HEPG2 CELLS; LIVER; RAT; INDUCTION AB Inflammatory mediators, including cytokines and chemokines, are associated with the pathology of chronic liver disease. Interleukin-8 (IL-8) in humans and macrophage inflammatory protein-2 (MIP-2) in rodents, both members of the C-X-C family of chemokines, are particularly potent neutrophil attractants and have been implicated in chronic liver diseases. In the liver, cytokine secretion is usually associated with nonparenchymal cells, particularly Kupffer cells. In the present studies, chemokine gene expression and secretion were investigated in hepatocytes treated with various stimulators. Using human Hep G2 cells, it was demonstrated that, in contrast to lipopolysaccharides (LPS), both tumor necrosis factor-alpha (TNF-alpha) and H2O2 are potent inducers of IL-8, presumably acting via protein kinase C (PKC)-dependent pathways. MIP-2 expression occurred in freshly isolated rat hepatocytes following treatment with TNF-alpha, LPS, and to a lesser degree, H2O2, Both IL-8 and MIP-2 secretion were inhibited, although to varying degrees, by such antioxidants as TMTU, DMSO, catalase, and N-acetylcysteine. Furthermore, in vitro TNF-alpha neutralization experiments and transfection of Hep G2 cells with an IL-8 construct confirmed that TNF-alpha and H2O2 directly stimulate IL-8 secretion. RT-PCR analyses indicated that chemokine secretion induced by these agents operates via increased gene expression. Furthermore, a variety of cytokine genes were found to be expressed by hepatocytes, including MCP-1, cytokine-induced neutrophil chemoattractant (CINC), and IL-6, Taken together, these studies indicate that hepatocytes respond to biologically relevant levels of common activators, including H2O2, to produce cytokines and chemokines that contribute to pathophysiologic and repair processes in the liver. C1 NIOSH, Toxicol & Mol Biol Branch, Hlth Effects Lab Div, Morgantown, WV 26505 USA. Univ Cattolica Sacro Cuore, Dept Pharmacol, I-00168 Rome, Italy. NIEHS, Environm Immunol & Neurobiol Sect, Res Triangle Pk, NC 27709 USA. RP Luster, MI (reprint author), NIOSH, Toxicol & Mol Biol Branch, Hlth Effects Lab Div, 1095 Willowdale Rd, Morgantown, WV 26505 USA. EM MYL6@CDC.GOV OI MONTUSCHI, Paolo/0000-0001-5589-1750 NR 36 TC 51 Z9 54 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 AUG PY 1998 VL 18 IS 8 BP 629 EP 638 DI 10.1089/jir.1998.18.629 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 112UE UT WOS:000075511900012 PM 9726445 ER PT J AU Perkins, SN Hursting, SD Phang, JM Haines, DC AF Perkins, SN Hursting, SD Phang, JM Haines, DC TI Calorie restriction reduces ulcerative dermatitis and infection-related mortality in p53-deficient and wild-type mice SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article DE carcinogenesis; gene dosage; glucocorticoids; immune system ID FOOD RESTRICTION; P53 GENE; DIETARY RESTRICTION; OXIDATIVE STRESS; MOUSE SKIN; TUMORIGENESIS; PROMOTION; SPECTRUM; TUMORS; GLUCOCORTICOIDS AB In rodents calorie restriction (CR) reduces cancer incidence, improves health by delaying age-related declines in physiologic measures, and extends both median and maximal life span. The mechanisms underlying the various beneficial effects of CR remain undefined. In this study, heterozygous p53-deficient (p53(+/-)) mice (in which the inactivation of one allele of the p53 tumor suppressor gene increases susceptibility to spontaneous and carcinogen-induced tumor development) and wild-type (WT) litter mates were subjected to a two-stage skin carcinogenesis protocol with 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate. Instead of skin carcinomas however, the chemical treatment protocol caused ulcerous skin lesions, and 89% of mice fed ad libitum died from infection/septicemia. When WT mice were restricted to 60% of the average calorie intake of the respective ad libitum group, however, only 33% developed such lesions, and the CR mice survived tu ice as long on average as the ad libitum mice. CR also extended life span in p53(+/-) mice, but 50% of p53(+/-) mice subjected to CR still developed skin ulcers and mean life span was shorter than that seen in WT mice. Differences in response to CR between WT and p53(+/-) mice may be due to the reduction in p53 gene dosage, dissimilarity in the application of the CR treatment, or both. These results suggest that some of the beneficial effects of CR may need full expression of p53 for complete realization. C1 NCI, Lab Nutr & Mol Regulat, FCRDC, Frederick, MD 21702 USA. Frederick Canc Res & Dev Ctr, Pathol Histotechnol Lab, SAIC Frederick, Frederick, MD USA. RP Perkins, SN (reprint author), NCI, Lab Nutr & Mol Regulat, FCRDC, Bldg 560,Room 12-91, Frederick, MD 21702 USA. FU NCI NIH HHS [CA 16672] NR 45 TC 20 Z9 20 U1 0 U2 4 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 1998 VL 111 IS 2 BP 292 EP 296 DI 10.1046/j.1523-1747.1998.00270.x PG 5 WC Dermatology SC Dermatology GA 104MB UT WOS:000075017900019 PM 9699732 ER PT J AU Lange, RW Germolec, DR Foley, JF Luster, MI AF Lange, RW Germolec, DR Foley, JF Luster, MI TI Antioxidants attenuate anthralin-induced skin inflammation in BALB/c mice: role of specific proinflammatory cytokines SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE anthralin skin lesions; free radical generation; reactive oxygen intermediates ID NECROSIS-FACTOR-ALPHA; NF-KAPPA-B; FREE-RADICALS; OXIDATIVE STRESS; TRANSCRIPTION FACTOR; HAIRLESS MICE; MESSENGER-RNA; VITAMIN-E; KERATINOCYTES; DITHRANOL AB Anthralin is the most common therapeutic agent among a small number of pro-oxidant, 9-anthrones effective in the topical treatment of psoriasis, However, the usefulness of this drug is diminished by toxic side effects, including skin irritation and inflammation. The activities of anthralin are believed to be mediated by the generation of reactive oxygen intermediates and anthrone radicals produced in the skin, in this study, the dermal inflammatory response to anthralin was determined using a mouse ear swelling test. Maximum ear swelling induced by anthralin coincided with the elevation of cytokine mRNA expression in the skin, including interleukin-6, granulocyte-macrophage colony-stimulating factor, macrophage inflammatory protein-2, and tumor necrosis factor alpha at 24 h post challenge, The role of free radical generation in ear swelling and cytokine modulation were examined by systemic administration of cell permeable and impermeable antioxidants before anthralin challenge, Superoxide dismutase and alpha-tocopherol acetate, but not the glutathione precursor N-acetyl cysteine, were effective inhibitors of anthralin-induced ear swelling and cytokine elevation, Maximum inflammatory cell infiltration occurred 72-96 h post anthralin challenge and Tvas also reduced by antioxidants. These data suggest that oxidative stress, generated at the site of anthralin treatment, alters the expression of dermal chemokines and other cytokines resulting in the recruitment of inflammatory cells, Systemic antioxidant administration may provide opportunities for therapeutic intervention against anthralin-associated toxicities. C1 NIEHS, Environm Immunol Sect, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, NIH, Res Triangle Pk, NC 27709 USA. N Carolina State Univ, Dept Toxicol, Raleigh, NC 27695 USA. NIOSH, Hlth Effects Lab Div, Toxicol & Mol Biol Branch, Morgantown, WV USA. RP Lange, RW (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Environm & Occupat Hlth, RIDC Pk,260 Kappa Dr, Pittsburgh, PA 15260 USA. EM lange@vms.cis.pitt.edu NR 46 TC 22 Z9 22 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 AUG PY 1998 VL 64 IS 2 BP 170 EP 176 PG 7 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 106CB UT WOS:000075111200005 PM 9715255 ER PT J AU Shankavaram, UT DeWitt, DL Wahl, LM AF Shankavaram, UT DeWitt, DL Wahl, LM TI Lipopolysaccharide induction of monocyte matrix metalloproteinases is regulated by the tyrosine phosphorylation of cytosolic phospholipase A(2) SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE inflammation; signal transduction; prostaglandins ID ACTIVATED PROTEIN-KINASE; MACROPHAGE COLLAGENASE PRODUCTION; HUMAN PERIPHERAL-BLOOD; TUMOR-NECROSIS-FACTOR; ARACHIDONIC-ACID; HUMAN PLATELETS; MONONUCLEAR PHAGOCYTES; EXTRACELLULAR-MATRIX; HUMAN NEUTROPHILS; GENE-EXPRESSION AB Activation of human monocytes with lipopolysaccharide (LPS) results in the production of matrix metalloproteinases (MMPs) through a prostaglandin E-2 (PGE(2))-cAMP-dependent pathway. In this study, the early signaling events involved in this signal transduction pathway were evaluated. Pretreatment of human peripheral blood monocytes with herbimycin A, a tyrosine kinase inhibitor; or arachidonyl trifluormethyl ketone (AACOCF(3)), a specific inhibitor of cytosolic phospholipase A(2) (cPLA(2)) inhibited the induction of PGE(2) by LPS, This resulted in the inhibition of protein expression of gelatinase B (MMP-9) and interstitial collagenase (MMP-1), two major MMPs secreted by activated monocytes. Addition of arachidonic acid (AA) reversed the inhibitory effect of herbimycin A or AACOCF(3) on monocyte MMP production, indicating the importance of tyrosine phosphorylation and the involvement of cPLA(2) at an early stage in the signal transduction pathway of MMPs. This finding was further supported by LPS-induced shift in cPLA(2) migration and tyrosine phosphorylation based on immunoblotting and immunoprecipitation studies. These results provide evidence that tyrosine phosphorylation of cPLA(2) is one of the initial steps needed for the LPS induced MMP production in human monocytes. C1 NIDR, Immunopathol Sect, NIH, Bethesda, MD 20892 USA. Michigan State Univ, Dept Biochem, E Lansing, MI 48824 USA. RP Wahl, LM (reprint author), NIDR, Immunopathol Sect, NIH, 30 Convent Dr,Bldg 30,Room 325, Bethesda, MD 20892 USA. NR 55 TC 35 Z9 35 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 AUG PY 1998 VL 64 IS 2 BP 221 EP 227 PG 7 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 106CB UT WOS:000075111200012 PM 9715262 ER PT J AU Yu, CR Young, HA Ortaldo, JR AF Yu, CR Young, HA Ortaldo, JR TI Characterization of cytokine differential induction of STAT complexes in primary human T and NK cells SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE perforin; Fc gamma RI GAS; cell activation ID NATURAL-KILLER-CELLS; IFN-GAMMA PRODUCTION; TRANSCRIPTION FACTOR; SIGNAL TRANSDUCER; DNA-BINDING; TYROSINE PHOSPHORYLATION; STIMULATORY FACTOR; GENE-EXPRESSION; IL-2 RECEPTOR; HUMAN-LYMPHOCYTES AB Cytokines IL-2, IL-4, IL-6, IL-7, IL-12, and IL-15 are hey regulators of human peripheral blood T and NK cell activation and differentiation but the precise mechanisms that give rise to their differential activities within these cells are not clear. Recent studies reveal that a family of transcription factors, signal transducers and activators of transcription (STATs) directly mediate many cytokine signals. We analyzed the activation of STATs in primary human T and NK cells by a variety of specific cytokines. We demonstrate that IL-12 induces STAT4 only in freshly isolated primary NK cells, hut not in primary T cells, consistent with the lack of the IL-12 receptor in resting T cells. hi contrast, IL-4 induces different C epsilon GAS DNA-protein binding complexes in both T and NIC cells. Moreover, IL-4 costimulation T,idl IL-2 or IL-12 does not alter their own preferential GAS-like DNA binding patterns when C epsilon-, Fc gamma RI-, and SIE GAS motif containing oligonucleotide probes are compared, suggesting that induction of GAS-like DNA-protein binding complexes by IL-2, IL-4, and IL-12 is highly selective and represents one important factor in determining specific gene activation. In addition, IL-6 and IL-2 synergistically induce homo- and heterodimerized STAT1 alpha and STAT3 in both NK and T cells, consistent with their reported synergism in modulating perforin gene expression. We further demonstrated that IL-2, -7, and. -15 induce multiple STAT proteins, including STAT5a, STAT5b, STAT1 alpha, STAT3, and another unidentified Fc gamma RI GAS DNA-binding protein. Finally, we observed that activated STAT5a and STAT5b proteins form distinct Fc gamma RI GAS binding patterns in T and NK cells, suggesting that they might hare different roles in gene regulation. Our data provide evidence that the differential responses in gene expression and cell activation seen in primary Nh and T cells on direct stimulation with different cytokines may be a direct result of distinct activation of STAT transcription factors. C1 NCI, Expt Immunol Lab, Div Basic Sci, Frederick Canc Res & Dev Ctr,NIH, Frederick, MD 21702 USA. RP Ortaldo, JR (reprint author), NCI, Expt Immunol Lab, Div Basic Sci, Frederick Canc Res & Dev Ctr,NIH, Bldg 560,Rm 31-93, Frederick, MD 21702 USA. EM Ortaldo@ncifcrf.gov NR 76 TC 42 Z9 42 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD AUG PY 1998 VL 64 IS 2 BP 245 EP 258 PG 14 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 106CB UT WOS:000075111200015 PM 9715265 ER PT J AU Brousseau, ME Wang, J Demosky, SJ Vaisman, BL Talley, GD Santamarina-Fojo, S Brewer, HB Hoeg, JM AF Brousseau, ME Wang, J Demosky, SJ Vaisman, BL Talley, GD Santamarina-Fojo, S Brewer, HB Hoeg, JM TI Correction of hypoalphalipoproteinemia in LDL receptor-deficient rabbits by lecithin : cholesterol acyltransferase SO JOURNAL OF LIPID RESEARCH LA English DT Article DE familial hypercholesterolemia; high density lipoproteins; apolipoprotein A-I; metabolism; lecithin : cholesterol acyltransferase; WHHL rabbit ID APOLIPOPROTEIN-A-I; HIGH-DENSITY-LIPOPROTEIN; HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA; FRACTIONAL CATABOLIC RATE; CORONARY HEART-DISEASE; TRANSGENIC RABBITS; WHHL-RABBIT; CELLULAR CHOLESTEROL; INVIVO METABOLISM; PLASMA AB Familial hypercholesterolemia (FH), a disease caused by a variety of mutations in the low density lipoprotein receptor (LDLr) gene, leads not only to elevated LDL-cholesterol (C) concentrations but to reduced high density lipoprotein (HDL)-C and apolipoprotein (apo) A-I concentrations as well. The reductions in HDL-C and apoA-I are the consequence of the combined metabolic defects of increased apoA-I catabolism and decreased apoA-I synthesis. The present studies were designed to test the hypothesis that overexpression of human lecithin:cholesterol acyltransferase (hLCAT), a pivotal enzyme involved in HDL metabolism, in LDLr defective rabbits would increase HDL-C and apoA-I concentrations. Two groups of hLCAT transgenic rabbits were established: 1) hLCAT+/LDLr heterozygotes (LDLr+/-) and 2) hLCAT+/LDLr homozygotes (LDLr-/-), Data for hLCAT+ rabbits were compared to those of nontransgenic (hLCAT-) rabbits of the same LDLr status. In LDLr+/- rabbits, HDL-C and apoA-I concentrations (mg/dl), respectively, were significantly greater in hLCAT+ (62 +/- 8, 59 +/- 4) relative to hLCAT- rabbits (21 +/- 1, 26 +/- 2). This was, likewise, the case when hLCAT+/LDLr-/- (27 +/- 2, 19 +/- 6) and hLCAT-/LDLr-/- (5 +/- 1, 6 +/- 2) rabbits were compared. Kinetic experiments demonstrated that the fractional catabolic rate (FCR, d(-1)) of apoA-I was substantially delayed in hLCAT+ (0.376 +/- 0.025) versus hLCAT- (0.588) LDLr+/- rabbits, as well as in hECAT+ (0.666 +/- 0.033) versus hLCAT- (1.194 +/- 0.138) LDLr-/- rabbits. ApoA-I production rate (PR, mg.kg.d(-1)) was greater in both hLCAT+/LDLr+/- (10 +/- 2 vs. 6) and hLCAT+/LDLr-/- (9 +/- 1 vs. 4 +/- 1) rabbits. Significant correlations (P < 0.02) were observed between plasma LCAT activity and HDL-C (r = 0.857), apoA-I FCR (r = -0.774), and apoA-I PR (r = 0.771), while HDL-C correlated with both apoA-I FCR (-0.812) and PR (0.751). In summary, these data indicate that hLCAT overexpression in LDLr defective rabbits increases HDL-C and apoA-I concentrations by both decreasing apoA-I catabolism and increasing apoA-I synthesis, thus correcting the metabolic defects responsible for the hypoalphalipoproteinemia observed in LDLr deficiency. C1 NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. RP Hoeg, JM (reprint author), NHLBI, Mol Dis Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 50 TC 16 Z9 17 U1 1 U2 2 PU LIPID RESEARCH INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD AUG PY 1998 VL 39 IS 8 BP 1558 EP 1567 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 107WH UT WOS:000075233600003 PM 9717715 ER PT J AU Long, JC Romero, FC Urbanek, M Goldman, D AF Long, JC Romero, FC Urbanek, M Goldman, D TI Mating patterns and gene dynamics of a population isolate of Native Americans SO JOURNAL OF MAMMALOGY LA English DT Article DE human-population isolate; F-statistics; pedigrees; marker typings ID SIZES AB Mating structure can have important effects on population genetic phenomena, including inbreeding and genetic drift. However, data necessary to test predictions based on mathematical models or identify sensitivity to simplifying assumptions are difficult to collect. We used two sources of such data, pedigrees and genotypes, collected in a human-population isolate. The population studied was Native American and located in New Mexico. It was founded in the mid-19th century by ca. 30 individuals, primarily of Navajo origin, and its size increased steadily thereafter. A complete tribal pedigree spanning ca. 100 years (up to 1948) was collected by anthropologists starting in the 1920s. Probabilities of allelic identity by descent (IBD) within and among individuals were calculated for all generations directly from the pedigree. Wright's F-statistics were calculated from the IBD probabilities, and N-e was obtained from the statistic F-ST. Genetic typings were performed on blood samples collected from the population between 1991-1993. A second set of F-statistics were calculated from genetic typings. Genetic kinship between individuals (F-ST) and average inbreeding within individuals (F-IT) stabilized after the first two generations. However, F-ST was always greater than F-IT of the next generation, suggesting that the net effect of social practices was inbreeding avoidance. In contrast to general expectations for growing populations, N-e increased over generations due to immigration. F-statistics estimated from the genetic typings were remarkably close to pedigree estimates, suggesting a drift-migration steady state. C1 NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Dept Human Genet, Philadelphia, PA 19104 USA. Univ New Mexico, Dept Anthropol, Albuquerque, NM 87131 USA. RP Long, JC (reprint author), NIAAA, Neurogenet Lab, NIH, Pk 5 Bldg,Room 451,MSC 8110,12420 Parklawn Dr, Bethesda, MD 20892 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 28 TC 9 Z9 9 U1 0 U2 0 PU AMER SOC MAMMALOGISTS PI PROVO PA BRIGHAM YOUNG UNIV, DEPT OF ZOOLOGY, PROVO, UT 84602 USA SN 0022-2372 J9 J MAMMAL JI J. Mammal. PD AUG PY 1998 VL 79 IS 3 BP 681 EP 691 DI 10.2307/1383080 PG 11 WC Zoology SC Zoology GA 114TJ UT WOS:000075624900003 ER PT J AU Stoner, GL Agostini, HT Ryschkewitsch, CF Mazlo, M Gullotta, F Wamukota, W Lucas, S AF Stoner, GL Agostini, HT Ryschkewitsch, CF Mazlo, M Gullotta, F Wamukota, W Lucas, S TI Detection of JC virus in two African cases of progressive multifocal leukoencephalopathy including identification of JCV type 3 in a Gambian AIDS patient SO JOURNAL OF MEDICAL MICROBIOLOGY LA English DT Article ID LYMPHOTROPIC PAPOVAVIRUS; DNA-SEQUENCE; BK VIRUS; BRAIN; IMMUNOCOMPETENT; INDIVIDUALS; PROTEIN; DISEASE; CELLS AB Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating central nervous system (CNS) infection, affecting mainly oligodendrocytes, but also occasional astrocytes, In the USA, Europe and Asia, PML is caused by the human polyomavirus JC virus (JCV) and in autopsy series occurs in about 4-7% of AIDS patients. In Africa, the prevalence of PML in AIDS patients is uncertain and the causative agent is unknown. This study reports immunocytochemical and PCR confirmation of PML in the CNS of an AIDS patient dying in Uganda, East Africa (case 1), In a Gambian patient infected with HIV-2 who died 3 months after onset of AIDS/PML in Germany (case 2), it was possible to confirm the identity of the virus by DNA sequencing of the PCR amplified JCV product. This African genotype of the virus (type 3) showed an unusual re-arrangement of the regulatory region, and could be distinguished at several sites from East African and African-American JCV strains described previously. This study has confirmed that PML is a complication of African AIDS as it is in Europe and the USA, and that JCV type 3 is pathogenic in African AIDS patients. Furthermore, the finding of an African genotype of JCV in a patient dying in Germany suggests that in this individual JCV represented a latent infection acquired in Africa. C1 NIH, Expt Neuropathol Lab, Bethesda, MD 20892 USA. Univ Munster, Inst Neuropathol, D-4400 Munster, Germany. Makerere Univ, Sch Med, Dept Pathol, Kampala, Uganda. United Med & Dent Sch Guys & St Thomas Hosp, St Thomas Hosp, Dept Histopathol, London SE1 7EH, England. RP Stoner, GL (reprint author), NIH, Expt Neuropathol Lab, Bldg 10, Bethesda, MD 20892 USA. NR 36 TC 10 Z9 11 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0022-2615 J9 J MED MICROBIOL JI J. Med. Microbiol. PD AUG PY 1998 VL 47 IS 8 BP 733 EP 742 PG 10 WC Microbiology SC Microbiology GA 105PY UT WOS:000075083800011 PM 9877195 ER PT J AU Valeyev, AY Schaffner, AE Skolnick, P Dunlap, VS Wong, G Barker, JL AF Valeyev, AY Schaffner, AE Skolnick, P Dunlap, VS Wong, G Barker, JL TI Embryonic rat hippocampal neurons and GABA(A) receptor subunit-transfected non-neuronal cells release GABA tonically SO JOURNAL OF MEMBRANE BIOLOGY LA English DT Article DE patch-clamp; GABA; GABA(A) receptor Cl- channels; hippocampus; embryonic rat ID GLUTAMIC-ACID DECARBOXYLASE; MESSENGER-RNAS; 2 FORMS; CULTURE; CONDUCTANCE; LOCALIZATION; SECRETION; CHANNELS AB We used patch-clamp recording techniques to investigate the contribution of GABA to baseline membrane properties in cultured embryonic rat hippocampal neurons. Almost all of the neurons recorded with Cl--filled pipettes and clamped at negative potentials exhibited baselines that were noticeably noisy, with microscopic fluctuations superimposed on the macroscopic holding current. A gentle steam of saline applied to the neuronal surface rapidly and reversibly reduced the baseline current and fluctuations, both of which were completely eliminated by bicuculline. Fluctuation analysis showed that the variance in the baseline current signal was exponentially distributed with estimated kinetics comparable to those activated by submicromolar concentrations of exogenous GABA, The kinetics of Cl- channels activated by endogenous GABA displayed a potential sensitivity comparable to those activated by exogenous GABA, Non-neuronal cells stably transfected with alpha(1) and gamma(2) GABA(A) receptor subunits exhibited little baseline current variance when recorded with Cl--filled pipettes. Addition of micromolar GABA to the extracellular saline or to the pipette solution induced a saline- and bicuculline-sensitive baseline current signal comparable to that recorded in hippocampal neurons. Thus, both intra- and extracellular sources of GABA could contribute to the baseline properties recorded in these cultured neurons. C1 NINDS, Neurophysiol Lab, Basic Neurosci Program, NIH, Bethesda, MD 20892 USA. NIDDKD, Neurosci Lab, NIH, Bethesda, MD 20892 USA. RP Valeyev, AY (reprint author), Univ Miami, Sch Med, POB 16960, Miami, FL 33101 USA. NR 22 TC 9 Z9 10 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0022-2631 J9 J MEMBRANE BIOL JI J. Membr. Biol. PD AUG 1 PY 1998 VL 164 IS 3 BP 239 EP 251 DI 10.1007/s002329900409 PG 13 WC Biochemistry & Molecular Biology; Cell Biology; Physiology SC Biochemistry & Molecular Biology; Cell Biology; Physiology GA 106DL UT WOS:000075114500004 PM 9691117 ER PT J AU Makalowski, W Boguski, MS AF Makalowski, W Boguski, MS TI Synonymous and nonsynonymous substitution distances are correlated in mouse and rat genes SO JOURNAL OF MOLECULAR EVOLUTION LA English DT Editorial Material ID EVOLUTIONARY RATES; NUMBERS C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Makalowski, W (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. RI Makalowski, Wojciech/I-2843-2016 NR 10 TC 33 Z9 34 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0022-2844 J9 J MOL EVOL JI J. Mol. Evol. PD AUG PY 1998 VL 47 IS 2 BP 119 EP 121 DI 10.1007/PL00006367 PG 3 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 106YE UT WOS:000075178400001 PM 9694659 ER PT J AU Cheatham, TE Brooks, BR AF Cheatham, TE Brooks, BR TI Unbiased forced sampling of complex conformational transitions SO JOURNAL OF MOLECULAR GRAPHICS & MODELLING LA English DT Meeting Abstract C1 NIH, Biophys Chem Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1093-3263 J9 J MOL GRAPH MODEL JI J. Mol. Graph. PD AUG-DEC PY 1998 VL 16 IS 4-6 BP 289 EP 290 PG 2 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Computer Science, Interdisciplinary Applications; Crystallography; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Computer Science; Crystallography; Mathematical & Computational Biology GA 248ZK UT WOS:000083306500069 ER PT J AU Hahm, SH Hsu, CM Eiden, LE AF Hahm, SH Hsu, CM Eiden, LE TI PACAP activates calcium influx-dependent and -independent pathways to couple met-enkephalin secretion and biosynthesis in chromaffin cells SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE PACAP; signal transduction; PKA; calcium; stimulus-secretion-synthesis coupling ID INDUCED CATECHOLAMINE SECRETION; PROENKEPHALIN GENE-EXPRESSION; MESSENGER-RNA; TYROSINE-HYDROXYLASE; ADRENAL-MEDULLA; SIGNAL-TRANSDUCTION; SECRETOGRANIN-II; PRIMARY CULTURES; CYCLIC-AMP; POLYPEPTIDE AB Pituitary adenylate cyclase activating polypeptide-27 (PACAP-27) caused a dose-dependent increase in met-enkephalin secretion and increased production of met-enkephalin peptide and proenkephalin A (PEnk) mRNA in bovine chromaffin cells, at concentrations as low as 300 pM. PACAP-38 was less potent than PACAP-27, but had similar effects. Vasoactive intestinal polypeptide (VIP) (1-100 nM) was without appreciable effect on either enkephalin secretion or biosynthesis, implicating PACAP type I receptors in PACAP-stimulated enkephalin secretion and synthesis. PACAP type I receptors can activate adenylate cyclase and stimulate phospholipase C through heterotrimeric G protein interactions, leading to increased intracellular cyclic AMP (cAMP), inositol triphosphate (IP3)-mediated calcium mobilization, and calcium- and diacylglycerol (DAG)-mediated protein kinase C (PKC) activation. Enkephalin secretion evoked by 10-100 nM PACAP-27 was not inhibited by 1 mu M (-)-202-791, an L-type specific dihydropyridine calcium channel blocker, but was inhibited 65-80% by the arylalkylamine calcium channel blocker D600. Forty mM potassium-evoked secretion was inhibited >90% by both D600 and (-)-202-791, 25 mu M forskolin-induced secretion was blocked <50% by D600 and was unaffected by (-)-202-791, and 100 nM phorbol myristate acetate (PMA)-induced secretion was unaffected by either D600 or (-)-202-791, Enkephalin biosynthesis was increased by 10 nM PACAP-27, as measured by increased met-enkephalin pentapeptide content and PEnk A mRNA levels. PACAP-, forskolin-, and PMA-stimulated enkephalin synthesis were not blocked by D600 or (-)-202-791. Elevated potassium-induced enkephalin biosynthesis upregulation was completely blocked by either D600 or (-)-202-791. at the same concentrations. PACAP acting through type I PACAP receptors couples calcium influx-dependent enkephalin secretion and calcium influx-independent enkephalin biosynthesis in chromaffin cells. Restriction of the effects of enhanced calcium influx to stimulation of secretion, but not of biosynthesis, is unique to PACAP. By contrast, potassium-induced enkephalin biosynthesis upregulation is completely calcium influx dependent, specifically via calcium influx through L-type calcium channels. We propose that subpopulations of voltage-dependent calcium channels are differentially linked to intracellular signal transduction pathways that control neuropeptide gene expression and secretion in chromaffin cells. C1 NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. RP Eiden, LE (reprint author), NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. OI Eiden, Lee/0000-0001-7524-944X NR 45 TC 27 Z9 27 U1 0 U2 0 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 AUG PY 1998 VL 11 IS 1 BP 43 EP 56 DI 10.1385/JMN:11:1:43 PG 14 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 139AH UT WOS:000077004900004 PM 9826785 ER PT J AU Cott, JM Fugh-Berman, A AF Cott, JM Fugh-Berman, A TI Is St. John's Wort (Hypericum perforatum) an effective antidepressant? SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Article C1 NIMH, Adult Psychopharmacol Program, Rockville, MD 20857 USA. Natl Womens Hlth Network, Washington, DC 20004 USA. RP Cott, JM (reprint author), NIMH, Adult Psychopharmacol Program, 5600 Fishers Lane,Room 10-75, Rockville, MD 20857 USA. NR 9 TC 12 Z9 12 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0022-3018 J9 J NERV MENT DIS JI J. Nerv. Ment. Dis. PD AUG PY 1998 VL 186 IS 8 BP 500 EP 501 DI 10.1097/00005053-199808000-00008 PG 2 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 110EW UT WOS:000075368100008 PM 9717868 ER PT J AU Cameron, HA Hazel, TG McKay, RDG AF Cameron, HA Hazel, TG McKay, RDG TI Regulation of neurogenesis by growth factors and neurotransmitters SO JOURNAL OF NEUROBIOLOGY LA English DT Review DE development; CNS; proliferation; cell fate; differentiation ID VASOACTIVE-INTESTINAL-PEPTIDE; CENTRAL-NERVOUS-SYSTEM; DEVELOPING RAT-BRAIN; CYCLASE-ACTIVATING POLYPEPTIDE; CEREBELLAR GRANULE CELLS; RECEPTOR MESSENGER-RNA; MAMMALIAN NEURAL CREST; DENTATE GYRUS; ADULT-RAT; PROGENITOR CELLS AB The generation of neurons and glia in the developing nervous system is likely to be regulated by extrinsic factors, including growth factors and neurotransmitters. Evidence from in vivo and/or in vitro systems indicates that basic fibroblast growth factor, transforming growth factor (TGF)-alpha, insulin-like growth factor-1, and the monoamine neurotransmitters act to increase proliferation of neural precursors. Conversely, glutamate, gamma-aminobutyric acid, and opioid peptides are likely to play a role in down-regulating proliferation in the developing nervous system. Several other factors, including the neuropeptides vasoactive intestinal peptide and pituitary adenylate cyclase-activating peptide, as well as the growth factors platelet-derived growth factor, ciliary neurotrophic factor, and members of the TGF-beta family, have different effects on proliferation and differentiation depending on the system examined. Expression of many of these factors and their receptors in germinal regions of the central nervous system suggests that they can act directly on precursor populations to control their proliferation. Together, the findings discussed here indicate that proliferation and cell fate determination in the developing brain are regulated extrinsically by complex interactions between a relatively large number of growth factors and neurotransmitters. (C) 1998 John Wiley & Sons, Inc.*. C1 NINDS, Mol Biol Lab, Bethesda, MD 20892 USA. RP Cameron, HA (reprint author), NINDS, Mol Biol Lab, Bethesda, MD 20892 USA. RI Cameron, Heather/E-6221-2011 OI Cameron, Heather/0000-0002-3245-5777 NR 166 TC 389 Z9 403 U1 2 U2 9 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 AUG PY 1998 VL 36 IS 2 BP 287 EP 306 DI 10.1002/(SICI)1097-4695(199808)36:2<287::AID-NEU13>3.0.CO;2-B PG 20 WC Neurosciences SC Neurosciences & Neurology GA 106EN UT WOS:000075117100013 PM 9712310 ER PT J AU Wu, VW Nishiyama, N Schwartz, JP AF Wu, VW Nishiyama, N Schwartz, JP TI A culture model of reactive astrocytes: Increased nerve growth factor synthesis and reexpression of cytokine responsiveness SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE adult astrocytes; gliosis; neurotrophic factor; interleukin-1 beta; interferon-gamma; 6-hydroxydopamine; tissue culture ID FIBRILLARY ACIDIC PROTEIN; NEUROTROPHIC FACTOR; GENE-EXPRESSION; GLIAL REACTION; MESSENGER-RNA; RAT-BRAIN; GLIOSIS; SYSTEM; DISEASE; INJURY AB Reactive gliosis, which occurs in response to damage to the central nervous system, has been recognized for years but is not yet understood. We describe here a tissue culture model of reactive astrocytes used to characterize their properties. Cultures are prepared 1 week following 6-hydroxydopamine (6-OHDA) lesion of rat substantia nigra and compared with astrocytes cultured from normal adult rats or rats injected with saline only. Astrocytes from the 6-OHDA-lesioned side contained elevated levels of glial fibrillary acidic protein (GFAP) and GFAP mRNA and were intensely immunoreactive for GFAP, vimentin, and two epitopes that in vivo are found only on reactive astrocytes. The basal content of nerve growth factor (NGF) mRNA and NGF in astrocytes from 6-OHDA-lesioned rats was significantly higher relative to control astrocytes. Two inflammatory cytokines, interleukin-1 beta and interferon-gamma, increased synthesis of NGF up to 20-fold in the reactive cells, whereas there was no response in the normal adult astrocytes. Astrocytes from postnatal day 2 rats shared many of the properties of the reactive adult astrocytes. These cultures offer the possibility to characterize the cellular and molecular properties of reactive astrocytes and to determine the factors responsible for activation of astrocytes. C1 NINDS, MGS, CNB, NIH, Bethesda, MD 20892 USA. RP Schwartz, JP (reprint author), NINDS, MGS, CNB, NIH, Bldg 10,Rm 3N256, Bethesda, MD 20892 USA. NR 31 TC 61 Z9 62 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 1998 VL 71 IS 2 BP 749 EP 756 PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 102FB UT WOS:000074912800033 PM 9681466 ER PT J AU Conant, K Ahmed, U Schwartz, JP Major, EO AF Conant, K Ahmed, U Schwartz, JP Major, EO TI IFN-gamma inhibits AP-1 binding activity in human brain-derived cells through a nitric oxide dependent mechanism SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE astrocytes; neurons; interferon-gamma; nitric oxide; nitric oxide synthase; transcription factor AP-1 ID NF-KAPPA-B; KINASE-C ACTIVITY; MAMMALIAN-CELLS; PROTEIN; INTERFERON; TRANSCRIPTION; GENE; EXPRESSION; VIRUS; FOS AB It has been demonstrated that CNS levels of the cytokine IFN-gamma are elevated in association with a number of neuro-inflammatory diseases. In the present study, we have examined the effect of this cytokine on human brain derived cells. We show that prolonged treatment (22 h) of such cells with IFN-gamma inhibits the DNA binding activity of transcription factor AP-1. Furthermore, we show that this effect can be reversed by either N-G-monomethyl-L-arginine (L-NMMA) or L-N-5-(1-iminoethyl)ornithine (L-NIO), competitive inhibitors of nitric oxide synthase activity [Rees et al., 1990]. In addition, we show that treatment of brain-derived cells with the nitric oxide donor 3-morpholinosydnonimine, HCl (SIN-1), or [N-(b-D-glucopyranosyl)-N-2-acetyl-S-nitroso-D,L-penicillaminamide] (glyco-SNAP-1), also inhibits the binding activity of AP-1. Together, these results suggest that IFN-gamma can inhibit AP-1 binding activity through a nitric oxide dependent mechanism. (C) 1998 Published by Elsevier Science B.V. All rights reserved. C1 NIH, Lab Mol Med & Neurosci, Bethesda, MD 20892 USA. NIH, Clin Neurosci Branch, Mol Genet Sect, Bethesda, MD 20892 USA. RP Conant, K (reprint author), NIH, Lab Mol Med & Neurosci, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM conant@codon.nih.gov NR 40 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 AUG 1 PY 1998 VL 88 IS 1-2 BP 39 EP 44 DI 10.1016/S0165-5728(98)00069-1 PG 6 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 103RR UT WOS:000074972100006 PM 9688322 ER PT J AU Silver, PB Rizzo, LV Sun, B Chan, CC Wiggert, B Nussenblatt, RB Caspi, RR AF Silver, PB Rizzo, LV Sun, B Chan, CC Wiggert, B Nussenblatt, RB Caspi, RR TI Heterologous epitopes of IRBP protect against autoimmune uveitis induced by the autologous epitope SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE oral tolerance; uveitis; peptides ID MYELIN BASIC-PROTEIN; ORAL TOLERANCE; II COLLAGEN; SUPPRESSION; ENCEPHALOMYELITIS; UVEORETINITIS; MICE; CELL; TOLERIZATION; MECHANISMS AB Peptide 161-180 of human interphotoreceptor retinoid-binding protein (IRBP) contains a major uveitogenic epitope for mice of the H-2(r) haplotype. The human and bovine homologs differ from the autologous murine homolog by three and four amino acid residues, respectively. We compare the immunogenicity and pathogenicity of the three homologs, and investigate their ability to induce oral tolerance to experimental autoimmune uveoretinitis (EAU) induced by the autologous peptide. All three 161-180 homologs were pathogenic, with a hierarchy: human > murine > bovine. All crossreacted with each other and with IRBP. Feeding any of the three homologs (6 x 200 mu g over 2 weeks) lowered antigen-specific responses and protected from EAU induced by the autologous homolog, and reduced EAU induced with whole IRBP. Peptide-fed mice had a reduced frequency of peptide-reactive T cells, suggesting a mechanism involving anergy and/or deletion. The results indicate that non-identical, but crossreactive, heterologous epitopes can protect against EAU induced by the corresponding autologous epitope, and even by the whole multi-epitope protein. These findings may impact on clinical trials in which uveitis patients are undergoing oral immunotherapy with bovine retinal antigens. Published by Elsevier Science B.V. C1 NEI, Immunol Lab, Bethesda, MD 20892 USA. NEI, Lab Cell & Mol Biol, Bethesda, MD 20892 USA. RP Silver, PB (reprint author), NEI, Immunol Lab, NIH Bldg 10,Room 10N 218, Bethesda, MD 20892 USA. RI Rizzo, Luiz Vicente/B-4458-2009 NR 33 TC 5 Z9 6 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD AUG 1 PY 1998 VL 88 IS 1-2 BP 128 EP 136 DI 10.1016/S0165-5728(98)00111-8 PG 9 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 103RR UT WOS:000074972100018 PM 9688334 ER PT J AU Mehta, PS Bruccoleri, A Brown, HW Harry, GJ AF Mehta, PS Bruccoleri, A Brown, HW Harry, GJ TI Increase in brain stem cytokine mRNA levels as an early response to chemical-induced myelin edema SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE demyelination; cytokines; triethyltin; TNF-alpha; IL-1 alpha; TGF-beta; MIP-1 alpha ID CENTRAL-NERVOUS-SYSTEM; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MACROPHAGE INFLAMMATORY PROTEIN-1; GENE-EXPRESSION; MESSENGER-RNA; CELLS; BETA; CHEMOKINES; MECHANISM AB This study examined the early response of pro-inflammatory and regulatory cytokines in the mouse brain following triethyltin (TET)-induced myelin injury characterized by edematous vacuolation. Following an acute intraperitoneal injection of triethyltin (TET) sulfate (3 mg/kg) to 17-day old CD1 mice, significant increases in brain stem TNF-alpha and IL-1 alpha mRNA levels occurred at 6 and 24 h, respectively with elevations in TGF-beta 1 and MIP-1 alpha at 1 h. In the cortex, responses were limited to elevations at 6 h in TNF-alpha, TGF-beta 1 and MIP-1 alpha. These data suggest that a chemokine/cytokine response can occur with minimal alterations to the integrity of the myelin sheath and may contribute to the initial signaling mechanisms associated with demyelinating disorders. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIEHS, Neurotoxicol Grp, Toxicol Lab, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. RP Harry, GJ (reprint author), NIEHS, Neurotoxicol Grp, Toxicol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM harry@niehs.nih.gov NR 34 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD AUG 1 PY 1998 VL 88 IS 1-2 BP 154 EP 164 DI 10.1016/S0165-5728(98)00116-7 PG 11 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 103RR UT WOS:000074972100021 PM 9688337 ER PT J AU Clay, JR AF Clay, JR TI Excitability of the squid giant axon revisited SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID SODIUM-CHANNEL; POTASSIUM CHANNEL; PERIAXONAL SPACE; GATING CURRENTS; NERVE MEMBRANE; SINGLE-CHANNEL; ACCUMULATION; INACTIVATION; PERMEABILITY; CONDUCTANCE AB The electrical properties of the giant axon from the common squid Loligo pealei have been reexamined. The primary motivation for this work was the observation that the refractoriness of the axon was significantly greater than the predictions of the standard model of nerve excitability. In particular, the axon fired only once in response to a sustained, suprathreshold stimulus. Similarly, only a single action potential was observed in response to the first pulse of a train of 1-ms duration current pulses, when the pulses were separated in time by similar to 10 ms. The axon was refractory to all subsequent pulses in the train. The underlying mechanisms for these results concern both the sodium and potassium ion currents I-Na and I-K. Specifically, Na+ channel activation has long been known to be coupled to inactivation during a depolarizing voltage-clamp step. This feature appears to be required to simulate the pulse train results in a revised model of nerve excitability. Moreover, the activation curve for I-K has a significantly steeper voltage dependence, especially near its threshold (approximately -60 mV), than in the standard model, which contributes to reduced excitability, and the fully activated current-voltage relation for I-K has a nonlinear, rather than a linear, dependence on driving force. An additional aspect of the revised model is accumulation/depeletion of K+ in the space between the axon and the glial cells surrounding the axon, which is significant even during a single action potential and which can account for the 15-20 mV difference between the potassium equilibrium potential E-K and the maximum afterhyperpolarization of the action potential. The modifications in I-K can also account for the shape of voltage changes near the foot of the action potential. C1 National Institute Neurological Diseases & Stroke, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. Marine Biol Lab, Woods Hole, MA 02543 USA. RP National Institute Neurological Diseases & Stroke, Neurophysiol Lab, NIH, Bldg 36,Rm 2C02, Bethesda, MD 20892 USA. NR 37 TC 44 Z9 44 U1 1 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 EI 1522-1598 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD AUG PY 1998 VL 80 IS 2 BP 903 EP 913 PG 11 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 110LL UT WOS:000075383000035 PM 9705477 ER PT J AU Cheng, CM Joncas, G Reinhardt, RR Farrer, R Quarles, R Janssen, J McDonald, MP Crawley, JN Powell-Braxton, L Bondy, CA AF Cheng, CM Joncas, G Reinhardt, RR Farrer, R Quarles, R Janssen, J McDonald, MP Crawley, JN Powell-Braxton, L Bondy, CA TI Biochemical and morphometric analyses show that myelination in the insulin-like growth factor 1 null brain is proportionate to its neuronal composition SO JOURNAL OF NEUROSCIENCE LA English DT Article DE IGF1; oligodendrocyte; olfactory bulb; myelin basic protein (MBP); myelin proteolipid protein (PLP); 2 ',3 '-cyclic nucleotide, 3 '-phosphodiesterase (CNPase); myelin-associated glycoprotein (MAG) ID RECEPTOR GENE-EXPRESSION; CENTRAL-NERVOUS-SYSTEM; FACTOR-I GENE; RAT-BRAIN; IGF-I; MESSENGER-RNA; TRANSGENIC MICE; LOCALIZATION; BINDING; AUTORADIOGRAPHY AB To elucidate the role of insulin-like growth factor 1 (IGF1) in the normal development of brain myelination, we used behavioral, biochemical, and histological analyses to compare the myelination of brains from Igf1(-/-) and wild-type (WT) littermate mice. The studies were conducted at postnatal day 40, at which time the Igf1(-/-) mice weighed similar to 66% less than wild-type mice. However, the Igf1(-/-) brain weight was only reduced by similar to 34%. Formal neurological testing showed no sign of central or peripheral myelinopathy in Igf1(-/-) mice. Myelin composition was not significantly different, and myelin concentration, normalized to brain weight or protein, was equal in Igf1(-/-) and WT mice. Likewise, concentrations of myelin-specific proteins (MBP, myelin proteolipid protein, MAG, and 2',3'-cyclic nucleotide,3'-phosphodiesterase) were not significantly different in Igf1(-/-) and WT mice. The myelin-associated lipids galactocerebroside and sulfatide were modestly reduced in Igf1(-/-) brains. Regional oligodendrocyte populations and myelin staining patterns were comparable in Igf1(-/-) and WT brains, with the notable exception of the olfactory system. The Igf1(-/-) olfactory bulb was profoundly reduced in size and was depleted of mitral neurons and oligodendrocytes, and its efferent tracts were depleted of myelin. In summary, this study shows that myelination of the Igf1(-/-) brain is proportionate to its neuronal composition. Where projection neurons are preserved despite the deletion of IGF1, as in the cerebellar system, oligodendrocytes and myelination are indistinguishable from wild type. Where projection neurons are depleted, as in the olfactory bulb, oligodendrocytes are also depleted, and myelination is reduced in proportion to the reduced projection neuron mass. These data make a strong case for the primacy of axonal factors, not including IGF1, in determining oligodendrocyte survival and myelination. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Myelin & Brain Dev Sect, Mol & Cellular Neurobiol Lab, NIH, Bethesda, MD 20892 USA. NIMH, Sect Behav Neuropharmacol, NIH, Bethesda, MD 20892 USA. Genentech Inc, Dept Cardiovasc Res, S San Francisco, CA 94080 USA. RP Cheng, CM (reprint author), NICHHD, Dev Endocrinol Branch, NIH, Bldg 10-10N262,10 Ctr Dr, Bethesda, MD 20892 USA. NR 36 TC 86 Z9 87 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 1 PY 1998 VL 18 IS 15 BP 5673 EP 5681 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 103RN UT WOS:000074971800012 PM 9671658 ER PT J AU Ernst, M Zametkin, AJ Matochik, JA Jons, PH Cohen, RM AF Ernst, M Zametkin, AJ Matochik, JA Jons, PH Cohen, RM TI DOPA decarboxylase activity in attention deficit hyperactivity disorder adults. A [fluorine-18]fluorodopa positron emission tomographic study SO JOURNAL OF NEUROSCIENCE LA English DT Article DE prefrontal cortex; nigrostriatal pathways; presynaptic dopaminergic function; attention deficit hyperactivity disorder; gender; neurodevelopment; PET; (F18)fluorodopa ID CEREBRAL GLUCOSE-METABOLISM; AMINO-ACID DECARBOXYLASE; PREFRONTAL CORTEX; HUMAN-BRAIN; EXTRACELLULAR DOPAMINE; MONOAMINE METABOLITES; PSYCHIATRIC STATUS; HOMOVANILLIC-ACID; CHILDHOOD-ONSET; BASAL GANGLIA AB Converging evidence implicates the dopaminergic system and the prefrontal and nigrostriatal regions in the pathophysiology of attention deficit hyperactivity disorder (ADHD). Using positron emission tomography (PET) with [fluorine-18]fluorodopa (F18-DOPA), we compared the integrity of the presynaptic dopaminergic function between 17 ADHD adults and 23 healthy controls. The ratio of the isotope concentration of specific regions to that of nonspecific regions reflects DOPA decarboxylase activity and dopamine storage processes. Of three composite regions (prefrontal cortex, striatum, and midbrain), only the prefrontal cortex showed significantly different F18-DOPA ratios in ADHD as compared with control adults (p < 0.01). The medial and left prefrontal areas were the most altered (lower F18-DOPA ratios by 52 and 51% in ADHD as compared with controls). Similarly, the interaction [sex x diagnosis] was significant only in the prefrontal cortex (p < 0.02). lower ratios in men than in women in ADHD and vice versa in controls. These findings suggest that a prefrontal dopaminergic dysfunction mediates ADHD symptoms in adults and that gender influences this abnormality. On the basis of previous neuroimaging findings in ADHD showing discrepant findings in adults and adolescents and on evidence for midbrain dopaminergic defect in adolescents, we hypothesize that the prefrontal dopaminergic abnormality in ADHD adults is secondary and results from an interaction of the primary subcortical dopaminergic deficit with processes of neural maturation and neural adaptation. C1 NIMH, Cerebral Metab Lab, NIH, Bethesda, MD 20892 USA. RP Cohen, RM (reprint author), NIMH, Cerebral Metab Lab, NIH, Bldg 36,Room 1A05,36 Convent Dr,MSC 4030, Bethesda, MD 20892 USA. NR 74 TC 222 Z9 226 U1 7 U2 14 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 1 PY 1998 VL 18 IS 15 BP 5901 EP 5907 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 103RN UT WOS:000074971800031 PM 9671677 ER PT J AU Stenger, DA Hickman, JJ Bateman, KE Ravenscroft, MS Ma, W Pancrazio, JJ Shaffer, K Schaffner, AE Cribbs, DH Cotman, CW AF Stenger, DA Hickman, JJ Bateman, KE Ravenscroft, MS Ma, W Pancrazio, JJ Shaffer, K Schaffner, AE Cribbs, DH Cotman, CW TI Microlithographic determination of axonal/dendritic polarity in cultured hippocampal neurons SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE hippocampal neuron; neuronal polarity; self-assembled monolayers ID SELF-ASSEMBLED MONOLAYERS; GROWTH; EXPRESSION; SURVIVAL; GUIDANCE; SURFACES; NETWORKS; ADHESION; CELLS AB High resolution substrates, created using patterned self-assembled monolayers, are shown to direct axonal and dendritic process extension at the level of a single hippocampal neuron. Areas and dendrites were identified using morphological characteristics and immunocytochemical markers. Patterns were formed on glass coverslips from a co-planar monolayer of cell adhesive aminosilanes and non-adhesive fluorinated silanes. On patterned surfaces, the percentage of the total number of cells attached to the 0.71 mm(2) substrate field with compliance to the 25-mu m diameter 'somal adhesion site' reached 41 +/- 7% (mean +/- S.D., 428 cells counted). A total of 76 +/- 11% of cells that adhered to a somal attachment site developed a lone process greater than or equal to 100 mu m oriented in the direction of the continuous aminosilane pathway which was shown to express axonal markers, dells on either the fluorinated silane, which is non-permissive for neurite outgrowth, or localized on a:? aminosilane region only 5 mu m wide failed to extend major processes. This approach is amenable to a variety of industry standard fabrication techniques and may be used to study the role of fine scale spatial cues in neuronal development and synapse formation. (C) 1998 Elsevier Science B,V. All rights reserved. C1 USN, Res Lab, Ctr Biomol Sci & Engn, Washington, DC 20375 USA. Sci Applicat Int Corp, Rockville, MD 20850 USA. NICHD, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. Univ Calif Irvine, Inst Brain Aging & Dementia, Irvine, CA 92717 USA. RP Stenger, DA (reprint author), USN, Res Lab, Ctr Biomol Sci & Engn, Code 6910, Washington, DC 20375 USA. RI Pancrazio, Joseph/M-3206-2015 OI Pancrazio, Joseph/0000-0001-8276-3690 NR 31 TC 119 Z9 122 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD AUG 1 PY 1998 VL 82 IS 2 BP 167 EP 173 DI 10.1016/S0165-0270(98)00047-8 PG 7 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 113LV UT WOS:000075553200006 PM 9700689 ER PT J AU Kim, S Buonanno, A Nelson, PG AF Kim, S Buonanno, A Nelson, PG TI Regulation of prothrombin, thrombin receptor, and protease nexin-1 expression during development and after denervation in muscle SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE innervation; denervation; activity-dependent synapse elimination ID ELECTRICAL-ACTIVITY; MESSENGER-RNA; NEURITE RETRACTION; CELL-PROLIFERATION; PERIPHERAL-NERVE; MYOGENIC FACTORS; SKELETAL-MUSCLE; RAT-BRAIN; ACTIVATION; SYNAPSE AB Prothrombin, thrombin receptor (ThR), and protease nexin-1 (PN-1) mRNA levels in mouse muscle were quantified using competitive reverse transcriptase-polymerase chain reaction during development and after denervation to examine the possible role of thrombin in activity-dependent synapse elimination at the neuromuscular junction, The results showed that the levels of prothrombin and ThR were maximal at birth and decreased by tno orders of magnitude by postnatal day 20 (P20), The level of PN-1 mRNA was fairly constant during development except for a 4-fold to 5-fold downregulation at P10 and P15, the periods of maximal synapse elimination at the rodent neuromuscular junction, The expression of prothrombin mRNA in muscle at birth was 41-fold and 22-fold lower than those of ThR and PN-1, respectively, and the level of difference between prothrombin and PN-1 reached almost three orders of magnitude at adulthood, Denervation of adult muscle resulted in a reversal of the relative expression levels of the three genes, There were rapid 8-fold and 10-fold increases in prothrombin and ThR mRNA, respectively, and a 2-fold decrease in PN-1 mRNA. The changes in mRNA levels of the three genes after denervation indicated that these genes were regulated in a innervation-dependent manner and that nerve activity may play an important regulatory role in the expression of prothrombin, ThR, and PN-1, The concurrent regulation of prothrombin and ThR suggests that thrombin-mediated cellular activities in muscle may be affected via the activation of ThR, An elevated le, el of local thrombin or thrombin-like activity might result from the decreased inhibitory activity of PN-1 during the period of peak synapse elimination in muscle development, J, Neurosci, Res, 53:304-311, 1998. (C) 1998 Wiley-Liss, Inc.(dagger.) C1 NICHHD, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Kim, S (reprint author), NICHHD, Dev Neurobiol Lab, NIH, Bldg 49,Room 5A38,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 37 TC 27 Z9 27 U1 1 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD AUG 1 PY 1998 VL 53 IS 3 BP 304 EP 311 DI 10.1002/(SICI)1097-4547(19980801)53:3<304::AID-JNR4>3.0.CO;2-E PG 8 WC Neurosciences SC Neurosciences & Neurology GA 104CN UT WOS:000074995100004 PM 9698158 ER PT J AU Eng, LF Lee, YL Kwan, H Brenner, M Messing, A AF Eng, LF Lee, YL Kwan, H Brenner, M Messing, A TI Astrocytes cultured from transgenic mice carrying the added human glial fibrillary acidic protein gene contain Rosenthal fibers SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE astrocytes; transgenic mouse; Rosenthal fibers; Alexander's disease ID ALPHA-B-CRYSTALLIN; ALEXANDERS DISEASE; GFAP; DEVELOP; STRESS; HSP27 AB Mice carrying copies of the human glial fibrillary acidic protein (hGFAP) gene driven by its own promoter have been generated that express the human transgene at different levels (Messing et al,: 152:391-398, 1998), Lines that expressed high levels of the gene died shortly after birth. Astrocyte cultures prepared from a low overexpressor (Tg73.2) exhibited abnormal cytoplasmic inclusions identical to those seen in vivo in the high overexpressors. Astrocytes in the Tg73,2 cultures appear odd-shaped and enlarged, express increased levels of GFAP (both human and mouse), and express alpha B crystallin protein, Hsp27 protein, and vimentin protein. At the light microscopic level, the Tg73,2 astrocytes are filled with eosinophilic deposits surrounded by positive GFAP immunostain, Ultrastructurally, the Tg73,2 astrocytes contain osmophilic deposits on a bed of intermediate filaments identical to Rosenthal fibers found in the brain in Alexander's disease. It seems that Tg73,2 mouse astrocytes in culture do not require additional stress from external sources or contact with other neuroectodermal cells to produce Rosenthal fibers. This suggests that the added hGFAP gene is sufficient to induce Rosenthal fibers and that an excess of GFAP in astrocytes may be detrimental to normal function. We hypothesize that the normal mechanism for GFAP turnover may be insufficient to handle the excess GFAP, thus causing an accumulation of stress proteins. The increased amounts of stress proteins and GFAP results in the formation of Rosenthal fibers, similar to those found in Alexander's disease. J, Neurosci, Res. 53:353-360, 1998, (C) 1998 Wiley-Liss, Inc. C1 VAPA Hlth Care Syst, Dept Pathol, Palo Alto, CA 94304 USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. Univ Wisconsin, Dept Pathobiol Sci, Madison, WI 53706 USA. RP Eng, LF (reprint author), VAPA Hlth Care Syst, Dept Pathol, 3801 Miranda Ave, Palo Alto, CA 94304 USA. FU NINDS NIH HHS [NS-11632] NR 24 TC 33 Z9 34 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 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD AUG 1 PY 1998 VL 53 IS 3 BP 353 EP 360 DI 10.1002/(SICI)1097-4547(19980801)53:3<353::AID-JNR9>3.0.CO;2-9 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 104CN UT WOS:000074995100009 PM 9698163 ER PT J AU Hou, J Major, EO AF Hou, J Major, EO TI The efficacy of nucleoside analogs against JC virus multiplication in a persistently infected human fetal brain cell line SO JOURNAL OF NEUROVIROLOGY LA English DT Article DE drug; antiviral; JC virus; nucleoside analogs ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; INDUCED DEMYELINATING DISEASE; DNA-REPLICATION; GLIAL-CELLS; CYTARABINE; REMISSION; AIDS AB The effectiveness of nucleoside analogs in blocking viral multiplication was evaluated using an immortalized human neuroglial cell line capable of sustaining a persistent JCV infection, SVG-TC. Results from in situ DNA hybridization and hemagglutination assays performed on drug treated cultures were used as a measure of viral DNA replication and multiplication, respectively. Of the three drugs tested, Ara-C (cytosine arabinoside), AZT (3'-azido-3'-deoxythymidine), and cidofovir (S)-1-[3-hydroxy-2-(phosphonylmethoxypropyl] cytosine), only Ara-C showed a significant effect in decreasing active JCV replication and multiplication. In vitro data, using different cell types and virus strains have shown that specific drugs can indeed modulate viral infection. However, such modulation has not previously been demonstrated in those cells of the CNS which are specifically targeted by JCV. The SVG-JC cells represent a unique system with which further studies can be conducted on the effects of drugs on brain derived cells that are susceptible to viral infection. C1 NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. RP Major, EO (reprint author), NINDS, Lab Mol Med & Neurosci, NIH, Bldg 36,room W21,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 27 TC 65 Z9 67 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD AUG PY 1998 VL 4 IS 4 BP 451 EP 456 PG 6 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 109BL UT WOS:000075301300010 PM 9718138 ER PT J AU Sedelnikova, OA Panyutin, IG Thierry, AR Neuman, RD AF Sedelnikova, OA Panyutin, IG Thierry, AR Neuman, RD TI Radiotoxicity of iodine-125-labeled oligodeoxyribonucleotides in mammalian cells SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE iodine-125; oligodeoxyribonucleotides; radiotoxicity; triplex; liposomal delivery system; liposomes ID ANTISENSE OLIGONUCLEOTIDES; INTRACELLULAR-DISTRIBUTION; DNA; I-125; DECAY; I125; EXPRESSION; DOSIMETRY AB We investigated the distribution, stability and radiotoxicity of I-125- oligodeoxyribonucleotides (I-125-ODN) in human fibrosarcoma HT-1080 cells to study the radiotoxic effects of the Auger electron emitter I-125 delivered to the cells by ODN. Methods: We delivered I-125-ODN into the cells via complexing with a liposomal delivery system. To assess the intracellular distribution and stability of I-125-ODN delivered by the liposomal delivery system, we used autoradiography, fluorescent and confocal microscopy and electrophoresis. To study the radiotoxicity of the unbound I-125-ODN, we used a clonogenic assay. The radiotoxicity of I-125-ODN delivered by the liposomal delivery system was compared with that of freely diffusible I-125-antipyrine, membrane-excluded I-125-bovine serum albumin and DNA incorporated I-125-deoxyuridine (I-125-UdR). Results: Oligodeoxyribonucleotides accumulated in the cell nucleus within a few hours of incubation, On the basis of the number of decays at 37% survival, I-125-ODN are 2 times more radiotoxic than I-125-antipyrine, which is freely diffusible into cells, and 8 times more radiotoxic than I-125-bovine serum albumin, which remains outside cells. However, the radiotoxicity of unbound I-125-ODN is almost 3 orders of magnitude lower than that of DNA-incorporated I-125-UdR. The I-125-ODN are not significantly degraded by intracellular nucleases during the time of uptake incubation. Conclusion: The dramatic difference in radiotoxicity between I-125-ODN and 125I-UdR confirms that, despite the nuclear localization, I-125-ODN are not bound to or incorporated within the genomic DNA. Our data demonstrate that the radiotoxicity of Auger electron emitters is determined by the radiation dose delivered to nuclear DNA, not necessarily to the nucleus. Therefore, relatively high intracellular concentrations of unbound I-125-ODN can be achieved without causing significant cell death. C1 NIH, Dept Nucl Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Biovector Therapeut SA, Labege, France. RP Neuman, RD (reprint author), NIH, Dept Nucl Med, Warren G Magnuson Clin Ctr, Bldg 10,Rm 1C401,10 Ctr Dr,MSC 1180, Bethesda, MD 20892 USA. RI thierry, alain/F-9492-2014 NR 35 TC 41 Z9 46 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 AUG PY 1998 VL 39 IS 8 BP 1412 EP 1418 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 108FG UT WOS:000075254900025 PM 9708519 ER PT J AU Ishii, EK Talbott, EO AF Ishii, EK Talbott, EO TI Race/ethnicity differences in the prevalence of noise-induced hearing loss in a group of metal fabricating workers SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID PERMANENT THRESHOLD SHIFT; EYE COLOR; SUSCEPTIBILITY; RACE AB The National Institute of Occupational Safety and Health rates noise-induced hearing loss as one of the top 10 work-related problems, involving at least 11 million workers. This retrospective study examines the differences between pure-tone hearing loss and race/ethnicity in 216 white and 70 non-white male metal fabricating workers. Significant variables upon univariate analysis found to be associated with race/ ethnicity were mean years of employment and proportion of time worked without hearing protection. Among whites, the permanent threshold average for 1, 2, 3 and 4 kHz was 25.99 dB, compared with 17.71 dB in non-whites (P < 0.01), Backwards stepwise regression indicated that race/ethnicity, after being adjusted for years of employment, was the major-effect variable. The results of this study suggest that occupational noise exposure alone does not alone account for the racial hearing differences. C1 Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. Natl Inst Deafness & Commun Disorders, Epidemiol Stat & Data Syst Branch, Bethesda, MD USA. RP Talbott, EO (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, A544 Crabtree Hall,130 DeSoto St, Pittsburgh, PA 15261 USA. NR 25 TC 31 Z9 33 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 1076-2752 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD AUG PY 1998 VL 40 IS 8 BP 661 EP 666 DI 10.1097/00043764-199808000-00001 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 112CT UT WOS:000075477100001 PM 9729747 ER PT J AU Pearson, JL Reinhart, MA Strommen, EA Donelson, E Barnes, C Blank, L Cebollero, AM Cornwell, K Kamptner, NL AF Pearson, JL Reinhart, MA Strommen, EA Donelson, E Barnes, C Blank, L Cebollero, AM Cornwell, K Kamptner, NL TI Connected and separate selves: Development of an inventory and initial validation SO JOURNAL OF PERSONALITY ASSESSMENT LA English DT Article ID GENDER DIFFERENCES; SEX-ROLE; SELF; PERSONALITY; ADOLESCENCE; DEPENDENCY; ATTACHMENT; INDIVIDUALISM; PSYCHOTHERAPY; AUTOBIOGRAPHY AB We describe the development and validation of the Relationship Self Inventory (RSI), which assesses 2 general self-orientations, (a) the Separate Self(SS) and (b) the Connected Self (CS), as well as two manifestations of connection, (a) Primacy of Other Care and (b) Self and Other Care. The CS reflects the importance of interconnectedness with others and a "voice of caring," whereas the SS reflects autonomy, independence, and a "voice of justice." Adequate reliability was demonstrated for the RSI on samples consisting of 927 women and 218 men ranging in age from 26 to 78. Construct validity of the RSI was also explored in a subsample (n = 604) by comparing its scales with measures of personality, temperament, and psychological adjustment. Although mean scores of men and women differed minimally on the CS and SS scales, gender differences in patterns of correlation with validity measures suggested that the meanings of the scales differed for men and women. The RSI appears to be an adequate survey tool for assessing these self-orientations. C1 NIMH, Rockville, MD 20857 USA. Amer Board Emergency Med, E Lansing, MI USA. Michigan State Univ, Dept Psychol, E Lansing, MI 48824 USA. Harvard Univ, Sch Med, Childrens Hosp, Dept Psychiat, Cambridge, MA 02138 USA. Texas Educ Agcy, Dept Informat Syst, Austin, TX USA. Calif State Univ San Bernardino, Dept Psychol, San Bernardino, CA 92407 USA. RP Pearson, JL (reprint author), NIMH, Room 10-75,5600 Fishers Lane, Rockville, MD 20857 USA. NR 69 TC 4 Z9 4 U1 2 U2 2 PU LAWRENCE ERLBAUM ASSOC INC PI MAHWAH PA 10 INDUSTRIAL AVE, MAHWAH, NJ 07430-2262 USA SN 0022-3891 J9 J PERS ASSESS JI J. Pers. Assess. PD AUG PY 1998 VL 71 IS 1 BP 29 EP 48 DI 10.1207/s15327752jpa7101_3 PG 20 WC Psychology, Clinical; Psychology, Social SC Psychology GA 132KQ UT WOS:000076629300003 PM 9807229 ER PT J AU Pascual, JMS McKenzie, A Yankaskas, JR Falck, JR Zeldin, DC AF Pascual, JMS McKenzie, A Yankaskas, JR Falck, JR Zeldin, DC TI Epoxygenase metabolites of arachidonic acid affect electrophysiologic properties of rat tracheal epithelial cells SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID GLOMERULAR MESANGIAL CELLS; EPOXYEICOSATRIENOIC ACIDS; ION-TRANSPORT; CYTOCHROME-P-450 MONOOXYGENASE; CYSTIC-FIBROSIS; RABBIT LUNG; CHLORIDE SECRETION; SMOOTH-MUSCLE; CLARA CELLS; EXPRESSION AB Epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids, products of the cytochrome P450 arachidonic acid epoxygenase pathway, have been shown to affect electrolyte transport in the kidney; however, the effects of these compounds on airway epithelial ion transport have not been investigated. Intact rat tracheas and primary cultures of rat tracheal epithelial cells were mounted in Ussing chambers to monitor changes in transepithelial voltage (Vt), short circuit current (Isc) and electrical resistance (Rt), with or without the addition of increasing concentrations (10(-9)-10(-6) M) of arachidonic acid, each of the four regioisomeric EETs and each of the corresponding dihydroxyeicosatrienoic acids. In intact tracheas, 11,12-EET caused dose-dependent decreases in Vt and Isc (Delta Vt = 0.4 +/- 0.1 mV, Delta Isc = -16.9 +/- 5.4 mu A/cm(2) at 10(-6) M, P < .05 vs. vehicle), whereas changes in Rt were not significantly different than vehicle alone. 11,12-dihydroxyeicosatrienoic acid caused less impressive decreases in Vt and Isc, although arachidonic acid and the other compounds tested were without significant effects. 11,12-EET induced similar changes in cultured tracheal epithelial cell electrical parameters at concentrations as low as 10(-9) M. The effects of 11,12-EET were highly stereoselective, with activity limited to 11(R),12(S)-EET, the least abundant rat lung enantiomer. Pretreatment with amiloride or mucosal exposure to sodium free media did not significantly alter the 11,12-EET-induced changes in Vt. In contrast, pretreatment with bumetanide abolished the 11,12-EET electrophysiologic effects, suggesting that these effects may be mediated through inhibition of a chloride conductive pathway. We conclude that arachidonic acid epoxygenase metabolites cause significant changes in rat airway electrical parameters and may be involved in the control of lung fluid and electrolyte transport. C1 NIEHS, Pulm Pathobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Div Pulm & Crit Care Med, Durham, NC USA. Univ N Carolina, Div Pulm Dis, Chapel Hill, NC 27515 USA. Univ Texas, SW Med Ctr, Dept Mol Genet, Dallas, TX 75235 USA. RP NIEHS, Pulm Pathobiol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. OI Falck, John/0000-0002-9219-7845 FU NIDDK NIH HHS [DK46004]; NIEHS NIH HHS [N01-ES-35357]; NIGMS NIH HHS [GM31278] NR 59 TC 22 Z9 23 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD AUG PY 1998 VL 286 IS 2 BP 772 EP 779 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 110BP UT WOS:000075359600027 PM 9694933 ER PT J AU Nowak, JE Gomez-Flores, R Calderon, SN Rice, KC Weber, RJ AF Nowak, JE Gomez-Flores, R Calderon, SN Rice, KC Weber, RJ TI Rat natural killer cell, T cell and macrophage functions after intracerebroventricular injection of SNC 80 SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID DELTA-OPIOID RECEPTOR; MORPHINE-MEDIATED SUPPRESSION; MURINE PERITONEAL-MACROPHAGES; INDUCED IMMUNOSUPPRESSION; PHAGOCYTIC FUNCTIONS; PERIAQUEDUCTAL GRAY; NERVOUS-SYSTEM; IMMUNE STATUS; NITRIC-OXIDE; AGONIST AB We investigated the effects of (+)-4-[(alpha R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC 80), a nonpeptidic delta-opioid receptor-selective agonist, on rat leukocyte functions. Intracerebroventricular injection of SNC 80 (20 nmol) in Fischer 344N male rats did not affect splenic natural killer cell activity compared with intracerebroventricular saline-injected controls. SNC 80 also had no effect on concanavalin A-, anti-T cell receptor-, interleukin-2- and anti-T cell receptor + interleukin-2-induced splenic and thymic lymphocyte proliferation in most experiments. In some experiments, however, SNG 80 significantly (P < .01) caused a 41 to 93% increase of concanavalin A-, anti-T cell receptor-, interleukin-2- and anti-T cell receptor + interleukin-2-induced splenic lymphocyte proliferation compared to controls. Additionally, SNC 80 did not significantly affect splenic T cell or natural killer cell populations as measured by the expression of T cell receptor(alpha beta), and T helper (CD4), T suppressor/cytotoxic (CD8) and natural killer cell surface markers. Finally, SNC 80 did not affect interferon-gamma- or lipopolysaccharide (LPS)-induced splenic nitric oxide, and LPS-induced tumor necrosis factor-alpha production by splenic macrophages. These results suggest that SNC 80 could be useful in the treatment of pain without suppressing immune function. However, the potential immunoenhancing properties of SNC 80 may be also valuable in immunocompromised individuals. C1 Univ Illinois, Coll Med, Dept Biomed & Therapeut Sci, Sect Med Sci, Peoria, IL 61656 USA. NIDDK, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RP Weber, RJ (reprint author), Univ Illinois, Coll Med, Dept Biomed & Therapeut Sci, Sect Med Sci, Box 1649, Peoria, IL 61656 USA. FU NIDA NIH HHS [DA/AI08988] NR 38 TC 16 Z9 16 U1 0 U2 0 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 AUG PY 1998 VL 286 IS 2 BP 931 EP 937 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 110BP UT WOS:000075359600046 PM 9694952 ER PT J AU Zhou, L Zhang, Q Stein, C Schafer, M AF Zhou, L Zhang, Q Stein, C Schafer, M TI Contribution of opioid receptors on primary afferent versus sympathetic neurons to peripheral opioid analgesia SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID NEONATAL CAPSAICIN TREATMENT; DORSAL-ROOT GANGLIA; RABBIT EAR ARTERY; RAT SPINAL-CORD; OPIATE RECEPTOR; NOCICEPTIVE NEURONS; GENE-EXPRESSION; C-FIBERS; INFLAMMATION; HYPERALGESIA AB Opioid receptors are synthesized in dorsal root ganglia and transported into peripheral terminals of primary afferent neurons. Activation of such receptors results in antinociceptive effects that are most prominent in inflammation. In addition, opioid receptors located on sympathetic postganglionic neuron terminals may be involved in these effects. This study investigates the peripheral analgesic efficacy of the mu, delta and kappa receptor agonists [D-Ala(2),N-Me-Phe(4),GIy-ol(5)]-enkephalin, [D-Pen(2,5)]-enkephalin and trans-(+/-)3,4-Dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide, the effective number of peripheral mu, delta and kappa receptors in relation to the development of inflammation and the contribution of sympathetic vs, sensory neurons by use of capsaicin and 6-hydroxydopamine, respectively. In Wistar rats with Freund's adjuvant-induced hindpaw inflammation, antinociceptive effects of intraplantar [D-Ala(2),N-Me-Phe(4),GIy-ol(5)]-enkephalin (1.0-32 mu g), [D-Pen(2,5)]-enkephalin (10-100 mu g) and trans-(+/-)3,4-Dichloro-N-methyl-N-[2-(1-pyrrolidiny)-cyclo-hexyl]-benzeneacetamide (10-100 mu g) were evaluated by paw pressure test. These effects increased linearly between 6 and 24 hr, but did not change between 24 and 96 hr of inflammation, whereas the doses of the irreversible antagonists beta-funaltrexamine, [D-Ala(2),Leu(5),Cys(6)]enkephalin or (+/-)-(5 beta,7a,8 beta)-3,4-dichloro-N-[3-methylene-2-oxo-8-(1-pyrrolidinyl)-1-oxaspir[4,5]dec-7-yl] benzeneacetamide required to abolish the respective agonist effects increased between 12 and 96 hr. Pretreatment with capsaicin (30, 50, 70 mg/kg s.c. over 3 days) but not with 6-hydroxydopamine (75 mg/kg i.p. over 3 days) reversed the hyperalgesia in inflamed paws and almost abolished antinociceptive effects of all three agonists. These results suggest that the increased opioid agonist efficacy is due to an increased number of peripheral opioid receptors at later stages of inflammation and that peripheral opioid antinociceptive effects are primarily mediated by mu, delta and kappa opioid receptors on primary afferent neurons. C1 NIDA, Behav Pharmacol & Genet Sect, Intramural Res Program, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. RP Schafer, M (reprint author), Free Univ Berlin, Hosp Benjamin Franklin, Dept Anesthesiol & Crit Care Med, Hindenburgdamm 30, D-12200 Berlin, Germany. OI Stein, Christoph/0000-0001-5240-6836 NR 53 TC 81 Z9 82 U1 0 U2 0 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 AUG PY 1998 VL 286 IS 2 BP 1000 EP 1006 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 110BP UT WOS:000075359600055 PM 9694961 ER PT J AU Xie, WW Solomons, KRH Freeman, S Kaetzel, MA Bruzik, KS Nelson, DJ Shears, SB AF Xie, WW Solomons, KRH Freeman, S Kaetzel, MA Bruzik, KS Nelson, DJ Shears, SB TI Regulation of Ca2+-dependent Cl- conductance in a human colonic epithelial cell line (T-84): Cross-talk between Ins(3,4,5,6)P-4 and protein phosphatases SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID CHLORIDE CONDUCTANCE; MICROCYSTIN-LR; OKADAIC ACID; ACINAR-CELLS; T84 CELLS; SECRETION; KINASE; CHANNELS; ACTIVATION; INHIBITOR AB 1. We have studied the regulation of whole-cell chloride current in T-84 colonic epithelial cells by inositol 3,4,5,6-tetrakisphosphate (Ins(3,4,5,6)P-4). New information was obtained using (a) microcystin and okadaic acid to inhibit serine/threonine protein phosphatases, and (b) a novel functional tetrakisphosphate analogue, 1,2-bisdeoxy-1,2-bisfluoro-Ins(3,4,5,6)P-4 (i.e. F-2-Ins(3,4,5,6)P-4). 2. Calmodulin-dependent protein kinase II (CaMKII) increased chloride current 20-fold. This current (I-Cl,I-CaMK) continued for 7 +/- 1.2 min before its deactivation, or running down, by approximately 60%. This run-down was prevented by okadaic acid, whereupon I-Cl,I-CaMK remained near its maximum value for greater than or equal to 14.3 +/- 0.6 min. 3. F-2-Ins(3,4,5,6)P-4 inhibited I-Cl,I-CaMK (IC50 = 100 mu M) stereo-specifically since its enantiomer, F-2-Ins(1,4,5,6)P-4 had no effect at less than or equal to 500 mu M. Dose-response data (Hill coefficient = 1.3) showed that F-2-Ins(3,4,5,6)P-4 imitated only the non-co-operative phase of inhibition by Ins(3,4,5,6)P-4, and not the co-operative phase. 4. Ins(3,4,5,6)P, was prevented from blocking I-Cl,I-CaMK by okadaic acid (IC50 = 1.5 nM) and microcystin (IC50 = 0.15 nM); these data lead to the novel conclusion that, in situ, protein phosphatase activity is essential for Ins(3,4,5,6)P, to function. The IC,, values indicate that more than one species of phosphatase was required. One of these may be PP1, since F-2- Ins(3,4,5,6)P-4-dependent current blocking was inhibited by okadaic acid and microcystin with IC50 values of 70 nM and 0.15 nM, respectively. C1 Univ Chicago, Dept Neurol, Chicago, IL 60637 USA. Univ Manchester, Sch Pharm & Pharmaceut Sci, Manchester M13 9PL, Lancs, England. Univ Cincinnati, Coll Med, Dept Mol & Cellular Physiol, Cincinnati, OH 45267 USA. Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, Chicago, IL 60612 USA. NIEHS, Inositide Signaling Sect, Lab Signal Transduct, NIH, Res Triangle Pk, NC USA. RP Shears, SB (reprint author), Univ Chicago, Dept Neurol, 5841 S Maryland Ave,MC2030, Chicago, IL 60637 USA. EM shears@niehs.nih.gov RI Freeman, Sally/G-1141-2015 OI Freeman, Sally/0000-0002-3831-9151 FU NIGMS NIH HHS [R01 GM036823, R01 GM36823, R01 GM54266] NR 38 TC 44 Z9 44 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 AUG 1 PY 1998 VL 510 IS 3 BP 661 EP 673 DI 10.1111/j.1469-7793.1998.661bj.x PG 13 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 111PW UT WOS:000075447700001 PM 9660883 ER PT J AU Liu, QY Schaffner, AE Barker, JL AF Liu, QY Schaffner, AE Barker, JL TI Kainate induces an intracellular Na+-activated K+ current in cultured embryonic rat hippocampal neurones SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID EXCITATORY AMINO-ACIDS; POTASSIUM CURRENT; GLUTAMATE TRANSPORTERS; LARGE-CONDUCTANCE; SENSORY NEURONS; NERVOUS-SYSTEM; CARDIAC-CELLS; ION CHANNELS; SODIUM; RECEPTORS AB 1. In embryonic rat hippocampal neurones cultured for <3 days, kainate induced an inward current at negative potentials that recovered to baseline levels immediately upon termination of agonist application. However, in neurones cultured for longer, the kainate-induced current was often followed by a long-lasting inward current that slowly recovered to baseline levels. The amplitude of the delayed current (I-delay) triggered by kainate was positively related both to the duration of application at constant agonist concentration and to concentration at constant application duration. 2. I-delay could last for several minutes and was accompanied by a conductance increase, which closely paralleled current amplitude. Depression of the kainate-induced current response at receptor level with CNQX or at ionic level with Na+-free solution had any effect on I-delay. Li+ effected the same response as Na+ in mediating kainate-induced I-delay. 3. GABA-activated Cl- current, which was associated with the same amount of inwardly directed charge flow at the same potential as that induced by kainate, did not trigger a longlasting delayed current. 4. I-delay depended on the existence of extracellular K+ and its amplitude increased with the increase in K+ concentration. Neither applying Cl-- or Ca2+-free solutions nor increasing intracellular Ca2+ buffering speed and capacity altered I-delay. Exposure to the specific K-Ca channel blockers apamin and charybdotoxin also failed to alter I-delay. However, I-delay could be blocked by Cs+, Ba2+ and high concentrations of 4-aminopyridine (4-AP) and TEA. 5. Inside-out excised patch-clamp recordings revealed that low density or highly clustered Na+- activated K+ channels were expressed in the cell bodies of cultured embryonic rat hippocampal neurones. These could be the elementary channels underlying I-delay. C1 NINCDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Liu, QY (reprint author), NINCDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. NR 48 TC 13 Z9 13 U1 1 U2 2 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 AUG 1 PY 1998 VL 510 IS 3 BP 721 EP 734 DI 10.1111/j.1469-7793.1998.721bj.x PG 14 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 111PW UT WOS:000075447700006 PM 9660888 ER PT J AU Anderson, CW Appella, E Sakaguchi, K AF Anderson, CW Appella, E Sakaguchi, K TI Posttranslational modifications involved in the DNA damage response. SO JOURNAL OF PROTEIN CHEMISTRY LA English DT Article; Proceedings Paper CT 12th International Conference on Methods in Protein Structure Analysis CY SEP 05-10, 1998 CL HALKIDIKI, GREECE C1 Brookhaven Natl Lab, Dept Biol, Upton, NY 11973 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Anderson, CW (reprint author), Brookhaven Natl Lab, Dept Biol, Upton, NY 11973 USA. NR 2 TC 8 Z9 8 U1 0 U2 1 PU PLENUM PUBL CORP PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0277-8033 J9 J PROTEIN CHEM JI J. Protein Chem. PD AUG PY 1998 VL 17 IS 6 BP 527 EP 527 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 112LQ UT WOS:000075496500021 PM 9723732 ER PT J AU Appella, E Nagaich, AK Zhurkin, VB Harrington, RE AF Appella, E Nagaich, AK Zhurkin, VB Harrington, RE TI Analysis of the interaction between the p53 binding domain and the p21/CIP1 DNA response element: A novel architectural organization. SO JOURNAL OF PROTEIN CHEMISTRY LA English DT Article; Proceedings Paper CT 12th International Conference on Methods in Protein Structure Analysis CY SEP 05-10, 1998 CL HALKIDIKI, GREECE ID PEPTIDES; COMPLEX; BEND C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Nevada, Dept Biochem, Reno, NV 89557 USA. Arizona State Univ, Lab Expt & Computat Biol, Tempe, AZ 85287 USA. RP Appella, E (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. NR 5 TC 4 Z9 4 U1 0 U2 0 PU PLENUM PUBL CORP PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0277-8033 J9 J PROTEIN CHEM JI J. Protein Chem. PD AUG PY 1998 VL 17 IS 6 BP 527 EP 528 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 112LQ UT WOS:000075496500022 PM 9723733 ER PT J AU Chi-Fishman, G Stone, M McCall, GN AF Chi-Fishman, G Stone, M McCall, GN TI Lingual action in normal sequential swallowing SO JOURNAL OF SPEECH LANGUAGE AND HEARING RESEARCH LA English DT Article DE sequential swallowing; tongue; swallowing physiology; electropalatography; ultrasound ID SPEECH MOVEMENTS; JAW MOVEMENTS; HUMAN ARM; MUSCLES; VELOCITY; COORDINATION; ULTRASOUND; DISORDERS; TRANSIT; HEAD AB Current knowledge about the flexibility in lingual motor control and performance during swallowing is incomplete. The present study aimed at gaining a better understanding of the tongue's motor flexibility and at identifying variable versus invariant lingual motor program parameters in light of changing swallowing task demands (discrete vs. sequential). Specifically, the timing and patterns of tongue-palate contact and the associated changes in tongue shape and action were examined in 5 normal adults using simultaneous electropalatography and ultrasound. Tasks for discrete swallowing included 5 and 30 cc of water; tasks for sequential swallowing involved drinking 200 cc of water at normal and fast rates. Results showed little variation in propulsive contact pattern as a function of task or subject. However, the tongue demonstrated shorter movement duration and overlapping gestures during sequential swallowing. Thus, continuous drinking was performed without changes in motor strategies per se but with changes in the timing coordination of the "drink" and "swallow" action sequences. These Findings support the theory that the deglutitive lingual motor program has both invariant and variant parameters, and that movement pattern and action sequence reflect fixed elements within the structure of the motor program, but movement timing can be modified according to the demands of the task at hand. C1 NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Elect & Comp Engn, Vocal Tract Visualizat Lab, Baltimore, MD 21218 USA. Johns Hopkins Univ, Dept Surg, Vocal Tract Visualizat Lab, Div Otolaryngol,Dept Surg, Baltimore, MD 21218 USA. Univ Maryland, Dept Speech & Hearing Sci, College Pk, MD 20742 USA. RP Chi-Fishman, G (reprint author), NIH, Room 6S235,Bldg 10,CC-RMD-SLP, Bethesda, MD 20892 USA. NR 48 TC 32 Z9 34 U1 0 U2 0 PU AMER SPEECH-LANGUAGE-HEARING ASSOC PI ROCKVILLE PA 10801 ROCKVILLE PIKE, ROCKVILLE, MD 20852-3279 USA SN 1092-4388 J9 J SPEECH LANG HEAR R JI J. Speech Lang. Hear. Res. PD AUG PY 1998 VL 41 IS 4 BP 771 EP 785 PG 15 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA 105WZ UT WOS:000075099500005 PM 9712125 ER PT J AU Jackson, DA Collier, CD Oshima, H Simons, SS AF Jackson, DA Collier, CD Oshima, H Simons, SS TI Modulation of TAT gene induction by glucocorticoids involves a neutralizing sequence SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article ID TYROSINE AMINOTRANSFERASE GENE; STEROID-HORMONE RECEPTORS; HUMAN ESTROGEN-RECEPTOR; MOUSE ALBUMIN ENHANCER; RAT HEPATOMA-CELLS; TRANSCRIPTIONAL ACTIVATION; RESPONSIVE ELEMENTS; NEGATIVE REGULATION; PROMOTER CONTEXT; AGONIST ACTIVITY AB Recent studies have indicated that two elements in addition to the glucocorticoid response element (GRE) are involved in the induction of the endogenous TAT gene in Fu5-5 rat hepatoma cells. The first is the 21 bp glucocorticoid modulatory element (GME) at -3648 bp, which causes reporter constructs to display both a left shift in the dose-response curve for glucocorticoids and increased percentages of agonist activity for antiglucocorticoids. The second is a negative element at -3340 to -3050 that blocks the action of the GME. This last observation raised the question of how GME activity can be expressed in Fu5-5 cells in the intact TAT gene that contains both the GME and the negative element. The present study identifies a third element, a "neutralizing" sequence, that restores the activity of the GME even when otherwise inactivated by the negative element. This neutralizing sequence was located within the region surrounding the GREs of the TAT gene but is separate from the GREs. The activity of the individual GME and negative elements was found to depend upon spacing. However, in combination with the natural GRE, the native TAT gene spacing of the GME and negative elements was able to reproduce the activity of the intact gene. Thus, a total of three additional elements (an activator, a negative element, and a neutralizer) appear to cooperate with the GREs in glucocorticoid induction of the TAT gene in Fu5-5 cells. While such a grouping of elements may be novel among steroid regulated genes, it is a not uncommon occurrence for the transcriptional control of other genes. (C) 1998 Elsevier Science Ltd. All rights reserved. RP Simons, SS (reprint author), NIDDK, Steroid Hormones Sect, LMCB, NIH, Bethesda, MD USA. RI Jackson, David/E-9984-2014 NR 49 TC 16 Z9 15 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 AUG PY 1998 VL 66 IS 3 BP 79 EP 91 DI 10.1016/S0960-0760(98)00048-X PG 13 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 108NE UT WOS:000075271700001 PM 9719442 ER PT J AU Jensen, PS Mrazek, D Knapp, PK Steinberg, L Pfeffer, C Schowalter, J Shapiro, T AF Jensen, PS Mrazek, D Knapp, PK Steinberg, L Pfeffer, C Schowalter, J Shapiro, T TI ADHD as a disorder of adaptation - Dr. Jensen et al. reply SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Letter C1 NIMH, Rockville, MD 20857 USA. George Washington Univ, Sch Med, Washington, DC USA. Univ Calif Davis, Dept Psychiat, Davis, CA USA. Temple Univ, Dept Psychol, Philadelphia, PA 19122 USA. Cornell Univ, Coll Med, New York, NY USA. Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT USA. RP Jensen, PS (reprint author), NIMH, Rockville, MD 20857 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD AUG PY 1998 VL 37 IS 8 BP 798 EP 799 DI 10.1097/00004583-199808000-00003 PG 2 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 103ZY UT WOS:000074988800003 ER PT J AU Jakob, T AF Jakob, T TI Regulation of E-cadherin function in skin-derived dendritic cells by proinflammatory epidermal cytokines: Implications for the mobilization of Langerhans cells in vivo SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; INTERLEUKIN-1 C1 NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Jakob, T (reprint author), NCI, Dermatol Branch, NIH, Bldg 10,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Jakob, Thilo/J-1621-2012 NR 8 TC 1 Z9 1 U1 0 U2 0 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 AUG PY 1998 VL 39 IS 2 BP 274 EP 275 PN 1 PG 2 WC Dermatology SC Dermatology GA 106ZV UT WOS:000075182100024 PM 9704845 ER PT J AU DiGiovanna, JJ AF DiGiovanna, JJ TI Retinoid chemoprevention in the high-risk patient SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article; Proceedings Paper CT Conference on the Evolving Role of Retinoids in the Management of Cutaneous Conditions CY MAY 02-04, 1997 CL NEW YORK, NEW YORK SP Cleveland Clin Fdn ID BASAL-CELL CARCINOMA; RENAL-TRANSPLANT RECIPIENTS; NONMELANOMA SKIN-CANCER; XERODERMA-PIGMENTOSUM; ORAL ISOTRETINOIN; PREVENTION; THERAPY; ETRETINATE C1 Rhode Isl Hosp, Dept Dermatol, Providence, RI 02903 USA. Brown Univ, Sch Med, Dept Dermatol, Div Dermatopharmacol, Providence, RI 02912 USA. NIAMSD, Skin Biol Lab, Providence, RI USA. RP DiGiovanna, JJ (reprint author), Rhode Isl Hosp, Dept Dermatol, 593 Eddy St, Providence, RI 02903 USA. NR 24 TC 31 Z9 31 U1 0 U2 0 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 AUG PY 1998 VL 39 IS 2 SU S BP S82 EP S85 DI 10.1016/S0190-9622(98)70451-7 PN 3 PG 4 WC Dermatology SC Dermatology GA 107NL UT WOS:000075215300016 PM 9703130 ER PT J AU Slavkin, HC AF Slavkin, HC TI Toward molecularly based diagnostics for the oral cavity SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article C1 NIDR, Bethesda, MD 20892 USA. RP Slavkin, HC (reprint author), NIDR, 31 Ctr Dr,MSC 2290,Bldg 31,Room 2C39, Bethesda, MD 20892 USA. NR 6 TC 25 Z9 26 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 AUG PY 1998 VL 129 IS 8 BP 1138 EP 1143 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 108JG UT WOS:000075262300018 PM 9715016 ER PT J AU Schaffer, DM Velie, EM Shaw, GM Todoroff, KP AF Schaffer, DM Velie, EM Shaw, GM Todoroff, KP TI Energy and nutrient intakes and health practices of Latinas and white non-Latinas in the 3 months before pregnancy SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRE; DIET HISTORY QUESTIONNAIRE; LIMITATIONS; VALIDATION; RECORDS; FOLATE AB Objective To describe the heath practices and energy and nutrient intakes from diet and supplements of foreign- and US-born Latinas and white non-Latinas in the 3 months before pregnancy. Design A descriptive study in which data were obtained retrospectively; from 2 questionnaires: an inteniewer-administered questionnaire on the subject's medical, reproductive, family, occupational, and lifestyle history and a subject-administered (and interviewer-assisted) 100-item food frequency questionnaire. Subjects/setting A population-based sample of California women (n=462) who gave birth between 1989 and 1991 to single, live-born infants. One third of women were Latinas, of whom 58.1% were foreign barn. Statistical analyses Means, standard deviations, and percentiles were computed for energy and nutrient intakes of the total population and for white non-Latinas: US-born Latinas; and foreign-born Latinas. One-way analysis of Valiance was used to compare group means. Results Mean and median energy intake in all ethnic groups exceeded 2,000 kcal/day, although less than half of the population consumed 5 servings of fruit and vegetables per day. Fur iron, half of the women were below the Recommended Dietary Allowance. In contrast to the dietary intake of white non-Latinas and US-born Latinas, foreign-born Latinas had the lowest contribution of fat to total energy intake and the highest dietary intake of carbohydrate, cholesterol, fiber, grain products, protein foods, folate, vitamin C, ir on, and zinc. Conclusions A woman's ethnicity, as well as as whether her place of birth was within or outside of the United States, may be predictors of her dietary and health practices before pregnancy. Vitamin, mineral, and food supplementation and consumption of cold breakfast cereal may be avenues for improving perinatal micronutrient intake. C1 Calif Birth Defects Monitoring Program, March Dimes Birth Defects Fdn, Emeryville, CA 94608 USA. Kaiser Permanente Med Care Program, Div Res, Oakland, CA 94611 USA. NCI, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. RP Shaw, GM (reprint author), Calif Birth Defects Monitoring Program, March Dimes Birth Defects Fdn, 1900 Powell St,Suite 1050, Emeryville, CA 94608 USA. NR 28 TC 25 Z9 26 U1 1 U2 1 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD AUG PY 1998 VL 98 IS 8 BP 876 EP 884 DI 10.1016/S0002-8223(98)00202-8 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 107NQ UT WOS:000075215700018 PM 9710657 ER PT J AU Konig, S Fales, HM AF Konig, S Fales, HM TI Formation and decomposition of water clusters as observed in a triple quadrupole mass spectrometer SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Article ID FREE JET EXPANSION; HYDRATED PROTONS; ELECTROSPRAY; IONIZATION; IONS AB Water clustering up to mass 4000 has been observed using the Finnigan TSQ-700 electrospray mass spectrometer operating in either the normal or discharge modes with the capillary just above room temperature. The mechanism of cluster formation and structure has been studied by changing instrumental parameters including capillary temperature, auxiliary gas flow, and tube lens (skimmer) voltage. As expected, and in agreement with earlier work, enhanced abundances were observed at clusters of n = 21 and 28 molecules of water. Abundances of these same clusters are enhanced after fragmentation of higher mass clusters by MS/MS. Existing models Including the clathrate structure are examined and it is suggested that with the exception of Me structures at n = 21 and 28, the clusters are based on ice I-c. Also in agreement with previous work, water clusters were found to contain both protons and ammonium ions and the presence of the latter was proved by accurate mass measurement. In one case, these ions also attached to decomposition products formed by the discharge from traces of residual polyethylene glycol. (C) 1998 American Society for Mass Spectrometry. C1 NHLBI, NIH, LBC, Bethesda, MD 20892 USA. RP Fales, HM (reprint author), NHLBI, NIH, LBC, Bldg 10,Rm 7N318,10 Ctr Dr,MSC 1676, Bethesda, MD 20892 USA. RI Konig, Simone/B-6504-2008 OI Konig, Simone/0000-0003-0672-7246 NR 24 TC 31 Z9 31 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1044-0305 J9 J AM SOC MASS SPECTR JI J. Am. Soc. Mass Spectrom. PD AUG PY 1998 VL 9 IS 8 BP 814 EP 822 DI 10.1016/S1044-0305(98)00044-0 PG 9 WC Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Chemistry; Spectroscopy GA 104VC UT WOS:000075035700008 ER PT J AU Ding, JM Barlow, T Dipple, A Vouros, P AF Ding, JM Barlow, T Dipple, A Vouros, P TI Separation and identification of positively charged and neutral nucleoside adducts by capillary electrochromatography microelectrospray mass spectrometry SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Article ID PROTEIN IDENTIFICATION; LIQUID-CHROMATOGRAPHY; ELECTROSPRAY; COLUMNS; PHASE; ELECTROPHORESIS; PERFORMANCE; PEPTIDES AB Capillary electrochromatography (CEC) is shown to be capable of separating mixtures containing both positively charged and neutral styrene oxide-adenosine adducts. In a study of the mechanism of deamination of positively charged 1-(2-hydroxy-1-phenylethyl) adenosine using O-18-labeled water, possible contamination of the chromatographically purified deamination product, 1-(2-hydroxy-1-phenylethyl:) inosine, with the positively charged 1-(2-hydroxy-1-phenylethyl) adenosine was observed. Because the deamination product and the presumed contamination have the same molecular weights and similar structures, CEC-microelectrospray mass spectrometry (CEC-mu ESI/MS) was used to confirm the presence and identity of the suspected impurity. A trace amount of the positively charged 1-(2-hydroxy-1-phenylethyl) adenosine, which could not be observed by either HPLC-UV or CEC-UV, was detected by CEC-mu ESI/MS. This discriminatory ability of CEC-mu ESI/MS is attributed to the fact that positive ion mode ESI-MS is a more sensitive detector for a positively charged compound than a UV detector, and that the combination of electroosmotic and electrophoretic flows and hydrophobic interactions with the stationary phase contributes to the separation of the positively charged compound. As a result, the positively charged compound was observed to elute much earlier and with much sharper peaks than the neutral compounds for which electroosmotic flow is the only "pumping" force for the solvent. (C) 1998 American Society for Mass Spectrometry. C1 Northeastern Univ, Dept Chem, Boston, MA 02115 USA. Northeastern Univ, Barnett Inst, Boston, MA 02115 USA. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Chem Carcinogenesis Lab, Frederick, MD USA. RP Vouros, P (reprint author), Northeastern Univ, Dept Chem, Boston, MA 02115 USA. FU NCI NIH HHS [1RO1CA 69390-02] NR 29 TC 33 Z9 33 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1044-0305 J9 J AM SOC MASS SPECTR JI J. Am. Soc. Mass Spectrom. PD AUG PY 1998 VL 9 IS 8 BP 823 EP 829 DI 10.1016/S1044-0305(98)00041-5 PG 7 WC Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Chemistry; Spectroscopy GA 104VC UT WOS:000075035700009 PM 9692254 ER PT J AU Bird, JE Durham, SK Giancarli, MR Gitlitz, PH Pandya, DG Dambach, DM Mozes, MM Kopp, JB AF Bird, JE Durham, SK Giancarli, MR Gitlitz, PH Pandya, DG Dambach, DM Mozes, MM Kopp, JB TI Captopril prevents nephropathy in HIV-transgenic mice SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID GROWTH-FACTOR-BETA; CONVERTING ENZYME-INHIBITION; SMOOTH-MUSCLE CELLS; GLOMERULAR INJURY; RAT; KIDNEY; GLOMERULOSCLEROSIS; EXPRESSION AB Transgenic mice (T26) bearing the envelope, regulatory, and accessory genes of HIV-1 develop renal disease resembling human HIV-associated nephropathy (HIVAN). Effects of vehicle (VEH) and the angiotensin-converting enzyme inhibitor captopril (CAP) were examined in wild-type (WT:) or T26 mice treated from 7 to 100 d of age. Mortality was lower in CAP T26 mice (30 mg/kg: 8%, 100 mg/kg: 12%) than VEH T26 mice (52%). The urinary protein/creatinine ratio was increased in VEH T26 mice (19.5 +/- 7.60) versus WT mice (6.1 +/- 0,83), but not in low-dose (7.3 +/- 0.94) or high-dose (8.2 +/- 1.02) CAP T26 mice. Blood urea nitrogen was higher in VEH T26 mice (52 +/- 16.2 mg/dl) than VEH WT mice (24 +/- 0.8), Blood urea nitrogen was also elevated in CAP WT (high dose: 43 +/- 2.1 mg/dl) and T26 mice (high dose: 42 +/- 2.4 mg/dl). Glomerular injury was higher in VEH T26 mice (6.8 +/- 0.58) than VEH WT mice (0.2 +/- 0.08) or CAP T26 mice (low dose: 1.1 +/- 0.17; high dose: 0.7 +/- 0.13). Tubulointerstitial injury was also greater in VEH T26 mice (1.1 +/- 0.10) than VEH WT mice (0.2 +/- 0.08) or CAP T26 mice (low dose: 0.4 +/- 0.10; high dose: 0.3 +/- 0.10). These data validate recent nonrandomized studies of captopril in HIV-infected patients, and suggest that an angiotensin-converting enzyme substrate is an important mediator in HIVAN. A randomized placebo-controlled trial of captopril in HIVAN may be warranted. C1 Bristol Myers Squibb, Div Cardiovasc Drug Discovery, Princeton, NJ 08543 USA. Bristol Myers Squibb, Dept Expt Pathol, Princeton, NJ 08543 USA. Bristol Myers Squibb, Dept Toxicol, Princeton, NJ 08543 USA. NIDDKD, Kidney Dis Sect, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Bird, JE (reprint author), Bristol Myers Squibb, Div Cardiovasc Drug Discovery, POB 4000, Princeton, NJ 08543 USA. RI Mozes, Miklos/E-9003-2011; OI Kopp, Jeffrey/0000-0001-9052-186X NR 20 TC 33 Z9 33 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD AUG PY 1998 VL 9 IS 8 BP 1441 EP 1447 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 103RD UT WOS:000074970900011 PM 9697666 ER PT J AU Wiest, PW Hartshorne, MF Inskip, PD Crooks, LA Vela, BS Telepak, RJ Williamson, MR Blumhardt, R Bauman, JM Tekkel, M AF Wiest, PW Hartshorne, MF Inskip, PD Crooks, LA Vela, BS Telepak, RJ Williamson, MR Blumhardt, R Bauman, JM Tekkel, M TI Thyroid palpation versus high-resolution thyroid ultrasonography in the detection of nodules SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE thyroid, nodules; nodules, thyroid; high-resolution ultrasonography; physical examination; palpation ID RADIATION; ULTRASOUND; GLAND; CHILDHOOD; FALLOUT; DISEASE; IRRADIATION; POPULATION; NEOPLASIA; CHILDREN AB Detection of thyroid nodules by physical examination and high-resolution ultrasonography was compared using small groups of blinded, experienced physician examiners working with a sample of 2441 persons from Estonia, most of whom were Chernobyl nuclear reactor clean-up workers. A random subsample of 113 (5%) persons was subjected to triple control examinations With both physical examination and high-resolution ultrasonography. Positive high resolution ultrasonographic findings were consider ably more reproducible among different observers than were positive physical examination findings. Agreement between methods was poor. Nodules were found in 169 (6.9%) subjects by physical examination and in 249 (10.2%) subjects by high-resolution ultrasonography. Physical examination found only 53 (21%) of the 249 nodules found by high-resolution ultrasonography. High-resolution ultrasonography did not confirm the existence of 115 (68%) of the 169 nodules found by physical examination. Only 6.6.4% of nodules less than 0.5 cm in diameter, as based on high-resolution ultrasonographic results, were detected by physical examination. Physical examination detection improved with increasing nodule size but was still only 48.2% for nodules larger than 2 cm. Physical examination was relatively effective in detecting nodules in the isthmus of the thyroid gland but much less so for nodules in the upper pole of the gland. Clinical evaluation and epidemiologic studies of nodular thyroid disease stand to benefit from the greater sensitivity and specificity of ultrasonographic examinations. C1 Univ New Mexico, Sch Med, Vet Affairs Med Ctr, Dept Radiol,Joint Imaging Serv 114, Albuquerque, NM 87108 USA. Univ New Mexico, Sch Med, Vet Affairs Med Ctr, Dept Pathol, Albuquerque, NM 87108 USA. Univ New Mexico, Sch Med, Vet Affairs Med Ctr, Dept Med, Albuquerque, NM 87108 USA. NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. Univ Texas, Hlth Sci Ctr, Dept Radiol, San Antonio, TX 78284 USA. Madigan Army Med Ctr, Dept Radiol, Tacoma, WA 98431 USA. Dept Epidemiol & Biostat, Inst Expt & Clin Med, Tallinn, Estonia. RP Hartshorne, MF (reprint author), Univ New Mexico, Sch Med, Vet Affairs Med Ctr, Dept Radiol,Joint Imaging Serv 114, 1501 San Pedro SE, Albuquerque, NM 87108 USA. NR 35 TC 103 Z9 108 U1 0 U2 1 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 J9 J ULTRAS MED JI J. Ultrasound Med. PD AUG PY 1998 VL 17 IS 8 BP 487 EP 496 PG 10 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 104DE UT WOS:000074997000002 PM 9697951 ER PT J AU Weirich, G Glenn, G Junker, K Merino, M Storkel, S Lubensky, I Choyke, P Pack, S Amin, M Walther, MM Linehan, WM Zbar, B AF Weirich, G Glenn, G Junker, K Merino, M Storkel, S Lubensky, I Choyke, P Pack, S Amin, M Walther, MM Linehan, WM Zbar, B TI Familial renal oncocytoma: Clinicopathological study of 5 families SO JOURNAL OF UROLOGY LA English DT Article DE kidney neoplasms; hereditary diseases ID CYTOGENETIC ABNORMALITIES; TUMORS AB Purpose: We analyzed familial renal oncocytoma to provide a foundation for studies aimed at defining genes involved in the pathogenesis of renal oncocytoma. Materials and Methods: We describe 5 families with multiple members affected with renal oncocytoma. Tumors were analyzed pathologically, and affected and nonaffected members were screened clinically and genetically. Results: We identified 12 affected male and 3 affected female (ratio 4:1) individuals in the 5 families. In affected family members renal oncocytomas were often multiple and bilateral. No metastatic disease was observed. Most renal oncocytomas were detected incidentally in asymptomatic individuals or during screening of asymptomatic members of renal oncocytoma families. One identical twin pair was affected with bilateral multiple renal oncocytomas. Conclusions: Renal oncocytoma may be inherited in some families. C1 NCI, Frederick Canc Res & Dev Ctr, Immunobiol Lab, Frederick, MD 21701 USA. NCI, Genet Epidemiol Branch, Urol Oncol Branch, Bethesda, MD 20892 USA. NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. Univ Jena, Dept Urol, D-6900 Jena, Germany. Univ Witten Herdecke, Inst Pathol, Witten, Germany. Henry Ford Hosp, Dept Pathol, Detroit, MI 48202 USA. RP Weirich, G (reprint author), NCI, Frederick Canc Res & Dev Ctr, Immunobiol Lab, Frederick, MD 21701 USA. RI Pack, Svetlana/C-2020-2014 NR 23 TC 86 Z9 89 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD AUG PY 1998 VL 160 IS 2 BP 335 EP 340 DI 10.1016/S0022-5347(01)62888-X PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 102MM UT WOS:000074928200009 PM 9679872 ER PT J AU Pise-Masison, CA Radonovich, M Sakaguchi, K Appella, E Brady, JN AF Pise-Masison, CA Radonovich, M Sakaguchi, K Appella, E Brady, JN TI Phosphorylation of p53: a novel pathway for p53 inactivation in human T-cell lymphotropic virus type 1-transformed cells SO JOURNAL OF VIROLOGY LA English DT Article ID WILD-TYPE P53; TUMOR-SUPPRESSOR PROTEIN; I ASSOCIATED MYELOPATHY; HTLV-I; TRANSCRIPTIONAL ACTIVATION; DNA-REPLICATION; BINDING-SITE; GROWTH; TRANSACTIVATION; LYMPHOCYTES AB Inhibition of p53 function, through either mutation or interaction with viral or cellular transforming proteins, correlates strongly with the oncogenic potential. Only a small percentage of human T cell lymphotropic virus type 1 (HTLV-1)-transformed cells carry p53 mutations, and mutated p53 genes have been found in only one-fourth of adult T-cell leukemia cases. In previous studies, we demonstrated that wild-type p53 is stabilized and transcriptionally inactive in HTLV-1-transformed cells. Further, the viral transcriptional activator Tax plays a role in both the stabilization and inactivation of p53 through a mechanism involving the first 52 amino acids of p53. Here we show for the first time that phosphorylation of p53 inactivates p53 by blocking its interaction with basal transcription factors. Using two-dimensional peptide mapping, we demonstrate that peptides corresponding to amino acids 1 to 19 and 387 to 393 are hyperphosphorylated in HTLV-1-transformed cells. Moreover, using antibodies specific for phosphorylated Ser15 and Ser392, we demonstrate increased phosphorylation of these amino acids. Since HTLV-1 p53 binds DNA in a sequence-specific manner but fails to interact with TFIID, we tested whether phosphorylation of the N terminus of p53 affected p53-TFIID interaction. Using biotinylated peptides, we show that phosphorylation of Ser15 alone inhibits p53-TFIID interaction. In contrast, phosphorylation at Ser15 and -37 restores TFIID binding and blocks MDM2 binding. Our studies provide evidence that HTLV-1 utilizes the posttranslational modification of p53 in vivo to inactivate function of the tumor suppressor protein. C1 NCI, Virus Tumor Biol Sect, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Brady, JN (reprint author), NCI, Virus Tumor Biol Sect, Lab Receptor Biol & Gene Express, NIH, Bldg 41-B403, Bethesda, MD 20892 USA. EM bradyj@dce41.nci.nih.gov NR 52 TC 108 Z9 110 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 1998 VL 72 IS 8 BP 6348 EP 6355 PG 8 WC Virology SC Virology GA ZZ446 UT WOS:000074730200010 PM 9658074 ER PT J AU Hirsch, VM Dapolito, G Hahn, A Lifson, J Montefiori, D Brown, CR Goeken, R AF Hirsch, VM Dapolito, G Hahn, A Lifson, J Montefiori, D Brown, CR Goeken, R TI Viral genetic evolution in macaques infected with molecularly cloned simian immunodeficiency virus correlates with the extent of persistent viremia SO JOURNAL OF VIROLOGY LA English DT Article ID ENHANCING ANTIBODY-RESPONSES; TERM HIV-1 INFECTION; RHESUS-MONKEYS; TYPE-1 INFECTION; IN-VIVO; PROGRESSION; DISEASE; AIDS; NONPROGRESSORS; PATHOGENICITY AB Genetic evolution of the simian immunodeficiency virus (SIV) envelope glycoprotein was evaluated in a group of six macaques (Macaca nemestrina) infected with the molecularly cloned, moderately pathogenic SIVsm62d. The extent of envelope evolution was subsequently evaluated within the context of the individual pattern of viremia and disease outcome. Two macaques in this cohort developed AIDS by 1.5 years postinoculation (progressors), whereas the remaining four macaques remained asymptomatic (nonprogressors). Compared with the nonprogressor macaques, the two progressor macaques exhibited higher persistent plasma viremia, higher homologous neutralizing antibody titers, and more extensive mutation and evolution in the V1 region of envelope. Although clearly distinct in each of these parameters from the progressors, the four nonprogressors exhibited more individual variability with respect to the extent of persistent viremia and genetic evolution of the V1 region of envelope. The extent of V1 envelope varied from no apparent V1 evolution in a macaque with good viral containment to extensive evolution in one macaque with persistent viremia. This study underscores the critical role of persistent replication in the genetic evolution of SIV. C1 NIAID, Mol Microbiol Lab, Twinbrook Facil 2, Rockville, MD 20852 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. Frederick Canc Res & Dev Ctr, SAIC, Frederick, MD 21701 USA. RP Hirsch, VM (reprint author), NIAID, Mol Microbiol Lab, Twinbrook Facil 2, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM vhirsch@atlas.niaid.nih.gov NR 54 TC 17 Z9 17 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 1998 VL 72 IS 8 BP 6482 EP 6489 PG 8 WC Virology SC Virology GA ZZ446 UT WOS:000074730200027 PM 9658091 ER PT J AU Dittmer, U Brooks, DM Hasenkrug, KJ AF Dittmer, U Brooks, DM Hasenkrug, KJ TI Characterization of a live-attenuated retroviral vaccine demonstrates protection via immune mechanisms SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; HOST GENETIC-CONTROL; FRIEND-VIRUS; INDUCED ERYTHROLEUKEMIA; ENVELOPE PROTEIN; RHESUS MACAQUES; SIV INFECTION; RECOMBINANT; COMPLEX; IMMUNIZATION AB Live-attenuated retroviruses have been shown to be effective retroviral vaccines, but currently little is known regarding the mechanisms of protection. In the present studies, we used Friend virus as a model to analyze characteristics of a live-attenuated vaccine in protection against virus-induced disease. Highly susceptible mice were immunized with nonpathogenic Friend murine leukemia helper virus (F-MuLV), which replicates poorly in adult mice. Further attenuation of the vaccine virus was achieved by crossing the Fv-l genetic resistance barrier. The minimum dose of vaccine virus required to protect 100% of the mice against challenge with pathogenic Friend virus complex was determined to be 10(3) focus-forming units of attenuated virus. Live vaccine virus was necessary for induction of immunity, since inactivated F-MuLV did not induce protection. To determine whether immune cells mediated protection, spleen cells from vaccinated donor mice were adoptively transferred into syngeneic recipients. The results indicated that immune mechanisms rather than viral interference mediated protection. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. RP Dittmer, U (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 38 TC 54 Z9 54 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 1998 VL 72 IS 8 BP 6554 EP 6558 PG 5 WC Virology SC Virology GA ZZ446 UT WOS:000074730200035 PM 9658099 ER PT J AU Hasenkrug, KJ Brooks, DM Dittmer, U AF Hasenkrug, KJ Brooks, DM Dittmer, U TI Critical role for CD4(+) T cells in controlling retrovirus replication and spread in persistently infected mice SO JOURNAL OF VIROLOGY LA English DT Article ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; VIRUS-INDUCED LEUKEMIA; FRIEND-ERYTHROLEUKEMIA; MONOCLONAL-ANTIBODIES; CYTOMEGALO-VIRUS; VIRAL-INFECTION; GENE; COMPLEX; RECOVERY; SUBSETS AB Reactivations of persistent viral infections pose a significant medical problem in immunocompromised cancer, transplant, and AIDS patients, yet little is known about how persistent viral infections are immunologically controlled. Here we describe a mouse model for investigating the role of the immune response in controlling a persistent retroviral infection. We demonstrate that, following recovery from acute Friend virus infection, a small number of B cells evade immunological destruction and harbor persistent virus. In vivo depletions of T-cell subsets in persistently infected mice revealed a critical role for CD4(+) T cells in controlling virus replication,spread to the erythroid lineage, and induction of erythroleukemia, The CD4(+) T-cell effect was independent of CD8(+) T cells and in some cases was also independent of virus-neutralizing antibody responses. Thus, the CD4(+) T cells may have had a direct antiviral effect. These results may have relevance for human immunodeficiency virus (HIV) infections where loss of CD4(+) T cells is associated,vith an increase in HIV replication, reactivation of persistent viruses, and a high incidence of virus-associated cancers. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. RP Hasenkrug, KJ (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM KHasenkrug@nih.gov NR 36 TC 95 Z9 96 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 1998 VL 72 IS 8 BP 6559 EP 6564 PG 6 WC Virology SC Virology GA ZZ446 UT WOS:000074730200036 PM 9658100 ER PT J AU Everett, RD Freemont, P Saitoh, H Dasso, M Orr, A Kathoria, M Parkinson, J AF Everett, RD Freemont, P Saitoh, H Dasso, M Orr, A Kathoria, M Parkinson, J TI The disruption of ND10 during herpes simplex virus infection correlates with the Vmw11O- and proteasome-dependent loss of several PML isoforms SO JOURNAL OF VIROLOGY LA English DT Article ID ACUTE PROMYELOCYTIC LEUKEMIA; EARLY PROTEIN VMW110; 135-KDA CELLULAR PROTEIN; IMMEDIATE-EARLY GENE-1; RETINOIC ACID; NUCLEAR DOMAIN-10; RAR-ALPHA; REGULATORY PROTEIN; DNA-REPLICATION; TYPE-1 AB The small nuclear structures known as ND10 or PML nuclear bodies have been implicated in a variety of cellular processes including response to stress and interferons, oncogenesis, and viral infection, but little is known about their biochemical properties. Recently, a ubiquitin-specific protease enzyme (named HAUSP) and a ubiquitin-homology family protein (PIC1) have been found associated with ND10. HAUSP binds strongly to Vmw110, a herpesvirus regulatory protein which has the ability to disrupt ND10, while PIC1 was identified as a protein which interacts with PML, the prototype ND10 protein. We have investigated the role of ubiquitin-related pathways in the mechanism of ND10 disruption by Vmw110 and the effect of virus infection on PML stability. The results show that the disruption of ND10 during virus infection correlates with the loss of several PML isoforms and this process is dependent on active proteasomes. The PML isoforms that are most sensitive to virus infection correspond closely to those which have recently been identified as being covalently conjugated to PIC1. In addition, a large number of PIC1-protein conjugates can be detected following transfection of a PIC1 expression plasmid, and many of these are also eliminated in a Vmw110-dependent manner during virus infection. These observations provide a biochemical mechanism to explain the observed effects of Vmw110 on ND10 and suggest a simple yet powerful mechanism by which Vmw110 might function during virus infection. C1 MRC, Virol Unit, Glasgow G11 5JR, Lanark, Scotland. Imperial Canc Res Fund, Prot Struct Lab, Res Labs, London WC2A 3PX, England. NICHHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. RP Everett, RD (reprint author), MRC, Virol Unit, Church St, Glasgow G11 5JR, Lanark, Scotland. EM r.everett@vir.gla.ac.uk NR 61 TC 305 Z9 308 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 1998 VL 72 IS 8 BP 6581 EP 6591 PG 11 WC Virology SC Virology GA ZZ446 UT WOS:000074730200039 PM 9658103 ER PT J AU Feigelstock, D Thompson, P Mattoo, P Zhang, YA Kaplan, GG AF Feigelstock, D Thompson, P Mattoo, P Zhang, YA Kaplan, GG TI The human homolog of HAVcr-1 codes for a hepatitis A virus cellular receptor SO JOURNAL OF VIROLOGY LA English DT Article ID A VIRUS; PATHOGENESIS; POLIOVIRUS; INFECTION; CELLS AB The hepatitis A virus cellular receptor 1 (HAVcr-1) cDNA was isolated from a cDNA expression library of African green monkey kidney (AGMK) cells by using protective monoclonal antibody (MAb) 190/4, which blocks the binding of hepatitis A virus (HAV) to AGMK cells. The HAVcr-1 cDNA codes for havcr-1, a 451-amino-acid class I integral-membrane mucin-like glycoprotein of unknown natural function. To determine the existence of a human homolog(s) of HAVcr-1 (huHAVcr-1), we used HAVcr-1-specific primers to amplify cDNAs from human liver and kidney mRNA by reverse transcription-PCR Nucleotide sequence analysis revealed that the amplified liver and kidney huHAVcr-1 cDNAs were identical and that they coded for a 359-amino-acid glycoprotein, termed huhavcr-1, which was approximately 79% identical to havcr-1. The six Cys residues of the extracellular domain of havcr-1 and its first N-glycosylation site were conserved in huhavcr-1. However, the number of hexameric repeats of the mucin-like region was reduced from 27 in havcr-1 to 13 in huhavcr-1. In addition, 12 C-terminaI amino acids in the cytoplasmic domain of huhavcr-1 were deleted. Northern blot analysis of poIy(A) RNA showed that huhavcr-1 is expressed in every organ analyzed, including the liver, small intestine, colon, and spleen, and that it is expressed at higher levels in the kidney and testis. Although dog cells transfected with the huHAVcr-1 cDNA did not express the protective 190/4 epitope, they bound hepatitis A virus (HAV) and gained limited susceptibility to HAV infection. Treatment with MAb 190/4 did not protect AGMK cell transfectants expressing huhavcr-1 against HAV, suggesting that HAV infected these cells via the huhavcr-l receptor and not the endogenously expressed havcr-1, which was blocked by MAI, 190/4. Our data demonstrate that huhavcr-l is a binding receptor for HAV and suggest that it is also a functional receptor for HAV. C1 NIH, Div Viral Prod, CBER, US FDA,Lab Hepatitis Virus, Bethesda, MD 20892 USA. RP Kaplan, GG (reprint author), NIH, Div Viral Prod, CBER, US FDA,Lab Hepatitis Virus, 880 Rockville Pike,Bldg 29A,Rm 1D10,HFM-448, Bethesda, MD 20892 USA. NR 20 TC 138 Z9 154 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 1998 VL 72 IS 8 BP 6621 EP 6628 PG 8 WC Virology SC Virology GA ZZ446 UT WOS:000074730200044 PM 9658108 ER PT J AU Guo, JH Wu, TY Bess, J Henderson, LE Levin, JG AF Guo, JH Wu, TY Bess, J Henderson, LE Levin, JG TI Actinomycin D inhibits human immunodeficiency virus type 1 minus-strand transfer in in vitro and endogenous reverse transcriptase assays SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; HIV-1 NUCLEOCAPSID PROTEIN; DEPENDENT DNA-POLYMERASE; HAMMERHEAD RIBOZYME CATALYSIS; RNASE-H ACTIVITIES; ESCHERICHIA-COLI; POLYPURINE TRACT; SARCOMA VIRUS; GENOMIC RNA; IN-VITRO AB In this report we demonstrate that human immunodeficiency virus type 1 (HIV-1) minus-strand transfer, assayed in vitro and in endogenous reactions, is greatly inhibited by actinomycin D. Previously we showed that HIV-1 nucleocapsid (NC) protein (a nucleic acid chaperone catalyzing nucleic acid rearrangements which lead to more thermodynamically stable conformations) dramatically stimulates HIV-1 minus-strand transfer by preventing TAR-dependent self-priming from minus-strand strong-stop DNA [(-) SSDNA]. Despite this potent activity, the addition of NC to in vitro reactions with actinomycin D results in only a modest increase in the 50% inhibitory concentration (IC50) for the drug. PCR analysis of HIV-1 endogenous reactions indicates that minus-strand transfer is inhibited by the drug with an IC50 similar to that observed when NC is present in the in vitro system, Taken together, these results demonstrate that NC cannot overcome the inhibitory effect of actinomycin D on minus-strand transfer. Other experiments reveal that at actinomycin D concentrations which severely curtail minus-strand transfer, neither the synthesis of (-) SSDNA nor RNase H degradation of donor RNA is affected; however, the annealing of (-) SSDNA to acceptor RNA is significantly reduced. Thus, inhibition of the annealing reaction is responsible for actinomycin D-mediated inhibition of strand transfer. Since NC (but not reverse transcriptase) is required for efficient annealing, we conclude that actinomycin D inhibits minus-strand transfer by blocking the nucleic acid chaperone activity of NC. Our findings also suggest that actinomycin D, already approved for treatment of certain tumors, might be useful in combination therapy for AIDS. C1 NICHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC, AIDS Vaccine Program, Frederick, MD 21702 USA. RP Levin, JG (reprint author), NICHD, Genet Mol Lab, NIH, Bldg 6B,Room 216, Bethesda, MD 20892 USA. RI Bess, Jr., Julian/B-5343-2012 NR 77 TC 58 Z9 59 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 1998 VL 72 IS 8 BP 6716 EP 6724 PG 9 WC Virology SC Virology GA ZZ446 UT WOS:000074730200055 PM 9658119 ER PT J AU Baumert, TF Marrone, A Vergalla, J Liang, TJ AF Baumert, TF Marrone, A Vergalla, J Liang, TJ TI Naturally occurring mutations define a novel function of the hepatitis B virus core promoter in core protein expression SO JOURNAL OF VIROLOGY LA English DT Article ID FULMINANT-HEPATITIS; PREGENOME ENCAPSIDATION; REVERSE TRANSCRIPTION; NUCLEOTIDE-SEQUENCE; VIRAL REPLICATION; GENE-EXPRESSION; MESSENGER-RNAS; DNA-SYNTHESIS; PRECORE; INITIATION AB Functional analysis of naturally occurring hepatitis B virus (HBV) mutations is crucial in understanding their impact on disease. We have recently identified two mutations in the REV core promoter of an HBV strain associated with fulminant hepatitis leading to highly (15-fold) enhanced replication as a result of increased viral encapsidation of pregenomic RNA into the core particles (T. F. Baumert et al., J. Clin. Invest, 98:2268-2276, 1996). Functional studies in an encapsidation assay had demonstrated that the increase in encapsidation was largely independent of pregenomic RNA transcription. In this study, we define the molecular mechanism whereby the two core promoter mutations (C to T at nucleotide [nt] 1768 and T to A at nt 1770) result in enhanced viral encapsidation and replication.,The effect of these mutations leading to increased encapsidation is mediated through enhanced core protein synthesis (W-fold) by the mutant virus. The marked increase in core protein synthesis is largely a result of posttranscriptional or translational effect of the mutations because the mutations resulted in only a twofold increase in pregenomic RNA transcription. In addition, this effect appears to be selective for core expression since reverse transcriptase-polymerase expression was increased only twofold. trans-complementation analyses of HBV replication demonstrated that enhanced replication occurred only when the mutations were provided together with the core protein in trans, confirming the functional association of the core promoter mutations and core protein expression. In addition, the effect of the mutations appears to be quantitatively dependent on the strain background to which the mutations were introduced. Our study suggests that the HBV core promoter regulates core protein expression at both transcriptional and posttranscriptional levels. C1 NIDDK, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. RP Liang, TJ (reprint author), NIDDK, Liver Dis Sect, NIH, 10 Ctr Dr,Rm 9B16, Bethesda, MD 20892 USA. NR 45 TC 65 Z9 67 U1 4 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 1998 VL 72 IS 8 BP 6785 EP 6795 PG 11 WC Virology SC Virology GA ZZ446 UT WOS:000074730200063 PM 9658127 ER PT J AU Sanz, P Moss, B AF Sanz, P Moss, B TI A new vaccinia virus intermediate transcription factor SO JOURNAL OF VIROLOGY LA English DT Article ID RNA-POLYMERASE; POLY(A) POLYMERASE; INITIATION-FACTOR; DNA-REPLICATION; CAPPING ENZYME; EARLY GENES; PURIFICATION; IDENTIFICATION; TERMINATION; TEMPLATE AB Transcription of the vaccinia virus genome is mediated by a virus-encoded multisubunit DNA-dependent RNA polymerase in conjunction with early-, intermediate-, and late-stage-specific factors. Previous studies indicated that two virus-encoded proteins (capping enzyme and VITF-1) and one unidentified cellular protein (VITF-2) are required for specific transcription of an intermediate promoter template in vitro. We have now extensively purified an additional virus-induced intermediate transcription factor with a native mass of approximately 100 kDa. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 4 Ctr Dr,MSC 0445, Bethesda, MD 20892 USA. NR 21 TC 7 Z9 7 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 1998 VL 72 IS 8 BP 6880 EP 6883 PG 4 WC Virology SC Virology GA ZZ446 UT WOS:000074730200074 PM 9658138 ER PT J AU Kim, WK Tang, Y Okada, Y Torrey, TA Chattopadhyay, SK Pfleiderer, M Falkner, FG Dorner, F Choi, W Hirokawa, N Morse, HC AF Kim, WK Tang, Y Okada, Y Torrey, TA Chattopadhyay, SK Pfleiderer, M Falkner, FG Dorner, F Choi, W Hirokawa, N Morse, HC TI Binding of murine leukemia virus Gag polyproteins to KIF4, a microtubule-based motor protein SO JOURNAL OF VIROLOGY LA English DT Article ID AXONAL-TRANSPORT; IN-VIVO; EXPRESSION; MICE; ACTIVATION; GENOMES; MCF AB A cDNA clone encoding a cellular protein that interacts with murine leukemia virus (MuLV) Gag proteins was isolated from a T-cell lymphoma library. The sequence of the clone is identical to the C terminus of a cellular protein, KIF4, a microtubule-assoclated motor protein that belongs to the kinesin superfamily. KTF4-MuLV Gag associations have been detected in vitro and in vivo in mammalian cells. We suggest that KIF4 could be involved in Gag polyprotein translocation from the cytoplasm to the cell membrane. C1 NIAID, Immunopathol Lab, LIP, NIH, Bethesda, MD 20892 USA. Univ Tokyo, Grad Sch, Dept Anat & Cell Biol, Tokyo, Japan. Immuno AG Wien, Vienna, Austria. Ajou Univ, Inst Med Sci, Mol Biol Lab, Kyonggi Do, South Korea. Ewha Womans Univ, Seoul, South Korea. RP Morse, HC (reprint author), NIAID, Immunopathol Lab, LIP, NIH, 7 Ctr Dr, Bethesda, MD 20892 USA. RI Okada, Yasushi/N-5067-2015; OI Okada, Yasushi/0000-0003-2601-3689; Morse, Herbert/0000-0002-9331-3705 NR 26 TC 45 Z9 45 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 1998 VL 72 IS 8 BP 6898 EP 6901 PG 4 WC Virology SC Virology GA ZZ446 UT WOS:000074730200078 PM 9658142 ER PT J AU Yedavalli, VRK Chappey, C Ahmad, N AF Yedavalli, VRK Chappey, C Ahmad, N TI Maintenance of an intact human immunodeficiency virus type 1 vpr gene following mother-to-infant transmission SO JOURNAL OF VIROLOGY LA English DT Article ID VIRAL PROTEIN-R; PRIMARY INFECTION; ACCESSORY GENES; GAG GENES; HIV-1; CELLS; RNA; SEQUENCES; LOCALIZATION; REPLICATION AB The vpr sequences from six human immunodeficiency virus type 1 (HIV-1)-infected mother-infant pairs following perinatal transmission were analyzed. We found that 153 of the 166 clones analyzed from uncultured peripheral blood mononuclear cell DNA samples showed a 92.17% frequency of intact vpr open reading frames. There was a low degree of heterogeneity of vpr genes within mothers, within infants, and between epidemiologically linked mother-infant pairs. The distances between vpr sequences were greater in epidemiologically unlinked individuals than in epidemiologically linked mother-infant pairs. Moreover, the infants' sequences displayed patterns similar to those seen in their mothers. The functional domains essential for Vpr activity, including virion incorporation, nuclear import, and cell cycle arrest and differentiation were highly conserved in most of the sequences. Phylogenetic analyses of 166 mother-infant pairs and 195 other available vpr sequences from HIV databases formed distinct clusters for each mother-infant pair and for other vpr sequences and grouped the six mother-infant pairs' sequences with subtype B sequences. A high degree of conservation of intact and functional vpr supports the notion that vpr plays an important role in HIV-1 infection and replication in mother-infant isolates that are involved in perinatal transmission. C1 Univ Arizona, Hlth Sci Ctr, Dept Microbiol & Immunol, Tucson, AZ 85724 USA. NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Ahmad, N (reprint author), Univ Arizona, Hlth Sci Ctr, Dept Microbiol & Immunol, Tucson, AZ 85724 USA. EM nafees@u.arizona.edu FU NIAID NIH HHS [AI 40378, R21 AI040378] NR 53 TC 36 Z9 36 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 1998 VL 72 IS 8 BP 6937 EP 6943 PG 7 WC Virology SC Virology GA ZZ446 UT WOS:000074730200086 PM 9658150 ER PT J AU Furukawa, S MacLennan, MJ Keller, BB AF Furukawa, S MacLennan, MJ Keller, BB TI Hemodynamic response to anesthesia in pregnant and nonpregnant ICR mice SO LABORATORY ANIMAL SCIENCE LA English DT Article ID BLOOD-PRESSURE; XYLAZINE; MOUSE; RAT; HYPERTENSION; KETAMINE; EMBRYO; SHEEP AB Mean arterial blood pressure (BP) and heart rate (HR) during and after recovery from anesthesia in pregnant and nonpregnant ICR mice were evaluated. Mice were evaluated during mechanical ventilation, from 15 to 60 min after induction of anesthesia, The anesthetic protocols were pentobarbital (80 mg/kg, given intraperitoneally [i.p.]); two low doses of ketamine and xylazine (90 mg/kg, 7.5 mg/kg, respectively, i.p., with a second dose given 20 min after the initial dose); and a single high dose of ketamine and xylazine (150 mg/kg, 12.5 mg/kg, respectively, i.p.). The BP was measured in the right carotid artery, using a fluid-filled catheter connected to a chamber containing a solid-state pressure transducer, Mechanical ventilation was performed via tracheotomy, using a normalized minute ventilation of 3.5 ml*min(-1)*g(-1) for nonpregnant mice and 3.0 ml*min(-1)*g(-1) for pregnant mice. Mean BP was lower and HR was higher in pregnant than in nonpregnant mice for each anesthetic protocol. Pentobarbital induced significantly greater tachycardia and hypotension than did the other protocols. The average BP and HR were similar between two low doses and a single high dose of ketamine and xylazine, During spontaneous breathing from 30 to 180 min after recovery from anesthesia by use of a single low dose, ketamine and xylazine induced similar HR profiles, but mean BP in pregnant mice recovered earlier than did that in nonpregnant mice. These results suggest that ketamine and xylazine induced adequate anesthesia for superficial surgical procedures in pregnant and nonpregnant mice while inducing small changes in HR and BP, and pregnancy resulted in a different hemodynamic reaction in response to ketamine and xylazine, These data will be useful for the design and interpretation of physiologic protocols using pregnant and nonpregnant genetically targeted mice. C1 Univ Rochester, Sch Med & Dent,Dept Pediat, Div Pediat Cardiol,Strong Childrens Res Ctr, NIH,Specialized Ctr Res Pediat Cardiovasc Dis, Rochester, NY 14642 USA. RP Keller, BB (reprint author), Univ Rochester, Sch Med & Dent,Dept Pediat, Div Pediat Cardiol,Strong Childrens Res Ctr, NIH,Specialized Ctr Res Pediat Cardiovasc Dis, 601 Elmwood Ave,Box 631, Rochester, NY 14642 USA. FU NHLBI NIH HHS [P50-HL51498] NR 37 TC 14 Z9 14 U1 0 U2 1 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI CORDOVA PA 70 TIMBERCREEK DR, SUITE 5, CORDOVA, TN 38018 USA SN 0023-6764 J9 LAB ANIM SCI JI Lab. Anim. Sci. PD AUG PY 1998 VL 48 IS 4 BP 357 EP 363 PG 7 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 115HW UT WOS:000075659200010 PM 10090043 ER PT J AU Miller, G Feinstein, L Azadegan, A Thomas, B Bacher, J AF Miller, G Feinstein, L Azadegan, A Thomas, B Bacher, J TI Systemic yeast infection in owl monkeys (Aotus vociferans): Ante-mortem screening and diagnosis by examination of bone marrow aspirates SO LABORATORY ANIMAL SCIENCE LA English DT Article ID HISTOPLASMOSIS C1 NIH, Vet Resources Program, Natl Ctr Res Resources, Bethesda, MD 20892 USA. RP Miller, G (reprint author), NIH, Vet Resources Program, Natl Ctr Res Resources, Bldg 10, Bethesda, MD 20892 USA. NR 7 TC 3 Z9 3 U1 0 U2 1 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI CORDOVA PA 70 TIMBERCREEK DR, SUITE 5, CORDOVA, TN 38018 USA SN 0023-6764 J9 LAB ANIM SCI JI Lab. Anim. Sci. PD AUG PY 1998 VL 48 IS 4 BP 391 EP 394 PG 4 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 115HW UT WOS:000075659200017 PM 10090050 ER PT J AU Matsukawa, A Miyazaki, S Maeda, T Tanase, S Feng, LL Ohkawara, S Yoshinaga, M Yoshimura, T AF Matsukawa, A Miyazaki, S Maeda, T Tanase, S Feng, LL Ohkawara, S Yoshinaga, M Yoshimura, T TI Production and regulation of monocyte chemoattractant protein-1 in lipopolysaccharide- or monosodium urate crystal-induced arthritis in rabbits: Roles of tumor necrosis factor alpha, interleukin-1, and interleukin-8 SO LABORATORY INVESTIGATION LA English DT Article ID IL-1 RECEPTOR ANTAGONIST; MONOCLONAL-ANTIBODY; EXPRESSION; MCP-1; RECRUITMENT; INFLAMMATION; CELLS; PURIFICATION; ACTIVATION; KINETICS AB The production of monocyte chemoattractant protein-1 (MCP-1) and its regulation by TNF alpha, IL-1, and IL-8 were investigated in two rabbit models of arthritis induced by intra-articular injection of lipopolysaccharide (LPS) or monosodium urate (MSU) crystals. We first prepared recombinant rabbit MCP-1 and antibodies and then developed an immunoassay. The immunoassay detected 3 pg/ml rabbit MCP-1 and did not cross-react with other rabbit chemokines such as IL-8 or GRO. MCP-1 was first detected in synovial fluid (SF) at 1 hour, and peaked at 4 or 2 hours after the injection of LPS or MSU crystals, respectively. Immunohistochemically, MCP-1 was detected in synovial lining cells and infiltrating neutrophils. The amounts of MCP-1 detected in SF from neutrophil-depleted rabbits were similar to those in normal rabbits, suggesting that synovial lining cells were the main source of MCP-1 detected in SF. The peak level of MCP-1 in SF after LPS-injection was inhibited by 57% with anti-TNF alpha mAb and by 41% with IL-1 receptor antagonist (IL-1Ra). Coadministration of anti-TNF alpha mAb and IL-1Ra inhibited 90% of MCP-1 production. In contrast, the peak level of MCP-1 in SF after MSU crystal-injection was not affected by any cytokine inhibitor, but was reduced by 52% with coadministration of anti-TNF alpha mAb and IL-1Ra. Anti-IL-8 IgG had no effect on the production of MCP-1 in either model. Thus, the production of MCP-1 in LPS-induced arthritis was mostly regulated by TNF alpha and IL-1, whereas half the extent of MCP-1 production in MSU crystal-induced arthritis was independent of TNF alpha or IL-1. IL-8 does not seem to regulate the production of MCP-1 in SF either directly or indirectly. Finally, administration of neutralizing anti-MCP-1 antibody inhibited LPS- and MSU crystal-induced monocyte infiltration by 58.4% and 44.9%, respectively, suggesting that synovial production of MCP-1 plays an important role in the recruitment of monocytes in these arthritis models. C1 Kumamoto Univ, Sch Med, Dept Pathol, Kumamoto 8600811, Japan. Kumamoto Univ, Sch Med, Dept Biochem, Kumamoto 8600811, Japan. Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA. NCI, Immunopathol Sect, Immunol Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. RP Matsukawa, A (reprint author), Kumamoto Univ, Sch Med, Dept Pathol, 2-2-1 Honjo, Kumamoto 8600811, Japan. NR 41 TC 46 Z9 46 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD AUG PY 1998 VL 78 IS 8 BP 973 EP 985 PG 13 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 110QK UT WOS:000075391700008 PM 9714185 ER PT J AU Sher, L AF Sher, L TI Elderly patients, use of antidepressants, and hip fracture SO LANCET LA English DT Letter C1 NIMH, Clin Psychobiol Branch, Bethesda, MD 20892 USA. RP Sher, L (reprint author), NIMH, Clin Psychobiol Branch, Bethesda, MD 20892 USA. NR 5 TC 2 Z9 2 U1 0 U2 0 PU LANCET LTD PI LONDON PA 42 BEDFORD SQUARE, LONDON WC1B 3SL, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD AUG 1 PY 1998 VL 352 IS 9125 BP 401 EP 401 DI 10.1016/S0140-6736(05)60496-5 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 106BU UT WOS:000075110500048 PM 9717949 ER PT J AU Sato, T Kim, S Selleri, C Young, NS Maciejewski, JP AF Sato, T Kim, S Selleri, C Young, NS Maciejewski, JP TI Measurement of secondary colony formation after 5 weeks in long-term cultures in patients with myelodysplastic syndrome SO LEUKEMIA LA English DT Article DE myelodysplastic syndrome; LTC-IC; hematopoietic stem cells; bone marrow cellularity; cytogenetics; aplastic anemia ID SEVERE APLASTIC-ANEMIA; BONE-MARROW CULTURES; HEMATOPOIETIC GROWTH-FACTORS; PROGENITOR CELLS; STIMULATING FACTORS; CD34(+) CELLS; G-CSF; DIFFERENTIATION; LEUKEMIA; PROLIFERATION AB Pancytopenia is a frequent manifestation of myelodysplastic syndromes (MDS). In the presence of an empty bone marrow, clinical distinction from aplastic anemia may be difficult. The hypoplastic marrow morphology seen in some cases of MDS raises questions about etiologic and pathophysiologic relationships between aplastic anemia and MDS. The goal of our study was to compare the degree of the hematopoietic failure in these diseases at the level of the most immature progenitor and stem cells that can be measured in vitro. In a systemic, prospective fashion, we have studied bone marrow (n=45) and peripheral blood (n=33) of patients with MDS for the number of long-term culture initiating cells (LTC-IC) in comparison to 17 normal controls and patients with new, untreated aplastic anemia (46 marrow; 62 blood samples). Due to the low numbers of cells available for the analysis, formal limiting dilution analysis could not be performed, instead secondary colony-forming cells (CFC) after 5 weeks of LTBMC were measured. As the number of these cells is proportional to the input number of LTC-IC, the number of secondary CFC per 10(6) mononuclear cells (MNC) initiating the LTBMC can be used as a measure of the content of immature stem cells in bone marrow and peripheral blood. The MDS group consisted of 34 RA, three RARS, eight RAEB and two RAEB-T patients with mean absolute neutrophil values of 1992, 1413, 1441, and 380 per mm(3), respectively. The diagnosis was established based on bone marrow morphology and results of cytogenetic studies. In comparison to controls (147 +/- 38/10(6) MNC), significantly decreased numbers of bone marrow secondary CFC were found in MDS: in patients with HA and RARS, 21 +/- 7 secondary CFC per 10(6) bone marrow MNC (P < 0.001); patients with RAEB and RAEB-T: 39 +/- 12 CFC per 106 marrow MNC (P < 0.001). In all groups tested, the decrease in peripheral blood secondary CFC numbers was consistently less pronounced. In MDS patients with hypocellular bone marrow, secondary CFC were lower but not significantly different in comparison to MDS with hypercellular marrow (18 +/- 6 vs 35 +/- 11; NS; hypoplastic bone marrow also was not associated with significantly lower neutrophil counts). However, in 24% of patients with MDS, bone marrow secondary CFC were within the normal range, while in the aplastic anemia group only one of the patients showed secondary CFC number within normal range. Bone marrow and blood secondary CFC numbers in hypoplastic RA were significantly higher than those in severe aplastic anemia 919 +/- 5 in bone marrow, P < 0.01; 7 +/- 2 in blood, P < 0.05). This trend was even more pronounced in hypoplastic RA with chromosomal abnormalities. However, no significant differences were found between the secondary CFC numbers in hypoplastic RA and moderate aplastic anemia. We concluded that, although the deficiency in the stem cell compartment is less severe in MDS than in aplastic anemia, depletion of early hematopoietic cells is an essential part of the pathophysiology in both diseases. C1 Univ Nevada, Dept Internal Med, Sch Med, Reno, NV 89557 USA. NHLBI, Hematol Branch, Bethesda, MD 20892 USA. Univ Nevada, Sch Med, Dept Internal Med, Reno, NV 89557 USA. RP Maciejewski, JP (reprint author), Univ Nevada, Dept Internal Med, Sch Med, Howard Med Bldg 320, Reno, NV 89557 USA. NR 50 TC 27 Z9 27 U1 0 U2 1 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD AUG PY 1998 VL 12 IS 8 BP 1187 EP 1194 DI 10.1038/sj.leu.2401084 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA 109JV UT WOS:000075319700004 PM 9697872 ER PT J AU Dunbar, CE AF Dunbar, CE TI Gene transfer to hematopoietic cells: Progress and problems SO LEUKEMIA & LYMPHOMA LA English DT Article ID PERIPHERAL-BLOOD; NONHUMAN-PRIMATES; IN-VIVO; TRANSPLANTATION; MARKING C1 NIH, Bethesda, MD 20892 USA. RP Dunbar, CE (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 12 TC 0 Z9 0 U1 0 U2 0 PU HARWOOD ACAD PUBL GMBH PI READING PA C/O STBS LTD, PO BOX 90, READING, BERKS, ENGLAND RG1 8JL SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD AUG PY 1998 VL 30 SU 1 BP 15 EP 16 DI 10.3109/10428199809058616 PG 2 WC Oncology; Hematology SC Oncology; Hematology GA 130WC UT WOS:000076542500008 ER PT J AU Thorgeirsson, SS AF Thorgeirsson, SS TI Progenitor cell tumors in human liver SO LIVER LA English DT Editorial Material ID EPITHELIAL-CELLS; STEM-CELL; DIFFERENTIATION; HEPATOCARCINOGENESIS; ORIGIN C1 NCI, Expt Carcinogenesis Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Thorgeirsson, SS (reprint author), NCI, Expt Carcinogenesis Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NR 15 TC 5 Z9 5 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0106-9543 J9 LIVER JI Liver PD AUG PY 1998 VL 18 IS 4 BP 227 EP 228 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 120HD UT WOS:000075950200001 PM 9766816 ER PT J AU Brooks, RA Vymazal, J Goldfarb, RB Bulte, JWM Aisen, P AF Brooks, RA Vymazal, J Goldfarb, RB Bulte, JWM Aisen, P TI Relaxometry and magnetometry of ferritin SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE ferritin; superparamagnetism; T-1; T-2; relaxometry ID BRAIN IRON; RELAXATION; CORE; MAGNETOFERRITIN; DEPENDENCE; COMPLEX; FIELD; RATS; IONS; MRI AB By combining nuclear magnetic relaxometry on 39 ferritin samples with different iron loading with magnetometry, results were obtained that suggest a new interpretation of the core structure and magnetic properties of ferritin. These studies provide evidence that, contrary to most earlier reports, the ferritin core is antiferromagnetic (AFM) even at body temperature and possesses a superparamagnetic (SPM) moment due to incomplete cancellation of antiparallel sublattices, as predicted by Neel's theory. This moment also provides a likely explanation for the anomalous T-2 shortening in ferritin solution. However, the number of SPM moments derived from this model is less than the number of ferritin molecules determined chemically, and a similar discrepancy was found by retrospectively fitting previously published magnetometry data. In other words, only a fraction of the ferritin molecules seem to be SPM. The studies also provide evidence for paramagnetic (PM) Curie-Weiss iron ions at the core surface, where the local Neel temperature is lower; these ions are apparently responsible for the weaker T-1 shortening. In fact, the conversion of uncompensated AFM lattice ions to PM ions could explain the small number of SPM particles. The apparent Curie Law behavior of ferritin thus appears to be a coincidental result of different temperature dependences of the PM and SPM components. C1 NINDS, Neuroimaging Branch, NIH, Bethesda, MD 20892 USA. NIH, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. Natl Inst Stand & Technol, Boulder, CO USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. RP NINDS, Neuroimaging Branch, NIH, Bldg 10,Room 5N214, Bethesda, MD 20892 USA. RI Bulte, Jeff/A-3240-2008; Goldfarb, Ronald/A-5493-2011 OI Bulte, Jeff/0000-0003-1202-1610; Goldfarb, Ronald/0000-0002-1942-7974 FU NIDDK NIH HHS [DK15056] NR 38 TC 91 Z9 91 U1 2 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD AUG PY 1998 VL 40 IS 2 BP 227 EP 235 DI 10.1002/mrm.1910400208 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 107NC UT WOS:000075214500007 PM 9702704 ER PT J AU Spencer, RGS AF Spencer, RGS TI Comparing individual signal-averaged spectra SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE spectra; statistics; signal averaging AB It is demonstrated here that individual signal-averaged NMR spectra can be compared statistically in a rigorous fashion. This is accomplished by considering the ensemble of single acquisitions, which are summed to produce spectra. Applications of this concept include assessment of the statistical significance of apparent metabolite variations in control preparations and quantitative comparison of signals obtained during the fast response period in functional MRI. C1 NIA, NMR Unit, NIH, Baltimore, MD 21224 USA. RP Spencer, RGS (reprint author), NIA, NMR Unit, NIH, GRC 4D-08,4940 Eastern Ave, Baltimore, MD 21224 USA. NR 3 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn.Reson.Med. PD AUG PY 1998 VL 40 IS 2 BP 327 EP 329 DI 10.1002/mrm.1910400218 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 107NC UT WOS:000075214500017 PM 9702714 ER PT J AU Opdecamp, K Vanvooren, P Riviere, M Arnheiter, H Motta, R Szpirer, J Szpirer, C AF Opdecamp, K Vanvooren, P Riviere, M Arnheiter, H Motta, R Szpirer, J Szpirer, C TI The rat microphthalmia-associated transcription factor gene (Mitf) maps at 4q34-q41 and is mutated in the mib rats SO MAMMALIAN GENOME LA English DT Article ID WAARDENBURG SYNDROME; NORWAY RAT; MOUSE; MUTATIONS; HYBRIDIZATION; CHROMOSOME; NORVEGICUS; ASSIGNMENT; PROTEIN AB The rat gene encoding the microphthalmia-associated transcription factor (Mitf) was assigned to rat Chromosome (Chr) 4q34-q41, as well as the Gata2 and Mem1 genes. Rat Chr 4 is homologous to mouse Chr 6 and human Chr 3, which carry the Mitf (MITF) gene in these species (MMU 6, 40.0 cM, and HSA 3p14.1-p12.3). mib/mib rats, which are characterized by depigmentation, microphtalmy, osteopetrosis, and neurological disorders were shown to bear a deletion covering several kilobases of genomic DNA in the Mitf gene and to lack Mitf mRNA. The Mitf mutation in the mib/mib rats is thus very likely to be a Mid null mutation, causing a phenotype similar to the one observed in the mi(VGA-9) mice, but including osteopetrosis as an additional feature. C1 Free Univ Brussels, Dept Biol Mol, B-1640 Rhode St Genese, Belgium. NINDS, Lab Dev Neurogenet, NIH, Bethesda, MD 20892 USA. CNRS, Lab Rech Genet Modeles Anim, F-45071 Orleans, France. RP Szpirer, C (reprint author), Free Univ Brussels, Dept Biol Mol, Rue Chevaux 67, B-1640 Rhode St Genese, Belgium. NR 31 TC 18 Z9 19 U1 0 U2 3 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 AUG PY 1998 VL 9 IS 8 BP 617 EP 621 DI 10.1007/s003359900832 PG 5 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 102LC UT WOS:000074925000004 PM 9680380 ER PT J AU Gabig, TG Crean, CD Klenk, A Long, HY Copeland, NG Gilbert, DJ Jenkins, NA Quincey, D Parente, F Lespinasse, F Carle, GF Gaudray, P Zhang, CX Calender, A Hoeppener, J Kas, K Thakker, RV Farnebo, F Teh, BT Larsson, C Piehl, F Lagercrantz, J Khodaei, S Carson, E Weber, G AF Gabig, TG Crean, CD Klenk, A Long, HY Copeland, NG Gilbert, DJ Jenkins, NA Quincey, D Parente, F Lespinasse, F Carle, GF Gaudray, P Zhang, CX Calender, A Hoeppener, J Kas, K Thakker, RV Farnebo, F Teh, BT Larsson, C Piehl, F Lagercrantz, J Khodaei, S Carson, E Weber, G TI Expression and chromosomal localization of the Requiem gene SO MAMMALIAN GENOME LA English DT Article ID LINKAGE MAP; PROTEIN; APOPTOSIS; FAMILY; TRANSLOCATION; GENOME AB Apoptosis in murine myeloid cell lines requires the expression of the Requiem gene, which encodes a putative zinc finger protein. We detected the protein in both cytoplasmic and nuclear subcellular fractions of murine myeloid cells and human K562 leukemia cells, which suggests that the protein might have a function distinct from a transcription factor. This distribution did not alter upon apoptosis induction by IL-3 deprivation. As an approach to investigate its role in development, we determined the spatio-temporal expression pattern in the mouse. Expression was detected in various tissues in earlier gestational age; however, confined to testes, spleen: thymus, and part of the hippocampus in the adult mouse. The expression profile is consistent with a functional role during rapid growth and cell turnover, and in agreement with a regulatory function for hematopoietic cells. The human cDNA clone sequenced showed high homology to its murine counterpart and extended the open reading frame by 20 codons upstream. The gene is located in the proximal region of mouse Chromosome (Chr) 19. In the homologous human region at 11q13, it is located at about 150 kb centromeric from MLK3. C1 Karolinska Hosp, CMM, Clin Genet Unit, Dept Mol Med, S-17176 Stockholm, Sweden. Indiana Univ, Sch Med, Dept Med, Div Hematol & Oncol, Indianapolis, IN USA. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Mammalian Genet Lab, Frederick, MD USA. Fac Med, UNSA, CNRS, UMR 6549, F-06107 Nice, France. Hop Edouard Herriot, Serv Genet, F-69437 Lyon, France. Univ Utrecht Hosp, Dept Pathol, NL-3508 GA Utrecht, Netherlands. Katholieke Univ Leuven, Ctr Human Genet, Mol Oncol Lab, B-3000 Louvain, Belgium. Hammersmith Hosp, Royal Postgrad Med Sch, MRC, Mol Endocrinol Grp, London W12 0NN, England. Karolinska Hosp, CMM, Dept Mol Med, Endocrine Tumor Unit, S-17176 Stockholm, Sweden. RP Weber, G (reprint author), Karolinska Hosp, CMM, Clin Genet Unit, Dept Mol Med, L8-02, S-17176 Stockholm, Sweden. RI Piehl, Fredrik/E-3451-2013; ZHANG, Chang /G-2905-2013; Weber, Gunther/F-3410-2016; OI Thakker, Rajesh/0000-0002-1438-3220 FU NCI NIH HHS [CA68134] NR 26 TC 14 Z9 17 U1 0 U2 5 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 AUG PY 1998 VL 9 IS 8 BP 660 EP 665 DI 10.1007/s003359900840 PG 6 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 102LC UT WOS:000074925000012 PM 9680388 ER PT J AU Bloom, ML Simon-Stoos, KL Mabon, ME AF Bloom, ML Simon-Stoos, KL Mabon, ME TI The hemoglobin-deficit mutation is located on mouse Chromosome 19 SO MAMMALIAN GENOME LA English DT Article ID MAP C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Bloom, ML (reprint author), NHLBI, NIH, Bldg 10,Room 7C 118, Bethesda, MD 20892 USA. FU NIDDK NIH HHS [R01 DK 27726] NR 14 TC 7 Z9 7 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 AUG PY 1998 VL 9 IS 8 BP 666 EP 667 DI 10.1007/s003359900841 PG 2 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 102LC UT WOS:000074925000013 PM 9680389 ER PT J AU Lenz, O Teichmann, U Langers, A Striker, LJ Striker, GE Pavan, WJ AF Lenz, O Teichmann, U Langers, A Striker, LJ Striker, GE Pavan, WJ TI Linkage disequilibrium mapping reveals suppressed recombination at the Os locus SO MAMMALIAN GENOME LA English DT Article ID LETHAL MUTATION; MOUSE C1 Natl Human Genome Res Inst, Labs Genet Dis Res, NIH, Bethesda, MD 20892 USA. NIDDKD, Renal Cell Biol Sect, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. IVAX Res Inst, Miami, FL 33137 USA. RP Pavan, WJ (reprint author), Natl Human Genome Res Inst, Labs Genet Dis Res, NIH, Bldg 49,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Lenz, Oliver/M-4672-2016 OI Lenz, Oliver/0000-0003-2997-3976 NR 15 TC 5 Z9 5 U1 1 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 AUG PY 1998 VL 9 IS 8 BP 681 EP 682 DI 10.1007/s003359900847 PG 2 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 102LC UT WOS:000074925000019 PM 9680395 ER PT J AU Wojnowski, L Stancato, LF Zimmer, AM Hahn, H Beck, TW Larner, AC Rapp, UR Zimmer, A AF Wojnowski, L Stancato, LF Zimmer, AM Hahn, H Beck, TW Larner, AC Rapp, UR Zimmer, A TI Craf-1 protein kinase is essential for mouse development SO MECHANISMS OF DEVELOPMENT LA English DT Article DE Craf-1 protein kinase; development; cell mutation; mouse embryo ID B-RAF; EGF RECEPTOR; A-RAF; DIFFERENTIAL REGULATION; TARGETED DISRUPTION; MICE LACKING; DEFECTS; CELLS; GENE; PATHWAY AB The three mammalian Raf serine/threonine protein kinases mediate the transduction of proliferative and differentiative signals from a variety of cell surface receptors to the nucleus. We report here that Craf-1 is essential for mouse development, as its mutation results in embryonic lethality. Developmental defects are: found in mutant placentas as well as in the skin and in the lungs of mutant embryos. Craf-1 mutants also display a generalized growth retardation which is consistent with the ubiquitous expression of Craf-1 and which could be due to the reduced proliferation of mutant cells. Interestingly, the time-point of embryonal death varies depending on the genetic background. This suggests that Craf-1-mediated signaling is affected by genetic background-specific alleles of other genes. (C) 1998 Elsevier Science Inland Ltd. All rights reserved. C1 NIMH, Genet Sect, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Div Cytokine Biol, Bethesda, MD 20892 USA. NCI, Intramural Res Support Program, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD USA. Univ Wurzburg, Inst Med Strahlenkunde & Zellforsch, Wurzburg, Germany. RP Zimmer, A (reprint author), NIMH, Genet Sect, 36 Convent Dr 3D06, Bethesda, MD 20892 USA. RI Zimmer, Andreas/B-8357-2009 NR 30 TC 84 Z9 84 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD AUG PY 1998 VL 76 IS 1-2 BP 141 EP 149 DI 10.1016/S0925-4773(98)00111-7 PG 9 WC Developmental Biology SC Developmental Biology GA 129FW UT WOS:000076454000012 PM 9767153 ER PT J AU Glasgow, E Tomarev, SI AF Glasgow, E Tomarev, SI TI Restricted expression of the homeobox gene prox 1 in developing zebrafish SO MECHANISMS OF DEVELOPMENT LA English DT Article DE transcription factor; prospero; eye; lens; hindbrain; spinal cord; lateral line; trigeminal ganglia; muscle; otic vesicle; homeobox; development; zebrafish ID DROSOPHILA-PROSPERO; PRECURSOR CELLS AB Prox 1 is a vertebrate homeobox gene which is homologous to the Drosophila transcription factor, prospero. We have isolated a prox 1 cDNA from zebrafish, which encodes a protein that has 82%, 84% and 83% amino acid identity with chicken, mouse and human Prox 1, respectively. Antibodies raised against human Prox 1 cross-react with zebrafish Prox 1 and are used here to determine the expression patterns of Prox 1 during zebrafish embryogenesis by whole-mount immunohistochemistry. In the 10-somite embryo, Prox 1 is expressed over the prospective lens placode and over a broad region of epithelium extending from the eye to the otic vesicle. As embryogenesis proceeds, Prox 1 expression in the eye lens becomes intense, and is detected in maturing muscle pioneer cells and superficial muscle cells. In the CNS, Prox 1 is expressed in a stripe along the forebrain-midbrain boundary, in a segmented pattern in the ventral hindbrain, and in selected cells of the ventral spinal cord. Additional sites of Prox 1 expression include the lateral line primordium, the trigeminal ganglia, the otic vesicle and occasional endodermal cells. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved. C1 NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Mol Genet Lab, Bethesda, MD 20892 USA. NEI, Mol & Dev Biol Lab, Bethesda, MD 20892 USA. RP Glasgow, E (reprint author), NINDS, Neurochem Lab, NIH, Bldg 36,Room 4D20, Bethesda, MD 20892 USA. OI Glasgow, Eric/0000-0001-7729-3954 NR 11 TC 81 Z9 84 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD AUG PY 1998 VL 76 IS 1-2 BP 175 EP 178 DI 10.1016/S0925-4773(98)00121-X PG 4 WC Developmental Biology SC Developmental Biology GA 129FW UT WOS:000076454000018 PM 9767161 ER PT J AU Stahl, SM AF Stahl, SM TI Views from funding agencies - The National Institute on Aging SO MEDICAL CARE LA English DT Editorial Material ID HEALTH-MAINTENANCE-ORGANIZATIONS; OUTCOMES; CARE; HMO C1 NIA, Behav & Social Res Program, Hlth Care Org & Older People Soc, NIH, Bethesda, MD 20892 USA. RP Stahl, SM (reprint author), NIA, Behav & Social Res Program, Hlth Care Org & Older People Soc, NIH, Bethesda, MD 20892 USA. NR 20 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0025-7079 J9 MED CARE JI Med. Care PD AUG PY 1998 VL 36 IS 8 BP 1123 EP 1125 DI 10.1097/00005650-199808000-00002 PG 3 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 107RY UT WOS:000075224200002 PM 9708586 ER PT J AU Kwon-Chung, KJ Goldman, WE Klein, B Szaniszlo, PJ AF Kwon-Chung, KJ Goldman, WE Klein, B Szaniszlo, PJ TI Fate of transforming DNA in pathogenic fungi SO MEDICAL MYCOLOGY LA English DT Article; Proceedings Paper CT XIVth Congress of the International-Society-for-Human-and-Animal-Mycology CY JUN 08-13, 1997 CL PARMA, ITALY SP Int Soc Human & Anim Mycol DE genetic transformation; gene disruption; pathogenic fungi ID BLASTOMYCES-DERMATITIDIS YEASTS; CRYPTOCOCCUS-NEOFORMANS; HISTOPLASMA-CAPSULATUM; GENETIC-TRANSFORMATION; SURFACE PROTEIN; VIRULENCE; SEQUENCES; ANTIGEN; COMPLEMENTATION; RESISTANCE AB Genetic engineering is an important tool in helping us to define the molecular basis of pathogenicity and is also useful in helping us to identify new therapeutic targets in pathogenic fungi. Molecular genetic manipulation of micro-organisms requires the development of plasmid-mediated transformation systems that include: (i) infusion of exogenous DNA into recipient cells, (ii) expression of genes present on the incoming DNA, and (iii) stable maintenance and replication of the inserted DNA leading to expression of the desired phenotypic trait. Transformation systems have been developed for only a handful of fungi that are pathogenic to humans including several species of Candida [1], Cryptococcus neoformans [2], Histoplasma capsulatum [3], Blastomyces dermatitidis [4], Aspergillus fumigatus [5], Wangiella dermatitidis (Exophiala dermatitidis) [6] and Coccidioides immitis [7]. Except for Candida species and A. fumigatus, where passage of exogenous DNA into recipient cells has been achieved readily using methods developed for transformation of Saccharomyces cerevisiae and Aspergillus nidulans, respectively, development of transformation systems in other pathogenic fungi has been delayed considerably and has only been possible recently with the introduction of electroporation and biolistic methods. Conventional spheroplasting methods or cell wall permeabilization methods using lithium acetate have not been successful for transformation of C. neoformans and work with only low efficiency in H. capsulatum. The fate of incoming DNA varies greatly in these pathogenic species regardless of their phylogenetic relationships. Understanding the fate of incoming DNA is critical for the construction of transforming vectors and the molecular manipulation of the organisms. Tn this symposium, recent advances in molecular genetic systems including transformation systems, the fate of incoming DNA and strategies for targeted integration are discussed in relation to four pathogenic fungi. C1 NHLBI, NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, St Louis, MO USA. Univ Wisconsin, Sch Med, Madison, WI USA. Univ Texas, Austin, TX 78712 USA. RP Kwon-Chung, KJ (reprint author), NHLBI, NIH, Bldg 10,Room 11C 120,10 Ctr Dr MSC, Bethesda, MD 20892 USA. OI Goldman, William/0000-0002-1551-6718 FU NIAID NIH HHS [AI 01308, AI 35681]; PHS HHS [A1 25584] NR 43 TC 25 Z9 27 U1 1 U2 3 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 1369-3786 J9 MED MYCOL JI Med. Mycol. PD AUG PY 1998 VL 36 SU 1 BP 38 EP 44 PG 7 WC Infectious Diseases; Mycology; Veterinary Sciences SC Infectious Diseases; Mycology; Veterinary Sciences GA 115LG UT WOS:000075665900004 PM 9988490 ER PT J AU Dixon, DM Casadevall, A Klein, B Mendoza, L Travassos, L Deepe, GS AF Dixon, DM Casadevall, A Klein, B Mendoza, L Travassos, L Deepe, GS TI Development of vaccines and their use in the prevention of fungal infections SO MEDICAL MYCOLOGY LA English DT Article; Proceedings Paper CT XIVth Congress of the International-Society-for-Human-and-Animal-Mycology CY JUN 08-13, 1997 CL PARMA, ITALY SP Int Soc Human & Anim Mycol DE vaccines; prevention; mycoses; pythiosis; immunization; therapeutic ID CRYPTOCOCCUS-NEOFORMANS GLUCURONOXYLOMANNAN; BLASTOMYCES-DERMATITIDIS YEASTS; CELL-MEDIATED-IMMUNITY; HEAT-SHOCK PROTEIN-60; PARACOCCIDIOIDES-BRASILIENSIS; HISTOPLASMA-CAPSULATUM; MONOCLONAL-ANTIBODIES; SURFACE PROTEIN; PULMONARY BLASTOMYCOSIS; EQUINE PHYCOMYCOSIS AB Vaccine approaches to infectious diseases are widely applied and appreciated. Disciplines such as bacteriology and virology have a rich history of successful vaccine development. The complexity of eukaryotic systems presents additional challenges to the development of vaccines against them. These challenges are being met in the fields of parasitology, and are being revisited for application in oncology. Vaccine opportunities exist in medical mycology. The National Institute of Allergy and Infectious Diseases has held a series of workshops in medical mycology where the need to develop vaccines for fungal diseases was noted and where important opportunities were discussed. Major advances in vaccinology and the technology of antigen preparation and delivery have increased feasibility and heightened interest. The recent epidemic of coccidioidomycosis in the American Southwest has demonstrated the need for developing a vaccine as an effective preventive measure for those living in and for those who subsequently move into regions with the endemic mycoses. The XIIth Congress of the International Society for Human and Animal Mycology included a symposium that summarized new vaccination strategies for selected fungi: Candida albicans, Coccidioides immitis, and Trichophyton verrucosum. The goal of the present summary is to provide representative examples of continuing efforts relating to vaccine development within the medical mycological community highlighting Blastomyces dermatidis, Cryptococcus neoformans, Histoplasma capsulatum, Paracoccidioides brasiliensis, and Pythium insidiosum. C1 NIAID, NIH, Bethesda, MD 20892 USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. Univ Wisconsin, Madison, WI USA. Michigan State Univ, Dept Microbiol, Med Technol Program, N Kedzie Lab 322, E Lansing, MI 48824 USA. Univ Fed Sao Paulo, Disciplina Biol Celular, BR-04023062 Sao Paulo, Brazil. Univ Cincinnati, Coll Med, Cincinnati, OH 45221 USA. RP Dixon, DM (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM dd24a@nih.gov RI Travassos, Luiz/J-3631-2012 NR 90 TC 44 Z9 46 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 1369-3786 J9 MED MYCOL JI Med. Mycol. PD AUG PY 1998 VL 36 SU 1 BP 57 EP 67 PG 11 WC Infectious Diseases; Mycology; Veterinary Sciences SC Infectious Diseases; Mycology; Veterinary Sciences GA 115LG UT WOS:000075665900007 PM 9988493 ER PT J AU Perfect, JR Wong, B Chang, YC Kwon-Chung, KJ Williamson, PR AF Perfect, JR Wong, B Chang, YC Kwon-Chung, KJ Williamson, PR TI Cryptococcus neoformans: virulence and host defences SO MEDICAL MYCOLOGY LA English DT Article; Proceedings Paper CT XIVth Congress of the International-Society-for-Human-and-Animal-Mycology CY JUN 08-13, 1997 CL PARMA, ITALY SP Int Soc Human & Anim Mycol DE Cryptococcus neoformans; molecular biology; virulence ID TRANSCRIPTIONAL ACTIVATION; SACCHAROMYCES-CEREVISIAE; GENE-EXPRESSION; D-MANNITOL; STRESS; MECHANISM; PROTECTS; DISTINCT; LACCASE; MUTANT AB Cryptococcus neoformans represents a model organism for the study of virulence and the host response. In this discussion, there is a focus on the genetic, molecular, and biochemical aspects of C. neoformans as it interacts with the host. Investigations into direct and indirect virulence phenotypes are now possible. The molecular aspects of two major virulence factors, capsule and melanin, are characterized. Yeast polyol metabolism through mannitol is examined as a potential biochemical pathway for virulence. The concept of C. neoformans differentially expressed genes within the host or in response to certain environmental cues can be used indirectly to identify potential virulence genes. However, despite significant progress in molecular pathogenesis with C. neoformans, the future of research in this area will require a certain critical mass of investigators to help share in the developmental costs which continue to occur. C1 Duke Univ, Med Ctr, Div Infect Dis, Durham, NC 27710 USA. Yale Univ, Sch Med, Infect Dis Sect, New Haven, CT USA. NIH, Clin Invest Lab, Bethesda, MD 20892 USA. Univ Illinois, Div Infect Dis, Urbana, IL 61801 USA. RP Perfect, JR (reprint author), Duke Univ, Med Ctr, Div Infect Dis, Durham, NC 27710 USA. NR 35 TC 53 Z9 60 U1 1 U2 3 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 1369-3786 J9 MED MYCOL JI Med. Mycol. PD AUG PY 1998 VL 36 SU 1 BP 79 EP 86 PG 8 WC Infectious Diseases; Mycology; Veterinary Sciences SC Infectious Diseases; Mycology; Veterinary Sciences GA 115LG UT WOS:000075665900009 PM 9988495 ER PT J AU Stevens, DA Walsh, TJ Bistoni, F Cenci, E Clemons, KV Del Sero, G D'Ostiani, CF Kullberg, BJ Mencacci, A Roilides, E Romani, L AF Stevens, DA Walsh, TJ Bistoni, F Cenci, E Clemons, KV Del Sero, G D'Ostiani, CF Kullberg, BJ Mencacci, A Roilides, E Romani, L TI Cytokines and mycoses SO MEDICAL MYCOLOGY LA English DT Article; Proceedings Paper CT XIVth Congress of the International-Society-for-Human-and-Animal-Mycology CY JUN 08-13, 1997 CL PARMA, ITALY SP Int Soc Human & Anim Mycol DE cytokines; immunotherapy; immunology; mycoses; cell-mediated immunity ID COLONY-STIMULATING FACTOR; CANDIDA-ALBICANS INFECTION; TUMOR-NECROSIS-FACTOR; ASPERGILLUS-FUMIGATUS HYPHAE; HUMAN POLYMORPHONUCLEAR NEUTROPHILS; BRONCHOALVEOLAR MACROPHAGE DEFENSE; INVASIVE PULMONARY ASPERGILLOSIS; HUMAN-IMMUNODEFICIENCY-VIRUS; RHIZOPUS-ORYZAE HYPHAE; ANTIFUNGAL ACTIVITY AB Cell-mediated immunity (CMI) has been shown, over many decades of clinical observation and bench research, to be central to the outcome of invasive fungal infections. In recent years, understanding the role of messenger molecules (cytokines), in coordinating and augmenting cellular immunity has been ascendant. These studies have made it possible to consider using cytokines, now available in abundant quantities via recombinant DNA technologies, to treat fungal infections. In this symposium, the most important fungal pathogens that cause infections in humans, particularly in immunocompromised patients, are considered, with emphasis on how recent experimental work may lead to a better understanding of the role of cytokines and their use in therapy. C1 Santa Clara Valley Med Ctr, Dept Med, San Jose, CA 95128 USA. Stanford Univ, Sch Med, San Jose, CA 95128 USA. NCI, Immunocompromised Host Sect, Pediat Branch, NIH, Bethesda, MD USA. Univ Perugia, Microbiol Sect, Dept Expt Med & Biochem Sci, I-06100 Perugia, Italy. Catholic Univ Nijmegen, Dept Med, Univ Nijmegen Hosp, Nijmegen, Netherlands. Aristotelian Univ Thessaloniki, Dept Pediat 3, Hippokrat Hosp, Thessloniki, Greece. RP Stevens, DA (reprint author), Santa Clara Valley Med Ctr, Dept Med, San Jose, CA 95128 USA. RI Kullberg, Bart Jan/C-8520-2013 NR 80 TC 25 Z9 26 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 1369-3786 J9 MED MYCOL JI Med. Mycol. PD AUG PY 1998 VL 36 SU 1 BP 174 EP 182 PG 9 WC Infectious Diseases; Mycology; Veterinary Sciences SC Infectious Diseases; Mycology; Veterinary Sciences GA 115LG UT WOS:000075665900020 PM 9988506 ER PT J AU Padhye, AA Bennett, JE McGinnis, MR Sigler, L Flis, A Salkin, IF AF Padhye, AA Bennett, JE McGinnis, MR Sigler, L Flis, A Salkin, IF TI Biosafety considerations in handling medically important fungi SO MEDICAL MYCOLOGY LA English DT Article; Proceedings Paper CT XIVth Congress of the International-Society-for-Human-and-Animal-Mycology CY JUN 08-13, 1997 CL PARMA, ITALY SP Int Soc Human & Anim Mycol DE biosafety principles; medically important fungi; fungal waste disposal; mailing of pathogenic fungi ID LABORATORY-ASSOCIATED INFECTIONS AB Over 500,000 workers in the USA alone are employed in laboratories that range from small physician offices to large clinical laboratories handling microbes for comprehensive research and/or diagnostic work. These workers are exposed to a variety of potential occupational health risks such as exposure to infectious clinical materials, environmental specimens, cultures, complex and inflammable chemicals, radiation, and electrical and mechanical hazards. As members of the International Society for human and Animal Mycology, we have no policy statement on biosafety standards for handling medically important fungi. The intent of the symposium is to cover some of the important aspects of biosafety. (1). standards in handling dimorphic fungal pathogenic; (2) the principles and criteria of biosafety levels and classification of known medically important fungi, aerobic actinomycetes, environmental fungi according to their biosafety levels; (3) medically important fungal waste and its safe disposal; and (4) biosafety and regulatory considerations in handling and mailing medically important fungi in a culture collection. C1 Ctr Dis Control & Prevent, Natl Ctr Infect Dis, Mycot Dis Branch, Atlanta, GA 30333 USA. NIAID, Clin Mycol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. Univ Texas, Med Branch, Med Mycol Res Ctr, Ctr Trop Dis,Dept Pathol, Galveston, TX 77550 USA. Univ Alberta, Microfungus Collect & Herbarium, Edmonton, AB, Canada. Wadsworth Ctr, New Jersey State Dept Hlth, Albany, NY USA. RP Padhye, AA (reprint author), Ctr Dis Control & Prevent, Natl Ctr Infect Dis, Mycot Dis Branch, Atlanta, GA 30333 USA. NR 27 TC 14 Z9 15 U1 0 U2 2 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 1369-3786 J9 MED MYCOL JI Med. Mycol. PD AUG PY 1998 VL 36 SU 1 BP 258 EP 265 PG 8 WC Infectious Diseases; Mycology; Veterinary Sciences SC Infectious Diseases; Mycology; Veterinary Sciences GA 115LG UT WOS:000075665900029 PM 9988515 ER PT J AU Boni, R Vortmeyer, AO Burg, G Hofbauer, G Zhuang, Z AF Boni, R Vortmeyer, AO Burg, G Hofbauer, G Zhuang, Z TI The PTEN tumour suppressor gene and malignant melanoma SO MELANOMA RESEARCH LA English DT Article DE Cowden syndrome; genetic mutation; malignant melanoma; PTEN; tumour suppressor gene ID DISEASE; PROGRESSION; INVOLVEMENT; MUTATIONS; BREAST; CANCER AB A candidate tumour suppressor gene, PTEN, has recently been identified within chromosome 10q23, the locus of the Cowden syndrome/Lhermitte-Duclos disease susceptibility gene. Cowden disease is an autosomal dominant cancer predisposition syndrome associated with tumours of the breast, thyroid and, less frequently, malignant melanoma. Based on the identification of mutations in sporadic breast, brain and prostate tumours, we decided to examine the potential role of PTEN in sporadic malignant melanoma. Frozen tissue from primary cutaneous melanomas (n = 23) and metastases (n = 17) were microdissected, and microsatellite markers D10S541 and D10S547, flanking the gene on both sides, were used to search for loss of heterozygosity (LOH) in the PTEN gene locus. To identify mutations within the putative tumour suppressor gene, we performed single strand conformation polymorphism (SSCP) analysis using intronic primers to amplify exons 5, 6, 7 and 8 of the PTEN gene. No LOH was detected using the polymorphic markers D10S541 and D105547. SSCP analysis revealed no aberrant bands in the tumour specimen. Our results suggest that the PTEN gene does not play a major role in the initiation and progression of melanoma. (C) 1998 Lippincott Williams & Wilkins. C1 Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Boni, R (reprint author), Univ Zurich Hosp, Dept Dermatol, Gloriastr 31, CH-8091 Zurich, Switzerland. RI Hofbauer, Gunther/B-2671-2010 OI Hofbauer, Gunther/0000-0003-0542-7989 NR 16 TC 29 Z9 31 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0960-8931 J9 MELANOMA RES JI Melanoma Res. PD AUG PY 1998 VL 8 IS 4 BP 300 EP 302 PG 3 WC Oncology; Dermatology; Medicine, Research & Experimental SC Oncology; Dermatology; Research & Experimental Medicine GA 122PM UT WOS:000076080700002 PM 9764804 ER PT J AU Fetsch, PA Fetsch, JF Marincola, FM Travis, W Batts, KP Abati, A AF Fetsch, PA Fetsch, JF Marincola, FM Travis, W Batts, KP Abati, A TI Comparison of melanoma antigen recognized by T cells (MART-1) to HMB-45: Additional evidence to support a common lineage for angiomyolipoma, lymphangiomyomatosis, and clear cell sugar tumor SO MODERN PATHOLOGY LA English DT Article DE angiomyolipoma; clear cell sugar tumor; immunohistochemistry; HMB-45; lymphangiomyoma(tosis); MART-1 ID PERIVASCULAR EPITHELIOID CELLS; ANTIBODY HMB-45; RENAL ANGIOMYOLIPOMA; MELANOCYTIC TUMORS; LESIONS; LUNG; LYMPHOCYTES; REACTIVITY; EXPRESSION; FAMILY AB The antibody to the melanoma antigen recognized by T cells (anti-MART-1, clone M2-7C10) is a newly described antibody to a transmembrane protein previously detected only in normal skin melanocytes, retinal tissue, and malignant melanoma (MM), This antibody is the basis for ongoing immunotherapy protocols at the National Institutes of Health/National Cancer Institute. HMB-45, an antibody directed against a premelanosome glycoprotein, although used predominantly for the diagnosis of MM, has shown consistent staining in angiomyolipoma (AML), lymphangiomyoma/lymphangiomyomatosis (LAM), and