FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Qi, CF Jessberger, R Torrey, TA Taddesse-Heath, L Ohta, Y Morse, HC AF Qi, CF Jessberger, R Torrey, TA Taddesse-Heath, L Ohta, Y Morse, HC TI Differential regulation of germinal center genes, BCL6 and SWAP-70, during the course of MAIDS SO MOLECULAR IMMUNOLOGY LA English DT Article DE BCL6; IgE; lymphoma; lymphoproliferation; MAIDS ID RETROVIRUS-INDUCED IMMUNODEFICIENCY; SEQUENCE-BINDING-PROTEIN; CD4+ T-CELLS; INDUCED MURINE AIDS; CENTER B-CELLS; C57BL/6 MICE; LACKING THY-1; EXPRESSION; MOUSE; DISEASE AB Germinal centers (GC) are the sites of antigen-driven B cell switch recombination, V(D)J gene hypermutation, and selection to generate hi,oh-affinity CD38(+) memory B cells. A marked expansion of GC associated with hypergammaglobulinemia followed by complete disruption of normal splenic architecture and a striking drop in immunoglobulin levels are prominent features of the murine retrovirus-induced immunodeficiency syndrome, MAIDS. B cell lymphomas are frequent in long-term infected mice. Normal GC formation is critically dependent on a number of genes including the transcription factor, Bcl6. Deregulated expression of BCL6 protein has been implicated in the development of human and mouse B cell lymphomas. Another nuclear protein, SWAP-70, has been identified as a subunit of the protein complex, SWAP, that recombines switch regions in vitro. To develop a fuller understanding of B cell biology in MAIDS, we examined the characteristics of BCL6, SWAP-70, CD38, and peanut agglutinin (PNA)-staining cells during the course of the disease. The levels of both nuclear proteins increased rapidly until 6-8 weeks after infection. During this time frame, BCL6 was expressed at highest levels in the usually rare CD4(+) Thy1(-) T cell subset as well as in B cells. Ar later times, BCL6 levels dropped to undetectable levels while SWAP-70 levels continued to increase. Changes in the levels of either protein could not be ascribed to transcriptional regulation. PNA-reactive cells decreased in concert with BCL6 while CD38 staining increased with SWAP-70. These results demonstrate that progression of MAIDS results in the massive accumulation of B cells with the morphology of secretory cells that behave like post-GC cells for expression of BCL6 and CD38. and for PNA-staining but with abnormally high-level expression of SWAP-70. Published by Elsevier Science Ltd. C1 NIAID, Immunopathol Lab, NIH, Bethesda, MD 20892 USA. Basel Inst Immunol, CH-4058 Basel, Switzerland. RP Qi, CF (reprint author), NIAID, Immunopathol Lab, NIH, 7 Ctr Dr,Room 7-304,MSC 0760, Bethesda, MD 20892 USA. EM cqi@atlas.niaid.nih.gov OI Morse, Herbert/0000-0002-9331-3705 NR 47 TC 6 Z9 6 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 OCT-NOV PY 1999 VL 36 IS 15-16 BP 1043 EP 1053 DI 10.1016/S0161-5890(99)00121-2 PG 11 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 283VR UT WOS:000085297200006 PM 10698307 ER PT J AU Iwahashi, M Milenic, DE Padlan, EA Bei, R Schlom, J Kashmiri, SVS AF Iwahashi, M Milenic, DE Padlan, EA Bei, R Schlom, J Kashmiri, SVS TI CDR substitutions of a humanized monoclonal antibody (CC49): contributions of individual CDRs to antigen binding and immunogenicity SO MOLECULAR IMMUNOLOGY LA English DT Article DE antigen binding; tumor immunity; anti-idiotypic antibodies; immunochemistry ID TUMOR-ASSOCIATED GLYCOPROTEIN-72; METASTATIC COLON-CARCINOMA; GAMMA-DETECTING PROBE; HUMAN IMMUNE-RESPONSE; RADIOIMMUNOTHERAPY TRIAL; OVARIAN-CANCER; I-131 CC49; PHASE-I; INTRAPERITONEAL RADIOIMMUNOTHERAPY; ANTIIDIOTYPIC ANTIBODIES AB One of the major obstacles in the successful clinical application of monoclonal antibodies has been the development of host immune responses to murine Ig constant and variable regions. While the CDR grafting of MAbs may alleviate many of these problems, the potential remains that one or more murine CDRs on the human Ig backbone of a "humanized" MAb may still be immunogenic. Studies were undertaken employing a MAb of potential clinical utility, CC49, to define those CDRs that are essential for antigen binding and those that may be immunogenic in humans. We previously developed a humanized CC49 (HuCC49) by grafting the MAb CC49 hypervariable regions onto frameworks of human MAbs. To identify those CDRs essential for binding, a panel of variant HuCC49 MAbs was generated here by systematically replacing each of the murine CDRs with their human counterparts. The relative affinity constant of each variant was determined. Serum from a patient who received murine CC49 was used to determine the potential immunogenicity of each CDR in humans. The serum was shown to react with the anti-CC49 variable region. Results showed that patients' anti-idiotypic responses are directed mainly against LCDR3 and moderately against LCDR1 and HCDR2. These studies demonstrate for the first time that variants containing individual CDR substitutions of a humanized MAb can be constructed, and each CDR can be defined for the two most important properties for potential clinical utility: antigen binding and immunogenicity. Published by Elsevier Science Ltd. 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, Bethesda, MD 20892 USA. NR 68 TC 25 Z9 28 U1 0 U2 2 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 OCT-NOV PY 1999 VL 36 IS 15-16 BP 1079 EP 1091 DI 10.1016/S0161-5890(99)00094-2 PG 13 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 283VR UT WOS:000085297200009 PM 10698310 ER PT J AU Schuck, P Radu, CG Ward, ES AF Schuck, P Radu, CG Ward, ES TI Sedimentation equilibrium analysis of recombinant mouse FcRn with murine IgG1 SO MOLECULAR IMMUNOLOGY LA English DT Article DE neonatal Fc receptor; sedimentation equilibrium; murine IgG1 ID I-RELATED RECEPTOR; BINDING; RAT; CATABOLISM; COMPLEX; MICE; AFFINITY; IGE; STOICHIOMETRY; LOCALIZATION AB The interaction of mouse IgG1 or IgG1-derived Fc fragment with recombinant, insect cell expressed mouse FcRn has been analyzed using sedimentation equilibrium. This results in a model for the interaction in which the two binding sites for FcRn on Fc or IgG1 have significantly different affinities with macroscopic binding constants of <130 nM and 6 mu M. This data indicates the formation of an asymmetric FcRn:Fe (or IgG1):FcRn complex which is consistent with earlier suggestions that for this form of recombinant FcRn, binding to IgG1 or Fe does not result in a symmetric 2:1 complex in which both binding sites are equivalent. (C) 2000 Elsevier Science Ltd. All rights reserved. C1 Univ Texas, SW Med Ctr, Ctr Immunol, Dallas, TX 75235 USA. Univ Texas, SW Med Ctr, Ctr Canc Immunobiol, Dallas, TX 75235 USA. NIH, Mol Interact Resource ORS, Bioengn & Phys Sci Program, Bethesda, MD 20892 USA. RP Ward, ES (reprint author), Univ Texas, SW Med Ctr, Ctr Immunol, 5323 Harry Hines Blvd, Dallas, TX 75235 USA. RI Radu, Caius/D-3936-2013; OI Radu, Caius/0000-0002-9338-5397; Schuck, Peter/0000-0002-8859-6966 FU NIAID NIH HHS [R01 AI39167] NR 36 TC 25 Z9 25 U1 0 U2 1 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 OCT-NOV PY 1999 VL 36 IS 15-16 BP 1117 EP 1125 DI 10.1016/S0161-5890(99)00093-0 PG 9 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 283VR UT WOS:000085297200012 PM 10698313 ER PT J AU Morgan, RA AF Morgan, RA TI Genetic strategies to inhibit HIV SO MOLECULAR MEDICINE TODAY LA English DT Review ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN T-CELLS; MUTATIONAL ANALYSIS; INFECTED PATIENTS; ANTISENSE RNAS; REPLICATION; THERAPY; LYMPHOCYTES; EXPRESSION; DELIVERY AB The worldwide incidence of HIV infection continues to rise despite more than a decade of intense research aimed at developing effective intervention strategies. Because the mechanisms of action of the essential HIV gene products are now known, these have become potential targets for intervention. Some of these targets are attractive candidates for intervention by gene therapy. This review will focus on the recent progress in gene therapy strategies, including approaches approved for clinical trials. The efficacy of these various anti-HIV strategies, as well as the advantages and drawbacks of the different existing gene delivery systems, will be discussed. C1 NIH, Gene Transfer Technol Sect, Clin Gene Therapy Branch, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. RP Morgan, RA (reprint author), NIH, Gene Transfer Technol Sect, Clin Gene Therapy Branch, Natl Human Genome Res Inst, Bldg 10, Bethesda, MD 20892 USA. NR 31 TC 13 Z9 13 U1 0 U2 0 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 OCT PY 1999 VL 5 IS 10 BP 454 EP 458 DI 10.1016/S1357-4310(99)01542-7 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 240LV UT WOS:000082828200013 PM 10498914 ER PT J AU Jiang, D Sibley, DR AF Jiang, D Sibley, DR TI Regulation of D-1 dopamine receptors with mutations of protein kinase phosphorylation sites: Attenuation of the rate of agonist-induced desensitization SO MOLECULAR PHARMACOLOGY LA English DT Article ID NS20Y NEUROBLASTOMA-CELLS; OPOSSUM KIDNEY-CELLS; HOMOLOGOUS DESENSITIZATION; COUPLED RECEPTORS; ADENYLYL-CYCLASE; CDNA AB Investigations of D-1 receptor regulation have suggested a role for cAMP-dependent protein kinase (PKA) in agonist-induced desensitization and down-regulation of receptor expression. Given the presence of at least four possible consensus recognition sites for PKA on the D-1 receptor protein, a reasonable hypothesis is that some of these PKA-mediated effects are caused by phosphorylation of the receptor. As an initial test of this hypothesis, we used site-directed mutagenesis to create a mutant D-1 receptor with substitutions at each of its four potential PKA phosphorylation sites. The modified amino acids are as follows: Thr135 to Val, Ser229 to Ala, Thr268 to Val, and Ser380 to Ala. Characterization of the wild-type and mutant receptors stably expressed in C6 glioma cells suggests that the mutations have no effect on receptor expression, antagonist or agonist affinities, or on functional coupling with respect to cAMP generation. Similarly, dopamine preincubation of the stably trans-fected C6 cells expressing either the wild-type or mutated D-1 receptors results in an agonist-induced loss of ligand binding activity (down-regulation) in an identical fashion. In contrast, the time of onset of dopamine-induced desensitization is greatly attenuated in the quadruple mutant receptor. After 1 h of dopamine pretreatment, the wild-type receptor exhibits similar to 80% desensitization of the cAMP response, whereas the mutant receptor is desensitized by only similar to 20%. Further analyses of single mutated receptors, in which only one of the four putative phosphorylation sites is modified, reveals that Thr268 in the third cytoplasmic loop of the receptor protein is primarily responsible for regulating the desensitization kinetics. These results are consistent with the hypothesis that phosphorylation of the D-1 receptor on Thr268 is important for rapid agonist-induced homologous desensitization. C1 NINDS, Mol Neuropharmacol Sect, Expt Therapeut Branch, NIH, Bethesda, MD 20205 USA. RP Sibley, DR (reprint author), NINDS, Mol Neuropharmacol Sect, Expt Therapeut Branch, NIH, Bldg 10,Room 5C108,10 Ctr Dr,MSC 1406, Bethesda, MD 20205 USA. NR 22 TC 46 Z9 47 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 OCT PY 1999 VL 56 IS 4 BP 675 EP 683 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 238RX UT WOS:000082726100002 PM 10496949 ER PT J AU Ciolino, HP Yeh, GC AF Ciolino, HP Yeh, GC TI Inhibition of aryl hydrocarbon-induced cytochrome P-450 1A1 enzyme activity and CYP1A1 expression by resveratrol SO MOLECULAR PHARMACOLOGY LA English DT Article ID MEDIATED SIGNAL-TRANSDUCTION; BENZOPYRENE METABOLISM; REGULATORY ELEMENTS; CATALYTIC ACTIVITY; AH RECEPTOR; PROTEIN; CANCER; CELLS; GENE; DISEASE AB We investigated the effect of resveratrol, a constituent of the human diet that has been shown to inhibit aryl hydrocarbon-induced carcinogenesis in animals, on the carcinogen activation pathway regulated by the aryl hydrocarbon receptor. Resveratrol inhibited the metabolism of the environmental aryl hydrocarbon benzo[a] pyrene (B[a]P) catalyzed by microsomes isolated from B[a]P-treated human hepatoma HepG2 cells. Resveratrol competitively inhibited, in a concentration-dependent manner, the activity of the carcinogen activating enzymes cytochrome P-450 (CYP) 1A1/CYP1A2 in microsomes and intact HepG2 cells. Resveratrol inhibited the B[a]P-induced expression of the CYP1A1 gene, as measured at the mRNA and transcriptional levels. Resveratrol abolished the binding of a]P-activated nuclear aryl hydrocarbon receptor to the xenobiotic-responsive element of the CYP1A1 promoter but did not itself bind to the receptor. Resveratrol was also effective in inhibiting CYP1A1 transcription induced by the aryl hydrocarbon dimethylbenz[a] anthracene in human mammary carcinoma MCF-7 cells. These data demonstrate that resveratrol inhibits aryl hydrocarbon-induced CYP1A activity in vitro by directly inhibiting CYP1A1/1A2 enzyme activity and by inhibiting the signal transduction pathway that up-regulates the expression of carcinogen activating enzymes. These activities may be an important part of the chemopreventive activity of resveratrol in vivo. C1 NCI, Cellular Def & Carcinogenesis Sect, Basic Res Lab, Div Basic Sci,Frederick Canc Res & Dev Ctr,NIH, Frederick, MD 21702 USA. RP Ciolino, HP (reprint author), NCI, Cellular Def & Carcinogenesis Sect, Basic Res Lab, Div Basic Sci,Frederick Canc Res & Dev Ctr,NIH, Bldg 560,Room 12-05, Frederick, MD 21702 USA. NR 37 TC 178 Z9 184 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD OCT PY 1999 VL 56 IS 4 BP 760 EP 767 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 238RX UT WOS:000082726100012 PM 10496959 ER PT J AU Waits, LP Sullivan, J O'Brien, SJ Ward, RH AF Waits, LP Sullivan, J O'Brien, SJ Ward, RH TI Rapid radiation events in the family Ursidae indicated by likelihood phylogenetic estimation from multiple fragments of mtDNA SO MOLECULAR PHYLOGENETICS AND EVOLUTION LA English DT Article ID MITOCHONDRIAL-DNA SEQUENCE; MOLECULAR CLOCK; BEARS URSUS; GIANT PANDA; EVOLUTION; PHYLOGEOGRAPHY; SUBSTITUTION; PEROMYSCUS; CARNIVORES; INFERENCE AB The bear family (Ursidae) presents a number of phylogenetic ambiguities as the evolutionary relationships of the six youngest members (ursine bears) are largely unresolved. Recent mitochondrial DNA analyses have produced conflicting results with respect to the phylogeny of ursine bears. In an attempt to resolve these issues, we obtained 1916 nucleotides of mitochondrial DNA sequence data from six gene segments for all eight bear species and conducted maximum likelihood and maximum parsimony analyses on all fragments separately and combined. All six single-region gene trees gave different phylogenetic estimates; however only for control region data was this significantly incongruent with the results from the combined data. The optimal phylogeny for the combined data set suggests that the giant panda is most basal followed by the spectacled bear. The sloth bear is the basal ursine bear, and there is weak support for a sister taxon relationship of the American and Asiatic black bears. The sun bear is sister taxon to the youngest clade containing brown bears and polar bears. Statistical analyses of alternate hypotheses revealed a lack of strong support for many of the relationships. We suggest that the difficulties surrounding the resolution of the evolutionary relationships of the Ursidae are linked to the existence of sequential rapid radiation events in bear evolution. Thus, unresolved branching orders during these time periods may represent an accurate representation of the evolutionary history of bear species. (C) 1999 Academic Press. C1 Univ Idaho, Dept Fish & Wildlife Resources, Moscow, ID 83844 USA. NCI, Viral Carcinogenesis Lab, Frederick, MD 21702 USA. Univ Oxford, Dept Biol Anthropol, Oxford, England. RP Waits, LP (reprint author), Univ Idaho, Dept Fish & Wildlife Resources, Moscow, ID 83844 USA. NR 65 TC 47 Z9 57 U1 3 U2 23 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1055-7903 J9 MOL PHYLOGENET EVOL JI Mol. Phylogenet. Evol. PD OCT PY 1999 VL 13 IS 1 BP 82 EP 92 DI 10.1006/mpev.1999.0637 PG 11 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 245VW UT WOS:000083129700008 PM 10508542 ER PT J AU Mannen, H Li, SSL AF Mannen, H Li, SSL TI Molecular evidence for a clade of turtles SO MOLECULAR PHYLOGENETICS AND EVOLUTION LA English DT Article DE turtles; phylogeny; molecular evolution; lactate dehydrogenase; alpha-enolase ID AMNIOTE PHYLOGENY; RNA SEQUENCES; EVOLUTION; MAMMALS; REPTILE; ORIGIN; TREES; BIRDS AB Although turtles have been generally grouped with the most primitive reptile species, the origin and phylogenetic relationships of turtles have remained unresolved to date. To confirm the phylogenetic position of turtles in amniotes, we have cloned and determined the cDNA sequences encoding for skink lactate dehydrogenase (LDH)-A and LDH-B, snake LDH-A, and African clawed frog LDH-A; four alpha-enolase cDNA sequences from turtle, alligator, skink, and snake were also cloned and determined. All of these eight cDNA sequences, as well as the previously published LDH-A, LDH-B, and alpha-enolase of mammals, birds, reptiles, and African clawed frog, were analyzed by the phylogenetic tree reconstruction methods of neighbor-joining, maximum parsimony, and maximum likelihood. In the phylogenetic analyses, the turtle was found to be closely related to the alligator. Also, we found that the turtle had diverged after the divergence of squamates and birds. This departs from previous hypotheses of turtle evolution and further suggests that turtles are the latest of divergent reptiles, having been derived from an ancestor of crocodilian lineage within the last 200 million years. (C) 1999 Academic Press. C1 Kobe Univ, Fac Agr, Lab Anim Breeding & Genet, Kobe, Hyogo 657, Japan. NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. Natl Sun Yat Sen Univ, Inst Biol Sci, Kaohsiung 80424, Taiwan. RP Mannen, H (reprint author), Kobe Univ, Fac Agr, Lab Anim Breeding & Genet, Kobe, Hyogo 657, Japan. NR 32 TC 40 Z9 49 U1 1 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1055-7903 J9 MOL PHYLOGENET EVOL JI Mol. Phylogenet. Evol. PD OCT PY 1999 VL 13 IS 1 BP 144 EP 148 DI 10.1006/mpev.1999.0640 PG 5 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 245VW UT WOS:000083129700013 PM 10508547 ER PT J AU Schwartzberg, PL AF Schwartzberg, PL TI A friendly signal SO NATURE GENETICS LA English DT News Item ID RECEPTOR; GROWTH; GENE; PHOSPHORYLATION; ACTIVATION; KINASES; CELLS; VIRUS C1 Natl Human Genet Dis Res Inst, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Schwartzberg, PL (reprint author), Natl Human Genet Dis Res Inst, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. NR 14 TC 0 Z9 0 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 OCT PY 1999 VL 23 IS 2 BP 128 EP 130 DI 10.1038/13753 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 240LM UT WOS:000082827500003 PM 10508499 ER PT J AU Castilla, LH Garrett, L Adya, N Orlic, D Dutra, A Anderson, S Owens, J Eckhaus, M Bodine, D Liu, PP AF Castilla, LH Garrett, L Adya, N Orlic, D Dutra, A Anderson, S Owens, J Eckhaus, M Bodine, D Liu, PP TI The fusion gene Cbfb-MYH11 blocks myeloid differentiation and predisposes mice to acute myelomonocytic leukaemia SO NATURE GENETICS LA English DT Letter ID CENTRAL-NERVOUS-SYSTEM; LEUKEMIA; HEMATOPOIESIS; MOUSE; INV(16)(P13Q22); TRANSLOCATIONS; AML1 C1 Natl Human Genome Res Inst, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. NIH, Vet Resources Program, Bethesda, MD 20892 USA. RP Liu, PP (reprint author), Natl Human Genome Res Inst, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RI Liu, Paul/A-7976-2012 OI Liu, Paul/0000-0002-6779-025X NR 15 TC 196 Z9 200 U1 1 U2 4 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 OCT PY 1999 VL 23 IS 2 BP 144 EP 146 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 240LM UT WOS:000082827500011 PM 10508507 ER PT J AU Hollander, MC Sheikh, MS Bulavin, DV Lundgren, K Augeri-Henmueller, L Shehee, R Molinaro, TA Kim, KE Tolosa, E Ashwell, JD Rosenberg, MP Zhan, QM Fernandez-Salguero, PM Morgan, WF Deng, CX Fornace, AJ AF Hollander, MC Sheikh, MS Bulavin, DV Lundgren, K Augeri-Henmueller, L Shehee, R Molinaro, TA Kim, KE Tolosa, E Ashwell, JD Rosenberg, MP Zhan, QM Fernandez-Salguero, PM Morgan, WF Deng, CX Fornace, AJ TI Genomic instability in Gadd45a-deficient mice SO NATURE GENETICS LA English DT Article ID CELL-CYCLE ARREST; P53-DEFICIENT MICE; P53; GADD45; DEFICIENT; PROTEIN; P21 AB Gadd45a-null mice generated by gene targeting exhibited several of the phenotypes characteristic of p53-deficient mice, including genomic instability, increased radiation carcinogenesis and a low frequency of exencephaly. Genomic instability was exemplified by aneuploidy, chromosome aberrations, gene amplification and centrosome amplification, and was accompanied by abnormalities in mitosis, cytokinesis and growth control. Unequal segregation of chromosomes due to multiple spindle poles during mitosis occurred in several Gadd45a(-/-) cell lineages and may contribute to the aneuploidy. Our results indicate that Gadd45a is one component of the p53 pathway that contributes to the maintenance of genomic stability. C1 NCI, Gene Response Sect, DBS, Bethesda, MD 20892 USA. Glaxo Wellcome Res & Dev Inc, Res Triangle Pk, NC 27709 USA. NCI, Lab Immune Cell Biol, DBS, Bethesda, MD 20892 USA. NCI, Lab Metab, DBS, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA 94143 USA. Univ Calif Berkeley, Lawrence Berkeley Lab, Div Life Sci, Berkeley, CA 94720 USA. NIDDKD, Genet Dev & Dis Branch, Bethesda, MD 20892 USA. RP Fornace, AJ (reprint author), NCI, Gene Response Sect, DBS, Bethesda, MD 20892 USA. RI deng, chuxia/N-6713-2016; OI Fernandez-Salguero, Pedro M./0000-0003-2839-5027 NR 30 TC 371 Z9 386 U1 0 U2 7 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD OCT PY 1999 VL 23 IS 2 BP 176 EP 184 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 240LM UT WOS:000082827500016 PM 10508513 ER PT J AU Gerard, M Hernandez, L Wevrick, R Stewart, CL AF Gerard, M Hernandez, L Wevrick, R Stewart, CL TI Disruption of the mouse necdin gene results in early post-natal lethality SO NATURE GENETICS LA English DT Article ID PRADER-WILLI-SYNDROME; SYNDROME REGION; GROWTH SUPPRESSOR; IMPRINTING-CENTER; NUCLEAR-PROTEIN; EXPRESSED GENE; DELETION; IDENTIFICATION; SNRPN AB Prader-Willi syndrome (PWS) is a neurobehavioural disorder characterized by neonatal respiratory depression, hypotonia and failure to thrive in infancy, followed by hyperphagia and obesity among other symptoms(1,2). PWS is caused by the loss of one or more paternally expressed genes on chromosome 15q11-q13, which can be due to gene deletions, maternal uniparental disomy or mutations disrupting the imprinting mechanism. Imprinted genes mapped to this region include SNRPN (refs 3,4), ZNF127 (ref. 5), IPW (ref. 6) and NDN (which encodes the DNA-binding protein necdin; refs 7-10). The mouse homologues of these genes map to mouse chromosome 7 in a region syntenic with human chromosome 15q11-q13 (refs 7,11). Imprinting of the human genes is under the control of an imprinting center (IC), a long-range, cis-acting element located in the 5 ' region of SNRPN (ref. 12). A related control element was isolated in the mouse Snrpn genomic region which, when deleted on the paternally inherited chromosome, resulted in the loss of expression of all four genes and early post-natal lethality(13). To determine the possible contribution of Ndn to the PWS phenotype, we generated Ndn mutant mice. Heterozygous mice inheriting the mutated maternal allele were indistinguishable from their wild-type littermates. Mice carrying a paternally inherited Ndn deletion allele demonstrated early post-natal lethality. This is the first example of a single gene being responsible for phenotypes associated with PWS. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Canc & Dev Biol Lab, Frederick, MD 21702 USA. Univ Alberta, Dept Med Genet, Edmonton, AB T6G 2H7, Canada. RP Stewart, CL (reprint author), CEA Saclay, SBGM, F-91191 Gif Sur Yvette, France. RI GERARD, Matthieu/D-2235-2014; OI GERARD, Matthieu/0000-0001-8956-0597; Wevrick, Rachel/0000-0002-3343-5794 NR 22 TC 151 Z9 156 U1 0 U2 2 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 OCT PY 1999 VL 23 IS 2 BP 199 EP 202 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 240LM UT WOS:000082827500020 PM 10508517 ER PT J AU Hahm, KB Cho, KN Lee, C Im, YH Chang, J Choi, SG Sorensen, PHB Thiele, CJ Kim, SJ AF Hahm, KB Cho, KN Lee, C Im, YH Chang, J Choi, SG Sorensen, PHB Thiele, CJ Kim, SJ TI Repression of the gene encoding the TGF-beta type II receptor is a major target of the EWS-FLI1 oncoprotein SO NATURE GENETICS LA English DT Article ID EWINGS-SARCOMA TRANSLOCATION; TRANSCRIPTION FACTOR; DNA-BINDING; FUSION PROTEIN; ETS-FAMILY; EWS GENE; EXPRESSION; SEQUENCE; CANCER; CELLS AB Chromosomal translocations resulting in the expression of chimaeric transcription factors are frequently observed in tumour cells(1), and have been suggested to be a common mechanism in human carcinogenesis. Ewing sarcoma and related peripheral primitive neuroectodermal tumours share recurrent translocations that fuse the gene EWSR1 (formerly EWS) from 22q-12 to FLI1 and genes encoding other ETS transcription factors(2-4) (which bind DNA through the conserved ETS domain(5,6)). It has been shown that transduction of the gene EWSR1-FLI1 (encoding EWS-FLI1 protein) can transform NIH3T3 cells, and that mutants containing a deletion in either the EWS domain or the DNA-binding domain in FLI1 lose this ability(5-8). This indicates that the EWS-FLI1 fusion protein may act as an aberrant transcription factor, but the exact mechanism of oncogenesis remains unknown. Because ETS transcription factors regulate expression of TGFBR2 (encoding the TGF-beta type II receptor, TGF-beta RII; refs 9,14), a putative tumour suppressor gene, we hypothesized that TGFBR2 may be a target of the EWS-FLI1 fusion protein. We show here that embryonic stem (ES) cell lines with the EWSR1-FLI1 fusion have reduced TGF-beta sensitivity, and that fusion-positive ES cells and primary tumours both express low or undetectable levels of TGFBR2 mRNA and protein product. Co-transfection of FLI1 and the TGFBR2 promoter induces promoter activity, whereas EWSR1-FLI1 leads to suppression of TGFBR2 promoter activity and FLI1-induced promoter activity. Introduction of EWSR1-FLI1 into cells lacking the EWSR1-FLI1 fusion suppresses TGF-beta RII expression, whereas antisense to EWSR1-FLI1 in ES cell lines positive for this gene fusion restores TGF-beta RII expression. Furthermore, introduction of normal TGF-beta RII into ES cell lines restores TGF-beta sensitivity and blocks tumorigenicity. Our results implicate TGF-beta RII as a direct target of EWS-FLI1. C1 NCI, Lab Cell Regulat & Carcinogenesis, DBS, Bethesda, MD 20892 USA. NCI, Pediat Oncol Branch, DCS, Bethesda, MD 20892 USA. British Columbia Childrens Hosp, Dept Pathol, Vancouver, BC V6H 3V4, Canada. RP Kim, SJ (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, DBS, Bethesda, MD 20892 USA. NR 20 TC 164 Z9 169 U1 0 U2 2 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 OCT PY 1999 VL 23 IS 2 BP 222 EP 227 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 240LM UT WOS:000082827500025 PM 10508522 ER PT J AU Grossman, Z Polis, M Feinberg, MB Grossman, Z Levi, I Jankelevich, S Yarchoan, R Boon, J de Wolf, F Lange, JMA Goudsmit, J Dimitrov, DS Paul, WE AF Grossman, Z Polis, M Feinberg, MB Grossman, Z Levi, I Jankelevich, S Yarchoan, R Boon, J de Wolf, F Lange, JMA Goudsmit, J Dimitrov, DS Paul, WE TI Ongoing HIV dissemination during HAART SO NATURE MEDICINE LA English DT Editorial Material ID T-CELL HOMEOSTASIS; ANTIRETROVIRAL THERAPY; INDUCTION THERAPY; DRUG-THERAPY; IN-VIVO; INFECTION; LYMPHOCYTES; REPLICATION; DYNAMICS; RNA C1 NIH, Off AIDS Res, Bethesda, MD 20892 USA. Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, IL-69978 Tel Aviv, Israel. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Emory Univ, Ctr AIDS Res, Atlanta, GA 30322 USA. Chaim Sheba Med Ctr, Inst Virol, IL-52621 Tel Hashomer, Israel. Chaim Sheba Med Ctr, Dept Infect Dis, IL-52621 Tel Hashomer, Israel. NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. NCI, Lab Expt & Computat Biol, Frederick Canc Res Ctr, NIH, Frederick, MD 21701 USA. Univ Amsterdam, Acad Med Ctr, Dept Human Retrovirol, NL-1012 WX Amsterdam, Netherlands. Univ Amsterdam, Acad Med Ctr, Dept Internal Med, NL-1012 WX Amsterdam, Netherlands. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Grossman, Z (reprint author), NIH, Off AIDS Res, Bldg 10, Bethesda, MD 20892 USA. EM grossman@helix.nih.gov RI Grossman, Zvi/A-9643-2008; OI Polis, Michael/0000-0002-9151-2268 NR 26 TC 116 Z9 119 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD OCT PY 1999 VL 5 IS 10 BP 1099 EP 1104 DI 10.1038/13410 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 242GY UT WOS:000082933200020 PM 10502799 ER PT J AU Bendandi, M Gocke, CD Kobrin, CB Benko, FA Sternas, LA Pennington, R Watson, TM Reynolds, CW Gause, BL Duffey, PL Jaffe, ES Creekmore, SP Longo, DL Kwak, LW AF Bendandi, M Gocke, CD Kobrin, CB Benko, FA Sternas, LA Pennington, R Watson, TM Reynolds, CW Gause, BL Duffey, PL Jaffe, ES Creekmore, SP Longo, DL Kwak, LW TI Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma SO NATURE MEDICINE LA English DT Article ID B-CELL LYMPHOMA; CYTOTOXIC T-LYMPHOCYTES; POLYMERASE CHAIN-REACTION; IN-VITRO; DENDRITIC CELLS; FOLLICULAR LYMPHOMAS; IMMUNE-RESPONSES; RESIDUAL CELLS; ANTI-IDIOTYPE; TUMOR-CELLS AB Lymphomas express a tumor-specific antigen which can be targeted by cancer vaccination. We evaluated the ability of a new idiotype protein Vaccine formulation to eradicate residual t(14;18)+ lymphoma cells in 20 patients in a homogeneous, chemotherapy-induced first clinical complete remission. All 11 patients with detectable translocations in their primary tumors had cells from the malignant clone detectable in their blood by PCR both at diagnosis and after chemotherapy, despite being in complete remission. However, 8 of 11 patients converted to lacking cells in their blood from the malignant clone detectable by PCR after vaccination and sustained their molecular remissions. Tumor-specific cytotoxic CD8(+) and CD4(+) T cells were uniformly found (19 of 20 patients), whereas antibodies were detected, but apparently were not required for molecular remission. Vaccination was thus associated with clearance of residual tumor cells from blood and long-term disease-free survival. The demonstration of molecular remissions, analysis of cytotoxic T lymphocytes against autologous tumor targets, and addition of granulocyte-monocyte colony-stimulating factor to the vaccine formulation provide principles relevant to the design of future clinical trials of other cancer vaccines administered in a minimal residual disease setting. C1 NCI, Dept Expt Transplantat & Immunol, Med Branch, Div Clin Sci, Bethesda, MD 20892 USA. NCI, Biol Resources Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. Penn State Univ, Dept Pathol, Hershey, PA 17033 USA. Sci Applicat Int Corp, Frederick, MD USA. NIA, NIH, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Kwak, LW (reprint author), NCI, Dept Expt Transplantat & Immunol, Med Branch, Div Clin Sci, Bethesda, MD 20892 USA. NR 31 TC 437 Z9 448 U1 0 U2 5 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 OCT PY 1999 VL 5 IS 10 BP 1171 EP 1177 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 242GY UT WOS:000082933200044 PM 10502821 ER PT J AU Hyman, SE AF Hyman, SE TI Selective gene expression increases behavioral sensitivity to cocaine SO NATURE NEUROSCIENCE LA English DT News Item ID NUCLEUS-ACCUMBENS; ADDICTION AB Addictive drugs induce a truncated form of fosB in the striatum. A new study shows that mice engineered to mimic this expression pattern are abnormally sensitive to cocaine. C1 NIMH, NIH, Bethesda, MD 20892 USA. RP Hyman, SE (reprint author), NIMH, NIH, 6001 Execut Blvd,Room 8235,MSC 9669, Bethesda, MD 20892 USA. NR 9 TC 1 Z9 1 U1 0 U2 0 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 OCT PY 1999 VL 2 IS 10 BP 855 EP 856 DI 10.1038/13147 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 259FE UT WOS:000083883200004 PM 10491599 ER PT J AU Oram, MW Richmon, BJ AF Oram, MW Richmon, BJ TI I see a face - a happy face SO NATURE NEUROSCIENCE LA English DT News Item ID INFERIOR TEMPORAL CORTEX; STRIATE CORTEX; MACAQUE MONKEY; MECHANISMS; LATENCY; CAT AB Information analysis shows that face-selective neurons in inferior temporal cortex encode different stimulus attributes early and late in their response to the same image. C1 Univ St Andrews, Sch Psychol, St Andrews KY16 9JU, Fife, Scotland. NIMH, NIH, Bethesda, MD 20892 USA. RP Oram, MW (reprint author), Univ St Andrews, Sch Psychol, St Andrews KY16 9JU, Fife, Scotland. RI Oram, Michael/A-2558-2010 NR 14 TC 6 Z9 6 U1 1 U2 2 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 OCT PY 1999 VL 2 IS 10 BP 856 EP 858 DI 10.1038/13149 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 259FE UT WOS:000083883200005 PM 10491600 ER PT J AU Giedd, JN Blumenthal, J Jeffries, NO Castellanos, FX Liu, H Zijdenbos, A Paus, T Evans, AC Rapoport, JL AF Giedd, JN Blumenthal, J Jeffries, NO Castellanos, FX Liu, H Zijdenbos, A Paus, T Evans, AC Rapoport, JL TI Brain development during childhood and adolescence: a longitudinal MRI study SO NATURE NEUROSCIENCE LA English DT Article ID CEREBRAL-CORTEX; SYNAPTOGENESIS; OVERPRODUCTION; IMAGES; AGE C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. NINDS, Biometry Branch, Bethesda, MD 20892 USA. McGill Univ, Montreal Neurol Inst, Montreal, PQ H3A 2B4, Canada. RP Giedd, JN (reprint author), NIMH, Child Psychiat Branch, Bldg 10,Room 4C110,10 Ctr Dr,MSC 1367, Bethesda, MD 20892 USA. RI Giedd, Jay/A-3080-2008; Henrich, Joseph/A-2403-2009; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 NR 15 TC 2390 Z9 2431 U1 30 U2 248 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 OCT PY 1999 VL 2 IS 10 BP 861 EP 863 DI 10.1038/13158 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 259FE UT WOS:000083883200008 PM 10491603 ER PT J AU Cameron, HA McKay, RDG AF Cameron, HA McKay, RDG TI Restoring production of hippocampal neurons in old age SO NATURE NEUROSCIENCE LA English DT Article ID RAT DENTATE GYRUS; ADULT-RAT; PYRAMIDAL NEURONS; ADRENAL-STEROIDS; CORTISOL-LEVELS; INDUCED ATROPHY; GRANULE CELLS; NEUROGENESIS; STRESS; PROLIFERATION AB The production of hippocampal granule neurons continues throughout adulthood but dramatically decreases in old age. Here we show that reducing corticosteroid levels in aged rats restored the rate of cell proliferation, resulting in increased numbers of new granule neurons. This result indicates that the neuronal precursor population in the dentate gyrus remains stable into old age, but that neurogenesis is normally slowed by high levels of corticosteroids. The findings further suggest that decreased neurogenesis may contribute to age-related memory deficits associated with high corticosteroids, and that these deficits may be reversible. C1 NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Cameron, HA (reprint author), NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RI Cameron, Heather/E-6221-2011 OI Cameron, Heather/0000-0002-3245-5777 NR 38 TC 494 Z9 510 U1 1 U2 21 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 OCT PY 1999 VL 2 IS 10 BP 894 EP 897 DI 10.1038/13197 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 259FE UT WOS:000083883200015 PM 10491610 ER PT J AU Gottlieb, J Goldberg, ME AF Gottlieb, J Goldberg, ME TI Activity of neurons in the lateral intraparietal area of the monkey during an antisaccade task SO NATURE NEUROSCIENCE LA English DT Article ID POSTERIOR PARIETAL CORTEX; SINGLE NEURONS; MOTOR PLAN; EYE FIELD; SACCADES; CONNECTIONS; INTENTION; PATTERNS; MACAQUE; LESIONS AB The close relationship between saccadic eye movements and vision complicates the identification of neural responses associated with each function. Visual and saccade-related responses are especially closely intertwined in a subdivision of posterior parietal cortex, the lateral parietal area (LIP). We analyzed LIP neurons using an antisaccade task in which monkeys made saccades away from a salient visual cue. The vast majority of neurons reliably signaled the location of the visual cue. In contrast, most neurons had only weak, if any, saccade-related activity independent of visual stimulation. Thus, whereas the great majority of LIP neurons reliably encoded cue location, only a small minority encoded the direction of the upcoming saccade. C1 NEI, Lab Sensorimotor Res, Bethesda, MD 20892 USA. Georgetown Univ, Sch Med, Dept Neurol, Washington, DC 20007 USA. RP Gottlieb, J (reprint author), NEI, Lab Sensorimotor Res, Bethesda, MD 20892 USA. NR 29 TC 162 Z9 162 U1 0 U2 5 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 OCT PY 1999 VL 2 IS 10 BP 906 EP 912 DI 10.1038/13209 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 259FE UT WOS:000083883200017 PM 10491612 ER PT J AU Chao, LL Haxby, JV Martin, A AF Chao, LL Haxby, JV Martin, A TI Attribute-based neural substrates in temporal cortex for perceiving and knowing about objects SO NATURE NEUROSCIENCE LA English DT Article ID HUMAN VISUAL-CORTEX; SEMANTIC CATEGORY; BIOLOGICAL MOTION; LEXICAL RETRIEVAL; KNOWLEDGE; RECOGNITION; ACTIVATION; IMPAIRMENT; SYSTEMS; REGIONS AB The cognitive and neural mechanisms underlying category-specific knowledge remain controversial. Here we report that, across multiple tasks (viewing, delayed match to sample, naming), pictures of animals and tools were associated with highly consistent, category-related patterns of activation in ventral (fusiform gyrus) and lateral (superior and middle temporal gyri) regions of the posterior temporal lobes. In addition, similar patterns of category-related activity occurred when subjects read the names of, and answered questions about, animals and tools. These findings suggest that semantic object information is represented in distributed networks that include sites for storing information about specific object attributes such as form (ventral temporal cortex) and motion (lateral temporal cortex). C1 NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Martin, A (reprint author), NIMH, Lab Brain & Cognit, Bldg 10,4C104, Bethesda, MD 20892 USA. RI martin, alex/B-6176-2009; Frank, David/E-8213-2012 NR 50 TC 702 Z9 711 U1 2 U2 21 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 OCT PY 1999 VL 2 IS 10 BP 913 EP 919 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 259FE UT WOS:000083883200018 PM 10491613 ER PT J AU Mitchison, HM Bernard, DJ Greene, NDE Cooper, JD Junaid, MA Pullarkat, RK de Vos, N Breuning, MH Owens, JW Mobley, WC Gardiner, RM Lake, BD Taschner, PEM Nussbaum, RL AF Mitchison, HM Bernard, DJ Greene, NDE Cooper, JD Junaid, MA Pullarkat, RK de Vos, N Breuning, MH Owens, JW Mobley, WC Gardiner, RM Lake, BD Taschner, PEM Nussbaum, RL TI Targeted disruption of the Cln3 gene provides a mouse model for Batten disease SO NEUROBIOLOGY OF DISEASE LA English DT Article ID NEURONAL CEROID-LIPOFUSCINOSIS; MITOCHONDRIAL ATP SYNTHASE; SUBUNIT-C; PROTEIN; MICE; DEGENERATION; ACCUMULATION; MUTATIONS; ENDOCYTOSIS; HOMOLOGY AB Batten disease, a degenerative neurological disorder with juvenile onset, is the most common form of the neuronal ceroid lipofuscinoses. Mutations in the CLN3 gene cause Batten disease. To facilitate studies of Batten disease pathogenesis and treatment, a murine model was created by targeted disruption of the Cln3 gene. Mice homozygous for the disrupted Cln3 allele had a neuronal storage disorder resembling that seen in Batten disease patients: there was widespread and progressive intracellular accumulation of autofluorescent material that by EM displayed a multilamellar rectilinear/ fingerprint appearance. Inclusions contained subunit c of mitochondrial ATP synthase. Mutant animals also showed neuropathological abnormalities with loss of certain cortical interneurons and hypertrophy of many interneuron populations in the hippocampus. Finally, as is true in Batten disease patients, there was increased activity in the brain of the lysosomal protease Cln2/TPP-1. Our findings are evidence that the Cln3-deficient mouse provides a valuable model for studying Batten disease. (C) 1999 Academic Press. C1 UCL Royal Free & UCL Med Sch, Dept Paediat, Rayne Inst, London WC1E 6JJ, England. NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. Stanford Univ, Neurosci Program, Stanford, CA 94305 USA. New York State Inst Basic Res Dev Disabil, Staten Isl, NY 10314 USA. Leiden Univ, Sylvius Labs, Dept Genet, Sect Human Genet, NL-2300 RA Leiden, Netherlands. NIH, Vet Resources Program, Off Res Serv, Bethesda, MD 20892 USA. Great Ormond St Hosp Sick Children, Dept Histopathol, London WC1N 3JH, England. RP Mitchison, HM (reprint author), UCL Royal Free & UCL Med Sch, Dept Paediat, Rayne Inst, Univ St, London WC1E 6JJ, England. RI Mitchison, Hannah/C-1891-2008; Breuning, Martijn/E-3429-2010; Cooper, Jonathan/C-8117-2009; Taschner, Peter/J-8853-2014; OI Cooper, Jonathan/0000-0003-1339-4750; Taschner, Peter/0000-0001-9621-465X; Greene, Nicholas/0000-0002-4170-5248 FU NINDS NIH HHS [NS 30147, NS 30152] NR 53 TC 119 Z9 120 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD OCT PY 1999 VL 6 IS 5 BP 321 EP 334 DI 10.1006/nbdi.1999.0267 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 245YH UT WOS:000083135900003 PM 10527801 ER PT J AU Foley, TD AF Foley, TD TI The lipid peroxidation product 4-hydroxynonenal potently and selectively inhibits synaptic plasma membrane ecto-ATPase activity, a putative regulator of synaptic ATP and adenosine SO NEUROCHEMICAL RESEARCH LA English DT Article DE 4-hydroxynonenal; ecto-ATPase; synaptic plasma membranes; excitotoxicity ID HIPPOCAMPAL-NEURONS; NERVOUS-SYSTEM; K+-ATPASE; RELEASE; BRAIN; RECEPTORS; BIOCHEMISTRY; SYNAPTOSOMES; VESICLES; PROTEINS AB Synaptic plasma membrane (SPM)-bound, extracellular-facing (ecto) ATPases are Mg2+- or Ca2+-activated enzymes that regulate the synaptic levels of the excitatory neurotransmitter ATP and provide ADP for the further ecto-nucleotidase-mediated production of the inhibitory neuromodulator adenosine. The present results show that low concentrations (IC (50) = 4 mu M) Of the lipid peroxidation product 4-hydroxynonenal (HNE) inhibited up to about 80% of the ectoATPase activity of SPM purified from rat brain cerebral cortex. In contrast, low concentrations of HNE did not inhibit the activity of the "intracellular"-facing Na+, K+, Mg2+-ATPase. In addition, the inhibition of SPM ecto-ATPase activity by HNE was largely irreversible and pH-dependent. Furthermore, structure-activity studies demonstrate that inhibition was dependent on the presence of the reactive functional groups of HNE. These findings suggest that HNE selectively inhibits SPM ecto-ATPase activity by a mechanism that may involve the covalent modification of functionally-critical nucleophilic amino acids. It is proposed that inhibition of SPM ecto-ATPase activity could contribute to the mechanisms by which lipid peroxidation and HNE formation promote excitotoxicity. C1 NIAAA, Sect Neurochem, LCS, DICBR,NIH, Rockville, MD 20852 USA. RP Foley, TD (reprint author), Univ Scranton, Dept Chem, Biochem Sect, Loyola Hall, Scranton, PA 18510 USA. NR 37 TC 5 Z9 6 U1 0 U2 1 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD OCT PY 1999 VL 24 IS 10 BP 1241 EP 1248 DI 10.1023/A:1020921006221 PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 233DD UT WOS:000082409500006 PM 10492519 ER PT J AU Hacke, W Brott, T Caplan, L Meier, D Fieschi, C von Kummer, R Donnan, G Heiss, WD Wahlgren, NG Spranger, M Boysen, G Marler, JR AF Hacke, W Brott, T Caplan, L Meier, D Fieschi, C von Kummer, R Donnan, G Heiss, WD Wahlgren, NG Spranger, M Boysen, G Marler, JR TI Thrombolysis in acute ischemic stroke: Controlled trials and clinical experience SO NEUROLOGY LA English DT Article ID TISSUE-PLASMINOGEN ACTIVATOR; INTRAVENOUS THROMBOLYSIS; THERAPY; ECASS AB Thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) is approved in the United States for treatment of acute ischemic stroke. Approval was granted after a large, randomized, placebo-controlled study by the National Institute of Neurological Disorders and Stroke (NINDS) showed a significant improvement in 3-month outcomes with rtPA despite a significant risk for symptomatic hemorrhage. Two other trials, the first and second European Cooperative Acute Stroke Study (ECASS I and II), have shown comparable results, but neither was statistically positive for the predefined primary end point. An analysis of the risk/benefit profile of rtPA therapy based on the results of these three trials indicates that the treatment is effective and, when administered within 3 hours of symptom onset at a dose of 0.9 mg/kg, the benefits by far outweigh the risks for eligible patients. Even with the 6-hour time window of the two ECASS trials, a combined analysis of the three studies shows the number of disabled or dead patients to be significantly reduced. Preliminary data collected on the use of rtPA outside of clinical trials in the United States and Europe suggest that, when rtPA is used according to the trial protocol, the risks and benefits are similar to those observed in clinical trials. However, even within the United States, rtPA is underutilized, The most substantial treatment barrier is the narrow time window, which may be expanded if long-term experience shows that this is possible. Most stroke patients arrive at the hospital too late to be eligible for screening and treatment. Education of the public and physicians may help to overcome this difficulty. C1 Univ Heidelberg, Dept Neurol, D-69120 Heidelberg, Germany. Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA USA. Boehringer Ingelheim Pharmaceut Inc, Ingelheim, Germany. Univ Rome, Dept Neurol Sci, Rome, Italy. Univ Dresden, Dept Neuroradiol, Dresden, Germany. Natl Stroke Res Inst, Austin & Repatriat Med Ctr, Heidelberg, Vic, Australia. Univ Cologne, Neurol Clin, Max Planck Inst Neurol Res, D-5000 Cologne, Germany. Karolinska Hosp, Dept Neurol, S-10401 Stockholm, Sweden. Ruprecht Karls Univ Hosp, Dept Neurol, Heidelberg, Germany. Bispebjerg Univ Hosp, Dept Neurol, DK-2400 Copenhagen NV, Denmark. NINDS, NIH, Bethesda, MD 20892 USA. RP Hacke, W (reprint author), Univ Heidelberg, Dept Neurol, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany. RI DONNAN, GEOFFREY/A-9947-2008 NR 12 TC 140 Z9 145 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD OCT PY 1999 VL 53 IS 7 SU 4 BP S3 EP S14 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA 247EH UT WOS:000083207300002 PM 10532643 ER PT J AU Crawley, JN AF Crawley, JN TI The role of galanin in feeding behavior SO NEUROPEPTIDES LA English DT Article ID HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; GROWTH-HORMONE SECRETION; OBESE ZUCKER RATS; HIGH-FAT DIET; NEUROPEPTIDE-Y; GENE-EXPRESSION; MACRONUTRIENT SELECTION; FOOD-INTAKE; BASE-LINE; RELEASE AB Galanin inhibits food consumption in satiated rats. Discovered relatively recently, galanin is a 29-amino-acid neuropeptide, not homologous with any other known peptide. Three G-protein-linked galanin receptor subtypes have been cloned. This review summarizes the mechanisms by which exogenously administered galanin may stimulate ingestion, discusses pharmacological and genetic investigations of the role of endogenous galanin on feeding and body weight, and speculates on the therapeutic potential of non-peptide galanin receptor antagonists for the treatment of appetite disorders. (C) 1999 Harcourt Publishers Ltd. C1 NIMH, Sect Behav Neuropharmacol, Expt Therapeut Branch, Bethesda, MD 20892 USA. RP Crawley, JN (reprint author), NIMH, Sect Behav Neuropharmacol, Expt Therapeut Branch, Bldg 10,Room 4D11, Bethesda, MD 20892 USA. NR 67 TC 106 Z9 108 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 OCT PY 1999 VL 33 IS 5 BP 369 EP 375 DI 10.1054/npep.1999.0049 PG 7 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 256UK UT WOS:000083744600006 PM 10657514 ER PT J AU Zahn, TP Grafman, J Tranel, D AF Zahn, TP Grafman, J Tranel, D TI Frontal lobe lesions and electrodermal activity: effects of significance SO NEUROPSYCHOLOGIA LA English DT Article DE skin conductance; brain damage; orienting response; autonomic nervous system; emotion ID SCHIZOPHRENIA; DISORDERS; INJURIES; AROUSAL; SYSTEM AB Several studies have shown that cortical damage, especially to the right hemisphere and to frontal lobes, may attenuate skin conductance responses selectively to psychologically significant stimuli. We tested this hypothesis in 32 patients with frontal lesions, verified by computer assisted tomography and magnetic resonance imaging, and 45 healthy controls. Patients and controls were given a protocol which included a rest period, a series of innocuous tones, and a reaction time task. Patients were given a second protocol in which they viewed slides with positive and negative emotional content and neutral slides. Results showed attenuated electrodermal activity (EDA) during task instructions and smaller skin conductance responses to reaction-time stimuli in patients compared to controls but few differences under passive conditions or in orienting responses to simple tones. Patients with lateral prefrontal and paraventricular lesions were especially low in EDA in the reaction time task, and those with right and bilateral lesions in the cingulate gyrus and/or frontal operculum had attenuated EDA in both protocols. We conclude that the effects of certain frontal lesions are on the psychological response to significance which is indexed by EDA rather than directly on EDA per se. Published by Elsevier Science Ltd. C1 NINDS, Cognit Neurosci Sect, Bethesda, MD 20892 USA. NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Univ Iowa, Coll Med, Div Behav Neurol & Cognit Neurosci, Dept Neurol, Iowa City, IA 52442 USA. Univ Iowa, Dept Psychol, Iowa City, IA 52442 USA. RP Grafman, J (reprint author), NINDS, Cognit Neurosci Sect, 10 Ctr Dr,MSC 1440, Bethesda, MD 20892 USA. EM jgr@box-j.nih.gov OI Grafman, Jordan H./0000-0001-8645-4457 NR 36 TC 43 Z9 43 U1 2 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD OCT PY 1999 VL 37 IS 11 BP 1227 EP 1241 DI 10.1016/S0028-3932(99)00020-2 PG 15 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 240NC UT WOS:000082831200002 PM 10530723 ER PT J AU Xiao, Y Harry, GJ Pennypacker, KR AF Xiao, Y Harry, GJ Pennypacker, KR TI Expression of AP-1 transcription factors in rat hippocampus and cerebellum after trimethyltin neurotoxicity SO NEUROTOXICOLOGY LA English DT Article DE fos-related antigen-2; neurotoxicity; Jun ID PROTEIN-KINASE-C; DNA-BINDING; GENE-EXPRESSION; CELL-DEATH; FOS; IDENTIFICATION; ACTIVATION; DAMAGE; INJURY; FAMILY AB Neurotoxic insult causes neurons to degenerate due to necrosis or apoptosis. After this neurodegenerative phase, gene expression in surviving neurons is altered to undergo regeneration and repair to adapt to changes in the cellular environment. In this study, we examined the expression of four AP-1 transcription factors, jun, JunB, JunD and FRA-2, and AP-1 DNA binding activity in the rat hippocampus to examine changes during the periods of degeneration and then of regeneration and repair after TMT-induced neurotoxicity The expression of these factors in the cerebellum was examined as a control since this Drain region is not grossly affected by TMT. AP-1 DNA binding slowly increased in both the cerebellum and hippocampus from one hour to eight days after TMT exposure. Levels of Jun in the hippocampus significantly increased at 12 hours after TMT while JunB and JunD expression did not change. On the otherhand, FRA-2 was induced at 8 days in the hippocampus after TMT treatment and was expressed only in hippocampi containing neurodegeneration as gauged by elevated glial fibrillary acidic protein levels. FRA-2 immunoreactivity was detected in the AP-1 DNA binding complex only in hippocampal extracts from rats after eight days post-trimethyltin administration. Thus, FRA-2 is a component of the AP-1 DNA binding complex suggesting that it is involved in regulating genes during a later stage of TMT neurotoxicity. (C) 1999 Intox Press, Inc. C1 Univ S Florida, Dept Pharmacol, Tampa, FL 33612 USA. NIEHS, Lab Environm Neurosci, Res Triangle Pk, NC 27709 USA. RP Pennypacker, KR (reprint author), Univ S Florida, Dept Pharmacol, 12901 Bruce B Downs Blvd,MDC 9, Tampa, FL 33612 USA. RI Pennypacker, Keith/I-5092-2012 NR 28 TC 10 Z9 10 U1 0 U2 0 PU INTOX PRESS INC PI LITTLE ROCK PA PO BOX 24865, LITTLE ROCK, AR 72221 USA SN 0161-813X J9 NEUROTOXICOLOGY JI Neurotoxicology PD OCT PY 1999 VL 20 IS 5 BP 761 EP 766 PG 6 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 259XX UT WOS:000083920200010 PM 10591512 ER PT J AU Savory, J Rao, JKS Huang, Y Letada, PR Herman, MM AF Savory, J Rao, JKS Huang, Y Letada, PR Herman, MM TI Age-related hippocampal changes in Bcl-2 : Bax ratio, oxidative stress, redox-active iron and apoptosis associated with aluminum-induced neurodegeneration: Increased susceptibility with aging SO NEUROTOXICOLOGY LA English DT Article DE aluminum; cerebral neurodegeneration; aged rabbits; oxidative stress; redox-active iron; apoptosis; Bcl-2; Bax ID PAIRED HELICAL FILAMENTS; ALZHEIMERS-DISEASE; NEUROFIBRILLARY DEGENERATION; BRAIN; PROTEIN; RABBITS; TAU; IMMUNOREACTIVITY; PHOSPHORYLATION; UBIQUITIN AB We propose that aging is an important factor in the susceptibiliy of neurons to oxidative stress and to subsequent apoptosis. In the present report we demonstrate that aged rabbits treated intracisternally with aluminum maltolate exhibit intense intraneuronal silver positivity indicative of the formation of neurofilamentous aggregates, together with oxidative stress. These changes occur in the CA1 region of the hippocampus as well as in cerebral cortical areas. Apoptosis, measured by the TUNEL in situ technique, colocalizes with oxidative stress. Young animals treated with aluminum show few of these alterations, while age-matched controls are essentially negative. Further studies on the time course of these and related changes demonstrate that oxidative stress and redox-active iron accumulation in hippocampal neurons occur very rapidly within a period of 3 hours, and increased in intensity at 72 hours. Changes suggestive of apoptosis are seen by 24 hours and are pronounced at 72 hours. In aged animals there is an initially intense immunopositivity at 3 hours for Bcl-2, with negative staining for Bax. By 72 hours, when apoptosis is strongly evident, Bcl-2 is negative and Bax strongly positive. In contrast to the aged rabbits, young animals treated similarly with aluminum exhibit much less oxidative stress with no apoptosis, and maintain Bcl-2 immunopositivity and negative Bax staining. Our findings strongly support the key role that oxidative damage plays in the process of neurodegeneration and in the increased vulnerability to aluminum-induced injury in the aged animal. These are novel observations which may have important implications for aiding in our understanding of the pathogenesis of neurodegeneration occurring in Alzheimer's disease. (C) 1999 Inter Press, Inc. C1 Univ Virginia, Hlth Sci Ctr, Dept Pathol, Charlottesville, VA 22908 USA. Univ Virginia, Hlth Sci Ctr, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. NIMH, Neuropathol Sect, Clin Brain Disorders Branch, IRP,NIH, Bethesda, MD 20892 USA. RP Savory, J (reprint author), Univ Virginia, Hlth Sci Ctr, Dept Pathol, Charlottesville, VA 22908 USA. NR 33 TC 102 Z9 115 U1 2 U2 3 PU INTOX PRESS INC PI LITTLE ROCK PA PO BOX 24865, LITTLE ROCK, AR 72221 USA SN 0161-813X J9 NEUROTOXICOLOGY JI Neurotoxicology PD OCT PY 1999 VL 20 IS 5 BP 805 EP 817 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 259XX UT WOS:000083920200014 PM 10591516 ER PT J AU Kao, WY Liu, QY Ma, W Ritchie, GD Lin, J Nordholm, AF Rossi, J Barker, JL Stenger, DA Pancrazio, JJ AF Kao, WY Liu, QY Ma, W Ritchie, GD Lin, J Nordholm, AF Rossi, J Barker, JL Stenger, DA Pancrazio, JJ TI Inhibition of spontaneous GABAergic transmission by trimethylolpropane phosphate SO NEUROTOXICOLOGY LA English DT Article DE GABA; hippocampal neuron; inhibitory post-synaptic current; lubricant; seizure; whole-cell patch clamp ID CULTURED HIPPOCAMPAL-NEURONS; ESTER TURBINE LUBRICANTS; POSTSYNAPTIC CURRENTS; NEUROTOXIN FORMATION; PYRAMIDAL CELLS; GABA RELEASE; RAT; RECEPTOR; BRAIN; ORGANOPHOSPHATES AB Trimethylolpropane phosphate (TMPP) is a neuroactive organophosphate generated during partial pyrolysis of a synthetic ester turbine engine lubricant, While TMPP had been shown to have little affinity for acetylcholinesterase, previous binding studies and Cl-36(-) flux measurements have implicated TMPP as an antagonist of GABA(A) receptor/Cl- channels. Using the whole-cell patch clamp method, spontaneous inhibitory postsynaptic currents (sIPSCs) mediated by bicuculline-sensitive GABA(A) receptors were measured in neurons cultured from the rat embryonic hippocamapus for 13-21 days. Experiments were conducted in the presence of tetrodotoxin and 6-cyano-7-nitroquinoxaline to inhibit spontaneous presynaptic action potentials and glutamate transmission, respectively, thus isolating GABAergic sPSCs for study TMPP induced a concentration-dependent inhibition of sIPSC amplitude and frequency suggesting both postsynaptic and presynaptic actions. Administration of 5 mu M TMPP reversibly diminished sIPSC amplitude by 23 +/- 8% (mean SEM, n=5 cells) while markedly decreasing the mean sIPSC frequency by 40 +/- 2% (n=5). The mean time constant of sIPSC decay was reversibly decreased by 20 +/- 4% (n=3) in the presence of 20 mu M TMPP: suggesting an increase in the rate of inactivation. To directly verify the blockade of ionotropic GABA receptors by TMPP, the effects of TMPP were examined on whole-cell Cl- current responses activated by exogenous GABA. Administration of TMPP (5 mu M) depressed peak whole-cell GABA-induced currents to 73 1% (n=4) of control levels, consistent with the results on sIPSC amplitude. Our data directly demonstrate that TMPP directly inhibits GABA, receptor function, as indicated by the blockade of whole-cell GABA-mediated Cl- current and the reduction in sIPSC amplitude. Furthermore, TMPP exerts a presynaptic effect on GABAergic transmission, as evidenced by the reduction in sIPSC frequency which may be independent of a GABA(A) receptor. The molecular basis for the presynaptic action of TMPP remains to be elucidated. (C) 1999 Inter Press, Inc. C1 USN, Res Lab, Ctr Biomol Sci & Engn, Washington, DC 20375 USA. NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. Mantech Environm Technol Inc, Dayton, OH 45437 USA. Naval Hlth Res Ctr Toxicol Deployment, Wright Patterson AFB, OH 45433 USA. RP Pancrazio, JJ (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 35 TC 16 Z9 17 U1 0 U2 4 PU INTOX PRESS INC PI LITTLE ROCK PA PO BOX 24865, LITTLE ROCK, AR 72221 USA SN 0161-813X J9 NEUROTOXICOLOGY JI Neurotoxicology PD OCT PY 1999 VL 20 IS 5 BP 843 EP 849 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 259XX UT WOS:000083920200018 PM 10591520 ER PT J AU Sedelnikova, OA Panyutin, IG Luu, AN Neumann, RD AF Sedelnikova, OA Panyutin, IG Luu, AN Neumann, RD TI The stability of DNA triplexes inside cells as studied by iodine-125 radioprinting SO NUCLEIC ACIDS RESEARCH LA English DT Article ID FORMING-OLIGONUCLEOTIDES; COVALENT MODIFICATION; MAMMALIAN-CELLS; HELIX FORMATION; GENE; TRANSCRIPTION; DECAY; SITE AB We studied the stability of a DNA tripler resulting from the binding of a 38 nt long purine motif triplex-forming oligonucleotide (TFO) to a covalently closed plasmid containing a target sequence from the human HPRT gene. Our in vitro experiments showed that the tripler formed at plasmid and TFO concentrations as low as 10(-9) M. Once formed, the triplex was remarkably stable and could withstand 10 min incubation at 65 degrees C. We next delivered these TFO-plasmid complexes into cultured human cells. To monitor the TFO-plasmid complexes inside cells we applied a new technique that we call 'radioprinting'. Because the TFO was (125)l labeled, we could quantitatively monitor the triplexes by measuring (125)l-induced DNA strand breaks in the target plasmid sequence. We found that the triplexes remain stable inside the cells for at least 48 h, Based on these findings we propose using TFO for indirect labeling of intact plasmid DNA. As a demonstration, we show that the. intracellular distribution of a fluorescein-labeled TFO was different when it was liposome-delivered into cultured human cells alone or in a complex with the plasmid. In the latter case, the fluorescence was detected in nearly all the cells while detection of the plasmid by use of a marker gene (beta-galactosidase) revealed expression of the gene in only half of the cells. C1 Warren G Magnuson Clin Ctr, Dept Nucl Med, NIH, Bethesda, MD 20892 USA. RP Panyutin, IG (reprint author), Warren G Magnuson Clin Ctr, Dept Nucl Med, NIH, Bethesda, MD 20892 USA. NR 28 TC 15 Z9 17 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT 1 PY 1999 VL 27 IS 19 BP 3844 EP 3850 DI 10.1093/nar/27.19.3844 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 243CZ UT WOS:000082980600009 PM 10481023 ER PT J AU Graunke, DM Fornace, AJ Pieper, RO AF Graunke, DM Fornace, AJ Pieper, RO TI Presetting of chromatin structure and transcription factor binding poise the human GADD45 gene for rapid transcriptional up-regulation SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DNA-DAMAGING AGENTS; POSITIONED NUCLEOSOMES; IN-VIVO; PHO5 PROMOTER; GROWTH ARREST; CPG ISLANDS; HEAT-SHOCK; CELLS; INDUCTION; P53 AB GADD45 has been suggested to coordinate cell cycle regulation with the repair of DNA damage following ionizing radiation (IR). Although the GADD45 gene is transcriptionally up-regulated in response to IR, alterations in in vivo transcription factor (TF) binding or chromatin structure associated with up-regulation have not been defined, To understand how chromatin structure might influence TF binding and GADD45 up-regulation, key regulatory regions of the gene were identified by in vivo DNase I hypersensitivity (HS) analysis. Chromatin structure and in vivo TF binding in these regions were subsequently monitored in both non-irradiated and irradiated human ML-1 cells. In non-irradiated cells expressing bas;al levels of GADD45, the gene exhibited a highly organized chromatin structure with distinctly positioned nucleosomes, Also identified in non-irradiated cells were DNA-protein interactions at octamer binding motifs and a CCAAT box in the promoter and at consensus binding sites for AP-1 and p53 within intron 3, Upon irradiation and a subsequent 15-fold increase in GADD45 mRNA levels, neither the chromatin structure nor the pattern of TF binding in key regulatory regions was altered. These results suggest that the GADD45 gene is poised far up-regulation and can be rapidly induced independent of gross changes in chromatin structure or TF binding. C1 Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. NCI, Div Basic Sci, Bethesda, MD 20982 USA. RP Pieper, RO (reprint author), Univ Calif San Francisco, Ctr Canc, 2340 Sutter St,Room N261,Box 0128, San Francisco, CA 94115 USA. FU NCI NIH HHS [CA-55064] NR 29 TC 23 Z9 23 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT 1 PY 1999 VL 27 IS 19 BP 3881 EP 3890 DI 10.1093/nar/27.19.3881 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 243CZ UT WOS:000082980600014 PM 10481028 ER PT J AU Koo, WWK Walters, JC Esterlitz, J Levine, RJ Bush, AJ Sibai, B AF Koo, WWK Walters, JC Esterlitz, J Levine, RJ Bush, AJ Sibai, B TI Maternal calcium supplementation and fetal bone mineralization SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID URINARY CALCIUM; DIETARY-SODIUM; PREECLAMPSIA; ABSORPTION; FETUSES; WOMEN; TRIAL AB Objective: To determine the effect of maternal calcium supplementation during pregnancy on fetal bone mineralization. Methods: Healthy mothers with early ultrasound confirmation of dates and singleton pregnancies were enrolled in a double-masked study and randomized before 22 weeks' gestation to 2 g/day of elemental calcium or placebo until delivery. Maternal dietary intake at randomization and at 32-33 weeks' gestation was recorded with 24-hour dietary recalls. Dual-energy x-ray absorptiometry measurements of the whole body and lumbar spine of the neonates were performed before hospital discharge. Results: The infants of 256 women (128 per group) had dual-energy x-ray absorptiometry measurements during the first week of life. There were no significant differences between treatment groups in gestational age, birth weight, or length of the infants, or in the total-body or lumbar spine bone mineral content. However, when bone mineral content was analyzed by treatment group within quintiles of maternal dietary calcium intake, total body bone mineral content (mean +/- standard error of the mean) was significantly greater in infants born to calcium-supplemented mothers (64.1 +/- 3.2 versus 55.7 +/- 2.7 g in the placebo group) in the lowest quintile of dietary calcium intake (less than 600 mg/day). The effect of calcium supplementation remained significant after adjustment for maternal age and maternal body mass index and after normalization for skeletal area and body length of the infant. Conclusion: Maternal calcium supplementation of up to 2 g/day during the second and third trimesters can increase fetal bone mineralization in women with low dietary calcium intake. However, calcium supplementation in pregnant women with adequate dietary calcium intake is unlikely to result in major improvement in fetal bone mineralization. (Obstet Gynecol 1999;94:577-82. (C) 1999 by The American College of Obstetricians and Gynecologists.). C1 Univ Tennessee, Dept Pediat, Memphis, TN USA. Univ Tennessee, Dept Obstet & Gynecol, Memphis, TN USA. Univ Tennessee, Dept Prevent Med, Memphis, TN USA. EMMES Corp, Potomac, MD USA. NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. RP Koo, WWK (reprint author), Hutzel Hosp, Dept Pediat, 4707 St Antoine Blvd, Detroit, MI 48201 USA. FU NCRR NIH HHS [RR00211, RR00211-29]; NICHD NIH HHS [N01-HD-13126] NR 24 TC 80 Z9 81 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD OCT PY 1999 VL 94 IS 4 BP 577 EP 582 DI 10.1016/S0029-7844(99)00371-3 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 239QN UT WOS:000082781300017 PM 10511362 ER PT J AU Herscher, LL Cook, JA Pacelli, R Pass, HI Russo, A Mitchell, JB AF Herscher, LL Cook, JA Pacelli, R Pass, HI Russo, A Mitchell, JB TI Principles of chemoradiation: Theoretical and practical considerations SO ONCOLOGY-NEW YORK LA English DT Article ID HUMAN-TUMOR-CELLS; NORMAL-TISSUES; DRUG-DELIVERY; SOLID TUMORS; CANCER; RADIATION; THERAPY; HYPOXIA; DAMAGE; DNA AB Chemotherapy agents known to enhance the effects of radiation in preclinical studies have been used concurrently with radiotherapy in numerous clinical trials with the prospect of further enhancing radiation-induced local tumor control. While some success in several tumor histologies has been achieved using this approach, a major concern has been enhancement in normal tissue toxicity. This brief review addresses both theoretical and practical issues with respect to chemoradiation clinical trials. Recommendations for clinical trials are provided that, if implemented, cart increase our understanding of basic mechanisms tin patients) and provide a more rational approach for future trials. C1 NCI, Radiat Biol Branch, Div Clin Sci, Bethesda, MD 20892 USA. Univ Naples 2, Inst Radiol Sci, Dept Radiotherapy, Naples, Italy. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. NCI, Radiat Oncol Branch, Div Clin Sci, Bethesda, MD 20892 USA. RP Mitchell, JB (reprint author), NCI, Radiat Biol Branch, Div Clin Sci, Bldg 10,Room B3-B69, Bethesda, MD 20892 USA. NR 55 TC 30 Z9 31 U1 0 U2 0 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD OCT PY 1999 VL 13 IS 10 SU 5 BP 11 EP 22 PG 12 WC Oncology SC Oncology GA 371KQ UT WOS:000165178500001 PM 10550823 ER PT J AU Saxman, SB Blatner, GL Cheson, BD AF Saxman, SB Blatner, GL Cheson, BD TI Clinical trials in non-small-cell lung cancer SO ONCOLOGY-NEW YORK LA English DT Article RP Saxman, SB (reprint author), NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD OCT PY 1999 VL 13 IS 10 BP 1384 EP + PG 3 WC Oncology SC Oncology GA 392WF UT WOS:000166435000015 PM 10549565 ER PT J AU Saxman, SB Blatner, GL Cheson, BD AF Saxman, SB Blatner, GL Cheson, BD TI Clinical trials - Referral resource SO ONCOLOGY-NEW YORK LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Saxman, SB (reprint author), NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD OCT PY 1999 VL 13 IS 10 BP 1384 EP 1384 PG 1 WC Oncology SC Oncology GA 392WF UT WOS:000166435000014 PM 10549565 ER PT J AU Hildesheim, ME Hoffman, HJ Overpeck, MD AF Hildesheim, ME Hoffman, HJ Overpeck, MD TI Frequent ear infections in association with child-care characteristics, based on the 1988 Child Health Supplement to the National Health Interview Survey SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article ID ACUTE OTITIS-MEDIA; RISK-FACTORS; YOUNG-CHILDREN AB Using the 1988 child Health Supplement to the National Health Interview Survey, we analysed the association between child-care characteristics and frequent ear infections among children under 6 years attending child care. We observed strong associations for 1- to 2-year-old children for variables involving exposure to many different children, including number of children in the main setting and one or more changes in child-care arrangement in the past year. No significant effects were observed for the children under 1 year, but sample sizes were small. Likewise, no strong associations were observed for the 3- to 5-year-old children, but they may have outgrown the detrimental effects of repeated respiratory tract infections. C1 NIDCD, Epidemiol Stat & Data Syst Branch, NIH, Bethesda, MD 20892 USA. NICHD, Epidemiol Branch, NIH, Bethesda, MD 20892 USA. RP Hoffman, HJ (reprint author), NIDCD, Epidemiol Stat & Data Syst Branch, NIH, Execut Plaza S,Room 432,6120 Execut Blvd,MSC 7180, Bethesda, MD 20892 USA. NR 13 TC 8 Z9 8 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD OCT PY 1999 VL 13 IS 4 BP 466 EP 472 PG 7 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 255HX UT WOS:000083664400012 PM 10563365 ER PT J AU Grether, JK Eaton, A Redline, R Bendon, R Benirschke, K Nelson, K AF Grether, JK Eaton, A Redline, R Bendon, R Benirschke, K Nelson, K TI Reliability of placental histology using archived specimens SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article ID OF-AMERICAN-PATHOLOGISTS; GESTATIONAL-AGE; OBSERVER RELIABILITY; FEATURES; PATTERNS AB Archived placental materials provide a resource for retrospective studies of perinatal outcomes. Using archived specimens, we evaluated inter-rater reliability in the assessment of placental histological features possibly associated with neonatal illness and long-term neurological outcome. Five expert placental pathologists independently reviewed archived placental specimens on 30 subjects born during 1983-85 in six different hospitals. Moderate to substantial agreement among the raters was observed for a variety of indicators of inflammation, presence of macrophages with pigment and indicators of villous maturity, increased syncytial knots and maternal vasculopathy., Existing pathology reports for these specimens from routine histology examinations conducted at the time of delivery were in substantial agreement with expert review for the presence of any subchorionitis/chorionitis/chorioamnionitis. In conclusion, considerable inter-rater agreement was observed for several relatively common and potentially important placental findings. Archived placental materials and pathology reports may be useful in retrospective studies. C1 Calif Dept Hlth Serv, Calif Birth Defects Monitoring Program, Emeryville, CA 94608 USA. Univ Calif Berkeley, Dept Epidemiol, Berkeley, CA USA. Case Western Reserve Univ, Inst Pathol, Cleveland, OH 44106 USA. Norton Hosp, Main Lab, Louisville, KY USA. Univ Calif San Diego, Dept Pathol, San Diego, CA USA. NINDS, Bethesda, MD 20892 USA. RP Grether, JK (reprint author), Calif Dept Hlth Serv, Calif Birth Defects Monitoring Program, 1900 Powell St,Suite 1050, Emeryville, CA 94608 USA. NR 16 TC 24 Z9 24 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD OCT PY 1999 VL 13 IS 4 BP 489 EP 495 PG 7 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 255HX UT WOS:000083664400015 PM 10563368 ER PT J AU Marcin, JP Pollack, MM Patel, KM Sprague, BM Ruttimann, UE AF Marcin, JP Pollack, MM Patel, KM Sprague, BM Ruttimann, UE TI Prognostication and certainty in the pediatric intensive care unit SO PEDIATRICS LA English DT Article DE mortality; prediction; certainty; severity of illness; pediatric intensive care; intensive care units ID MORTALITY RISK; PREDICTION; JUDGMENTS; FAILURE; SYSTEM; SCORE AB Objective. Prognostication is central to developing treatment plans and relaying information to patients, family members, and other health care providers. The degree of confidence or certainty that a health care provider has in his or her mortality risk assessment is also important, because a provider may deliver care differently depending on their assuredness in the assessment. We assessed the performance of nurse and physician mortality risk estimates with and without weighting the estimates with their respective degrees of certainty. Methods. Subjective mortality risk estimates from critical care attendings (n = 5), critical care fellows (n = 9), pediatric residents (n = 34), and nurses (n = 52) were prospectively collected on at least 94% of 642 eligible, consecutive admissions to a tertiary pediatric intensive care unit (PICU). A measure of certainty (continuous scale from 0 to 5) accompanied each mortality estimate. Estimates were evaluated with 2 x 2 outcome probabilities, the kappa statistic, the area under the receiver operating characteristics curve, and the Hosmer and Lemeshow goodness-of-fit chi(2) statistic. The estimates were then reevaluated after weighting predictions by their respective degree of certainty. Results. Overall, there was a significant difference in the predictive accuracy between groups. The mean mortality predictions from the attendings (6.09%) more closely approximated the true mortality rate (36 deaths, 5.61%) whereas fellows (7.87%), residents (10.00%), and nurses (16.29%) overestimated the mean overall PICU mortality. Attendings were more certain of their predictions (4.27) than the fellows (4.01), nurses (3.79), and residents (3.75). All groups discriminated well (area under receiver operating characteristics curve range, 0.86-0.93). Only PICU attendings and fellows did not significantly differ from ideal calibration ( x 2). When mortality predictions were weighted with their respective certainties, their performance improved. Conclusions. The level of medical training correlated with the provider's ability to predict mortality risk. The higher the level of certainty associated with the mortality prediction, the more accurate the prediction; however, high levels of certainty did not guarantee accurate predictions. Measures of certainty should be considered when assessing the performance of mortality risk estimates or other subjective outcome predictions. C1 Univ Calif Davis, Dept Pediat, Sect Crit Care Med, Sacramento, CA USA. Childrens Natl Med Ctr, Dept Crit Care Med, Washington, DC 20010 USA. George Washington Univ, Sch Med, Childrens Res Inst, Ctr Hlth Serv & Clin Res, Washington, DC USA. NIAAA, Washington, DC USA. RP Marcin, JP (reprint author), Univ Calif Davis, Med Ctr, Dept Pediat, Sect Crit Care, TICON II 384,2516 Stockton Blvd, Sacramento, CA 95817 USA. NR 20 TC 21 Z9 21 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 OCT PY 1999 VL 104 IS 4 BP 868 EP 873 DI 10.1542/peds.104.4.868 PG 6 WC Pediatrics SC Pediatrics GA 241WR UT WOS:000082907300002 PM 10506227 ER PT J AU Gerber, MA Tanz, RR Kabat, W Bell, GL Siddiqui, PN Lerer, TJ Lepow, ML Kaplan, EL Shulman, ST AF Gerber, MA Tanz, RR Kabat, W Bell, GL Siddiqui, PN Lerer, TJ Lepow, ML Kaplan, EL Shulman, ST TI Potential mechanisms for failure to eradicate group A streptococci from the pharynx SO PEDIATRICS LA English DT Article DE Streptococcus pyogenes; group A streptococci; pharyngitis; treatment ID GROUP-A STREPTOCOCCI; UPPER RESPIRATORY-TRACT; LACTAMASE-PRODUCING BACTERIA; NORMAL THROAT FLORA; PENICILLIN-V; CARRIER STATE; THERAPY; INTERFERENCE; PHARYNGOTONSILLITIS; CEPHALOSPORINS AB Objective. To investigate the relative efficacy of orally administered cefadroxil and penicillin V in the treatment of group A streptococcal (GABHS) pharyngitis and the mechanism(s) responsible for failure of antimicrobial therapy to eradicate GABHS from the pharynx. Study Design. A prospective, randomized clinical trial was conducted in four pediatric offices in which 462 patients with acute pharyngitis and positive culture for GABHS were randomly assigned to receive cefadroxil (n = 232) or penicillin V (n = 230). Results. Bacteriologic treatment success rates for patients in cefadroxil and penicillin groups were 94% and 86%, respectively. However, among patients classified clinically as likely to have bona fide GABHS pharyngitis, there was no difference in bacteriologic treatment success rates in cefadroxil and penicillin groups (95% and 94%, respectively). Among patients classified clinically as likely to be streptococcal carriers, bacteriologic treatment success rates in cefadroxil and penicillin groups were 92% and 73%, respectively. The presence of beta-lactamase and/or bacteriocin-producing pharyngeal flora had no consistent effect on bacteriologic eradication rates among patients in either penicillin or cefadroxil treatment groups or among patients classified as having either GABHS pharyngitis or streptococcal carriage. Conclusions. Neither beta-lactamase nor bacteriocin produced by normal pharyngeal flora are related to bacteriologic treatment failures in GABHS pharyngitis. Cefadroxil seems to be more effective than penicillin V in eradicating GABHS from patients classified as more likely to be streptococcal carriers. However, among patients we classified as more likely to have bona fide GABHS pharyngitis, the effectiveness of cefadroxil and penicillin V seems to be comparable. C1 Univ Connecticut, Connecticut Childrens Med Ctr, Sch Med, Dept Pediat, Hartford, CT USA. Northwestern Univ, Childrens Mem Hosp, Sch Med, Dept Pediat, Chicago, IL 60611 USA. Univ Connecticut, Sch Med, Dept Pediat, Farmington, CT 06032 USA. Albany Med Coll, Dept Pediat, Albany, NY 12208 USA. Univ Minnesota, Sch Med, Dept Pediat, Minneapolis, MN 55455 USA. Childrens Mem Hosp, Chicago, IL 60614 USA. RP Gerber, MA (reprint author), NIAID, DMID, CRAB, Rm 3104,6700 B Rockledge Dr, Bethesda, MD 20892 USA. NR 39 TC 46 Z9 48 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD OCT PY 1999 VL 104 IS 4 BP 911 EP 917 DI 10.1542/peds.104.4.911 PG 7 WC Pediatrics SC Pediatrics GA 241WR UT WOS:000082907300009 PM 10506234 ER PT J AU Heyman, RB Anglin, TM Copperman, SM Joffe, A McDonald, CA Rogers, PD Shah, RZ Armentano, M Boyd, GM Czechowicz, D AF Heyman, RB Anglin, TM Copperman, SM Joffe, A McDonald, CA Rogers, PD Shah, RZ Armentano, M Boyd, GM Czechowicz, D CA Comm Substance Abuse TI Marijuana: A continuing concern for pediatricians SO PEDIATRICS LA English DT Article ID CANNABINOID RECEPTOR; IMMUNE FUNCTION; MARIHUANA; DELTA-9-TETRAHYDROCANNABINOL; BRAIN; MECHANISMS; ACTIVATION; SMOKING; ALCOHOL; DRIVERS AB Marijuana, the common name for products derived from the plant Cannabis sativa, is the most common illicit drug used by children and adolescents in the United States.(1) Despite growing concerns by the medical profession about the physical and psychological effects of its active ingredient, Delta-9-tetrahydrocannabinol, survey data continue to show that increasing numbers of young people are using the drug as they become less concerned about its dangers.(1). C1 Comm Subst Abuse, Elk Grove Village, IL 60007 USA. Amer Acad Child & Adolescent Psychiat, Washington, DC USA. NIAAA, Rockville, MD USA. NIDA, Lexington, KY USA. RP Heyman, RB (reprint author), Comm Subst Abuse, Elk Grove Village, IL 60007 USA. NR 58 TC 25 Z9 26 U1 2 U2 6 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 OCT PY 1999 VL 104 IS 4 BP 982 EP 985 PG 4 WC Pediatrics SC Pediatrics GA 241WR UT WOS:000082907300037 PM 10506247 ER PT J AU Bull, M Agran, P Laraque, D Pollack, SH Smith, GA Spivak, HR Tenenbein, M Tully, SB Brenner, RA Bryn, S Neverman, C Schieber, RA Stanwick, R Tinsworth, D Tully, WP Garcia, V Katcher, ML AF Bull, M Agran, P Laraque, D Pollack, SH Smith, GA Spivak, HR Tenenbein, M Tully, SB Brenner, RA Bryn, S Neverman, C Schieber, RA Stanwick, R Tinsworth, D Tully, WP Garcia, V Katcher, ML CA Comm Injury Poison Prevention TI Safe transportation of newborns at hospital discharge SO PEDIATRICS LA English DT Article AB All hospitals should set policies that require the discharge of every newborn in a car safety seat that is appropriate for the infant's maturity and medical condition. Discharge policies for newborns should include a parent education component, regular review of educational materials, and periodic in-service education for responsible staff. Appropriate child restraint systems should become a benefit of coverage by Medicaid, managed care organizations, and other third-party insurers. C1 Comm Injury & Poison Prevent, Sect Surg, Elk Grove Village, IL USA. NICHHD, Bethesda, MD USA. Maternal & Child Hlth Bur, Rockville, MD USA. Natl Highway Traff Safety Adm US, Washington, DC 20590 USA. Ctr Dis Control & Prevent, Bethesda, MD USA. Canadian Paediat Soc, Ottawa, ON, Canada. US Consumer Prod Safety Commiss, Washington, DC USA. RP Bull, M (reprint author), Comm Injury & Poison Prevent, Sect Surg, Elk Grove Village, IL USA. NR 11 TC 39 Z9 41 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD OCT PY 1999 VL 104 IS 4 BP 986 EP 987 PG 2 WC Pediatrics SC Pediatrics GA 241WR UT WOS:000082907300038 PM 10506248 ER PT J AU Bull, M Agran, P Laraque, D Pollack, SH Smith, GA Spivak, HR Tenenbein, M Tully, SB Brenner, RA Bryn, S Neverman, C Schieber, RA Stanwick, R Tinsworth, D Tully, WP Garcia, V Katcher, ML AF Bull, M Agran, P Laraque, D Pollack, SH Smith, GA Spivak, HR Tenenbein, M Tully, SB Brenner, RA Bryn, S Neverman, C Schieber, RA Stanwick, R Tinsworth, D Tully, WP Garcia, V Katcher, ML CA Comm Injury Poison Prevention TI Transporting children with special health care needs SO PEDIATRICS LA English DT Article ID SEAT AB Children with special health care needs should have access to proper resources for safe transportation. This statement reviews important considerations for transporting children with special health care needs and provides current guidelines for the protection of children with specific health care needs, including those with a tracheostomy, a spica cast, challenging behaviors, or muscle tone abnormalities as well as those transported in wheelchairs. C1 Comm Injury & Poison Prevent, Sect Surg, Elk Grove Village, IL 60007 USA. NICHHD, Bethesda, MD USA. Maternal & Child Hlth Bur, Rockville, MD USA. Natl Highway Traff Safety Adm US, Washington, DC 20590 USA. Ctr Dis Control & Prevent, Bethesda, MD USA. Canadian Pediat Soc, Ottawa, ON, Canada. US Consumer Prod Safety Commiss, Washington, DC USA. RP Bull, M (reprint author), Comm Injury & Poison Prevent, Sect Surg, Elk Grove Village, IL 60007 USA. NR 14 TC 26 Z9 28 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 OCT PY 1999 VL 104 IS 4 BP 988 EP 992 PG 5 WC Pediatrics SC Pediatrics GA 241WR UT WOS:000082907300039 PM 10506249 ER PT J AU Antoun, MD Martinez, E Caballero, R Oquendo, I Proctor, GR Weislow, OS McCloud, TG Kiser, R Staley, P Clanton, D AF Antoun, MD Martinez, E Caballero, R Oquendo, I Proctor, GR Weislow, OS McCloud, TG Kiser, R Staley, P Clanton, D TI Evaluation of the flora of Puerto Rico for in vitro cytotoxic and anti-HIV activities SO PHARMACEUTICAL BIOLOGY LA English DT Article DE anti-HIV activity; cytotoxicity; medicinal plants; Puerto Rico ID DYNAMICS IN-VIVO; REVERSE-TRANSCRIPTASE; AIDS AGENTS; PRINCIPLES AB A total of 38 plant species belonging to 29 families were screened against HIV at the National Cancer Institute, Frederick Cancer Research and Development Center: In this assay, the virus is replicated in CEM SS cells, which are malignant cells of lymphocytic origin. It is therefore possible to measure the cytotoxicity of the extracts simultaneously, which is indicative of possible anticancer activity. Anti-MN activity was found in eight extracts, whereas 13 extracts demonstrated cytotoxicity at an IC50 of 25 mu g/ml or less. C1 Univ Puerto Rico, Sch Pharm, Dept Pharmaceut Sci, San Juan, PR 00936 USA. Govt Puerto Rico, Dept Nat Resources, San Juan, PR 00906 USA. SRA Technol Inc, Rockville, MD USA. NCI, SAIC, CRDC17, Ft Detrick, MD 21702 USA. RP Antoun, MD (reprint author), Univ Puerto Rico, Sch Pharm, Dept Pharmaceut Sci, Med Sci Campus, San Juan, PR 00936 USA. NR 23 TC 2 Z9 2 U1 0 U2 5 PU SWETS ZEITLINGER PUBLISHERS PI LISSE PA P O BOX 825, 2160 SZ LISSE, NETHERLANDS SN 1388-0209 J9 PHARM BIOL JI Pharm. Biol. PD OCT PY 1999 VL 37 IS 4 BP 277 EP 280 DI 10.1076/phbi.37.4.277.5805 PG 4 WC Plant Sciences; Medical Laboratory Technology; Pharmacology & Pharmacy SC Plant Sciences; Medical Laboratory Technology; Pharmacology & Pharmacy GA 263YA UT WOS:000084151800005 ER PT J AU Shafer, WS AF Shafer, WS TI Tips for getting your research grant application funded on the first try! SO PHARMACEUTICAL RESEARCH LA English DT Article C1 Natl Inst Gen Med Sci, NIH, Bethesda, MD USA. RP Shafer, WS (reprint author), Natl Inst Gen Med Sci, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 J9 PHARMACEUT RES JI Pharm. Res. PD OCT PY 1999 VL 16 IS 10 BP 1495 EP 1497 PG 3 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 249TY UT WOS:000083350400001 ER PT J AU Fricker, G Gutmann, H Droulle, A Drewe, J Miller, DS AF Fricker, G Gutmann, H Droulle, A Drewe, J Miller, DS TI Epithelial transport of anthelmintic ivermectin in a novel model of isolated proximal kidney tubules SO PHARMACEUTICAL RESEARCH LA English DT Article DE ivermectin; p-glycoprotein; kidney; renal secretion; killifish ID MDR1A P-GLYCOPROTEIN; MULTIDRUG-RESISTANCE; ORGANIC ANION; CYCLOSPORINE-A; DEFICIENCY; SECRETION; DRUGS AB Purpose. The mechanism of excretion of the anthelmintic drug ivermectin was investigated in a novel experimental model of functionally intact proximal tubules isolated from a teleost fish (Fundulus heteroclitus). Methods. Secretion into the lumens of freshly isolated proximal tubules wits studied by means of confocal laser scanning microscopy and digital image analysis using ivermectin and fluorescent labelled ivermectin (BODIPY-ivermectin; BI) as substrates. Results. The tubular cells rapidly accumulated BI from the medium and attained steady state within 25 minutes. Luminal fluorescence in the steady state was 5-7 times higher as compared to intracellular fluorescence. The secretion of BI into the tubular lumens was inhibited in a dose dependent manner by unlabelled ivermectin and inhibitors of the renal excretory membrane pump p-glycoprotein, namely SDZ PSC-833 and verapamil, but not by leukotriene C-4, a substrate of the renal export protein mrp2. Accumulation inside the tubular cells was not affected by the added inhibitors. Ivermectin inhibited the renal secretion of the fluorescent cyclosporin derivative NBDL-CS, a substrate of p-glycoprotein, but not the secretion of the mrp2-substrate fluorescein-methotrexate, nor the secretion of fluorescein, a substrate of the classical renal organic anion transporter. Conclusions. The data are consistent with BI and ivermectin interacting in teleost kidney tubules exclusively with p-glycoprotein, but not with one of the ether known excretory transport systems. In addition, the studies demonstrate that freshly isolated functionally intact kidney tubules from killifish are a useful tool to differentiate the substrate specificity of renal transport systems with respect to drug elimination. C1 Mt Desert Isl Biol Lab, Salsbury Cove, ME 04672 USA. Univ Heidelberg, Inst Pharmaceut Technol & Biopharm, D-69120 Heidelberg, Germany. Lycee Roosevelt, F-51100 Reims, France. Univ Clin, Kantonsspital, Dept Internal Med, Div Clin Pharmacol, Basel, Switzerland. Univ Clin, Kantonsspital, Dept Res, Div Clin Pharmacol, Basel, Switzerland. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RP Fricker, G (reprint author), Mt Desert Isl Biol Lab, Salsbury Cove, ME 04672 USA. FU NIEHS NIH HHS [ES 03828] NR 27 TC 20 Z9 20 U1 1 U2 2 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 J9 PHARMACEUT RES JI Pharm. Res. PD OCT PY 1999 VL 16 IS 10 BP 1570 EP 1575 DI 10.1023/A:1018956621376 PG 6 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 249TY UT WOS:000083350400012 PM 10554099 ER PT J AU Chida, M Yokoi, T Kosaka, Y Chiba, K Nakamura, H Ishizaki, T Yokota, J Kinoshita, M Sato, K Inaba, M Aoki, Y Gonzalez, FJ Kamataki, T AF Chida, M Yokoi, T Kosaka, Y Chiba, K Nakamura, H Ishizaki, T Yokota, J Kinoshita, M Sato, K Inaba, M Aoki, Y Gonzalez, FJ Kamataki, T TI Genetic polymorphism of CYP2D6 in the Japanese population SO PHARMACOGENETICS LA English DT Article DE CYP2D6*3; CYP2D6*4; CYP2D6*5; CYP2D6*18; population study; cancer risk; Parkinson's disease ID POOR METABOLIZER PHENOTYPE; OXIDATIVE DRUG-METABOLISM; CYTOCHROME-P450 CYP2D6; PARKINSONS-DISEASE; SPARTEINE METABOLISM; CHINESE SUBJECTS; LOWER PREVALENCE; DEBRISOQUINE; HYDROXYLATION; ALLELE AB The frequencies of CYP2D6 mutations in a Japanese population were investigated. Individuals were classified into three groups: control individuals, cancer patients and Parkinsonians, Genotyping for CYP2D6*3, CYP2D6*4 and CYP2D6*18 was carried out using the polymerase chain reaction, and that for CYP2D6*5 was also carried out using XbaI restriction fragment length polymorphism. The frequencies of the CYP2D6*3, CYP2D6*4, CYP2D6*5 and CYP2D6*18 mutant alleles were 0%, 0.77%, 4.10% and 0.53% in more than 256 Japanese control individuals, respectively. Based on these data, the population frequency of the CYP2D6 poor metabolizer phenotype was estimated to be 0.29%. The distribution of the four mutated alleles was not significantly different between control individuals and cancer patients or Parkinsonians. Pharmacogenetics 9:601-605 (C) 1999 Lippincott Williams & Wilkins. C1 Hokkaido Univ, Grad Sch Pharmaceut Sci, Lab Drug Metab, Div Pharmacobiodynam,Kita Ku, Sapporo, Hokkaido 0600812, Japan. Chiba Univ, Dept Pharmaceut Sci, Chiba, Japan. Int Med Ctr Japan, Res Inst, Dept Clin Pharmacol, Tokyo, Japan. Kumamoto Univ, Dept Pharmaceut Sci, Kumamoto, Japan. Natl Canc Ctr, Res Inst, Tokyo 104, Japan. Otsuka Pharmaceut Co Ltd, Tokushima 77101, Japan. Gunma Univ, Sch Med, Dept Internal Med, Maebashi, Gumma 371, Japan. Japanese Fdn Canc Res, Ctr Canc Chemotherapy, Tokyo 170, Japan. Iwate Med Univ Sch, Dept Forens Med, Morioka, Iwate, Japan. NCI, Mol Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Kamataki, T (reprint author), Hokkaido Univ, Grad Sch Pharmaceut Sci, Lab Drug Metab, Div Pharmacobiodynam,Kita Ku, N12W6, Sapporo, Hokkaido 0600812, Japan. RI yokoi, tsuyoshi/I-7115-2014 NR 40 TC 23 Z9 25 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0960-314X J9 PHARMACOGENETICS JI Pharmacogenetics PD OCT PY 1999 VL 9 IS 5 BP 601 EP 605 PG 5 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 258QT UT WOS:000083850400007 PM 10591540 ER PT J AU Tarasov, SG Casas-Finet, JR Cholody, WM Michejda, CJ AF Tarasov, SG Casas-Finet, JR Cholody, WM Michejda, CJ TI Bisimidazoacridones: Effect of molecular environment on conformation and photophysical properties SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID PHASE AB Bisimidazoacridones (BIA) are highly selective antineoplastic and antiviral agents. Ultraviolet-visible spectroscopy and steady-state and time-resolved fluorescence spectroscopy studies were carried out to probe the behavior of BLA in aqueoms and nonaqueous (organic solvents, colloid micelles) solutions. Three ranges of fluorescence lifetimes were revealed: similar to 0.2-0.5 ns (presumably reflecting the chromophore-chromophore interaction), similar to 1-5 ns (interpreted as linker-perturbed chromophore decay) and similar to 6-12 ns (nonperturbed chromophore decay). The pre-exponential and steady-state contributions of these components to the decay signal as well as the data on steady-state fluorescence intensities, wavelength maxima and bandwidths showed that the BIA conformations in solution were sensitive to the environment and influenced strongly by their propensity to minimize hydrophobic interactions. In water, the molecules tend to adopt condensed conformations that bring the two imidazoacridone moieties into close proximity (resulting in intramolecular fluorescence energy transfer), while in nonaqueous systems the conformations become more relaxed, The transfer from a polar to more lipophilic environment of macromolecules is suggested to he the main driving force for binding of BW to biomacromolecules, such as nucleic acids. C1 NCI, Frederick Canc Res & Dev Ctr, BRP, ABL, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, AIDS Vaccine Program, SAIC Frederick, Frederick, MD 21702 USA. RP Tarasov, SG (reprint author), NCI, Frederick Canc Res & Dev Ctr, BRP, ABL, POB B, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 22 TC 6 Z9 6 U1 0 U2 0 PU AMER SOC PHOTOBIOLOGY PI AUGUSTA PA BIOTECH PARK, 1021 15TH ST, SUITE 9, AUGUSTA, GA 30901-3158 USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD OCT PY 1999 VL 70 IS 4 BP 568 EP 578 DI 10.1111/j.1751-1097.1999.tb08253.x PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 249VQ UT WOS:000083354300016 PM 10546554 ER PT J AU Chen, YD Yan, B Miura, R AF Chen, YD Yan, B Miura, R TI Asymmetry and direction reversal in fluctuation-induced biased Brownian motion SO PHYSICAL REVIEW E LA English DT Article ID MOLECULAR MOTORS; DRIVEN RATCHETS; PARTICLES AB The biased movement of a Brownian particle in a periodic potential fluctuating between a flat and a kinked ratchet state, as first studied by Chauwin, Ajdari, and Frost, [3], is examined.;The purpose is to study the physical origin of the frequency-dependent direction reversal: of the biased Brownian motion in this system. We show that the existence of the directional reversal depends not only on the lengths of the projections of the two ratchet arms on the potential axis (the arm-projection asymmetry), but also the overall spatial geometry of the potential in a period. In particular, we show that the direction reversal can be obtained in this kinked ratchet model even when the two arm projections are equal. Since this two-state model is the simplest to generate direction reversal and particles can be separated more efficiently in a fluctuating potential if direction reversal exists, the results obtained in this study should be useful for future application in particle separation. [S1063-651X(99)08810-8]. C1 NIDDKD, Math Res Branch, NIH, Bethesda, MD 20892 USA. Univ British Columbia, Dept Math, Vancouver, BC V6T 1Z2, Canada. RP Chen, YD (reprint author), NIDDKD, Math Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 10 TC 10 Z9 10 U1 0 U2 1 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 OCT PY 1999 VL 60 IS 4 BP 3771 EP 3775 DI 10.1103/PhysRevE.60.3771 PN A PG 5 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 250XD UT WOS:000083414800040 PM 11970210 ER PT J AU Yaffe, SJ Canosa, C AF Yaffe, SJ Canosa, C TI Global strategies to prevent perinatal HIV transmission - Introduction SO PRENATAL AND NEONATAL MEDICINE LA English DT Editorial Material C1 NICHHD, Ctr Res Mothers & Children, Bethesda, MD 20892 USA. Hosp Casa Salud, Dept Pediat, Valencia, Spain. RP Yaffe, SJ (reprint author), NICHHD, Ctr Res Mothers & Children, Execut Bldg,Room 4B05,6100 Execut Blvd MSC 7510, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PARTHENON PUBLISHING GROUP PI CARNFORTH LANCASHIRE PA CASTERTON HALL, CARNFORTH LANCASHIRE LA6 2LA, ENGLAND SN 1359-8635 J9 PRENAT NEONAT MED JI Prenat. Neonatal Med. PD OCT PY 1999 VL 4 IS 5 BP 331 EP 332 PG 2 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 263LG UT WOS:000084125700001 ER PT J AU Read, JS AF Read, JS TI Preventing mother-to-child transmission of HIV: the USA experience SO PRENATAL AND NEONATAL MEDICINE LA English DT Article DE vertical transmission; prevention; United States of America; HIV ID HUMAN-IMMUNODEFICIENCY-VIRUS; UNITED-STATES; PERINATAL TRANSMISSION; INFECTION; WOMEN; PREVALENCE; ANTIBODY; TRENDS; AIDS; RISK AB Since the beginning of the worldwide epidemic of HIV infection, thousands of children have acquired HIV infection from their mothers. Significant progress has been made in preventing vertical transmission of HIV in the USA. Continued progress will depend upon successful implementation of existing national guidelines regarding prevention of mother-to-child transmission of HIV, as well as upon temporal trends in other factors including HIV counselling and testing, reproductive choices of HIV-infected women, and the medical management of HIV-infected pregnant women. As new potential interventions to decrease mother-to-child transmission of HIV are developed, the relative impact of such interventions on Vertical transmission of HIV in the USA will depend not only upon the intervention's efficacy, but also upon the acceptability of and women's access to the intervention. C1 NICHD, Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD 20892 USA. RP Read, JS (reprint author), NICHD, Adolescent & Maternal AIDS Branch, NIH, Execut Bldg,Room 4B11F,6100 Execut Blvd,MSC 7510, Bethesda, MD 20892 USA. NR 35 TC 4 Z9 4 U1 0 U2 2 PU PARTHENON PUBLISHING GROUP PI CARNFORTH LANCASHIRE PA CASTERTON HALL, CARNFORTH LANCASHIRE LA6 2LA, ENGLAND SN 