clear cell sugar tumor (CCST), a group of tumors proposed to be related on the basis of their common perivascular epithelioid cells, which exhibit various degrees of smooth muscle differentiation, melanogenesis, and intracytoplasmic membrane bound granules. To compare the immunoreactive patterns of anti-MART-1 with those of HMB-45, we performed avidin-biotin immunoperoxidase testing on nonmelanocytic neoplasms (AMLs, LAMs, CCSTs) known to express HMB-45, Microwave pretreatment was necessary for anti-MART-1 staining on paraffin-embedded material, Our results showed that all of the 10 cases of AML were immunoreactive for both anti-MART-1 and HMB-45; that all of the 4 cases of LAM were positive for HMB-45, with 1 of the 4 reacting with anti-MART-1; and that 3 of the 4 cases of CCST expressed HMB-45, whereas 1 of the 4 was positive for anti-MART-1. Our findings lent additional support to previous studies that proposed a relationship between AML, LAM, and CCST, Anti-MART-1 and HMB-45 share similar specificities for these nonnelanocytic tumors, but the former seems to be a less sensitive marker for these lesions. In similar circumstances, anti-MART-1 and HMB-45 are potentially useful clinical markers. C1 NCI, NIH, Bethesda, MD 20892 USA. Mayo Clin, Rochester, MN USA. Armed Forces Inst Pathol, Washington, DC 20306 USA. RP Abati, A (reprint author), Pathol Lab, Cytopathol Sect, Bldg 10,Room 2A19,10 Ctr Dr,MSC 1500, Bethesda, MD 20892 USA. NR 30 TC 69 Z9 69 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD AUG PY 1998 VL 11 IS 8 BP 699 EP 703 PG 5 WC Pathology SC Pathology GA 109WT UT WOS:000075347900001 PM 9720495 ER PT J AU Fogt, F Vortmeyer, AO Poremba, C Minda, M Harris, CA Tomaszewski, JE AF Fogt, F Vortmeyer, AO Poremba, C Minda, M Harris, CA Tomaszewski, JE TI bcl-2 expression in normal adrenal glands and in adrenal neoplasms SO MODERN PATHOLOGY LA English DT Article DE adrenal gland; apoptosis; bcl-2; immunohistochemistry ID OUTER MITOCHONDRIAL-MEMBRANE; NORMAL BREAST-TISSUE; MENSTRUAL-CYCLE; ADRENOCORTICAL CARCINOMA; DIFFERENTIAL-DIAGNOSIS; ELECTRON-MICROSCOPY; INDUCED APOPTOSIS; CORTICAL TUMORS; PROTEIN; PHEOCHROMOCYTOMAS AB Archival paraffin-embedded tissue from 5 normal adrenal glands (including 1 from a fetus of 28 weeks' gestation), 6 cases of adrenal cortical hyperplasia, 9 cortical adenomas, 14 cortical carcinomas, and 11 pheochromocytomas were immunostained with monoclonal antibody against bcl-2. Ultrastructural localization of bcl-2 protein was also performed on selected cases. Positive immunostaining for bcl-2 was seen in all of the layers of the normal adrenal cortex, with different staining characteristics. bcl-2 expression was never observed in the normal adrenal medulla Electron microscopic studies revealed bcl-2 to be localized predominantly to mitochondria, with a small number of labels along the nuclear envelope. Analysis of adrenal neoplasms showed expression of bcl-2 in cortical tumors, but only one positive case in pheochromocytomas. Restriction of bcl-2 expression to adrenal cortex-derived tissue versus adrenal medulla-derived tissue might prove to be helpful for the differential diagnosis between cortical and medullary tumors. C1 Univ Penn, Dept Pathol, Philadelphia, PA 19104 USA. Univ Munster, Dept Pathol, Munster, Germany. NCI, NIH, Pathol Lab, Bethesda, MD 20892 USA. RP Fogt, F (reprint author), Univ Penn, Presbyterian Med Ctr, Dept Pathol & Lab Med, 39th & Market St, Philadelphia, PA 19104 USA. NR 28 TC 12 Z9 13 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD AUG PY 1998 VL 11 IS 8 BP 716 EP 720 PG 5 WC Pathology SC Pathology GA 109WT UT WOS:000075347900004 PM 9720498 ER PT J AU Elenitoba-Johnson, KSJ Zarate-Osorno, A Meneses, A Krenacs, L Kingma, DW Raffeld, M Jaffe, ES AF Elenitoba-Johnson, KSJ Zarate-Osorno, A Meneses, A Krenacs, L Kingma, DW Raffeld, M Jaffe, ES TI Cytotoxic granular protein expression, Epstein-Barr virus strain type, and latent membrane protein-1 oncogene deletions in nasal T-lymphocyte natural killer cell lymphomas from Mexico SO MODERN PATHOLOGY LA English DT Article DE Epstein-Barr virus; latent membrane protein; nasal lymphoma ID LYMPHOPROLIFERATIVE DISORDERS; NASOPHARYNGEAL CARCINOMA; POLYMORPHIC RETICULOSIS; MOLECULAR EPIDEMIOLOGY; HODGKINS-DISEASE; B-CELLS; GENE; LMP1; IDENTIFICATION; ACTIVATION AB Nasal T-lymphocyte/natural killer cell lymphomas (nT/NKLs) are a distinct group of neoplasms highly associated with Epstein-Barr virus (EBV), with a high prevalence in Asia but rare in Western countries. Recent studies indicate that these neoplasms are of cytotoxic T- or NK-cell derivation. Previous studies identifying a characteristic 30-base pair deletion within the 3' end of latent membrane protein-1 (del-LMP-l) in other EBV-associated lymphomas suggested a pathogenetic role for del-LMP-1 in those neoplasms. We examined 23 cases of nT/NKL from Mexico for expression of the cytolytic granular proteins TIA-1 and perforin (PRF), and for the presence of EBV by irt situ hybridization (ISH). Polymerase chain reaction was performed to identify the EBV (EBNA-2) strain type and the status of the LMP-1 gene (del-LMP-1). Controls consisted of 11 sinonasal B-cell lymphomas (nBLs) and 30 reactive tonsils (RTs) from healthy Mexican individuals. The nT/NKLs expressed TIA-1 in 21 (91%) of 23 cases and PRF in 15 (65%) of 23 cases. In contrast, all of the nBLs were negative for TIA-1 and PRF. Twenty-two (96%) of 23 nT/NKLs were positive for EBV by ISH. In contrast, only 2 (18%) of 11 nBLs were positive for EBV by ISH. EBV strain Type A was identified in 21 (91%) of 23 cases, whereas strain Type B was present in 2 (9%) of the 23 nT/NKLs. A similar percentage (80%) of Type A was noted in 12 of the 15 RTs. del-LMP-1 was detected in 6 (26%) of 23 nT/NKLs, comprising 4 cases of Type A and 2 of Type B. del-LMP-l was detected in 9 (45%) of 20 RTs, Our results indicated that TIA-I and PRF were sensitive markers of nT/NKL. The presence of del-LMP-1 in comparable frequencies in the RTs and nT/NKLs suggested to us that this genotype was common in the Mexican population and argued against a definite pathogenetic role for del-LMP-l in nT/NKL. C1 NCI, Hematopathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. Hosp Cent Militar, Lomas De Sotelo, Mexico. Inst Natl Cancerol, Mexico City, DF, Mexico. RP Jaffe, ES (reprint author), NCI, Hematopathol Sect, Pathol Lab, NIH, Bldg 10,Room 2N202,10 Ctr Dr,MSC 1500, Bethesda, MD 20892 USA. EM elainejaffe@nih.gov RI Krenacs, Laszlo/L-8063-2014 OI Krenacs, Laszlo/0000-0001-6541-3031 NR 39 TC 48 Z9 51 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD AUG PY 1998 VL 11 IS 8 BP 754 EP 761 PG 8 WC Pathology SC Pathology GA 109WT UT WOS:000075347900010 PM 9720504 ER PT J AU Tse, C Sera, T Wolffe, AP Hansen, JC AF Tse, C Sera, T Wolffe, AP Hansen, JC TI Disruption of higher-order folding by core histone acetylation dramatically enhances transcription of nucleosomal arrays by RNA polymerase III SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID AGAROSE-GEL ELECTROPHORESIS; TAIL DOMAINS; CHROMATIN; DNA; HYPERACETYLATION; GENES; ACTIVATION; STABILITY; BINDING; OLIGONUCLEOSOMES AB We have examined the effects of core histone acetylation on the transcriptional activity and higher-order folding of defined 12-mer nucleosomal arrays. Purified HeLa core histone octamers containing an average of 2, 6, or 12 acetates per octamer (8, 23, or 46% maximal site occupancy, respectively) were assembled onto a DNA template consisting of 12 tandem repeats of a 208-bp Lytechinus 5S rRNA gene fragment. Reconstituted nucleosomal arrays were transcribed in a Xenopus oocyte nuclear extract and analyzed by analytical hydrodynamic and electrophoretic approaches to determine the extent of array compaction. Results indicated that in buffer containing 5 mM free Mg2+ and 50 mM KCI, high levels of acetylation (12 acetates/octamer) completely inhibited higher-order folding and concurrently led to a Is'-fold enhancement of transcription by RNA polymerase III. The molecular mechanisms underlying the acetylation effects on chromatin condensation were investigated by analyzing the ability of differentially acetylated nucleosomal arrays to fold and oligomerize. In MgCl2-containing buffer the folding of 12-mer nucleosomal arrays containing an average of two or six acetates per histone octamer was indistinguishable, while a level of 12 acetates per octamer completely disrupted the ability of nucleosomal arrays to form higher-order folded structures at all ionic conditions tested. In contrast, there was a linear relationship between the extent of histone octamer acetylation and the extent of disruption of Mg2+-dependent oligomerization. These results have yielded new insight into the molecular basis of acetylation effects on both transcription and higher-order compaction of nucleosomal arrays. C1 Univ Texas, Hlth Sci Ctr, Dept Biochem, San Antonio, TX 78284 USA. NICHHD, NIH, Mol Embryol Lab, Bethesda, MD 20892 USA. RP Hansen, JC (reprint author), Univ Texas, Hlth Sci Ctr, Dept Biochem, 7703 Floyd Curl Dr, San Antonio, TX 78284 USA. FU NIGMS NIH HHS [GM45916, R01 GM045916] NR 71 TC 397 Z9 405 U1 2 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 1998 VL 18 IS 8 BP 4629 EP 4638 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 102WX UT WOS:000074950000024 PM 9671473 ER PT J AU Phan, L Zhang, XL Asano, K Anderson, J Vornlocher, HP Greenberg, JR Qin, J Hinnebusch, AG AF Phan, L Zhang, XL Asano, K Anderson, J Vornlocher, HP Greenberg, JR Qin, J Hinnebusch, AG TI Identification of a translation initiation factor 3 (eIF3) core complex, conserved in yeast and mammals, that interacts with eIF5 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PROTEIN-SYNTHESIS INITIATION; SACCHAROMYCES-CEREVISIAE; RABBIT RETICULOCYTES; WHEAT-GERM; START-SITE; FACTOR-III; SUBUNIT; BINDING; GENE; SELECTION AB Only five of the nine subunits of human eukaryotic translation initiation factor 3 (eIF3) have recognizable homologs encoded in the Saccharomyces cerevisiae genome, and only two of these (Prt1p and Tif34p) were identified previously as subunits of yeast eIF3. We purified a polyhistidine-tagged form of Prt1p (His-Prt1p) by Ni2+ affinity and gel filtration chromatography and obtained a complex of approximate to 600 kDa composed of six polypeptides whose copurification was completely dependent on the polyhistidine tag on His-Prt1p. All five polypeptides associated with His-Prt1p were identified by mass spectrometry, and four were found to be the other putative homologs of human eIF3 subunits encoded in S. cerevisiae: YBR079c/Tif32p, Nip1p, Tif34p, and YDR429c/Tif35p. The fifth Prt1p-associated protein was eIF5, an initiation factor not previously known to interact with eIF3. The purified complex could rescue Met-tRNA(i)(Met) binding to 40S ribosomes in defective extracts from a prt1 mutant or extracts from which Nip1p had been depleted, indicating that it possesses a known biochemical activity of eIF3. These findings suggest that Tif32p, Nip1p, Prt1p, Tif34p, and Tif35p comprise an eIF3 core complex, conserved between yeast and mammals, that stably interacts with eIF5. Nip1p bound to eIF5 in yeast two-hybrid and in vitro protein binding assays. Interestingly, Sui1p also interacts with Nip1p, and both eIF5 and Sui1p have been implicated in accurate recognition of the AUG start codon. Thus, eIF5 and Sui1p may be recruited to the 40S ribosomes through physical interactions with the Nip1p subunit of eIF3. C1 NICHHD, Lab Eukayot Gene Regulat, NIH, Bethesda, MD 20892 USA. NHLBI, Biophys Chem Lab, Bethesda, MD 20892 USA. Univ Calif Davis, Dept Biol Chem, Davis, CA USA. Univ Rochester, Dept Biol, Rochester, NY 14627 USA. RP Hinnebusch, AG (reprint author), NICHHD, Lab Eukayot Gene Regulat, NIH, Bldg 6A,Room B1A-13, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov NR 62 TC 137 Z9 145 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 1998 VL 18 IS 8 BP 4935 EP 4946 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 102WX UT WOS:000074950000052 PM 9671501 ER PT J AU Kustova, Y Espey, MG Sung, EG Morse, D Sei, Y Basile, AS AF Kustova, Y Espey, MG Sung, EG Morse, D Sei, Y Basile, AS TI Evidence of neuronal degeneration in C57Bl/6 mice infected with the LP-BM5 leukemia retrovirus mixture SO MOLECULAR AND CHEMICAL NEUROPATHOLOGY LA English DT Article DE AIDS dementia complex; mice; murine leukemia virus; neuron damage ID INDUCED IMMUNODEFICIENCY SYNDROME; CENTRAL-NERVOUS-SYSTEM; NMDA RECEPTOR; NEOCORTICAL DAMAGE; DEFECTIVE VIRUS; QUINOLINIC ACID; BRAIN INJURY; HIV DEMENTIA; MURINE AIDS; GLUTAMATE AB Mice infected with LP-BM5 develop a severe immunodeficiency accompanied by learning and memory deficits, gliosis, and neurotransmitter abnormalities. The neurochemical alterations are consistent with elevated excitotoxin levels, suggesting that infected mice may incur neuronal damage. Although the number of neocortical neurons was unchanged in mice 12 wk after LP-BM5 infection, the expression of cytoskeletal proteins declined, particularly in the frontal and parietal cortex as indicated by MAP2 NF-200, and synaptophysin immunoreactivity. In contrast, the number of striatal neurons decreased 19%. The remaining neurons were smaller, with fewer synaptic boutons, and showed decreased synaptophysin and NF-200, immunoreactivity. Immunoblots of cortex and striatum confirmed decreases in MAP2, NF-200 and synaptophysin expression. Finally, although NCAM expression decreased in the striatum, it increased in the cortex. These results indicate that LP-BM5-infected mice sustain significant neuronal damage, which may contribute to their behavioral deficits. Moreover, the increase in cortical NCAM expression suggests active synaptic remodeling to compensate for the persistent excitotoxic environment in these mice, whereas striatal neurons degenerate. These concurrent degenerative and compensatory processes may also occur in the brains of patients with AIDS dementia complex (ADC), who suffer extensive degeneration of the basal ganglia and cerebral cortex. C1 NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Yeungnam Univ, Med Ctr, Dept Anat, Taegu, South Korea. Uniformed Serv Univ Hlth Sci, Dept Anesthesiol, Bethesda, MD 20814 USA. RP Basile, AS (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NR 35 TC 20 Z9 20 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1044-7393 J9 MOL CHEM NEUROPATHOL JI Mol. Chem. Neuropathol. PD AUG-DEC PY 1998 VL 35 IS 1-3 BP 39 EP 59 DI 10.1007/BF02815115 PG 21 WC Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 196MH UT WOS:000080311800004 PM 10343970 ER PT J AU Ardini, E Pesole, G Tagliabue, E Magnifico, A Castronovo, V Sobel, ME Colnaghi, MI Menard, S AF Ardini, E Pesole, G Tagliabue, E Magnifico, A Castronovo, V Sobel, ME Colnaghi, MI Menard, S TI The 67-kDa laminin receptor originated from a ribosomal protein that acquired a dual function during evolution SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE evolution; ribosomal proteins; monomeric laminin receptor; adhesion molecules; tumor aggressiveness; metastasis ID BINDING-PROTEIN; DIFFERENTIAL EXPRESSION; MESSENGER-RNAS; CELL; METASTASIS; HOMOLOGY; SEQUENCE; CANCER; GENE; CARCINOMAS AB The 67-kDa laminin receptor (67LR) is a nonintegrin cell surface receptor that mediates high-affinity interactions between cells and laminin. Overexpression of this protein in tumor cells has been related to tumor invasion and metastasis. Thus far, only a full-length gene encoding a 37-kDa precursor protein (37LRP) has been isolated. The finding that the cDNA for the 37LRP is virtually identical to a cDNA encoding the ribosomal protein p40 has suggested that 37LRP is actually a component of the translational machinery, with no laminin-binding activity. On the other hand, a peptide of 20 amino acids deduced from the sequence of 37LRP/p40 was shown to exhibit high laminin-binding activity. The evolutionary relationship between 23 sequences of 37LRP/p40 proteins was analyzed. This phylogenetic analysis indicated that all of the protein sequences derive from orthologous genes and that the 37LRP is indeed a ribosomal protein that acquired the novel function of laminin receptor during evolution. The evolutionary analysis of the sequence identified as the laminin-binding site in the human protein suggested that the acquisition of the laminin-binding capability is linked to the palindromic sequence LMWWML, which appeared during evolution concomitantly with laminin. C1 Ist Nazl Tumori, Div Expt Oncol E, I-20133 Milan, Italy. Univ Basilicata, Dept Biol DBAF, I-85100 Potenza, Italy. Univ Liege, Metastasis Res Lab, Liege, Belgium. NCI, Mol Biol Sect, Bethesda, MD USA. RP Menard, S (reprint author), Ist Nazl Tumori, Div Expt Oncol E, Via Venezian 1, I-20133 Milan, Italy. EM menard@istitutotumori.mi.it RI Pesole, Graziano/C-1408-2009; Pesole, Graziano/E-9051-2014; Tagliabue, Elda/B-9377-2017 OI Pesole, Graziano/0000-0003-3663-0859; Pesole, Graziano/0000-0003-3663-0859; Tagliabue, Elda/0000-0001-9877-2903 NR 46 TC 95 Z9 103 U1 0 U2 7 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 AUG PY 1998 VL 15 IS 8 BP 1017 EP 1025 PG 9 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 109PR UT WOS:000075332400009 PM 9718729 ER PT J AU Frolenkov, GI Atzori, M Kalinec, F Mammano, F Kachar, B AF Frolenkov, GI Atzori, M Kalinec, F Mammano, F Kachar, B TI The membrane-based mechanism of cell motility in cochlear outer hair cells SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID ELECTROKINETIC SHAPE CHANGES; VOLTAGE SENSOR; RESPONSES; AMPLIFIER; ORGAN; ELECTROMOTILITY; STIMULATION; CAPACITANCE; INHIBITION; SPECTRIN C1 NIDODS, Sect Struct Cell Biol, NIH, Bethesda, MD 20852 USA. House Ear Inst, Dept Cell & Mol Biol, Los Angeles, CA 90057 USA. Int Sch Adv Studies, Biophys Lab, Trieste, Italy. RP Frolenkov, GI (reprint author), NIDODS, Sect Struct Cell Biol, NIH, Bethesda, MD 20852 USA. RI Mammano, Fabio/I-5064-2012 OI Mammano, Fabio/0000-0003-3751-1691 NR 50 TC 31 Z9 33 U1 0 U2 4 PU AMER SOC CELL BIOLOGY PI BETHESDA PA PUBL OFFICE, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD AUG PY 1998 VL 9 IS 8 BP 1961 EP 1968 PG 8 WC Cell Biology SC Cell Biology GA 109WY UT WOS:000075348400002 PM 9693359 ER PT J AU Yu, WP Simmons-Menchaca, M You, HH Brown, P Birrer, MJ Sanders, BG Kline, K AF Yu, WP Simmons-Menchaca, M You, HH Brown, P Birrer, MJ Sanders, BG Kline, K TI RRR-alpha-tocopheryl succinate induction of prolonged activation of c-jun amino-terminal kinase and c-jun during induction of apoptosis in human MDA-MB-435 breast cancer cells SO MOLECULAR CARCINOGENESIS LA English DT Article DE AP-1 transactivation; apoptosis; c-Jun; JNK; human breast cancer cells; vitamin E succinate ID VITAMIN-E SUCCINATE; GROWTH-FACTOR-BETA; DOMINANT-NEGATIVE MUTANT; PROTEIN-KINASES; TRANSFORMING GROWTH-FACTOR-BETA-1; INHIBITS PROLIFERATION; TRANSCRIPTION FACTORS; SIGNAL-TRANSDUCTION; PERILLYL ALCOHOL; GENE-EXPRESSION AB We have demonstrated that RRR-alpha-tocopheryl succinate (10 mu g/mL vitamin E succinate (VES) treatment of estrogen receptor-negative MDA-MB-435 human breast cancer cells induces 9, 19, 51, and 72% apoptotic cells on days 1-4, respectively, after treatment, which involves transforming growth factor-beta signaling. Here, we show that VES-triggered apoptosis of MDA-MB-435 cells induced prolonged elevated expression of c-jun mRNA and protein (neither of which was caused by major increases in stability) and also induced enhanced activator protein-1 (AP-1) binding to the consensus DNA oligomer. Furthermore, VES treatments resulted in increased AP-1 transactivation activity, as measured with an AP-1 promoter/luciferase reporter construct and by the measurement of increased mRNA expression of the AP-1-dependent endogenous gene collagenase. Evidence of VES-induced involvement of the c-jun amino-terminal kinase in these AP-1-dependent events was suggested by data showing prolonged activity of this kinase, as measured by a kinase assay using glutathione S-transferase-c-jun as the substrate. The c-jun-dependent transcriptional activity was verified by cotransfection of a chimeric transcription factor having a galactose 4 DNA-binding domain coupled with the transactivation domain of c-jun plus the reporter plasmid 5X GAL4-luciferase. MDA-MB-435 cells infected with an adenovirus expression Vector containing the TAM-67 sequence for dominant/negative-acting mutant c-jun or transiently transfected with c-jun antisense exhibited a 50-77% reduction in VES-mediated apoptosis as compared with control adenovirus-infected or control sense oligomer-transfected cells. Mel. Carcinog. 22:247-257, 1998. (C) 1998 Wiley-Liss. Inc. C1 Univ Texas, Div Nutr, Austin, TX 78712 USA. Univ Texas, Dept Zool, Austin, TX 78712 USA. Univ Texas, Hlth Sci Ctr, Div Med Oncol, San Antonio, TX USA. NCI, NIH, Rockville, MD USA. RP Univ Texas, Div Nutr, A2703, Austin, TX 78712 USA. FU NCI NIH HHS [CA 59739] NR 61 TC 48 Z9 53 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 EI 1098-2744 J9 MOL CARCINOGEN JI Mol. Carcinog. PD AUG PY 1998 VL 22 IS 4 BP 247 EP 257 DI 10.1002/(SICI)1098-2744(199808)22:4<247::AID-MC6>3.3.CO;2-P PG 11 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 112YD UT WOS:000075521700005 PM 9726817 ER PT J AU Iwata, F Kuehl, EM Reed, GF McCain, LM Gahl, WA Kaiser-Kupfer, MI AF Iwata, F Kuehl, EM Reed, GF McCain, LM Gahl, WA Kaiser-Kupfer, MI TI A randomized clinical trial of topical cysteamine disulfide (cystamine) versus free thiol (cysteamine) in the treatment of corneal cystine crystals in cystinosis SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE cysteamine; cystamine; cystinosis; corneal crystals; cystine ID NEPHROPATHIC CYSTINOSIS; EYE DROPS; THERAPY; CHILDREN; REGION; 17P13; GENE AB In nephropathic cystinosis, corneal cystine crystals cause severe photophobia and corneal erosions. Topical cysteamine dissolves these crystals, but cannot be marketed because it rapidly oxidizes to the disulfide form, cystamine, at room temperature. Since cystamine itself could be used commercially, we compared the efficacy of cystamine and cysteamine with respect to cystine crystal dissolution in a randomized, double-masked clinical trial. One eye each of 14 patients with cystinosis was randomized to either cystamine or cysteamine, 0.5%, with 0.01% benzalkonium chloride; the companion eye was treated with the alternate preparation. Corneal crystals were photographed and a density score was assigned to each slide based on 13 standard slides. After 8-20 months, 6 patients showed significant reduction of the corneal crystal score in only one eye. In each case, the improved eye was the cysteamine-treated eye. Theoretically, cysteamine should dissolve both intracellular and extracellular crystals, whereas cystamine should dissolve only intracellular crystals because it must first be reduced to the free thiol by the cytoplasmic-reducing environment. Hence, the lack of efficacy of the disulfide cystamine suggests that some corneal cystine crystals in cystinosis patients are extracellular, and that another form of stable, topical cysteamine must be developed for cystinosis patients, (C) 1998 Academic Press. C1 NEI, Ophthalm Genet & Clin Serv Branch, NIH, Bethesda, MD 20892 USA. NEI, Biometry Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Sect Human Biochem Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Kaiser-Kupfer, MI (reprint author), NEI, Ophthalm Genet & Clin Serv Branch, NIH, 10 Ctr Dr,MSC 1860,Bldg 10,Room 10N-226, Bethesda, MD 20892 USA. EM kaiserm@box-k.nih.gov NR 22 TC 23 Z9 26 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD AUG PY 1998 VL 64 IS 4 BP 237 EP 242 DI 10.1006/mgme.1998.2725 PG 6 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 125FQ UT WOS:000076227100003 PM 9758713 ER PT J AU Wu, SM Stratakis, CA Chan, CHY Hallermeier, KM Bourdony, CJ Rennert, OM Chan, WY AF Wu, SM Stratakis, CA Chan, CHY Hallermeier, KM Bourdony, CJ Rennert, OM Chan, WY TI Genetic heterogeneity of adrenocorticotropin (ACTH) resistance syndromes: Identification of a novel mutation of the ACTH receptor gene in hereditary glucocorticoid deficiency SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE glucocorticoid deficiency; ACTH receptor; inactivation; signal transduction ID TRIPLE-A SYNDROME; MELANOCORTIN RECEPTORS; HORMONE; UNRESPONSIVENESS; ABNORMALITIES; ACHALASIA; SEQUENCE; FAMILIES AB Hereditary primary adrenal insufficiency syndromes due to ACTH resistance include hereditary glucocorticoid deficiency (HGD) and Allgrove's syndrome (AS). Patients with both conditions present in childhood with failure to thrive, weakness, and fatigue or adrenal crisis; patients with AS in addition have alacrima and achalasia (triple A syndrome). me studied four kindreds with HGD and four kindreds with AS for abnormalities of the ACTH receptor (ACTHR) gene. The ACTHR coding sequence in all AS kindreds and two HGD kindreds was normal. Analysis of the ACTHR gene of the proband in one of the HGD kindreds showed him to be homozygous for the previously described G221T transition causing a Ser74Ile substitution of the protein, which has been shown to inactivate the ACTHR in signal transduction. The proband in another HGD kindred was found to be a compound heterozygote with the G221T transition in one allele and a novel C818A transition in the other allele of ACTHR The C818A transition caused the substitution of the highly conserved Pro273 by His in the receptor protein. In vitro expression of the mutated ACTHR in mouse melanoma M3 cells showed that at a medium ACTH concentration of 3 nM, cells transfected with the wild-type ACTHR produced twofold and threefold, respectively, of the amount of intracellular cAMP when compared to cells transfected with the ACTHR carrying the Pro273His and the Ser74Ile mutation, respectively, confirming that HGD in this kindred is caused by loss-of-function mutations of the ACTHR, These results showed that the genetic cause of the ACTH-resistant syndromes is heterogeneous. (C) 1998 Academic Press. C1 Georgetown Univ, Childrens Med Ctr, Dept Pediat, Washington, DC 20007 USA. Georgetown Univ, Dept Biochem Mol Biol & Cell Biol, Washington, DC 20007 USA. Georgetown Univ, Dept Biol, Washington, DC 20007 USA. NICHHD, Unit Genet & Endocrinol, Sect Pediat Endocrinol, Dev Endocrinol Branch, Bethesda, MD 20892 USA. San Juan City Hosp, Dept Pediat, San Juan, PR 00907 USA. RP Chan, WY (reprint author), Georgetown Univ, Childrens Med Ctr, Dept Pediat, 3800 Reservoir Rd NW, Washington, DC 20007 USA. EM wchan02@gumedlib.dml.georgetown.edu FU NICHD NIH HHS [HD-31553] NR 32 TC 32 Z9 34 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD AUG PY 1998 VL 64 IS 4 BP 256 EP 265 DI 10.1006/mgme.1998.2724 PG 10 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 125FQ UT WOS:000076227100006 PM 9758716 ER PT J AU Parolini, O Ressmann, G Haas, OA Klepal, W Nelson, D Gadner, H Knapp, W Holter, W AF Parolini, O Ressmann, G Haas, OA Klepal, W Nelson, D Gadner, H Knapp, W Holter, W TI Molecular and cellular characterization of X-linked was in a girl SO MOLECULAR IMMUNOLOGY LA English DT Meeting Abstract C1 Univ Vienna, Inst Immunol, Vienna, Austria. Univ Vienna, Inst Zool, Vienna, Austria. St Anna Childrens Hosp, A-1090 Vienna, Austria. NIH, Metab Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 3 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 AUG PY 1998 VL 35 IS 11-12 BP 718 EP 718 DI 10.1016/S0161-5890(98)90379-0 PG 1 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 131BA UT WOS:000076554800047 ER PT J AU Facchetti, F Blanzuoli, L Vermi, W Notarangelo, LD Nelson, DL AF Facchetti, F Blanzuoli, L Vermi, W Notarangelo, LD Nelson, DL TI Defective actin polymerization in patients with the Wiskott-Aldrich syndrome. SO MOLECULAR IMMUNOLOGY LA English DT Meeting Abstract C1 Univ Brescia, Dept Pathol, Brescia, Italy. Univ Brescia, Dept Pediat, Brescia, Italy. NCI, Immunopathol Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. RI Notarangelo, Luigi/F-9718-2016; Facchetti, Fabio/E-7190-2010 OI Notarangelo, Luigi/0000-0002-8335-0262; Facchetti, Fabio/0000-0003-4975-2388 NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD AUG PY 1998 VL 35 IS 11-12 BP 734 EP 734 DI 10.1016/S0161-5890(98)90405-9 PG 1 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 131BA UT WOS:000076554800073 ER PT J AU Grimbacher, B Dutra, A Holland, S Gallin, J Puck, J AF Grimbacher, B Dutra, A Holland, S Gallin, J Puck, J TI Hyper-IgE recurrent infection syndrome (HIERIS): New clinical features, family studies and a case with cytogenetic anomaly SO MOLECULAR IMMUNOLOGY LA English DT Meeting Abstract C1 NHGRI, NIH, Bethesda, MD USA. NIAID, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD AUG PY 1998 VL 35 IS 11-12 BP 750 EP 750 DI 10.1016/S0161-5890(98)90437-0 PG 1 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 131BA UT WOS:000076554800105 ER PT J AU Ming, JE Roessler, E Muenke, M AF Ming, JE Roessler, E Muenke, M TI Human developmental disorders and the Sonic hedgehog pathway SO MOLECULAR MEDICINE TODAY LA English DT Review ID CELL CARCINOMA SYNDROME; CANDIDATE GENE; HUMAN HOMOLOG; MUTATIONS; DROSOPHILA; RECEPTOR; ENCODES; PROTEIN AB Sonic hedgehog (Shh) is a morphogen that is crucial for normal development of a variety of organ systems, including the brain and spinal cord, the eye, craniofacial structures, and the limbs, Mutations in the human SHH gene and genes that encode its downstream Intracellular signaling pathway cause several clinical disorders, These include holoprosencephaly (HPE, the most common anomaly of the developing forebrain), nevoid basal cell carcinoma syndrome, sporadic tumors, including basal cell carcinomas, and three distinct congenital disorders: Greig syndrome Pallister-Hall syndrome, and isolated postaxial polydactyly, These conditions caused by abnormalities in the SHH pathway demonstrate the crucial role of SHH in complex developmental processes, and molecular analyses of these disorders provide insight into the normal function of the SHH pathway in human development. C1 Univ Penn, Childrens Hosp Philadelphia, Sch Med, Dept Pediat,Div Human Genet & Mol Biol, Philadelphia, PA 19104 USA. Natl Human Genome Res Inst, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Penn, Childrens Hosp Philadelphia, Sch Med, Dept Pediat,Div Neurol, Philadelphia, PA 19104 USA. Univ Penn, Childrens Hosp Philadelphia, Sch Med, Dept Genet,Div Neurol, Philadelphia, PA 19104 USA. RP Ming, JE (reprint author), Univ Penn, Childrens Hosp Philadelphia, Sch Med, Dept Pediat,Div Human Genet & Mol Biol, Philadelphia, PA 19104 USA. EM mmuenke@nhgri.nih.gov FU NICHD NIH HHS [5T32HD07107, HD28732, HD29862] NR 49 TC 112 Z9 116 U1 1 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1357-4310 J9 MOL MED TODAY JI Mol. Med. Today PD AUG PY 1998 VL 4 IS 8 BP 343 EP 349 DI 10.1016/S1357-4310(98)01299-4 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 108HN UT WOS:000075260400011 PM 9755453 ER PT J AU Tang, WJ Hurley, JH AF Tang, WJ Hurley, JH TI Catalytic mechanism and regulation of mammalian adenylyl cyclases SO MOLECULAR PHARMACOLOGY LA English DT Review ID PROTEIN-KINASE-C; CALMODULIN-BINDING DOMAIN; BETA-GAMMA-SUBUNITS; GUANYLYL CYCLASE; NCB-20 CELLS; IN-VIVO; INHIBITION; FORSKOLIN; PURIFICATION; ALPHA C1 Univ Chicago, Dept Pharmacol & Physiol Sci, Chicago, IL 60637 USA. NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Tang, WJ (reprint author), Univ Chicago, Dept Pharmacol & Physiol Sci, 947 E 58Th St,MC 0926, Chicago, IL 60637 USA. EM tang@drugs.bsd.uchicngo.edu OI Tang, Wei-Jen/0000-0002-8267-8995 FU NIGMS NIH HHS [GM53459] NR 77 TC 154 Z9 157 U1 0 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 AUG PY 1998 VL 54 IS 2 BP 231 EP 240 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 108CW UT WOS:000075249300001 PM 9687563 ER PT J AU Neamati, N Mazumder, A Sunder, S Owen, JM Tandon, M Lown, JW Pommier, Y AF Neamati, N Mazumder, A Sunder, S Owen, JM Tandon, M Lown, JW Pommier, Y TI Highly potent synthetic polyamides, bisdistamycins, and lexitropsins as inhibitors of human immunodeficiency virus type 1 integrase SO MOLECULAR PHARMACOLOGY LA English DT Article ID COMBINATION THERAPY; ANTIVIRAL ACTIVITY; DNA INTEGRATION; AGENTS; DISTAMYCIN; BINDING; RESISTANCE; STRATEGIES; INFECTIONS; MECHANISM AB Alignment of the available human immunodeficiency virus type 1 (HIV-1) viral DNA termini [U5 and U3 long terminal repeats (LTRs)] shows a high degree of conservation and the presence of a stretch of five or six consecutive adenine and thymine (AT) sequences similar to 10 nucleotides away from each LTR end. A series of AT-selective minor-groove binders, including distamycin and bisdistamycins, bisnetropsins, novel lexitropsins, and the classic monomeric DNA binders Hoechst 33258, 4'-diamino-2-phenylindole, pentamidine, berenil, spermine, and spermidine, were tested for their inhibitory activities against HIV-1 integrase (IN). Although netropsin, distamycin, and all other monomeric DNA binders showed weak activities in the range of 50-200 mu M, some of the polyamides, bisdistamycins, and lexitropsins were remarkably active at nanomolar concentrations. Bisdistamycins were 200 times less potent when the conserved AAAAT stretch present in the U5 LTR was replaced with GGGGG, consistent with the preferred binding of these drugs to AT sequences. DNase I footprinting of the U5 LTR further demonstrated the selectivity of these bisdistamycins for the conserved AT sequence. The tested compounds were more potent in Mg+2 than in Mn+2 and inhibited IN50-212 deletion mutant in disintegration assays and the formation of IN/DNA complexes. The lexitropsins also were active against HIV-2 IN. Some of the synthetic polyamides exhibited significant antiviral activity. Taken together, these data suggest that selective targeting of the U5 and U3 ends of the HIV-1 LTRs can inhibit IN function. Polyamides might represent new leads for the development of antiviral agents against acquired immune deficiency syndrome. C1 NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Univ Alberta, Dept Chem, Edmonton, AB T6G 2G2, Canada. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bldg 37,Rm 5D02, Bethesda, MD 20892 USA. EM pommier@nih.gov NR 39 TC 58 Z9 61 U1 0 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 AUG PY 1998 VL 54 IS 2 BP 280 EP 290 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 108CW UT WOS:000075249300007 PM 9687569 ER PT J AU Zaher, H Fernandez-Salguero, PM Letterio, J Sheikh, MS Fornace, AJ Roberts, AB Gonzalez, FJ AF Zaher, H Fernandez-Salguero, PM Letterio, J Sheikh, MS Fornace, AJ Roberts, AB Gonzalez, FJ TI The involvement of aryl hydrocarbon receptor in the activation of transforming growth factor-beta and apoptosis SO MOLECULAR PHARMACOLOGY LA English DT Article ID ADULT-RAT HEPATOCYTES; AH-RECEPTOR; IMMUNOHISTOCHEMICAL DETECTION; PRIMARY CULTURE; FACTOR-BETA-1; LIVER; INDUCTION; TISSUE; MOUSE; MICE AB The aryl hydrocarbon receptor (AHR) is believed to mediate many of the toxic, carcinogenic, and teratogenic effects of environmental contaminants such as dioxins, polycyclic aromatic hydrocarbons, and polyhalogenated biphenyls. Ligands for the AHR have been shown to influence cell proliferation, differentiation, and apoptosis, but the mechanism by which the AHR affects the cell cycle is not known. Increased levels of mature transforming growth factor-beta (TGF beta) has been correlated with reduced cell proliferation and increased rates of apoptosis and fibrosis. Based on the increase in portal fibrosis and small liver size observed in AHR-null (Ahr(-/-)) mice, the relationship between TGF beta expression and apoptosis in this mouse line was analyzed. Livers from Ahr(-/-) mice had marked increase in active TGF beta 1 and TGF beta 3 proteins and elevated numbers of hepatocytes undergoing apoptosis compared with wild-type mice. Furthermore, increases in TGF beta and apoptotic cells were found in the portal areas of the liver, where fibrosis is found in the Ahr(-/-) mice. In vitro, primary hepatocyte cultures from Ahr(-/-) mice exhibited a high number of cells in later stages of apoptosis and an elevated secretion of active TGF beta into the media compared with cultures from wild-type mice, which have previously been shown to secrete only latent forms of the molecule. Conditioned media from Ahr(-/-) hepatocytes stimulated apoptosis in cultured hepatocytes from wild-type mice. Taken together, these findings suggest that the phenotypic abnormalities in Ahr(-/-) mice could be mediated in part by abnormal levels of active TGF beta and altered cell cycle control. C1 NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. NCI, Chemoprevent Lab, NIH, Bethesda, MD 20892 USA. RP NCI, Lab Metab, NIH, Bldg 37,Rm 3E-24, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X NR 51 TC 105 Z9 107 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X EI 1521-0111 J9 MOL PHARMACOL JI Mol. Pharmacol. PD AUG PY 1998 VL 54 IS 2 BP 313 EP 321 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 108CW UT WOS:000075249300011 PM 9687573 ER PT J AU Silvente-Poirot, S Escrieut, C Wank, SA AF Silvente-Poirot, S Escrieut, C Wank, SA TI Role of the extracellular domains of the cholecystokinin receptor in agonist binding SO MOLECULAR PHARMACOLOGY LA English DT Article ID LIGAND-BINDING; FUNCTIONAL EXPRESSION; A RECEPTOR; IDENTIFICATION; ANTAGONIST; RESIDUES; AFFINITY; PURIFICATION; LOCALIZATION; MUTAGENESIS AB The cholecystokinin (CCK) receptor types A and B (CCKAR and CCKBR) are G protein-coupled receptors with approximately 50% amino acid identity; both have high affinity for the sulfated CCK octapeptide (CCK-8), whereas only the CCKBR has high affinity for gastrin. Previously, we identified five amino acids in the second extracellular loop (ECL) of the CCKBR that were essential for gastrin selectivity. Subsequent mutagenesis of one of these five amino acids (H207F) resulted in the loss of radiolabeled CCK-8 binding. CCK-8 stimulated total inositol phosphate accumulation in COS-1 cells transiently expressing the CCKBR-H207F with full efficacy and a 3044-fold reduced potency, which suggests that the loss of radioligand binding was caused by a loss in affinity. Alanine scanning mutagenesis was performed on the amino terminus near the top of transmembrane domain I (TM) and on ECL1, two extracellular domains implicated in ligand binding by previous mutagenesis studies. (125)-Bolton-Hunter-CCK-8 binding to mutant receptors transiently expressed in COS-1 identified one nonconserved amino acid, R57A, at the top of TMI that caused a 21-fold reduction in CCK-8 affinity and four conserved amino acids, N115A, L116A, F120A and F122A, in the ECL1 that caused a 15.6-, 6-, 440-, and 8-fold reduction in affinity or efficacy. Alanine substitution of the equivalent amino acids in the CCKAR corresponding to each of the five amino acids in ECL1 and ECL2 affecting CCK-8 affinity for the CCKBR revealed only two mutations, L103A and F107A, that decreased CCK-8 affinity (68- and 2885-fold, respectively). These data suggest that CCK-8 interacts at multiple contact points in the extracellular domains of CCK receptors and that the CCKAR and CCKBR have distinct binding sites despite their shared high affinity for CCK-8. C1 NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. CHU Rangueil, INSERM, U151, F-31403 Toulouse, France. RP Wank, SA (reprint author), NIDDKD, Digest Dis Branch, NIH, Bldg 10,Room 9C-103, Bethesda, MD 20892 USA. EM stevew@bdg10.niddk.nih.gov RI Poirot, Sandrine/D-5448-2017 NR 35 TC 58 Z9 59 U1 2 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD AUG PY 1998 VL 54 IS 2 BP 364 EP 371 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 108CW UT WOS:000075249300016 PM 9687578 ER PT J AU Hunyady, L Ji, H Jagadeesh, G Zhang, M Gaborik, Z Mihalik, B Catt, KJ AF Hunyady, L Ji, H Jagadeesh, G Zhang, M Gaborik, Z Mihalik, B Catt, KJ TI Dependence of AT(1) angiotensin receptor function on adjacent asparagine residues in the seventh transmembrane helix SO MOLECULAR PHARMACOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; ADRENAL GLOMERULOSA CELLS; II RECEPTOR; SIGNAL-TRANSDUCTION; PROJECTION STRUCTURE; BINDING-SITE; NONPEPTIDE; AGONIST; ANTAGONISTS; ACTIVATION AB For several G protein-coupled receptors, amino acids in the seventh transmembrane helix have been implicated in ligand binding and receptor activation. The function of this region in the AT(1) angiotensin receptor was further investigated by mutation of two conserved polar residues (Asn294 and Asn295) and the adjacent Phe293 residue. Analysis of the properties of the mutant receptors expressed in COS-7 cells revealed that alanine replacement of Phe293 had no major effect on AT(1) receptor function. Substitution of the adjacent Asn294 residue with alanine (N294A) reduced receptor binding affinities for angiotensin II, two nonpeptide agonists (L-162,313 and L-163,491), and the AT(1)-selective nonpeptide antagonist losartan but not that for the peptide antagonist [Sar(1),Ile(8)]angiotensin II. The N294A receptor also showed impaired G protein coupling and severely attenuated inositol phosphate generation. In contrast, alanine replacement of Asn295 decreased receptor binding affinities for all angiotensin II ligands but did not impair signal transduction. Additional substitutions of Asn295 with a variety of amino acids did not identify specific structural elements for ligand binding. These findings indicate that Asn295 is required for the integrity of the intramembrane binding pocket of the AT(1a) receptor but is not essential for signal generation. They also demonstrate the importance of transmembrane helices in the formation of the binding site for nonpeptide AT(1) receptor agonists. We conclude that the Asn294 residue of the AT(1) receptor is an essential determinant of receptor activation and that the adjacent Asn295 residue is required for normal ligand binding. C1 NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. Semmelweis Univ Med, Dept Physiol, H-1088 Budapest, Hungary. US FDA, Div Cardiorenal Drug Prod, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. RP Catt, KJ (reprint author), NICHHD, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Room 6A-36, Bethesda, MD 20892 USA. EM catt@helix.nih.gov RI Jagadeesh, Gowraganahalli/G-6408-2010 NR 41 TC 44 Z9 44 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD AUG PY 1998 VL 54 IS 2 BP 427 EP 434 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 108CW UT WOS:000075249300023 PM 9687585 ER PT J AU Hirotsune, S Fleck, MW Gambello, MJ Bix, GJ Chen, A Clark, GD Ledbetter, DH McBain, CJ Wynshaw-Boris, A AF Hirotsune, S Fleck, MW Gambello, MJ Bix, GJ Chen, A Clark, GD Ledbetter, DH McBain, CJ Wynshaw-Boris, A TI Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethality SO NATURE GENETICS LA English DT Article ID PLATELET-ACTIVATING-FACTOR; DIEKER LISSENCEPHALY GENE; CYCLIN-DEPENDENT KINASE-5; CORTICAL DEVELOPMENT; ASPERGILLUS-NIDULANS; CELL-MIGRATION; REELER MICE; BRAIN; PROTEIN; SUBUNIT AB Heterozygous mutation or deletion of the beta subunit of platelet-activating factor acetylhydrolase (PAFAH1B1, also known as LIS1) in humans is associated with type I lissencephaly, a severe developmental brain disorder thought to result from abnormal neuronal migration. To further understand the function of PAFAH1B1, we produced three different mutant alleles in mouse Pafah1b1. Homozygous null mice die early in embryogenesis soon after implantation. Mice with one inactive allele display cortical, hippocampal and olfactory bulb disorganization resulting from delayed neuronal migration by a cell-autonomous neuronal pathway.. Mice with further reduction of Pafah1b1 activity display more severe brain disorganization as well as cerebellar defects. Our results demonstrate an essential, dosage-sensitive neuronal-specific role for Pafah1b1 in neuronal migration throughout the brain, and an essential role in early embryonic development. The phenotypes observed are distinct from those of other mouse mutants with neuronal migration defects, suggesting that Pafah1b1 participates in a novel pathway for neuronal migration. C1 NICHHD, Genet Dis Res Branch, Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. NICHHD, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. Baylor Coll Med, Cain Fdn Res Labs, Dept Pediat, Houston, TX 77030 USA. Baylor Coll Med, Cain Fdn Res Labs, Div Neurosci, Houston, TX 77030 USA. RP Wynshaw-Boris, A (reprint author), NICHHD, Genet Dis Res Branch, Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. FU NINDS NIH HHS [NS37146] NR 43 TC 408 Z9 412 U1 1 U2 17 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 AUG PY 1998 VL 19 IS 4 BP 333 EP 339 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 106AM UT WOS:000075107600015 PM 9697693 ER PT J AU Woitach, JT Zhang, MH Niu, CH Thorgeirsson, SS AF Woitach, JT Zhang, MH Niu, CH Thorgeirsson, SS TI A retinoblastoma-binding protein that affects cell-cycle control and confers transforming ability SO NATURE GENETICS LA English DT Article ID LIVER EPITHELIAL-CELLS; GENE-PRODUCT; RB GENE; GROWTH FACTOR-BETA-1; TUMOR SUPPRESSOR; CARCINOMA-CELLS; IDENTIFICATION; EXPRESSION AB The retinoblastoma (RB) gene is one of the most extensively studied tumour-suppressor genes(1). Deletion or inactivation of both RE alleles is an essential, rate-limiting step in the formation of retinoblastoma and osteosarcoma that arise in families that carry mutant RE (ref. 2). RE inactivation is also found in other human tumours(3-8). Whereas loss of RE function is associated with the loss of cellular proliferative control, introduction of a wild-type RE can suppress cell growth and tumorigenicity(5,9-12). Thus, identification of factors that interfere with and/or control the function of the RE protein is critical for understanding both cell-cycle control and oncogenesis. Here we describe a new gene, Bog (for B5T over-expressed gene), which was identified and shown to be overexpressed in several transformed rat liver epithelial (RLE) cell lines resistant to the growth-inhibitory effect of TGF-beta 1, as well as in primary human liver tumours. The Bog protein shares homology with other retinoblastoma-binding proteins and contains the Rb-binding motif LXCXE. Using the yeast two-hybrid system and co-immunoprecipitation. we demonstrated that Bog binds to Rb. In vivo, Bog/Rb complexes do not contain E2F-1, and Bog can displace E2F-1 from E2F-1/Rb complexes in vitro. Overexpression of Bog in normal RFE cells conferred resistance to the growth-inhibitory effect of TGF-beta 1. Furthermore, normal RLE cells are rapidly transformed when Bog is continuously overexpressed and form hepatoblastoma-like tumours when transplanted into nude mice. These data suggest that Bog may be important in the transformation process, in part due to its capacity to confer resistance to the growth-inhibitory effects of TGF-beta 1 through interaction with Rb and the subsequent displacement of E2F-1. C1 NCI, Expt Carcinogenesis Lab, Div Basic Sci, Bethesda, MD 20892 USA. RP Thorgeirsson, SS (reprint author), NCI, Expt Carcinogenesis Lab, Div Basic Sci, Bethesda, MD 20892 USA. EM snorri_thorgeirsson@nih.gov NR 26 TC 38 Z9 40 U1 0 U2 0 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 AUG PY 1998 VL 19 IS 4 BP 371 EP 374 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 106AM UT WOS:000075107600021 PM 9697699 ER PT J AU Street, VA McKee-Johnson, JW Fonseca, RC Tempel, BL Noben-Trauth, K AF Street, VA McKee-Johnson, JW Fonseca, RC Tempel, BL Noben-Trauth, K TI Mutations in a plasma membrane Ca2+-ATPase gene cause deafness in deafwaddler mice SO NATURE GENETICS LA English DT Article ID HAIR-CELLS; GERBIL COCHLEA; CA-ATPASE; TRANSDUCTION; EXPRESSION AB Hearing loss is the most common sensory deficit in humans. Because the auditory systems of mice and humans are conserved, studies on mouse models have predicted several human deafness genes and identified new genes involved in hearing(1,2). The deafwaddler (dfw) mouse mutant is deaf and displays vestibular/motor imbalance. Here we report that the gene encoding a plasma membrane Ca2+-ATPase type 2 pump (Atp2b2, also known as Pmca2) is mutated in dfw. An A-->G nucleotide transition in dfw DNA causes a glycine-to-serine substitution at a highly conserved amino-acid position, whereas in a second allele, dfw(2J), a 2-base-pair deletion causes a frameshift that predicts a truncated protein. In the cochlea, the protein Atp2b2 is localized to stereocilia and the basolateral wall of hair cells in wild-type mice, but is not detected in dfw(2J) mice. This indicates that mutation of Atp2b2 may cause deafness and imbalance by affecting sensory transduction in stereocilia(3) as well as neurotransmitter release from the basolateral membrane(4). These mutations affecting Atp2b2 in dfw and dfw(2J) are the first to be found in a mammalian plasma membrane calcium pump and define a new class of deafness genes that directly affect hair-cell physiology. C1 Univ Washington, Sch Med, Virginia Merrill Bloedel Hearing Res Ctr, Seattle, WA 98195 USA. Univ Washington, Sch Med, Dept Otolaryngol Head & Neck Surg, Seattle, WA 98195 USA. Natl Inst Deafness & Commun Disorders, Sect Murine Genet, NIH, Rockville, MD 20850 USA. RP Tempel, BL (reprint author), Univ Washington, Sch Med, Virginia Merrill Bloedel Hearing Res Ctr, Box 357923, Seattle, WA 98195 USA. NR 23 TC 191 Z9 199 U1 0 U2 3 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 AUG PY 1998 VL 19 IS 4 BP 390 EP 394 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 106AM UT WOS:000075107600025 PM 9697703 ER PT J AU Goldfarb, LG Park, KY Cervenakova, L Gorokhova, S Lee, HS Vasconcelos, O Nagle, JW Semino-Mora, C Sivakumar, K Dalakas, MC AF Goldfarb, LG Park, KY Cervenakova, L Gorokhova, S Lee, HS Vasconcelos, O Nagle, JW Semino-Mora, C Sivakumar, K Dalakas, MC TI Missense mutations in desmin associated with familial cardiac and skeletal myopathy SO NATURE GENETICS LA English DT Article ID ELECTRON-MICROSCOPY; CELLS AB Desmin-related myopathy (OMIM 601419) is a familial disorder characterized by skeletal muscle weakness associated with cardiac conduction blocks, arrhythmias and restrictive heart failure, and by intracytoplasmic accumulation of desmin-reactive deposits in cardiac and skeletal muscle cells(1-4). The underlying molecular mechanisms are unknown. Involvement of the desmin gene (DES) has been excluded in three families diagnosed with desmin-related myopathy(5), We report two new families with desmin-related cardioskeletal myopathy associated with mutations in the highly conserved carboxy-terminal end of the desmin rod domain. A heterozygous A337P mutation was identified in a family with an adult-onset skeletal myopathy and mild cardiac involvement. Compound heterozygosity for two other mutations, A360P and N393I, was detected in a second family characterized by childhood-onset aggressive course of cardiac and skeletal myopathy. C1 NINDS, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Cent Nervous Syst Studies Lab, NIH, Bethesda, MD 20892 USA. Amer Red Cross, Jerome H Holland Lab, Rockville, MD 20855 USA. Barrow Neurol Inst, Phoenix, AZ 85013 USA. RP Goldfarb, LG (reprint author), NINDS, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. NR 11 TC 320 Z9 330 U1 1 U2 11 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 AUG PY 1998 VL 19 IS 4 BP 402 EP 403 DI 10.1038/1300 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 106AM UT WOS:000075107600028 PM 9697706 ER PT J AU Nathanson, N AF Nathanson, N TI Harnessing research to control AIDS SO NATURE MEDICINE LA English DT Editorial Material C1 NIH, Off AIDS Res, US Dept HHS, Bethesda, MD 20892 USA. RP Nathanson, N (reprint author), NIH, Off AIDS Res, US Dept HHS, Bldg 31 4C02,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD AUG PY 1998 VL 4 IS 8 BP 879 EP 881 DI 10.1038/nm0898-879 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 106AK UT WOS:000075107400019 PM 9701229 ER PT J AU Lodmell, DL Ray, NB Parnell, MJ Ewalt, LC Hanlon, CA Shaddock, JH Sanderlin, DS Rupprecht, CE AF Lodmell, DL Ray, NB Parnell, MJ Ewalt, LC Hanlon, CA Shaddock, JH Sanderlin, DS Rupprecht, CE TI DNA immunization protects nonhuman primates against rabies virus SO NATURE MEDICINE LA English DT Article ID VACCINE; DISEASE; CELLS AB More than 40,000 people die annually from rabies worldwide(1). Most of these fatalities occur in developing countries, where rabies is endemic, public health resources are inadequate and there is limited access to preventive treatment(2). Because of the high cost of vaccines derived from cell culture, many countries still use vaccines produced in sheep, goat or suckling mouse brain(3). The stability and low cost for mass production of DNA vaccines would make them ideal for use in developing countries(4). To investigate the potential of DNA vaccines for rabies immunization in humans, we vaccinated Macaca fascicularis (Cynomolgus) monkeys with DNA encoding the glycoprotein of the challenge virus standard rabies virus, or with a human diploid cell vaccine (HDCV). The monkeys then were challenged with a non-passaged rabies virus. DNA or HDCV vaccination elicited comparable primary and anamnestic neutralizing antibody responses. All ten vaccinated monkeys (DNA or HDCV) survived a rabies virus challenge, whereas monkeys vaccinated with only the DNA vector developed rabies. Furthermore, serum samples from DNA- or HDCV-vaccinated monkeys neutralized a global spectrum of rabies virus variants in vitro. This study shows that DNA immunization elicits protective immunity in nonhuman primates against lethal challenge with a human viral pathogen of the central nervous system. Our findings indicate that DNA vaccines may have a promising future in human rabies immunization. C1 NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. Ctr Dis Control & Prevent, Rabies Sect, Viral & Rickettsial Zooneses Branch, Div Viral & Rickettsial Dis,Natl Ctr Infect Dis, Atlanta, GA 30333 USA. RP Lodmell, DL (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. NR 23 TC 98 Z9 100 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD AUG PY 1998 VL 4 IS 8 BP 949 EP 952 DI 10.1038/nm0898-949 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 106AK UT WOS:000075107400040 PM 9701249 ER PT J AU Studer, L Tabar, V McKay, RDG AF Studer, L Tabar, V McKay, RDG TI Transplantation of expanded mesencephalic precursors leads to recovery in parkinsonian rats SO NATURE NEUROSCIENCE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; MIDBRAIN DOPAMINERGIC-NEURONS; FETAL VENTRAL MESENCEPHALON; LONG-TERM SURVIVAL; STEM-CELLS; NEURAL PROGENITORS; SONIC HEDGEHOG; GRAFT-SURVIVAL; GENE-THERAPY; IN-VIVO AB In vitro expansion of central nervous system (CNS) precursors might overcome the limited availability of dopaminergic neurons in transplantation for Parkinson's disease, but generating dopaminergic neurons from in vitro dividing precursors has proven difficult. Here a three-dimensional cell differentiation system was used to convert precursor cells derived from E12 rat ventral mesencephalon into dopaminergic neurons. We demonstrate that CNS precursor cell populations expanded in vitro can efficiently differentiate into dopaminergic neurons, survive intrastriatal transplantation and induce functional recovery in hemiparkinsonian rats. The numerical expansion of primary CNS precursor cells is a new approach that could improve both the ethical and the technical outlook for the use of human fetal tissue in clinical transplantation. C1 NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Massachusetts, Div Neurosurg, Worcester, MA 01655 USA. RP McKay, RDG (reprint author), NINDS, Mol Biol Lab, NIH, 36 Convent Dr,Bldg 36,Room 5A29, Bethesda, MD 20892 USA. NR 45 TC 417 Z9 452 U1 2 U2 16 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD AUG PY 1998 VL 1 IS 4 BP 290 EP 295 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 127QD UT WOS:000076361300012 PM 10195162 ER PT J AU Berger, EA AF Berger, EA TI And the Best Picture is - the HIV gp120 envelope, please! SO NATURE STRUCTURAL BIOLOGY LA English DT Article ID HUMAN CD4; FRAGMENT; BINDING AB X-ray crystallographic structure of the gp 120 core coupled with mutagenesis analyses reveal details of receptor interactions and multiple layers of immune evasion. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Berger, EA (reprint author), NIAID, Viral Dis Lab, NIH, Bldg 4,Room 236, Bethesda, MD 20892 USA. NR 11 TC 6 Z9 6 U1 0 U2 1 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1072-8368 J9 NAT STRUCT BIOL JI Nat. Struct. Biol. PD AUG PY 1998 VL 5 IS 8 BP 671 EP 674 DI 10.1038/1362 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 104YM UT WOS:000075044600006 PM 9699624 ER PT J AU Spatz, M Kawai, N Bembry, J Lenz, F McCarron, RM AF Spatz, M Kawai, N Bembry, J Lenz, F McCarron, RM TI Human brain capillary endothelium: Modulation of K+ efflux and K+, Ca2+ uptake by endothelin SO NEUROCHEMICAL RESEARCH LA English DT Article DE human brain capillary endothelium; endothelin-1; K+ efflux; K+ uptake; Ca2+ uptake ID IMMUNOREACTIVE ENDOTHELIN-1; SIGNAL-TRANSDUCTION; ET(A) RECEPTORS; CELLS; BIOCHEMISTRY; ISCHEMIA; BARRIER; SODIUM AB This report describes K+ efflux, K+ and Ca2+ uptake responses to endothelins (ET-1 and ET-3) in cultured endothelium derived from capillaries of human brain (HBEC). ET-1 dose dependently increased K+ efflux, K+ and Ca2+ uptake in these cells. ET-1 stimulated K+ efflux occurred prior to that of K+ uptake. ET-3 was ineffective. The main contributor to the ET-1 induced K+ uptake was ouabain but not bumetanide-sensitive (Na+-K+-ATPase and Na+-K+-Cl- cotransport activity, respectively). All tested paradigms of ET-1 effects in HBEC were inhibited by selective antagonist of ETA but not ETB receptors and inhibitors of phospholipase C and receptor-operated Ca2+ channels. Activation of protein kinase C (PKC) decreased whereas inhibition of PKC increased the ET-1 stimulated K+ efflux, K+ and Ca2+ uptake in HBEC. The results indicate that ET-1 affects the HBEC ionic transport systems through activation of ETA receptors linked to PLC and modulated by intracellular Ca2+ mobilization and PKC. C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ Hosp, Baltimore, MD 21205 USA. USN, Resuscitat Med Program, Med Res Inst, Bethesda, MD 20889 USA. RP Spatz, M (reprint author), NINDS, Stroke Branch, NIH, 36 Convent Dr,MSC 4128, Bethesda, MD 20892 USA. NR 25 TC 4 Z9 4 U1 0 U2 0 PU PLENUM PUBL CORP PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD AUG PY 1998 VL 23 IS 8 BP 1125 EP 1132 DI 10.1023/A:1020772422266 PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 105TE UT WOS:000075089000014 PM 9704603 ER PT J AU Fry, HJH Hallett, M Mastroianni, T Dang, N Dambrosia, J AF Fry, HJH Hallett, M Mastroianni, T Dang, N Dambrosia, J TI Incoordination in pianists with overuse syndrome SO NEUROLOGY LA English DT Article ID CUMULATIVE TRAUMA DISORDERS; MUSICIANS AB To investigate claims that painful musculoligamentous overuse in the arms and hands of pianists is accompanied by loss of motor control, we studied 18 pianists with overuse syndrome of one or both arms and hands and 22 skill-matched pianists with no history of overuse. All of the pianists performed continuous repetitions of a five-finger exercise on a piano keyboard at metronome-paced tempos. The main outcome measures were quantitative analysis of four measurements of performance (duration of key presses, interval between key presses, velocity of key presses [loudness], and time off the metronome beat [difference between actual and expected time of key press]); comparison of the errors in the two groups; and comparison of the performances by a listening panel. The two groups had significant differences in performance, and a classification tree had a sensitivity of 0.886 and a specificity of 0.862 in identifying the affected hands. The pianists with overuse syndrome made more skill-based errors. The listening panel could distinguish between the affected and unaffected hands. We conclude that pianists with overuse syndrome have a coordination disturbance. C1 NINCDS, Med Neurol Branch, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. NINCDS, Biometry & Field Studies Branch, Bethesda, MD 20892 USA. Bethesda Hosp, Victoria, Australia. Catholic Univ Amer, Benjamin T Rome Sch Mus, Piano Div, Washington, DC 20064 USA. RP Hallett, M (reprint author), NINCDS, Med Neurol Branch, Human Motor Control Sect, NIH, Bldg 10,Room 5N226,10 Ctr Dr MSC-1428, Bethesda, MD 20892 USA. NR 27 TC 15 Z9 16 U1 3 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG PY 1998 VL 51 IS 2 BP 512 EP 519 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 110NN UT WOS:000075387400035 PM 9710027 ER PT J AU Chapman, J Cervenakova, L Lee, HS Estupinan, J Richardson, S Vnencak-Jones, CL Gajdusek, DC Korczyn, AD Brown, P Goldfarb, LG AF Chapman, J Cervenakova, L Lee, HS Estupinan, J Richardson, S Vnencak-Jones, CL Gajdusek, DC Korczyn, AD Brown, P Goldfarb, LG TI APOE in non-Alzheimer amyloidoses - Transmissible spongiform encephalopathies SO NEUROLOGY LA English DT Article; Proceedings Paper CT 48th Annual Meeting of the American-Academy-of-Neurology CY MAR 23-30, 1996 CL SAN FRANCISCO, CALIFORNIA SP Amer Acad Neurol ID CREUTZFELDT-JAKOB-DISEASE; PRION PROTEIN GENE; APOLIPOPROTEIN-E ALLELES; PRNP GENE; MUTATION; ONSET; FREQUENCY; GENOTYPE; POLYMORPHISM; CODON-200 AB Background: The APOE genotype has been shown to influence the risk of developing sporadic and familial AD. This effect is isoform-dependent, the APOE epsilon 4 allele increasing susceptibility and the APOE epsilon 2 allele providing protection. Amyloid formation is an important part of the pathogenesis in AD as well as in spongiform encephalopathies; apoE deposition in amyloid plaques has been documented in both conditions. Methods: We examined the frequency of the APOE alleles in patients with various forms of transmissible spongiform encephalopathies, or prion diseases, including sporadic and iatrogenic Creutzfeldt-Jakob disease; familial Creutzfeldt-Jakob disease associated with PRNP 178N/129V and 200K/129M point mutations and a 24-nucleotide repeat expansion; fatal familial insomnia caused by the 178N/129M mutation; Gerstmann-Straussler-Scheinker disease associated with 102L/129M mutation; and kuru. Results: None of the groups we studied had a significant excess of APOE epsilon 4 allele when compared with appropriate controls. Conclusion: Our results do not support the contention that the APOE E4 allele is a risk factor for developing Creutzfeldt-Jakob disease or related disorders. C1 NINCDS, Med Neurol Branch, Clin Neurogenet Unit, NIH, Bethesda, MD 20892 USA. NINCDS, Lab Cent Nervous Syst Studies, NIH, Bethesda, MD 20892 USA. Tel Aviv Univ, Dept Neurol, Ramat Aviv, Israel. Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. Vanderbilt Univ, Med Ctr, Dept Pathol, Nashville, TN USA. RP Goldfarb, LG (reprint author), NINCDS, Med Neurol Branch, Clin Neurogenet Unit, NIH, Room 4D08,36 Convent Dr MSC 4129, Bethesda, MD 20892 USA. RI Chapman, Joab/E-4598-2010; Korczyn, Amos/C-3461-2017 OI Korczyn, Amos/0000-0003-0125-2579 NR 40 TC 20 Z9 21 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG PY 1998 VL 51 IS 2 BP 548 EP 553 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 110NN UT WOS:000075387400041 PM 9710033 ER PT J AU Frei, KP Patronas, NJ Crutchfield, KE Altarescu, G Schiffmann, R AF Frei, KP Patronas, NJ Crutchfield, KE Altarescu, G Schiffmann, R TI Mucolipidosis type IV - Characteristic MRI findings SO NEUROLOGY LA English DT Article ID CORPUS-CALLOSUM; SIZE; DYSGENESIS; CHILDREN; INFANTS; DISEASE; BRAIN AB Objective: The objective of this study is to characterize the brain abnormalities on head MRI of patients with mucolipidosis type IV. Background: Mucolipidosis type TV is an autosomal recessive lysosomal storage disease of unknown etiology. Patients develop corneal clouding, retinal degeneration, spastic quadriparesis, and mental retardation. Patients with this disorder have not been studied systematically. Methods: We studied prospectively 15 consecutive patients with mucolipidosis type IV using cranial MRI. Results: Fourteen patients with these typical clinical findings had a hypoplastic corpus callosum with absent rostrum and a dysplastic or absent splenium, signal abnormalities on T1-weighted head MRI images in the white matter, and increased ferritin deposition in the thalamus and basal ganglia. Atrophy of the cerebellum and cerebrum was observed in older patients, which may reflect disease progression. One patient with a mild clinical variant had a normal corpus callosum. Conclusion: Patients with mucolipidosis type IV have characteristic cranial MRI findings that suggest that this disorder causes both developmental and neurodegenerative abnormalities. C1 NIH, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. NINDS, Dev & Metab Neurol Branch, Bethesda, MD 20892 USA. RP Schiffmann, R (reprint author), NIH, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, Bldg 10,Room 3D03,10 Ctr Dr,MSC 1260, Bethesda, MD 20892 USA. NR 24 TC 43 Z9 44 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG PY 1998 VL 51 IS 2 BP 565 EP 569 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 110NN UT WOS:000075387400044 PM 9710036 ER PT J AU Zhou, YX Wang, GX Tang, BS Li, WD Wang, DA Lee, HS Sambuughin, N Zhou, LS Tsuji, S Yang, BX Goldfarb, LG AF Zhou, YX Wang, GX Tang, BS Li, WD Wang, DA Lee, HS Sambuughin, N Zhou, LS Tsuji, S Yang, BX Goldfarb, LG TI Spinocerebellar ataxia type 2 in China: Molecular analysis and genotype-phenotype correlation in nine families SO NEUROLOGY LA English DT Article ID CLINICAL CORRELATIONS; REPEAT; EXPANSION; CLONING; LOCUS; GENE AB Sixteen patients from nine Chinese families with spinocerebellar ataxia type 2 (SCA2) were heterozygous for a CAG repeat expansion in the SCA2 gene containing 37 to 56 repeats, whereas the normal alleles carried 14 to 28 repeats. One or two CAA triplets within the CAG tract were seen in normal, but not in the expanded alleles, A strong inverse correlation was established between the number of CAG repeats and the age of disease onset. SCA2 accounted for 12% of the known Chinese families with spinocerebellar ataxia. C1 NINDS, Clin Neurogenet Unit, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. China Japan Friendship Hosp, Neurogenet Unit, Beijing, Peoples R China. China Japan Friendship Hosp, Dept Neurol, Beijing, Peoples R China. Hunan Med Univ, Dept Neurol, Changsha, Peoples R China. Hunan Med Univ, Inst Neurol, Changsha, Peoples R China. Peking Union Med Coll, Chinese Acad Med Sci, Inst Canc, Natl Lab Mol Oncol, Beijing, Peoples R China. First Peoples Hosp XuZhou, Dept Neurol, XuZhou, Peoples R China. Niigata Univ, Brain Res Inst, Dept Neurol, Niigata 951, Japan. RP Goldfarb, LG (reprint author), NINDS, Clin Neurogenet Unit, Med Neurol Branch, NIH, Bldg 36,Room 4D03,36 Convent Dr,MSC 4129, Bethesda, MD 20892 USA. NR 10 TC 16 Z9 19 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG PY 1998 VL 51 IS 2 BP 595 EP 598 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 110NN UT WOS:000075387400052 PM 9710044 ER PT J AU Chase, TN Oh, JD Blanchet, PJ AF Chase, TN Oh, JD Blanchet, PJ TI Neostriatal mechanisms in Parkinson's disease SO NEUROLOGY LA English DT Article; Proceedings Paper CT 2nd International Symposium on the Treatment of Parkinsons Disease CY 1997 CL KOBE, JAPAN ID MOTOR RESPONSE ALTERATIONS; NMDA RECEPTOR BLOCKADE; D-ASPARTATE RECEPTOR; PROTEIN-KINASE-A; BASAL GANGLIA; RAT STRIATUM; GLUTAMATE ANTAGONIST; PHOSPHORYLATION SITE; SYNAPTIC PLASTICITY; DOPAMINE NEURONS AB Normal motor function is dependent on the highly regulated synthesis and release of dopamine (DA) by neurons projecting from substantia nigra to corpus striatum. Cardinal symptoms of Parkinson's disease (PD) arise as a consequence of a deficiency in striatal DA due to the progressive degeneration of this neuronal system. Under such circumstances, the subunit composition and/or phosphorylation state of glutamatergic receptors of the N-methyl-D-aspartate (NMDA) subtype expressed on the dendritic spines of medium-sized striatal neurons changes in ways that compromise motor performance. Although levodopa acts, after conversion to DA, to reverse these changes by restoring striatal dopaminergic transmission, significant differences exist between the normally functioning DA system and the restoration of function provided by standard levodopa therapy. The nonphysiologic stimulation of DA receptors on striatal spiny neurons associated with current levodopa regimens now appears to contribute to the motor response complications that ultimately affect most parkinsonian patients. Current evidence suggests that alterations in signaling systems linking dopaminergic and glutamatergic receptors within these GABAergic efferent neurons induce NMDA receptor modification. Functionally, the resultant long-term change in glutamatergic synaptic efficacy leads to alterations in spiny neuron output, favoring the appearance of motor complications. Although dopaminomimetic replacement strategies that provide more continuous DA receptor stimulation should alleviate these disabling complications, more innovative approaches to the interdiction of pathologic changes in signal transduction components or glutamate receptor sensitivity could ultimately prove safer and more effective for the treatment of all stages of PD. C1 NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Chase, TN (reprint author), NINDS, Expt Therapeut Branch, NIH, Bldg 10,Room 5C103,10 Ctr Dr,MSC 1406, Bethesda, MD 20892 USA. NR 69 TC 62 Z9 66 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG PY 1998 VL 51 IS 2 SU 2 BP S30 EP S35 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 111ND UT WOS:000075443200007 PM 9711978 ER PT J AU Moser, HW Moser, AB Frayer, KK Chen, W Schulman, JD O'Neill, BP Kishimoto, Y AF Moser, HW Moser, AB Frayer, KK Chen, W Schulman, JD O'Neill, BP Kishimoto, Y TI Adrenoleukodystrophy: Increased plasma content of saturated very long chain fatty acids SO NEUROLOGY LA English DT Article ID CHOLESTEROL ESTERS; BRAIN; ADRENOMYELONEUROPATHY; VARIANT; LIPIDS AB With a new method we measured the saturated very long chain fatty acids in the plasma of adrenoleukodystrophy (ALD) hemizygotes, ALD heterozygotes, and controls. ALD hemizygotes showed increased levels of hexacosanoate (C26 fatty acid) which represented 0.081 +/- 0.0066% (SEM) of total fatty acids, compared to 0.015 +/- 0.0032% in the controls. C25, C24, and C23 fatty acids were also increased, but the C22 and C20 fatty acids were normal. C26 levels were also increased in most ALD heterozygotes, with a mean level 0.057 +/- 0.0063% of total fatty acids. The technique can be used for diagnosis and carrier identification, and in the evaluation of therapy. C1 Kennedy Inst, Baltimore, MD 21205 USA. Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. Johns Hopkins Univ, Dept Pediat, Baltimore, MD 21218 USA. Natl Inst Hlth Child Hlth & Human Dev, Bethesda, MD USA. Mayo Clin & Mayo Fdn, Dept Neurol, Rochester, MN 55905 USA. RP Moser, HW (reprint author), Kennedy Inst, 707 N Broadway, Baltimore, MD 21205 USA. NR 25 TC 0 Z9 0 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG PY 1998 VL 51 IS 2 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 110NN UT WOS:000075387400005 ER PT J AU LeFebvre, RA Crawley, JN AF LeFebvre, RA Crawley, JN TI First Joint Meeting of the European Neuropeptide Club (8th Annual Meeting) and the Summer Neuropeptide Conference (8th Annual Meeting) 6-9 May 1998, Gent, Belgium SO NEUROPEPTIDES LA English DT Editorial Material C1 NIMH, Bethesda, MD 20892 USA. State Univ Ghent, Heymans Inst Pharmacol, Ghent, Belgium. RP Crawley, JN (reprint author), NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 0143-4179 J9 NEUROPEPTIDES JI Neuropeptides PD AUG PY 1998 VL 32 IS 4 BP 361 EP 361 DI 10.1016/S0143-4179(98)90059-2 PG 1 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 120BU UT WOS:000075935300008 ER PT J AU Zangen, A Herzberg, U Vogel, Z Yadid, G AF Zangen, A Herzberg, U Vogel, Z Yadid, G TI Nociceptive stimulus induces release of endogenous beta-endorphin in the rat brain SO NEUROSCIENCE LA English DT Article DE beta-endorphin; formalin-test; microdialysis; nociception; pain ID FORMALIN TEST; INDUCED PAIN; IMMUNOREACTIVITY; LIPOTROPIN; ENKEPHALIN; ANALGESIA; PEPTIDES AB The hypothesis that the naturally occurring analgesic peptide, beta-endorphin, is released in the brain in response to pain had never been directly validated. In this study, we applied a brain microdialysis method for monitoring beta-endorphin release in vivo, to test this hypothesis in the brains of conscious, freely moving rats. Herein we first show that endogenous beta-endorphin can be measured in vivo in the brain under physiological conditions. Upon induction of a nociceptive stimulus by injection of formalin into the hind-paws of rats, the extracellular levels of beta-endorphin in their arcuate nucleus increased by 88%, corresponding to their nociceptive response, This direct evidence for the release of endogenous beta-endorphin in the brain in response to nociceptive stimulus indicates a possible mechanism for organisms to cope with pain. (C) 1998 IBRO. Published by Elsevier Science Ltd. C1 Bar Ilan Univ, Dept Life Sci, Ramat Gan, Israel. NINDS, NIH, Bethesda, MD 20892 USA. Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. RP Yadid, G (reprint author), Bar Ilan Univ, Dept Life Sci, Ramat Gan, Israel. NR 19 TC 52 Z9 55 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD AUG PY 1998 VL 85 IS 3 BP 659 EP 662 DI 10.1016/S0306-4522(98)00050-5 PG 4 WC Neurosciences SC Neurosciences & Neurology GA ZN623 UT WOS:000073664500002 PM 9639262 ER PT J AU Asanuma, M Hirata, H Cadet, JL AF Asanuma, M Hirata, H Cadet, JL TI Attenuation of 6-hydroxydopamine-induced dopaminergic nigrostriatal lesions in superoxide dismutase transgenic mice SO NEUROSCIENCE LA English DT Article DE 6-hydroxydopamine; superoxide dismutase; transgenic mice; superoxide anion; dopamine transporter; Parkinson's disease ID PARKINSONS-DISEASE; FREE-RADICALS; MOUSE-BRAIN; METHYLENEDIOXYMETHAMPHETAMINE MDMA; AUTORADIOGRAPHIC EVIDENCE; LIPID-PEROXIDATION; NERVOUS-SYSTEM; ASCORBIC-ACID; RAT-BRAIN; METHAMPHETAMINE AB 6-Hydroxydopamine is a neurotoxin that produces degeneration of the nigrostriatal dopaminergic pathway in rodents. Its toxicity is thought to involve the generation of superoxide anion secondary to its autoxidation. To examine the effects of the overexpression of Cu,Zn-superoxide dismutase activity on 6-hydroxydopamine-induced dopaminergic neuronal damage, we have measured the effects of 6-hydroxydopamine on striatal and nigral dopamine transporters and nigral tyrosine hydroxylase-immunoreactive neurons in Cu,Zn-superoxide dismutase transgenic mice. Intracerebroventricular injection of 6-hydroxydopamine (50 mu g) in non-transgenic mice produced reductions in the size of striatal area and an enlargement of the cerebral ventricle on both sides of the brains of mice killed two weeks after the injection. In addition, 6-hydroxydopamine caused marked decreases in striatal and nigral [I-125]RTI-121-labelled dopamine transporters not only on the injected side but also on the non-injected side of non-transgenic mice; this was associated with decreased cell number and size of tyrosine hydroxylase-immunoreactive dopamine neurons in the substantia nigra pars compacta on both sides in these mice. In contrast, superoxide dismutase transgenic mice were protected against these neurotoxic effects of 6-hydroxydopamine, with the homozygous transgenic mice showing almost complete protection. These results provide further support for a role of superoxide anion in the toxic effects of 6-hydroxydopamine. They also provide further evidence that reactive oxygen species may be the main determining factors in the neurodegenerative effects of catecholamines. C1 NIDA, Mol Neuropsychiat Sect, NIH, Div Intramural Res, Baltimore, MD 21224 USA. RP Cadet, JL (reprint author), NIDA, Mol Neuropsychiat Sect, NIH, Div Intramural Res, Baltimore, MD 21224 USA. NR 46 TC 73 Z9 74 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD AUG PY 1998 VL 85 IS 3 BP 907 EP 917 DI 10.1016/S0306-4522(97)00665-9 PG 11 WC Neurosciences SC Neurosciences & Neurology GA ZN623 UT WOS:000073664500023 PM 9639283 ER PT J AU Sziraki, I Mohanakumar, KP Rauhala, P Kim, HG Yeh, KJ Chiueh, CC AF Sziraki, I Mohanakumar, KP Rauhala, P Kim, HG Yeh, KJ Chiueh, CC TI Manganese: A transition metal protects nigrostriatal neurons from oxidative stress in the iron-induced animal model of parkinsonism SO NEUROSCIENCE LA English DT Article DE dopamine; ferrous citrate; lipid peroxidation; substantia nigra; hydroxyl radical; Parkinson's disease ID CELLULAR DEFENSE-MECHANISMS; LIPID-PEROXIDATION; GLUTAMINE-SYNTHETASE; RAT-BRAIN; IN-VIVO; NEURODEGENERATIVE DISEASES; RADICAL FORMATION; SUBSTANTIA-NIGRA; BASAL GANGLIA; TRACE-METALS AB It has been suggested that transition metals such as iron and manganese produce oxidative injury to the dopaminergic nigrostriatal system, which may play a critical role in the pathogenesis of Parkinson's disease. Intranigral infusion of ferrous citrate (0 to 5.4 nmol. i.n.) acutely increased lipid peroxidation in the substantia nigra and dopamine turnover in the caudate nucleus. Subsequently, it caused a severe depletion of dopamine levels in the rat caudate nucleus. In contrast to iron's pro-oxidant effect, manganese (up to 30 nmol, i.n.) causes neither lipid peroxidation nor nigral injury/dopamine depletion. Manganese (1.05 to 4.2 nmol, i.n.) dose-dependently protected nigral neurons from iron-induced oxidative injury and dopamine depletion. Manganese also suppressed acute increase in dopamine turnover and contralateral turning behaviour induced by iron. In brain homogenates manganese (0 to 10 mu M) concentration-dependently inhibited propagation of lipid peroxidation caused by iron (0 to 5 mu M). Without the contribution of manganese-superoxide dismutase manganese was still effective in sodium azide and/or heat-pretreated brain homogenates. Surprisingly, iron but not manganese, catalysed the Fenton reaction or the conversion of hydrogen peroxide to hydroxyl radicals. The results indicate that iron and manganese are two transition metals mediating opposite effects in the nigrostriatal system, as pro-oxidant and antioxidant, respectively. In conclusion, intranigral infusion of iron, but not manganese, provides an animal model for studying the pathophysiological role of oxidant and oxidative stress in nigrostriatal degeneration and Parkinsonism. The present results further suggest that the atypical antioxidative properties of manganese may protect substantia nigra compacta neurons from iron-induced oxidative stress. (C) 1998 IBRO. Published by Elsevier Science Ltd. C1 NIMH, NIH 10 3D41, Unit Neurodegenerat & Neuroprotect, Clin Sci Lab, Bethesda, MD 20892 USA. RP Chiueh, CC (reprint author), NIMH, NIH 10 3D41, Unit Neurodegenerat & Neuroprotect, Clin Sci Lab, Bethesda, MD 20892 USA. NR 75 TC 84 Z9 85 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD AUG PY 1998 VL 85 IS 4 BP 1101 EP 1111 DI 10.1016/S0306-4522(97)00660-X PG 11 WC Neurosciences SC Neurosciences & Neurology GA ZT531 UT WOS:000074097200010 PM 9681949 ER PT J AU Kim, MK Song, BJ Seidel, J Soh, Y Jeong, KS Kim, IS Kobayashi, H Green, MV Carrasquillo, JA Paik, CH AF Kim, MK Song, BJ Seidel, J Soh, Y Jeong, KS Kim, IS Kobayashi, H Green, MV Carrasquillo, JA Paik, CH TI Use of Tc-99m-mercaptoacetyltriglycine (MAG3)-biocytin hepatobiliary scintigraphy to study the protective effect of a synthetic enzyme inhibitor on acute hepatotoxicity in mice SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article; Proceedings Paper CT 44th Annual Meeting of the Society-of-Nuclear-Medicine CY JUN 01-04, 1997 CL SAN ANTONIO, TEXAS SP Soc Nucl Med DE pharmacokinetics; cytochrome P450 2E1; YH439; acute hepatitis; in vivo imaging ID CYTOCHROME-P450 2E1 EXPRESSION; CARBON-TETRACHLORIDE; LIVER; ETHANOL; RATS; ACETAMINOPHEN; DEGRADATION; INDUCTION; CYP2E1 AB Recent data suggest that inhibitors of ethanol-inducible cytochrome P450 (CYP2E1) can protect the liver from injury caused by various substrates of CYP2E1. In this study, we measured the protective effect of isopropyl-2-(1,3-dithioetane-2-ylidene)-2[N-(4-methylthiazol-2-yl)-carbamoyl]acetate (YH439), a transcriptional inhibitor of CYP2E1, against carbon tetrachloride (CCl4)-induced hepatotoxicity by using various conventional methods and dynamic scintigraphy with Tc-99m-mercaptoacetyltriglycine (MAG3)-biocytin, a recently developed scintigraphic agent. Balb/c mice were pretreated with two doses of YH439 (50 or 150 mg/kg per day) at 48 h and 24 h and one dose of CCl4 (0.25 mL/kg) at 18 h before scintigraphy. The results were compared with those of two other groups, one that received CCl4 but not YH439, and the other that received neither (control). Scintigraphic images were acquired continuously at 15-sec intervals for 30 min. Pharmacokinetic parameters, such as peak liver/heart ratio (r(max)), peak liver uptake time (t(max)), and hepatic half-clearance time (HCT), were obtained from time-activity curves derived from regions-of-interest (ROI) over the liver and the heart. Acute administration of CCl4 alone caused centrilobular necrosis and serum transaminase levels to rise more than 5 times higher than those of the control group. Pharmacokinetic parameters also changed significantly from those of the control group. Administration of YH439 prevented centrilobular necrosis and significantly improved pharmacokinetic parameters. This study demonstrates for the first time that hepatobiliary scintigraphy can be used to study in vivo biochemistry of the CYP2E1 inhibitor (YH439) against liver toxicity. NUCL MED BIOL 25;6:561-568, 1998. (C) 1998 Elsevier Science Inc. C1 NIAAA, Dept Nucl Med, Warren G Magnuson Clin Ctr, NIH, Bethesda, MD USA. NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. RP Paik, CH (reprint author), NIH, Dept Nucl Med, Warren G Magnuson Clin Ctr, Bldg 21,Room 136, Bethesda, MD 20892 USA. RI Carrasquillo, Jorge/E-7120-2010; OI Carrasquillo, Jorge/0000-0002-8513-5734 NR 30 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD AUG PY 1998 VL 25 IS 6 BP 561 EP 568 DI 10.1016/S0969-8051(98)00019-5 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 104QG UT WOS:000075024800008 PM 9751424 ER PT J AU Clements, AP Singer, MF AF Clements, AP Singer, MF TI The human LINE-1 reverse transcriptase: effect of deletions outside the common reverse transcriptase domain SO NUCLEIC ACIDS RESEARCH LA English DT Article ID TERMINAL-REPEAT RETROTRANSPOSONS; HUMAN TRANSPOSABLE ELEMENT; DNA-SEQUENCES; HUMAN-CELLS; L1; INSERTION; EVOLUTION; PROTEINS; BINDING; IDENTIFICATION AB Heterologous expression of human LINE-1 ORF2 in yeast yielded a single polypeptide (M-r 145 000) which reacted with specific antibodies and co-purified with a reverse transcriptase activity not present in the host cells. Various deletion derivatives of the ORF2 polypeptide were also synthesized. Reverse transcriptase assays using synthetic polynucleotides as template and primer revealed that ORF2 protein missing a significant portion of the N-terminal endonuclease domain still retains some activity. Deletion of the C-terminal cysteine-rich motif reduces activity only a small amount. Three non-overlapping deletions spanning 144 amino acids just N-terminal to the common polymerase domain of the ORF2 protein were analyzed for their effect on reverse transcriptase activity; this region contains the previously-noted conserved Z motif. The two deletions most proximal to the polymerase domain eliminate activity while the third, most-distal deletion had no effect. An inactive enzyme was also produced by substitution of two different amino acids in a highly-conserved octapeptide sequence, Z(8), located within the region removed to make the deletion most proximal to the polymerase domain; substitution of a third had no effect. We conclude that the octapeptide sequence and neighboring amino acids in the Z region are essential for reverse transcriptase activity, while the endonuclease and cysteine-rich domains are not absolutely required. C1 Carnegie Inst Washington, Washington, DC 20005 USA. NCI, Biochem Lab, Bethesda, MD 20892 USA. RP Singer, MF (reprint author), Carnegie Inst Washington, 1530 P St NW, Washington, DC 20005 USA. NR 41 TC 24 Z9 27 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD AUG 1 PY 1998 VL 26 IS 15 BP 3528 EP 3535 DI 10.1093/nar/26.15.3528 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 107CZ UT WOS:000075190600011 PM 9671814 ER PT J AU Baris, D Zahm, SH Cantor, KP Blair, A AF Baris, D Zahm, SH Cantor, KP Blair, A TI Agricultural use of DDT and risk of non-Hodgkin's lymphoma: pooled analysis of three case-control studies in the United States SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article DE case-control; non-Hodgkin's lymphoma; DDT ID SOFT-TISSUE SARCOMA; ORGANIC-SOLVENTS; ADIPOSE-TISSUE; PESTICIDES; EXPOSURE; CHLOROPHENOLS; MINNESOTA; ACIDS; IOWA; MEN AB Objectives-The objective of this pooled analysis was to examine whether exposure to DDT was associated with the risk of non-Hodgkin's lymphoma among male farmers. Methods-Data from three case-control studies from four midwestern states in the United States (Nebraska, Iowa, Minnesota, Kansas) were pooled to carry out analyses of 993 cases and 2918 controls. Information on use of agricultural pesticides and other risk factors was based on interviews. Non-farmers (people who had never lived or worked on a farm) were used as a reference category. Results-There were 161 cases and 340 controls who reported use of DDT on animals or crops, or on both, yielding an odds ratio (OR) of 1.2 (95% confidence intervals (95% CI) 1.0 to 1.6). Farmers who had used DDT for greater than or equal to 15 years had an OR of 1.5 (95% CI 1.0 to 2.3). Adjustment for respondent status and use of other pesticides resulted in slightly reduced ORs. Analyses by the number of days of use a year was limited to the Nebraska data. The most notable increase was found among farmers who used DDT for greater than or equal to 5 days a year (OR 2.6, 95% CI 1.1 to 5.9); however, additional adjustment for use of organophosphates, phenoxyacetic acids, and the individual pesticides lindane, malathion, and atrazine reduced the ORs to 1.0, 0.9, 1.1, 1.6, and 1.9 respectively. Conclusions-No strong consistent evidence was found for an association between exposure to DDT and risk of non-Hodgkin's lymphoma. It seems that the excess risk initially found may be explained by use of other pesticides. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Baris, D (reprint author), NCI, Div Canc Epidemiol & Genet, Execut Plaza N,Room 415, Bethesda, MD 20892 USA. NR 23 TC 48 Z9 48 U1 0 U2 1 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD AUG PY 1998 VL 55 IS 8 BP 522 EP 527 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 103VZ UT WOS:000074979700003 PM 9849538 ER PT J AU Eliav, E Gracely, RH AF Eliav, E Gracely, RH TI Sensory changes in the territory of the lingual and inferior alveolar nerves following lower third molar extraction SO PAIN LA English DT Article DE human; orofacial; inflammation; electrical stimulation; touch ID TOOTH-PULP EXTIRPATIONS; VERBAL PAIN DESCRIPTORS; TRIGEMINAL NEURALGIA; SECONDARY HYPERALGESIA; NEUROPATHIC PAIN; EXPERIMENTAL INFLAMMATION; MECHANICAL HYPERALGESIA; CENTRAL SENSITIZATION; FLEXOR REFLEX; RATIO SCALES AB Post-injury inflammation activates nociceptive systems and recruits normally non-nociceptive efferents into a pain processing role. During inflammation, A beta low threshold mechanoreceptor afferents that usually mediate tactile sensation acquire properties of nociceptors, allowing them to participate in post-injury spontaneous pain and evoked abnormalities such as tenderness and pain to light touch. This study assessed the sensory consequences of post-injury inflammation following extraction of a single, lower third molar tooth. Extensive bilateral evaluations were performed in the territory of nerves assumed to be exposed to both inflammation and mechanical trauma, inflammation alone, or only the central consequences of peripheral inflammation. Testing at the distal termination of nerves assumed to be exposed to local inflammation (mental and lingual nerve territory) revealed decreased detection thresholds (P < 0.05) to electrical stimulation and to mechanical stimulation by sensitive, disposable filaments developed and validated for this application. Testing at sites of assumed inflammation and mechanical trauma (mental nerve territory) showed reduced pain thresholds to electrical stimulation. Thermal detection and pain thresholds were not altered at any location in patients, and no effects were observed in control subjects receiving only local anesthetic injections. These results in humans are consistent with recent experimental evidence that inflammatory processes alter the central consequence of activity in large-diameter A beta touch primary afferents evoked under natural conditions by gentle mechanical stimulation. These effects result in hyperesthesia, increased sensitivity to light touch, and mechanical allodynia, pain evoked by normally innocuous stimulation of A beta primary afferents. (C) 1998 International Association for the Study of Pain. Published by Elsevier Science B.V. C1 NIDR, Clin Measurement & Mechanisms Unit, Pain & Neurosensory Mechanisms Branch, NIH, Bethesda, MD 20892 USA. RP Gracely, RH (reprint author), NIDR, Clin Measurement & Mechanisms Unit, Pain & Neurosensory Mechanisms Branch, NIH, Bldg 10,Room 1N-103, Bethesda, MD 20892 USA. NR 52 TC 63 Z9 64 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD AUG PY 1998 VL 77 IS 2 BP 191 EP 199 DI 10.1016/S0304-3959(98)00100-6 PG 9 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 120YP UT WOS:000075985700009 PM 9766837 ER PT J AU Hahm, KB Kim, JH You, BM Kim, YS Cho, SW Yim, H Ahn, BO Kim, WB AF Hahm, KB Kim, JH You, BM Kim, YS Cho, SW Yim, H Ahn, BO Kim, WB TI Induction of apoptosis with an extract of Artemisia asiatica attenuates the severity of cerulein-induced pancreatitis in rats SO PANCREAS LA English DT Article DE apoptosis; Artemisia asiatica; pancreatitis ID FREE-RADICALS; OXYGEN; PATHOGENESIS AB The aim of this study was to test the hypothesis that apoptosis can protect against experimental pancreatitis and induction of apoptosis by an extract of Artemisia asiatica (DA-9601) is beneficial in cerulein-induced pancreatis in rats. Pancreatitis was induced in 6-week-old male SPF Sprague-Dawley rats by two intravenous (iv) administrations of 40 mu g/kg cerulein. To investigate the effects of DA-9601 on the severity of pancreatitis and extent of apoptosis, rats were treated with intragastric DA-9601, 30 mg/kg (D30), 100 mg/kg (D100), or 300 mu g/kg (D300), intraperitoneal superoxide dismutase, 10,000 U/kg (SOD), and iv gabexate mesilate, 40 mg/kg (Foy), three times (30 min before cerulein injection, 30 and 90 min after cerulein injection). The control group was administered vehicle alone. Ten rats were included in each treatment group and control group. Rats were sacrificed 5 h after cerulein treatment. Serum amylase, histological activity index (HAI), pan creatic lipid peroxide levels, and apoptotic index [in situ hybridization by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL)] were determined. Gel electrophoresis was performed for the presence of DNA fragmentations. The results were as follows. Serum amylase was significantly increased in all cerulein-treated groups compared to normal controls (p < 0.001). The HAI was significantly decreased in only the D300 group compared to the controls (p < 0.05). The apoptotic index of the cerulein-alone group was 3.8 +/- 2.7, but the mean apoptotic indexes of the SOD and Foy groups were 16.4 +/- 4.6 and 13.3 +/- 1.8, respectively, a significant increase (p < 0.01). The apoptotic index was more significantly increased in the DA-9601-treated groups, dose dependently (8.4 +/- 3.4 in D30, 14.8 +/- 4.3 in D100, 24.2 +/- 4.7 in D300). A smearing pattern of DNA electrophoresis was noted in the DA-9601-treated groups. In conclusion, DA-9601, an extract of Artemisia, induced apoptosis of pancreatic acinar cells dose dependently and concomitantly attenuated the severity of pancreatitis. C1 Dong A Pharmaceut Co, Res Lab, Yongin, South Korea. Ajou Univ, Sch Med, Dept Gastroenterol, Suwon, South Korea. Ajou Univ, Sch Med, Dept Anat Pathol, Suwon, South Korea. RP Hahm, KB (reprint author), NCI, Chemoprevent Lab, Bldg 41,Room B1111,Lib Dr, Bethesda, MD 20892 USA. NR 22 TC 66 Z9 72 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD AUG PY 1998 VL 17 IS 2 BP 153 EP 157 DI 10.1097/00006676-199808000-00007 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 103VG UT WOS:000074978100007 PM 9700946 ER PT J AU Granovsky, MO Minkoff, HL Tess, BH Waters, D Hatzakis, A Devoid, DE Landesman, SH Rubinstein, A Di Bisceglie, AM Goedert, JJ AF Granovsky, MO Minkoff, HL Tess, BH Waters, D Hatzakis, A Devoid, DE Landesman, SH Rubinstein, A Di Bisceglie, AM Goedert, JJ TI Hepatitis C virus infection in the Mothers and Infants Cohort Study SO PEDIATRICS LA English DT Article DE hepatitis C virus; human immunodeficiency virus; vertical transmission; children ID HUMAN-IMMUNODEFICIENCY-VIRUS; NON-B-HEPATITIS; NON-A; VERTICAL TRANSMISSION; LIVER-DISEASE; RISK; ASSOCIATION; ANTIBODIES; POPULATION; MEMBRANES AB Objectives. To estimate the hepatitis C virus (HCV) vertical transmission rate, the effect of potential risk factors, and the pattern of HCV antibody response and viremia in HCV-infected infants. Study Design. The Mothers and Infants Cohort Study enrolled both human immunodeficiency virus (HIV)-seropositive and HIV-seronegative pregnant women at five obstetric clinics in New York City in a prospective cohort study between January 1986 and January 1991. HCV-infected mothers and their 122 offspring were followed-up for a minimum of 12 months for evidence of HCV infection as determined by persistent HCV antibodies or detection of HCV RNA by reverse transcription polymerase chain reaction. Comparisons among groups for categorical variables were performed using the Fisher's exact test. Results. Seven (6%; 95% confidence interval, 2%-11%) of the 122 infants were HCV-infected. There was a tendency for increased risk of transmission with maternal viral and obstetrical factors, such as coinfection with HIV (7% vs 4%), high HIV viral load (13% vs 6%), HCV viremia (8% vs 3%), vaginal delivery (6% vs 0%), and female gender of offspring (8% vs 3%), although none of the associations reached statistical significance. After loss of maternal antibody, HCV antibody seroconversion occurred at a mean age of 26 months in 3 HIV-coinfected infants compared with 7 months of age in 4 HCV-infected HIV-uninfected infants. Serial samples showed that HCV RNA persisted in 6 infants for at least 18 to 54 months. Conclusions. Our study is in accordance with other studies that have shown low overall HCV vertical transmission risk and a trend toward higher risk with maternal risk factors such as HIV-coinfection or HCV viremia. A delay in infant HCV antibody response may be associated with HIV coinfection although larger studies are needed to confirm these findings. C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. SUNY Hlth Sci Ctr, Dept Obstet & Gynecol, Brooklyn, NY 11203 USA. SUNY Hlth Sci Ctr, Dept Med, Brooklyn, NY 11203 USA. Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp, Frederick, MD USA. Univ Athens, Dept Hyg & Epidemiol, Athens, Greece. Univ Athens, Sch Med, GR-11527 Athens, Greece. Walter Reed Army Med Ctr, Dept Pediat, Washington, DC 20307 USA. Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA. St Louis Univ, Sch Med, Dept Med, St Louis, MO 63104 USA. RP Granovsky, MO (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6130 Execut Blvd,EPN-434, Rockville, MD 20852 USA. FU NICHD NIH HHS [N0-1-HD-4-3208] NR 34 TC 93 Z9 97 U1 0 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD AUG PY 1998 VL 102 IS 2 BP 355 EP 359 DI 10.1542/peds.102.2.355 PG 5 WC Pediatrics SC Pediatrics GA 106JH UT WOS:000075125800011 PM 9685438 ER PT J AU Lemons, JA Blackmon, LR Fanaroff, AA MacDonald, HM Miller, CA Papile, LA Rosenfeld, W Shoemaker, CT Speer, ME AF Lemons, JA Blackmon, LR Fanaroff, AA MacDonald, HM Miller, CA Papile, LA Rosenfeld, W Shoemaker, CT Speer, ME CA Comm Fetus Newborn TI Hospital discharge of the high-risk neonate - Proposed guidelines SO PEDIATRICS LA English DT Review ID LOW-BIRTH-WEIGHT; HOME OXYGEN-THERAPY; INTENSIVE-CARE UNIT; PRETERM INFANTS; BRONCHOPULMONARY DYSPLASIA; CHILD-ABUSE; FOLLOW-UP; RANDOMIZED TRIAL; TERM NEONATE; HEALTH AB This policy statement is the first formal statement of the American Academy of Pediatrics on the issue of hospital discharge of the high-risk neonate. It has been developed, to the extent possible, on the basis of published, scientifically derived information. Four categories of high risk are identified: 1) the preterm infant, 2) the infant who requires technological support, 3) the infant primarily at risk because of family issues, and 4) the infant whose irreversible condition will result in an early death. The unique home care issues for each are reviewed within a common framework. Recommendations are given for four areas of readiness for hospital discharge: infant, home care planning, family and home environment, and the community and health care system. The need for individualized planning and physician judgment is emphasized. C1 Amer Nurses Assoc, Washington, DC 20024 USA. Assoc Womens Hlth Obstet & Neonatal Nurses, Washington, DC 20005 USA. Amer Coll Obstetricians & Gynecologists, Washington, DC 20024 USA. Canadian Paediat Soc, Ottawa, ON, Canada. Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. NICHHD, Bethesda, MD USA. NR 101 TC 62 Z9 67 U1 0 U2 2 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD AUG PY 1998 VL 102 IS 2 BP 411 EP 417 PG 7 WC Pediatrics SC Pediatrics GA 106JH UT WOS:000075125800024 ER PT J AU Berlin, CM McCarver, DG Notterman, DA Ward, RM Weismann, DN Wilson, GS Wilson, JT AF Berlin, CM McCarver, DG Notterman, DA Ward, RM Weismann, DN Wilson, GS Wilson, JT CA Comm Drugs TI Prevention of medication errors in the pediatric inpatient setting SO PEDIATRICS LA English DT Article ID ADVERSE DRUG EVENTS AB Medication errors that occur on a pediatric medical/surgical inpatient care unit are usually avoidable. Several steps are recommended to reduce these errors, beginning with the physician and including every member of the health care team. Pediatricians should help hospitals develop effective programs for safely providing treatment with medications to hospitalized children. C1 Amer Coll Obstetricians & Gynecologists, Washington, DC USA. Pharmaceut Res & Manufacturers Assoc Amer, Washington, DC USA. Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. Canadian Paediat Soc, Ottawa, ON, Canada. US FDA, Rockville, MD 20857 USA. Amer Acad Child & Adolescent Psychiat, Washington, DC USA. NIH, Bethesda, MD USA. Amer Acad Family Phys, Kansas City, MO USA. Natl Assoc Childrens Hosp & Related Inst, Alexandria, VA USA. Joint Commis Accreditat Healthcare Org, Chicago, IL USA. NR 11 TC 31 Z9 34 U1 1 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD AUG PY 1998 VL 102 IS 2 BP 428 EP 430 PG 3 WC Pediatrics SC Pediatrics GA 106JH UT WOS:000075125800026 ER PT J AU Long, RM AF Long, RM TI Part I: What is the scope of institutional training programs (T32s) supported by the NIGMS? Where is more information available? SO PHARMACEUTICAL RESEARCH LA English DT Editorial Material C1 NIGMS, Pharmacol & Physiol Sci Branch, Div Pharmacol Physiol & Biol Chem, NIH, Bethesda, MD 20892 USA. RP Long, RM (reprint author), NIGMS, Pharmacol & Physiol Sci Branch, Div Pharmacol Physiol & Biol Chem, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PLENUM PUBL CORP PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 J9 PHARMACEUT RES JI Pharm. Res. PD AUG PY 1998 VL 15 IS 8 BP 1149 EP 1151 PG 3 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 106KW UT WOS:000075129300001 ER PT J AU Fant, RV Heishman, SJ Bunker, EB Pickworth, WB AF Fant, RV Heishman, SJ Bunker, EB Pickworth, WB TI Acute and residual effects of marijuana in humans SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE marijuana; THC; subjective effects; performance effects; cardiovascular effects; pupillary effects; smooth pursuit eye tracking; cognitive tasks; psychomotor tasks; human behavioral pharmacology ID AIRCRAFT PILOT PERFORMANCE; SMOKED MARIJUANA; TASK-PERFORMANCE; LIGHT REFLEX; HEART-RATE; SMOKING; ALCOHOL; HANGOVER; PROFILES; INTOXICATION AB Marijuana continues to be the most commonly abused illicit drug in the United States, Because many people abuse marijuana during the evening and on weekends and then go to work or school the next day, more research is needed on the residual effects of marijuana. The current study sought to examine both acute and residual subjective, physiologic, and performance effects of smoking a single marijuana cigarette. Ten healthy male volunteers who reported recent use of marijuana resided, on a residential research ward. On three separate days, subjects smoked one NIDA marijuana cigarette containing either 0%, 1.8%, or 3.6% Delta(9)-tetrahydrocannabinol (THC) according to a paced puffing procedure. Subjective, physiologic, and performance measures were collected prior to smoking, five times following smoking on that day, and three times on the following morning. Subjects reported robust subjective effects following both active doses of marijuana, which returned to baseline levels within 3.5 h. Heart rate increased and the pupillary light reflex decreased following active dose administration with return to baseline on that day. A new finding was that marijuana smoking acutely produced decrements in smooth pursuit eye tracking. Although robust acute effects of marijuana were found on subjective and physiological measures, and on smooth pursuit eye tracking performance, no effects were evident the day following administration, indicating that the residual effects of smoking a single marijuana cigarette are minimal. (C) 1998 Elsevier Science Inc. C1 NIDA, Clin Pharmacol Branch, Intramural Res Program, Addict Res Ctr, Baltimore, MD 21224 USA. RP Fant, RV (reprint author), NIDA, Clin Pharmacol Branch, Intramural Res Program, Addict Res Ctr, POB 5180, Baltimore, MD 21224 USA. NR 47 TC 62 Z9 64 U1 5 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD AUG PY 1998 VL 60 IS 4 BP 777 EP 784 DI 10.1016/S0091-3057(97)00386-9 PG 8 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 105CQ UT WOS:000075055200001 PM 9700958 ER PT J AU Pickworth, WB Fant, RV Nelson, RA Henningfield, JE AF Pickworth, WB Fant, RV Nelson, RA Henningfield, JE TI Effects of cigarette smoking through a partially occluded filter SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE nicotine; EEG; carbon monoxide; tobacco smoke exposure ID TOBACCO ABSTINENCE; EEG CHANGES; WITHDRAWAL; HUMANS AB The effects of a commercially available corn syrup solution that is applied to the filter end of a cigarette causing an occlusive barrier to cigarette smoke were evaluated. The manufacturer claims that the solution reduces exposure to nicotine, carbon monoxide (CO), and other constituents of tobacco smoke and may aid in smoking cessation by providing a means of gradual nicotine dose reduction. Nineteen volunteers (10 men) smoked commercial cigarettes treated with 0, 1, 2, or 3 drops of the corn syrup solution in a double-blind, crossover experiment. Increases in plasma nicotine after smelting averaged 13.3, 10.5, 9.7, and 6.0 ng/ml in the 0, 1, 2, and 3 drop conditions, respectively. In the 3 drop condition, there was a significant reduction in exhaled CO levels. Subjects reported increased difficulty in cigarette draw and a trend toward decreased strength as a function of the number of drops applied. Cardiovascular and EEG measures of smoking were not significantly affected by the application of the drops. Cigarettes treated with 0, 1, 2, or 3 drops of the solution were machine smoked using methods of the Federal Trade Commission (FTC); nicotine yields were 1.0, 1.0, 0.78, and 0.73 mg of nicotine. These results indicate that Take Out drops reduce exposure to nicotine and other constituents of tobacco smoke from a single cigarette. (C) 998 Elsevier Science Inc. C1 NIDA, Clin Pharmacol Branch, Div Intramural Res, Addict Res Ctr, Baltimore, MD 21224 USA. RP Pickworth, WB (reprint author), NIDA, Clin Pharmacol Branch, Div Intramural Res, Addict Res Ctr, POB 5180, Baltimore, MD 21224 USA. NR 21 TC 4 Z9 4 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD AUG PY 1998 VL 60 IS 4 BP 817 EP 821 DI 10.1016/S0091-3057(98)00042-2 PG 5 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 105CQ UT WOS:000075055200006 PM 9700963 ER PT J AU Vonderhaar, BK AF Vonderhaar, BK TI Prolactin: The forgotten hormone of human breast cancer SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE prolactin; prolactin receptors; mammary gland; human breast cancer; tamoxifen; antilactogen binding site ID GROWTH-FACTOR-BETA; PROTEIN-KINASE-C; MOUSE MAMMARY-GLAND; IN-VITRO; CELL-LINE; RECEPTOR ANTAGONISTS; BIOLOGICAL-ACTIVITY; ESTROGEN-RECEPTOR; PORCINE PROLACTIN; EPITHELIAL-CELLS AB Prolactin (PRL) is both a mitogen and a differentiating agent in the mammary gland. It has been shown to be involved in mammary cancer development in rodents, but in human breast cancer, its role has long been overlooked. Three criteria are applied to demonstrate PRL's involvement in this disease: (1) PRL receptors are present in human breast cancer cells, (2) human breast cancer cells in culture respond to PRL as a mitogen, and (3) PRL is synthesized by human breast cancer cells and inhibition of the binding of PRL to its receptors inhibits cell growth. PHARMACOL. THER. 79(2):169-178, 1998. (C) 1998 Elsevier Science Inc. C1 NCI, Tumor Immunol & Biol Lab, Mol & Cellular Endocrinol Sect, NIH, Bethesda, MD 20892 USA. RP Vonderhaar, BK (reprint author), NCI, Tumor Immunol & Biol Lab, Mol & Cellular Endocrinol Sect, NIH, Bldg 10,Room 5B56, Bethesda, MD 20892 USA. NR 90 TC 65 Z9 68 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD AUG PY 1998 VL 79 IS 2 BP 169 EP 178 DI 10.1016/S0163-7258(98)00017-5 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 103WP UT WOS:000074981100004 PM 9749881 ER PT J AU Bicout, DJ Berezhkovskii, AM Weiss, GH AF Bicout, DJ Berezhkovskii, AM Weiss, GH TI Turnover in the mean survival time for a particle moving between two traps SO PHYSICA A LA English DT Article DE activationless rate processes; trapping problem; persistent random walks AB There is presently no solution to the problem of characterizing the statistics of trapping of a one-dimensional Brownian particle that moves between two traps, when velocity is relevant. We analyze a simplified version of this problem in which the continuous velocity is replaced by three velocities, +/-upsilon and 0, allowing the particle to make random transitions between these states. This model is easily solved and exhibits turnover behavior as a function of the noise intensity (i.e., the jump rate). (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIH, Math & Stat Comp Lab, Div Comp Res & Technol, Bethesda, MD 20892 USA. NIDDKD, Chem Phys Lab, Bethesda, MD 20892 USA. RP Weiss, GH (reprint author), NIH, Math & Stat Comp Lab, Div Comp Res & Technol, Bldg 10, Bethesda, MD 20892 USA. NR 5 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-4371 J9 PHYSICA A JI Physica A PD AUG 1 PY 1998 VL 256 IS 3-4 BP 342 EP 350 DI 10.1016/S0378-4371(98)00120-4 PG 9 WC Physics, Multidisciplinary SC Physics GA 114TQ UT WOS:000075625600005 ER PT J AU Malley, JD AF Malley, JD TI Quantum conditional probability and hidden-variables models SO PHYSICAL REVIEW A LA English DT Article ID BELL INEQUALITIES; DISTRIBUTIONS; THEOREMS AB We discuss quantum conditional probability and its applications to deterministic hidden-variable models. We derive empirical tests corresponding to mathematical no-go proofs, providing rigorous statistical tests based on experimental outcomes. Evidently, it now possible to examine the statistical power of the empirical tests, and place confidence intervals on the parameters that precisely measure the departure of hidden-variable models from quantum experimental outcomes. Moreover, reinterpretation of well-known results in the light of quantum conditional probability provides other experimental demonstrations and no-go proofs: outcomes for the familiar Young double-slit experiment show that there are no deterministic hidden-variable models of the type considered by Kochen and Specker [J. Math. Mech. 17, 59 (1967)] or Bell [Rev. Mod. Phys. 38, 447 (1966)]. [S1050-2947(98)07908-6]. C1 NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Malley, JD (reprint author), NIH, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. OI Malley, James/0000-0002-9895-7454 NR 31 TC 6 Z9 6 U1 0 U2 1 PU AMERICAN PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1050-2947 J9 PHYS REV A JI Phys. Rev. A PD AUG PY 1998 VL 58 IS 2 BP 812 EP 820 DI 10.1103/PhysRevA.58.812 PG 9 WC Optics; Physics, Atomic, Molecular & Chemical SC Optics; Physics GA 110NA UT WOS:000075386200008 ER PT J AU Hansen, PL Miao, L Ipsen, JH AF Hansen, PL Miao, L Ipsen, JH TI Fluid lipid bilayers: Intermonolayer coupling and its thermodynamic manifestations SO PHYSICAL REVIEW E LA English DT Article ID PHOSPHATIDYLCHOLINE-CHOLESTEROL SYSTEM; RIPPLE PHASE; PHOSPHOLIPID-BILAYERS; 2-COMPONENT MEMBRANES; CURVATURE ELASTICITY; BENDING ELASTICITY; SEGREGATION LIMIT; CHAIN-LENGTH; VESICLES; TENSION AB A fluid membrane of lipid bilayer consists of two individual molecular monolayers physically opposed to each other. This unique molecular architecture naturally necessitates the need to treat a lipid-bilayer membrane as one entity of two coupled two-dimensional systems (monolayers), each of which possesses "in-plane" degrees of freedom that characterize its physical or chemical state. Thermally excitable deformations of a Lipid bilayer in its geometrical conformation further impart to it ''out-of-plane'' degrees of freedom. In this paper we discuss the issue of intermonolayer coupling in terms of a phenomenological model that describes the necessary types of degrees of freedom and their interplay, which reflects different modes of intermonolayer coupling. Furthermore, we investigate! based on the phenomenological model, the manifestations of the intermonolayer coupling both in the lateral ordering processes of the "in-plane" degrees of freedom and in the conformational behavior of the bilayer membrane. C1 Tech Univ Denmark, Dept Chem, DK-2800 Lyngby, Denmark. RP Hansen, PL (reprint author), NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. NR 59 TC 32 Z9 32 U1 0 U2 5 PU AMERICAN PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1063-651X J9 PHYS REV E JI Phys. Rev. E PD AUG PY 1998 VL 58 IS 2 BP 2311 EP 2324 DI 10.1103/PhysRevE.58.2311 PN B PG 14 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 110LW UT WOS:000075381500040 ER PT J AU Berglund, BA Boring, DL Wilken, GH Makriyannis, A Howlett, AC AF Berglund, BA Boring, DL Wilken, GH Makriyannis, A Howlett, AC TI Structural requirements for arachidonylethanolamide interaction with CB1 and CB2 cannabinoid receptors: pharmacology of the carbonyl and ethanolamide groups SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article ID ANANDAMIDE ANALOGS; PHENOLIC HYDROXYL; BINDING; MEMBRANES AB Analogs of arachidonylethanolamide (anandamide) were prepared to investigate the structural requirements for ligand binding to and activation of the CB1 and CB2 cannabinoid receptors. The importance of the presence and the placement of the carbonyl was examined with analogs lacking the carbonyl or with the carbonyl amide order reversed. The presence and location of the carbonyl is essential for high-affinity binding to both cannabinoid receptor subtypes, and for determination of signal transduction via G-proteins. Methyl groups were substituted on the 1'- and 2'-positions of arachidonylethanolamide and the significance of chirality was examined. Stereochemical differences in the ethanolamide group influence the affinity for both cannabinoid receptor subtypes and the signal transduction capabilities of the methanandamide derivatives. C1 St Louis Univ, Sch Med, Dept Pharmacol & Physiol Sci, St Louis, MO 63104 USA. US FDA, Ctr Drug Evaluat & Res, Div New Drug Synth, Rockville, MD 20857 USA. NIDDKD, Med Chem Lab, NIH, Bethesda, MD 20962 USA. Univ Connecticut, Sch Pharm, Storrs, CT 06269 USA. Univ Connecticut, Inst Sci Mat, Storrs, CT 06269 USA. RP Howlett, AC (reprint author), St Louis Univ, Sch Med, Dept Pharmacol & Physiol Sci, 1402 S Grand, St Louis, MO 63104 USA. OI Howlett, Allyn/0000-0002-2810-0164 FU NIDA NIH HHS [R01-DA06312, R01-DA07215]; PHS HHS [K05-00182] NR 19 TC 19 Z9 19 U1 0 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0952-3278 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD AUG PY 1998 VL 59 IS 2 BP 111 EP 118 DI 10.1016/S0952-3278(98)90089-8 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 120YL UT WOS:000075985400005 PM 9774174 ER PT J AU Secor, WE Powell, MR Morgan, J Wynn, TA Funk, CD AF Secor, WE Powell, MR Morgan, J Wynn, TA Funk, CD TI Mice deficient for 5-lipoxygenase, but not leukocyte-type 12-lipoxygenase, display altered immune responses during infection with Schistosoma mansoni SO PROSTAGLANDINS & OTHER LIPID MEDIATORS LA English DT Article DE schistosomasis; lipoxygenase; granuloma; hypersensitivity ID EOSINOPHIL-STIMULATION PROMOTER; ARACHIDONIC-ACID METABOLISM; GRANULOMA-FORMATION; LIPOXYGENASE PRODUCTS; PULMONARY GRANULOMA; EXPRESSION; EGG; MACROPHAGES; DISRUPTION; PATHOLOGY AB Periovular granuloma formation during Schistosoma mansoni infection is a complex, multifaceted immunologic response. Products of arachidonic acid metabolism have been shown to contribute to this response through studies in which general inhibitors of lipoxygenase function reduce granulomatous inflammation. To determine which lipoxygenases are important for granuloma development in schistosomiasis, wild type mice or mice deficient for 5-lipoxygenase (5-LO) or "leukocyte-type" 12-lipoxygenase (12-LO) were infected with S. mansoni and studied for responses to schistosome eggs and egg antigens. At the acute stage of infection, when granuloma formation is usually maximal, 5-LO deficient mice developed smaller granulomas around liver-deposited schistosome eggs compared with wild type or 12-LO deficient mice. 5-LO mice also displayed less antibody-mediated (5 h) and cell-mediated, delayed-type (24 h) hypersensitivity to schistosome egg antigens than did the other two infection groups, in an attempt to determine possible mechanisms for the reduced inflammatory responses, we also measured hepatic mRNA levels of cytokines that have been shown to influence granuloma size (IL-4, IL-10, and IFN-gamma). The mRNA levels for IL-10 were significantly lower in 5-LO-deficient mice, but SEA-stimulated spleen cells did not demonstrate a significant difference in IL-10 production between wild type and 5-LO mice. These data suggest that 5-LO plays a role in host responses to schistosomiasis via a mechanism that cannot be explained solely by changes in expression of these cytokines. C1 Ctr Dis Control & Prevent, Immunol Branch, Div Parasit Dis, Natl Ctr Infect Dis, Atlanta, GA 30341 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Univ Penn, Ctr Expt Therapeut, Stellar Chance Labs, Philadelphia, PA 19104 USA. RP Secor, WE (reprint author), Ctr Dis Control & Prevent, Immunol Branch, Div Parasit Dis, Natl Ctr Infect Dis, 4770 Buford Hwy NE,MS-F13, Atlanta, GA 30341 USA. RI Funk, Colin/A-9518-2010; Wynn, Thomas/C-2797-2011 FU NHLBI NIH HHS [HL53558] NR 22 TC 11 Z9 11 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-6980 J9 PROSTAG OTH LIPID M JI Prostaglandins Other Lipid Mediat. PD AUG PY 1998 VL 56 IS 5-6 BP 291 EP 304 DI 10.1016/S0090-6980(98)00059-8 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 218FY UT WOS:000081543600003 PM 9990674 ER PT J AU Culig, Z Hittmair, A Hobisch, A Bartsch, G Klocker, H Pai, LH Pastan, I AF Culig, Z Hittmair, A Hobisch, A Bartsch, G Klocker, H Pai, LH Pastan, I TI Expression of Lewis carbohydrate antigens in metastatic lesions from human prostatic carcinoma SO PROSTATE LA English DT Article DE monoclonal antibodies; Lewis carbohydrate antigens; prostate cancer metastases; immunotoxins ID PSEUDOMONAS EXOTOXIN; MONOCLONAL-ANTIBODY; CANCER; IMMUNOTOXIN; SURFACE; CELLS; PR1; FV AB BACKGROUND. Monoclonal antibodies B1 and B3 react with Lewis(y) and related carbohydrate antigens, which are abundant in many solid tumors. These antibodies, when conjugated 'to a toxin, have been used to target a variety of cancers. Treatment options for advanced prostate cancer are very limited, and there is a need to develop new therapies. In this study, we have asked whether antibodies B1 and B3 react with metastatic lesions from human prostatic carcinoma. METHODS. Indirect streptavidin-biotin peroxidase immunohistochemistry was performed on formalin-fixed specimens from prostate cancer metastases. A total of 6 lymph node metastatic samples from patients who did not receive endocrine treatment and specimens of 14 distant metastases from patients who failed hormonal therapy were obtained. RESULTS. Of the samples, 6 lymph node and 11 distant metastases stained for B1. In the case of B3 staining, 6 lymph node and 10 distant metastatic lesions were positive. In about half of these metastatic samples, more than 40% of cells were immunoreactive with either antibody. Two metastatic samples stained neither for B1 nor for B3 antibody. In general, B1 staining intensity was stronger in samples in which more than 40% of cells were positive. CONCLUSIONS. Our results suggest that B1 and B3 immunoconjugates could be applied to target a substantial percentage of prostate cancer metastases. Prostate 36:162-167, 1998. (C) 1998 Wiley-Liss, Inc. C1 NCI, Mol Biol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Univ Innsbruck, Dept Urol, A-6020 Innsbruck, Austria. Univ Innsbruck, Dept Pathol, A-6020 Innsbruck, Austria. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Div Basic Sci, NIH, Bldg 37,Room 4E16,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM pasta@helix.nih.gov NR 24 TC 8 Z9 8 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-4137 J9 PROSTATE JI Prostate PD AUG 1 PY 1998 VL 36 IS 3 BP 162 EP 167 PG 6 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 102PA UT WOS:000074932000003 PM 9687987 ER PT J AU Trumbore, MW Manrow, RE Berger, SL AF Trumbore, MW Manrow, RE Berger, SL TI Prothymosin alpha is not found in yeast SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article ID SACCHAROMYCES-CEREVISIAE; GENE FAMILY; DIVISION; MUTANT AB According to published accounts, prothymosin alpha exhibits high evolutionary conservation from yeast to man (Makarova, T., Grebenshikov, N., Egorov, C., Vartapetian, A., and Bogdanov, A. FEES Lett. 257, 247-250, 1989). We report here our failure to find evidence for prothymosin alpha in yeast using three biochemical approaches: hybridization of yeast mRNA and genomic DNA with human prothymosin a coding region probes, performance of the polymerase chain reaction with yeast genomic template DNA and three sets of primers recognizing human prothymosin a coding region sequences, and isolation of yeast proteins essentially as described in the publication above. A survey of the Saccharomyces cerevisiae complete genome database using the program BLASTp verified our findings: there is no prothymosin alpha-homologue in yeast. Furthermore, DNA representing organisms from bacteria to amphibians also failed to hybridize with the same probes. Therefore, the presence of a prothymosin alpha gene in animals other than mammals is highly unlikely. (C) 1998 Academic Press. C1 NCI, Sect Genes & Gene Prod, Div Basic Sci, Bethesda, MD 20892 USA. RP NCI, Sect Genes & Gene Prod, Div Basic Sci, Bethesda, MD 20892 USA. NR 21 TC 11 Z9 11 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 EI 1096-0279 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD AUG PY 1998 VL 13 IS 3 BP 383 EP 388 DI 10.1006/prep.1998.0909 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 108DH UT WOS:000075250400012 PM 9693063 ER PT J AU Rick, SW Topol, IA Erickson, JW Burt, SK AF Rick, SW Topol, IA Erickson, JW Burt, SK TI Molecular mechanisms of resistance: Free energy calculations of mutation effects on inhibitor binding to HIV-1 protease SO PROTEIN SCIENCE LA English DT Article DE cavities; drug resistance; free energy calculations; HIV protease; mutations ID GLOBULAR-PROTEINS; PERTURBATION; SIMULATION; STABILITY; VARIANTS; CAVITIES; MUTANTS AB The changes in the inhibitor binding constants due to the mutation of isoleucine to valine at position 84 of HIV-I protease are calculated using molecular dynamics simulations. The calculations are done for three potent inhibitors-KNI-272, L-735,524 (indinavir or MK-639), and Ro 31-8959 (saquinavir). The calculations agree with the experimental data both in terms of an overall trend and in thr magnitude of the resulting free energy change. HIV-1 protease is a homodimer, so each mutation causes two changes in the enzyme, The decrease in the binding free energy From each mutated side chain differs among thr three inhibitors and correlates well with the size of the cavities induced in the protein interior near the mutated residue, The cavities are created as a result of a mutation to a smaller side chain, but the cavities are less than would be predicted from the wild-type structures, indicating that there is significant relaxation to partially fill the cavities. C1 NCI, Frederick Biomed Supercomp Ctr, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, Struct Biochem Program, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Rick, SW (reprint author), NCI, Frederick Biomed Supercomp Ctr, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. EM rick@ncierf.gov FU NCRR NIH HHS [RR-01081] NR 44 TC 19 Z9 19 U1 1 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 1998 VL 7 IS 8 BP 1750 EP 1756 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 170NW UT WOS:000078813300009 PM 10082371 ER PT J AU Galperin, MY Bairoch, A Koonin, EV AF Galperin, MY Bairoch, A Koonin, EV TI A superfamily of metalloenzymes unifies phosphopentomutase and cofactor-independent phosphoglycerate mutase with alkaline phosphatases and sulfatases SO PROTEIN SCIENCE LA English DT Article DE alkaline phosphatase; autotaxin; inherited disease; mucopolysaccharidosis; nucleotide pyrophosphatase PC-1; phosphoglycerate mutase; phosphopentomutase; sulfatase deficiency ID COMPLETE GENOME SEQUENCE; INFANTILE METACHROMATIC LEUKODYSTROPHY; PSEUDOMONAS-FLUORESCENS 23F; BACILLUS-MEGATERIUM; ESCHERICHIA-COLI; NUCLEOTIDE PYROPHOSPHATASE; PHOSPHONOACETATE HYDROLASE; 3-PHOSPHOGLYCERATE MUTASE; METHANOCOCCUS-JANNASCHII; MANGANESE(II) ACTIVATION AB Sequence analysis of the probable archaeal phosphoglycerate mutase resulted in the identification of a superfamily of metalloenzymes with similar metal-binding sites and predicted conserved structural fold. This superfamily unites alkaline phosphatase, N-acetylgalactosamine-4-sulfatase, and cerebroside sulfatase, enzymes with known three-dimensional structures, with phosphopentomutase, 2,3-bisphosphoglycerate-independent phosphoglycerate mutase, phosphoglycerol transferase, phosphonate monoesterase, streptomycin-6-phosphate phosphatase, alkaline phosphodiesterase/nucleotide pyrophosphatase PC-1, and several closely related sulfatases. In addition to the metal-binding motifs, all these enzymes contain a set of conserved amino acid residues that are likely to be required for the enzymatic activity. Mutational changes in the vicinity of these residues in several sulfatases cause mucopolysaccharidosis (Hunter, Maroteaux-Lamy, Morquio, and Sanfilippo syndromes) and metachromatic leucodystrophy. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Univ Geneva, Dept Biochim Med, CH-1211 Geneva 4, Switzerland. RP Galperin, MY (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RI Galperin, Michael/B-5859-2013; OI Galperin, Michael/0000-0002-2265-5572; Bairoch, Amos/0000-0003-2826-6444 NR 63 TC 107 Z9 110 U1 0 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 1998 VL 7 IS 8 BP 1829 EP 1835 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 170NW UT WOS:000078813300019 PM 10082381 ER PT J AU Sandak, B Wolfson, HJ Nussinov, R AF Sandak, B Wolfson, HJ Nussinov, R TI Flexible docking allowing induced fit in proteins: Insights from an open to closed conformational isomers SO PROTEINS-STRUCTURE FUNCTION AND GENETICS LA English DT Article DE molecular recognition; flexible docking; protein-ligand interaction; induced fit; structure-based drug design ID MALTODEXTRIN-BINDING-PROTEIN; MOLECULAR RECOGNITION; AUTOMATED DOCKING; 2.3-A RESOLUTION; ACTIVE-TRANSPORT; PEPTIDE COMPLEX; LIGAND DOCKING; DOMAIN CLOSURE; RECEPTOR-SITES; CALMODULIN AB Here we dock a ligand onto a receptor surface allowing hinge-bending domain/substructural movements. Our approach mimics and manifests induced fit in molecular recognition. All angular rotations are allowed on the one hand, while a conformational space search is avoided on the other. Rather than dock each of the molecular parts separately with subsequent reconstruction of the consistently docked molecules, all parts are docked simultaneously while still utilizing the position of the hinge from the start. Like pliers closing on a screw, the receptor automatically closes on its ligand in the best surface-matching way. Movements are allowed either in the ligand or in the larger receptor, hence reproducing induced molecular fit. Hinge bending movements are frequently observed when molecules associate. There are numerous examples of open versus closed conformations taking place upon binding. Such movements are observed when the substrate binds to its respective enzyme. In particular, such movements are of interest in allosteric enzymes. The movements can involve entire domains, subdomains, loops, (other) secondary structure elements, or between any groups of atoms connected by flexible joints. We have implemented the hinges at points and at bonds. By allowing 3-dimensional (3-D) rotation at the hinge, several rotations about (consecutive or nearby) bonds are implicitly taken into account. Alternatively, if required, the point rotation can be restricted to bond rotation. Here we illustrate this hinge-bending docking approach and the insight into flexibility it provides on a complex of the calmodulin with its M13 ligand, positioning the hinges either in the ligand or in the larger receptor. This automated and efficient method is adapted hom computer vision and robotics. It enables utilizing entire molecular surfaces rather than focusing a priori on active sites. Hence, allows attaining the overall optimally matching surfaces, the extent and type of motions which are involved. Here we do not treat the conformational flexibility of side-chains or of very small pieces of the molecules. Therefore, currently available methods addressing these issues and the method presented here, are complementary to each other, expanding the repertoire of computational docking tools foreseen to aid in studies of recognition, conformational flexibility and drug design. Proteins 32:159-174, 1998, (C) 1998 Wiley-Liss, Inc. C1 NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, SAIC, Frederick, MD 21702 USA. Weizmann Inst Sci, Dept Appl Math & Comp Sci, IL-76100 Rehovot, Israel. Tel Aviv Univ, Sackler Fac Exact Sci, Dept Comp Sci, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Fac Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, SAIC, Bldg 469,Room 151, Frederick, MD 21702 USA. RI Wolfson, Haim/A-1837-2011 FU NCI NIH HHS [I-CO-74102] NR 66 TC 89 Z9 91 U1 0 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-3585 J9 PROTEINS JI Proteins PD AUG 1 PY 1998 VL 32 IS 2 BP 159 EP 174 DI 10.1002/(SICI)1097-0134(19980801)32:2<159::AID-PROT3>3.0.CO;2-G PG 16 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 106KP UT WOS:000075128700003 PM 9714156 ER PT J AU Weingartner, HJ Rawlings, R George, DT Eckardt, M AF Weingartner, HJ Rawlings, R George, DT Eckardt, M TI Triazolam-induced changes in alcoholic thought processes SO PSYCHOPHARMACOLOGY LA English DT Article DE triazolam; cognitive effect; alcohol ID MEMORY IMPAIRMENTS; BEHAVIOR; BENZODIAZEPINES; RISK; DISSOCIATION; SENSITIVITY; FLUMAZENIL; AGE AB This study was designed to examine and contrast cognitive effects (explicit memory and access to semantic knowledge) of the benzodiazepine Halcion (triazolam) in ten normal volunteers and ten cognitively unimpaired detoxified alcoholics. The two groups were indistinguishable from one another under placebo conditions on all measures of cognitive functioning. Under Halcion test conditions (0.375 mg PO), both groups were about equally impaired in their recall of to-be-remembered information. However, alcoholics, were more likely to recall information that they were not asked to remember (intrusion errors) on all measures of explicit remembering. Alcoholics also generated relatively uncommon (low frequency) responses from semantic memory, rather than common, categorically related associations in response to stimuli such as types of vegetables, flowers, and fruit following the administration of Halcion, but were not different from normal volunteers in the types of responses generated under placebo conditions. These findings suggest that a drug challenge that simulates many of the effects of acute alcohol administration induces alcoholics to think and remember differently (qualitatively) from normal volunteers. C1 NIAAA, Cognit Neurosci Sect, LCS, Bethesda, MD 20892 USA. NIAAA, Clin Studies Lab, Bethesda, MD 20892 USA. RP Weingartner, HJ (reprint author), NIAAA, Cognit Neurosci Sect, LCS, 10 Ctr Dr MSC 1250,Room 6S240, Bethesda, MD 20892 USA. NR 37 TC 8 Z9 8 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD AUG PY 1998 VL 138 IS 3-4 BP 311 EP 317 DI 10.1007/s002130050676 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 110KM UT WOS:000075380000010 PM 9725753 ER PT J AU Stone, HB Dewey, WC Wallace, SS Coleman, CN AF Stone, HB Dewey, WC Wallace, SS Coleman, CN TI Molecular biology to radiation oncology: A model for translational research? Opportunities in basic and translational research - From a workshop sponsored by the National Cancer Institute, Radiation Research Program, January 26-28, 1997, Bethesda, Maryland SO RADIATION RESEARCH LA English DT Review ID IRRADIATED MURINE TUMORS; DEPENDENT PROTEIN-KINASE; EWINGS-SARCOMA CELLS; KAPPA-B-ALPHA; ATAXIA-TELANGIECTASIA; V(D)J RECOMBINATION; DNA-DAMAGE; IONIZING-RADIATION; INDUCED APOPTOSIS; MAMMALIAN-CELLS AB Many exciting discoveries are being made that are providing new insights into how molecules, cells and tissues respond to ionizing radiation. There remains a need, however, to translate these findings into more effective treatments for cancer patients, including those treated with radiation therapy. This complex task will require the collaboration of scientists studying molecular, cellular and tissue responses, and those performing clinical trials of emerging therapies. The Radiation Research Program of the National Cancer Institute sponsored a workshop entitled "Molecular Biology to Radiation Oncology: A Model for Translational Research?" to bring together basic scientists and clinicians to exchange ideas and fundamental concepts and to identify opportunities for future research and collaboration. Four broad topics were addressed: signal transduction and apoptosis, the cell cycle, repair of radiation damage, and the microenvironment. The development, selection and use of appropriate experimental models is crucial to finding and developing new therapies, and opportunities exist in this area as well. This paper and the accompanying paper by Coleman and Harris that provides the viewpoint of radiation oncologists (Radiat. Res. 150, 134-147, 1998) will summarize the background concepts and opportunities for translational research identified by the workshop participants. (C) 1998 by Radiation Research Society. C1 NCI, Radiat Res Program, Bethesda, MD 20892 USA. Univ Calif San Francisco, Radiat Oncol Res Lab, San Francisco, CA 94113 USA. Univ Vermont, Dept Microbiol Mol Genet, Burlington, VT 05405 USA. Joint Ctr Radiat Therapy, Boston, MA 02215 USA. RP Stone, HB (reprint author), NCI, Radiat Res Program, Bethesda, MD 20892 USA. NR 122 TC 7 Z9 8 U1 0 U2 1 PU RADIATION RESEARCH SOC PI OAK BROOK PA 2021 SPRING RD, STE 600, OAK BROOK, IL 60521 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD AUG PY 1998 VL 150 IS 2 BP 134 EP 147 DI 10.2307/3579849 PG 14 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 105RT UT WOS:000075087900015 PM 9692359 ER PT J AU Okunieff, P Mester, M Wang, J Maddox, T Gong, XQ Tang, DL Coffee, M Ding, I AF Okunieff, P Mester, M Wang, J Maddox, T Gong, XQ Tang, DL Coffee, M Ding, I TI In vivo radioprotective effects of angiogenic growth factors on the small bowel of C3H mice SO RADIATION RESEARCH LA English DT Article ID SUPEROXIDE-DISMUTASE; ENDOTHELIAL-CELLS; BONE-MARROW; INTESTINAL CRYPTS; STEM-CELLS; RADIATION; INTERLEUKIN-1; PROTECTS; SURVIVAL; TUMORS AB This study was undertaken to determine if acidic or basic fibroblast growth factor (FGF1 or FGF2) or vascular endothelial growth factor (VEGF) alters the radiation response of small bowel after total-body irradiation (TBI). Female C3H mice were treated with various doses of angiogenic growth factor administered intravenously 24 h before or 1 h after TBI. Radiation doses ranged from 7 to 18 Gy. End points measured were the number of crypts in three portions of the small bowel, the frequency of apoptosis of crypt cells at various times after TBI, and the LD,,,,, (bone marrow syndrome) and LD50/6 (GI syndrome). Fibroblast growth factors alone, without TBI, decreased the number of crypts per circumference significantly. Among the factors tested, FGF2 caused the greatest decline in baseline crypt number. Despite this decrease in the baseline crypt number, after irradiation the number of surviving crypts was greater in animals treated with growth factor. The greatest radioprotection occurred at intermediate doses of growth factor (6 to 18 mu g/mouse). Mice treated with FGF1 and FGF2 had crypt survival curves with a slope that was more shallow than that for saline-treated animals, indicating radiation resistance of crypt stem cells in FOE-treated mice. The LD50/6 was increased by approximately 10% for all treatments with angiogenic growth factors, whether given before or after TBI. Apoptosis of crypt cells was maximum at 4 to 8 h after TBI. The cumulative apoptosis was decreased significantly in animals treated with angiogenic growth factors, and the greatest protection against apoptosis was seen in animals treated with FGF2 prior to TBI. All three angiogenic growth factors tested were radioprotective in small bowel whether given 24 h before or 1 h after irradiation. The mechanism of protection is unlikely to involve proliferation of crypt stem cells, but probably does involve prevention of radiation-induced apoptosis or enhanced repair of DNA damage of crypt cells. (C) 1998 by Radiation Research Society. C1 Univ Rochester, Sch Med & Dent, Dept Radiat Oncol, Rochester, NY 14642 USA. Gastroenterol & Oncol Surg, BR-04002 Sao Paulo, Brazil. NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Mol Hematol Sect, NIH, Bethesda, MD 20892 USA. RP Okunieff, P (reprint author), Univ Rochester, Sch Med & Dent, Dept Radiat Oncol, 601 Elmwood Ave,Box 647, Rochester, NY 14642 USA. FU NCI NIH HHS [2-P01-CA11051-2582] NR 29 TC 75 Z9 87 U1 0 U2 0 PU RADIATION RESEARCH SOC PI OAK BROOK PA 2021 SPRING RD, STE 600, OAK BROOK, IL 60521 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD AUG PY 1998 VL 150 IS 2 BP 204 EP 211 DI 10.2307/3579856 PG 8 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 105RT UT WOS:000075087900007 PM 9692366 ER PT J AU Littlefield, LG McFee, AF Salomaa, SI Tucker, JD Inskip, PD Sayer, AM Lindholm, C Makinen, S Mustonen, R Sorensen, K Tekkel, M Veidebaum, T Auvinen, A Boice, JD AF Littlefield, LG McFee, AF Salomaa, SI Tucker, JD Inskip, PD Sayer, AM Lindholm, C Makinen, S Mustonen, R Sorensen, K Tekkel, M Veidebaum, T Auvinen, A Boice, JD TI Do recorded doses overestimate true doses received by Chernobyl cleanup workers? Results of cytogenetic analyses of Estonian workers by fluorescence in situ hybridization SO RADIATION RESEARCH LA English DT Article ID CHROMOSOME-ABERRATIONS; IONIZING-RADIATION; LYMPHOCYTES; ACCIDENT; EXPOSURE; SMOKING; CANCER; FISH; AGE AB Studies of workers who were sent to Chernobyl after the 1986 reactor accident are being conducted to provide a better understanding of the effects of chronic low-dose radiation exposures. A crucial component to these investigations is an accurate assessment of the radiation doses received during the cleanup activities. To provide information on biological measurements of dose, fluorescence in situ hybridization (FISH) with whole-chromosome painting probes has been applied to quantify stable chromosome aberrations (translocations and insertions) among a defined cohort of 4,833 cleanup workers from Estonia. Cytogenetic analysis of 48-h lymphocyte cultures from 118 Estonian cleanup workers (10.3 cGy mean recorded dose; 25 cGy maximum), 29 Estonian population controls and 21 American controls was conducted by three laboratories. More than 258,000 painted metaphases were evaluated. Overall, we observed lower translocation frequencies than has been reported in previous studies using FISH among Chernobyl cleanup workers. In our data, a clear association with increased levels of translocations was seen with increasing age at blood drawing. There was no correlation, however, between aberration frequency and recorded measurements of physical dose or any category of potential high-dose and high-dose-rate exposure such as being sent to Chernobyl in 1986, working on the roof near the damaged nuclear reactor, working in special zones or having multiple tours. In fact, the translocation frequency was lower among the exposed workers than the controls, though not significantly so. To estimate the level of effect that would have been expected in a population of men having an average dose of similar to 10 cGy, blood from six donors was exposed to low-LET radiation, and more than 32,000 metaphases were scored to estimate dose-response coefficients for radiation-induced translocations in chromosome pairs 1, 2 and 4. Based on these results, we estimate that had this group of 118 men received an average whole-body dose of 10-11 cGy, as chronic or acute exposures, an increase in the mean frequency of chromosome translocations of more than 40-65% would have been observed in their lymphocytes compared to findings in nonirradiated controls. In spite of evaluating more than a quarter of a million metaphases, we were unable to detect any increase in the mean, median or range in chromosome aberrations in lymphocyte cultures from a group of Estonian men who took part in the cleanup of the Chernobyl nuclear power site and those who did not. We conclude that it is likely that recorded doses for these cleanup workers overestimate their average bone marrow doses, perhaps substantially. These results are consistent with several negative studies of cancer incidence in Chernobyl cleanup workers and, if borne out, suggest that future studies may not be sufficiently powerful to detect increases in leukemia or cancer, much less distinguish differences between the effects of chronic compared to brief radiation exposures. (C) 1998 by Radiation Research Society. C1 Oak Ridge Inst Sci & Educ, Oak Ridge, TN 37830 USA. STUK Radiat & Nucl Safety Author, Helsinki, Finland. Lawrence Livermore Natl Lab, Livermore, CA 94551 USA. NCI, Radiat Epidemiol Branch, Bethesda, MD 20852 USA. NCI, Biostat Program, Div Canc Epidemiol & Genet, Bethesda, MD 20852 USA. Inst Clin & Expt Med, Tallinn, Estonia. Finnish Canc Registry, FIN-00170 Helsinki, Finland. RP Littlefield, LG (reprint author), Oak Ridge Inst Sci & Educ, Oak Ridge, TN 37830 USA. OI Auvinen, Anssi/0000-0003-1125-4818 FU NCI NIH HHS [N01-CP-50520, N01-CP-85638-03, Y01-CP4-0599] NR 44 TC 54 Z9 59 U1 0 U2 2 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD AUG PY 1998 VL 150 IS 2 BP 237 EP 249 DI 10.2307/3579859 PG 13 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 105RT UT WOS:000075087900010 PM 9692369 ER PT J AU Lubin, JH AF Lubin, JH TI The influence of residential radon exposure on the estimation of exposure-response trends for lung cancer in underground miners exposed to radon SO RADIATION RESEARCH LA English DT Letter C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. RP Lubin, JH (reprint author), NCI, Div Canc Epidemiol & Genet, 6130 Execut Blvd,EPN-403, Rockville, MD 20892 USA. NR 5 TC 8 Z9 9 U1 0 U2 0 PU RADIATION RESEARCH SOC PI OAK BROOK PA 2021 SPRING RD, STE 600, OAK BROOK, IL 60521 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD AUG PY 1998 VL 150 IS 2 BP 259 EP 261 DI 10.2307/3579862 PG 3 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 105RT UT WOS:000075087900013 PM 9692372 ER PT J AU Summers, RM Selbie, WS Malley, JD Pusanik, LM Dwyer, AJ Courcoutsakis, NA Shaw, DJ Kleiner, DE Sneller, MC Langford, CA Holland, SM Shelhamer, JH AF Summers, RM Selbie, WS Malley, JD Pusanik, LM Dwyer, AJ Courcoutsakis, NA Shaw, DJ Kleiner, DE Sneller, MC Langford, CA Holland, SM Shelhamer, JH TI Polypoid lesions of airways: Early experience with computer-assisted detection by using virtual bronchoscopy and surface curvature SO RADIOLOGY LA English DT Article DE bronchi, CT; bronchi, neoplasms; computers, diagnostic aid ID SEGMENTATION; CT AB PURPOSE: To test the application of a technique developed by the authors for the computer-assisted diagnosis of polypoid airway lesions from surface-rendered virtual bronchoscopic reconstructions. MATERIALS AND METHODS: A computer algorithm was developed to detect polypoid airway lesions by means of segmentation of the bronchial surface with curvature classification. This method was tested with a bronchial phantom, five cadaveric lung specimens, and virtual bronchoscopic studies in 16 patients. RESULTS: For the patient studies, the sensitivity and specificity of the method were 47%-88% and 58%-89%, respectively, depending on the value of an adjustable parameter (the mean curvature threshold). The sensitivity increased (by 20% to 34%) when only lesions larger than 5 mm in diameter were considered. CONCLUSION: With this method, polypoid airway lesions can be detected automatically, although false-positive diagnoses present an important limitation. C1 Natl Inst Deafness & Other Commun Disorders, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, Voice & Speech Sect,NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, Div Crit Care Med, Warren Grant Magnuson Clin Ctr, Voice & Speech Sect,NIH, Bethesda, MD 20892 USA. NIH, Off Assistant Director, Div Comp Res & Technol, Bethesda, MD 20892 USA. NIH, Pathol Lab, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Summers, RM (reprint author), Natl Inst Deafness & Other Commun Disorders, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, Voice & Speech Sect,NIH, Bldg 10,Rm 1C660,10 Ctr Dr,MSC 1182, Bethesda, MD 20892 USA. OI Kleiner, David/0000-0003-3442-4453 NR 20 TC 60 Z9 60 U1 1 U2 1 PU RADIOLOGICAL SOC NORTH AMER PI EASTON PA 20TH AND NORTHAMPTON STS, EASTON, PA 18042 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD AUG PY 1998 VL 208 IS 2 BP 331 EP 337 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 101WP UT WOS:000074891400010 PM 9680555 ER PT J AU Eddy, EM AF Eddy, EM TI Regulation of gene expression during spermatogenesis SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Review DE gene expression; spermatogenesis; testis; transcription; translation ID EPIDERMAL GROWTH-FACTOR; TESTIS-SPECIFIC TRANSCRIPTION; MESSENGER-RNA; TRANSLATIONAL REGULATION; MOUSE TESTIS; MUTANT MICE; GERM-CELLS; PROTEIN; BINDING; REPRESSOR AB Spermatogenesis occurs in successive mitotic, meiotic and post-meiotic phases and genes expressed during this process encode proteins necessary for processes specific to the different phases of germ cell development. Some genes encode proteins with essential roles in structures or functions specific to spermatogenic cells, are expressed in developmentally regulated patterns and are transcribed only in, or produce mRNAs unique to, spermatogenic cells. They are referred to as chauvinist genes, because male germ favor their expression with such strong prejudice. The expression of these genes is influenced by extrinsic cues, but is determined primarily by the intrinsic genetic program of spermatogenic cells. These processes are subject to transcriptional, translational and post-translational regulation. However, many aspects of the mechanisms regulating gene expression in spermatogenic cells remain to be determined. C1 NIEHS, Reprod & Dev Toxicol Lab, Gamete Biol Sect, NIH, Res Triangle Pk, NC 27709 USA. RP Eddy, EM (reprint author), NIEHS, Reprod & Dev Toxicol Lab, Gamete Biol Sect, NIH, Res Triangle Pk, NC 27709 USA. NR 40 TC 122 Z9 134 U1 1 U2 6 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD AUG PY 1998 VL 9 IS 4 BP 451 EP 457 DI 10.1006/scdb.1998.0201 PG 7 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 140LH UT WOS:000077088400009 PM 9813192 ER PT J AU Carney, JA Stratakis, CA AF Carney, JA Stratakis, CA TI Epithelioid blue nevus and psammomatous melanotic schwannoma: The unusual pigmented skin tumors of the Carney complex SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Article; Proceedings Paper CT 34th Annual Meeting of the American-Society-of-Dermatopathology CY MAR 09-20, 1997 CL SAN FRANCISCO, CALIFORNIA SP Amer Soc Dermatopathol ID ENDOCRINE OVERACTIVITY; ATRIAL-MYXOMA; LENTIGINOSIS AB Carney complex, a familial multitumoral syndrome, comprises spotty skin pigmentation (lentigines and blue nevi), myxomas (heart, skin, and breast), endocrine tumors (adrenal cortex, pituitary, testis, and thyroid), and schwannomas. The skin pigmentary abnormality included two unusual conditions, epithelioid blue nevus and psammomatous melanotic schwannoma. The former tumor occurred on the extremities and trunk, less frequently on the head and neck; was multiple; and did not recur or metastasize. Clinically, it was pigmented, domed, and small (<1 cm). Microscopically, it displayed two types of melanocytes-one intensely pigmented, globular, and fusiform and the other lightly pigmented, polygonal, and spindle. Nuclei of the latter cells were vesicular, with pale chromatin and single prominent nucleolus. None recurred or metastasized. The psammomatous melanotic schwannoma occurred in posterior spinal nerve roots, upper alimentary tract, bone, and skin. Microscopically, it was circumscribed but incompletely encapsulated and contained spindle and epithelioid cells, melanin, psammoma bodies, and fat. The spindle cells were arranged in interlacing fascicles, with whorling and occasional nuclear palisading. Twenty-one patients (68%) were alive without evidence of the neoplasm; two of these each had two local recurrences. Seven patients died, three (10%) as a result of metastasis. Copyright (C) 1998 by W.B. Saunders Company. C1 Mayo Clin & Mayo Fdn, Dept Lab Med & Pathol, Rochester, MN 55905 USA. NICHD, Pediat Unit Genet & Endocrinol, Sect Pediat Endocrinol, Dev Endocrinol Branch, Bethesda, MD USA. RP Carney, JA (reprint author), Mayo Clin & Mayo Fdn, Dept Lab Med & Pathol, 200 1st St SW, Rochester, MN 55905 USA. NR 14 TC 57 Z9 60 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 0740-2570 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD AUG PY 1998 VL 15 IS 3 BP 216 EP 224 PG 9 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 110UZ UT WOS:000075400400007 PM 9711672 ER PT J AU Stern, JB Haupt, HM AF Stern, JB Haupt, HM TI Pagetoid melanocytosis: Tease or tocsin? SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Article; Proceedings Paper CT 34th Annual Meeting of the American-Society-of-Dermatopathology CY MAR 09-20, 1997 CL SAN FRANCISCO, CALIFORNIA SP Amer Soc Dermatopathol DE pagetoid melanocytosis; melanoma; nevus ID SPINDLE CELL NEVUS; NEVOCELLULAR NEVI AB Pagetoid melanocytosis (PM) represents a more precise formulation of the histological phenomenon previously referred to as pagetoid scatter/spread. PM is defined as the upward discontinuous extension of melanocytes into the superficial epidermis, Three histological criteria are presented. PM is a frequent finding in malignant melanoma, occurring in approximately 76% of lesions, PM also occurs in a significant number of certain benign melanocytic lesions: Spitz nevi, nevi of palms and soles, pigmented spindle cell nevi, recurrent nevi, vulvar nevi, and nevi of infancy and childhood, Histological features of PM favoring malignant melanoma over benign melanocytic lesions are a diffuse and dense extension over a wide area, prominent melanocytic atypia, and PM without an underlying junctional melanocytic component (free-floating PM), PM should alert the pathologist to the possibility of melanoma but does not of necessity require a malignant interpretation, The final interpretation of a melanocytic lesion requires evaluation of all the pertinent histological and clinical findings, Copyright (C) 1998 by W.B. Saunders Company. C1 Dermatopathol Consultat Serv, Damascus, MD 20872 USA. NIH, Pathol Lab, Bethesda, MD 20892 USA. Penn Hosp, Dept Pathol, Philadelphia, PA 19107 USA. RP Stern, JB (reprint author), Dermatopathol Consultat Serv, POB 10, Damascus, MD 20872 USA. NR 16 TC 6 Z9 6 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 0740-2570 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD AUG PY 1998 VL 15 IS 3 BP 225 EP 229 PG 5 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 110UZ UT WOS:000075400400008 PM 9711673 ER PT J AU Herman, EH Ferrans, V AF Herman, EH Ferrans, V TI Preclinical animal models of cardiac protection from anthracycline-induced cardiotoxicity SO SEMINARS IN ONCOLOGY LA English DT Review ID CHRONIC DOXORUBICIN CARDIOTOXICITY; SPONTANEOUSLY HYPERTENSIVE RATS; AGENT ICRF-187 (+)-1,2-BIS(3,5-DIOXOPIPERAZINYL-1-YL)PROPANE; CHRONIC DAUNORUBICIN CARDIOTOXICITY; CONGESTIVE HEART-FAILURE; VITAMIN-E; INDUCED CARDIOMYOPATHY; (+/-)-1,2-BIS(3,5-DIOXOPIPERAZINYL-1-YL)PROPANE ICRF-187; ADRIAMYCIN CARDIOTOXICITY; RENAL TOXICITY C1 US FDA, Ctr Drug Evaluat & Res, Div Appl Pharmacol Res HFD 910, Laurel, MD 20708 USA. NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. RP Herman, EH (reprint author), US FDA, Ctr Drug Evaluat & Res, Div Appl Pharmacol Res HFD 910, 8301 Muirkirk Rd, Laurel, MD 20708 USA. NR 49 TC 62 Z9 62 U1 0 U2 7 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD AUG PY 1998 VL 25 IS 4 SU 10 BP 15 EP 21 PG 7 WC Oncology SC Oncology GA 124WT UT WOS:000076206300004 PM 9768819 ER PT J AU Korn, EL Baumrind, S AF Korn, EL Baumrind, S TI Clinician preferences and the estimation of causal treatment differences SO STATISTICAL SCIENCE LA English DT Article DE Bayesian methods; causal effects; ethics; instrumental variables; randomized clinical trials; observational studies; selection bias ID INTRACRANIAL ARTERIAL BYPASS; BREAST-CANCER; TRIALS; ENCEPHALITIS; DECISION; DESIGNS; RANDOMIZATION; EXPERIENCES; ASSIGNMENT; OPINION AB Clinician treatment preferences affect the ability to perform randomized clinical trials and the ability to analyze observational data for treatment effects. In clinical trials, clinician preferences that are based on a subjective analysis of the patient can make it difficult to define eligibility criteria for which clinicians would agree to randomize all patients who satisfy the criteria. In addition, since each clinician typically has some preference for the choice of treatment for a given patient, there are concerns about how strong that preference needs to be before it is inappropriate for him to randomize the choice of treatment. In observational studies, the fact that clinician preferences affect the choice of treatment is a major source of selection bias when estimating treatment effects. In this paper we review alternative designs that have been proposed in the literature for randomized clinical trials that utilize clinician preferences differently than the standard randomized trial design. We also examine the effects of clinician preferences on the ability to estimate causal treatment differences from observational data, and propose an alternative method of analysis for observational data that uses clinician preferences explicitly. We report on our experience to date in using our alternative randomized clinical trial design and our new method of observational analysis to compare two treatments at the orthodontic clinics at the University of California San Francisco and the University of the Pacific, San Francisco. C1 NCI, Clin Trials Sect, Biometr Res Branch, Bethesda, MD 20892 USA. Univ Pacific, San Francisco, CA USA. Univ Med & Dent New Jersey, Newark, NJ 07103 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Korn, EL (reprint author), NCI, Clin Trials Sect, Biometr Res Branch, Execut Plaza N 739, Bethesda, MD 20892 USA. NR 90 TC 21 Z9 21 U1 1 U2 5 PU INST MATHEMATICAL STATISTICS PI HAYWARD PA IMS BUSINESS OFFICE-SUITE 7, 3401 INVESTMENT BLVD, HAYWARD, CA 94545 USA SN 0883-4237 J9 STAT SCI JI Stat. Sci. PD AUG PY 1998 VL 13 IS 3 BP 209 EP 227 PG 19 WC Statistics & Probability SC Mathematics GA 141PQ UT WOS:000077152700001 ER PT J AU Marler, JR Walker, MD AF Marler, JR Walker, MD TI Progress in acute stroke research SO STROKE LA English DT Editorial Material C1 NINDS, Div Stroke Trauma & Neurodegenerat Disorders, NIH, Bethesda, MD 20892 USA. RP Marler, JR (reprint author), NINDS, Div Stroke Trauma & Neurodegenerat Disorders, NIH, Room 8A08,Fed Bldg,7550 Wisconsin Ave, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD AUG PY 1998 VL 29 IS 8 BP 1491 EP 1492 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 107AE UT WOS:000075183000002 PM 9707179 ER PT J AU Haffner, SM D'Agostino, R Mykkanen, L Hales, CN Savage, PJ Bergman, RN O'Leary, D Rewers, M Selby, J Tracy, R Saad, MF AF Haffner, SM D'Agostino, R Mykkanen, L Hales, CN Savage, PJ Bergman, RN O'Leary, D Rewers, M Selby, J Tracy, R Saad, MF TI Proinsulin and insulin concentrations in relation to carotid wall thickness - Insulin Resistance Atherosclerosis Study SO STROKE LA English DT Article DE atherosclerosis; insulin; plasminogen activator inhibitor-1; proinsulin ID DEPENDENT DIABETES-MELLITUS; CARDIOVASCULAR RISK-FACTORS; INTIMA-MEDIA THICKNESS; CORONARY-ARTERY DISEASE; ACTIVATOR INHIBITOR TYPE-1; B-MODE ULTRASOUND; GLUCOSE-TOLERANCE; NONDIABETIC SUBJECTS; SPLIT PROINSULIN; PLASMA-INSULIN AB Background and Purpose-insulin resistance and hyperinsulinemia have been associated with atherosclerosis. Recent attention has focused on the possible role of proinsulin because most radioimmunoassays for insulin cross-react with proinsulin. Therefore, it is not known which of the two, insulin per se or proinsulin, is more strongly related to atherosclerosis. Methods-We examined the relation between fasting proinsulin, fasting split proinsulin, fasting and 2-hour insulin (after oral glucose load), and intima-media wall thickness (IMT) in the common carotid artery (CCA) and internal carotid artery (ICA) in 985 nondiabetic subjects from the Insulin Resistance Atherosclerosis Study, a multiethnic study of insulin resistance and atherosclerosis. Results-In the overall population, a weak but significant relation between proinsulin and CCA IMT was observed (r=0.07, P=0.029), However, the relation between proinsulin and IMT was stronger in Hispanics and non-Hispanic whites than in African Americans. In non-Hispanic whites and Hispanics, significant correlations between CCA and proinsulin (r=0.087) and between ICA and proinsulin (r=0.101), split proinsulin (r=0.092), and fasting insulin (r=0.087) were observed. The significant correlations became more attenuated (and nonsignificant) after adjustment for cardiovascular risk factors, especially plasminogen activator inhibitor-1 (PAI-1), Conclusions-The association between proinsulin and IMT, while weak, appears to be stronger than the association between insulin and IMT. Adjustment for PAI-1 markedly attenuated the association between proinsulin and IMT, suggesting a possible mediating role for PAI-1 in this association, It is possible that proinsulin may represent a marker of atherosclerosis rather than a causal factor for atherosclerosis, Studies of the insulin resistance syndrome and atherosclerosis that use insulin as a surrogate for insulin resistance should consider the use of specific insulin assays as well as determination of proinsulin concentrations. C1 Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78284 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27103 USA. Univ Cambridge, Dept Clin Biochem, Cambridge, England. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ So Calif, Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90033 USA. Tufts Univ, Sch Med, Dept Radiol, Boston, MA 02111 USA. Univ Colorado, Sch Med, Dept Prevent Med & Biometr, Denver, CO USA. Kaiser Permanente, Div Res, Oakland, CA USA. Univ Vermont, Sch Med, Dept Pathol, Burlington, VT 05405 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. RP Haffner, SM (reprint author), Univ Texas, Hlth Sci Ctr, Dept Med, 7703 Floyd Curl Dr, San Antonio, TX 78284 USA. RI Dagostino Jr, Ralph/C-4060-2017 OI Dagostino Jr, Ralph/0000-0002-3550-8395 FU NHLBI NIH HHS [HL47887, HL47889, HL47890] NR 62 TC 72 Z9 81 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD AUG PY 1998 VL 29 IS 8 BP 1498 EP 1503 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 107AE UT WOS:000075183000006 PM 9707183 ER PT J AU Brott, T Lu, M Kothari, R Fagan, SC Frankel, M Grotta, JC Broderick, J Kwiatkowski, T Lewandowski, C Haley, EC Marler, JR Tilley, BC AF Brott, T Lu, M Kothari, R Fagan, SC Frankel, M Grotta, JC Broderick, J Kwiatkowski, T Lewandowski, C Haley, EC Marler, JR Tilley, BC CA NINDS rt-PA Stroke Study Grp TI Hypertension and its treatment in the NINDS rt-PA Stroke Trial SO STROKE LA English DT Article DE blood pressure; clinical trials; hypertension; plasminogen activator, tissue type; stroke ID TISSUE-PLASMINOGEN-ACTIVATOR; ACUTE ISCHEMIC STROKE; URGENT THERAPY; MINUTES AB Background and Purpose-We examined the frequency, course, and treatment of hypertension in the NINDS rt-PA Stroke Trial. Methods-Blood pressure (BP) was measured at the time of admission, at randomization, and then 36 times during the first 24 hours after randomization. Patients with a systolic BP of >185 mm Hg and a diastolic BP of >110 mm Hg at admission were defined as hypertensive before randomization, and those with a systolic BP of >180 mm Hg Or a diastolic BP of >105 mmHg within the first 24 hours after randomization were defined as hypertensive after randomization. Standardized clinical assessments were conducted at 24 hours and at 3 months. Post hoc analyses were conducted to evaluate the association of antihypertensive therapy with clinical outcomes. Results-Of the 624 patients, 121(19%) had hypertension on admission and 372 (60%) had hypertension in the 24 hours after randomization. The use of antihypertensive therapy before randomization (tPA 9%, placebo 9%) and after randomization (tPA 24%, placebo 29%) was similar between placebo- and tPA-treated patients, No adverse effects of prerandomization antihypertensive therapy on 3-month favorable outcome were detected for either the placebo- or tPA-treated groups. For placebo patients with hypertension in the 24 hours after randomization, clinical outcome measures were similar for those patients who did and did not receive antihypertensive therapy after randomization (P greater than or equal to 0.26); antihypertensive therapy was not associated with declines in BP (P=0.44) or with abrupt declines (P=0.14). Those tPA patients who were hypertensive after randomization and received antihypertensive therapy were less likely to have a favorable outcome at 3 months (P<0.01) than those who were hypertensive and did not receive antihypertensive therapy. Conclusions-The frequency of hypertension and the use of antihypertensive therapy were similar between the tPA and placebo groups in the NINDS rt-PA Stroke Trial. In the placebo,group, antihypertensive therapy was not associated with less favorable outcomes at 3 months; postrandomization antihypertensive therapy was associated with less favorable outcomes for the tPA patients who were hypertensive. However, because of the nonrandomized use of antihypertensive therapy and the many post hoc comparisons leading to type I errors, the significance of this observation is unclear. Careful attention to BP and gentle management remain warranted for stroke patients treated with tPA. C1 Univ Cincinnati, Coll Med, Dept Neurol, Cincinnati, OH 45267 USA. Henry Ford Hlth Syst, Dept Biostat & Res Epidemiol, Detroit, MI USA. Univ Cincinnati, Dept Emergency Med, Cincinnati, OH USA. Henry Ford Hosp, Dept Pharm Serv, Detroit, MI 48202 USA. Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. Univ Texas, Dept Neurol, Ctr Med, Houston, TX USA. Long Isl Jewish Med Ctr, Dept Emergency Med, New Hyde Park, NY 11042 USA. Henry Ford Hosp, Dept Emergency Med, Detroit, MI 48202 USA. Univ Virginia, Hlth Sci Ctr, Dept Neurol, Charlottesville, VA 22908 USA. NINDS, Div Stroke & Trauma, Bethesda, MD 20892 USA. RP Brott, T (reprint author), Univ Cincinnati, Coll Med, Dept Neurol, 231 Bethesda Ave, Cincinnati, OH 45267 USA. EM thomas.brott@uc.edu RI Fagan, Susan /D-3281-2009 FU NINDS NIH HHS [N01-NS-02374, N01-NS-02377, N01-NS-02382] NR 18 TC 116 Z9 117 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD AUG PY 1998 VL 29 IS 8 BP 1504 EP 1509 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 107AE UT WOS:000075183000007 PM 9707184 ER PT J AU Wijman, CAC Wolf, PA Kase, CS Kelly-Hayes, M Beiser, AS AF Wijman, CAC Wolf, PA Kase, CS Kelly-Hayes, M Beiser, AS TI Migrainous visual accompaniments are not rare in late life - The Framingham Study SO STROKE LA English DT Article DE epidemiology; migraine; vision disorders ID ISCHEMIC STROKE; RISK; HEADACHE; EXPERIENCE; INFARCTION AB Background and Purpose-Questionnaires to elicit symptoms of transient ischemic attacks (TIAs) may detect late-life transient visual symptoms similar to the visual aura of migraine, often without headache. We determined the frequency, characteristics, and stroke outcome of these symptoms in the Framingham Study. Methods-During 1971-1989, at biennial examinations, 2110 subjects of the Framingham cohort were systematically queried about the occurrence of sudden visual symptoms. Results-Visual migrainous symptoms were reported by 1.23% (26/2110) of subjects (1.33% of women and 1.08% of men). In 65% of subjects the episodes were stereotyped, and they began after age 50 years in 77%, Mean+/-SD age at onset of the episodes was 56.2+/-18.7 years. In 58% of subjects the episodes were never accompanied by headaches, and 42% had no headache history. The number of episodes ranged from 1 to 500 and was 10 or more in 69% of subjects. The episodes lasted 15 to 60 minutes in 50% of subjects. Sixty-five percent of the subjects were examined by a study neurologist, and only 19% of them met the criteria of the International Headache Society. Twelve percent of subjects sustained a stroke after the onset of migrainous visual symptoms: a subarachnoid hemorrhage 1 year later, an atherothrombotic brain stem infarct 3 years later, and a cardioembolic stroke 27 years later. In contrast, of 87 subjects with TIAs in the same cohort, 33% developed a stroke (P=0.030), two thirds within 6 months of TIA onset. Conclusions-Late-life-onset transient visual phenomena similar to the visual aura of migraine are not rare and often occur in the absence of headache. These symptoms appear not to be associated with an increased risk of stroke, and invasive diagnostic procedures or therapeutic measures are generally not indicated. C1 Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA 02215 USA. NHLBI, Framingham Study, Framingham, MA USA. RP Wolf, PA (reprint author), Boston Univ, Sch Med, Dept Neurol, B608,715 Albany St, Boston, MA 02118 USA. FU NHLBI NIH HHS [N01-HC-38038]; NINDS NIH HHS [2-RO1-NS-17950-16] NR 31 TC 32 Z9 32 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD AUG PY 1998 VL 29 IS 8 BP 1539 EP 1543 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 107AE UT WOS:000075183000012 PM 9707189 ER PT J AU Knechtle, SJ Fechner, JH Dong, YC Stavrou, S Neville, DM Oberley, T Buckley, P Armstrong, N Rusterholz, K Hong, XN Tsuchida, M Hamawy, MM AF Knechtle, SJ Fechner, JH Dong, YC Stavrou, S Neville, DM Oberley, T Buckley, P Armstrong, N Rusterholz, K Hong, XN Tsuchida, M Hamawy, MM TI Primate renal transplants using immunotoxin SO SURGERY LA English DT Article; Proceedings Paper CT 59th Annual Meeting of the Society-of-University-Surgeons CY FEB 12-14, 1998 CL MILWAUKEE, WISCONSIN SP Soc Univ Surgeons ID TOTAL LYMPHOID IRRADIATION; TOLERANCE; DISEASE; MONKEYS AB Background. T-lymphocyte depletion 7 days before transplantation with immunotoxin FN 18-CRM9 has resulted in tolerance to subsequent renal allografts. We tested the effect of giving immunotoxin on the day of the transplantation and evaluated its effect on rhesus monkey renal allograft survival, on antibody production, and on T-cell recovery. Methods. Major histocompatibility complex mismatched renal allografts were performed in rhesus monkeys. Immunotoxin was given starting on the day of transplantation, with and without prednisone and mycophenolate mofetil for 3 days. T-cell subsets and alloantibody levels were measured by flow cytometry. The ability of treated monkeys to develop antibody to tetanus, diphtheria, and xenoantibody was measured. Histology of renal transplants was read in a blinded manner. Results. Immunotoxin started on the day of transplantation resulted in prolonged allograft survival in all treatment groups. Graft loss between days 50 and 135 was most often due to interstitial nephritis. Later graft loss was due to chronic rejection. Monkeys had intact antibody responses to alloantigen, tetanus, diphtheric, and xenoantibody. Their CD4 cells recovered gradually over 6 months. Conclusions. Immunotoxin reliably prolongs renal allograft survival when started on the day of transplantation, but interstitial nephritis and chronic rejection limit the development of long-term tolerance. T-cell-dependent B-cell responses remain intact after treatment. C1 Univ Wisconsin, Dept Surg, Madison, WI USA. Univ Wisconsin, Dept Pathol, Madison, WI 53706 USA. NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Knechtle, SJ (reprint author), Univ Wisconsin Hosp, Dept Surg, 600 Highland Ave, Madison, WI 53792 USA. RI Fechner, John/C-5962-2016 OI Fechner, John/0000-0002-8220-7237 NR 19 TC 51 Z9 51 U1 0 U2 0 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0039-6060 J9 SURGERY JI Surgery PD AUG PY 1998 VL 124 IS 2 BP 438 EP 446 DI 10.1016/S0039-6060(98)70151-5 PG 9 WC Surgery SC Surgery GA 108EC UT WOS:000075252200080 PM 9706169 ER PT J AU Bellahcene, A Albert, V Pollina, L Basolo, F Fisher, LW Castronovo, V AF Bellahcene, A Albert, V Pollina, L Basolo, F Fisher, LW Castronovo, V TI Ectopic expression of bone sialoprotein in human thyroid cancer SO THYROID LA English DT Article ID HUMAN BREAST-CANCER; HORMONE-RELATED PROTEIN; IMMUNOHISTOCHEMICAL LOCALIZATION; ADHESION MOLECULES; MATRIX PROTEINS; METASTASES; TISSUE; BSP; OSTEOPONTIN; INTEGRINS AB Bone sialoprotein (BSP) is a small, highly posttranslationally modified integrin binding protein found in the mineral compartment of developing bone. The recent discovery that BSP can be detected in a variety of human cancers, particularly those that metastasize preferentially to the skeleton, shed light on potential new biological functions for this protein. The demonstration of a positive association between BSP expression in primary breast tumors and the development of bone metastases suggests that this glycoprotein could play a role in the selective implantation of breast cancer cells in bone. BSP is also expressed in most lung and prostate cancers as well as in multiple myeloma, three other osteotropic malignancies. Because thyroid carcinoma also metastasizes preferentially to the skeleton, we decided to look at the expression of BSP in a collection of 145 thyroid malignant lesions including 24 follicular thyroid carcinomas (FTCs), 55 papillary thyroid carcinomas (PTCs), 19 medullary thyroid carcinomas (MTCs), 23 anaplastic carcinomas (ACs), and 24 poorly differentiated carcinomas (PDCs). BSP expression was evaluated by immunoperoxidase technique using two specific polyclonal antibodies. Most of the thyroid carcinomas (72%) examined expressed high levels of BSP. Expression of BSP was significantly lower in FTCs and MTCs compared with PDCs, which are more aggressive (p = 0.0009 and 0.0003, respectively). Our study demonstrates for the first time that ectopic BSP expression is a common feature of thyroid cancer. The prognostic value of BSP detection in thyroid adenocarcinoma and the potential role of BSP in the propension of this type of cancer to metastasize to bone are currently under investigation. C1 Univ Liege, Metastasis Res Lab, B-4000 Liege, Belgium. Univ Pisa, Inst Pathol, I-56100 Pisa, Italy. NIDR, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. RP Bellahcene, A (reprint author), Univ Liege, Metastasis Res Lab, Tour Pathol,1 Bat B23,Sart Tilman Via, B-4000 Liege, Belgium. NR 33 TC 42 Z9 44 U1 0 U2 2 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1050-7256 J9 THYROID JI Thyroid PD AUG PY 1998 VL 8 IS 8 BP 637 EP 641 DI 10.1089/thy.1998.8.637 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 113KE UT WOS:000075549500001 PM 9737356 ER PT J AU Dong, WM Simeonova, PP Gallucci, R Matheson, J Flood, L Wang, SY Hubbs, A Luster, MI AF Dong, WM Simeonova, PP Gallucci, R Matheson, J Flood, L Wang, SY Hubbs, A Luster, MI TI Toxic metals stimulate inflammatory cytokines in hepatocytes through oxidative stress mechanisms SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE hepatotoxicity; interleukin-8; chemokines; vanadium pentoxide; cadmium; Hep G2; hepatocytes; reactive oxygen species; oxidative stress ID TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; FACTOR-ALPHA; INDUCED HEPATOTOXICITY; LIPID-PEROXIDATION; INTERLEUKIN-8 GENE; CADMIUM CHLORIDE; REACTIVE OXYGEN; HEPG2 CELLS; LIVER AB Hepatocytes, as well as nonparenchymal cells, secrete proinflammatory cytokines and chemokines that are involved in the pathology of many liver diseases. In particular, tumor necrosis factor-alpha (TNF alpha), as well as members of the CXC family of chemokines, including interleukin (IL)-8 in humans and macrophage inflammatory protein (MIP)-2 in rodents, have been implicated in both damage and repair processes associated with various hepatotoxins. In the liver, cytokine secretion is usually associated with nonparenchymal cells, particularly Kupffer cells. In the present studies, cytokine gene expression and secretion were investigated in hepatocytes treated with cadmium chloride (CdCl2) or vanadium pentoxide (V2O5). Using human Hep G2 cells and freshly isolated rodent hepatocytes, it was demonstrated that metals increase gene expression and secretion of CXC chemokines and TNF alpha. IL-8 and MIP-2 secretion induced either by the metals or H2O2 were inhibited by antioxidants such as tetramethyl-thiourea and N-acetyl-cysteine. In vitro neutralization experiments with TNF alpha and in vivo studies with TNF alpha receptor knockout mice indicated that the metals directly stimulate CXC chemokine secretion without the need for TNF alpha. Taken together these studies indicate that, in addition to other inflammatory mediators and acute phase proteins, cytokines and chemokines are produced by hepatocytes, which may participate in hepatotoxic responses. The events responsible for their expression involve cellular redox changes. C1 NIEHS, Environm Immunol & Neurobiol Sect, Res Triangle Pk, NC 27709 USA. NIOSH, Pathol & Physiol Res Branch, Hlth Effects Lab Div, Morgantown, WV 26505 USA. RP Dong, WM (reprint author), US EPA, Immunotoxicol Branch, Res Triangle Pk, NC 27711 USA. NR 41 TC 76 Z9 78 U1 0 U2 6 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 AUG PY 1998 VL 151 IS 2 BP 359 EP 366 DI 10.1006/taap.1998.8481 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 117BQ UT WOS:000075760600016 PM 9707512 ER EF