1359-8635 J9 PRENAT NEONAT MED JI Prenat. Neonatal Med. PD OCT PY 1999 VL 4 IS 5 BP 391 EP 397 PG 7 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 263LG UT WOS:000084125700013 ER PT J AU Sackett, DL Ruvinov, SB Thompson, J AF Sackett, DL Ruvinov, SB Thompson, J TI N-5-(L-1-carboxyethyl)-L-ornithine synthase: Physical and spectral characterization of the enzyme and its unusual low pK(a) fluorescent tyrosine residues SO PROTEIN SCIENCE LA English DT Article DE N-5-(L-1-carboxyethyl) ornithine synthase; proteolysis; tryptophan fluorescence; tyrosine; tyrosine pK(a) ID GLUTATHIONE-S-TRANSFERASE; O-SPECIFIC POLYSACCHARIDE; STREPTOCOCCUS-LACTIS; LACTOCOCCUS-LACTIS; ACTIVE-SITE; PURIFICATION; PROTEIN; N5-(L-1-CARBOXYETHYL)-L-ORNITHINE; N-5-(1-CARBOXYETHYL)ORNITHINE; DEHYDROGENASE AB N-5-(L-1-carboxyethyl)-L-ornithine synthase [E.C. 1.5.1.24] (CEOS) from Lactococcus lactis has been cloned, ex pressed, and purified from Escherichia coli in quantities sufficient for characterization by biophysical methods. The NADPH-dependent enzyme is a homotetramer (M-r congruent to 140,000) and in the native state is stabilized by noncovalent interactions between the monomers, The far-ultraviolet circular dichroism spectrum shows that the folding pattern of the enzyme is typical of the alpha,beta family of proteins. CEOS contains one tryptophan (Trp) and 19 tyrosines (Tyr) per monomer, and the fluorescence spectrum of the protein shows emission from both Trp and Sr residues. Relative to N-acetyltyrosinamide, the Tyr quantum yield of the native enzyme is about 0.5. All 19 Tyr residues are titratable and, of these, two exhibit the uncommonly low pK(a) of similar to 8.5, 11 have pK(a) similar to 10.75, and the remaining six titrate with pK(a) 11.3. The two residues with pK(a) similar to 8.5 contribute approximately 40% of the total tyrosine emission, implying a relative quantum yield >1, probably indicating Tyr-Tyr energy transfer. In the presence of NADPH, Sr fluorescence is reduced by 40%, and Trp fluorescence is quenched completely. The latter result suggests that the single Trp residue is either at the active site, or in proximity to the sequence GSGNVA, that constitutes the beta alpha beta fold of the nucleotide-binding domain. Chymotrypsin specifically cleaves native CEOS after Phe255. Although inactivated by this single-site cleavage of the subunit, the enzyme retains the capacity to bind NADPH and tetramer stability is maintained. Possible roles in catalysis for the chymotrypsin sensitive loop and for the low pK(a) Tyr residues are discussed. C1 NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. NHLBI, Biochem Lab, Sect Prot Chem, NIH, Bethesda, MD 20892 USA. NIDCR, Microbial Biochem & Genet Unit, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Sackett, DL (reprint author), NICHD, Lab Integrat & Med Biophys, NIH, Bldg 37,Room 2B-17, Bethesda, MD 20892 USA. EM sackettd@mail.nih.gov NR 38 TC 4 Z9 6 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD OCT PY 1999 VL 8 IS 10 BP 2121 EP 2129 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 246XD UT WOS:000083189400025 PM 10548058 ER PT J AU Ma, BY Nussinov, R AF Ma, BY Nussinov, R TI Explicit and implicit water simulations of a beta-hairpin peptide SO PROTEINS-STRUCTURE FUNCTION AND GENETICS LA English DT Article DE beta-hairpin peptide; conformational energy; peptide conformation; continuum solvation model; explicit water model; free-energy simulation; hydrophobic interaction; vibrational entropy ID SOLVATION FREE-ENERGIES; FORMING LINEAR PEPTIDE; DYNAMIC PROPERTIES; FORCE-FIELDS; MODEL; THERMODYNAMICS; CONFORMATIONS; METHODOLOGY; RELAXATION; MOLECULES AB The conformational properties of a beta-hairpin peptide (YITNSDGTWT) were studied by using both explicit and implicit water simulations, The conformational space of the peptide was scanned by using a restricted hydrogen-bonding search method. The search method used generated the conformational space with enough diversity and good representation of beta-hairpin structures. By using a total surface area-based treatment of hydrophobic interactions, implicit water simulations failed to discriminate between experimental beta-hairpin structures from the rest of the conformers present in the authors' conformation library. However, with inclusion of vibrational free energy and accounting separately for polar and nonpolar surface areas, the nuclear magnetic resonance structure was ranked successfully as the most stable conformation. There is a loose correlation between the conformational energies by the continuum model and the conformational energies by explicit water simulation for conformers with similar structures. However, in terms of solvation energy, both approaches have a much better correlation. By using proper treatment of surface effect (partition of the surface area into polar and nonpolar areas) and including vibrational free-energy contribution, the continuum models should be reliable. Furthermore, the authors found that, for this peptide, beta-hairpin structures have large vibrational entropy that contributes decisively to the stability of folded beta-hairpin structures. (C) 1999 Wiley-Liss, Inc. C1 NCI, FCRF, FCRDC, Lab Expt & Computat Biol, Frederick, MD 21702 USA. SAIC, Intramural Res Support Program, Lab Expt & Computat Biol, Frederick, MD USA. Tel Aviv Univ, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, FCRF, FCRDC, Lab Expt & Computat Biol, Bldg 469,Room 151, Frederick, MD 21702 USA. RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU NCI NIH HHS [N01-CO-56000] NR 33 TC 17 Z9 17 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 0887-3585 J9 PROTEINS JI Proteins PD OCT 1 PY 1999 VL 37 IS 1 BP 73 EP 87 DI 10.1002/(SICI)1097-0134(19991001)37:1<73::AID-PROT8>3.0.CO;2-Z PG 15 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 227WQ UT WOS:000082103300008 PM 10451552 ER PT J AU Geter-Douglass, B Witkin, JM AF Geter-Douglass, B Witkin, JM TI Behavioral effects and anticonvulsant efficacies of low-affinity, uncompetitive NMDA antagonists in mice SO PSYCHOPHARMACOLOGY LA English DT Article DE NMDA antagonist; discriminative stimulus effect; locomotor activity; convulsion; mice ID STRUCTURAL ANALOGS DIZOCILPINE; RECEPTOR-CHANNEL COMPLEX; ANTI-ADDICTIVE DRUG; DISCRIMINATIVE STIMULUS; PHENCYCLIDINE-LIKE; PARKINSONS-DISEASE; IN-VIVO; RAT-BRAIN; IBOGAINE; MEMANTINE AB Rationale: It has been hypothesized that low-affinity, uncompetitive N-methyl-D-aspartate (NMDA) antagonists may have therapeutic efficacy (e.g., in epilepsy, stroke, drug dependence) without the adverse side effects associated with high-affinity ligands (e.g., dizocilpine, phencyclidine). Objectives: To determine whether low-affinity NMDA antagonists have a larger predicted therapeutic window than high-affinity ligands. Methods: In Swiss-Webster mice, we compared the effects of uncompetitive antagonists having a range of affinities for the NMDA receptor ion channel [dizocilpine, memantine, ibogaine, amantadine and 5-aminocarbonyl-10,11-dihydro-5h-dibenzo[a,d] cyclohepten-5,10-imine (ADCI)] in three behavioral assays typically used to assess NMDA receptor antagonism. Behavioral side effects were compared with the efficacy of the compounds to protect against NMDA-induced seizures. Results: Only dizocilpine and memantine substituted fully in mice trained to discriminate dizocilpine from saline. Dizocilpine (K-i similar to 0.003 mu M) protected against NMDA-induced convulsions at doses that produced ataxia and stimulation of locomotor activity. Conversely, memantine (K-i similar to 0.54 mu M) prevented convulsions at doses that were 8- to 18-fold lower than those producing ataxia or effects on locomotion, respectively. Indeed, in contrast to dizocilpine, memantine did not stimulate locomotor activity but only produced dose-dependent reductions. The low-affinity antagonists ibogaine (K-i similar to 1 mu M) and ADCI (K-i similar to 11 mu M) protected against convulsions at doses that produced significant dizocilpine-like discriminative stimulus effects, ataxia and decreases in locomotor activity. Amantadine (K-i similar to 11 mu M) was ineffective against NMDA-induced convulsions up to doses that produced significant behavioral side effects. Conclusions: These findings indicate that only certain low-affinity, uncompetitive NMDA antagonists (e.g., memantine) may have therapeutic efficacy at doses that do not produce an adverse side-effect profile. For other therapeutic endpoints, different estimates of efficacy and safety require derivation. C1 Natl Inst Drug Abuse, Addict Res Ctr, Drug Dev Grp, Baltimore, MD 21224 USA. RP Witkin, JM (reprint author), Natl Inst Drug Abuse, Addict Res Ctr, Drug Dev Grp, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 64 TC 32 Z9 32 U1 0 U2 2 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 1999 VL 146 IS 3 BP 280 EP 289 DI 10.1007/s002130051118 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 245GR UT WOS:000083098400007 PM 10541728 ER PT J AU Westergaard, GC Suomi, SJ Higley, JD Mehlman, PT AF Westergaard, GC Suomi, SJ Higley, JD Mehlman, PT TI CSF5-HIAA and aggression in female macaque monkeys: species and interindividual differences SO PSYCHOPHARMACOLOGY LA English DT Article DE aggression; female; impulsivity; primates; serotonin; social dominance ID 5-HYDROXYINDOLEACETIC ACID CONCENTRATIONS; CEREBROSPINAL-FLUID MONOAMINE; NONHUMAN PRIMATE MODEL; DIMINISHED SOCIAL COMPETENCE; MALE VERVET MONKEYS; AMINE METABOLITES; VIOLENT OFFENDERS; FIRE SETTERS; CSF 5-HIAA; SEROTONERGIC ACTIVITY AB Rationale: While the relationship among CSF 5-HIAA, impulsivity, and aggression is well characterized in males, its investigation in females is limited, and no studies have assessed its generalizability across primates by making simultaneous comparisons between and within closely-related species. Objectives: We tested three hypotheses. First, that female rhesus macaques would have lower CSF 5-HIAA concentrations and be more aggressive than would female pigtailed macaques. Second, that females of both macaque species would exhibit an inverse relationship between interindividual differences in CSF 5-HIAA concentrations and rates of severe aggression. Third, that subjects with high CSF 5-HIAA concentrations would be higher in social dominance within their respective groups than would subjects with low CSF 5-HIAA concentrations. Methods: We obtained CSF samples from 61 individually housed female primates of two closely related species: rhesus macaques (Macaca mulatta) and pigtailed macaques (Macaca nemestrina). We later placed subjects in unisex social groups, and correlated interindividual differences in CSF 5-HIAA with aggression, wounding, and acquisition of social dominance rank, Results: Between-species analyses indicated higher CSF 5-HIAA concentrations in pig-tailed macaques, and higher rates of high-intensity aggression, escalated aggression, and wounds requiring medical treatment in rhesus macaques. Within-species analyses indicated that interindividual differences in CSF 5-HIAA concentrations were inversely correlated with escalated aggression and positively correlated with social dominance rank. Conclusions: These findings show that agonistic and social differences between closely-related species are correlated with CNS serotonin activity, as species that show relatively high rates of severe aggression also tend to have low concentrations of CSF 5-HIAA. We conclude that serotonergic functioning plays an important role in controlling impulses that regulate severe aggression and social dominance relationships in both male and female primates, and that between-species differences in agonistic temperament can be predicted by species typical CNS serotonin functioning. C1 LABS Virginia Inc, Div Res, Yemassee, SC 29945 USA. NICHHD, Lab Comparat Ethol, Anim Ctr, NIH, Poolesville, MD 20837 USA. NIAAA, Clin Studies Lab, Anim Ctr, NIH, Poolesville, MD 20837 USA. RP Westergaard, GC (reprint author), LABS Virginia Inc, Div Res, 95 Castle Hall Rd,POB 557, Yemassee, SC 29945 USA. FU NCRR NIH HHS [5U42RR05083, R24 RR09983] NR 52 TC 73 Z9 73 U1 0 U2 7 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 1999 VL 146 IS 4 BP 440 EP 446 DI 10.1007/PL00005489 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 253BW UT WOS:000083537600010 PM 10550494 ER PT J AU Cologne, JE Tokuoka, S Beebe, GW Fukuhara, T Mabuchi, K AF Cologne, JE Tokuoka, S Beebe, GW Fukuhara, T Mabuchi, K TI Effects of radiation on incidence of primary liver cancer among atomic bomb survivors SO RADIATION RESEARCH LA English DT Article ID B SURFACE-ANTIGEN; HEPATOCELLULAR-CARCINOMA; MORTALITY; THOROTRAST; HIROSHIMA; RISKS AB We describe the radiation risk for primary liver cancers between 1958 and 1987 in a cohort of atomic bomb survivors in Hiroshima and Nagasaki, Japan. The analysis Is based on a comprehensive pathology review of known or suspected liver neoplasms that generated 518 incident, first primary cases, mostly hepatocellular carcinoma, Excess relative risk from atomic bomb radiation was linear: 0.81 per sievert weighted liver dose (95% CI [0.32, 1.43]; P < 0.001). Males and females had similar relative risk so that, given a threefold higher background incidence in males, the radiation-related excess incidence was substantially higher in males. Excess risk peaked for those with age at exposure in the early 20s; there was essentially no excess risk in those exposed before age 10 or after age 45. Whether this was due to a difference in sensitivity or possible confounding by other factors could not be addressed retrospectively in the full cohort. A paucity of cholangiocarcinoma and hemangiosarcoma cases suggested that they are not significantly associated with whole-body radiation exposure, as they are with the internal or-particle-emitting radiological contrast medium Thorotrast, Because most of the radiation-related excess eases occurred among males, it is important to ascertain what factors put men at greater risk of radiation-related liver cancer. (C) 1999 by Radiation Research Society. C1 Radiat Effects Res Fdn, Dept Stat, Minami Ku, Hiroshima 7320815, Japan. Radiat Effects Res Fdn, Dept Epidemiol, Minami Ku, Hiroshima 7320815, Japan. NCI, Div Canc Etiol & Genet, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. Hiroshima Prefectural Hosp, Dept Pathol, Hiroshima, Japan. RP Cologne, JE (reprint author), Radiat Effects Res Fdn, Dept Stat, Minami Ku, 5-2 Hijiyama Pk, Hiroshima 7320815, Japan. OI Cologne, John/0000-0003-1540-6639 FU NCPDCID CDC HHS [NCI-4893-8-001] NR 29 TC 29 Z9 30 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 OCT PY 1999 VL 152 IS 4 BP 364 EP 373 DI 10.2307/3580221 PG 10 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 242VZ UT WOS:000082963500003 PM 10477913 ER PT J AU Ames, BN Gold, LS AF Ames, BN Gold, LS TI Science's sifter applied to nine misconceptions SO RECHERCHE LA French DT Article ID CANCER PREVENTION; UNITED-STATES; RISK; VEGETABLES; DAMAGE; TESTS; FRUIT; DNA C1 Natl Inst Environm Hlth Sci Ctr, Res Triangle Pk, NC 27709 USA. Univ Calif Berkeley, Berkeley, CA 94720 USA. RP Ames, BN (reprint author), Natl Inst Environm Hlth Sci Ctr, Res Triangle Pk, NC 27709 USA. NR 32 TC 0 Z9 0 U1 0 U2 1 PU SOC ED SCIENTIFIQUES PI PARIS 06 PA 57 RUE DE SEINE, 75280 PARIS 06, FRANCE SN 0029-5671 J9 RECHERCHE JI Recherche PD OCT PY 1999 IS 324 BP 47 EP 53 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 243JR UT WOS:000082994600015 ER PT J AU Black, JB Pellett, PE AF Black, JB Pellett, PE TI Human herpesvirus 7 SO REVIEWS IN MEDICAL VIROLOGY LA English DT Review ID POLYMERASE-CHAIN-REACTION; HUMAN-IMMUNODEFICIENCY-VIRUS; CD4(+) T-CELLS; EPSTEIN-BARR-VIRUS; HUMAN-HERPESVIRUS-7 HHV-7 DNA; CHRONIC FATIGUE SYNDROME; GLYCOPROTEIN-B; MONOCLONAL-ANTIBODIES; HUMAN CYTOMEGALOVIRUS; BLOOD-DONORS AB Human herpesvirus 7, reported in 1990 is a lymphotropic member of the betaherpesvirus subfamily of herpesviruses. The virus is highly seroprevalent, primary infection usually occurs during childhood, and it has been associated with cases of exanthem subitum, pityriasis rosea, neurological manifestations and transplant complications. The latter two may warrant antiviral intervention, in vitro studies have shown that HHV-7 is susceptible to several nucleoside phosphonate compounds. In vitro, the virus has approximately a 5 day growth cycle in cultured lymphocytes; in vivo, latency is established in peripheral blood T-cells and a persistent infection is established in salivary gland tissue from which infectious virus is constitutively shed in saliva. The HHV-7 genome is approximately 145 kb and encodes at least 84 different proteins. Studies characterising HHV-7 gene products and the required interactions between viral and cellular genes necessary for virus replication, persistence and latency are in their infancy. HHV-7 infection has a variety of effects on host cells including upregulation of interleukin 15 and down-modulation of the cell surface molecule CD4; the latter serves as the cellular membrane receptor for HHV-7. Since HIV also infects T-cells via the CD4 molecule, the interactions of these viruses within T-cells during the course of AIDS are important areas of investigation. C1 Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. RP Black, JB (reprint author), NCI, NIH, HIV & AIDS Malignancy Branch, 10 Ctr Dr,Bldg 10,Room 13N240, Bethesda, MD 20892 USA. NR 113 TC 76 Z9 81 U1 2 U2 4 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 1052-9276 J9 REV MED VIROL JI Rev. Med. Virol. PD OCT-DEC PY 1999 VL 9 IS 4 BP 245 EP 262 DI 10.1002/(SICI)1099-1654(199910/12)9:4<245::AID-RMV253>3.0.CO;2-I PG 18 WC Virology SC Virology GA 260KN UT WOS:000083948900006 PM 10578120 ER PT J AU Breidert, M Miehlke, S Glasow, A Orban, Z Stolte, M Ehninger, G Bayerdorffer, E Nettesheim, O Halm, U Haidan, A Bornstein, SR AF Breidert, M Miehlke, S Glasow, A Orban, Z Stolte, M Ehninger, G Bayerdorffer, E Nettesheim, O Halm, U Haidan, A Bornstein, SR TI Leptin and its receptor in normal human gastric mucosa and in Helicobacter pylori-associated gastritis SO SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY LA English DT Article DE gastritis; Helicobacter pylori; laser capture microdissection; leptin; leptin receptor ID SERUM LEPTIN; CHOLECYSTOKININ; MICE; IDENTIFICATION; EXPRESSION; DISEASE; CLONING; TISSUE; CELL AB Background: Leptin, a newly discovered weight-reducing hormone, is mainly produced in fat cells. Recently, this hormone has been reported to be produced in rat gastric mucose cells. In the present study we analyzed the localization and expression of leptin and its receptors in normal human gastric mucosa and in patients with Helicobacter pylori-associated gastritis. Methods: Plasma leptin levels and gastric mucose leptin content were determined in 39 patients with dyspepsia. Cellular localization of leptin and of the signaling receptor (Ob-R-L) were assessed by immunohistochemistry. Reverse transcriptase polymerase chain reaction (RT-PCR) for leptin receptor isoforms was performed on gastric epithelial cells isolated by laser-capture-microdissection. Results: Leptin content of the corpus gastric mucosa in H. pylori-negative group patients was significantly increased (4.6 +/- 1.2, n = 15) as compared with the H. pylori-negative group (2.5 +/- 0.5 pg/mg, n = 24, P = 0.006). The presence of leptin immunoreactivity was shown in the lower half of corpus epithelial glands. By RT-PCR no leptin mRNA was detectable in human gastric tissue. In contrast, expression of both Ob-R-L and the leptin receptor isoforms could be detected in gastric epithelial cells. Leptin receptor protein was detected throughout the mucosa. Conclusions: Leptin itself is stored and secreted but not produced in human gastric mucosa. The functional receptor and all isoforms are present in human gastric mucosa. H. pylori-associated gastritis leads to significant increases in local leptin concentration in the gastric corpus. C1 Tech Univ Dresden, Hosp Carl Gustav Carus, Dept Med 1, D-01307 Dresden, Germany. Univ Leipzig, Dept Internal Med 2, D-7010 Leipzig, Germany. Univ Leipzig, Dept Internal Med 3, D-7010 Leipzig, Germany. Klinikum Beyreuth, Inst Pathol, Bayreuth, Germany. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Breidert, M (reprint author), Tech Univ Dresden, Hosp Carl Gustav Carus, Dept Med 1, Fetscherstr 74, D-01307 Dresden, Germany. NR 37 TC 54 Z9 55 U1 0 U2 1 PU SCANDINAVIAN UNIVERSITY PRESS PI OSLO PA PO BOX 2959 TOYEN, JOURNAL DIVISION CUSTOMER SERVICE, N-0608 OSLO, NORWAY SN 0036-5521 J9 SCAND J GASTROENTERO JI Scand. J. Gastroenterol. PD OCT PY 1999 VL 34 IS 10 BP 954 EP 961 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 247YX UT WOS:000083249500003 PM 10563663 ER PT J AU Mullbacher, A Lobigs, M Yewdell, JW Bennink, JR Hla, RT Blanden, RV AF Mullbacher, A Lobigs, M Yewdell, JW Bennink, JR Hla, RT Blanden, RV TI High peptide affinity for MHC class I does not correlate with immunodominance SO SCANDINAVIAN JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL RESPONSE; LYMPHOCYTES-T; HISTOCOMPATIBILITY ANTIGENS; VACCINIA VIRUS; WEST NILE; MOLECULES; RECOGNITION; FLAVIVIRUS; TOLERANCE; INFLUENZA AB Cytotoxic T (Tc)-cell responses against influenza virus infection in BALB/c (H-2(d)) mice are dominated by Tc clones reactive to the viral nucleoprotein (NP). Here, we report investigations using recombinant vaccinia viruses (VV) encoding major histocompatibility complex (MHC) class I H-2K(d) molecules differing by a single amino acid from glutamine (wild-type, K-dw) to histidine (mutant, K-dm) at position 114 located in the floor of the peptide-binding groove. Influenza-infected target cells expressing K-dw were strongly lysed by K-d-restricted Tc cells against A/WSN influenza virus or the immunodominant peptide of viral NP (NpP147-155), whereas infected K-dm-expressing targets gave little or no lysis, respectively, thus showing the immunodominance of NPP147-155. K-dm-expressing target cells saturated with synthetic Npp(147-155) (10(-5) M) were lysed similarly to K-dw-expressing targets by NPP147-155-specific Tc cells. Thus the defect in influenza-infected Kdm-expressing targets was quantitative; insufficient K-dm-peptide complexes were expressed. Tc-cell responses against four other viruses or alloantigens showed no effect of K-dm. When peptide transport-defective cells were infected with VV-K-dw or VV-K-dm and co-infected with a recombinant VV encoding an endoplasmic reticulum-targeted viral peptide, two influenza haemaglutinin peptides caused higher expression of K-dw than NPP147-155 indicating their higher affinity for K-dw. These results are inconsistent with the hypothesis that immunodominance in the anti-influenza response reflects high affinity of the immunodominant peptide, but are consistent with skewing of the Tc-cell receptor repertoire. C1 Australian Natl Univ, John Curtin Sch Med Res, Div Cell Biol & Immunol, Canberra, ACT 2601, Australia. NIAID, Viral Immunol & Cellular Biol Lab Viral Dis, NIH, Bethesda, MD 20892 USA. RP Mullbacher, A (reprint author), Australian Natl Univ, John Curtin Sch Med Res, Div Cell Biol & Immunol, POB 334, Canberra, ACT 2601, Australia. RI yewdell, jyewdell@nih.gov/A-1702-2012 NR 26 TC 15 Z9 15 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0300-9475 J9 SCAND J IMMUNOL JI Scand. J. Immunol. PD OCT PY 1999 VL 50 IS 4 BP 420 EP 426 DI 10.1046/j.1365-3083.1999.00619.x PG 7 WC Immunology SC Immunology GA 241PK UT WOS:000082891600012 PM 10520183 ER PT J AU Jones, PL Wolffe, AP AF Jones, PL Wolffe, AP TI Relationships between chromatin organization and DNA methylation in determining gene expression SO SEMINARS IN CANCER BIOLOGY LA English DT Article DE methyl CpG binding proteins; transcriptional silencing; co-repressors; histone deacetylase; epigenetic control; oncogenic transformation ID CPG-BINDING-PROTEIN; TRANSCRIPTION IN-VIVO; TUMOR-SUPPRESSOR GENE; HISTONE DEACETYLASE; CHROMOSOMAL PROTEIN; NUCLEOSOMAL ARRAYS; MAMMALIAN NUCLEI; HSP70 PROMOTER; CELL-LINES; RNA GENE AB Chromatin ir the natural substrate for the control of gene expression. Chromatin contains DNA, the transcriptional machinery and structural proteins such as histones. Recent advances demonstrate that transcriotional activity of a gene Is Inr largely controlled by the packaging of the template within chromatin. The covalent modification of chromatin provides an attractive mechanism for establishing and maintaining stable states of gene activity. DNA methylation and histone acetylation alter the nucleosomal infrastructure to repress or activate transcription. These covalent modifications have causal roles in both promoter-specific events and the global control of chromosomal activity. DNA methylation and histone acetylation have a major impact in both oncogenic transformation and normal development. C1 NICHHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. RP Wolffe, AP (reprint author), NICHHD, Mol Embryol Lab, NIH, Bldg 18T,Rm 106, Bethesda, MD 20892 USA. NR 92 TC 129 Z9 135 U1 0 U2 2 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-579X J9 SEMIN CANCER BIOL JI Semin. Cancer Biol. PD OCT PY 1999 VL 9 IS 5 BP 339 EP 347 DI 10.1006/scbi.1999.0134 PG 9 WC Oncology SC Oncology GA 252XG UT WOS:000083527100003 PM 10547342 ER PT J AU Brown, KE AF Brown, KE TI Molecular diagnosis of viral disease in hematology patients SO SEMINARS IN HEMATOLOGY LA English DT Article ID POLYMERASE CHAIN-REACTION; BONE-MARROW TRANSPLANTATION; HUMAN-IMMUNODEFICIENCY-VIRUS; PARVOVIRUS B19 DNA; HEPATITIS-G VIRUS; HEMOPHAGOCYTIC SYNDROME; ZOSTER INFECTION; KAPOSIS-SARCOMA; REACTION ASSAY; PCR C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Brown, KE (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Room 7C218,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 49 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD OCT PY 1999 VL 36 IS 4 BP 352 EP 360 PG 9 WC Hematology SC Hematology GA 246LB UT WOS:000083164300004 PM 10530717 ER PT J AU Howell, MR Gaydos, JC McKee, KT Quinn, TC Gaydos, CA AF Howell, MR Gaydos, JC McKee, KT Quinn, TC Gaydos, CA TI Control of Chlamydia trachomatis infections in female army recruits: Cost-effective screening and treatment in training cohorts to prevent pelvic inflammatory disease SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID FAMILY-PLANNING CLINICS; MILITARY POPULATION; AZITHROMYCIN; WOMEN; TRENDS AB Context: Chlamydia trachomatis genitourinary infections in females can lead to serious and costly sequelae, Programs such as basic (initial entry) military training with controlled points of entry offer an opportunity to screen large cohorts of women at risk for infection. Objective: To assess the cost-effectiveness of three interventions for C. trachomatis infections in women beginning Army training: 1) screening using urine ligase chain reaction (LCR) by age, 2) unrestricted testing using urine LCR, and 3) universal antibiotic treatment with azithromycin, Design: Cost-effectiveness analysis from a military perspective, Setting and Patients: A hypothetical cohort of 10,000 women who intended to complete at least 2 years of military service was studied. Analysis was based on data from 13,204 female trainees screened for chlamydial infection at Fort Jackson, SC. Outcomes: Program and training costs, cost of illness averted, and pelvic inflammatory disease (PID) prevented were determined for a 1-year follow-up period. Using sensitivity analysis, outcomes over 2 years were studied. Results: At a 9.2% prevalence, no screening resulted in $220,900 in training and sequelae costs and 276 cases of PID, Screening by age produced the lowest cost $217,600, over a 1-year period and prevented 222 cases of PID for a cost-savings of $15 per case of PID prevented. Universal testing prevented an additional 11 cases of PID at a cost of $226,400, or costing $800 per additional case of PID prevented over age-targeted screening. Universal treatment prevented an additional 32 cases of PID and cost $221,100, saving $167 per additional cases of PID prevented over universal screening. Over a 2-year period, universal treatment provided the highest cost-savings and prevented the most disease. Conclusion: Screening by age provided a cost-savings to the Army over a 1-year period. Other organizations accessing large cohorts of young women could also benefit, even in the short term, from implementation of an age-based chlamydial screening program. Universal testing or universal treatment may be warranted in which long-term societal goals, such as maximum reduction of PID, are relevant. C1 Johns Hopkins Univ, Div Infect Dis, Baltimore, MD 21205 USA. Henry M Jackson Fdn, Rockville, MD USA. Walter Reed Army Med Ctr, Walter Reed Army Inst Res, Washington, DC 20307 USA. Womack Army Med Ctr, Ft Bragg, NC USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Howell, MR (reprint author), Johns Hopkins Univ, Div Infect Dis, Ross Res Bldg,Room 1159,720 Rutland Ave, Baltimore, MD 21205 USA. RI Gaydos, Charlotte/E-9937-2010 NR 19 TC 49 Z9 49 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD OCT PY 1999 VL 26 IS 9 BP 519 EP 526 DI 10.1097/00007435-199910000-00007 PG 8 WC Infectious Diseases SC Infectious Diseases GA 244UF UT WOS:000083068600007 PM 10534206 ER PT J AU Oakley, RH Webster, JC Jewell, CM Sar, M Cidlowski, JA AF Oakley, RH Webster, JC Jewell, CM Sar, M Cidlowski, JA TI Immunocytochemical analysis of the glucocorticoid receptor alpha isoform (GR alpha) using a GR alpha-specific antibody SO STEROIDS LA English DT Article DE glucocorticoid receptor; alpha-isoform; subcellular distribution; translocation; immunocytochemistry; glucocorticoids ID HEAT-SHOCK PROTEIN-90; DEOXYRIBONUCLEIC-ACID; STEROID-RECEPTORS; BETA-ISOFORM; ANTIPEPTIDE ANTIBODIES; INTRACELLULAR-LOCALIZATION; SUBCELLULAR-DISTRIBUTION; MONOCLONAL-ANTIBODY; RAT-BRAIN; C-JUN AB The alpha isoform of the glucocorticoid receptor (GR alpha) binds glucocorticoids and functions as a ligand-dependent transcription factor. Although GR alpha is expressed in almost all tissues and cells, its subcellular distribution is controversial. Many studies have reported that GR alpha translocates from the cytoplasm to the nucleus in a hormone-dependent manner whereas others have concluded that GR alpha is constitutively located in the nucleus. These conflicting data may result from the use of antibodies that do not discriminate GR alpha from a splice variant of the GR gene termed GR beta. Using a CR beta-specific antibody, we have recently demonstrated that CR beta resides in the nucleus of cells independent of glucocorticoid treatment. In the following study we have generated a novel GR alpha-specific antibody (AShGR) in order to assess, unambiguously, the subcellular distribution of GR alpha. AShGR recognizes recombinant GR alpha on Western blots and in immunoprecipitation experiments but does not cross-react with recombinant GR beta. Endogenous GR alpha is detected by AShGR in a variety of human cell lines including HeLa S-3, CEM-C7, HEK-293,MCF-7, Hep G2, and secondary lung epithelial cells. In addition, AShGR detects endogenous rat and mouse GR alpha. Immunocytochemistry was performed with AShGR on COS-1 cells transfected with human GR alpha and on HTC rat hepatoma cells expressing endogenous GR alpha. In both systems, GR alpha was found in the cytoplasm of cells in the absence of hormone and in the nucleus after hormone treatment. These studies mark the first time a GR alpha-specific antibody has been employed to examine the expression and subcellular distribution of endogenous GR alpha. Published by Elsevier Science Inc. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 41 TC 40 Z9 40 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0039-128X J9 STEROIDS JI Steroids PD OCT PY 1999 VL 64 IS 10 BP 742 EP 751 DI 10.1016/S0039-128X(99)00059-8 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 238PT UT WOS:000082719200005 PM 10498033 ER PT J AU Lipp, MN Anderson, DE AF Lipp, MN Anderson, DE TI Cardiovascular reactivity to simulated social stress SO STRESS MEDICINE LA English DT Article DE blood pressure; heart rate; hypertension; pCO(2); reactivity; social stress ID BLOOD-PRESSURE CONTROL; TIDAL CO2 ASSOCIATION; ESSENTIAL-HYPERTENSION; GENDER DIFFERENCES; SODIUM; ANGER; HYPOVENTILATION; PERSONALITY; ADOLESCENTS; INHIBITION AB This study tested the hypotheses that blood pressure reactivity to simulated social stress would be positively correlated with resting pCO(2) and with increased variability of blood pressure in the natural environment, Sixty white and black men and women participated in a role-playing task involving scenarios describing common infringements of their rights, Blood pressure was higher during the role playing task than during a preceding structured interview and an intervening rest period, and decreased after role playing. Heart rate changes were small by comparison, though heart rate reactivity of women was greater than that of men. Blood pressure reactivity was not correlated with resting pCO(2) and was inversely correlated with ambulatory systolic blood pressure variability. Resting pCO(2) was, however, correlated with mean 24-h ambulatory systolic and diastolic blood pressure. This study confirms that social stress elevated blood pressure acutely via a vascular mechanism, is consistent with the view that hyperresponsive individuals tend to avoid arousing situations, and further implicates pCO(2), in long-term blood pressure regulation. Copyright (C) 1999 John Wiley & Sons, Ltd. C1 NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. Catholic Univ Campinas, Campinas, SP, Brazil. RP Anderson, DE (reprint author), NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 45 TC 2 Z9 4 U1 1 U2 1 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0748-8386 J9 STRESS MEDICINE JI Stress Med. PD OCT PY 1999 VL 15 IS 4 BP 249 EP 257 DI 10.1002/(SICI)1099-1700(199910)15:4<249::AID-SMI821>3.0.CO;2-3 PG 9 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 248EU UT WOS:000083262900006 ER PT J AU Hartmann, LC Sellers, TA Schaid, DJ Nayfield, S Grant, CS Bjoraker, JA Woods, J Couch, F AF Hartmann, LC Sellers, TA Schaid, DJ Nayfield, S Grant, CS Bjoraker, JA Woods, J Couch, F TI Clinical options for women at high risk for breast cancer SO SURGICAL CLINICS OF NORTH AMERICA LA English DT Article ID PROPHYLACTIC MASTECTOMY; SUBCUTANEOUS MASTECTOMY; FAMILY HISTORY; SCREENING MAMMOGRAPHY; OVARIAN-CANCER; CURRENT STATE; BRCA1; TAMOXIFEN; PREVENTION; ADHERENCE AB For women with high genetic risk of breast cancer, three management options generally are considered: cancer surveillance, prophylactic surgery (i.e., mastectomy or oophorectomy), and chemoprevention. in this article, the authors examine the available data for all three options, and pay particular attention to a study of prophylactic mastectomy performed at the Mayo Clinic. C1 Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. NCI, Bethesda, MD 20892 USA. RP Hartmann, LC (reprint author), Mayo Clin & Mayo Fdn, 200 1st St SW, Rochester, MN 55905 USA. NR 59 TC 12 Z9 13 U1 1 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0039-6109 J9 SURG CLIN N AM JI Surg. Clin.-North Am. PD OCT PY 1999 VL 79 IS 5 BP 1189 EP + DI 10.1016/S0039-6109(05)70068-2 PG 19 WC Surgery SC Surgery GA 245RP UT WOS:000083122200015 PM 10572558 ER PT J AU Costagliola, S Sunthorntepvarakul, T Migeotte, I Van Sande, J Kajava, AM Refetoff, S Vassart, G AF Costagliola, S Sunthorntepvarakul, T Migeotte, I Van Sande, J Kajava, AM Refetoff, S Vassart, G TI Structure-function relationships of two loss-of-function mutations of the thyrotropin receptor gene SO THYROID LA English DT Article ID LEUCINE-RICH REPEATS; MONOCLONAL-ANTIBODIES; PROTEIN; BINDING AB The functional and structural characteristics of two previously described "loss-of-function" mutants of the thyrotropin receptor (TSHR) gene were analyzed by transient transfection in COS cells. Both mutations (Pro162Ala, Ile167Asn) are located in the putative extracellular hormone-binding domain of the receptor. The following parameters were analyzed: expression of native receptor on the cell surface (as measured by binding of labeled thyrotropin [TSH] to intact cells, or flow cytometry of intact cells); total TSHR expression (measured by flow cytometry of permeabilized cells); response to TSH measured as cyclic adenosine monophosphate (cAMP) accumulation. The total cellular expression of both mutant receptors was similar. Cell surface expression of Pro162Ala mutant was reduced about twofold and the EC50 for TSH stimulation was increased twofold. In contrast, the Ile167Asn mutant did not reach the cell surface and the intracellularly expressed mutant protein did not react with a monoclonal antibody (BA8) recognizing only the native TSHR. Based on the current model of the three-dimensional structure of the TSHR, the Pro162Ala substitution maps at the surface of the molecule, while the Ile167Asn mutation affects a residue whose side chain contributes to the hydrophobic core characteristic of proteins harboring leucine repeat motifs. These results are consistent with Ile167Asn causing a gross destabilization of receptor structure incompatible with its normal routing through the intracellular membrane system of the cell. C1 Free Univ Brussels, Fac Med, IRIBHN, Dept Med Genet, B-1070 Brussels, Belgium. Rajavithi Hosp, Inst Rech Interdisciplinaire, Bangkok, Thailand. Rajavithi Hosp, Dept Med, Bangkok, Thailand. NIH, Ctr Mol Modeling, CIT, Bethesda, MD USA. Univ Chicago, Dept Med & Pediat, Chicago, IL 60637 USA. RP Vassart, G (reprint author), Free Univ Brussels, Fac Med, IRIBHN, Dept Med Genet, 808 Route Lennik,Campus Erasme, B-1070 Brussels, Belgium. RI Kajava, Andrey/E-1107-2014 OI Kajava, Andrey/0000-0002-2342-6886 FU NIDDK NIH HHS [DK 15070] NR 17 TC 22 Z9 23 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1050-7256 J9 THYROID JI Thyroid PD OCT PY 1999 VL 9 IS 10 BP 995 EP 1000 DI 10.1089/thy.1999.9.995 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 253CY UT WOS:000083540100004 PM 10560953 ER PT J AU Sanchez, AM Schreiber, GB Glynn, SA Wu, Y McCurdy, PR Williams, AE AF Sanchez, AM Schreiber, GB Glynn, SA Wu, Y McCurdy, PR Williams, AE TI Unreported deferrable risk and frequency of hemochromatosis and polycythemia in blood donors SO TRANSFUSION LA English DT Meeting Abstract C1 Westat Inc, Rockville, MD USA. NHLBI, Bethesda, MD 20892 USA. Amer Red Cross, Jerome H Holland Lab, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 1999 VL 39 IS 10 SU S BP 1S EP 1S PG 1 WC Hematology SC Hematology GA 247EK UT WOS:000083207500002 ER PT J AU Schreiber, GB McCurdy, P Sanchez, AM Glynn, SA Wright, DJ AF Schreiber, GB McCurdy, P Sanchez, AM Glynn, SA Wright, DJ TI Frequency of blood donation and reserve capacity of the blood supply SO TRANSFUSION LA English DT Meeting Abstract C1 Westat Inc, FR Epidemiol Donor Study, Rockville, MD USA. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 1999 VL 39 IS 10 SU S BP 32S EP 32S PG 1 WC Hematology SC Hematology GA 247EK UT WOS:000083207500154 ER PT J AU Wong, EC Oblitas, J Leitman, SF Stroncek, DF AF Wong, EC Oblitas, J Leitman, SF Stroncek, DF TI Whole blood platelet von Willebrand bead reactivity in plateletpheresis donors: Effect of age, gender and medications SO TRANSFUSION LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 1999 VL 39 IS 10 SU S BP 38S EP 38S PG 1 WC Hematology SC Hematology GA 247EK UT WOS:000083207500182 ER PT J AU Moses, LA Stroncek, DF Cipolone, KM Marincola, FM AF Moses, LA Stroncek, DF Cipolone, KM Marincola, FM TI Detection of HLA antibodies using flow cytometry and latex beads coated with HLA antigens SO TRANSFUSION LA English DT Meeting Abstract C1 NIH, CC, DTM, Bethesda, MD 20892 USA. NCI, CC, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 1999 VL 39 IS 10 SU S BP 39S EP 39S PG 1 WC Hematology SC Hematology GA 247EK UT WOS:000083207500186 ER PT J AU Stroncek, DF Procter, JL Mosses, LA Bolan, CD Conry-Cantilena, C Pomper, GJ Leitman, SF AF Stroncek, DF Procter, JL Mosses, LA Bolan, CD Conry-Cantilena, C Pomper, GJ Leitman, SF TI Rh immune globulin prevents alloimmunization in D-granulocyte recipients, but obscures detection of alloantibodies SO TRANSFUSION LA English DT Meeting Abstract C1 NIH, Dept Transfus Med, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 1999 VL 39 IS 10 SU S BP 61S EP 61S PG 1 WC Hematology SC Hematology GA 247EK UT WOS:000083207500293 ER PT J AU Pomper, GJ Carter, CS Leitman, SF Read, EJ AF Pomper, GJ Carter, CS Leitman, SF Read, EJ TI Cellular composition of normal donor leukapheresis products before and after G-CSF mobilization. SO TRANSFUSION LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 1999 VL 39 IS 10 SU S BP 79S EP 79S PG 1 WC Hematology SC Hematology GA 247EK UT WOS:000083207500379 ER PT J AU Stroncek, DF Carter, LB Procter, JL AF Stroncek, DF Carter, LB Procter, JL TI The direct antiglobulin test in autoimmune lymphoproliferative syndrome SO TRANSFUSION LA English DT Meeting Abstract C1 NIH, Dept Transfus Med, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 1999 VL 39 IS 10 SU S BP 81S EP 82S PG 2 WC Hematology SC Hematology GA 247EK UT WOS:000083207500391 ER PT J AU Bolan, CD Childs, RC Procter, JL Barrett, AJ Leitman, SF AF Bolan, CD Childs, RC Procter, JL Barrett, AJ Leitman, SF TI Severe immune hemolysis due to minor ABP incompatibility after peripheral blood stem cell (PBSC) transplantation SO TRANSFUSION LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 1999 VL 39 IS 10 SU S BP 85S EP 85S PG 1 WC Hematology SC Hematology GA 247EK UT WOS:000083207500406 ER PT J AU Lightfoot, TG Gallelli, JF Matsuo, K Leitman, SF Stroncek, DF AF Lightfoot, TG Gallelli, JF Matsuo, K Leitman, SF Stroncek, DF TI Comparison of solutions for sustained storage of granulocyte concentrates SO TRANSFUSION LA English DT Meeting Abstract C1 NIH, Dept Transfus Med, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 1999 VL 39 IS 10 SU S BP 88S EP 88S PG 1 WC Hematology SC Hematology GA 247EK UT WOS:000083207500422 ER PT J AU Wong, EC Oblitas, J Rivera, C Leitman, SF Stroncek, DF AF Wong, EC Oblitas, J Rivera, C Leitman, SF Stroncek, DF TI Von Willebrand factor (VWF) coated bead reactivity and flow cytometric markers of platelet activation in apheresis platelets. SO TRANSFUSION LA English DT Meeting Abstract C1 Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 1999 VL 39 IS 10 SU S BP 89S EP 90S PG 2 WC Hematology SC Hematology GA 247EK UT WOS:000083207500428 ER PT J AU Lazarus, EF Hines, KA Norman, JE Read, EJ AF Lazarus, EF Hines, KA Norman, JE Read, EJ TI Quantitation of megakaryocyte progenitors in allogeneic peripheral blood stem cell products: Correlation with standard progenitor assays SO TRANSFUSION LA English DT Meeting Abstract C1 NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 1999 VL 39 IS 10 SU S BP 101S EP 101S PG 1 WC Hematology SC Hematology GA 247EK UT WOS:000083207500480 ER PT J AU Luban, NL Post, J Glymph, C Fishlowitz, R Baxter, C Cain, C Alter, HJ AF Luban, NL Post, J Glymph, C Fishlowitz, R Baxter, C Cain, C Alter, HJ TI Transfusion associated hepatitis C and G in pediatric patients identified through a universal look back approach SO TRANSFUSION LA English DT Meeting Abstract C1 Acad Natl Med Ctr, Washington, DC USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. Westat Inc, Rockville, MD USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 1999 VL 39 IS 10 SU S BP 110S EP 111S PG 2 WC Hematology SC Hematology GA 247EK UT WOS:000083207500525 ER PT J AU Leitman, SF Werden, RA Garvey, MA Feldman, E Swedo, SE AF Leitman, SF Werden, RA Garvey, MA Feldman, E Swedo, SE TI Randomized trial of plasma exchange vs immune globulin in childhood-onset obsessive compulsive disorder (OCD) SO TRANSFUSION LA English DT Meeting Abstract C1 NIH, Dept Transfus Med, Bethesda, MD 20892 USA. NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 1999 VL 39 IS 10 SU S BP 112S EP 112S PG 1 WC Hematology SC Hematology GA 247EK UT WOS:000083207500533 ER PT J AU Pomper, GJ Rick, ME Epstein, JS Read, EJ AF Pomper, GJ Rick, ME Epstein, JS Read, EJ TI Management of severe von Willebrand's disease with cryoprecipitate collected by repeated apheresis of a single dedicated donor SO TRANSFUSION LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. US FDA, Bethesda, MD 20014 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 1999 VL 39 IS 10 SU S BP 112S EP 113S PG 2 WC Hematology SC Hematology GA 247EK UT WOS:000083207500535 ER PT J AU Williams, AE Watanabe, K Ameti, D Kleinman, S Busch, M Orton, S Nemo, G AF Williams, AE Watanabe, K Ameti, D Kleinman, S Busch, M Orton, S Nemo, G TI Relationship of anti-HBC and serologic tests for syphilis (STS) to blood donor behavioral risks SO TRANSFUSION LA English DT Meeting Abstract C1 NHLBI, REDS Study, Rockville, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 1999 VL 39 IS 10 SU S BP 114S EP 114S PG 1 WC Hematology SC Hematology GA 247EK UT WOS:000083207500540 ER PT J AU Kessler, JA Alter, HJ Yeo, A Melpolder, J AF Kessler, JA Alter, HJ Yeo, A Melpolder, J TI Evaluation of alt elevations in volunteer blood donors: Etiology, persistence and morbidity SO TRANSFUSION LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 1999 VL 39 IS 10 SU S BP 115S EP 115S PG 1 WC Hematology SC Hematology GA 247EK UT WOS:000083207500548 ER PT J AU Bolan, CD Rehak, NN Remaley, A Pomper, GJ Birmingham, GC Gladden, SD Leitman, SF AF Bolan, CD Rehak, NN Remaley, A Pomper, GJ Birmingham, GC Gladden, SD Leitman, SF TI Clinical and laboratory evaluation of citrate effects and calcium replacement therapy in large volume leukapheresis (LVL). SO TRANSFUSION LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 1999 VL 39 IS 10 SU S BP 122S EP 123S PG 2 WC Hematology SC Hematology GA 247EK UT WOS:000083207500582 ER PT J AU Dever, TE AF Dever, TE TI Translation initiation: adept at adapting SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review ID DOUBLE-STRANDED-RNA; DEPENDENT PROTEIN-KINASE; FACTOR 4G EIF4G; MESSENGER-RNA; SACCHAROMYCES-CEREVISIAE; EIF-2-ALPHA KINASE; DROSOPHILA-MELANOGASTER; BINDING-PROTEIN; YEAST; PHOSPHORYLATION AB Initiation of protein synthesis requires both an mRNA and the initiator methionyl (Met)-tRNA to be bound to the ribosome. Most mRNAs are recruited to the ribosome through recognition of the 5' m(7)G cap by a group of proteins referred to as the cap-binding complex or eIF4F. Evidence is accumulating that eIF4G, the largest subunit of the cap-binding complex, serves as a central adapter by binding to various translation factors and regulators. Other translation factors also have modular structures that facilitate multiple protein-protein interactions, which suggests that adapter functions are common among the translation initiation factors. By linking different regulatory domains to a conserved eIF2-kinase domain, cells adapt to stress and changing growth conditions by altering the translational capacity through phosphorylation of eIF2, which mediates the binding of the initiator Met-tRNA to the ribosome. C1 NICHHD, Lab Eukaryot Gene Regulat, NIH, Bethesda, MD 20892 USA. RP Dever, TE (reprint author), NICHHD, Lab Eukaryot Gene Regulat, NIH, Bethesda, MD 20892 USA. NR 57 TC 136 Z9 139 U1 0 U2 5 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD OCT PY 1999 VL 24 IS 10 BP 398 EP 403 DI 10.1016/S0968-0004(99)01457-7 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 243FA UT WOS:000082985300008 PM 10500305 ER PT J AU Simon, TJ AF Simon, TJ TI The foundations of numerical thinking in a brain without numbers SO TRENDS IN COGNITIVE SCIENCES LA English DT Editorial Material ID SPATIAL ATTENTION C1 NIDA, Ctr Neurosci, NIH, Bethesda, MD 20893 USA. RP Simon, TJ (reprint author), NIDA, Ctr Neurosci, NIH, Bethesda, MD 20893 USA. NR 21 TC 62 Z9 62 U1 3 U2 3 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1364-6613 J9 TRENDS COGN SCI JI TRENDS COGN. SCI. PD OCT PY 1999 VL 3 IS 10 BP 363 EP 365 DI 10.1016/S1364-6613(99)01383-2 PG 3 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 240PN UT WOS:000082834500001 ER PT J AU Vottero, A Chrousos, GP AF Vottero, A Chrousos, GP TI Glucocorticoid receptor beta: View I SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID HORMONE-BINDING DOMAIN; DEPENDENT TRANSCRIPTIONAL ACTIVATION; DNA-BINDING; RESISTANT PRIMATE; CUSHINGS-DISEASE; GENE-EXPRESSION; ISOFORM; TRANSACTIVATION; SUPERFAMILY; PROTEIN C1 NICHHD, Sect Pediat Endocrinol, DEB, NIH, Bethesda, MD 20892 USA. RP Vottero, A (reprint author), NICHHD, Sect Pediat Endocrinol, DEB, NIH, Bethesda, MD 20892 USA. NR 60 TC 55 Z9 59 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD OCT PY 1999 VL 10 IS 8 BP 333 EP 338 DI 10.1016/S1043-2760(99)00179-4 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 237RJ UT WOS:000082669600008 ER PT J AU Forns, X Purcell, RH Bukh, J AF Forns, X Purcell, RH Bukh, J TI Quasispecies in viral persistence and pathogenesis of hepatitis C virus SO TRENDS IN MICROBIOLOGY LA English DT Review ID SENSITIVITY-DETERMINING REGION; T-LYMPHOCYTE RESPONSE; HYPERVARIABLE REGION-1; ENVELOPE GLYCOPROTEINS; LIVER-TRANSPLANTATION; ANTIBODY-RESPONSE; CHRONIC INFECTION; DYNAMIC BEHAVIOR; IMMUNE-RESPONSE; HCV INFECTION AB Hepatitis C virus (HCV) is an important cause of chronic liver disease worldwide. This RNA virus circulates as a quasispecies and its genetic heterogeneity has been implicated in the lack of protective immunity against HCV and in its persistence following infection. HCV might escape from immune surveillance by developing mutations in proteins that are subject to immune pressure. C1 NIAID, Hepatitis Viruses Sect, NIH, Bethesda, MD 20892 USA. RP Forns, X (reprint author), NIAID, Hepatitis Viruses Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 78 TC 80 Z9 86 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0966-842X J9 TRENDS MICROBIOL JI Trends Microbiol. PD OCT PY 1999 VL 7 IS 10 BP 402 EP 410 DI 10.1016/S0966-842X(99)01590-5 PG 9 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 241CN UT WOS:000082864900010 PM 10498948 ER PT J AU Hikosaka, O Nakahara, H Rand, MK Sakai, K Lu, XF Nakamura, K Miyachi, S Doya, K AF Hikosaka, O Nakahara, H Rand, MK Sakai, K Lu, XF Nakamura, K Miyachi, S Doya, K TI Parallel neural networks for learning sequential procedures SO TRENDS IN NEUROSCIENCES LA English DT Review ID SUPPLEMENTARY MOTOR AREA; NEURONAL-ACTIVITY; BASAL GANGLIA; DIFFERENTIAL ROLES; PARIETAL CORTEX; CEREBRAL-CORTEX; MACAQUE MONKEY; FRONTAL-CORTEX; MOVEMENT; MEMORY AB Recent studies have shown that multiple brain areas contribute to different stages and aspects of procedural learning. On the basis of a series of studies using a sequence-learning taste with trial-and-. error,we propose a hypothetical scheme in which a sequential procedure is acquired independently by two cortical systems, one using spatial coordinates and the other using motor coordinates. They are active preferentially in the early and late stages of learning, respectively. Both of the two systems are supported by loop circuits formed with the basal ganglia and the cerebellum, the former for reward-based evaluation and the latter for processing of timing. The proposed neural architecture would operate in a flexible manner to acquire and execute multiple sequential procedures. C1 Juntendo Univ, Sch Med, Dept Physiol, Tokyo 1130033, Japan. Inst Phys & Chem Res, RIKEN, Lab Informat Synth, Brain Sci Inst, Wako, Saitama 3510198, Japan. Arizona State Univ, Dept Exercise Sci & Phys Educ, Tempe, AZ 85287 USA. Univ Pittsburgh, Dept Neurosci, Ctr Neural Basic Cognit, Pittsburgh, PA 15213 USA. NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. Japan Sci & Technol Corp, ERATO, Kawata Dynam Brain Project, Kyoto 6190288, Japan. RP Hikosaka, O (reprint author), Juntendo Univ, Sch Med, Dept Physiol, Tokyo 1130033, Japan. RI Doya, Kenji/B-5841-2015; Nakahara, Hiroyuki/N-5411-2015 OI Doya, Kenji/0000-0002-2446-6820; Nakahara, Hiroyuki/0000-0001-6891-1175 NR 78 TC 425 Z9 428 U1 4 U2 39 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD OCT PY 1999 VL 22 IS 10 BP 464 EP 471 DI 10.1016/S0166-2236(99)01439-3 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 239NC UT WOS:000082773400013 PM 10481194 ER PT J AU Mitra, S Dagher, A Kage, R Dagher, RK Luber-Narod, J AF Mitra, S Dagher, A Kage, R Dagher, RK Luber-Narod, J TI Experimental autoimmune cystitis: further characterization and serum autoantibodies SO UROLOGICAL RESEARCH LA English DT Article DE interstitial cystitis; animal models; autoantibodies; urinary frequency; autoimmunity ID INTERSTITIAL CYSTITIS; IDENTIFICATION; RAT AB Previously, we described an animal model for interstitial cystitis (IC), experimental autoimmune cystitis (EAC) [Luber-Narod et al. Urol Res 24:367]. Further characterization of animals with EAC indicates that peak and mean urinary frequency are elevated compared with sham-injected controls and that the disease progresses with at least two cycles of exacerbations and remissions. We had shown evidence suggesting EAC to be autoimmune in nature. In this paper, we identify serum autoantibodies from 9/10 EAC animals which bind to a protein specific to rat bladder with a relative molecular weight of 12-kDa. Such autoantibodies are absent in 12/13 normal and sham-injected animals as well as animals which fail to develop EAC despite disease induction. These findings suggest that EAC is a reproducible model of cyclical increases of urinary frequency, and that a 12-kDa antigen is the target of autoantibodies which correlate with those elevations. Identification of this target antigen may explain the pathogenesis of increased urinary frequency in these animals and potentially in IC as well. C1 Univ Massachusetts, Med Ctr, Dept Urol Surg, Worcester, MA 01655 USA. NIAID, NIH, Bethesda, MD 20892 USA. Henry Ford Hosp, Detroit, MI 48202 USA. RP Luber-Narod, J (reprint author), Univ Massachusetts, Med Ctr, Dept Urol Surg, 55 Lake Ave N, Worcester, MA 01655 USA. FU NIDDK NIH HHS [DK47527] NR 13 TC 7 Z9 7 U1 0 U2 1 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0300-5623 J9 UROL RES JI Urol. Res. PD OCT PY 1999 VL 27 IS 5 BP 351 EP 356 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 252LH UT WOS:000083502600009 PM 10550523 ER PT J AU Meldrum, ML AF Meldrum, ML TI The historical feud over polio vaccine: how could a killed vaccine contain a natural disease? SO WESTERN JOURNAL OF MEDICINE LA English DT Article C1 NIH, Hist Off, Bethesda, MD 20892 USA. RP Meldrum, ML (reprint author), NIH, Hist Off, Bethesda, MD 20892 USA. NR 18 TC 2 Z9 2 U1 0 U2 1 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 0093-0415 J9 WESTERN J MED JI West. J. Med. PD OCT PY 1999 VL 171 IS 4 BP 271 EP 273 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 253AX UT WOS:000083535400024 PM 10578685 ER PT J AU Adams, JD Sayer, JM Chadha, A Shirai, N Lehr, RE Kumar, S Jerina, DM AF Adams, JD Sayer, JM Chadha, A Shirai, N Lehr, RE Kumar, S Jerina, DM TI The proximate carcinogen trans-3,4-dihydroxy-3,4-dihydro-dibenz[c,h]acridine is oxidized stereoselectively and regioselectively by cytochrome 1Al, epoxide hydrolase and hepatic microsomes from 3-methylcholanthrene-treated rats SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE dibenz[c,h]acridine; bay region epoxides; cytochrome P4501Al ID REGION DIOL EPOXIDES; POLYCYCLIC AROMATIC-HYDROCARBONS; LIVER MICROSOMES; POLYCHLORINATED-BIPHENYLS; ABSOLUTE-CONFIGURATION; PURIFICATION; DIBENZACRIDINE; METABOLISM; HYDRASE; SYSTEM AB Metabolism of the proximate carcinogen trans-3,4-dihydroxy-3,4dihydrodibenz[c,h]acridine has been examined with rat liver enzymes. The dihydrodiol is metabolized at a rate of 2.4 nmol/nmol of cytochrome P450 1A1/min with microsomes from 3-methylcholanthrene-treated rats, a rate more than 10-fold higher than that observed with microsomes from control or phenobarbital-treated rats. Major metabolises consisted of a diastereomeric pair of bis-dihydrodiols (68-83%), where the new dihydrodiol group has been introduced at the 8,9-position, tetraols derived From bay region 3,4-diol-1,2-epoxides (15-23%), and a small amount of a phenolic dihydrodiol(s) where the new hydroxy group is at the 8,9-position of the substrate. A highly purified monooxygenase system reconstituted with cytochrome P450 1A1 and epoxide hydrolase (17 nmol of metabolites/nmol of cytochrome P450 1A1/min) gave a metabolite profile very similar to that observed with liver microsomes from 3-methylcholanthrene-treated rats. Study of the stereoselectivity of these microsomes established that the (+)-(3S,4S)-dihydrodiol gave mainly the diol epoxide-1 diastereomer, in which the benzylic 4-hydroxyl group and epoxide oxygen are cis. The (-)-(3R,4R)-dihydrodiol gave mainly diol epoxide-2 where these same groups are trans. The major enantiomers of the diastereomeric bis-dihydrodiols are shown to have the same absolute configuration at the 8,9-position. Correlations of circular dichroism spectra suggest this configuration to be (8R,9R). The (8R,9S)-oxide may be their common precursor. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ So Calif, Sch Pharm, Los Angeles, CA 90089 USA. Natl Inst Arthrit Diabet & Digest & Kidney Dis, Bioorgan Chem Lab, NIH, Bethesda, MD 20205 USA. Univ Oklahoma, Dept Chem, Norman, OK 73019 USA. RP Adams, JD (reprint author), Univ So Calif, Sch Pharm, 1985 Zonal Ave,PSC 508, Los Angeles, CA 90089 USA. NR 35 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD SEP 30 PY 1999 VL 122 IS 2 BP 117 EP 135 DI 10.1016/S0009-2797(99)00116-7 PG 19 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 240ZA UT WOS:000082855600004 PM 10528997 ER PT J AU Saxena, RK Adler, WH AF Saxena, RK Adler, WH TI Cytolytic activity of mitogen activated old and young mouse spleen cells against tumor target cells expressing high or low revels of Fas antigen SO EXPERIMENTAL AND MOLECULAR MEDICINE LA English DT Article DE cytotoxic cells; mitogen; Fas; Fas ligand; aging ID AGE-RELATED-CHANGES; T-CELLS; LYMPHOKINE PRODUCTION; APOPTOSIS; LIGAND; MICE AB Sensitivity of Fas expressing tumor cells (high levels in Hut78 & Jurkat; low levels in P815) toward the cytotoxic Con-A (5 mu g/ml) activated spleen cells from young (12 to 16 week old males) and old (2 year old males) mice were studied. The spleen cells from young mice activated for a day showed high levels of cytotoxic activity against Hut78 and Jurkat cell lines but not against P815 cells. The cytotoxic activity against P815 cells were detected in the spleen cells from old but not young mice following a longer period of Con-A activation (three days). Comparable levels of cytotoxic activity against Hut78 and Jurkat cells were observed in the spleen cells from both young and old mice following three days of activation. Treatment of Hut78 cells with anti-fas antibody affected the tumor cells become resistant against the cytotoxic activity of the spleen cells from young mice in a dose dependent manner however P815 cells were not affect by the anti-fas antibody treatment. These results show that there are differences in the sensitivity of target tumor cells toward Con-A induced cytotoxic spleen cells from young and old mouse. Mitogen-induced cytotoxic lymphocytes from young mouse spleen appear to kill targets through mechanisms involving Fas antigen, specially in early stage (1 day) of activation. Old mouse spleen cells generated high levels of cytotoxic cells in later phase (3 days), which appear to kill through Fas-unrelated mechanisms. C1 Jawaharlal Nehru Univ, Sch Life Sci, New Delhi 110067, India. NIA, Clin Immunol Sect, NIH, Baltimore, MD 21224 USA. NR 18 TC 2 Z9 2 U1 0 U2 0 PU KOREAN SOC MED BIOCHEMISTRY MOLECULAR BIOLOGY PI SEOUL PA #812 KOFST, 635-4 YOKSAM-DONG KANGNAM-GU, SEOUL 135-703, SOUTH KOREA SN 1226-3613 J9 EXP MOL MED JI Exp. Mol. Med. PD SEP 30 PY 1999 VL 31 IS 3 BP 137 EP 141 PG 5 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 241VT UT WOS:000082905100005 PM 10551262 ER PT J AU Wheelan, SJ Boguski, MS Duret, L Makalowski, W AF Wheelan, SJ Boguski, MS Duret, L Makalowski, W TI Human and nematode orthologs - lessons from the analysis of 1800 human genes and the proteome of Caenorhabditis elegans SO GENE LA English DT Article; Proceedings Paper CT Symposium of the International-Society-of-Molecular-Evolution on Evolutionary Genomics CY JAN 11-15, 1999 CL PUNTARENAS, COSTA RICA SP Int Soc Molec Evolut DE comparative genomics; molecular evolution ID SEQUENCE ALIGNMENT; DIVERGENCE; GENOME; YEAST; MOUSE AB Recently, we have defined and analyzed over 1800 orthologous human and rodent genes. Here we extend this work to compare human and Caenorhabditis elegans coding sequences. 1880 human proteins were compared with about 20000 predicted nematode proteins presumably comprising nearly the complete proteome of C. elegans, We found that 44% of human/rodent orthologs have convincing nematode counterparts. On average, the amino acid similarity and identity between aligned human and C. elegans orthologous gene products are 69.3% and 49.1% respectively, and the nucleotide identity is 49.8%. Detailed investigation of our results suggests that some nematode gene predictions are incorrect, leading to erroneous pairing with human genes (e.g. calcineurin and polymerase II elongation factor III). Furthermore, other proteins (i.e. homologs of human ribosomal proteins S20 and L41, thymosin) are missing entirely from the nematode proteome, suggesting that it may not be complete. These results underscore the fact that metazoan gene prediction is a very challenging task and that most computer-predicted nematode genes require supporting evidence of their existence from comparative genomics and/or laboratory investigation. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. Univ Lyon 1, CNRS, Lab BGBP UMR 5558, F-69622 Villeurbanne, France. RP Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. EM makalowski@ncbi.nim.nih.gov RI Makalowski, Wojciech/I-2843-2016 NR 15 TC 34 Z9 37 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 EI 1879-0038 J9 GENE JI Gene PD SEP 30 PY 1999 VL 238 IS 1 BP 163 EP 170 DI 10.1016/S0378-1119(99)00298-X PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 243PA UT WOS:000083005400017 PM 10570994 ER PT J AU Schoket, B Poirier, MC Mayer, G Torok, G Kolozsi-Ringelhann, A Bognar, G Bigbee, WL Vincze, I AF Schoket, B Poirier, MC Mayer, G Torok, G Kolozsi-Ringelhann, A Bognar, G Bigbee, WL Vincze, I TI Biomonitoring of human genotoxicity induced by complex occupational exposures SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article; Proceedings Paper CT Workshop on Biomarkers in Monitoring Occupational and Environmental Exposure to Organic Genotoxic Substances CY OCT 23-27, 1997 CL USTRON, POLAND SP Polish State Comm Sci Res, Batory Fdn DE polycyclic aromatic hydrocarbon; 1-hydroxypyrene; aromatic DNA adduct; P-32-postlabelling; competitive immunoassay; glycophorin A; occupational exposure; biomarker; human biomonitoring ID POLYCYCLIC AROMATIC-HYDROCARBONS; PERIPHERAL-BLOOD LYMPHOCYTES; DNA-ADDUCTS; RUBBER INDUSTRY; URINARY 1-HYDROXYPYRENE; ALUMINUM WORKERS; FOUNDRY WORKERS; PLANT WORKERS; GLYCOPHORIN; SENSITIVITY AB Sensitivity, specificity and correlations among several biomarkers for monitoring occupational exposure to complex mixtures of genotoxic agents were assessed in occupational environments in Hungarian study populations. The studies have been focused on DNA adduct formation, urinary metabolites, mutations and micronuclei induced by exposures to complex organic mixtures. In two Hungarian aluminium plants, increased DNA adduct and l-hydroxypyrene (1-OH-PY) levels were observed in workers as compared to controls. However, no association between the biomarker levels was evident on an individual basis. In Hungarian garage mechanics, DNA adduct determinations did not show increased genotoxic exposure as compared to the controls. However, ambient air measurements, significantly enhanced 1-OH-PY levels, and slightly enhanced frequency of micronuclei indicated increased polycyclic aromatic hydrocarbon (PAH) exposure in the garages, as compared to the general environment. In a Hungarian vulcanizing plant, DNA adduct determinations and 1-OH-PY did not show significantly elevated exposure levels as compared to controls. The glycophorin A (GPA) somatic mutation assay was also negative for this occupational exposure. The results support previous observations of a lack of correlation between DNA adducts detectable by P-32-postlabelling and those measured by the PAH-DNA immunoassay in the same DNA sample. These studies also demonstrate a lack of close correlation between levels of DNA adducts and urinary I-OH-PY in the same individual. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Natl Inst Environm Hlth, Jozsef Fodor Natl Ctr Publ Hlth, H-1097 Budapest, Hungary. NCI, NIH, Bethesda, MD 20892 USA. Natl Publ Hlth Serv, Capital Inst, Budapest, Hungary. Freder Joliot Curie Natl Res Inst Radiobiol & Rad, Budapest, Hungary. Univ Pittsburgh, Ctr Environm & Occupat Hlth & Toxicol, Pittsburgh, PA USA. RP Schoket, B (reprint author), Natl Inst Environm Hlth, Jozsef Fodor Natl Ctr Publ Hlth, Gyali 2-6, H-1097 Budapest, Hungary. NR 33 TC 38 Z9 39 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD SEP 30 PY 1999 VL 445 IS 2 BP 193 EP 203 DI 10.1016/S1383-5718(99)00126-6 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 253CC UT WOS:000083538200008 PM 10575430 ER PT J AU Plenz, D AF Plenz, D TI Fast oscillations in cortical circuits SO NATURE LA English DT Book Review C1 NIMH, Unit Neural Network Physiol, Lab Syst Neurosci, Bethesda, MD 20892 USA. RP Plenz, D (reprint author), NIMH, Unit Neural Network Physiol, Lab Syst Neurosci, Bldg 36 2D-30, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 30 PY 1999 VL 401 IS 6752 BP 428 EP 428 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 243DF UT WOS:000082981200027 ER PT J AU Andreu, AL Hanna, MG Reichmann, H Bruno, C Penn, AS Tanji, K Pallotti, F Iwata, S Bonilla, E Lach, B Morgan-Hughes, J DiMauro, S AF Andreu, AL Hanna, MG Reichmann, H Bruno, C Penn, AS Tanji, K Pallotti, F Iwata, S Bonilla, E Lach, B Morgan-Hughes, J DiMauro, S TI Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID COMPLEX-III DEFICIENCY; C-OXIDASE DEFICIENCY; SKELETAL-MUSCLE; POINT MUTATION; MYOPATHY; MTDNA; PATIENT; DISEASE; GENOME AB Background The mitochondrial myopathies typically affect many organ systems and are associated with mutations in mitochondrial DNA (mtDNA) that are maternally inherited. However, there is also a sporadic form of mitochondrial myopathy in which exercise intolerance is the predominant symptom. We studied the biochemical and molecular characteristics of this sporadic myopathy. Methods We sequenced the mtDNA cytochrome b gene in blood and muscle specimens from five patients with severe exercise intolerance, lactic acidosis in the resting state (in four patients), and biochemical evidence of complex III deficiency. We compared the clinical and molecular features of these patients with those previously described in four other patients with mutations in the cytochrome b gene. Results We found a total of three different nonsense mutations (G15084A, G15168A, and G15723A), one missense mutation (G14846A), and a 24-bp deletion (nucleotides 15498 to 15521) in the cytochrome b gene in the five patients. Each of these mutations impairs the enzymatic function of the cytochrome b protein. In these patients and those previously described, the clinical manifestations included progressive exercise intolerance, proximal limb weakness, and in some cases, attacks of myoglobinuria. There was no maternal inheritance and there were no mutations in tissues other than muscle. The absence of these findings suggests that the disorder is due to somatic mutations in myogenic stem cells after germ-layer differentiation. All the point mutations involved the substitution of adenine for guanine, but all were in different locations. Conclusions The sporadic form of mitochondrial myopathy is associated with somatic mutations in the cytochrome b gene of mtDNA. This myopathy is one cause of the common and often elusive syndrome of exercise intolerance. (N Engl J Med 1999; 341:1037-44.) (C)1999, Massachusetts Medical Society. C1 Columbia Univ Coll Phys & Surg, H Houston Merritt Clin Res Ctr Muscular Dystrophy, Dept Neurol, New York, NY 10032 USA. Hosp Valle De Hebron, Ctr Invest Bioquim & Biol Mol, Barcelona, Spain. UCL, Inst Neurol, London, England. Tech Univ Dresden, Klinikum Carl Gustav Carus, Neurol Klin, D-8027 Dresden, Germany. Univ Genoa, Ist Giannina Gaslini, Dept Pediat, Genoa, Italy. NINDS, NIH, Bethesda, MD 20892 USA. Uppsala Univ, Dept Biochem, Uppsala, Sweden. Ottawa Hosp, Dept Lab Med, Ottawa, ON, Canada. RP DiMauro, S (reprint author), 4 420 Coll Phys & Surg, 630 W 168th St, New York, NY 10032 USA. EM sd12@columbia.edu RI Hanna, Michael/B-1995-2009; Bruno, Claudio/A-3148-2015 OI Bruno, Claudio/0000-0002-3426-2901 FU NICHD NIH HHS [P01HD32062]; NINDS NIH HHS [NS11766]; Wellcome Trust NR 28 TC 248 Z9 256 U1 0 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 30 PY 1999 VL 341 IS 14 BP 1037 EP 1044 DI 10.1056/NEJM199909303411404 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 241JX UT WOS:000082880500004 PM 10502593 ER PT J AU Fauci, AS AF Fauci, AS TI The AIDS epidemic - Considerations for the 21st century SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; HIV-INFECTION; UNITED-STATES; TRANSMISSION; RESERVOIR; MORTALITY C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 48 TC 165 Z9 172 U1 1 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 30 PY 1999 VL 341 IS 14 BP 1046 EP 1050 DI 10.1056/NEJM199909303411406 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 241JX UT WOS:000082880500006 PM 10502595 ER PT J AU Sakaguchi, K Lorenzi, MV Matsushita, H Miki, T AF Sakaguchi, K Lorenzi, MV Matsushita, H Miki, T TI Identification of a novel activated form of the keratinocyte growth factor receptor by expression cloning from parathyroid adenoma tissue SO ONCOGENE LA English DT Article DE fibroblast growth factor receptor 2; alternative splicing; receptor tyrosine kinase; morphological transformation ID GTP-BINDING PROTEINS; CDNA CLONING; MOLECULAR-CLONING; POINT MUTATION; K-SAM; GENE; ONCOGENE; MITOGENESIS; REGULATORS; CANCER AB Parathyroid adenomas are benign tumors in the parathyroid glands, whose pathogenesis is largely unknown, We utilized an expression cDNA cloning strategy to identify oncogenes activated in parathyroid adenomas, An expression cDNA library was prepared directly from a clinical sample of parathyroid adenoma tissue, transfected into NIH3T3 cells, and foci of morphologically transformed cells were isolated, Following plasmid rescue, we identified cDNAs for the keratinocyte growth factor receptor at a high frequency, Interestingly, approximately half of the clones encoded a variant receptor containing an altered C-terminus, Analysis of the transforming activity of the variant receptor revealed that the altered C-terminus upregulated the transforming activity in a ligand-independent manner, The higher transforming activity was not accompanied by increase of dimerization or overall autophosphorylation of the receptor. However, tyrosine phosphorylation of downstream receptor substrates, including Shc isoforms and possibly FRS2, are increased in the transfectants expressing the parathyroid tumor-derived receptor. Genomic analysis showed that a previously unidentified exon was used to form the novel isoform, This alternative splicing appears to occur preferentially in parathyroid adenomas. C1 NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. NIDR, Glycobiol Program, Bethesda, MD 20892 USA. Toranomon Gen Hosp, Dept Pathol, Minato Ku, Tokyo 105, Japan. RP Miki, T (reprint author), NCI, Cellular & Mol Biol Lab, Bldg 37 Room 1E24,37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. NR 20 TC 4 Z9 4 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 30 PY 1999 VL 18 IS 40 BP 5497 EP 5505 DI 10.1038/sj.onc.1202947 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 241QU UT WOS:000082894700002 PM 10523826 ER PT J AU Shisler, JL Isaacs, SN Moss, B AF Shisler, JL Isaacs, SN Moss, B TI Vaccinia virus serpin-1 deletion mutant exhibits a host range defect characterized by low levels of intermediate and late mRNAs SO VIROLOGY LA English DT Article ID HAMSTER OVARY CELLS; SERINE PROTEINASE-INHIBITORS; RNA-LIKE SEQUENCES; COWPOX VIRUS; MYXOMA VIRUS; INTERLEUKIN-1-BETA-CONVERTING ENZYME; STAGE GENES; MURINE GAMMAHERPESVIRUS-68; PROTEASE INHIBITOR; INDUCED APOPTOSIS AB Orthopoxviruses encode three serpin homologs-SPI-1, SPI-2 and SPI-3-of which SPI-2 has been well characterized as an inhibitor of ICE-like proteases. A rabbitpox virus SPI-1 deletion mutant exhibited a host range restriction in human lung A549 and pig kidney 15 cell lines that was attributed to apoptosis. Here we report that replication of a vaccinia virus SPI-1 deletion mutant (Delta SPI-1) was restricted in primary human keratinocytes as well as A549 cells. Although chromatin condensation was detected in some A549 cells, other morphological or biochemical signs of apoptosis including DNA fragmentation, cleavage of poly(ADP-ribose)polymerase or nuclear mitotic apparatus protein, or caspase 3 activation were not found. Moreover, Delta SPI-1 protected A549 cells from apoptosis induced by tumor necrosis factor, whereas the corresponding Delta SPI-2 mutant did not Further studies indicated undiminished amounts of vaccinia virus early mRNA and replicated DNA in the absence of the SPI-1 product However, there were reduced amounts of Viral intermediate and late mRNAs, Viral late proteins, cleaved core proteins, and virus particles. These data suggested that apoptosis is not the determining factor in the host range restriction of Delta SPI-1. and that the SPI-1 gene product is needed to allow efficient expression of intermediate and late genes in A549 cells. 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 54 TC 21 Z9 22 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 SEP 30 PY 1999 VL 262 IS 2 BP 298 EP 311 DI 10.1006/viro.1999.9884 PG 14 WC Virology SC Virology GA 244FA UT WOS:000083040100003 PM 10502509 ER PT J AU Shuh, M Hill, SA Derse, D AF Shuh, M Hill, SA Derse, D TI Defective and wild-type human T-cell leukemia virus type I proviruses: Characterization of gene products and trans-interactions between proviruses SO VIROLOGY LA English DT Article ID LONG TERMINAL REPEAT; VACUOLAR H+-ATPASE; PX MESSENGER-RNA; HTLV-I; PARTIAL DELETION; MOLECULAR CLONE; PROTEIN; EXPRESSION; LYMPHOMA; REGION AB Defective provirus genomes of human T-cell leukemia virus type I are frequently detected in lymphocytes from infected individuals and in infected cell lines. One type of defective provirus contains internal deletions spanning gag, pol, and env genes but retains portions of open reading frames for trans-regulatory proteins. The deleted proviruses could potentially contribute to viral pathology by producing novel gene products that directly affect cell metabolism or that modulate expression of resident, wild-type proviruses. Virus gene products and the control of their expression were examined in cells transfected with defined molecular clones of wild-type and defective proviruses. Internally deleted provirus clones, which are unable to produce functional Tax and Rex proteins, were transcriptionally inactive in transfected cells. Ectopic expression of p40Tax activated transcription of the deleted provirus, resulting in the accumulation of a two-axon mRNA that yields a truncated form of Rex (p21Rex). Although this two-exon mRNA also has a potential initiation codon in the tax frame, a truncated form of Tax was not detected by immunoblotting or in transactivation assays. When complemented with p40Tax and p27Rex, cells transfected with deleted proviruses accumulated an unspliced mRNA that could potentially encode gag-pX fusion proteins. Although expression of deleted proviruses was dependent on trans-acting factors produced from intact proviruses, gene products from defective proviruses did not significantly affect expression of a cotransfected, full-length provirus. C1 NCI, Basic Res Lab, Div Basic Sci, Frederick, MD 21702 USA. RP Derse, D (reprint author), NCI, Basic Res Lab, Div Basic Sci, Frederick, MD 21702 USA. NR 39 TC 27 Z9 28 U1 0 U2 1 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 SEP 30 PY 1999 VL 262 IS 2 BP 442 EP 451 DI 10.1006/viro.1999.9909 PG 10 WC Virology SC Virology GA 244FA UT WOS:000083040100016 PM 10502522 ER PT J AU Bukh, J Apgar, CL Yanagi, M AF Bukh, J Apgar, CL Yanagi, M TI Toward a surrogate model for hepatitis C virus: An infectious molecular clone of the GB virus-B hepatitis agent SO VIROLOGY LA English DT Article ID CDNA CLONE; GENETIC-ANALYSIS; RNA; IDENTIFICATION; FLAVIVIRIDAE; TRANSMISSION; CHIMPANZEES; 3'-TERMINUS; TRANSCRIPTS; ELEMENTS AB GB virus-B (GBV-B) is a member of the Flaviviridae family of viruses. This RNA virus infects tamarins, but its natural host is not known. GBV-B has special interest because it is the virus that is most closely related to hepatitis C virus (HCV), an important human pathogen. In the present study, we identified a previously unrecognized sequence at the 3' end of the GBV-B genome. This new 3' terminal sequence can farm several predicted stem-loop structures as is typical for other members of the Flaviviridae family. We constructed molecular clones and showed that the new 3' UTR sequence was critical for in vivo infectivity. After intrahepatic transfection of two tamarins with RNA transcripts of the full-length GBV-B clone, we detected high viral titers from Week 1 postinoculation with peak titers of similar to 10(8) genome equivalents/ml. The viremic pattern of GBV-B infection in the transfected animals was the same as in animals inoculated intravenously with the virus pool used as the cloning source. The sequence of the recombinant virus was recovered from one of the tamarins and shown to be identical to that of the infectious clone. The development of severe hepatitis in both tamarins infected with the recombinant GBV-B virus provides formal proof that GBV-B is a true hepatitis virus. (C) 1999 Academic Press. C1 NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Bukh, J (reprint author), NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bldg 7,Room 201,7 Ctr Dr,MSC 0740, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CO-56000]; NIAID NIH HHS [N01-AI-52705] NR 30 TC 104 Z9 107 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 SEP 30 PY 1999 VL 262 IS 2 BP 470 EP 478 DI 10.1006/viro.1999.9941 PG 9 WC Virology SC Virology GA 244FA UT WOS:000083040100019 PM 10502525 ER PT J AU Feller, SE Huster, D Gawrisch, K AF Feller, SE Huster, D Gawrisch, K TI Interpretation of NOESY cross-relaxation rates from molecular dynamics simulation of a lipid bilayer SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID MODEL C1 Wabash Coll, Dept Chem, Crawfordsville, IN 47933 USA. NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. RP Feller, SE (reprint author), Wabash Coll, Dept Chem, Crawfordsville, IN 47933 USA. NR 8 TC 82 Z9 83 U1 1 U2 9 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 SEP 29 PY 1999 VL 121 IS 38 BP 8963 EP 8964 DI 10.1021/ja991456n PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 244BT UT WOS:000083032500041 ER PT J AU Chao, LL Martin, A Haxby, JV AF Chao, LL Martin, A Haxby, JV TI Are face-responsive regions selective only for faces? SO NEUROREPORT LA English DT Article DE animals; face perception; fusiform gyrus; fMRI; superior temporal sulcus ID HUMAN VISUAL-CORTEX; BIOLOGICAL MOTION; STIMULI; REPRESENTATION; PERCEPTION; AREA AB To examine the specificity of face-responsive regions for face processing, we used fMRI to measure the response of the fusiform gyrus and the superior temporal sulcus (STS) to pictures of human faces, animals, faceless animals, and houses. Results indicate that faces, animals, and faceless animals all elicited greater activity than houses, and had identical peaks of activation in the lateral fusiform gyrus, bilaterally, and in the right posterior STS. Moreover, within the lateral fusiform gyrus the, responses to faces, animals and faceless animals were all greater than the responses to these stimuli in the medial aspect of the fusiform gyrus, a region that responds more strongly to other objects (e.g. houses). These findings suggest that the neural respresentation of animals in the fusiform gyrus and the posterior STS suggest that the neural representation of relies strongly on the same neural substrates that represent faces. (C) 1999 Lippincott Williams & Wilkins. C1 NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Chao, LL (reprint author), NIMH, Lab Brain & Cognit, Bldg 10,Room 4C104, Bethesda, MD 20892 USA. RI martin, alex/B-6176-2009 NR 25 TC 102 Z9 103 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD SEP 29 PY 1999 VL 10 IS 14 BP 2945 EP 2950 DI 10.1097/00001756-199909290-00013 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 241CV UT WOS:000082865500016 PM 10549802 ER PT J AU Wildenauer, DB Schwab, SG Maier, W Detera-Wadleigh, SD AF Wildenauer, DB Schwab, SG Maier, W Detera-Wadleigh, SD TI Do schizophrenia and affective disorder share susceptibility genes? SO SCHIZOPHRENIA RESEARCH LA English DT Article; Proceedings Paper CT Symposium on Are Schizophrenia and Bipolar Disorders 1 Disease or 2 CY APR 17, 1999 CL SANTA FE, NEW MEXICO DE affective disorder; environmental factor; multigenic inheritance; schizophrenia; shared locus; susceptibility gene ID BIPOLAR DISORDER; SCHIZOAFFECTIVE DISORDER; CONTROLLED FAMILY; LINKAGE ANALYSIS; GENOME SCAN; PSYCHOSES; LOCUS; PEDIGREES; CHROMOSOME-18; ASSOCIATION AB Schizophrenia and affective disorders are relatively common neuropsychiatric diseases with a complex genetic etiology. A multigenic inheritance with variable influence of unknown environmental factors may be involved. Family studies have demonstrated the existence of both phenotypes in the same kindreds, and in certain cases, a transition from one phenotype to another occurs. In addition, intermediate phenotypes such as schizoaffective disorders are found in families with schizophrenia and affective illness. Recent genome and chromosomal scans appear to support these epidemiologic data, since susceptibility regions for both schizophrenia and affective disorders have been found to overlap, on chromosomes 10p13-p12, 13q32, 18p and 22q11-q13. These studies were performed in independently ascertained family samples with index patients afflicted either with schizophrenia or bipolar disorder. Taken together, these findings imply shared loci for schizophrenia and affective disorders among those required for the full expression of the phenotype. Identification and molecular characterization of the genetic components conferring risk to both disorders would impact positively on diagnosis, prevention, and treatment. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Univ Bonn, Dept Psychiat, Genet Mol Lab, D-53111 Bonn, Germany. Univ Bonn, Dept Psychiat, D-53105 Bonn, Germany. NIMH, Bethesda, MD 20892 USA. RP Wildenauer, DB (reprint author), Univ Bonn, Dept Psychiat, Genet Mol Lab, Wilhelmstr 31, D-53111 Bonn, Germany. NR 27 TC 72 Z9 74 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD SEP 29 PY 1999 VL 39 IS 2 BP 107 EP 111 DI 10.1016/S0920-9964(99)00108-5 PG 5 WC Psychiatry SC Psychiatry GA 238PN UT WOS:000082718800004 PM 10507520 ER PT J AU Goldberg, TE AF Goldberg, TE TI Some fairly obvious distinctions between schizophrenia and bipolar disorder SO SCHIZOPHRENIA RESEARCH LA English DT Article; Proceedings Paper CT Symposium on Are Schizophrenia and Bipolar Disorders 1 Disease or 2 CY APR 17, 1999 CL SANTA FE, NEW MEXICO DE bipolar disorder; cognitive abnormalities; neurocognitive findings; schizophrenia; working memory ID BACKWARD-MASKING; MANIA; PERFORMANCE; DYSFUNCTION; ATTENTION AB In examining the ratio of 'famous' individuals with bipolar disorder to those with schizophrenia, it is evident that the ratio greatly favors those with bipolar disorder, suggesting that schizophrenia somehow precludes expert performance or high-level accomplishment. Why might this be so? One possible explanation lies in neurocognitive findings. In this review, I suggest that patients with schizophrenia perform consistently worse than patients with bipolar disorder on a variety of higher level cognitive tasks (though bipolar patients themselves often evince impairment in comparison to healthy controls). Working memory, in particular, appears to discriminate between the groups. However, questions remain, including the effects of state and medications, and the conclusion that I reach does not exclude the possibility that the two disorders share some but not all etiologic or pathophysiologic features. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. RP Goldberg, TE (reprint author), NIMH, Clin Brain Disorders Branch, 10 Ctr Dr,MSC 1379,Room 4S 235, Bethesda, MD 20892 USA. NR 25 TC 41 Z9 41 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD SEP 29 PY 1999 VL 39 IS 2 BP 127 EP 132 DI 10.1016/S0920-9964(99)00111-5 PG 6 WC Psychiatry SC Psychiatry GA 238PN UT WOS:000082718800007 PM 10507523 ER PT J AU Post, RM AF Post, RM TI Comparative pharmacology of bipolar disorder and schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article; Proceedings Paper CT Symposium on Are Schizophrenia and Bipolar Disorders 1 Disease or 2 CY APR 17, 1999 CL SANTA FE, NEW MEXICO DE bipolar disorder; comparative pharmacology; schizophrenia ID TRANSCRANIAL MAGNETIC STIMULATION; TARDIVE-DYSKINESIA; MOOD STABILIZERS; RECEPTOR DENSITY; MANIA; CARBAMAZEPINE; RISPERIDONE; LITHIUM; NIMODIPINE; DEPRESSION AB The treatment of acute mania and schizophrenia overlap considerably in terms of the typical and atypical neuroleptics, but begin to diverge with the recognized mood stabilizers for bipolar affective illness - lithium, carbamazepine, and valproate - which are substantially less effective in schizophrenia than in affective illness. Moreover, the L-type calcium channel blocker verapamil is reported to be effective in mania, but it may exacerbate schizophrenia. A series of new putative mood stabilizing anticonvulsants (such as lamotrigine, gabapentin, and topiramate) and possible second-messenger targeted treatments (tamoxifen and omega-3 fatty acids) deserve further study in both affective and schizophrenic syndromes. Repeated transcranial magnetic stimulation (rTMS) of the brain offers considerable promise in the treatment of a variety of neuropsychiatric syndromes, especially with preliminary evidence of frequency-dependent effects on regional cerebral brood flow. New insights about the potential neurotrophic effects of lithium and the gene transcriptional effects of other psychotropics offer exciting new targets for therapeutics and strategies for future clinical trials and therapeutic applications in both syndromes. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. RP Post, RM (reprint author), NIMH, Biol Psychiat Branch, 10 Ctr Dr,MSC 1272,Bldg 10,Rm 3N212, Bethesda, MD 20892 USA. NR 47 TC 27 Z9 27 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD SEP 29 PY 1999 VL 39 IS 2 BP 153 EP 158 DI 10.1016/S0920-9964(99)00115-2 PG 6 WC Psychiatry SC Psychiatry GA 238PN UT WOS:000082718800011 PM 10507527 ER PT J AU Torrey, F Jablensky, A Pearlson, G Knable, M Adityanjee Ingraham, L Africa, B De Lisi, L Wildenauer, D Copolov, D Buka, S Murray, R Stevens, J Jones, P Rund, B Goldberg, T Gallhofer, B Falkai, P Tsuang, M Schroder, J Bogerts, B Friedman, L Bogerts, B Lawson, B Bachus, S Post, R Haas, G AF Torrey, F Jablensky, A Pearlson, G Knable, M Adityanjee Ingraham, L Africa, B De Lisi, L Wildenauer, D Copolov, D Buka, S Murray, R Stevens, J Jones, P Rund, B Goldberg, T Gallhofer, B Falkai, P Tsuang, M Schroder, J Bogerts, B Friedman, L Bogerts, B Lawson, B Bachus, S Post, R Haas, G TI Stanley Foundation Satellite Symposium, Santa Fe, New Mexico, Saturday, April 17, 1999 SO SCHIZOPHRENIA RESEARCH LA English DT Editorial Material C1 Johns Hopkins Univ, Baltimore, MD 21218 USA. Wright State Univ, Dayton, OH 45435 USA. George Washington Univ, Washington, DC 20052 USA. SUNY Stony Brook, Stony Brook, NY 11794 USA. Univ Melbourne, Parkville, Vic 3052, Australia. Inst Psychiat, London, England. Univ Oregon, Eugene, OR 97403 USA. Univ Oslo, N-0316 Oslo, Norway. Univ Giessen, D-35390 Giessen, Germany. Univ Bonn, D-5300 Bonn, Germany. Univ Nottingham, Nottingham NG7 2RD, England. Harvard Univ, Cambridge, MA 02138 USA. Univ Bonn, D-5300 Bonn, Germany. Univ Heidelberg, D-6900 Heidelberg, Germany. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Magdeburg, D-39106 Magdeburg, Germany. Indiana Univ, Bloomington, IN 47405 USA. NIMH, Intramural Res Program, Bethesda, MD 20892 USA. Univ Melbourne, Parkville, Vic 3052, Australia. Univ Pittsburgh, Pittsburgh, PA 15260 USA. RI Buka, Stephen/H-7335-2014; Jablensky, Assen/H-5116-2014 OI Buka, Stephen/0000-0002-8578-9308; NR 0 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD SEP 29 PY 1999 VL 39 IS 2 BP 159 EP 163 PG 5 WC Psychiatry SC Psychiatry GA 238PN UT WOS:000082718800012 ER PT J AU Arezi, B Kirk, BW Copeland, WC Kuchta, RD AF Arezi, B Kirk, BW Copeland, WC Kuchta, RD TI Interactions of DNA with human DNA primase monitored with photoactivatable cross-linking agents: Implications for the role of the p58 subunit SO BIOCHEMISTRY LA English DT Article ID POLYMERASE ALPHA-PRIMASE; DROSOPHILA-MELANOGASTER EMBRYOS; CALF THYMUS; BETA; INITIATION; MECHANISM; SITES; CELLS; TRIPHOSPHATES; PURIFICATION AB Regulation of the p49-p58 primase complex during primer synthesis and the interaction of the primase subunits with DNA were examined. After primase synthesizes a primer that DNA polymerase alpha (pol alpha) can readily elongate, further primase activity is negatively regulated. This occurs within both the context of the four-subunit pol alpha-primase complex and in the p49-p58 primase complex, indicating that the newly generated primer-template species need not interact with pol alpha to regulate further primase activity, Photo-cross-linking of single-stranded DNA-primase complexes revealed that whereas the isolated p49 and p58 subunits both reacted with DNA upon photolysis, only the p58 subunit reacted with the DNA when photolysis was performed using the p49-p58 primase complex. After primer synthesis by the complex, p58 was again the only subunit that reacted with the DNA, These results suggest a model for regulation of primer synthesis in which the newly synthesized primer-template species binds to p58 and regulates further primer synthesis. Additionally, the ability of p58 to interact with primer-template species suggests that p58 mediates the transfer of primers from the primase active site to pol alpha. C1 Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA. NIEHS, Genet Mol Lab, Res Triangle Pk, NC 27709 USA. RP Kuchta, RD (reprint author), Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA. FU NIGMS NIH HHS [GM54194] NR 30 TC 32 Z9 32 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 28 PY 1999 VL 38 IS 39 BP 12899 EP 12907 DI 10.1021/bi9908991 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 243VQ UT WOS:000083018500041 PM 10504261 ER PT J AU Iruela-Arispe, ML Lombardo, M Krutzsch, HC Lawler, J Roberts, DD AF Iruela-Arispe, ML Lombardo, M Krutzsch, HC Lawler, J Roberts, DD TI Inhibition of angiogenesis by thrombospondin-1 is mediated by 2 independent regions within the type 1 repeats SO CIRCULATION LA English DT Article DE angiogenesis; endothelium; vessels ID TRANSFORMING GROWTH-FACTOR; ENDOTHELIAL-CELLS; PEPTIDES; PROTEIN; BETA; ADHESION; CD36; GENE AB Background-Suppression of tumor growth by thrombospondin-1 (TSP-1) has been associated with its ability to inhibit neovascularization. The antiangiogenic activity of TSP-1, as defined by cornea pocket assays, was previously mapped to the amino-terminal portion of the protein within the procollagen region and the type 1 repeats. Methods and Results-We evaluated the specificity and efficacy of different regions of TSP-1 using recombinant fragments of the protein on chorioallantoic membrane (CAM) angiogenesis and endothelial cell proliferation assays. In both assays, fragments containing the second and third type 1 repeats but not the procollagen region inhibited angiogenesis and endothelial cell proliferation. To further define the sequences responsible for the angiostatic effect of TSP-1, we used synthetic peptides. The CAM assay defined 2 sequences that independently suppressed angiogenesis. The amino-terminal end of the type 1 repeats showed higher potency for inhibiting angiogenesis driven by basic fibroblast growth factor (FGF-2), whereas the second region;equally blocked angiogenesis driven by either FGF-2 or vascular endothelial growth factor (VEGF). Modifications of the active peptides revealed the specific amino acids required for the inhibitory response. One sequence included the conserved tryptophan residues in the amino-terminal end of the second and third type 1 repeats, and the other involved the amino acids that follow the CSVTCG sequence in the carboxy-terminus of these repeats. Both inhibition in the CAM assay and inhibition of breast tumor xenograft growth in nude mice were independent of the TGF-beta-activating sequence located in the second type 1 repeat. Conclusions-These results indicate that the type 1 repeats of TSP-1 contain 2 subdomains that may independently inhibit neovascularization. They also identify 2 independent pathways by which TSP-1 can block FGF-2 and VEGF angiogenic signals on endothelial cells. C1 Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA. Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Iruela-Arispe, ML (reprint author), Univ Calif Los Angeles, Inst Mol Biol, 611 Charles Young Dr E, Los Angeles, CA 90095 USA. RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU NCI NIH HHS [CA-63356-01]; NHLBI NIH HHS [HL-28749] NR 24 TC 219 Z9 228 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 28 PY 1999 VL 100 IS 13 BP 1423 EP 1431 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 239YP UT WOS:000082798400013 PM 10500044 ER PT J AU Chun, TW Fauci, AS AF Chun, TW Fauci, AS TI Latent reservoirs of HIV: Obstacles to the eradication of virus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; CD4(+) T-CELLS; INTRAVENOUS INTERLEUKIN-2; COMBINATION THERAPY; ANTIVIRAL THERAPY; CONTROLLED TRIAL; VIRAL-LOAD; IN-VIVO; INFECTION AB The use of highly active antiretroviral therapy (HAART) in the treatment of HIV-l-infected individuals has provided a considerable amount of information regarding the dynamics of viral replication and has resulted in enormous advances in HIV therapeutics. The profound suppression of plasma viremia in HIV-infected individuals receiving HAART has resulted in a highly beneficial clinical effect and a dramatic decrease in the death rate attributable to AIDS. Nonetheless, the persistence of reservoirs of HIV, including latently infected, resting CD4(+) T cells that can give rise to infectious HIV upon stimulation in vitro, has posed a sobering challenge to the long-term control or eradication of HIV in infected individuals receiving HAART. Although a recent study has demonstrated that the size of the pool of latently infected, resting CD4(+) T cells can be markedly diminished with intermittent interleukin (IL)-2 and continuous HAART, complete eradication of HIV in infected individuals remains extremely problematic. Here, we discuss recent developments in studies of the latent reservoir of HIV in patients receiving HAART and implications for the long-term treatment of infected individuals and eradication of the infection. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Chun, TW (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Room 6A32, Bethesda, MD 20892 USA. NR 61 TC 253 Z9 258 U1 0 U2 14 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 SEP 28 PY 1999 VL 96 IS 20 BP 10958 EP 10961 DI 10.1073/pnas.96.20.10958 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 241DY UT WOS:000082868500006 PM 10500107 ER PT J AU Sharma, P Sharma, M Amin, ND Albers, RW Pant, HC AF Sharma, P Sharma, M Amin, ND Albers, RW Pant, HC TI Regulation of cyclin-dependent kinase 5 catalytic activity by phosphorylation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CDC2-LIKE KINASE; PROTEIN-KINASE; STRUCTURAL BASIS; CDK5 ACTIVATOR; EXPRESSION; COMPLEX AB Cyclin-dependent kinase 5 (cdk5) is found in an active form only in neuronal cells. Activation by virtue of association with the cyclin-like neuronal proteins p35 (or its truncated form p25) and p39 is the only mechanism currently shown to regulate cdk5 catalytic activity, In addition to cyclin binding, other members of the cdk family require for maximal activation phosphorylation of a Ser/Thr residue (Thr(160) in the case of cdk-2) that is conserved in all cdks except cdk8, This site is phosphorylated by cdk-activating kinases, which, however, do not phosphorylate cdk5, To examine the possible existence of a phosphorylation-dependent regulatory mechanism in the case of cdk5, we have metabolically labeled PC12 cells with P-32(i) and shown that the endogenous cdk5 is phosphorylated. Bacterially expressed cdk5 also can be phosphorylated by PC12 cell lysates. Phosphorylation of cdk5 by a PC12 cell lysate results in a significant increase in cdk5/p25 catalytic activity. Ser(159) in cdk5 is homologous to the regulatory Thr(160) in cdk2, A Ser(159)-to-Ala (S159A) cdk5 mutant did not show similar activation, which suggests that cdk5 is also regulated by phosphorylation at this site. Like other members of the cdk family, cdk5 catalytic activity is influenced by both p25 binding and phosphorylation, We show that the cdk5-activating kinase (cdk5AK) is distinct from the cdk-activating kinase (cyclin H/cdk7) that was reported previously to neither phosphorylate cdk5 nor affect its activity, We also show that casein kinase I, but not casein kinase II, can phosphorylate and activate cdk5 in vitro. C1 NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Pant, HC (reprint author), NINDS, Neurochem Lab, NIH, Bldg 36,Room 4D20, Bethesda, MD 20892 USA. NR 25 TC 76 Z9 85 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 SEP 28 PY 1999 VL 96 IS 20 BP 11156 EP 11160 DI 10.1073/pnas.96.20.11156 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 241DY UT WOS:000082868500045 PM 10500146 ER PT J AU Bermingham, A Collins, PL AF Bermingham, A Collins, PL TI The M2-2 protein of human respiratory syncytial virus is a regulatory factor involved in the balance between RNA replication and transcription SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE paramyxovirus; reverse genetics; RNA regulation; vaccine development ID MESSENGER-RNA; SENDAI-VIRUS; V-PROTEIN; ELONGATION-FACTOR; SEQUENCE-ANALYSIS; CULTURED-CELLS; C-PROTEINS; N-PROTEIN; SH-GENE; EXPRESSION AB The M2 mRNA of human respiratory syncytial virus (RSV) contains two overlapping ORFs, encoding the transcription antitermination protein (M2-1) and the 90-aa M2-2 protein of unknown function. Viable recombinant RSV was recovered in which expression of M2-2 was ablated, identifying it as an accessory factor dispensable for growth in vitro. Virus lacking M2-2 grew less efficiently than did the wild-type parent in vitro, with titers that were reduced 1,000-fold during the initial 2-5 days and 10-fold by days 7-8. Compared with wild-type virus, the intracellular accumulation of RNA by M2-2 knockout virus was reduced 3- to 4-fold or more for genomic RNA and increased 2- to 4-fold or more for mRNA, Synthesis of the F and G glycoproteins, the major RSV neutralization and protective antigens, was increased in proportion with that of mRNA. In cells infected with wild-type RSV, mRNA accumulation increased dramatically up to ap proximately 12-15 hr after infection and then leveled off, whereas accumulation continued to increase in cells infected with the M2-2 knockout viruses. These findings suggest that M2-2 mediates a regulatory "switch" from transcription to RNA replication, one that provides an initial high level of mRNA synthesis followed by a shift in the RNA synthetic program in favor of genomic RNA for virion assembly. With regard to vaccine development, the M2-2 knockout has a highly desirable phenotype in which virus growth is attenuated while gene expression is concomitantly increased. C1 NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Collins, PL (reprint author), NIAID, Infect Dis Lab, 7 Ctr Dr MSC 0720, Bethesda, MD 20892 USA. NR 29 TC 118 Z9 129 U1 1 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 28 PY 1999 VL 96 IS 20 BP 11259 EP 11264 DI 10.1073/pnas.96.20.11259 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 241DY UT WOS:000082868500063 PM 10500164 ER PT J AU Munoz, V Eaton, WA AF Munoz, V Eaton, WA TI A simple model for calculating the kinetics of protein folding from three-dimensional structures SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SINGLE-DOMAIN PROTEINS; TRANSITION-STATE; CHYMOTRYPSIN INHIBITOR-2; STATISTICAL-MECHANICS; LANDSCAPE PERSPECTIVE; FUNNELS; STABILITY; DYNAMICS; RATES AB An elementary statistical mechanical model was used to calculate the folding rates for 22 proteins from their known three-dimensional structures. In this model, residues come into contact only after ail of the intervening chain is in the native conformation. An additional simplifying assumption is that native structure grows from localized regions that then fuse to form the complete native molecule, The free energy function for this model contains just two contributions-conformational entropy of the backbone and the energy of the inter-residue contacts. The matrix of interresidue interactions is obtained from the atomic coordinates of the three-dimensional structure. For the 18 proteins that exhibit two-state equilibrium and kinetic behavior, profiles of the free energy versus the number of native peptide bonds show two deep minima, corresponding to the native and denatured states, For four proteins known to exhibit intermediates in folding, the free energy profiles show additional deep minima. The calculated rates of folding the two-state proteins, obtained by solving a diffusion equation for motion on the free energy profiles, reproduce the experimentally determined values surprisingly well, The success of these calculations suggests that folding speed is largely determined by the distribution and strength of contacts in the native structure. We also calculated the effect of mutations on the folding kinetics of chymotrypsin inhibitor 2, the most intensively studied two-state protein, with some success. C1 NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Munoz, V (reprint author), NIDDK, Phys Chem Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. EM vmunoz@helix.nih.gov; eaton@helix.nih.gov NR 41 TC 467 Z9 474 U1 3 U2 27 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 SEP 28 PY 1999 VL 96 IS 20 BP 11311 EP 11316 DI 10.1073/pnas.96.20.11311 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 241DY UT WOS:000082868500072 PM 10500173 ER PT J AU Lorick, KL Jensen, JP Fang, SY Ong, AM Hatakeyama, S Weissman, AM AF Lorick, KL Jensen, JP Fang, SY Ong, AM Hatakeyama, S Weissman, AM TI RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID EPITHELIAL NA+ CHANNEL; PROTEIN; DEGRADATION; BRCA1; GENES; IDENTIFICATION; COMPLEX; MOUSE; SUPPRESSION; ACTIVATION AB A RING finger-containing protein (AO7) that binds ubiquitin-conjugating enzymes (E2s) and is a substrate for E2-dependent ubiquitination was identified. Mutations of cation-coordinating residues within AO7's RING finger abolished ubiquitination,as did chelation of zinc. Several otherwise-unrelated RING finger proteins, including BRCA1, Siah-1, TRC8, NF-X1, kf-1, and Praja1, were assessed for their ability to facilitate E2-dependent ubiquitination, In all cases, ubiquitination was observed. The RING fingers were implicated directly in this activity through mutations of metal-coordinating residues or chelation of zinc. These findings suggest that a large number of RING finger-containing proteins, with otherwise diverse structures and functions, may play previously unappreciated roles in modulating protein levels via ubiquitination. C1 NCI, Lab Immune Cell Biol, Div Basic Sci, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Weissman, AM (reprint author), NCI, Lab Immune Cell Biol, Div Basic Sci, Natl Inst Hlth, Bldg 10,Room 1B34,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Fang, Shengyun/H-3802-2011; Hatakeyama, Shigetsugu/C-8333-2012; Tang, Amy/L-3226-2016 OI Hatakeyama, Shigetsugu/0000-0002-2150-9979; Tang, Amy/0000-0002-5772-2878 NR 39 TC 762 Z9 794 U1 3 U2 17 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 SEP 28 PY 1999 VL 96 IS 20 BP 11364 EP 11369 DI 10.1073/pnas.96.20.11364 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 241DY UT WOS:000082868500081 PM 10500182 ER PT J AU Xiang, Y Moss, B AF Xiang, Y Moss, B TI IL-18 binding and inhibition of interferon gamma induction by human poxvirus-encoded proteins SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MOLLUSCUM CONTAGIOSUM VIRUS; VACCINIA VIRUS; INTERLEUKIN-18 RECEPTOR; SPECIES-SPECIFICITY; ESCHERICHIA-COLI; IMMUNE-RESPONSE; T-CELLS; HOMOLOG; EXPRESSION; APOPTOSIS AB Molluscum contagiosum virus (MCV) is a common, human poxvirus that causes small papular skin lesions that persist for long periods without signs of inflammation. Previous studies revealed that MCV encodes a family of proteins with homology to mammalian IL-18 binding proteins. IL-18 is a proinflammatory cytokine that induces synthesis of interferon gamma, activates NK cells, and is required for a T-lymphocyte helper type 1 response. We expressed and purified the proteins encoded by the MC53L and MC54L genes of MCV, as well as their human and murine homologs. All four recombinant proteins were able to bind with high affinity to human and murine IL-18 molecules and inhibited IL-18 mediated interferon gamma production in a dose-dependent manner. The pirating of IL-18 binding proteins by poxviruses and their use as decoy receptors is consistent with the critical role of IL-18 in defense against virus infections and provides a mechanism for evasion of the immune system by MCV. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. NR 43 TC 144 Z9 150 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 28 PY 1999 VL 96 IS 20 BP 11537 EP 11542 DI 10.1073/pnas.96.20.11537 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 241DY UT WOS:000082868500111 PM 10500212 ER PT J AU Arnaout, RA Lloyd, AL O'Brien, TR Goedert, JJ Leonard, JM Nowak, MA AF Arnaout, RA Lloyd, AL O'Brien, TR Goedert, JJ Leonard, JM Nowak, MA TI A simple relationship between viral load and survival time in HIV-1 infection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE prognosis; CD4(+) cell count; CD4(+) cell decline; antiviral therapy; statistical analysis ID HUMAN-IMMUNODEFICIENCY-VIRUS; DYNAMICS IN-VIVO; RNA LEVELS; HOMOSEXUAL MEN; RAPID TURNOVER; PLASMA; AIDS; THERAPY; SEROCONVERSION; LYMPHOCYTES AB Despite important recent insights into the short-term dynamics of HIV-1 infection, our understanding of the long-term pathogenesis of AIDS remains unclear. Using an approach that places rapid progressors, typical progressors, and nonprogressors on a single clinical spectrum of disease progression, we quantitate the previously reported relationship between viral load and survival time. We introduce the concept of viral constant, present evidence that this quantity is conserved across patients, and explore the immunopathological implications of this finding. We conclude with a quantitative approach for assessing the benefits of a given regime of antiviral therapy. C1 Inst Adv Study, Princeton, NJ USA. Univ Oxford, Dept Zool, Wellcome Trust Ctr Epidemiol Infect Dis, Oxford OX1 3PS, England. Natl Canc Inst, Viral Epidemiol Branch, Publ Hlth Serv, US Dept HHS, Rockville, MD 20852 USA. Abbott Labs, Div Pharmaceut Prod, Abbott Pk, IL 60064 USA. RP Nowak, MA (reprint author), Inst Adv Study, Olden Lane, Princeton, NJ USA. RI Nowak, Martin/A-6977-2008; Lloyd, Alun/H-4944-2012 NR 36 TC 25 Z9 27 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 SEP 28 PY 1999 VL 96 IS 20 BP 11549 EP 11553 DI 10.1073/pnas.96.20.11549 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 241DY UT WOS:000082868500113 PM 10500214 ER PT J AU Gallia, GL Darbinian, N Tretiakova, A Ansari, SA Rappaport, J Brady, J Wortman, MJ Johnson, EM Khalili, K AF Gallia, GL Darbinian, N Tretiakova, A Ansari, SA Rappaport, J Brady, J Wortman, MJ Johnson, EM Khalili, K TI Association of HIV-1 Tat with the cellular protein, Pur alpha, is mediated by RNA SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SINGLE-STRANDED-DNA; HUMAN-IMMUNODEFICIENCY-VIRUS; BINDING PROTEIN; GLIAL-CELLS; TRANSCRIPTIONAL REGULATION; GENE-TRANSCRIPTION; CONTROL ELEMENT; LATE PROMOTER; T-ANTIGEN; SEQUENCE AB The interaction between two regulatory proteins plays a crucial role in the control of several biological events, including gene transcription. In this report, we demonstrate that the interaction between the cellular sequence-specific single-stranded DNA binding protein Pur alpha and the HIV type 1 (HIV-1) Tat protein is mediated by specific ribonucleic acids. The region of Tat that is important for its interaction with Pur alpha includes the region demonstrated to bind Tat's viral RNA target, TAR. A 10-nucleotide CC-rich consensus sequence identified in RNAs associated with Pur alpha derived from human U-87MG cells plays an important role in the Pur alpha:Tat interaction as examined by an in vitro reconstitution assay. Furthermore, expression of the Pur alpha-associated RNA in these cells enhances transcriptional activation of the HIV-1 promoter by Tat and Pur alpha. C1 Med Coll Penn & Hahnemann Univ, Ctr NeuroVirol & NeuroOncol, Philadelphia, PA 19102 USA. NCI, Virus Tumor Biol Sect, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. CUNY Mt Sinai Sch Med, Dept Pathol, Brookdale Ctr Mol & Dev Biol, New York, NY 10029 USA. RP Khalili, K (reprint author), Temple Univ, Ctr Neurovirol & Canc Biol, Biol Life Sci Bldg,Room 203-N,1900 N 12th St, Philadelphia, PA 19122 USA. NR 30 TC 47 Z9 47 U1 1 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 SEP 28 PY 1999 VL 96 IS 20 BP 11572 EP 11577 DI 10.1073/pnas.96.20.11572 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 241DY UT WOS:000082868500117 PM 10500218 ER PT J AU Galbraith, JA Reese, TS Schlief, ML Gallant, PE AF Galbraith, JA Reese, TS Schlief, ML Gallant, PE TI Slow transport of unpolymerized tubulin and polymerized neurofilament in the squid giant axon SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE slow axonal transport; diffusion; axoplasmic transport; cytoskeleton ID GROWING AXONS; FROG NEURONS; PC12 CELLS; MICROTUBULES; NEURITES; DYNAMICS; ACTIN; ORGANELLES; FILAMENTS; NETWORKS AB A major issue in the slow transport of cytoskeletal proteins is the form in which they are transported. We have investigated the possibility that unpolymerized as well as polymerized cytoskeletal proteins can be actively transported in axons. We report the active transport of highly diffusible tubulin oligomers, as well as transport of the less diffusible neurofilament polymers. After injection into the squid giant axon, tubulin was transported in an anterograde direction at an average rate of 2.3 mm/day, whereas neurofilament was moved at 1.1 mm/day. Addition of the metabolic poisons cyanide or dinitrophenol reduced the active transport of both proteins to less than 10% of control values, whereas disruption of microtubules by treatment of the axon with cold in the presence of nocodazole reduced transport of both proteins to approximate to 20% of control levels, Passive diffusion of these proteins occurred in parallel with transport. The diffusion coefficient of the moving tubulin in axoplasm was 8.6 mu m(2)/s compared with only 0.43 mu m(2)/s for neurofilament. These results suggest that the tubulin,vas transported in the unpolymerized state and that the neurofilament was transported in the polymerized state by an energy-dependent nocodazole/cold-sensitive transport mechanism. C1 NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. Marine Biol Lab, Woods Hole, MA 02543 USA. RP NINDS, Neurobiol Lab, NIH, Bldg 36,2A21, Bethesda, MD 20892 USA. EM jgalbrai@codon.nih.gov; gallant@codon.nih.gov NR 44 TC 59 Z9 59 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 SEP 28 PY 1999 VL 96 IS 20 BP 11589 EP 11594 DI 10.1073/pnas.96.20.11589 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 241DY UT WOS:000082868500120 PM 10500221 ER PT J AU Houenou, LJ D'Costa, AP Li, LX Turgeon, TL Enyadike, C Alberdi, E Becerra, SP AF Houenou, LJ D'Costa, AP Li, LX Turgeon, TL Enyadike, C Alberdi, E Becerra, SP TI Pigment epithelium-derived factor promotes the survival and differentiation of developing spinal motor neurons SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE serine protease inhibitor; neurotrophic factor; cell culture; neonatal mouse; cell death ID CEREBELLAR GRANULE CELLS; NEUROTROPHIC FACTOR PREVENTS; SERINE-PROTEASE INHIBITOR; FACTOR PEDF; IN-VIVO; NEXIN-I; MOTONEURON SURVIVAL; NERVOUS-SYSTEM; DEATH; THROMBIN AB Pigment epithelium-derived factor (PEDF) is a member of the serine protease inhibitor (serpin) superfamily that has been shown previously to promote the survival and/or differentiation of rat cerebellar granule neurons and human retinoblastoma cells in vitro. However, in contrast to most serpins, PEDF has no inhibitory activity against any known proteases and its described biological activities do not appear to require the serpin-reactive loop located toward the carboxy end of the polypeptide. Because another serpin, protease nexin-l, has been shown to promote the in vivo survival and growth of motor neurons, the authors investigated the potential neurotrophic effects of PEDF on spinal cord motor neurons in highly enriched cultures and in vivo after injury. Here, it is shown that native bovine and recombinant human PEDF promoted the survival and differentiation (neurite outgrowth) of embryonic chick spinal cord motor neurons in vitro in a dose-dependent manner. A truncated form of PEDF that lacks approximate to 62% of the carboxy end of the polypeptide comprising the homologous serpin-reactive loop also exhibited neurotrophic activities similar to those of the full-length protein. Furthermore, the data here showed that PEDF was transported retrogradely and prevented the death and atrophy of spinal motor neurons in the developing neonatal mouse after axotomy. These results indicate that PEDF exerts trophic effects on motor neurons, and, together with previous reports, these findings suggest that this protein may be useful as a pharmacologic agent to promote the development and maintenance of motor neurons. Published 1999 Wiley-Liss, Inc.dagger. C1 Wake Forest Univ, Sch Med, Dept Neurobiol & Anat, Winston Salem, NC 27157 USA. Prosperon Pharmaceut Inc, Winston Salem, NC 27103 USA. NEI, Lab Retinal Cell Mol Biol, NIH, Bethesda, MD 20892 USA. RP Houenou, LJ (reprint author), Wake Forest Univ, Sch Med, Dept Neurobiol & Anat, Med Ctr Blvd, Winston Salem, NC 27157 USA. NR 43 TC 99 Z9 102 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 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD SEP 27 PY 1999 VL 412 IS 3 BP 506 EP 514 PG 9 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 227TN UT WOS:000082096200009 PM 10441236 ER PT J AU Huang, CA Yamada, K Murphy, MC Shimizu, A Colvin, RB Neville, DM Sachs, DH AF Huang, CA Yamada, K Murphy, MC Shimizu, A Colvin, RB Neville, DM Sachs, DH TI In vivo T cell depletion in miniature swine using the swine CD3 immunotoxin, pCD3-CRM9 SO TRANSPLANTATION LA English DT Article ID MIXED ALLOGENEIC CHIMERAS; DIPHTHERIA-TOXIN; MONOCLONAL-ANTIBODIES; TRANSPLANTATION TOLERANCE; RENAL-ALLOGRAFTS; GROWTH-FACTOR; INDUCTION; BLOOD; EXPRESSION; RECEPTOR AB Background. Partially inbred miniature swine developed in this laboratory provide a unique preclinical large animal model for studying transplant tolerance. The importance of in vivo T cell depletion for establishing stable mixed hematopoietic cell chimerism using a clinically relevant sublethal regimen has been well documented in murine studies (1). Until now, the lack of an effective in vivo T cell-depleting reagent in swine has limited the progress of studies involving hematopoietic cell transplants. Methods. The swine CD3 immunotoxin, pCD3-CRM9, was prepared by conjugating our porcine-specific CD3 monoclonal antibody 898H2-6-15 to the diphtheria toxin derivative, CRM9, The resultant immunotoxin was administered i.v, to several miniature swine at doses ranging from 0.15-0.2 mg/kg either in a single dose or two doses 2 days apart. T-cell depletion was monitored in the peripheral blood, mesenteric lymph node, and thymus by flow cytometric analysis and histological examination. Results, T cells were depleted to less than 1% of their pretreatment levels based on absolute numbers in the peripheral blood. Fluorescence activated cell sorter analysis and histological examination of serial lymph node biopsies confirmed depletion of the CD3+ T cells rather than down modulation or masking of the surface CD3 expression. Depletion of the CD3 bright medullary thymocytes could also be detected by flow cytometry and histological examination after immunotoxin treatment. Conclusions. Administration of the immunotoxin i.v. drastically depletes mature T cells from the peripheral blood, lymph node, and thymus compartments of the pig. This first description of an effective in vivo T-cell depleting reagent for the pig provides a valuable tool for studies of transplant tolerance in this large animal model. It also makes possible preclinical studies of T cell depletion with anti-CD3 immunotoxin in this large animal model. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr,Dept Pathol, Boston, MA 02129 USA. NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Sachs, DH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr,Dept Pathol, MGH E,Bldg 149-9019,13th St, Boston, MA 02129 USA. FU NCI NIH HHS [1RO1 CA61537]; NIAID NIH HHS [5RO1 AI39755] NR 33 TC 42 Z9 42 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD SEP 27 PY 1999 VL 68 IS 6 BP 855 EP 860 DI 10.1097/00007890-199909270-00019 PG 6 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 241NH UT WOS:000082889100019 PM 10515387 ER PT J AU Friedman, TB Sellers, JR Avraham, KB AF Friedman, TB Sellers, JR Avraham, KB TI Unconventional myosins and the genetics of hearing loss SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE unconventional myosin; deafness; hearing loss; myosin VIIA; myosin VI; myosin XV ID SYNDROME TYPE-I; USHER-SYNDROME; VIIA GENE; RECESSIVE DEAFNESS; HEAVY-CHAIN; HAIR-CELLS; PERICENTROMERIC REGION; SHAKER-1 MUTATIONS; MUSCLE-CONTRACTION; DROSOPHILA EMBRYOS AB Mutations of the unconventional myosins genes encoding myosin VI, myosin VIIA and myosin XV cause hearing loss and thus these motor proteins perform fundamental functions in the auditory system. A null mutation in myosin VI in the congenitally deaf Snell's waltzer mice (Myo6(sv)) results in fusion of stereocilia and subsequent progressive loss of hair cells, beginning soon after birth, thus reinforcing the vital role of cytoskeletal proteins in inner ear hair cells. To date, there are no human families segregating hereditary hearing loss that show linkage to MYO6 on chromosome 6q13. The discovery that the mouse shaker1 (Myo7(ash1)) locus encodes myosin VIIA led immediately to the identification of mutations in this gene in Usher syndrome type 1B; subsequently, mutations in this gene were also found associated with recessive and dominant nonsyndromic hearing loss (DFNB2 and DFNA11). Stereocilla of sh1 mice are severely disorganized, and eventually degenerate as well. Myosin VIIA has been implicated in membrane trafficking and/or endocytosis in the inner ear. Mutant alleles of a third unconventional myosin, myosin XV, are associated with nonsyndromic, recessive, congenital deafness DFNB3 on human chromosome 17p11.2 and deafness in shaker2 (Myo15(sh2)) mice. In outer and inner hair cells, myosin XV protein is detectable in the cell body and stereocilia. Hair cells are present in homozygous sh2 mutant mice, but the stereocilia are approximately 1/10 of the normal length. This review focuses on what we know about the molecular genetics and biochemistry of myosins V1, VIIA and XV as relates to hereditary hearing loss. Published 2000 Wiley-Liss, Inc.(dagger) C1 NIDOCD, Mol Genet Lab, NIH, Rockville, MD 20854 USA. NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. RP Friedman, TB (reprint author), NIDOCD, Mol Genet Lab, NIH, Rockville, MD 20854 USA. NR 79 TC 68 Z9 69 U1 2 U2 12 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD SEP 24 PY 1999 VL 89 IS 3 BP 147 EP 157 DI 10.1002/(SICI)1096-8628(19990924)89:3<147::AID-AJMG5>3.0.CO;2-6 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 287ZZ UT WOS:000085538500005 PM 10704189 ER PT J AU Geng, Y Tsai-Morris, CH Zhang, Y Dufau, ML AF Geng, Y Tsai-Morris, CH Zhang, Y Dufau, ML TI The human luteinizing hormone receptor gene promoter: Activation by Sp1 and Sp3 and inhibitory regulation SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID HUMAN CHORIONIC-GONADOTROPIN; HUMAN CHORIOCARCINOMA CELLS; TRANSCRIPTION FACTOR; EXPRESSION; ELEMENTS; PROTEINS; DOMAINS; BINDING; FAMILY AB To understand the transcriptional mechanism(s) of human LH receptor (LHR) gene expression, we have identified the dominant functional cis-elements that regulate the activity of the promoter domain (-1 to -176 bp from ATG). Mutagenesis demonstrated that the promoter activity was dependent on two Spl domains (-79 bp, -120 bp) in a transformed normal placental cell (PLC) and the choriocarcinoma JAR cell. Both elements interacted with endogenous Spl and Sp3 factors but not with Sp2 or Sp4. In Drosophila SL2 cells, the promoter was activated by either Spl or Sp3. An ERE half-site (EREhs) at -174 bp was inhibitory (by 100%), but was unresponsive to estradiol and did not bind the estrogen receptor or orphan receptors ERR1 and SF-1. The 5 ' upstream sequence (-177 to -2056 bp) inhibited promoter activity in PLC by 60%, but only minimally in JAR cells. Activation of the human LHR promoter through Sp1/3 factors is negatively regulated through EREhs and upstream sequences to exert control of gene expression. (C) 1999 Academic Press. C1 NICHHD, Sect Mol Endocrinol, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Dufau, ML (reprint author), NICHHD, Sect Mol Endocrinol, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Room 6A-36,49 Convent Rd, Bethesda, MD 20892 USA. NR 26 TC 33 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 24 PY 1999 VL 263 IS 2 BP 366 EP 371 DI 10.1006/bbrc.1999.1374 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 243UV UT WOS:000083016400018 PM 10491299 ER PT J AU Valasek, L Hasek, J Trachsel, H Imre, EM Ruis, H AF Valasek, L Hasek, J Trachsel, H Imre, EM Ruis, H TI The Saccharomyces cerevisiae HCR1 gene encoding a homologue of the p35 subunit of human translation initiation factor 3 (eIF3) is a high copy suppressor of a temperature-sensitive mutation in the Rpg1p subunit of yeast eIF3 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-SYNTHESIS; RNA-BINDING; PRT1 PROTEIN; COMPLEX; IDENTIFICATION; GCN4; INTERACTS; PHASE AB The complex eukaryotic initiation factor 3 (eIF3) was shown to promote the formation of the 43 S preinitiation complex by dissociating 40 S and 60 S ribosomal subunits, stabilizing the ternary complex, and aiding mRNA binding to 40 S ribosomal subunits. Recently, we described the identification of RPG1 (TIF32), the p110 subunit of the eIF3 core complex in yeast. In a screen for Saccharomyces cerevisiae multicopy suppressors of the rpg1-1 temperature-sensitive mutant, an unknown gene corresponding to the open reading frame YLR192C was identified. When overexpressed, the 30-kDa gene product, named Hcr1p, was able to support, under restrictive conditions, growth of the rpg1-1 temperature-sensitive mutant, but not of a Rpg1p-depleted mutant. An hcr1 null mutant was viable, but showed slight reduction of growth when compared with the wild-type strain. Physical interaction between the Hcr1 and Rpg1 proteins was shown by co-immunoprecipitation analysis. The combination of Delta hcr1 and rpg1-1 mutations resulted in a synthetic enhancement of the slow growth phenotype at a semipermissive temperature. In a computer search, a significant homology to the human p35 subunit of the eIF3 complex was found. We assume that the yeast Hcr1 protein participates in translation initiation likely as a protein associated with the eIF3 complex. C1 Univ Vienna, Inst Biochem & Mol Cell Biol, Vienna Bioctr, A-1030 Vienna, Austria. Ludwig Boltzmann Forsch Stelle Biochem, A-1030 Vienna, Austria. Acad Sci Czech Republ, Inst Microbiol, CR-14220 Prague, Czech Republic. Univ Bern, Inst Biochem & Mol Biol, CH-3012 Bern, Switzerland. RP Valasek, L (reprint author), NICHD, Lab Eukaryot Gene Regulat, NIH, Bethesda, MD 20892 USA. RI Valasek, Leos/I-5743-2014; Hasek, Jiri/H-2427-2014 NR 44 TC 32 Z9 34 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 SEP 24 PY 1999 VL 274 IS 39 BP 27567 EP 27572 DI 10.1074/jbc.274.39.27567 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 238XB UT WOS:000082739100032 PM 10488093 ER PT J AU Ray, K Hauschild, BC Steinbach, PJ Goldsmith, PK Hauache, O Spiegel, AM AF Ray, K Hauschild, BC Steinbach, PJ Goldsmith, PK Hauache, O Spiegel, AM TI Identification of the cysteine residues in the amino-terminal extracellular domain of the human Ca2+ receptor critical for dimerization - Implications for function of monomeric Ca2+ receptor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PUTATIVE PHEROMONE RECEPTORS; CALCIUM-SENSING RECEPTOR; CELL-SURFACE EXPRESSION; N-LINKED GLYCOSYLATION; SIGNAL-TRANSDUCTION; MOLECULAR-CLONING; MULTIGENE FAMILY; PROTEIN; MAMMALS; DIMER AB We analyzed the effect of substituting serine for each of the 19 cysteine residues within the amino-terminal extracellular domain of the human Ca2+ receptor on cell surface expression and receptor dimerization. C129S, C131S, C437S, C449S, and C482S were similar to wild type receptor; the other 14 cysteine to serine mutants were retained intracellularly. Four of these, C60S, C101S, C358S and C395S, were unable to dimerize. A C129S/C131S double mutant failed to dimerize but was unique in that the monomeric form expressed at the cell surface. Substitution of a cysteine for serine 132 within the C129S/C131S mutant restored receptor dimerization. Mutation of residues Cys-129, Cys-131, and Ser-132, singly and in various combinations caused a left shift in Ca2+ response compared with wild type receptor. These results identify cysteines 129 and 131 as critical in formation of intermolecular disulfide bond(s) responsible for receptor dimerization. In a "venus flytrap" model of the receptor extracellular domain, Cys-129 and Cys-131 are located within a region protruding from one lobe of the flytrap. We suggest that this region represents a dimer interface for the receptor and that mutation of residues within the interface causes important changes in Ca2+ response of the receptor. C1 NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Spiegel, AM (reprint author), NIDDK, Metab Dis Branch, NIH, 10-9N-222, Bethesda, MD 20892 USA. NR 37 TC 140 Z9 142 U1 0 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 SEP 24 PY 1999 VL 274 IS 39 BP 27642 EP 27650 DI 10.1074/jbc.274.39.27642 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 238XB UT WOS:000082739100043 PM 10488104 ER PT J AU Oakley, RH Jewell, CM Yudt, MR Bofetiado, DM Cidlowski, JA AF Oakley, RH Jewell, CM Yudt, MR Bofetiado, DM Cidlowski, JA TI The dominant negative activity of the human glucocorticoid receptor beta isoform - Specificity and mechanisms of action SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AFFINITY DNA-BINDING; NF-KAPPA-B; STEROID-RECEPTORS; FUNCTIONAL ANTAGONISM; MUTUAL INHIBITION; ESTROGEN-RECEPTOR; GENE-EXPRESSION; C-JUN; HORMONE; NUCLEAR AB Alternative splicing of the human glucocorticoid receptor gene generates a nonhormone binding splice variant (hGR beta) that differs from the wild-type receptor (hGR alpha) only at the carboxyl terminus. Previously we have shown that hGR beta inhibits the transcriptional activity of hGR alpha, which is consistent with reports of ele vated hGR beta expression in patients with generalized and tissue-specific glucocorticoid resistance. The potential role of hGR beta in the regulation of target cell sensitivity to glucocorticoids prompted us to further evaluate its dominant negative activity in other model systems and to investigate its mode of action. We demonstrate in multiple cell types that hGR beta inhibits hGR alpha-mediated activation of the mouse mammary tumor virus promoter. In contrast, the ability of the progesterone and androgen receptors to activate this promoter is only weakly affected by hGR beta. hGR beta also inhibits hGR alpha-mediated repression of an NF-kappa B-responsive promoter but does not interfere with homologous down-regulation of hGR alpha. We show that hGR beta can associate with the heat shock protein hsp90 although with lower affinity than hGR alpha. In addition, hGR beta binds GRE-containing DNA with a greater capacity than hGR alpha in the absence of glucocorticoids. Glucocorticoid treatment enhances hGR alpha, but not hGR beta, binding to DNA. Moreover, we demonstrate that hGR alpha and hGR beta can physically associate with each other in a heterodimer. Finally, we show that the dominant negative activity of hGR beta resides within its unique carboxyl-terminal 15 amino acids. Taken together, our results suggest that formation of transcriptionally impaired hGR alpha-hGR beta heterodimers is an important component of the mechanism responsible for the dominant negative activity of hGR beta. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233,MD E2-02, Res Triangle Pk, NC 27709 USA. NR 54 TC 282 Z9 300 U1 0 U2 8 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 SEP 24 PY 1999 VL 274 IS 39 BP 27857 EP 27866 DI 10.1074/jbc.274.39.27857 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 238XB UT WOS:000082739100071 PM 10488132 ER PT J AU Lindholm, CK Gylfe, E Zhang, WG Samelson, LE Welsh, M AF Lindholm, CK Gylfe, E Zhang, WG Samelson, LE Welsh, M TI Requirement of the Src homology 2 domain protein Shb for T cell receptor-dependent activation of the interleukin-2 gene nuclear factor for activation of T cells element in Jurkat T cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TYROSINE PHOSPHORYLATION; SIGNAL-TRANSDUCTION; ANTIGEN-RECEPTOR; KINASE-C; P21(RAS); CALCINEURIN; STIMULATION; APOPTOSIS; EFFECTOR; GRB2 AB Stimulation of the T cell antigen receptor (TCR) induces tyrosine phosphorylation of numerous intracellular proteins. We have recently investigated the role of the adaptor protein Shb in the early events of T cell signaling and observed that Shb associates with Grb2, linker for activation of T cells (LAT) and the TCR zeta-chain in Jurkat cells. We now report that Shb also associates with phospholipase C-gamma 1 (PLC-gamma 1) in these cells. Overexpression of Src homology 2 domain defective Shb caused diminished phosphorylation of LAT and consequently the activation of mitogen-activated protein kinases was decreased upon TCR stimulation. In addition, the Shb mutant also blocked phosphorylation of PLC-gamma 1 and the increase in cytoplasmic Ca2+ following TCR stimulation. Nuclear factor for activation of T cells is a major target for Ras and calcium signaling pathways in T cells following TCR stimulation, and the overexpression of the mutant Shb prevented TCR-dependent activation of the nuclear factor for activation of T cells. Consequently, endogenous interleukin-2 production was decreased under these conditions. The results indicate a role for Shb as a link between the TCR and downstream signaling events involving LAT and PLC-gamma 1 and resulting in the activation of transcription of the interleukin-2 gene. C1 Univ Uppsala, Biomedicum, Dept Med Cell Biol, S-75123 Uppsala, Sweden. NCI, Cellular & Mol Biol Lab, DBS, NIH, Bethesda, MD 20892 USA. RP Welsh, M (reprint author), Univ Uppsala, Biomedicum, Dept Med Cell Biol, Box 571, S-75123 Uppsala, Sweden. NR 29 TC 28 Z9 31 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 SEP 24 PY 1999 VL 274 IS 39 BP 28050 EP 28057 DI 10.1074/jbc.274.39.28050 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 238XB UT WOS:000082739100096 PM 10488157 ER PT J AU Phillips, LR Bramhall, C Buckley, J Daw, TW Stinson, SF AF Phillips, LR Bramhall, C Buckley, J Daw, TW Stinson, SF TI Analysis of 2-(3-methyl-4-aminophenyl)-benzothiazole (NSC 674495) in plasma by gas chromatography with mass-selective detection SO JOURNAL OF CHROMATOGRAPHY B LA English DT Article DE benzothiazole; 2-(3-methyl-4-aminophenyl)-benzothiazole; NSC 674495 ID ESTROGEN-RECEPTOR AFFINITY; TUMOR INHIBITING ACTIVITY; BENZOTHIAZOLES; GENISTEIN AB Certain naturally occurring isoflavonoids have been shown to inhibit protein-tyrosine kinases, and this has led to investigations of ring-modified structural analogs. Most recently, 2-(3-methyl-4-aminophenyl)-benzothiazole (MAB: NSC 674495) was shown to possess significant activity against certain breast cell cancer Lines in vitro and in vivo. Our efforts thus focussed on developing a simple and sensitive method for quantitating MAB in plasma using GC-MS. The GC-MS assay was found to be linear over the range of 0.050 to 5.0 mu g/ml, and was applied to monitor the plasma concentration of MAB in a rat dosed with 25 mg/kg as a 1 min intravenous infusion. Plasma was collected at intervals from 3 through 180 min, and concentrations of MAB were determined. Non-linear regression analysis of the plasma concentration-time data revealed that levels declined from a maximum at 3 min of 18 mu g/ml to 1 mu g/ml at 3 h in a biphasic manner. In another investigation, significant plasma concentrations of a major metabolite was detected and determined to be mono-N-acetylated MAB. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program, Div Canc Treatment Diagnosis & Ctr, Frederick, MD 21701 USA. Frederick Canc Res & Dev Ctr, SAIC Frederick, Frederick, MD 21701 USA. RP Phillips, LR (reprint author), NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program, Div Canc Treatment Diagnosis & Ctr, Frederick, MD 21701 USA. FU NCI NIH HHS [N01-CO-56000] NR 9 TC 0 Z9 0 U1 1 U2 1 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 SEP 24 PY 1999 VL 732 IS 2 BP 315 EP 321 DI 10.1016/S0378-4347(99)00295-9 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 240RV UT WOS:000082839700007 PM 10517353 ER PT J AU Yao, ZJ Gao, Y Burke, TR AF Yao, ZJ Gao, Y Burke, TR TI Preparation of L-N-alpha-Fmoc-4-[di-(tert-butyl)-phosphonomethyl]phenylalanine from L-tyrosine SO TETRAHEDRON-ASYMMETRY LA English DT Article ID ENANTIOSELECTIVE SYNTHESIS; PHOSPHORYLATED TYROSINE; ASYMMETRIC-SYNTHESIS; RESOLUTION; ANALOG AB The unnatural amino acid analogue, 4-(phosphonomethyl)phenylalanine (Pmp, 2), has proven to be a valuable tool for studying protein-tyrosine kinase dependent signal transduction, where it is most often incorporated into peptides or peptide mimetics as a phosphatase-stable phosphotyrosyl mimetic. Although Pmp has been prepared previously bearing a number of protection strategies, the N-alpha-Fmoc 4- [di-(tert-butyl)phosphonomethyl] phenylalanine form [(N alpha-Fmoc-L-Pmp('Bu-2)-OH, 3] is particularly attractive since it can be cleanly introduced into peptides using standard Fmoc protocols. Synthesis of 3 was first reported as its (D/L)-racemate, and subsequently as its L-3 enantiomer, with the latter synthesis having relied on induction of chirality using a camphor sultam auxiliary. Reported herein is an alternate enantioselective synthesis of L-3 in high ensantiomeric purity by procedures which derive the stereochemistry of the final product directly from the starting amino acid, without the need for chiral induction. A key feature of the route is the racemization-free nucleophilic substitution of lithium di-tert-butyl phosphite onto protected 4-bromomethylphenylalanine (17). (C) 1999 Elsevier Science Ltd. All rights reserved. C1 NCI, Med Chem Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Burke, TR (reprint author), NCI, Med Chem Lab, Div Basic Sci, NIH, Bldg 37,Rm 5C06, Bethesda, MD 20892 USA. RI Burke, Terrence/N-2601-2014; Yao, Zhu-Jun/E-7635-2015 NR 17 TC 16 Z9 16 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0957-4166 J9 TETRAHEDRON-ASYMMETR JI Tetrahedron: Asymmetry PD SEP 24 PY 1999 VL 10 IS 19 BP 3727 EP 3734 DI 10.1016/S0957-4166(99)00385-7 PG 8 WC Chemistry, Inorganic & Nuclear; Chemistry, Organic; Chemistry, Physical SC Chemistry GA 253UP UT WOS:000083574400010 ER PT J AU Pattabiraman, N AF Pattabiraman, N TI Occluded molecular surface analysis of ligand-macromolecule contacts: Application to HIV-1 protease-inhibitor complexes SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID FREE-ENERGY; CRYSTAL-STRUCTURE; BINDING; PACKING; POTENT; ENZYME; DESIGN AB Herein is described a method of quantifying and visualizing ligand-macromolecule contacts with the occluded surface algorithm by utilizing Connolly's van der Waals molecular surface dots together with the associated normals, to scoop out surrounding macromolecule atoms within a distance of 6.4 Angstrom from any ligand atom. On the basis of the intersections of surface normals with the van der Waals spheres of surrounding macromolecule atoms, the van der Waals molecular surface area for each atom is divided into occluded and nonoccluded surface areas. Also, we calculate a packing parameter for each secluded surface, measuring the closeness of the occluded surface against the macromolecule atom in contact. From the partial charges of ligand and macromolecule atoms and the occluded and nonoccluded surface areas due to the contact, we were able to identify favorable and unfavorable contacts. From the value of occluded surface constant, nonoccluded surface constant, and solvent-exposed constant for ligands, we qualitatively rank order the binding of ligands to the same target. From the individual parameters, group parameters for groups of atoms in a ligand or for each residue in a ligand-binding pocket of a macromolecule could be calculated. The group and the residue-based parameters could be used in structure-based ligand design and protein engineering experiments. In this paper, we present our analysis of ligand-macromolecule contacts, using five X-ray crystal structures of HIV-1 protease-ligand complexes. C1 NCI, Adv Biomed Comp Ctr, SAIC, FCRDC, Frederick, MD 21701 USA. RP Pattabiraman, N (reprint author), NCI, Adv Biomed Comp Ctr, SAIC, FCRDC, POB B, Frederick, MD 21701 USA. FU NCI NIH HHS [N01-CO-56000] NR 22 TC 10 Z9 10 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 23 PY 1999 VL 42 IS 19 BP 3821 EP 3834 DI 10.1021/jm980512c PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 239RJ UT WOS:000082783200007 PM 10508431 ER PT J AU Estiu, G Rama, J Pereira, A Cachau, RE Ventura, ON AF Estiu, G Rama, J Pereira, A Cachau, RE Ventura, ON TI A theoretical study of excited state proton transfer in 3-hydroxychromone and related molecules SO JOURNAL OF MOLECULAR STRUCTURE-THEOCHEM LA English DT Article DE excited state proton transfer; 3-hydroxychromone; geometry optimizations ID GROUND-STATE; TRANSFER LASER; TRIPLET-STATE; 3-HYDROXYFLAVONE; DYNAMICS; FLUORESCENCE; EXCHANGE; APPROXIMATION; SPECTROSCOPY; COMPLEXES AB Semiempirical, ab initio and DFT methods were applied to the study of proton transfer in the ground and some of the excited states of 3-hydroxyflavone, 3-hydroxychromone and the gamma-pyrone ring contained in both molecules. Geometry optimizations and reaction-path potential energy curves for the normal and proton-transferred isomers were performed employing AM 1 and B3LYP methodologies tin the last case both with the 3-21G and 6-31G(d,p) basis sets). Electronic transitions were calculated employing the ZINDO-S/CI method, while the reaction path for the proton transfer in the lowest singlet and triplet excited states were calculated employing the CIS/6-31G(d,p) method on the gamma-pyrone ring. The singlet-singlet excitation in 3HF is calculated at 302 nm (experimental 325 nm) while the fluorescence band is calculated at 526 nm (experimental 525 nm). The data calculated for 3HC and the gamma-pyrone explain the intervention of the triplet states in the dynamics of ESIPT in these molecules. (C) 1999 Elsevier Science B.V. All rights reserved. C1 MTC Lab, Fac Quim, Montevideo 11800, Uruguay. Natl Univ La Plata, Fac Ciencias Exactas, Dept Quim, CEQUINOR, RA-1900 La Plata, Argentina. Frederick Biomed Supercomp Ctr, Natl Canc Inst, Frederick, MD 21702 USA. RP Ventura, ON (reprint author), MTC Lab, Fac Quim, CC 1157, Montevideo 11800, Uruguay. NR 34 TC 10 Z9 10 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-1280 J9 J MOL STRUC-THEOCHEM JI Theochem-J. Mol. Struct. PD SEP 23 PY 1999 VL 487 IS 3 BP 221 EP 230 DI 10.1016/S0166-1280(98)00602-2 PG 10 WC Chemistry, Physical SC Chemistry GA 238DQ UT WOS:000082696000002 ER PT J AU Davis, RL Shrimpton, AE Holohan, PD Bradshaw, C Feiglin, D Collins, GH Sonderegger, P Kinter, J Becker, LM Lacbawan, F Krasnewich, D Muenke, M Lawrence, DA Yerby, MS Shaw, CM Gooptu, B Elliott, PR Finch, JT Carrell, RW Lomas, DA AF Davis, RL Shrimpton, AE Holohan, PD Bradshaw, C Feiglin, D Collins, GH Sonderegger, P Kinter, J Becker, LM Lacbawan, F Krasnewich, D Muenke, M Lawrence, DA Yerby, MS Shaw, CM Gooptu, B Elliott, PR Finch, JT Carrell, RW Lomas, DA TI Familial dementia caused by polymlerization of mutant neurosergin SO NATURE LA English DT Article ID ALPHA-1-ANTITRYPSIN; INHIBITOR; MUTATION; DISEASE; LOOP; POLYMERIZATION; SERPINS; LIVER AB Aberrant protein processing with tissue deposition is associated with many common neurodegenerative disorders(1,2); however, the complex interplay of genetic and environmental factors has made it difficult to decipher the sequence of events linking protein aggregation with clinical disease(3). Substantial progress has been made toward understanding the pathophysiology of prototypical conformational diseases and protein polymerization in the super-family of serine proteinase inhibitors (serpins)(4,5). Here we describe a new disease, familial encephalopathy with neuroserpin inclusion bodies, characterized clinically as an autosomal dominantly inherited dementia, histologically by unique neuronal inclusion bodies and biochemically by polymers of the neuron-specific serpin, neuroserpin(6,7). We report the cosegregation of point mutations in the neuroserpin gene (PI12) with the disease in two families. The significance of one mutation, S49P, is evident from its homology to a previously described serpin mutation(8), whereas that of the other, S52R, is predicted by modelling of the serpin template. Our findings provide a molecular mechanism for a familial dementia and imply that inhibitors of protein polymerization may be effective therapies for this disorder and perhaps for other more common neurodegenerative diseases. C1 SUNY Hlth Sci Ctr, Dept Clin Pathol, Syracuse, NY 13210 USA. SUNY Hlth Sci Ctr, Dept Pharmacol, Syracuse, NY 13210 USA. SUNY Hlth Sci Ctr, Dept Neurol, Syracuse, NY 13210 USA. SUNY Hlth Sci Ctr, Dept Radiol, Syracuse, NY 13210 USA. Univ Zurich, Dept Biochem, CH-8057 Zurich, Switzerland. Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. Amer Red Cross, Holland Labs, Rockville, MD 20855 USA. Oregon Hlth Sci Univ, Dept Neurol, Portland, OR 97210 USA. Oregon Hlth Sci Univ, Dept Publ Hlth, Portland, OR 97210 USA. Oregon Hlth Sci Univ, Dept Obstet Gynecol, Portland, OR 97210 USA. Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98104 USA. Univ Cambridge, Cambridge Inst Med Res, Dept Haematol, Cambridge CB2 2XY, England. Univ Cambridge, Cambridge Inst Med Res, Dept Med, Cambridge CB2 2XY, England. MRC Ctr, Mol Biol Lab, Cambridge CB2 2XY, England. RP Shrimpton, AE (reprint author), SUNY Hlth Sci Ctr, Dept Clin Pathol, 750 E Adams St, Syracuse, NY 13210 USA. RI Kinter, Jochen/C-4515-2008 FU Wellcome Trust NR 26 TC 238 Z9 244 U1 0 U2 11 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 23 PY 1999 VL 401 IS 6751 BP 376 EP 379 DI 10.1038/43897 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 240JJ UT WOS:000082822600051 PM 10517635 ER PT J AU Emanuel, EJ Fairclough, DL Slutsman, J Alpert, H Baldwin, D Emanuel, LL AF Emanuel, EJ Fairclough, DL Slutsman, J Alpert, H Baldwin, D Emanuel, LL TI Assistance from family members, friends, paid care givers, and volunteers in the care of terminally ill patients SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HOSPITALIZED ADULTS; ALZHEIMERS-DISEASE; MENTAL-HEALTH; BURDEN; CANCER; NEEDS AB Background In addition to medical care, dying patients often need many types of assistance, including help with transportation, nursing care, homemaking services, and personal care. We interviewed terminally ill adults and their care givers in six randomly selected areas of the United States (five metropolitan areas and one rural county) to determine how their needs for assistance were met and the frequency with which they received such assistance from family members and paid and volunteer care givers. Methods The patients, whose physicians estimated them to have less than six months to live and who had clinically significant illness other than human immunodeficiency virus infection or the acquired immunodeficiency syndrome, were referred to the study by their physicians. Of the 1131 eligible patients, 988 (87.4 percent) consented to a detailed in-person interview conducted in English, as did 893 of the 915 eligible primary care givers (97.6 percent). Results Of the 988 terminally ill patients, 59.4 percent: were over the age of 65 years, and 51.5 percent were women; The most frequent terminal illness was cancer (in 51.8 percent of the patients), followed by heart disease (18.0 percent) and chronic obstructive pulmonary disease (10.9 percent). Four percent of the patients were in an institution, such as a nursing home, residential hospice, or hospital; the rest were living in a private residence. A need for assistance was reported by 86.8 percent of the patients; they required help with transportation (reported by 62.0 percent), homemaking services (55.2 percent), nursing care (28.7 percent), and personal care (26.0 percent). Of the care givers, 72.1 percent were women. Primary care givers were family members in 96.0 percent of cases; only 4.0 percent were unrelated. Most patients relied completely on family members and friends for assistance. A total of 15.5 percent of patients relied only on paid assistance for more than half of the types of care that they needed. Volunteers (that is, unpaid helpers who were not family members or friends) provided less than 3 percent of all care. Conclusions In our survey of terminally ill patients, family members, usually women, provided the majority of assistance with nonmedical care. Although many people received assistance from paid care givers, very few had assistance from volunteers; (N Engl J Med 1999;341:956-63.) (C) 1999, Massachusetts Medical Society. C1 NIH, Dept Clin Bioeth, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Amer Med Ctr, Canc Res Ctr, Ctr Res Methodol & Biometr, Denver, CO USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. Vital Sci & Hlth, Newtonville, MA USA. Amer Med Assoc, Inst Eth, Chicago, IL 60610 USA. RP Emanuel, EJ (reprint author), NIH, Dept Clin Bioeth, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NR 30 TC 190 Z9 193 U1 1 U2 9 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 23 PY 1999 VL 341 IS 13 BP 956 EP 963 DI 10.1056/NEJM199909233411306 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 237LP UT WOS:000082658100006 PM 10498492 ER PT J AU Maroulakou, IG Shibata, MA Anver, M Jorcyk, CL Liu, ML Roche, N Roberts, AB Tsarfaty, I Reseau, J Ward, J Green, JE AF Maroulakou, IG Shibata, MA Anver, M Jorcyk, CL Liu, ML Roche, N Roberts, AB Tsarfaty, I Reseau, J Ward, J Green, JE TI Heterotopic endochondrial ossification with mixed tumor formation in C3(1)/Tag transgenic mice is associated with elevated TGF-beta1 and BMP-2 expression SO ONCOGENE LA English DT Article DE heterotopic bone; endochondrial ossification; mixed tumors; transgenic mice; transforming growth factor-beta; bone morphogenetic protein-2 ID LARGE T-ANTIGEN; BONE-FORMATION; TRANSFORMING GROWTH-FACTOR-BETA-1; SV40-TRANSFORMED CELLS; P53 MUTATIONS; PROGRESSION; GROWTH; GENE; OVEREXPRESSION; TUMORIGENESIS AB Transgenic mice which express the simian virus 40 large T-antigen (Tag) under the regulatory control of the hormone responsive rat C3(1) gene develop unusual lesions of heterotopic bone growth associated with mixed tumor formation arising from eccrine sweat glands found only in the foot pads of mice, ischiocavernosus muscle adjacent to bulbourethral glands and occasionally the salivary and mammary glands. These lesions are very similar to mixed tumors arising in several types of human cancers. Based upon electron microscopic examination and immunocytochemical analyses of cellular differentiation markers, the mixed proliferative lesions in this transgenic mouse model begin with the Tag-induced proliferation of epithelial and myoepithelial cells. The proliferation of these two types of cells results in hyperplasia and adenomatous transformation of the epithelial component, whereas the proliferating myoepithelial cells undergo metaplasia to form chondrocytes which deposit extracellular matrix, including collagen fibers. Cartilage develops focally between areas of epithelial proliferation and subsequently ossifies through process of endochondrial bone formation, The metaplasia of myoepithelial cells to chondrocytes appears to require the inductive interaction of factors produced by the closely associated proliferating epithelial cells, including members of the TGF-beta superfamily, We demonstrate that TGF-beta1 protein accumulates in the extracellular matrix of the lesions, whereas RNA in situ hybridization reveals that BMP-2, another strong inducer of heterotopic bone formation, is overexpressed by the proliferating epithelial cells during the development of ectopic bone. The formation of sarcomatous tumors within the mixed tumors appears to be androgen-dependent and more frequent in mice lacking a normal allele of p53. This process of cartilage and bone induction may mimic epithelial-mesenchymal interactions which occur during embryonic bone formation. These transgenic mice may provide new insights into the processes of ectopic endochondrial bone formation associated with mixed tumor formation and serve as a useful model for human heterotopic bone disease. C1 NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, Pathol Histol Lab, SAIC, Frederick, MD 21702 USA. Sackler Sch Med, Tel Aviv, Israel. NCI, Frederick Canc Res & Dev Ctr, ABL, Frederick, MD 21702 USA. NCI, OLAS, Frederick, MD 21702 USA. RP Green, JE (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01CO56000] NR 62 TC 11 Z9 11 U1 0 U2 2 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 23 PY 1999 VL 18 IS 39 BP 5435 EP 5447 DI 10.1038/sj.onc.1202926 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 238PL UT WOS:000082718600008 PM 10498897 ER PT J AU Harris, MI AF Harris, MI TI Diabetes and decline in heart disease mortality - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID ACUTE MYOCARDIAL-INFARCTION C1 NIH, Bethesda, MD 20892 USA. RP Harris, MI (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 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 SEP 22 PY 1999 VL 282 IS 12 BP 1132 EP 1132 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 236JJ UT WOS:000082596200024 ER PT J AU Fushman, D Tjandra, N Cowburn, D AF Fushman, D Tjandra, N Cowburn, D TI An approach to direct determination of protein dynamics from N-15 NMR relaxation at multiple fields, independent of variable N-15 chemical shift anisotropy and chemical exchange contributions SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ROTATIONAL DIFFUSION ANISOTROPY; MODEL-FREE APPROACH; ORDER PARAMETERS; POWDER PATTERNS; PEPTIDE-BOND; SOLID-STATE; TENSORS; DIPOLAR; SPECTROSCOPY; MACROMOLECULES AB An approach to protein dynamics analysis from N-15 relaxation data is demonstrated, based on multiple-field relaxation data. This provides a direct, residue-specific determination of both the spectral density components, the N-15 chemical shift anisotropy (CSA) and the conformational exchange contribution to the N-15 line width. Measurements of R-1, R-2, and N-15{H-1} NOE are used. The approach is free from any assumption about the values of the CSA. or of the conformational exchange. Using this approach, the spectral densities, the values of N-15 CSA, and the conformational exchange contribution to the N-15 line width are directly determined from the relaxation data for human ubiquitin, collected at 360, 500, and 600 MHz. The spectral densities are analyzed in terms of the order parameter and the correlation time of local motion, using an axially symmetric overall rotational diffusion model. The residue-specific values of N-15 CSA and the spectral densities obtained using this approach are in agreement with those derived previously [Fushman, Tjandra, and Cowburn. J. Am. Chem. Sec. 1998, 120, 10947-10952] from CSA/dipolar cross-correlation analysis. Accurate determination of spectral densities and order parameters from N-15 relaxation may be accomplished by analysis of multiple-field data without assumption of constant CSA or zero chemical exchange contributions. C1 Rockefeller Univ, New York, NY 10021 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Cowburn, D (reprint author), Rockefeller Univ, 1230 York Ave, New York, NY 10021 USA. RI Cowburn, David/A-8448-2008; OI Cowburn, David/0000-0001-6770-7172 NR 30 TC 69 Z9 70 U1 0 U2 12 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 SEP 22 PY 1999 VL 121 IS 37 BP 8577 EP 8582 DI 10.1021/ja9904991 PG 6 WC Chemistry, Multidisciplinary SC Chemistry GA 240DC UT WOS:000082809600020 ER PT J AU Theodore, W Wasterlain, CG AF Theodore, W Wasterlain, CG TI Do early seizures beget epilepsy? SO NEUROLOGY LA English DT Editorial Material ID RECURRENT SEIZURES; INJURY C1 NINDS, NIH, ERB, Bethesda, MD 20817 USA. Vet Adm Med Ctr, Dept Neurol, Sepulveda, CA 91343 USA. RP Theodore, W (reprint author), NINDS, NIH, ERB, 6328 Lenox Rd, Bethesda, MD 20817 USA. NR 11 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP 22 PY 1999 VL 53 IS 5 BP 898 EP 899 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 236DG UT WOS:000082582500002 PM 10496241 ER PT J AU Espey, MG Ellis, RJ Heaton, RK Basile, AS AF Espey, MG Ellis, RJ Heaton, RK Basile, AS TI Relevance of glutamate levels in the CSF of patients with HIV-1-associated dementia complex SO NEUROLOGY LA English DT Article DE CSF; HIV; HIV-1 associated dementia complex ID CEREBROSPINAL-FLUID; QUINOLINIC ACID; IMMUNODEFICIENCY; NEUROTOXICITY AB Chronic hyperactivation of excitatory amino acid pathways in the CNS of patients infected with HIV-1 may contribute to the pathogenesis of HIV-l-associated dementia complex. However, no correlation between the concentration of glutamate in CSF (mean 3.3 mu mol/L) and either HIV-1 infection or HTV-1-associated dementia complex was observed. The results clarify several important issues regarding analysis of glutamate in the CSF and the role of excitotoxins in HIV-1-associated dementia complex. C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. HIV Neurobeh Res Ctr, San Diego, CA USA. RP Espey, MG (reprint author), NCI, Radiat Biol Branch, NIH, Bldg 10,B3-B69, Bethesda, MD 20892 USA. RI Ellis, Ronald/K-3543-2015 OI Ellis, Ronald/0000-0003-4931-752X FU NIMH NIH HHS [MH45294, MH58076] NR 10 TC 15 Z9 15 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP 22 PY 1999 VL 53 IS 5 BP 1144 EP 1145 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 236DG UT WOS:000082582500047 PM 10496286 ER PT J AU Ketter, TA Post, RM Theodore, WH AF Ketter, TA Post, RM Theodore, WH TI Positive and negative psychiatric effects of antiepileptic drugs in patients with seizure disorders SO NEUROLOGY LA English DT Article; Proceedings Paper CT Symposium on Behavioral Issues in Epilepsy, A Practical Approach to Diagnosis and Management CY MAR 27-28, 1998 CL NEW YORK, NEW YORK ID GAMMA-AMINOBUTYRIC-ACID; TRANSAMINASE INHIBITOR VIGABATRIN; INSENSITIVE GLYCINE RECEPTORS; REFRACTORY PARTIAL EPILEPSY; COMPLEX PARTIAL SEIZURES; BEHAVIORAL DESPAIR TEST; LENNOX-GASTAUT SYNDROME; TONIC CLONIC SEIZURES; GABA UPTAKE INHIBITOR; SODIUM VALPROATE AB Antiepileptic drugs (AEDs) have various mechanisms of actions and therefore have diverse anticonvulsant, psychiatric, and adverse effect profiles. Two global categories of AEDs are identified on the basis of their predominant psychotropic profiles. One group has "sedating" effects in association with fatigue, cognitive slowing, and weight gain, as well as possible anxiolytic and antimanic effects. These actions may be related to a predominance of potentiation of gamma-aminobutyric acid (GABA) inhibitory neurotransmission induced by drugs such as barbiturates, benzodiazepines, valproate, gabapentin, tiagabine, and vigabatrin. The other group is associated with predominant attenuation of glutamate excitatory neurotransmission and has "activating" effects, with activation, weight loss, and possibly anxiogenic and antidepressant effects. This group includes agents such as felbamate and lamotrigine. Agents such as topiramate, with both GABAergic and antiglutamatergic actions, may have "mixed" profiles. Mechanisms of actions, activity in animal models of anxiety and depression, and clinical psychotropic effects of AEDs in psychiatric and epilepsy patients are reviewed in relationship to this proposed categorization. These considerations suggest the testable hypothesis that better psychiatric outcomes in seizure disorder patients could be achieved by treating patients with baseline "activated" profiles (insomnia, agitation, anxiety, racing thoughts, weight loss) with "sedating" predominantly GABAergic drugs, and conversely those with baseline "sedated" or anergic profiles (hypersomnia, fatigue, apathy, depression, sluggish cognition, weight gain) with "activating" predominantly antiglutamatergic agents. Systematic clinical investigation of more precise relationships of discrete mechanisms of actions to psychotropic profiles of AEDs is needed to assess the utility of this general proposition and define exceptions to this broad principle. C1 Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. NINDS, Epilepsy Res Branch, Bethesda, MD 20892 USA. RP Ketter, TA (reprint author), Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, 401 Quarry Rd,Room 2124, Stanford, CA 94305 USA. NR 288 TC 116 Z9 119 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP 22 PY 1999 VL 53 IS 5 SU 2 BP S53 EP S67 PG 15 WC Clinical Neurology SC Neurosciences & Neurology GA 237HL UT WOS:000082649700009 PM 10496235 ER PT J AU Dunn, DE Tanawattanacharoen, P Boccuni, P Nagakura, S Green, SW Kirby, MR Kumar, MSA Rosenfeld, S Young, NS AF Dunn, DE Tanawattanacharoen, P Boccuni, P Nagakura, S Green, SW Kirby, MR Kumar, MSA Rosenfeld, S Young, NS TI Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID ACQUIRED APLASTIC-ANEMIA; MYELODYSPLASTIC SYNDROMES; FLOW-CYTOMETRY; MONOCLONAL-ANTIBODIES; ANCHORED PROTEINS; PATHOGENETIC LINK; PNH PHENOTYPE; DEFICIENCY; DIAGNOSIS; DISEASE AB Background: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem-cell disorder in which the affected cells are deficient in glycosylphosphatidylinositol (GPI)-anchored proteins. Paroxysmal nocturnal hemoglobinuria is frequently associated with aplastic anemia, although the basis of this relation is unknown. Objective: To assess the PNH status of patients with diverse marrow failure syndromes. Design: Correlation of cytofluorometric data with clinical features. Setting: Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland. Patients: 115 patients with aplastic anemia, 39 patients with myelodysplasia, 28 patients who had recently undergone bone marrow transplantation, 18 patients with cancer that was treated with chemotherapy, 13 patients with large granular lymphocytosis, 20 controls who had received renal allografts, and 21 healthy participants. Intervention: Patients with aplastic anemia, myelodysplasia, or renal allografts received antithymocyte globulin. Measurements: Flow cytometry was used to assess expression of GPI-anchored proteins on granulocytes. Results: Evidence of PNH was found in 25 of 115 (22%) patients with aplastic anemia. No patient with normal CPI-anchored protein expression at presentation developed PNH after therapy (n = 16). Nine of 39 (23%) patients with myelodysplasia had CPI-anchored protein-deficient cells. Abnormal cells were not detected in patients with constitutional or other forms of bone marrow failure or in renal allograft recipients who had received antithymocyte globulin. Aplastic anemia is known to respond to immunosuppressive therapy; in myelodysplasia, the presence of a PNH population was strongly correlated with hematologic improvement after administration of antithymocyte globulin (P = 0.0015). Conclusions: Flow cytometric analysis is superior to the Ham test and permits concomitant diagnosis of PNH in about 20% of patients with myelodysplasia (a rate similar to that seen in patients with aplastic anemia). The presence of GPI-anchored protein-deficient cells in myelodysplasia predicts responsiveness to immunosuppressive therapy. Early emergence of GPI-anchored protein-deficient hematopoiesis in a patient with marrow failure may point to an underlying immune pathogenesis. C1 NHLBI, Bethesda, MD 20892 USA. MCP Hahnemann Univ Hosp, Philadelphia, PA USA. RP Dunn, DE (reprint author), 309 E Osceola St,Suite 208, Stuart, FL 34994 USA. NR 41 TC 177 Z9 185 U1 0 U2 2 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 SEP 21 PY 1999 VL 131 IS 6 BP 401 EP 408 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 237DY UT WOS:000082641100001 PM 10498555 ER PT J AU King, C Eisenberg, E Greene, LE AF King, C Eisenberg, E Greene, LE TI Interaction between Hsc70 and DnaJ homologues: Relationship between Hsc70 polymerization and ATPase activity SO BIOCHEMISTRY LA English DT Article ID HEAT-SHOCK PROTEIN; ESCHERICHIA-COLI DNAJ; MOLECULAR CHAPERONE; UNCOATING ATPASE; COATED VESICLES; TRANSCRIPTION FACTOR; CLATHRIN BASKETS; J-DOMAIN; HSP70; BINDING AB We previously found that, in the presence of ATP, DnaJ homologues catalytically induce formation of a metastable Hsc70 polymer and, similarly, the DnaJ homologue auxilin catalytically induces formation of a metastable Hsc70-clathrin basket complex. Since this suggests that the induction of metastable complexes, which form in ATP but dissociate in ADP, may be a general property of DnaJ homologues, in the present study we investigated in more detail the ability of DnaJ homologues to induce polymerization of Hsc70. This study shows that DnaT homologues induce polymerization of Hsc70 at the same rate as they induce an initial burst of Hsc70 ATPase activity, showing that polymerization is a specific effect of DnaJ homologue binding to Hsc70. However, polymerization does not always accompany the initial burst of ATPase activity. The dependence of the rates of ATPase activity and polymerization on DnaJ homologue concentration shows that DnaT homologues bind very weakly to Hsc70 in the presence of ATP and do not bind at all in ADP(-). Surprisingly, however, under certain conditions the rate of polymerization appears to be independent of Hsc70 concentration, suggesting that polymerization is a first-order reaction, perhaps occurring when two Hsc70 molecules bind to a single DnaJ molecule and then shift their binding to each other. We propose that both the polymerization of Hsc70 by DnaJ homologues and the presentation of substrate by DnaJ homologues to Hsc70 involve the bringing of substrate into proximity with Hsc70 and then independently inducing rapid ATP hydrolysis to cause formation of a metastable Hsc70-substrate complex. C1 NHLBI, Cell Biol Lab, Sect Cellular Physiol, NIH, Bethesda, MD 20892 USA. RP Greene, LE (reprint author), NHLBI, Cell Biol Lab, Sect Cellular Physiol, NIH, Bldg 3,Room B1-22, Bethesda, MD 20892 USA. NR 52 TC 18 Z9 18 U1 2 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 21 PY 1999 VL 38 IS 38 BP 12452 EP 12459 DI 10.1021/bi9902788 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 239RD UT WOS:000082782700030 PM 10493815 ER PT J AU Jain, PT Seth, P Gewirtz, DA AF Jain, PT Seth, P Gewirtz, DA TI Estradiol enhances liposome-mediated uptake, preferential nuclear accumulation and functional expression of exogenous genes in MDA-MB231 breast tumor cells SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE estradiol; p53; breast tumor; nuclear accumulation; liposome ID P53 PROTEIN EXPRESSION; CANCER CELLS; MUTANT P53; LINES; DELIVERY; CULTURE AB Exposure of p53 mutated estrogen-receptor-negative MDA-MB231 human breast tumor cells to a pharmacological concentration of estradiol enhances liposome-mediated uptake and expression of SV-40 luciferase. Unexpectedly, the effect of estradiol on SV-40 expression is evident even when estradiol exposure occurs after the initial uptake phase; this suggests that estradiol may influence gene expression by mechanisms other than increasing gene uptake alone, such as altering the intracellular distribution of the gene, We determined that while uptake of SV-40 luciferase is increased only three-fold by estradiol, there is a 30-fold increase in the nuclear/cytoplasmic ratio of the gene. In order to demonstrate that the influence of estradiol on gene uptake and expression is translated into a functional response, the effects of estradiol on the function of an exogenous gene, in this case the apoptotic function of p53, were assessed in the p53 mutated MDA-MB23 I breast tumor cell. While liposome-mediated delivery of CMV-p53 alone was ineffective in promoting cell death, incubation with estradiol and the liposomal p53 complex resulted in a two-fold increase in cell killing over that observed in cells transfected with the corresponding mock vector (empty vector for p53), Evidence that cell killing was occurring through apoptosis included apoptotic body formation, cell shrinkage and an increase in fluorescence after terminal transferase end-labeling. The capacity of estradiol to promote apoptosis in MDA-MB231 cells by a p53-liposome complex is likely to be related to the preferential redistribution of the gene from the cytoplasm to the nucleus which could occur during both the uptake and post-uptake phases. Consequently, although direct effects on gene expression, and the stability of message and protein cannot be ruled out, the predominant effect of estradiol in this experimental system appears to be to influence DNA translocation from the cytoplasm to the cell nucleus. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Virginia Commonwealth Univ, Med Coll Virginia, Dept Med, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Pharmacol, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Toxicol, Richmond, VA 23298 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Gewirtz, DA (reprint author), Virginia Commonwealth Univ, Med Coll Virginia, Dept Med, POB 980230, Richmond, VA 23298 USA. FU NCI NIH HHS [5T32CA09564] NR 18 TC 10 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD SEP 21 PY 1999 VL 1451 IS 2-3 BP 224 EP 232 DI 10.1016/S0167-4889(99)00094-4 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 239FZ UT WOS:000082759300002 PM 10556577 ER PT J AU Cooper, HA Dries, DL Davis, CE Shen, YL Domanski, MJ AF Cooper, HA Dries, DL Davis, CE Shen, YL Domanski, MJ TI Diuretics and risk of arrhythmic death in patients with left ventricular dysfunction SO CIRCULATION LA English DT Article DE diuretics; heart failure; arrhythmia; potassium ID CONGESTIVE-HEART-FAILURE; CONVERTING ENZYME-INHIBITOR; INTRACELLULAR ELECTROLYTES; CARDIAC-ARREST; EXTRA-SYSTOLES; HYPERTENSION; POTASSIUM; THERAPY; MAGNESIUM; HYPOKALEMIA AB Background-Treatment with diuretics has been reported to increase the risk of arrhythmic death in patients with hypertension. The effect of diuretic therapy on arrhythmic death in patients with left ventricular dysfunction is unknown. Methods and Results-We conducted a retrospective analysis of 6797 patients with an ejection fraction <0.36 enrolled in the Studies Of Left Ventricular Dysfunction (SOLVD) to assess the relation between diuretic use at baseline and the subsequent risk of arrhythmic death. Participants receiving a diuretic at baseline were more likely to have an arrhythmic death than those not receiving a diuretic (3.1 vs 1.7 arrhythmic deaths per 100 person-years, P=0.001). On univariate analysis, diuretic use was associated with an increased risk of arrhythmic death (relative risk [RR] 1.85, P=0.0001). After controlling for important covariates, diuretic use remained significantly associated with an increased risk of arrhythmic death (RR 1.37, P=0.009). Only non-potassium-sparing diuretic use was independently associated with arrhythmic death (RR 1.33, P=0.02). Use of a potassium-sparing diuretic, alone or in combination with a non-potassium-sparing diuretic, was not independently associated with an increased risk of arrhythmic death (RR 0.90, P=0.6). Conclusions-In SOLVD, baseline use of a non-potassium-sparing diuretic was associated with an increased risk of arrhythmic death, whereas baseline use of a potassium-sparing diuretic was not. These data suggest that diuretic-induced electrolyte disturbances may result in fatal arrhythmias in patients with systolic left ventricular dysfunction. C1 NHLBI, Clin Trials Sci Res Grp, Rockledge Ctr 2, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Div Cardiol, Washington, DC 20007 USA. Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. RP Cooper, HA (reprint author), NHLBI, Clin Trials Sci Res Grp, Rockledge Ctr 2, Div Epidemiol & Clin Applicat, Room 8149,6701 Rockledge Dr,MSC 7936, Bethesda, MD 20892 USA. NR 29 TC 185 Z9 192 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 21 PY 1999 VL 100 IS 12 BP 1311 EP 1315 PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 237CU UT WOS:000082638400011 PM 10491376 ER PT J AU Liu, JM Kim, S Read, EJ Futaki, M Dokal, I Carter, CS Leitman, SF Pensiero, M Young, NS Walsh, CE AF Liu, JM Kim, S Read, EJ Futaki, M Dokal, I Carter, CS Leitman, SF Pensiero, M Young, NS Walsh, CE TI Engraftment of hematopoietic progenitor cells transduced with the Fanconi anemia group C gene (FANCC) SO HUMAN GENE THERAPY LA English DT Article ID UMBILICAL-CORD BLOOD; BONE-MARROW; PERIPHERAL-BLOOD; FAC GENE; TRANSPLANTATION; THERAPY; RECONSTITUTION; VECTOR AB Fanconi anemia (FA) is an autosomal recessive disorder that leads to aplastic anemia. Mutations in the FANCC gene account for 10-15% of cases. FA cells are abnormally sensitive to DNA-damaging agents such as mitomycin C (MMC). Transfection of normal FANCC into mutant cells corrects this hypersensitivity and improves their viability in vitro. Four FA patients, representing the three major FANCC mutation subgroups, were entered into a clinical trial of gene transduction aimed at correction of the hematopoietic defect. Three patients received three or four cycles of gene transfer, each consisting of one or two infusions of autologous hematopoietic progenitor cells that had been transduced ex vivo with a retroviral vector carrying the normal FANCC gene. Prior to infusion, the FANCC transgene was demonstrated in transduced CD34-enriched progenitor cells. After infusion, FANCC was also present transiently in peripheral blood (PB) and bone marrow (BM) cells. Function of the normal FANCC transgene was suggested by a marked increase in hematopoietic colonies measured by in vitro cultures, including colonies grown in the presence of MMC, after successive gene therapy cycles in all patients. Transient improvement in BM cellularity coincided with this expansion of hematopoietic progenitors. A fourth patient, who received a single infusion of transduced CD34-enriched BM cells, was given radiation therapy for a concurrent gynecologic malignancy. The FANCC transgene was detected in her PB and BM cells only after recovery from radiation-induced aplasia, suggesting that FANCC gene transduction confers a selective engraftment advantage. These experiments highlight both the potential and difficulties in applying gene therapy to FA. C1 NHLBI, Hematol Branch, ACRF, Bethesda, MD 20892 USA. NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. Hammersmith Hosp, Dept Haematol, London, England. Genet Therapy Inc Novartis, Gaithersburg, MD 20878 USA. Univ N Carolina, Sch Med, Ctr Gene Therapy, Chapel Hill, NC 27599 USA. RP Liu, JM (reprint author), NHLBI, Hematol Branch, ACRF, Bldg 10,Rm 7C103, Bethesda, MD 20892 USA. NR 31 TC 78 Z9 81 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD SEP 20 PY 1999 VL 10 IS 14 BP 2337 EP 2346 DI 10.1089/10430349950016988 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 239JT UT WOS:000082765500007 PM 10515453 ER PT J AU Klausner, RD AF Klausner, RD TI Studying cancer in the mouse SO ONCOGENE LA English DT Article DE mouse; cancer; MMHCC; genetics; preclinical models C1 NCI, Bethesda, MD 20892 USA. RP Klausner, RD (reprint author), NCI, Bldg 31,Room 11A48,31 Ctr Dr,MSC 2590, Bethesda, MD 20892 USA. NR 0 TC 23 Z9 23 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 20 PY 1999 VL 18 IS 38 BP 5249 EP 5252 DI 10.1038/sj.onc.1203089 PG 4 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 240CP UT WOS:000082808400002 PM 10498876 ER PT J AU Fisher, GH Orsulic, S Holland, E Hively, WP Li, Y Lewis, BC Williams, BO Varmus, HE AF Fisher, GH Orsulic, S Holland, E Hively, WP Li, Y Lewis, BC Williams, BO Varmus, HE TI Development of a flexible and specific gene delivery system for production of murine tumor models SO ONCOGENE LA English DT Article DE avian sarcoma leukosis virus; breast cancer; cancer models; gliomagenesis; melanoma; retroviral gene vectors ID ROUS-SARCOMA VIRUS; A AVIAN-LEUKOSIS; RETROVIRAL VECTORS; TRANSGENIC MICE; LUNG-TUMORS; II CELL; EXPRESSION; MOUSE; SUSCEPTIBILITY; GLIOBLASTOMAS AB To develop models of human cancer ne have expressed the avian retroviral receptor, TVA, under a variety of mammalian promoters in transgenic mice, thus rendering mice susceptible to infection with avian leukosis virus-derived gene vectors. TVA-based retroviral gene transfer offers advantages ol er current murine models of human cancer. A single transgenic mouse line can be used to evaluate multiple genetic lesions, individually and in combination. Furthermore, mutant genes are introduced somatically into animals, as occurs in the majority of naturally occurring turners. Because the avian viral vectors replicate only in avian cells, the viral receptor in infected transgenic mouse cells remains available for multiple rounds of infection with different ASLV vectors. We discuss the theoretical and practical aspects of using recombinant avian retroviruses with TVA transgenic mice to generate cancer models. C1 NCI, Varmus Lab, NIH, DBS, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA. RP Varmus, HE (reprint author), NCI, Varmus Lab, NIH, DBS, 49 Convent Dr,Bldg 49,4A56, Bethesda, MD 20892 USA. RI Williams, Bart/A-3539-2013; OI Williams, Bart/0000-0002-5261-5301; Li, Yi/0000-0002-9976-518X NR 37 TC 104 Z9 108 U1 0 U2 2 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 20 PY 1999 VL 18 IS 38 BP 5253 EP 5260 DI 10.1038/sj.onc.1203087 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 240CP UT WOS:000082808400003 PM 10498877 ER PT J AU Merlino, G Helman, LJ AF Merlino, G Helman, LJ TI Rhabdomyosarcoma - working out the pathways SO ONCOGENE LA English DT Review DE rhabdomyosarcoma; myogenesis; cell cycle regulation; terminal differentiation ID HEPATOCYTE GROWTH-FACTOR; MUSCLE SATELLITE CELLS; FACTOR SCATTER FACTOR; SOFT-TISSUE SARCOMAS; COMPARATIVE GENOMIC HYBRIDIZATION; DEPENDENT KINASE-ACTIVITY; PAX3-FKHR FUSION PROTEIN; II GENE-EXPRESSION; C-MET RECEPTOR; SKELETAL-MUSCLE AB Rhabdomyosarcomas constitute a collection of childhood malignancies thought to arise as a consequence of regulatory disruption of skeletal muscle progenitor cell growth and differentiation. Our understanding of the pathogenesis of this neoplasm has recently benefited from the study of normal and malignant myogenic cells in vitro, facilitating the identification of diagnostic cytogenetic markers and the elucidation of mechanisms by which myogenesis is regulated. It is now appreciated that the delicate balance between proliferation and differentiation, mutually exclusive yet intimately associated processes, is normally controlled in large part through the action of a multitude of growth factors, whose signals are interpreted ba members of the MyoD family of helix - loop - helix proteins, and key regulatory cell cycle factors. The latter have proven to be frequent targets of mutational events that subvert myogenesis and promote the development of rhabdomyosarcoma. Although significant progress has been made in the treatment of rhabdomyosarcoma, patients presenting with metastatic disease or certain high risk features are still faced with a dismal prognosis. Only now are genetically engineered mouse models becoming available that are certain to provide fresh insights into the molecular/genetic pathways ba which rhabdomyosarcomas arise and progress, and to suggest novel avenues of therapeutic opportunity. C1 NCI, Mol Genet Sect, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Mol Oncol Sect, Pediat Branch, Bethesda, MD 20892 USA. RP Merlino, G (reprint author), NCI, Mol Genet Sect, Mol Biol Lab, NIH, Bldg 37,Room 2E24, Bethesda, MD 20892 USA. NR 136 TC 172 Z9 177 U1 0 U2 2 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 20 PY 1999 VL 18 IS 38 BP 5340 EP 5348 DI 10.1038/sj.onc.1203038 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 240CP UT WOS:000082808400013 PM 10498887 ER PT J AU Bengzon, J Hansson, SR Hoffman, BJ Lindvall, O AF Bengzon, J Hansson, SR Hoffman, BJ Lindvall, O TI Regulation of norepinephrine transporter and tyrosine hydroxylase mRNAs after kainic acid-induced seizures SO BRAIN RESEARCH LA English DT Article DE monoamine transporter; norepinephrine; locus coeruleus; epilepsy; rat ID MESSENGER-RNA LEVELS; LOCUS-CERULEUS; RAT-BRAIN; ADRENAL-MEDULLA; STIMULATION; COERULEUS; EXPRESSION; POTENTIATION; RESERPINE; MEDIATION AB Noradrenergic locus coeruleus (LC) efferents to the forebrain suppress seizures in several models of epilepsy. Using in situ hybridization, we demonstrate that tyrosine hydroxylase (TH) and norepinephrine transporter (NET) but not vesicular monoamine transporter 2 (VMAT2) mRNA levels an transiently elevated in LC neurons following kainic acid-induced status epilepticus. These increases of TH and NET mRNAs and presumably of the proteins themselves might enhance synthesis and reuptake of NE postictally. (C) 1999 Published by Elsevier Science B.V. All rights reserved. C1 Univ Lund Hosp, Wallenberg Neurosci Ctr, Sect Restorat Neurol, S-22185 Lund, Sweden. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Hansson, SR (reprint author), Univ Lund, Wallenberg Neurosci Ctr, Dept Physiol & Neurosci, Div Mol Neurobiol, S-22100 Lund, Sweden. NR 25 TC 14 Z9 14 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD SEP 18 PY 1999 VL 842 IS 1 BP 239 EP 242 DI 10.1016/S0006-8993(99)01874-0 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 240CZ UT WOS:000082809300030 PM 10526118 ER PT J AU Shotelersuk, V Tifft, CJ Vacha, S Peters, KF Biesecker, LG AF Shotelersuk, V Tifft, CJ Vacha, S Peters, KF Biesecker, LG TI Discordance of oral-facial-digital syndrome type 1 in monozygotic twin girls SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE oral-facial-digital syndrome type 1 (OFD1); discordant MZ twins; postzygotic mutation; X-inactivation ID X-INACTIVATION; MZ TWINS; CHROMOSOME; PATTERNS; DISEASE; PAIRS AB The oral-facial-digital syndrome type 1 (OFD1) includes limb, facial, intraoral malformations and the gene for the disorder was recently mapped to Xp22.3-p22.2. We report on monozygotic twin girls discordant for OFD1, Monozygosity is supported by placental pathology (monochorionic diamniotic) and molecular studies with probability of dizygosity <1 x 10(-6). The affected twin has oral cavity abnormalities including median cleft lip, cleft palate, lobulated hamartomatous tongue, aberrant hyperplastic oral frenula, alveolar notches, and absent lateral incisors. Facial manifestations include telecanthus, hypoplastic alae nasi, and transient neonatal facial milia, The patient also has short and deviated fingers with partial cutaneous syndactyly, At 10 years, she has not had central nervous system or kidney problems, X-inactivation study revealed similar X-inactivation patterns in the lymphoblasts of both twins. We conclude that skewed X-inactivation is an unlikely cause for the discordance, which is more likely due to a postzygotic mutation in the affected twin. (C) 1999 Wiley-Liss, Inc. C1 Natl Human Genome Res Inst, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Dept Med Genet, Washington, DC 20010 USA. Natl Human Genome Res Inst, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), Natl Human Genome Res Inst, Genet Dis Res Branch, NIH, 49 Convent Dr,Room 4A80, Bethesda, MD 20892 USA. NR 13 TC 14 Z9 14 U1 1 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD SEP 17 PY 1999 VL 86 IS 3 BP 269 EP 273 DI 10.1002/(SICI)1096-8628(19990917)86:3<269::AID-AJMG14>3.0.CO;2-G PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 238MP UT WOS:000082714300014 PM 10482878 ER PT J AU Barber, TD Barber, MC Cloutier, TE Friedman, TB AF Barber, TD Barber, MC Cloutier, TE Friedman, TB TI PAX3 gene structure, alternative splicing and evolution SO GENE LA English DT Article DE intron retention; isoform; paired box; splotch; Waardenburg syndrome ID BOVINE GROWTH-HORMONE; DNA-BINDING ACTIVITY; PAIRED DOMAIN; WAARDENBURG SYNDROME; MESSENGER-RNA; ALVEOLAR RHABDOMYOSARCOMA; SEQUENCE STATISTICS; MOUSE MUTANT; EXPRESSION; MUTATION AB PAX3 is a member of the paired box family of transcription factors that function during embryogenesis and cancer epigenesis. Mutations in PAX3 cause Waardenburg syndrome (types 1 and 3), Craniofacial-deafness-hand syndrome and alveolar rhabdomyosarcoma in humans and the Splotch phenotype in mice. In this study, we describe the genomic structure of PAX3, including novel coding sequences and the complete 3' UTR. Alternative transcripts of PAX3 were identified in various tissues, including human adult skeletal muscle and mouse embryos. One of the novel alternative transcripts is evolutionarily conserved in quail and can transactivate a reporter construct containing the mouse c-met promoter. The sequences and alternative transcripts reported herein extend our understanding of the function and evolution of PAX3 in vertebrates and enable a comprehensive mutation screen for individuals with Waardenburg syndrome. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Natl Inst Deafness & Other Commun Disorders, NIH, Rockville, MD 20850 USA. Michigan State Univ, Grad Program Genet, E Lansing, MI 48824 USA. Human Genome Sci Inc, Dept Mol Biol, Rockville, MD USA. Albert Einstein Coll Med, Dept Biochem, Bronx, NY 10467 USA. RP Friedman, TB (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, 5 Res Court, Rockville, MD 20850 USA. EM friedman@nidcd.nih.gov FU NIDCD NIH HHS [Z01 DC 00035, Z01 DC 00038] NR 33 TC 47 Z9 49 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 EI 1879-0038 J9 GENE JI Gene PD SEP 17 PY 1999 VL 237 IS 2 BP 311 EP 319 DI 10.1016/S0378-1119(99)00339-X PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 239KB UT WOS:000082766300003 PM 10521655 ER PT J AU Xu, ASL Labotka, RJ London, RE AF Xu, ASL Labotka, RJ London, RE TI Acetylation of human hemoglobin by methyl acetylphosphate - Evidence of broad regio-selectivity revealed by NMR studies SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SICKLE-CELL HEMOGLOBIN; PHOSPHATE; BINDING; ASPIRIN; CHAINS; AGENT; SITES AB The development of chemical modification agents that reduce the tendency of sickle hemoglobin (HbS) to aggregate represents an important chemotherapeutic goal. Methyl acetylphosphate (MAP) has been reported to bind to the 2,3-diphosphoglycerate (2,3-DPG) binding site of hemoglobin, where it selectively acetylates residues, resulting in increased solubility of HbS. We have prepared [1-C-13]MAP and evaluated the adduct formation with hemoglobin using H-1-C-13 HMQC and HSQC NMR studies. These spectra of the acetylated hemoglobin adducts showed 10-11 well resolved adduct peaks, indicating that the acetylation was not highly residue specific. The chemical shift pattern observed is in general similar to that obtained recently using [1'-C-13]aspirin as the acetylating agent (Xu, A. S. L., Macdonald, J. M,, Labotka, R, J., and London, R. E. (1999) Biochim, Biophys. Acta 1432, 333-349). Blocking the 2,3-DPG binding site with inositol hexaphosphate (IHP) resulted in, a selective reduction in intensity of adduct resonances, presumably corresponding to residues located in the 2,3-DPG binding cleft. The pattern of residue protection appeared to be identical to that observed in our previous study using IHP and labeled aspirin, Pre-acetylation of hemoglobin using unlabeled MAP, followed by acetylation with [1'-C-13]aspirin indicated a general protective effect, with the greatest reduction of intensity for resonances corresponding to acetylated residues in the 2,3-DPG binding site. These studies indicated that both MAP and aspirin exhibit similar, although not identical, acetylation profiles and target primarily the beta Lys-82 residue in the 2,3-DPG binding site, as well as sites such as beta Lys-59 and alpha Lys-90, which are not located in the beta-cleft of hemoglobin. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Illinois, Dept Pediat, Chicago, IL 60612 USA. RP London, RE (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. FU NHLBI NIH HHS [5RO1 HL57604] NR 22 TC 12 Z9 12 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 SEP 17 PY 1999 VL 274 IS 38 BP 26629 EP 26632 DI 10.1074/jbc.274.38.26629 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 235YD UT WOS:000082570700002 PM 10480863 ER PT J AU Ye, JP Young, HA Zhang, XY Castranova, V Vallyathan, V Shi, XL AF Ye, JP Young, HA Zhang, XY Castranova, V Vallyathan, V Shi, XL TI Regulation of a cell type-specific silencer in the human interleukin-3 gene promoter by the transcription factor YY1 and an AP2 sequence-recognizing factor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FACTOR-ALPHA GENE; NF-KAPPA-B; INTERFERON-GAMMA; T-CELL; EXPRESSION; ELEMENTS; ACTIVATION; BINDING; SITE; IDENTIFICATION AB Negative regulation of cytokine gene transcription is an important mechanism in maintaining homeostasis of immune function. In this study, we characterized a silencer element in the human interleukin-3 gene promoter that is responsible for the cell-specific expression of interleukin-3. This silencer activity was proposed to be mediated by an unidentified nuclear inhibitory protein (NIP). In this study, we have identified two nuclear factors that are responsible for the silencer activity in T cells. The NIP element forms four specific DNA-protein complexes (designated as complexes A-D) with the Jurkat nuclear proteins. Complex A contains a nuclear protein that shares DNA-binding specificity with the transcription factor AP2 (designated as an AP2 sequence-recognizing factor (ASRF)). Formation of this ASRF complex is required for the NIP silencer function, as mutation of the ASRF-binding site abrogated the silencer activity. Complex B contains the nuclear factor YY1 ((Y) under bar in-(Y) under bar ang (1) under bar), whose function is to down-regulate ASRF activity in the silencer. YY1 activity is supported by data from mutation and cotransfection analyses. Complexes C and D are formed by nonspecific binding proteins and do not express any regulatory activity in the NIP element. These data indicate that a cell type-specific silencer activity might be determined by a unique profile of ubiquitous transcription factors. C1 NIOSH, Pathol & Physiol Res Branch, Hlth Effects Lab Div, NIH, Morgantown, WV 26505 USA. NCI, Expt Immunol Lab, Frederick Canc Res & Dev Ctr, NIH, Frederick, MD 21702 USA. RP Ye, JP (reprint author), NIOSH, Pathol & Physiol Res Branch, Hlth Effects Lab Div, NIH, 1095 Willowdale Rd, Morgantown, WV 26505 USA. RI Young, Howard/A-6350-2008; Shi, Xianglin/B-8588-2012 OI Young, Howard/0000-0002-3118-5111; NR 31 TC 16 Z9 16 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 SEP 17 PY 1999 VL 274 IS 38 BP 26661 EP 26667 DI 10.1074/jbc.274.38.26661 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 235YD UT WOS:000082570700007 PM 10480868 ER PT J AU Wibbenmeyer, JA Schuck, P Smith-Gill, SJ Willson, RC AF Wibbenmeyer, JA Schuck, P Smith-Gill, SJ Willson, RC TI Salt links dominate affinity of antibody HyHEL-5 for lysozyme through enthalpic contributions SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEN EGG LYSOZYME; BINDING-ENERGY; WHITE LYSOZYME; AVIAN LYSOZYME; ANTIGEN; ASSOCIATION; COMPLEX; STABILITY; THERMODYNAMICS; MUTAGENESIS AB The binding of murine monoclonal antibody HyHEL-5 to lysozyme has been the subject of extensive crystallographic, computational, and experimental investigations. The complex of HyHEL-5 with hen egg lysozyme (HEL) features salt bridges between Fab heavy chain residue Glu(50), and Arg(45) Arg(68) of HEL. This interaction has been predicted to play a dominant role in the association on the basis of molecular electrostatics calculations. The association of aspartic acid and glutamine mutants at position 50(H) of the cloned HyHEL-5 Fab with HEL and bobwhite quail lysozyme (BQL), an avian variant bearing an Arg(68) --> Lys substitution in the epitope, was characterized by isothermal titration calorimetry and sedimentation equilibrium. Affinities for HEL were reduced by 400-fold (E50(H)D) and 40,000-fold (E50(H)Q) (Delta Delta G degrees estimated at 4.0 and 6.4 kcal mol(-1), respectively). The same mutations reduce affinity for BQL by only 7- and 55-fold, respectively, indicating a reduced specificity for HEL. The loss of affinity upon mutation is in each case primarily due to an unfavorable change in the enthalpy of the interaction; the entropic contribution is virtually unchanged. An enthalpy-entropy compensation exists for each interaction; Delta H degrees decreases, while Delta S degrees increases with temperature. The Delta Cp for each mutant interaction is less negative than the wild-type. Mutant-cycle analysis suggests the mutations present in the HyHEL-5 Fab mutants are linked to those present in the BQL with coupling energies between 3 and 4 kcal mol(-1). C1 Univ Houston, Dept Biol & Biochem, Houston, TX 77024 USA. NIH, Mol Interact Resource Bioengn & Phys Sci Program, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, NIH, Frederick, MD 21702 USA. Univ Houston, Dept Chem Engn, Houston, TX 77024 USA. RP Willson, RC (reprint author), Univ Houston, Dept Biol & Biochem, Houston, TX 77024 USA. OI Schuck, Peter/0000-0002-8859-6966 NR 37 TC 21 Z9 21 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 SEP 17 PY 1999 VL 274 IS 38 BP 26838 EP 26842 DI 10.1074/jbc.274.38.26838 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 235YD UT WOS:000082570700030 PM 10480891 ER PT J AU Gordon, VM Nelson, KL Buckley, JT Stevens, VL Tweten, RK Elwood, PC Leppla, SH AF Gordon, VM Nelson, KL Buckley, JT Stevens, VL Tweten, RK Elwood, PC Leppla, SH TI Clostridium septicum alpha toxin uses glycosylphosphatidylinositol-anchored protein receptors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHANNEL-FORMING TOXIN; ERYTHROCYTE RECEPTOR; AEROLYSIN; BIOSYNTHESIS; EXPRESSION; MUTANT; CELLS; PURIFICATION; ACTIVATION; SYSTEM AB The alpha toxin produced by Clostridium septicum is a channel-forming protein that is an important contributor to the virulence of the organism. Chinese hamster ovary (CHO) cells are sensitive to low concentrations of the toxin, indicating that they contain toxin receptors. Using retroviral mutagenesis, a mutant CHO line (BAG15) was generated that is resistant to alpha toxin. FACS analysis showed that the mutant cells have lost the ability to bind the toxin, indicating that they lack an alpha toxin receptor. The mutant cells are also resistant to aerolysin, a channel-forming protein secreted by Aeromonas spp., which is structurally and functionally related to alpha toxin and which is known to bind to glycosylphosphatidylinositol (GPI)-anchored proteins, such as Thy-1. We obtained evidence that the BAG15 cells lack N-acetylglucosaminyl-phosphatidylinositol deacetylase-L, needed for the second step in GPI anchor biosynthesis, Several lymphocyte cell lines lacking GPI-anchored proteins were also shown to be less sensitive to alpha toxin. On the other hand, the sensitivity of CHO cells to alpha toxin was increased when the cells were transfected with the GPI-anchored folate receptor. We conclude that alpha toxin, like aerolysin, binds to GPI-anchored protein receptors. Evidence is also presented that the two toxins bind to different subsets of GPI-anchored proteins. C1 NIDCR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. Univ Victoria, Dept Biochem & Microbiol, Victoria, BC V8W 3P6, Canada. Emory Univ, Sch Med, Dept Radiat Oncol, Div Canc Biol, Atlanta, GA 30335 USA. Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73190 USA. NCI, Med Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Leppla, SH (reprint author), NIDCR, Oral Infect & Immun Branch, NIH, Bldg 30,Rm 316,30 Convent Dr,MSC 4350, Bethesda, MD 20892 USA. FU NIAID NIH HHS [R01 AI032097, AI37657]; NIGMS NIH HHS [R01GM51419] NR 40 TC 87 Z9 90 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 17 PY 1999 VL 274 IS 38 BP 27274 EP 27280 DI 10.1074/jbc.274.38.27274 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 235YD UT WOS:000082570700086 PM 10480947 ER PT J AU Mazur, SJ Sakaguchi, K Appella, E Wang, XW Harris, CC Bohr, VA AF Mazur, SJ Sakaguchi, K Appella, E Wang, XW Harris, CC Bohr, VA TI Preferential binding of tumor suppressor p53 to positively or negatively supercoiled DNA involves the C-terminal domain SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE p53; C-terminal domain; negative supercoiling; positive supercoiling; transcription ID NUCLEOTIDE EXCISION-REPAIR; WILD-TYPE; PYRIMIDINE DIMERS; TOPOISOMERASE-I; CELL-CYCLE; DHFR GENE; DAMAGE; PROTEIN; TRANSCRIPTION; APOPTOSIS AB The C-terminal domain of the tumor suppressor protein p53 is the site of non-specific DNA binding. Purified p53 produced from baculovirus-infected insect cells binds preferentially to supercoiled DNA, forming bands with lower electrophoretic mobility. This non-covalent binding does not change the linking number of the DNA. An anti-p53 antibody targeting the C-terminal domain partially competes with supercoiled DNA in binding to p53, while antibodies targeted to the N terminus of p53 supershift the complex bands. A synthetic peptide corresponding to amino acid residues 319-393 of human p53 also displays preferential binding to supercoiled DNA, while a mutant peptide, which is unable to form tetramers, is inactive. The center of the equilibrium distribution of topoisomers formed by relaxation with topoisomerase I is not shifted in the presence of p53 although the distribution is broadened. The preferential binding of p53 is exhibited toward both positively and negatively supercoiled DNA. These observations are consistent with a model in which p53 binds to right-handed or left-handed strand crossings. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NIA, Mol Genet Lab, NIH, Baltimore, MD 21224 USA. NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Mazur, SJ (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37,B37, Bethesda, MD 20892 USA. RI Wang, Xin/B-6162-2009 NR 61 TC 31 Z9 31 U1 0 U2 3 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 SEP 17 PY 1999 VL 292 IS 2 BP 241 EP 249 DI 10.1006/jmbi.1999.3064 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 236JX UT WOS:000082597400005 PM 10493872 ER PT J AU Markus, MA Gerstner, RB Draper, DE Torchia, DA AF Markus, MA Gerstner, RB Draper, DE Torchia, DA TI Refining the overall structure and subdomain orientation of ribosomal protein S4 Delta 41 with dipolar couplings measured by NMR in uniaxial liquid crystalline phases SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE ribosomal protein; atomic-resolution protein structure; NMR spectroscopy; dipolar couplings; RNA-protein interactions ID ROTATIONAL DIFFUSION ANISOTROPY; N-15 NMR; RNA; MACROMOLECULES; BINDING; SPECIFICITY; FIBRONECTIN; RELAXATION; DYNAMICS; COMPLEX AB Prokaryotic protein S4 initiates assembly of the small ribosomal subunit by binding to 16 S rRNA. Residues 43-200 of S4 from Bacillus stearothermophilus (S4 Delta 41) bind to both 16 S rRNA and to a mRNA pseudoknot. In order to obtain structure-based insights regarding RNA binding, we previously determined the solution structure of 54 Delta 41 using NOE, hydrogen bond, and torsion angle restraints. S4 Delta 41 is elongated, with two distinct: subdomains, one all helical, the other including a P-sheet. In contrast to the high resolution structures obtained for each individual subdomain, their relative orientation was not precisely defined because only 17 intersubdomain NOE restraints were determined. Compared to the 1.7 Angstrom crystal structure, when the sheet-containing subdomains are superimposed, the helical subdomain is twisted by almost 45 degrees about the long axis of the molecule in the solution structure. Because variations in subdomain orientation may explain how the protein recognizes multiple RNA targets, our current goal is to determine the orientation of the subdomains in solution with high precision. To this end, NOE assignments were re-examined. NOESY experiments on a specifically labeled sample revealed that one of the intersubdomain restraints had been misassigned. However, the revised set of NOE restraints produces solution structures that still have imprecisely defined subdomain orientations and that lie between the original NMR structure and the crystal structure. In contrast, augmenting the NOE restraints with N-H dipolar couplings, measured in uniaxial liquid crystalline phases, clearly establishes the relative orientation of the subdomains. Data obtained from two independent liquid crystalline milieux, DMPC/DHPC bicelles and the filamentous bacteriophage Pf1, show that the relative orientation of the subdomains in solution is quite similar to the subdomain orientation in the crystal structure. The solution structure, refined with dipolar data, is presented and its implications for S4's RNA binding activity are discussed. (C) 1999 Academic Press. C1 Natl Inst Dent & Craniofacial Res, Struct Mol Biol Unit, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Chem, Baltimore, MD 21218 USA. RP Torchia, DA (reprint author), Natl Inst Dent & Craniofacial Res, Struct Mol Biol Unit, 30 Convent Dr,Room 106, Bethesda, MD 20892 USA. NR 35 TC 31 Z9 33 U1 0 U2 1 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD SEP 17 PY 1999 VL 292 IS 2 BP 375 EP 387 DI 10.1006/jmbi.1999.3061 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 236JX UT WOS:000082597400015 PM 10493882 ER PT J AU Pozsgay, V AF Pozsgay, V TI A practical route to multifunctional 2-azido-2-deoxy-D-glucopyranosyl donors SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID SHIGELLA-DYSENTERIAE TYPE-1; OLIGOSACCHARIDE SYNTHESIS; FACILE PREPARATION; GLYCOSYL DONORS; BUILDING-BLOCKS; DIAZO TRANSFER; DERIVATIVES; CONVENIENT; 1,3,4,6-TETRA-O-ACETYL-2-AZIDO-2-DEOXY-BETA-D-GLUCOPYRANOSE; POLYSACCHARIDE C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP Pozsgay, V (reprint author), NICHHD, NIH, 6 Ctr Dr,MSC 2720, Bethesda, MD 20892 USA. NR 36 TC 15 Z9 15 U1 1 U2 1 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 SEP 17 PY 1999 VL 64 IS 19 BP 7277 EP 7280 DI 10.1021/jo990811p PG 4 WC Chemistry, Organic SC Chemistry GA 238XG UT WOS:000082739600052 ER PT J AU Balijepalli, S Annepu, J Boyd, MR Ravindranath, V AF Balijepalli, S Annepu, J Boyd, MR Ravindranath, V TI Effect of thiol modification on brain mitochondrial complex I activity SO NEUROSCIENCE LETTERS LA English DT Article DE brain; mitochondria; complex I; oxidative stress; protein thiol; electron transport ID PARKINSONS-DISEASE; CHAIN AB We have studied the effect of altered thiol status on brain mitochondrial complex I activity. Exposure of mouse brain slices to diethyl maleate resulted in significant loss in complex I activity with concomitant loss of thiol antioxidant, glutathione. However, incubation of mitochondria isolated from diethyl maleate treated slices with dithiothreitol completely regenerated activity of complex I. Incubation of mouse brain slices with iodoacetic acid, a thiol modifier, also resulted in inhibition of complex I activity, which was reversed by glutathione. The present study demonstrates sensitivity of complex I to thiol modifying agents. Reversal of this inhibition by thiol reductants indicates that secondary oxidation of thiol groups in complex I as a consequence of thiol modification is responsible for the loss in activity. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 Natl Inst Mental Hlth & Neurosci, Dept Neurochem, Bangalore 560029, Karnataka, India. NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program, FCRDC, Frederick, MD 21702 USA. RP Ravindranath, V (reprint author), Natl Inst Mental Hlth & Neurosci, Dept Neurochem, Hosur Rd, Bangalore 560029, Karnataka, India. NR 13 TC 19 Z9 20 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 SEP 17 PY 1999 VL 272 IS 3 BP 203 EP 206 DI 10.1016/S0304-3940(99)00593-5 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 238NW UT WOS:000082717200016 PM 10505616 ER PT J AU Coop, A Rice, KC AF Coop, A Rice, KC TI Studies into the direct oxidation of codeinone to 14-hydroxycodeinone SO TETRAHEDRON LA English DT Article DE alkaloids; oxidation; cobalt and compounds ID COBALT(III); MANGANESE(III); OXYGEN; IONS AB The direct oxidation of codeinone (5) to 14-hydroxycodeinone (6) was investigated with a wide range of oxidizing agents. The majority of reagents gave little or no desired product. Peracids were found to be moderately successful, with dimethyl peracetic acid giving the greatest yield (37%). Metallic oxidants generally gave rise to competing oxidations, however Co(AcO)(3) was found to conveniently oxidize 5 to 6 in 51 % yield, representing a practical, non-chromatographic procedure for the preparation of 14-hydroxycodeinone. Published by Elsevier Science Ltd. C1 NIDDKD, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RP Rice, KC (reprint author), NIDDKD, Med Chem Lab, NIH, Bldg 8,Room B1-23, Bethesda, MD 20892 USA. NR 33 TC 11 Z9 11 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4020 J9 TETRAHEDRON JI Tetrahedron PD SEP 17 PY 1999 VL 55 IS 38 BP 11429 EP 11436 DI 10.1016/S0040-4020(99)00665-1 PG 8 WC Chemistry, Organic SC Chemistry GA 234RW UT WOS:000082499000002 ER PT J AU Scita, G Nordstrom, J Carbone, R Tenca, P Giardina, G Gutkind, S Bjarnegard, M Betsholtz, C Di Fiore, PP AF Scita, G Nordstrom, J Carbone, R Tenca, P Giardina, G Gutkind, S Bjarnegard, M Betsholtz, C Di Fiore, PP TI EPS8 and E3B1 transduce signals from Ras to Rac SO NATURE LA English DT Article ID SH3 DOMAIN; BINDING-PROTEIN; RHO-GTPASES; GROWTH; KINASE; CDC42; AFFINITY; PATHWAYS AB The small guanine nucleotide (GTP)-binding protein Rac regulates mitogen-induced cytoskeletal changes and c-Jun aminoterminal kinase (JNK), and its activity is required for Ras-mediated cell transformation(1). Epistatic analysis placed Rac as a key downstream target in pas signalling(2); however, the biochemical mechanism regulating the cross-talk among these small GTP-binding proteins remains to be elucidated. Eps8 (relative molecular mass 97,000) is a substrate of receptors with tyrosine kinase activity(3) which binds, through its SH3 domain, to a protein designated E3b1/Abi-1 (refs 4, 5). Here we show that Eps8 and E3b1/Abi-1 participate in the transduction of signals from pas to Rac, by regulating Rac-specific guanine nucleotide exchange factor (GEF) activities. We also show that Eps8, E3b1 and Sos-1 form a tri-complex in vivo that exhibits Rac-specific GEF activity in vitro. We propose a model in which Eps8 mediates the transfer of signals between Ras and pac, by forming a complex with E3b1 and Sos-1. C1 European Inst Oncol, Dept Expt Oncol, I-20141 Milan, Italy. Univ Gothenburg, Dept Med Biochem, SE-40530 Gothenburg, Sweden. Univ Bari, Ist Microbiol, I-70124 Bari, Italy. NIH, Mol Signaling Unit, Cellular Dev & Oncol Lab, Bethesda, MD 20892 USA. RP Di Fiore, PP (reprint author), European Inst Oncol, Dept Expt Oncol, Via Ripamonti 435, I-20141 Milan, Italy. RI Gutkind, J. Silvio/A-1053-2009; Di Fiore, Pier Paolo/K-2130-2012; OI Di Fiore, Pier Paolo/0000-0002-2252-0950; Scita, Giorgio/0000-0001-7984-1889 NR 23 TC 245 Z9 255 U1 1 U2 5 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 16 PY 1999 VL 401 IS 6750 BP 290 EP 293 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 237VZ UT WOS:000082678400057 PM 10499589 ER PT J AU Cantor, KP Lynch, CF Hildesheim, ME Dosemeci, M Lubin, J Alavanja, M Craun, G AF Cantor, KP Lynch, CF Hildesheim, ME Dosemeci, M Lubin, J Alavanja, M Craun, G TI Drinking water source and chlorination byproducts in Iowa. III. Risk of brain cancer SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE brain neoplasms; case-control studies; smoking; trihalomethanes; water supply ID BLADDER-CANCER; UNITED-STATES; OCCUPATIONAL EXPOSURE; WASHINGTON COUNTY; TUMORS; GLIOMAS; IDENTIFICATION; MALIGNANCIES; CARCINOGENS; MORTALITY AB The authors conducted a population-based case-control study in lowa of 375 brain cancer patients and 2,434 controls. A postal questionnaire was used to gather information on lifetime residential history, sources of drinking water, beverage intake, and other potential risk factors. Exposure to chlorination byproducts in drinking water was estimated by combining questionnaire data with historical information from water utilities and trihalomethane levels in recent samples. The analysis included 291 cases (77.6%) and 1,983 controls (81.5%), for whom water quality information was available for at least 70% of lifetime years. Proxies represented 74.4% of cases. The mean number and mean duration of places of residence were comparable between direct and proxy respondents, suggesting little contribution to bias. After multivariate adjustment, odds ratios for brain cancer were 1.0, 1.1, 1.6, and 1.3 for exposure to chlorinated surface water of 0, 1-19, 20-39, and greater than or equal to 40 years (p trend = 0.1), Among men, odds ratios were 1.0, 1.3, 1.7, and 2.5 (p trend = 0.04), and among women, 1.0, 1.0, 1.6, and 0.7 (p trend = 0.7)). Similar findings were found with estimates of average lifetime level of trihalomethanes. The association was stronger among men with above-median tap water consumption. These observations deserve further attention, especially in view of increasing glioma rates. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Iowa, Coll Med, Dept Prevent Med & Genet, Iowa City, IA USA. US EPA, Cincinnati, OH 45268 USA. RP Cantor, KP (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8106, Bethesda, MD 20892 USA. FU NCI NIH HHS [5 KO7 CA01181-05, N01-CP-51026, N01-CP-85614] NR 40 TC 33 Z9 35 U1 1 U2 8 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 SEP 15 PY 1999 VL 150 IS 6 BP 552 EP 560 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 236MA UT WOS:000082602300002 PM 10489993 ER PT J AU Ursin, G Wu, AH Hoover, RN West, DW Nomura, AMY Kolonel, LN Pike, MC Ziegler, RG AF Ursin, G Wu, AH Hoover, RN West, DW Nomura, AMY Kolonel, LN Pike, MC Ziegler, RG TI Breast cancer and oral contraceptive use in Asian-American women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Asian Americans; breast neoplasms; contraceptives; oral; transients and migrants ID CHINESE-WOMEN; RISK-FACTORS; YOUNG-WOMEN; REPRODUCTIVE FACTORS; CELL-PROLIFERATION; AGE; ESTROGENS; SHANGHAI; PHASE; JAPAN AB Breast cancer incidence has historically been 4-7 times higher in the United States than in Asia. A previous study by the authors in Asian-American women demonstrated a substantial increase in breast cancer risk in women who migrated from Asia to the United States, with the risk almost doubling during the first decade after migration. Increased use of oral contraceptives soon after migration to the United States could possibly explain this rapid rise in risk. In a population-based case-control study of Chinese, Filipino, and Japanese-American women, aged 20-55 years, who lived in San Francisco-Oakland, California; Los Angeles, California; and Oahu, Hawaii during 1983-1987, 597 cases (70% of those eligible) and 966 controls (75%) were interviewed. Controls were matched to cases on age, ethnicity, and area of residence. Oral contraceptive (OC) use increased with time since migration; 15.0% of Asian-born women who had been in the West <8 years, 33.4% of Asian-born women who had been in the West greater than or equal to 8 years, and 49.6% of Asian women born in the West had ever used OCs. However, duration of OC use (adjusted for age, ethnicity, study area, years since migration, education, family history of breast cancer and age at first full-term birth) was not associated with increased risk of breast cancer. Moreover, neither OC use before age 25 years nor before first full-term birth was associated with increased risk. Results were unchanged when restricted to women under age 45 years or under age 40 years. After adjustment for duration of OC use, women who had been in the United States greater than or equal to 8 years were still at almost twice the risk of breast cancer compared with women who had been in the United States 2-7 years. This study suggests that OC use cannot explain the elevated risk observed in Asian women who migrated to the United States greater than or equal to 7 years ago. C1 Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. No Calif Canc Ctr, Union City, CA USA. Univ Hawaii, Program Epidemiol, Canc Res Ctr Hawaii, Honolulu, HI 96822 USA. RP Ursin, G (reprint author), Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Dept Prevent Med, 1441 Eastlake Ave,Room 4408, Los Angeles, CA 90033 USA. NR 45 TC 30 Z9 31 U1 1 U2 1 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 SEP 15 PY 1999 VL 150 IS 6 BP 561 EP 567 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 236MA UT WOS:000082602300003 PM 10489994 ER PT J AU Velie, EM Block, G Shaw, GM Samuels, SJ Schaffer, DM Kulldorff, M AF Velie, EM Block, G Shaw, GM Samuels, SJ Schaffer, DM Kulldorff, M TI Maternal supplemental and dietary zinc intake and the occurrence of neural tube defects in California SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE abnormalities; anencephaly; diet; food habits; meat; proteins; spina bifida cystica; zinc ID QUESTIONNAIRE; PREGNANCY; RECORDS; HUMANS; WOMEN; ABSORPTION; PREVALENCE; NUTRITURE; BALANCE; RISK AB The authors investigated the association between maternal preconceptional supplemental and dietary zinc intake and risk of neural tube defects (NTDs) in a population-based case-control study conducted between 1989 and 1991 in California. Cases were 430 NTD-affected fetuses/infants, and controls were 429 randomly selected non-malformed infants. Mothers reported their preconceptional use of vitamin, mineral, and food supplements, and completed a 98-item food frequency questionnaire. Increased total preconceptional zinc intake was associated with a reduced risk for NTDs (quintiie 5 vs, quintile 1, odds ratio (OR) = 0.65, 95% confidence interval (CI) 0.43, 0.99). Phytate intake, a constituent of the diet known to impede zinc absorption, appeared to modify the zinc - NTD association. In addition, increased servings of animal products, the most bioavailable food source of zinc, was associated with a reduced risk for NTDs (quintile 5 vs. quintile 1, OR = 0.49, 95% CI 0.32, 0.76). Risk estimates for zinc intake were changed little after controlling for multiple sociodemographic factors and total folate intake, but were attenuated after controlling for nutrients highly correlated with dietary sources of zinc, such as protein. In sum, the analyses indicate that risk of NTDs in infants and fetuses decreased with increasing maternal preconceptional zinc intake. However, it remains unclear whether increased zinc intake, or another nutrient or combination of nutrients highly correlated with zinc intake in the diet, is causally associated with reduced NTD risk. C1 Univ Calif Berkeley, Dept Epidemiol, Berkeley, CA 94720 USA. Calif Birth Defects Monitoring Program, Emeryville, CA USA. Univ Calif Davis, Dept Community & Int Hlth, Davis, CA 95616 USA. Kaiser Permanente Med Care Program, Div Res, Oakland, CA 94611 USA. NCI, Div Canc Prevent, Biometry Branch, Bethesda, MD 20892 USA. RP Velie, EM (reprint author), NCI, Nutrit Epidemiol Branch, Bldg EPS,Room 7026,6120 Execut Plaza Blvd, Bethesda, MD 20892 USA. RI Block, Gladys/E-3304-2010; Kulldorff, Martin/H-4282-2011; OI Kulldorff, Martin/0000-0002-5284-2993 NR 45 TC 60 Z9 62 U1 2 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 SEP 15 PY 1999 VL 150 IS 6 BP 605 EP 616 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 236MA UT WOS:000082602300009 PM 10490000 ER PT J AU Hemila, H Kaprio, J Pietinen, P Albanes, D Heinonen, OP AF Hemila, H Kaprio, J Pietinen, P Albanes, D Heinonen, OP TI Vitamin C and other compounds in vitamin C rich food in relation to risk of tuberculosis in male smokers SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE alpha-tocopherol; ascorbic acid; beta-carotene; body mass index; diet; smoking; tuberculosis ID ASCORBIC-ACID; COMMON COLD; ELDERLY POPULATION; PULMONARY-FUNCTION; BLOOD-PRESSURE; DIETARY; SUPPLEMENTATION; SUSCEPTIBILITY; DEFICIENCY; SYMPTOMS AB To examine whether vitamin C rich food consumption and related vitamin C intake are associated with the risk of tuberculosis, the authors analyzed 167 incident cases of tuberculosis during a median follow-up time of 6.7 years in a clinical trial cohort of 26,975 Finnish men for whom they had baseline dietary data. A highly statistically significant inverse association between calculated vitamin C intake and the incidence of tuberculosis was found, but adjustment for non-dietary factors weakened the association to nonsignificant. Furthermore, the risk of tuberculosis decreased with increasing intake of fruits, vegetables, and berries independent of vitamin C intake. Subjects who had dietary vitamin C intake >90 mg/day and who consumed more than the average amount of fruits, vegetables, and berries had a significantly lower risk of tuberculosis (adjusted relative risk = 0.40; 95% confidence interval 0.24, 0.69). Associations between dietary vitamin C intake and occurrence of various diseases without proper control of confounding have often been interpreted as causal. These findings show that such associations can be confounded even by some other dietary components. Lower tuberculosis incidence in subjects who consumed more fruits, vegetables, and berries poor in vitamin C suggests that other compounds in such a diet may reduce the risk of tuberculosis. C1 Univ Helsinki, Dept Publ Hlth, FIN-00014 Helsinki, Finland. Natl Publ Hlth Inst, Helsinki, Finland. NCI, Bethesda, MD 20892 USA. RP Hemila, H (reprint author), Univ Helsinki, Dept Publ Hlth, POB 41, FIN-00014 Helsinki, Finland. RI Kaprio, Jaakko/A-1820-2008; Albanes, Demetrius/B-9749-2015; OI Hemila, Harri/0000-0002-4710-307X; Kaprio, Jaakko/0000-0002-3716-2455 FU NCI NIH HHS [N01-CN-45165] NR 60 TC 24 Z9 25 U1 0 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 SEP 15 PY 1999 VL 150 IS 6 BP 632 EP 641 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 236MA UT WOS:000082602300012 PM 10490003 ER PT J AU Kipnis, V Carroll, RJ Freedman, LS Li, L AF Kipnis, V Carroll, RJ Freedman, LS Li, L TI Implications of a new dietary measurement error model for estimation of relative risk: Application to four calibration studies SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE dietary assessment methods; epidemiologic methods; measurement error; models; statistical; nutrient intake; regression analysis ID FOOD FREQUENCY QUESTIONNAIRE; LOGISTIC-REGRESSION MODELS; DOUBLY LABELED WATER; BREAST-CANCER; CONFIDENCE-INTERVALS; PARAMETER-ESTIMATION; ENERGY-EXPENDITURE; WOMEN; VALIDITY; OBESE AB Food records or 24-hour recalls are currently used to calibrate food frequency questionnaires (FFQs) and to correct disease risks for measurement error. The standard regression calibration approach requires that these reference measures contain only random within-person errors uncorrelated with errors in FFQs. Increasing evidence suggests that records/recalls are likely to be also flawed with systematic person-specific biases, so that for any individual the average of multiple replicate assessments may not converge to her/his true usual nutrient intake. The authors propose a new measurement error model to accommodate person-specific bias in the reference measure and its correlation with systematic error in the FFQ. Sensitivity analysis using calibration data from four studies demonstrates that failure to account for person-specific bias in the reference measure can often lead to substantial underestimation of the relative risk for a nutrient. These results indicate that in the absence of information on the extent of person-specific biases in reference instruments and their relation to biases in FFQs, the adequacy of the standard methods of correcting relative risks for measurement error is in question, as is the interpretation of negative findings from nutritional epidemiology such as failure to detect an important relation between fat intake and breast cancer. C1 NCI, Biometry Branch, Div Canc Prevent, Bethesda, MD 20892 USA. Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. Bar Ilan Univ, Dept Math Stat & Comp Sci, Ramat Gan, Israel. Chaim Sheba Med Ctr, Gertner Inst Epidemiol & Hlth Policy Res, IL-52621 Tel Hashomer, Israel. Univ Kentucky, Dept Family Practice, Lexington, KY USA. RP Kipnis, V (reprint author), NCI, Biometry Branch, Div Canc Prevent, Execut Plaza N,Room 344,6130 Execut Blvd,MSC 7354, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA-57030]; PHS HHS [P30-E509106] NR 34 TC 97 Z9 99 U1 2 U2 7 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 SEP 15 PY 1999 VL 150 IS 6 BP 642 EP 651 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 236MA UT WOS:000082602300013 PM 10490004 ER PT J AU Waddell, BL Blair, A Zahm, SH AF Waddell, BL Blair, A Zahm, SH TI Re: "Relation of cigarette smoking to non-Hodgkin's lymphoma among middle-aged men" SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter C1 NIH, Howard Hughes Med Inst, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Waddell, BL (reprint author), NIH, Howard Hughes Med Inst, Bldg 10, Bethesda, MD 20892 USA. NR 2 TC 6 Z9 6 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 SEP 15 PY 1999 VL 150 IS 6 BP 661 EP 662 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 236MA UT WOS:000082602300015 PM 10490006 ER PT J AU Ekholm, D Mulloy, JC Gao, G Degerman, E Franchini, G Manganiello, VC AF Ekholm, D Mulloy, JC Gao, G Degerman, E Franchini, G Manganiello, VC TI Cyclic nucleotide phosphodiesterases (PDE) 3 and 4 in normal, malignant, and HTLV-1 transformed human lymphocytes SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE cyclic nucleotide phosphodiesterases; PDE3; PDE4; human lymphocytes; HTLV-1 ID CELL LEUKEMIA-VIRUS; CAMP-SPECIFIC PHOSPHODIESTERASE; ACTIVATED PROTEIN-KINASE; CALMODULIN-DEPENDENT PHOSPHODIESTERASE; BLOOD MONONUCLEAR-CELLS; I-ASSOCIATED MYELOPATHY; MYELIN BASIC-PROTEIN; N-TERMINAL KINASE; T-CELL; RAT ADIPOCYTES AB Intracellular cyclic AMP, determined in part by cyclic nucleotide phosphodiesterases (PDEs), regulates proliferation and immune functions in lymphoid cells. Total PDE, PDE3, and PDE4 activities were measured in phytohemagglutinin (PHA)-activated peripheral blood mononuclear cells (PBMC-PHA), normal natural killer (NK) cells, Jurkat and Kit225-K6 leukemic T-cells, T-cell lines transformed with human T-lymphotropic virus (HTLV)-1 (a retrovirus that causes adult T cell leukemia/lymphoma) and HTLV-II (a nonpathogenic retrovirus), normal B-cells, and B-cells transformed with Epstein Barr virus (EBV). All cells exhibited PDES and PDE4 activities but in different proportions. In EBV-transformed B cells, PDE4 was much higher than PDE3. HTLV-I+ T-cells differed significantly from other T-lymphocyte-derived cells in also having a higher proportion of PDE4 activities, which apparently were not related to selective induction of any one PDE4 mRNA (judged by reverse transcription-polymerase chain reaction) or expression of the HTLV-I regulatory protein Tax. In MJ cells (an HTLV-I+ T-cell line), Jurkat cells, and PBMC-PHA cells, the tyrosine kinase inhibitor herbimycin A strongly inhibited PDE activity. Growth of MJ cells was inhibited by herbimycin A and a protein kinase C (PKC) inhibitor, and was arrested in G(1) by rolipram, a specific PDE4 inhibitor. Proliferation of several HTLV-I+ T-cell lines, PBMC-PHA, and Jurkat cells was inhibited differentially by forskolin (which activates adenylyl cyclase), the selective PDE inhibitors cilostamide and rolipram, and the nonselective PDE inhibitors pentoxifylline and isobutyl methylxanthine. These results suggest that PDE4 isoforms may be functionally up-regulated in HTLV-I+ T cells and may contribute to the virus induced proliferation, and that PDEs could be therapeutic targets in immune/inflammatory and neoplastic diseases. BIOCHEM PHARMACOL 58;6: 935-950, 1999. (C) 1999 Elsevier Science Inc. C1 NHLBI, PCCMB, NIH, Bethesda, MD 20892 USA. NCI, Basic Res Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Univ Lund, Dept Cell & Mol Biol, Lund, Sweden. RP Manganiello, VC (reprint author), NHLBI, PCCMB, NIH, Bldg 10,Room 5N-307,10 Ctr Dr, Bethesda, MD 20892 USA. NR 85 TC 17 Z9 17 U1 0 U2 1 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 SEP 15 PY 1999 VL 58 IS 6 BP 935 EP 950 DI 10.1016/S0006-2952(99)00188-4 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 226UB UT WOS:000082039500004 PM 10509746 ER PT J AU Verdier-Pinard, P Gares, M Wright, M AF Verdier-Pinard, P Gares, M Wright, M TI Differential in vitro association of vinca alkaloid-induced tubulin spiral filaments into aggregated spirals SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE vinca alkaloids; tubulin; microtubule-associated proteins; paracrystals; spirals; turbidity ID VINBLASTINE-INDUCED AGGREGATION; INDUCED POLYMERS; BINDING; MICROTUBULES; VINCRISTINE; INVITRO; AGENTS; TEMPERATURE; NUCLEOTIDES; INSTABILITY AB Vinblastine, vincristine, vindesine, and vinorelbine, the four vinca alkaloids used in cancer therapy, differ in their antitumoral spectra and toxicities, but not in their inhibitory effects on microtubule assembly in vitro. At higher drug concentrations, vinca alkaloids induce the assembly of spiral filaments of tubulin, which, in turn, can interact laterally and form paracrystals. Using methods that distinguish spiral filaments and paracrystals (aggregated spirals), we found that spiral filament formation was largely independent of the incubation temperature, of the alkaloid used, and of the presence or absence of microtubule-associated proteins (MAPs). In contrast, the formation of aggregated spirals was markedly dependent on the alkaloid used, on the incubation temperature, and on the absence or presence of MAPs. Aggregated spirals failed to assemble in the presence of high concentrations of MAP-1A or MAP-1B, whereas they assembled readily with tau and MAP-2. Differences in patterns of turbidity development using pure tubulin allowed the classification of thirteen cytotoxic vinca alkaloids into five distinct groups, with centrifugal recovery of aggregated spirals in close agreement with the various turbidity patterns. With microtubule protein, i.e. tubulin preparations containing MAPs, only four groups were defined by turbidity patterns, and centrifugal protein recovery was more divergent. Vinblastine, vincristine, vindesine, and vinorelbine fell into distinct groups under both reaction conditions, and thus they appear to have qualitatively distinguishable in vitro interactions with tubulin. These differential effects on spiral filament and aggregated spiral assembly revealed that the four drugs induce different constraints on the tubulin molecule. BIOCHEM PHARMACOL 58;6:959-971, 1999. (C) 1999 Elsevier Science Inc. C1 CNRS, Inst Pharmacol & Biol Struct, F-31077 Toulouse, France. RP Verdier-Pinard, P (reprint author), NCI, NIH, Lab Drug Discovery Res & Dev, Bldg 37,5D02,9000 Rockville Pike, Bethesda, MD 20892 USA. OI Verdier-Pinard, Pascal/0000-0002-6149-6578 NR 41 TC 15 Z9 16 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 SEP 15 PY 1999 VL 58 IS 6 BP 959 EP 971 DI 10.1016/S0006-2952(99)00190-2 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 226UB UT WOS:000082039500006 PM 10509748 ER PT J AU Walker, DL Reid, JM Svingen, PA Rios, R Covey, JM Alley, MC Hollingshead, MG Budihardjo, II Eckdahl, S Boerner, SA Kaufmann, SH Ames, MM AF Walker, DL Reid, JM Svingen, PA Rios, R Covey, JM Alley, MC Hollingshead, MG Budihardjo, II Eckdahl, S Boerner, SA Kaufmann, SH Ames, MM TI Murine pharmacokinetics of 6-aminonicotinamide (NSC 21206), a novel biochemical modulating agent SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE 6-aminonicotinamide; cisplatin; pharmacokinetics ID TUMOR-CELL ENERGY; MASS-SPECTROMETRY; POLY(ADP-RIBOSE) POLYMERASE; IN-VITRO; PLATINUM; CISPLATIN; PLASMA; NICOTINAMIDE; INHIBITION; METABOLISM AB The pyridine nucleotide 6-aminonicotinamide (6AN) was shown recently to sensitize a number of human tumor cell lines to cisplatin in vitro. The present studies were undertaken to compare the drug concentrations and length of exposure required for this sensitization in vitro with the drug exposure that could be achieved in mice in vivo. Human K562 leukemia cells and A549 lung cancer cells were incubated with 6AN for various lengths of time, exposed to cisplatin for 1-2 hr, and assayed for Pt-DNA adducts as well as the ability to form colonies. K562 cells displayed progressive increases in Pt-DNA adducts and cisplatin sensitivity during the first 10 hr of 6AN exposure. An 18-hr 6AN exposure was likewise more effective than a 6 hr 6AN exposure in sensitizing A549 cells to cisplatin. HPLC analysis of 6AN and its metabolite, 6-amino NAD(+), permitted assessment of exposures achieved in vivo after i.v. administration of 10 mg/kg of 6AN to CD2F(1), mice. 6AN reached peak serum concentrations of 80-90 mu M and was cleared rapidly, with T-1/2 alpha and T-1/2 beta Values of 7.4 and 31.3 min, respectively. Bioavailability was 80-100% with identical plasma pharmacokinetics after i.p. administration. At least 25% of the 6AN was excreted unchanged in the urine. The metabolite 6-amino-NAD(+) was detected in perchloric acid extracts of brain, liver, kidney, and spleen, but not in serum. Efforts to prolong systemic 6AN exposure by administering multiple i.p. doses or using osmotic pumps resulted in lethal toxicity. These results demonstrated that 6AN exposures required to sensitize tumor cells to cisplatin in vitro are difficult to achieve in vivo. (C) 1999 Elsevier Science Inc. C1 Mayo Clin, Div Dev Oncol Res, Dept Oncol, Rochester, MN 55905 USA. Mayo Med Sch, Dept Pharmacol, Rochester, MN 55905 USA. NCI, Div Canc Treatment & Diag, Dev Therapeut Program, Rockville, MD 20852 USA. RP Ames, MM (reprint author), Mayo Clin, Div Dev Oncol Res, Dept Oncol, Guggenheim 1301,200 1st St SW, Rochester, MN 55905 USA. FU NCI NIH HHS [N01-CM57200, R01-CA67818] NR 33 TC 20 Z9 20 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 SEP 15 PY 1999 VL 58 IS 6 BP 1057 EP 1066 DI 10.1016/S0006-2952(99)00179-3 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 226UB UT WOS:000082039500016 PM 10509758 ER PT J AU Davis, KL Braff, DL Weinberger, DR AF Davis, KL Braff, DL Weinberger, DR TI Protecting research subjects and psychiatric research: We can do both SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material C1 Mt Sinai Sch Med, New York, NY 10029 USA. Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. NIMH, Intramural Res Program, Bethesda, MD 20992 USA. RP Davis, KL (reprint author), Mt Sinai Sch Med, 1 Gustave Levy Pl, New York, NY 10029 USA. NR 0 TC 2 Z9 2 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 SEP 15 PY 1999 VL 46 IS 6 BP 727 EP 728 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 235ZZ UT WOS:000082574900001 PM 10494439 ER PT J AU Sunderland, T Wolozin, B Galasko, D Levy, J Dukoff, R Bahro, M Lasser, R Motter, R Lehtimaki, T Seubert, P AF Sunderland, T Wolozin, B Galasko, D Levy, J Dukoff, R Bahro, M Lasser, R Motter, R Lehtimaki, T Seubert, P TI Longitudinal stability of CSF tau levels in Alzheimer patients SO BIOLOGICAL PSYCHIATRY LA English DT Article DE cerebrospinal fluid; tau; dementia; surrogate marker ID CEREBROSPINAL-FLUID TAU; APOLIPOPROTEIN-E; CLINICAL-DIAGNOSIS; PROTEIN-TAU; FOLLOW-UP; DISEASE; DEMENTIA; MARKER; ALLELE; ASSAY AB Background: Antemortem levels of tau in the cerebrospinal fluid (CSF) of Alzheimer's disease (RD) patients have: repeatedly been demonstrated to be elevated when compared to controls. Although CSF tau has been reported to be elevated even in very mild AD, it is unknown how tau levels change during the course of the disease. Methods: We have followed 29 mild-to-moderately affected AD subjects over 2 years with repeated CSF taps. Clinical measures of dementia severity (Clinical Dementia Rating Scale, Global Deterioration Scale and Mini-Mental Status Examination) were obtained at the start and conclusion of the observation period, and CSF tau was measured with a standard enzyme-linked immunoabsorbent assay (ELISA) using two monoclonal antibodies. Results: Despite significant changes in the clinical measures consistent with progression of the disease, no significant overall change in CSF tau levels (548 +/- 355 vs. 557 +/- 275 pg/mL, NS) was observed None of the clinical variables was significantly correlated with either baseline measures of CSI; tau or delta CSF tau (last-first). Similarly, CSF tau at baseline and changes over time were not significantly related to Apolipoprotein E (APO E) phenotype. Conclusions: These data suggest that CSF tau levels are stable over extended periods of time in a group of mild-to-moderately demented AD subjects and that CSF tau levels do not predict the severity or rate of progression of AD, at least not during the middle stages of the illness. C1 NIMH, Ctr Clin, Geriatr Psychiat Branch, NIH, Bethesda, MD 20892 USA. Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. Tampere Univ, Dept Clin Chem, FIN-33101 Tampere, Finland. Athena Neurosci Inc, San Francisco, CA USA. RP Sunderland, T (reprint author), NIMH, Ctr Clin, Geriatr Psychiat Branch, NIH, Bldg 10,Rm 3N228,10 Ctr Dr,MSC 1275, Bethesda, MD 20892 USA. NR 46 TC 75 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD SEP 15 PY 1999 VL 46 IS 6 BP 750 EP 755 DI 10.1016/S0006-3223(99)00143-2 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 235ZZ UT WOS:000082574900004 PM 10494442 ER PT J AU Raskind, MA Peskind, ER Holmes, C Goldstein, DS AF Raskind, MA Peskind, ER Holmes, C Goldstein, DS TI Patterns of cerebrospinal fluid catechols support increased central noradrenergic responsiveness in aging and Alzheimer's disease SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Alzheimer's disease; aging; cerebrospinal fluid; norepinephrine; dihydroxyphenylglycol; dihydroxyphenylacetic acid ID TYROSINE-HYDROXYLASE ACTIVITY; LOCUS-CERULEUS; RAT-BRAIN; SENILE DEMENTIA; NOREPINEPHRINE KINETICS; SUBTOTAL DESTRUCTION; ADRENERGIC-RECEPTORS; L-DOPA; PLASMA; NEURONS AB Background: High cerebrospinal fluid (CSF) norepinephrine (NE) concentrations in aging and Alzheimer's disease (AD) could reflect decreased NE clearance from central nervous system (CNS) extracellular fluid or increased release of NE into CNS extracellular fluid, Measuring CSF concentrations of the intraneuronal NE metabolite dihydroxyphenylglycol (DHPG), an estimate of NE clearance, and the NE precursor dihydroxyphenylacetic acid (DOPA), an estimate of NE biosynthesis, can help differentiate these mechanisms. Methods: NE, DHPG, and DOPA were determined by HPLC in CSF and plasma obtained following yohimbine, clonidine, and placebo. Ten AD, 10 older and II young subjects were studied. Results: CSF DOPA following yohimbine was higher in alder and AD than in young subjects. CSF DHPG did not differ among groups. Plasma DOPA following yohimbine was higher in AD than in young subjects. Conclusions: During alpha-2 adrenoreceptor blockade in bath aging and AD, there are increased responses of CNS NE biosynthesis and release with unchanged CNS NE clearance, This pattern is consistent with partial lass of CNS noradrenergic neurons with compensatory activation of remaining CNS noradrenergic neurons. Given the marked loss of locus coeruleus (LC) noradrenergic neurons in AD, achievement of high CSF NE suggests particularly prominent compensatory activation of remaining LC neurons in this disorder. (C) 1999 Society of Biological Psychiatry. C1 NW Network Mental Illness Res Educ & Clin Ctr, Dept Vet Affairs, Seattle, WA USA. Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. NINDS, Clin Neurosci Branch, NIH, Bethesda, MD 20892 USA. RP Raskind, MA (reprint author), VA Puget Sound Hlth Care Syst, Mental Hlth Serv, 116,1660 S Columbian Way, Seattle, WA 98108 USA. NR 50 TC 54 Z9 55 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD SEP 15 PY 1999 VL 46 IS 6 BP 756 EP 765 DI 10.1016/S0006-3223(99)00008-6 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 235ZZ UT WOS:000082574900005 PM 10494443 ER PT J AU Lappalainen, J Long, JC Virkkunen, M Ozaki, N Goldman, D Linnoila, M AF Lappalainen, J Long, JC Virkkunen, M Ozaki, N Goldman, D Linnoila, M TI HTR2C Cys23Ser polymorphism in relation to CSF monoamine metabolite concentrations and DSM-III-R psychiatric diagnoses SO BIOLOGICAL PSYCHIATRY LA English DT Article DE serotonin; 5-HT2C receptors; MHPG; alcoholism; polymorphism ID CEREBROSPINAL-FLUID; 5-HYDROXYINDOLEACETIC ACID; M-CHLOROPHENYLPIPERAZINE; RECEPTOR SUBTYPE; SEROTONIN; RAT; NOREPINEPHRINE; MECHANISMS; DISORDER; ALCOHOL AB Background: Heritable variation in brain monoaminergic activity has been suggested to lead to interindividual differences in vulnerability to alcoholism, and many other behavioral disorders. We evaluated if a functional Cys23Ser polymorphism in the 5-HT2C receptor gene, the principal serotonin receptor in the brain, contributes to variation in serotonin, norepinephrine and dopamine activity, as indexed by their major metabolite concentrations in cerebrospinal fluid (CSF). Genotype-monoamine metabolite concentration associations were subsequently correlated to risk for alcoholism. Methods: The study sample consisted of unrelated Finnish males, including 214 alcoholic, violent offenders and 222 population controls who were interviewed using the Structured Clinical Interview for DSM-III-R, blind rated for psychiatric diagnoses and typed for the HTR2C Cys23Ser polymorphism. CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA) the major metabolite of serotonin, 3-methoxy4-hydroxyphenylethyleneglycol (MHPG) the major metabolite of norepinephrine, and homovanillic acid (HVA), the major metabolite of dopamine were available from 195 individuals. Results: The major finding in this study was that HTR2C CysSer23 significantly contributed to CSF MHPG concentrations (p = .012), Higher concentrations of CSF MHPG were observed both in alcoholic violent offenders and population controls with HTR2C Ser23 genotype. Despite the association of Cys23Ser to CSF MHPG, HTR2C genotype was not associated with alcoholism, nor with other psychiatric disorders present in this sample. Conclusions: We conclude that a functional HTR2C Cys23Ser polymorphism contributes to the interindividual generic variation of CSF MHPG explaining 3% of the total variance. This finding suggests that 5-HT2C receptors are involved in the regulation of norepinephrine turnover in humans; however, HTR2C Cys23Ser does not appear to contribute to the risk of alcoholism, or its contribution to this complex and heterogenous disorder is too small to be detected by a sample of this size and structure. (C) 1999 Society of Biological Psychiatry. C1 NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. NIAAA, Sect Populat Genet & Linkage, NIH, Rockville, MD 20852 USA. NIAAA, Clin Studies Lab, NIH, Rockville, MD 20852 USA. Univ Helsinki, Dept Psychiat, SF-00180 Helsinki, Finland. RP Goldman, D (reprint author), NIAAA, Neurogenet Lab, NIH, 12420 Parklawn Dr,Pk 5 Bldg,Room 451, Rockville, MD 20852 USA. RI Ozaki, Norio/M-8908-2014; Goldman, David/F-9772-2010 OI Ozaki, Norio/0000-0002-7360-4898; Goldman, David/0000-0002-1724-5405 NR 27 TC 43 Z9 43 U1 0 U2 1 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 SEP 15 PY 1999 VL 46 IS 6 BP 821 EP 826 DI 10.1016/S0006-3223(98)00361-8 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 235ZZ UT WOS:000082574900013 PM 10494451 ER PT J AU Broudy, VC Lin, NL Liles, WC Corey, SJ O'Laughlin, B Mou, S Linnekin, D AF Broudy, VC Lin, NL Liles, WC Corey, SJ O'Laughlin, B Mou, S Linnekin, D TI Signaling via Src family kinases is required for normal internalization of the receptor c-Kit SO BLOOD LA English DT Article ID STEM-CELL FACTOR; GROWTH-FACTOR RECEPTOR; HEMATOPOIETIC PROGENITOR CELLS; INDUCED DOWN-REGULATION; TYROSINE KINASE; MAST-CELLS; PHOSPHATIDYLINOSITOL 3-KINASE; CROSS-LINKING; SH3 DOMAINS; IN-VITRO AB Stem cell factor (SCF) exerts its biological effects by binding to a specific receptor, the tyrosine kinase c-Kit, which is expressed on the cell surface. Although normal cellular trafficking of growth factor receptors may play a critical role in the modulation of receptor function, the mechanisms that regulate the distribution of c-Kit on the cell surface and the internalization of c-Kit have not been fully defined. We investigated whether signal transduction via Src family kinases is required for normal c-Kit trafficking. Treatment of the SCF-responsive human hematopoietic cell line MO7e with the inhibitor of Src family kinases PP1 blocked SCF-induced capping of c-Kit and internalization of c-Kit, c-Kit was able to associate with clathrin in the presence of PP1, suggesting that entry of c-Kit into clathrin-coated pits occurs independently of Src family kinases, SCF-induced internalization of c-Kit was also diminished in the D33-3 lymphoid cell line in which expression of Lyn kinase was disrupted by homologous recombination, These results indicate that Src family kinases play a role in ligand-induced trafficking of c-Kit, (C) 1999 by The American Society of Hematology. C1 Univ Washington, Div Hematol, Seattle, WA 98195 USA. Univ Washington, Dept Med, Div Allergy & Infect Dis, Seattle, WA 98195 USA. Childrens Hosp Pittsburgh, Div Hematol Oncol, Pittsburgh, PA 15213 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res & Support Program, Frederick, MD USA. NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Lab Leukocyte Biol, Frederick, MD USA. RP Broudy, VC (reprint author), Univ Washington, Div Hematol, Box 357710, Seattle, WA 98195 USA. FU NCI NIH HHS [CA31615]; NIDDK NIH HHS [DK43719, DK44194] NR 59 TC 64 Z9 65 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1200 19TH ST, NW, STE 300, WASHINGTON, DC 20036-2422 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 15 PY 1999 VL 94 IS 6 BP 1979 EP 1986 PG 8 WC Hematology SC Hematology GA 234KU UT WOS:000082484500017 PM 10477727 ER PT J AU Olman, MA Hagood, JS Simmons, WL Fuller, GM Vinson, C White, KE AF Olman, MA Hagood, JS Simmons, WL Fuller, GM Vinson, C White, KE TI Fibrin fragment induction of plasminogen activator inhibitor transcription is mediated by activator protein-1 through a highly conserved element SO BLOOD LA English DT Article ID HUMAN-LUNG FIBROBLASTS; GROWTH-FACTOR-BETA; ENDOTHELIAL-CELLS; REGULATORY SEQUENCES; UROKINASE RECEPTOR; CROSSLINKED FIBRIN; GENE-EXPRESSION; BINDING; FOS; SITES AB Plasminogen activator inhibitor type-1 (PAI-1), a serine protease inhibitor, affects the processes of fibrinolysis, wound healing, and vascular remodeling. We have demonstrated that PAI-1 transcription is induced by D dimer, a plasmin proteolytic fragment of fibrin, supporting its role in negative feedback on peri-cellular proteolysis, The focus of this study was to define the mechanism of D dimer's effects on PAI-1 transcription. D dimer increased the binding activity of the transcription factor activator protein-1 components c-fos/ junD and c-fos mRNA levels in a time- and concentration-dependent manner to a greater extent than fibrinogen, Both basal and D dimer-induced PAI-1 transcriptional activity were entirely dependent on elements within the -161 to -48 bp region of the PAI-1 gene in fibroblasts. Mutations within the AP-l-like element (-59 to -52 bp) in the PAI-1 gene affected D dimer-induced transcriptional activity, c-fos/junD DNA binding, and basal and c-fos inducible PAI-1 transcriptional activity. Furthermore, expression of either wild-type or mutant c-fos proteins augmented or diminished the response of the PAI-1 promoter (-161 to +26 bp) to D dimer, respectively. D dimer-induced binding of c-fos/junD to the highly conserved and unique AP-1 like element in the PAI-1 gene provides a mechanism whereby specific fibrin fragments control fibrin persistence at sites of inflammation, fibrosis, and neoplasia. (C) 1999 by The American Society of Hematology. C1 Univ Alabama, Dept Med, Div Pulm & Crit Care Med, Birmingham, AL 35294 USA. Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. Univ Alabama, Dept Pediat, Birmingham, AL 35294 USA. Univ Alabama, Dept Cell Biol, Birmingham, AL 35294 USA. Natl Canc Inst, Biochem Lab, Bethesda, MD USA. RP Olman, MA (reprint author), Univ Alabama, Med Ctr, Dept Med, Div Pulm & Crit Care Med, 1900 Univ Blvd,215 THT, Birmingham, AL 35294 USA. FU NHLBI NIH HHS [HL-58655, HL-03239]; NICHD NIH HHS [HD-28831] NR 54 TC 41 Z9 43 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1200 19TH ST, NW, STE 300, WASHINGTON, DC 20036-2422 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 15 PY 1999 VL 94 IS 6 BP 2029 EP 2038 PG 10 WC Hematology SC Hematology GA 234KU UT WOS:000082484500022 PM 10477732 ER PT J AU Rivadeneira, ED Ferrari, MG Jarrett, RF Armstrong, AA Markham, P Birkebak, T Takemoto, S Johnson-Delaney, C Pecon-Slattery, J Clark, EA Franchini, G AF Rivadeneira, ED Ferrari, MG Jarrett, RF Armstrong, AA Markham, P Birkebak, T Takemoto, S Johnson-Delaney, C Pecon-Slattery, J Clark, EA Franchini, G TI A novel Epstein-Barr virus-like virus, HVMNE, in a Macaca nemestrina with mycosis fungoides SO BLOOD LA English DT Article ID CUTANEOUS T-CELL; SARCOMA-ASSOCIATED HERPESVIRUS; MALIGNANT-LYMPHOMA INDUCTION; CAVITY-BASED LYMPHOMAS; EBV-LIKE VIRUS; LINE SI-IIA; KAPOSIS-SARCOMA; CONSTITUTIVE ACTIVATION; SEZARY-SYNDROME; LYMPHOPROLIFERATIVE DISORDERS AB Epstein-Barr virus (EBV) infection of humans has been associated with the development of lymphoid malignancies mainly of B-cell lineage, although occasionally T-cell lymphomas have been reported. We describe here the characterization of a novel EBV-like virus (HVMNE) isolated from a simian T-cell lymphotropic virus type I/II (STLV-I/II) seronegative pigtailed macaque (Macaca nemestrina) with a cutaneous T-cell lymphoma. Immunohistochemistry studies on the skin lesions demonstrated that the infiltrating cells were of the CD3(+)/CD8(+) phenotype. Two primary transformed CD8(+); T-cell lines were obtained from cultures of peripheral blood mononuclear cells (PBMC) and skin, and, with time, both cell lines became interleukin-2-independent and acquired the constitutive activation of STAT proteins. Polymerase chain reaction analysis of the DNA from the cell lines and tissues from the lymphomatous animal demonstrated the presence of a 536-bp DNA fragment that was 90% identical to EBV polymerase gene sequences, whereas the same DNA was consistently negative for STLV-I/II sequences. Electron microscopy performed on both cell lines, after sodium butyrate treatment, showed the presence of a herpes-like virus that was designated HVMNE according to the existing nomenclature, In situ hybridization studies using EBV Epstein-Barr viral-encoded RNA probes showed viral RNA expression in both CD8(+) T-cell lines as well as in the infiltrating CD8(+) T cells of skin-tissue biopsies. Phylogenetic analysis of a 465-bp fragment from the polymerase gene of HVMNE placed this virus within the Lymphocryptovirus genus and demonstrated that HVMNE is a distinct virus, clearly related to human EBV and other EBV-like herpesviruses found in nonhuman primates. (C) 1999 by The American Society of Hematology. C1 NCI, Sect Anin Models & Retrovirus Vaccines, Basic Res Labs, Div Basic Sci,NIH, Bethesda, MD 20892 USA. Univ Glasgow, Dept Vet Pathol, Glasgow, Lanark, Scotland. Adv Biotechnol Lab, Rockville, MD USA. Univ Washington, Dept Comparat Med, Seattle, WA 98195 USA. Univ Washington, Washington Reg Primate Res Ctr, Seattle, WA 98195 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD USA. RP Franchini, G (reprint author), NCI, Sect Anin Models & Retrovirus Vaccines, Basic Res Labs, Div Basic Sci,NIH, 41 Lib Dr,Bldg 41,Room D804, Bethesda, MD 20892 USA. RI Clark, Edward/K-3462-2012; OI Takemoto, Shigeki/0000-0003-4130-074X FU NCRR NIH HHS [RR00166] NR 58 TC 20 Z9 21 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1200 19TH ST, NW, STE 300, WASHINGTON, DC 20036-2422 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 15 PY 1999 VL 94 IS 6 BP 2090 EP 2101 PG 12 WC Hematology SC Hematology GA 234KU UT WOS:000082484500029 PM 10477739 ER PT J AU Baruch, DI Ma, XC Pasloske, B Howard, RJ Miller, LH AF Baruch, DI Ma, XC Pasloske, B Howard, RJ Miller, LH TI CD36 peptides that block cytoadherence define the CD36 binding region for Plasmodium falciparum-infected erythrocytes SO BLOOD LA English DT Article ID INTERCELLULAR-ADHESION MOLECULE-1; LOW-DENSITY-LIPOPROTEIN; CEREBRAL MALARIA; MONOCLONAL-ANTIBODIES; CHONDROITIN SULFATE; FUNCTIONAL DOMAIN; SURFACE-RECEPTOR; GENE FAMILY; SR-BI; IDENTIFICATION AB Mature Plasmodium falciparum parasitized erythrocytes (PE) sequester from the circulation by adhering to microvascular endothelial cells. PE sequestration contributes directly to the virulence and severe pathology of falciparum malaria. The scavenger receptor, CD36, is a major host receptor for PE adherence. PE adhesion to CD36 is mediated by the malarial variant antigen, P. falciparum erythrocyte membrane protein 1 (PfEMP1), and particularly by its cysteine-rich interdomain region 1 (CIDR-1). Several peptides from the extended immunodominant domain of CD36 (residues 139-184), including CD36 139-155, CD36 145-171, CD36 146-164, and CD36 156-184 interfered with the CD36-PfEMP1 interaction. Each of these peptides affected binding at the low micromolar range in 2 independent assays. Two peptides, CD36 145-171 and CD36 156-184, specifically blocked PE adhesion to CD36 without affecting binding to the host receptor intercellular adhesion molecule-1 (ICAM-1). Moreover, an adhesion blocking peptide from the ICAM-1 sequence inhibits the PfEMP1-ICAM-1 interaction without affecting adhesion to CD36, These results confirm earlier observations that PfEMP1 is also a receptor for ICAM-1, Thus, the region 139-184 and particularly the 146-164 or the 145-171 regions of CD36 form the adhesion region for P. falciparum PE, Adherence blocking peptides from this region may be useful for modeling the PE/PfEMP1 interaction with CD36 and for development of potential anti-adhesion therapeutics. (C) 1999 by The American Society of Hematology. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Affymax Res Inst, Santa Clara, CA USA. RP Baruch, DI (reprint author), NIAID, Parasit Dis Lab, NIH, NIH Bldg 4,Room B1-37,4 Ctr Dr,MSC 0425, Bethesda, MD 20892 USA. NR 47 TC 40 Z9 41 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1200 19TH ST, NW, STE 300, WASHINGTON, DC 20036-2422 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 15 PY 1999 VL 94 IS 6 BP 2121 EP 2127 PG 7 WC Hematology SC Hematology GA 234KU UT WOS:000082484500032 PM 10477742 ER PT J AU Ebert, AD Wechselberger, C Frank, S Wallace-Jones, B Seno, M Martinez-Lacaci, I Bianco, C De Santis, M Weitzel, HK Salomon, DS AF Ebert, AD Wechselberger, C Frank, S Wallace-Jones, B Seno, M Martinez-Lacaci, I Bianco, C De Santis, M Weitzel, HK Salomon, DS TI Cripto-1 induces phosphatidylinositol 3 '-kinase-dependent phosphorylation of AKT and glycogen synthase kinase 3 beta in human cervical carcinoma cells SO CANCER RESEARCH LA English DT Article ID MAMMARY EPITHELIAL-CELLS; BETA-CATENIN; SURVIVAL; PROTEIN; APOPTOSIS; PATHWAY; IDENTIFICATION; ACTIVATION; RECEPTORS; CLEAVAGE AB Cripto-1 (CR-1), a member of the epidermal growth factor-CFC peptide family, activates the ras/raf/mitogen-activated protein/extracellular signal-regulated kinase/mitogen-activated protein kinase pathway. In the present study, the role of CR-1 in the phosphatidylinositol 3'-kinase (PI3K)/AKT (protein kinase B)/glycogen synthase kinase 3 beta (GSK-3 beta)dependent signaling pathway was evaluated in human SiHa cervical carcinoma cells. Our data demonstrate that CR-1 can enhance the tyrosine phosphorylation of the p85 regulatory subunit of PI3K and transiently induce the phosphorylation of AKT in a time- and dose-dependent manner. In addition, CR-1 was found to induce the phosphorylation of GSK-3 beta. Phosphorylation of AKT and GSK-3 beta by CR-1 can be blocked by LY294002, a specific inhibitor of PI3K;, thus leading to apoptosis. Finally, the apoptotic effect of LY294002 can be partially rescued by exogenous CR-1. In summary, our data suggest that human CR-1 may function as a survival factor through a PI3K-dependent signaling pathway involving AKT and GSK-3 beta. C1 NCI, Tumor Immunol & Biol Lab, Tumor Growth Factor Sect, NIH, Bethesda, MD 20892 USA. NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Free Univ Berlin, Med Ctr Benjamin Franklin, Dept Obstet & Gynecol, D-12200 Berlin, Germany. Okayama Univ, Dept Biosci & Biotechnol, Fac Engn, Okayama 7008530, Japan. Walter Reed Army Med Ctr, Walter Reed Army Inst Res, Dept Mol Pathol, Washington, DC 20307 USA. RP Salomon, DS (reprint author), NCI, Tumor Immunol & Biol Lab, Tumor Growth Factor Sect, NIH, Bldg 10,Room 5B39,10 Ctr Dr,MSC-1750, Bethesda, MD 20892 USA. EM davetgfa@helix.nih.gov RI SENO, Masaharu /B-2092-2011 OI SENO, Masaharu /0000-0001-8547-6259 NR 26 TC 54 Z9 56 U1 0 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 SEP 15 PY 1999 VL 59 IS 18 BP 4502 EP 4505 PG 4 WC Oncology SC Oncology GA 235KV UT WOS:000082541600003 PM 10493495 ER PT J AU John, CS Vilner, BJ Geyer, BC Moody, T Bowen, WD AF John, CS Vilner, BJ Geyer, BC Moody, T Bowen, WD TI Targeting sigma receptor-binding benzamides as in vivo diagnostic and therapeutic agents for human prostate tumors SO CANCER RESEARCH LA English DT Article ID SOMATOSTATIN RECEPTORS; CELL-PROLIFERATION; BREAST-CANCER; IN-VITRO; ENDOCRINE; LIGAND; CARCINOMA; LINES; SITES AB Sigma receptors are known to be expressed in a variety of human tumor cells, including breast, neural, and melanoma tumors. A very high density (1.0-1.5 million receptors/cell) of sigma receptors was also reported in a human androgen-dependent prostate tumor cell line (LNCaP). In this study, me show that a very high density of sigma receptors is also expressed in an androgen-independent human prostate tumor cell line (DU-145). Pharmacological binding studies using the sigma-1-selective ligand [H-3](+)-pentazocine showed a high-affinity binding (K-d = 5.80 nhl, B-max = 1800 fmol/mg protein). Similarly, binding studies with [3H]1,3-di-o-tolylguanidine in the presence of dextrallorphan also showed a high-affinity binding (K-d = 15.71 nar, B-max = 1930 fmol/mg protein). Radioiodinated benzamide N-[2-(1'-piperidinyl)ethyl]-3-[I-125]iodo benzamide ([I-125]PIMBA) was also shown to bind DU-145 cells in a dose-dependent manner. Three different radioiodinated benzamides, [T-125]PIMBA, 4-[(125)r]iodo-N-[2-(1'-piperidinyl)ethyl] and 2-[I-125]-N-(N-benzylpiperidin-4-yl)-2-iodobemzamide were screened for their potential to image human prostate tumors in nude mice bearing human prostate cells (DU-145) xenografts. All three compounds showed a fast clearance from the blood pool and a high uptake and retention In the tumor. Therapeutic potential of nonradioactive PIMBA was studied using in vitro colonogenic assays. A dose-dependent inhibition of cell colony formation was found in two different human prostate cells. These results demonstrate the potential use of sigma receptor binding ligands in noninvasive diagnostic imaging of prostate cancer and its treatment. C1 George Washington Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20037 USA. NIDDKD, Unit Receptor Biochem & Pharmacol, Med Chem Lab, NIH, Bethesda, MD 20892 USA. NCI, Cell & Canc Biol Dept, Med Branch, Rockville, MD 20850 USA. RP John, CS (reprint author), George Washington Univ, Med Ctr, Dept Biochem & Mol Biol, 2300 I St NW,530 Ross Hall, Washington, DC 20037 USA. FU NCI NIH HHS [CA 58496] NR 30 TC 71 Z9 73 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 1999 VL 59 IS 18 BP 4578 EP 4583 PG 6 WC Oncology SC Oncology GA 235KV UT WOS:000082541600019 PM 10493511 ER PT J AU Carlson, B Lahusen, T Singh, S Loaiza-Perez, A Worland, PJ Pestell, R Albanese, C Sausville, EA Senderowicz, AM AF Carlson, B Lahusen, T Singh, S Loaiza-Perez, A Worland, PJ Pestell, R Albanese, C Sausville, EA Senderowicz, AM TI Down-regulation of cyclin D1 by transcriptional repression in MCF-7 human breast carcinoma cells induced by flavopiridol SO CANCER RESEARCH LA English DT Article ID DEPENDENT KINASE-ACTIVITY; GENE-EXPRESSION; RETINOBLASTOMA PROTEIN; ESTROGEN-RECEPTOR; MESSENGER-RNA; CANCER CELLS; FAMILY PROTEINS; TRANSGENIC MICE; G1 PROGRESSION; GROWTH ARREST AB Flavopiridol is a novel flavonoid that induces cell cycle arrest at different stages of the cell cycle because of the inhibition of cyclin-dependent kinases (cdks). In previous studies from our laboratory, (B. A. Carlson et al., Cancer Res., 56: 2973-2978, 1996), we observed that exposure of the MCF-7 breast carcinoma cell line to flavopiridol resulted in G(1)-S arrest, which was associated with the loss of cdk4 and cdk2 activity by 24 h of exposure. Along with this inhibition, flavopiridol decreased total cyclin-D protein levels in this cell line. In this work, we demonstrate that using isoform-specific antibodies, flavopiridol induces an early (by 6 h) decrease in cyclin D1 protein levels. This decline is followed by a decline in cyclin D3 with no effect on cyclin D2 or cyclin E levels by 10 h. Furthermore, at early time points (up to 8 h), the activity of cdk4 and the expression of endogenous phosphorylated retinoblastoma species from intact cells exposed to flavopiridol are unchanged. Thus, the decline in cdk4 activity and the induction of retinoblastoma hypophosphorylation follows cyclin D1 decline. Turnover studies demonstrate that the half life of cyclin D1 (similar to 30 min) is not shortened in flavopiridol-exposed cells, and that the turnover of cdk4-bound cyclin D1 is unaltered. However, steady-state levels of cyclin D1 mRNA display a significant decrease by 24 h of flavopiridol treatment, with total disappearance by 8 h. This mRNA decline is not abrogated by the presence of cycloheximide. Furthermore, we have found that flavopiridol specifically represses the activity of the full-length cyclin D1 promoter linked to a luciferase reporter gene. In summary, we have found that the flavopiridol-induced decline in cyclin D1 is an early event, specific and, at least in part, due to the transcriptional repression of the cyclin D1 promoter. These results extend our understanding of flavopiridol's action to include regulation of cyclin D1 transcription. C1 NCI, DTP Clin Trials Unit, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Dev Therapeut Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. Albert Einstein Canc Ctr, Dept Med & Dev & Mol Biol, Bronx, NY 10461 USA. Mitotix Inc, Cambridge, MA 02139 USA. RP Senderowicz, AM (reprint author), NCI, DTP Clin Trials Unit, Div Canc Treatment & Diag, 10 Ctr Dr,Bldg 10,Room 6N113, Bethesda, MD 20892 USA. FU NCI NIH HHS [5-P30-CA13330-26, R01CA75503, R29CA70897] NR 84 TC 221 Z9 225 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 1999 VL 59 IS 18 BP 4634 EP 4641 PG 8 WC Oncology SC Oncology GA 235KV UT WOS:000082541600026 PM 10493518 ER PT J AU Gnant, MFX Berger, AC Huang, J Puhlmann, M Wu, PC Merino, MJ Bartlett, DL Alexander, HR Libutti, SK AF Gnant, MFX Berger, AC Huang, J Puhlmann, M Wu, PC Merino, MJ Bartlett, DL Alexander, HR Libutti, SK TI Sensitization of tumor necrosis factor alpha-resistant human melanoma by tumor-specific in vivo transfer of the gene encoding endothelial monocyte-activating polypeptide II using recombinant vaccinia virus SO CANCER RESEARCH LA English DT Article ID ISOLATED LIMB PERFUSION; ISOLATED HEPATIC PERFUSION; SOFT-TISSUE SARCOMAS; FACTOR CACHECTIN; TNF-ALPHA; PHASE-II; IN-VITRO; THERAPY; EXPRESSION; CANCER AB Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine with potent experimental antitumor activity. Its clinical use in cancer treatment is severely limited by its considerable toxicity after systemic administration, and it is currently confined to isolated limb and organ perfusion settings. In this report, we introduce a novel concept of TNF-alpha-based gene therapy using the TNF-sensitizing properties of endothelial cell monocyte activating polypeptide II (EMAP-II). We hypothesized that transfer of the EMAP-II gene into established TNF-resistant human melanomas would render these tumors sensitive to subsequent systemic TNF-alpha treatment. To achieve tumor selective gene delivery, we constructed a recombinant vaccinia virus encoding the human EMAP-II gene (vvEMAP). In vitro transfection of human melanoma cells led to the production of EMAP-II by these cells. Supernatants of vvEMAP-transfected tumor cells mediated the induction of tissue factor in endothelial cells. We characterized the pattern of gene expression after systemic administration of a recombinant vaccinia virus encoding a reporter gene in a murine in vivo model of s.c. human melanoma. Gene expression in tumor tissue was increased 100-fold as compared with normal tissue, providing evidence for tumor-selective gene delivery. Finally, human melanomas in nude mice were sensitized in vivo by transferring the EMAP-II gene using vvEMAP. Subsequent systemic administration of TMF-alpha led to tumor regression and growth inhibition of these previously TNF-resistant tumors (P < 0.05). This approach using gene therapy to sensitize primarily unresponsive tumors toward TNF-alpha may enhance the usefulness of TNF-alpha in clinical treatment strategies by increasing the window for the therapeutic application of the cytokine, thus reducing the dose necessary for antitumor responses and subsequently reduce toxicity. C1 NCI, Surg Metab Sect, Surg Branch, NIH, Bethesda, MD 20892 USA. Univ Vienna, Dept Surg, A-1090 Vienna, Austria. Tech Univ Munich, Dept Surg, D-81675 Munich, Germany. RP Libutti, SK (reprint author), NCI, Surg Metab Sect, Surg Branch, NIH, Bldg 10,Room 2B07,9000 Rockville Pike, Bethesda, MD 20892 USA. OI Gnant, Michael/0000-0003-1002-2118 NR 69 TC 36 Z9 37 U1 0 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 SEP 15 PY 1999 VL 59 IS 18 BP 4668 EP 4674 PG 7 WC Oncology SC Oncology GA 235KV UT WOS:000082541600031 PM 10493523 ER PT J AU Aloj, L Caraco, C Jagoda, E Eckelman, WC Neumann, RD AF Aloj, L Caraco, C Jagoda, E Eckelman, WC Neumann, RD TI Glut-1 and hexokinase expression: Relationship with 2-fluoro-2-deoxy-D-glucose uptake in A431 and T47D cells in culture SO CANCER RESEARCH LA English DT Article ID RAT HEPATOMA-CELLS; MITOCHONDRIAL HEXOKINASE; GLUCOSE TRANSPORTERS; F-18 FDG; IN-VITRO; PET; TUMORS; ESTABLISHMENT; METABOLISM; CARCINOMA AB Uptake of 2-[F-18]-2-deoxy-D-glucose (FDG) has been used as a marker of increased glucose metabolism to visualize, stage, and monitor progression of human cancers with positron emission tomography. Many human tumors have been shown to overexpress the Glut-1 glucose transport protein. The aim of this study is to define whether a quantitative relationship exists between the amount of Glut-1 expressed by cells and their ability to accumulate FDG, We characterized the expression of the known facilitative and sodium-dependent glucose transporter isoforms in six different cancer cell lines used in our laboratory (A431, MDA-MB-231, T47D, CaCo II, MCF7, and HepG2). A431 and T47D cells express, respectively, the highest and lowest amount of Glut-1 mRNA by Northern blot of all of the cells analyzed, and no other glucose transporter isoforms were detectable by this method in both cell lines. Both total and plasma membrane-associated Glut-1 protein levels were higher in A431 than in T47D cells, consistent with the higher Glut-1 mRNA levels. However, T47D cells accumulate FDG more rapidly than do A431 cells. 3-O-Methylglucose transport is higher in A431 cells. Although hexokinase I and II mRNA levels are higher in A431 cells than in T47D cells, the ability of mitochondrial preparations to phosphorylate FDG is higher in T47D cells, Our data indicate that in these cultured cells, FDG uptake correlates better with FDG phosphorylating activity of mitochondrial preparations rather than the level of expression of the Glut-1 or hexokinase I and ZI genes. C1 NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD 20892 USA. NIH, Positron Emiss Tomog Dept, Ctr Clin, Bethesda, MD 20892 USA. RP Neumann, RD (reprint author), NIH, Dept Nucl Med, Ctr Clin, Bldg 10,Room 1C401,10 Ctr Dr,MSC 1180, Bethesda, MD 20892 USA. NR 25 TC 126 Z9 130 U1 0 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 SEP 15 PY 1999 VL 59 IS 18 BP 4709 EP 4714 PG 6 WC Oncology SC Oncology GA 235KV UT WOS:000082541600037 PM 10493529 ER PT J AU Hajko, J Liptak, A Pozsgay, V AF Hajko, J Liptak, A Pozsgay, V TI Synthesis of L-glucose from D-gulono-1,4-lactone SO CARBOHYDRATE RESEARCH LA English DT Article DE monosaccharide; L-glucose; unnatural carbohydrate ID O-SPECIFIC POLYSACCHARIDE; DESS-MARTIN PERIODINANE; SECONDARY ALCOHOLS; ENZYMATIC-SYNTHESIS; SHIGELLA-SONNEI; OXIDATION; DERIVATIVES; CONVERSION; ALDEHYDES; SUGARS AB An efficient method for the synthesis of L-glucose from D-gulono-1,4-lactone via 1,2,3,4,5-penta-O-benzyl/acetyl/benzoyl-D-gulitol is described in 34-53% overall yield. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 Hungarian Acad Sci, Res Grp Carbohydrates, H-4010 Debrecen, Hungary. NICHHD, NIH, Bethesda, MD 20892 USA. RP Liptak, A (reprint author), Hungarian Acad Sci, Res Grp Carbohydrates, POB 55, H-4010 Debrecen, Hungary. NR 33 TC 11 Z9 11 U1 2 U2 6 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 SEP 15 PY 1999 VL 321 IS 1-2 BP 116 EP 120 DI 10.1016/S0008-6215(99)00192-5 PG 5 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 260ET UT WOS:000083937100013 PM 10612005 ER PT J AU Kodjabachian, L Dawid, IB Toyama, R AF Kodjabachian, L Dawid, IB Toyama, R TI Gastrulation in zebrafish: What mutants teach us SO DEVELOPMENTAL BIOLOGY LA English DT Review ID DORSOVENTRAL PATTERN-FORMATION; BONE-MORPHOGENETIC PROTEIN; CENTRAL-NERVOUS-SYSTEM; YOLK SYNCYTIAL LAYER; FLOOR PLATE; SPEMANN ORGANIZER; SONIC HEDGEHOG; XENOPUS-LAEVIS; HOMEOBOX GENE; CELL FATES AB A major approach to the study of development is to compare the phenotypes of normal and mutant individuals for a given genetic locus. Understanding the development of a complex metazoan therefore requires examination of many mutants. Relatively few organisms are being studied this way, and zebrafish is currently the best example of a vertebrate for which large-scale mutagenesis screens have successfully been carried out. The number of genes mutated in zebrafish that have been cloned expands rapidly, bringing new insights into a number of developmental pathways operating in vertebrates. Here, we discuss work on zebrafish mutants affecting gastrulation and patterning of the early embryo. Gastrulation is orchestrated by the dorsal organizer, which forms in a region where maternally derived beta-catenin signaling is active. Mutation in the zygotic homeobox gene bozozok disrupts the organizer genetic program and leads to severe axial deficiencies, indicating that this gene is a functional target of beta-catenin signaling. Once established, the organizer releases inhibitors of ventralizing signals, such as BMPs, and promotes dorsoanterior fates within all germ layers. In zebrafish, several mutations affecting dorsal-ventral (D/V) patterning inactivate genes functioning in the BMP pathway, stressing the central role of this pathway in the gastrula embryo. Cells derived from the organizer differentiate into several axial structures, such as notochord and prechordal mesoderm, which are thought to induce various fates in adjacent tissues, such as the floor plate, after the completion of gastrulation. Studies with mutants in nodal-related genes, in one-eyed pinhead, which is required for nodal signaling, and in the Notch pathway reveal that midline cell fate specification is, in fact, initiated during gastrulation. Furthermore, the organizer coordinates morphogenetic movements, and zebrafish mutants in T-box mesoderm-specific genes help clarify the mechanism of convergence movements required for the formation of axial and paraxial mesoderm. (C) 1999 Academic Press. C1 NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Kodjabachian, L (reprint author), NICHHD, Mol Genet Lab, NIH, Bldg 6B,Room 420, Bethesda, MD 20892 USA. NR 113 TC 40 Z9 40 U1 0 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD SEP 15 PY 1999 VL 213 IS 2 BP 231 EP 245 DI 10.1006/dbio.1999.9392 PG 15 WC Developmental Biology SC Developmental Biology GA 238WA UT WOS:000082736400001 PM 10479444 ER PT J AU Mishina, Y Crombie, R Bradley, A Behringer, RR AF Mishina, Y Crombie, R Bradley, A Behringer, RR TI Multiple roles for activin-like kinase-2 signaling during mouse embryogenesis SO DEVELOPMENTAL BIOLOGY LA English DT Article DE gastrulation; mesoderm; TGF-beta gene family; signal transduction ID TGF-BETA-SUPERFAMILY; BONE MORPHOGENETIC PROTEIN-4; GROWTH-FACTOR-BETA; MESODERM-INDUCING SIGNALS; EARLY XENOPUS DEVELOPMENT; SERINE THREONINE KINASE; EMBRYONIC STEM-CELLS; I RECEPTORS; PRIMITIVE STREAK; T-GENE AB The members of the transforming growth factor-beta (TGE-beta) superfamily are secreted proteins that interact with cell-surface receptors to elicit signals that regulate a variety of biological processes during vertebrate embryogenesis. Alk2, also known as ActRIA, Tsk7L, and SKR1, encodes a type I TGF-beta family receptor for activins and BMP-7. Initially, Alk2 transcripts are detected in the visceral endoderm of gastrula stage mouse embryos, suggesting a signaling role in extraembryonic tissues during development. To study the role of Alk2 during mammalian development, Alk2 mutant mice were generated. After embryonic day 9.5 (E9.5), no homozygous mutants were recovered from heterozygote matings. Homozygous mutants with morphological defects were first detected at E7.0 and were smaller than controls. Morphological and molecular examination demonstrated that Alk2 mutant embryos formed a primitive streak, although abnormally thickened, and were arrested in their development around the late streak stage. These gastrulation defects were rescued in chimeric embryos generated by injection of Alk2 mutant embryonic stem (ES) cells into wild-type blastocysts. This rescue of gastrulation defects was also observed in chimeric embryos generated by aggregation of Alk2 homozygous mutant ES cells with tetraploid wild-type embryos. However, at E9.5, these embryos that were completely ES-derived also had defects. In contrast, chimeric embryos generated by injection of wild-type E3 cells into Alk2 mutant blastocysts did not show rescue of the gastrulation defects. These results suggest that signaling through this type I receptor is essential in extraembryonic tissues at the time of gastrulation for normal mesoderm formation and also suggest that subsequent Alk2 signaling is essential far normal development after gastrulation. (C) 1999 Academic Press. C1 Univ Texas, MD Anderson Canc Ctr, Dept Mol Genet, Houston, TX 77030 USA. NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. Baylor Coll Med, Dept Human & Mol Genet, Houston, TX 77030 USA. Baylor Coll Med, Howard Hughes Med Inst, Houston, TX 77030 USA. RP Behringer, RR (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Mol Genet, Houston, TX 77030 USA. FU NICHD NIH HHS [HD30284] NR 89 TC 111 Z9 115 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD SEP 15 PY 1999 VL 213 IS 2 BP 314 EP 326 DI 10.1006/dbio.1999.9378 PG 13 WC Developmental Biology SC Developmental Biology GA 238WA UT WOS:000082736400007 PM 10479450 ER PT J AU Harlan, DM Kirk, AD AF Harlan, DM Kirk, AD TI The future of organ and tissue transplantation - Can T-cell costimulatory pathway modifiers revolutionize the prevention of graft rejection? SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CARDIAC ALLOGRAFT-REJECTION; LONG-TERM ACCEPTANCE; ISLET ALLOGRAFTS; CD40 LIGAND; LYMPHOPROLIFERATIVE DISORDERS; ACTIVATION ANTIGEN-B7; DENDRITIC CELL; BLOCKADE; CTLA-4; EXPRESSION AB Transplantation therapies have revolutionized care for patients with endstage organ (kidney, liver, heart, lung, and pancreatic g-cell) failure, yet significant problems persist with treatments designed to prevent graft rejection. Antirejection therapies are not always effective, must be taken daily, and are both expensive and associated with well-known toxic effects; Recent advances have suggested that the immune system has more self-regulatory capability than previously appreciated. In this review, we discuss immune system function and new therapeutic agents that modify so-called costimulatory receptor signaling to support transplant function without generally suppressing the immune system. C1 NIDDK, USN, Med Res Ctr, Transplantat & Autoimmun Branch, Bethesda, MD 20889 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. Walter Reed Army Med Ctr, Organ Transplant Serv, Washington, DC USA. RP Harlan, DM (reprint author), NIDDK, USN, Med Res Ctr, Transplantat & Autoimmun Branch, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. RI Kirk, Allan/B-6905-2012 NR 67 TC 51 Z9 55 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 SEP 15 PY 1999 VL 282 IS 11 BP 1076 EP 1082 DI 10.1001/jama.282.11.1076 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 234YQ UT WOS:000082512300033 PM 10493208 ER PT J AU Feng, LX Balakir, R Precht, P Horton, WE AF Feng, LX Balakir, R Precht, P Horton, WE TI Bcl-2 regulates chondrocyte morphology and aggrecan gene expression independent of caspase activation and full apoptosis SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE apoptosis; chondrocyte; gene regulation; cartilage; aging ID HORMONE-RELATED PEPTIDE; NF-KAPPA-B; PROGRAMMED CELL-DEATH; NERVE GROWTH-FACTOR; SKELETAL DEVELOPMENT; TARGETED DISRUPTION; PROTEIN EXPRESSION; HL-60 CELLS; DIFFERENTIATION; CARTILAGE AB Bcl-2 is widely expressed in a variety of cell types and is known to block apoptosis through a conserved pathway. However, recent reports have demonstrated that Bcl-2 regulates cell behavior independent of its control of apoptosis. Chondrocytes express a unique set of matrix proteins, including the proteoglycan aggrecan, and have been widely used to study the relationship between trophic factors and apoptosis. In this article, we report that Bcl-2 affects the morphology and regulates the expression of aggrecan in a rat chondrocyte cell line (IRC). Endogenous Bcl-2 and aggrecan mRNA were both down-regulated in response to serum withdrawal in parental IRC cells, while constitutive expression of Bcl-2 maintained aggrecan levels under conditions of serum withdrawal. In addition, expression of anti-sense Bcl-2 resulted in decreased aggrecan mRNA and produced a fibroblastic morphology compared with parental cells. The caspase inhibitor ZVAD-fmk effectively blocked full apoptosis of IRC cells in response to serum withdrawal or anti-sense Bcl-2 but did not prevent the down-regulation of aggrecan expression from either signal. These results suggest a novel role for Bcl-2 in regulating the differentiated phenotype of chondrocytes and the expression of a differentiation-specific gene independent of its control of apoptosis. (C) 1999 Wiley-Liss, Inc. C1 NE Ohio Univ, Coll Med, Dept Anat, Rootstown, OH 44272 USA. NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Horton, WE (reprint author), NE Ohio Univ, Coll Med, Dept Anat, 4209 State Route 44,POB 95, Rootstown, OH 44272 USA. NR 60 TC 32 Z9 33 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 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD SEP 15 PY 1999 VL 74 IS 4 BP 576 EP 586 DI 10.1002/(SICI)1097-4644(19990915)74:4<576::AID-JCB7>3.0.CO;2-N PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 223JD UT WOS:000081837200007 PM 10440927 ER PT J AU Zhang, JY Somani, AK Yuen, D Yang, Y Love, PE Siminovitch, KA AF Zhang, JY Somani, AK Yuen, D Yang, Y Love, PE Siminovitch, KA TI Involvement of the SHP-1 tyrosine phosphatase in regulation of T cell selection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RECEPTOR SIGNAL-TRANSDUCTION; HEAT-STABLE ANTIGEN; BONE-MARROW CELLS; NEGATIVE SELECTION; POSITIVE SELECTION; INHIBITORY RECEPTOR; TRANSGENIC MICE; B-LYMPHOCYTES; MOTH-EATEN; PROTEIN AB The selection events shaping T cell development in the thymus represent the outcome of TCR-driven intracellular signaling cascades evoked by Ag receptor interaction with cognate ligand, In view of data indicating TCR-evoked thymocyte proliferation to be negatively modulated by the SHP-1 tyrosine phosphatase, a potential role for SHP-1 in regulating selection processes was investigated by analysis of T cell development in H-Y TCR transgenic mice rendered SHP-1 deficient by introduction of the viable motheaten mutation or a dominant negative SHP-1-encoding transgene, Characterization of thymocyte and peripheral T cell populations in H-Y TCR-viable motheaten mice revealed TCR-evoked proliferation as well as the positive and negative selection of H-Y-specific thymocytes to be enhanced in these mice, thus implicating SHP-1 in the negative regulation of each of these processes, T cell selection processes mere also augmented in H-Y TCR mice carrying a transgene driving lymphoid-restricted expression of a catalytically inert, dominant-negative form of SHP-1. SHP-1-negative effects on thymocyte TCR signaling were not influenced by co-cross-linking of the CD28 costimulatory and/or CTLA-4 inhibitory receptors and appear, accordingly, to be realized independently of these comodulators. These observations indicate that SHP-1 raises the signaling threshold required for both positive and negative selection and reveal the inhibitory effects of SHP-1 on TCR signaling to be cell autonomous. The demonstrated capacity for SHP-1 to inhibit TCR-evoked proliferation and selection indicate SHP-1 modulatory effects on the magnitude of TCR-generated signal to be a key factor in determining the cellular consequences of TCR-ligand interaction. C1 Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Dept Immunol, Toronto, ON M5G 1X5, Canada. Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Dept Med, Toronto, ON M5G 1X5, Canada. Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Dept Mol & Med Genet, Toronto, ON M5G 1X5, Canada. NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Siminovitch, KA (reprint author), Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Dept Immunol, 600 Univ Ave,Room 656A, Toronto, ON M5G 1X5, Canada. RI Siminovitch, Katherine/K-1475-2013 NR 62 TC 49 Z9 49 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 SEP 15 PY 1999 VL 163 IS 6 BP 3012 EP 3021 PG 10 WC Immunology SC Immunology GA 235QH UT WOS:000082553700006 PM 10477564 ER PT J AU Zella, D Barabitskaja, O Casareto, L Romerio, F Secchiero, P Reitz, MS Gallo, RC Weichold, FF AF Zella, D Barabitskaja, O Casareto, L Romerio, F Secchiero, P Reitz, MS Gallo, RC Weichold, FF TI Recombinant IFN-alpha (2b) increases the expression of apoptosis receptor CD95 and chemokine receptors CCR1 and CCR3 in monocytoid cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CHRONIC MYELOGENOUS LEUKEMIA; BLOOD MONONUCLEAR-CELLS; INTERFERON-ALPHA; DENDRITIC CELLS; CHEMOTACTIC RESPONSIVENESS; GAMMA; INHIBITION; CYTOKINE; SUSCEPTIBILITY AB IFN-alpha-2b, known as potent immune modulator, can either inhibit or enhance immune cell activity within the tightly regulated microenvironment of inflammation, depending upon the concentration of the cytokine and the activation stage of the cell. Chemokine receptors, which not only mediate chemotaxis of immune cells to the site of inflammation but also affect cellular activation by transferring corresponding signals, represent yet another level of immune regulation. Here we demonstrate that IFN-alpha increases the expression of CCR1 and CCR3 in primary mononuclear phagocytes, as well as in the monocytoid cell line U937, Enhanced receptor mRNA expression correlated with functional readouts such as increased intracellular calcium mobilization and cell migration in response to ligands, Expression of CCR2b, CCR4, CCR5, and CXCR4 was unchanged or decreased after IFN-alpha treatment. These observations indicate a differentially regulated cellular signaling relationship of IFN-alpha pathways and chemokine receptor expression. We also provide evidence that, under these conditions, IFN-alpha treatment increased the expression of CD95 (Fas, Apo1), resulting in enhanced susceptibility to apoptosis, Taken together, these data add important information for the rational application of IFN-alpha (2b) in immune and cancer therapies. C1 Univ Maryland, Inst Biotechnol, Inst Human Virol, Baltimore, MD 21201 USA. NCI, Lab Basic Sci, NIH, Bethesda, MD 20814 USA. Dept Morphol & Embriol, Human Anat Sect, Ferrara, Italy. RP Weichold, FF (reprint author), Univ Maryland, Inst Biotechnol, Inst Human Virol, 725 W Lombard St, Baltimore, MD 21201 USA. RI secchiero, paola/G-9689-2015 OI secchiero, paola/0000-0003-4101-7987 FU NIAID NIH HHS [R03-AI43204] NR 30 TC 36 Z9 37 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 1999 VL 163 IS 6 BP 3169 EP 3175 PG 7 WC Immunology SC Immunology GA 235QH UT WOS:000082553700026 PM 10477584 ER PT J AU Shi, CS Leonardi, A Kyriakis, J Siebenlist, U Kehrl, JH AF Shi, CS Leonardi, A Kyriakis, J Siebenlist, U Kehrl, JH TI TNF-Mediated activation of the stress-activated protein kinase pathway: TNF receptor-associated factor 2 recruits and activates germinal center kinase related SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; TERMINAL KINASE; CELL-DEATH; TRAF2; RIP; APOPTOSIS; COMPLEX; HOMOLOG; DOMAIN AB TNF-induced activation of stress activated protein kinases (SAPKs, Jun NH2-terminal kinases) requires TNF receptor associated factor 2 (TRAF2). TRAF2 is a potent activator of a 95-kDa serine/threonine kinase termed germinal center kinase related (GCKR, also referred to as KHS1), which signals activation of the SAPK pathway. Consistent with a role for GCKR in TNF- induced SARK activation, a kinase-inactive mutant of GCKR is a dominant negative inhibitor of TRAF2-induced SAPK activation. Here we show that TRAF2 interacts with GCKR, This interaction depended upon the TRAF domain of TRAF2 and the C-terminal 150 aa of GCKR, The full activation of GCKR by TRAF2 required the TRAF2 RING finger domain. TNF treatment of a T cell line, Jurkat, increased both GCRK and SAPK activity and enhanced the coimmunoprecipitation of GCKR with TRAF2, Similar results were found with the B cell line HS-Sultan. These findings are consistent with a model whereby TNF signaling results in the recruitment and activation of GCKR by TRAF2 which leads to SAPK activation. C1 NIAID, Immunoregulat Lab, B Cell Mol Immunol Sect, NIH, Bethesda, MD 20892 USA. NIAID, Immunoregulat Lab, Immune Activat Sect, NIH, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Diabet Res Lab, Charlestown, MA 02129 USA. RP Kehrl, JH (reprint author), NIAID, Immunoregulat Lab, B Cell Mol Immunol Sect, NIH, Bldg 10, Bethesda, MD 20892 USA. OI Kehrl, John/0000-0002-6526-159X; LEONARDI, Antonio/0000-0001-8636-9623 NR 28 TC 42 Z9 42 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 1999 VL 163 IS 6 BP 3279 EP 3285 PG 7 WC Immunology SC Immunology GA 235QH UT WOS:000082553700039 PM 10477597 ER PT J AU Ragheb, JA Deen, M Schwartz, RH AF Ragheb, JA Deen, M Schwartz, RH TI The destabilization of IL-2 mRNA by a premature stop codon and its differential stabilization by trans-acting inhibitors of protein synthesis do not support a role for active translation in mRNA stability SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MESSENGER-RNA DECAY; INTERLEUKIN-2 GENE-EXPRESSION; T-CELL ACTIVATION; NONSENSE CODONS; C-FOS; CHROMOSOMAL TRANSLOCATION; 3' TRUNCATION; LYMPHOCYTES-T; FREE SYSTEM; DEGRADATION AB To investigate the role that translation plays in the stabilization of the IL-2 mRNA, we inhibited protein synthesis in both cis and trans, To block translation in trans, we utilized the inhibitors puromycin (PUR) and cycloheximide (CHX), which differentially effect polysome structure. We found that CHX enhances the stability of IL-2 mRNA in cells stimulated with anti-TCR Ab alone, but it inhibits CD28-induced message stabilization in costimulated cells. In contrast, PUR had a minimal effect on IL-2 mRNA stability in either the presence or absence of costimulation. The differential effects of these two inhibitors suggest that: 1) CHX is unlikely to stabilize the IL-2 mRNA by inhibiting the expression of a labile RNase; 2) CD28-mediated IL-2 mRNA stabilization does not require translation; and 3) IL-2 mRNA decay is not coupled to translation, To block translation in cis, we generated sequence-tagged IL-2 genomic reporters that contain a premature termination codon (PTC), In both the presence and absence of costimulation, these PTC-containing mRNAs exhibit drastically diminished stability, Interestingly, the addition of CHX but not PUR completely restored CD28-mediated stabilization, suggesting that CHX can block the enhanced decay induced by a PTC, Finally, CHX was able to superinduce IL-2 mRNA levels in anti-TCR Ab-stimulated cells but not in CD28-costimulated cells, suggesting that CHX may also act by other mechanisms. C1 NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Ragheb, JA (reprint author), NIAID, Cellular & Mol Immunol Lab, NIH, Bldg 10,Room 10N112,10 Ctr Dr,MSC-1857, Bethesda, MD 20892 USA. NR 56 TC 14 Z9 14 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 SEP 15 PY 1999 VL 163 IS 6 BP 3321 EP 3330 PG 10 WC Immunology SC Immunology GA 235QH UT WOS:000082553700044 PM 10477602 ER PT J AU Adachi, S Nakano, T Vliagoftis, H Metcalfe, DD AF Adachi, S Nakano, T Vliagoftis, H Metcalfe, DD TI Receptor-mediated modulation of murine mast cell function by alpha-melanocyte stimulating hormone SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PROOPIOMELANOCORTIN-DERIVED PEPTIDES; GENE-RELATED PEPTIDE; ULTRAVIOLET-B; MELANOCORTIN RECEPTORS; HUMAN MONOCYTES; AQUEOUS-HUMOR; IN-VITRO; MSH; EXPRESSION; NEUROPEPTIDES AB The proopiomelanocortin (POMC)-derived neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) is known to modulate some aspects of inflammation through direct effects on T cells, B cells, and monocytes, To determine whether alpha-MSH might similarly influence mast cell responsiveness, mast cells were examined to see if they expressed the receptor for alpha-MSH, melanocortin-1 (MC-1), and whether alpha-MSH altered mast cell function. We thus first identified MC-1 on bone marrow cultured murine mast cells (BMCMC) and a murine mast cell line (MCP5) employing flow cytometry and through detection of specific binding. Subsequent treatment of mast cells with alpha-MSH increased the cAMP concentration in a characteristic biphasic pattern, demonstrating that alpha-MSH could affect intracellular processes, We next examined the effect of alpha-MSH on mediator release and cytokine expression. IgE/DNP-human serum albumin-stimulated histamine release from mast cells was inhibited by similar to 60% in the presence of alpha-MSH. Although activation of BMCMC induced the expression of mRNAs for the inflammatory cytokines IL-1 beta, IL-4, IL-6, TNF-alpha, and the chemokine lymphotactin, mRNAs for IL-1 beta, TNF-alpha, and lymphotactin were down-modulated in the presence of alpha-MSH, Finally, IL-3-dependent proliferative activity of BMCMC was slightly but significantly augmented by alpha-MSH. Taken together, these observations suggest that rr-MSH may exert an inhibitory effect on the mast cell-dependent component of a specific inflammatory response. 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 NR 54 TC 53 Z9 53 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 1999 VL 163 IS 6 BP 3363 EP 3368 PG 6 WC Immunology SC Immunology GA 235QH UT WOS:000082553700048 PM 10477606 ER PT J AU Tomic, M Zivadinovic, D Van Goor, F Yuan, D Koshimizu, TA Stojilkovic, SS AF Tomic, M Zivadinovic, D Van Goor, F Yuan, D Koshimizu, TA Stojilkovic, SS TI Expression of Ca2+-mobilizing endothelin(A) receptors and their role in the control of Ca2+ influx and growth hormone secretion in pituitary somatotrophs SO JOURNAL OF NEUROSCIENCE LA English DT Article DE somatotrophs; growth hormone; calcium; endothelin; somatostatin; electrical activity ID PURIFIED RAT SOMATOTROPHS; GH-RELEASING FACTOR; ANTERIOR-PITUITARY; PROLACTIN SECRETION; INTRACELLULAR CALCIUM; FUNCTIONAL EXPRESSION; CONCENTRATION I; CELL-LINE; SOMATOSTATIN; INHIBITION AB The expression and coupling of endothelin (ET) receptors were studied in rat pituitary somatotrophs. These cells exhibited periods of spontaneous action potential firing that generated high-amplitude fluctuations in cytosolic calcium concentration ([Ca2+](i)). The message and the specific binding sites for ETA, but not ETB, receptors were found in mixed pituitary cells and in highly purified somatotrophs. The activation of these receptors by ET-1 led to an increase in inositol 1,4,5-trisphosphate production and the associated rise in [Ca2+](i) and growth hormone (GH) secretion. The Ca2+-mobilizing action of ET-1 lasted for 2-3 min and was followed by an inhibition of action potential-driven Ca2+ influx and GH secretion to below the basal levels. As in somatostatin-treated cells, the ET-1-induced inhibition of spontaneous electrical activity and Ca2+ influx was accompanied by the inhibition of adenylyl cyclase and by the stimulation of inward rectifier potassium current. In contrast to somatostatin, ET-1 did not inhibit voltage-gated Ca2+ channels. During prolonged agonist stimulation a gradual recovery of Ca2+ influx and GH secretion occurred. In somatotrophs treated with pertussis toxin overnight, the ET-1-induced Ca2+-mobilizing phase was preserved, but it was followed immediately by facilitated Ca2+ influx and GH secretion. Both somatostatin- and ET-1-induced inhibitions of adenylyl cyclase activity were abolished in pertussis toxin-treated cells. These results indicate that the transient cross-coupling of Ca2+ mobilizing ETA receptors to the G(i)/G(o) pathway in somatotrophs provides an effective mechanism to change the rhythm of [Ca2+](i) signaling and GH secretion during continuous agonist stimulation. C1 NICHHD, Sect Cellular Signaling, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Stojilkovic, SS (reprint author), NICHHD, Sect Cellular Signaling, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Room 6A-36,49 Convent Dr, Bethesda, MD 20892 USA. RI Tomic, Melanija/C-3371-2016; OI Koshimizu, Taka-aki/0000-0001-5292-7535 NR 48 TC 31 Z9 32 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 15 PY 1999 VL 19 IS 18 BP 7721 EP 7731 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 235KB UT WOS:000082539900008 PM 10479676 ER PT J AU Bruccoleri, A Pennypacker, KR Harry, GJ AF Bruccoleri, A Pennypacker, KR Harry, GJ TI Effect of dexamethasone on elevated cytokine mRNA levels in chemical-induced hippocampal injury SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE trimethyltin; dexamethasone; hippocampus; GFAP; cytokines ID NECROSIS-FACTOR-ALPHA; INTERCELLULAR-ADHESION MOLECULE-1; PITUITARY-ADRENAL AXIS; ISCHEMIC BRAIN-DAMAGE; SPINAL-CORD INJURY; GENE-EXPRESSION; GLUCOCORTICOID RECEPTOR; INTERFERON-GAMMA; MESSENGER-RNA; C-JUN AB An acute administration of the hippocampal toxicant trimethyltin (TMT) produced a specific pattern of neuronal necrosis in dentate granule cells with accompanying astrogliosis and initiation of a cytokine response within 24 hours. The purpose of this study was to examine the effects of the anti-inflammatory agent, dexamethasone (DEX), on the pattern of cytokine expression and neuronal degeneration occurring after an acute TMT injection. Dexamethasone (0.2 mg/kg or 10 mg/kg) was administered to 21-day-old male mice 1 hour prior to an injection of TMT hydroxide (2.5 mg/kg, i.p.), Mice receiving 0.2 mg/kg DEX received a second injection 6 hours after TMT. Twenty-four hours later, neuronal necrosis and astrogliosis were assessed and found to be similar in animals treated with TMT, either in the presence or absence of dexamethasone, Pretreatment with dexamethasone failed to prevent the neurodegeneration and astrogliosis, The TMT-induced injury response was represented in elevations of mRNA levels for the injury-associated host response genes glial fibrillary acidic protein(GFAP), EB22/5.3, and intercellular adhesion molecule-1 (ICAM-1), The combination of DEX and TMT produced increased elevation in mRNA levels for EB22/5.3 and ICAM, while GFAP levels remained the same as with TMT alone. The injury response from TMT was accompanied by elevations in mRNA levels for the cytokines tumor necrosis factor (TNF) at, TNF beta, and interleukin (IL)-1 alpha, Treatment with dexamethasone prior to TMT resulted in significantly elevated levels of TNF alpha, TNF beta, and IL-lar as compared to TMT alone. These data represent the inability of glucocorticoids to downregulate the injury response in rat hippocampus following a systemic injection of TMT and suggest a stimulation and "priming" of hippocampal cells by dexamethasone, Published 1999 Wiley-Liss, Inc.(dagger). C1 NIEHS, Neurotoxicol Grp, Toxicol Lab, Res Triangle Pk, NC 27709 USA. Univ S Florida, Dept Pharmacol, Tampa, FL USA. RP Harry, GJ (reprint author), NIEHS, Neurotoxicol Grp, Toxicol Lab, POB 12233,MD C1-04, Res Triangle Pk, NC 27709 USA. RI Pennypacker, Keith/I-5092-2012 NR 74 TC 26 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 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD SEP 15 PY 1999 VL 57 IS 6 BP 916 EP 926 DI 10.1002/(SICI)1097-4547(19990915)57:6<916::AID-JNR17>3.0.CO;2-J PG 11 WC Neurosciences SC Neurosciences & Neurology GA 230WE UT WOS:000082274000017 PM 10467263 ER PT J AU Kaye, FJ AF Kaye, FJ TI Closing in on another renal cancer suppressor locus near chromosome 3p14 SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID CARCINOMA CELL-LINE; GENE; MUTATIONS; FHIT C1 Natl Naval Med Ctr, NIH, Bethesda, MD 20889 USA. NCI, Div Clin Sci, Med Branch, Bethesda, MD 20892 USA. RP Kaye, FJ (reprint author), Natl Naval Med Ctr, NIH, Bldg 8,Rm 5101, Bethesda, MD 20889 USA. RI kaye, frederic/E-2437-2011 NR 21 TC 0 Z9 0 U1 0 U2 0 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 15 PY 1999 VL 91 IS 18 BP 1528 EP 1529 DI 10.1093/jnci/91.18.1528 PG 2 WC Oncology SC Oncology GA 237EB UT WOS:000082641400002 PM 10491421 ER PT J AU Costantino, JP Gail, MH Pee, D Anderson, S Redmond, CK Benichou, J Wieand, HS AF Costantino, JP Gail, MH Pee, D Anderson, S Redmond, CK Benichou, J Wieand, HS TI Validation studies for models projecting the risk of invasive and total breast cancer incidence SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID INDIVIDUALIZED PROBABILITIES; WOMEN; PROGRAM AB Background: In 1989, Gall and colleagues developed a model for estimating the risk of breast cancer in women participating in a program of annual mammographic screening (designated herein as model 1), A modification of this model to project the absolute risk of developing only invasive breast cancer is referred to herein as model 2, We assessed the validity of both models by employing data from women enrolled in the Breast Cancer Prevention Trial, Methods: We used data from 5969 white women who were at least 35 years of age and without a history of breast cancer. These women were in the placebo arm of the trial and were screened annually. The average follow-up period was 48.4 months. We compared the observed number of breast cancers with the predicted numbers from the models. Results: In terms of absolute risk, the ratios of total expected to observed numbers of cancers (95% confidence intervals [CIs]) were 0.84 (0.73-0.97) for model 1 and 1.03 (0.88-1.21) for model 2, respectively. Within the age groups of 49 years or less, 50-59 years, and 60 years or more, the ratios of expected to observed numbers of breast cancers (95% CIs) for model 1 were 0.91 (0.73-1.14), 0.96 (0.73-1.28), and 0.66 (0.52-0.86), respectively. Thus, model 1 underestimated breast cancer risk in women more than 59 years of age. For model 2, the risk ratios (95% CIs) were 0.93 (0.72-1.22), 1.13 (0.83-1.55), and 1.05 (0.80-1.41), respectively. Both models exhibited a tendency to overestimate risk for women classified in the higher quintiles of predicted 5-year risk and to underestimate risk for those in the lower quintiles of the same. Conclusion: Despite some limitations, these methods provide useful information on breast cancer risk for women who plan to participate in an annual mammographic screening program. C1 Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. NCI, Div Epidemiol & Genet, Bethesda, MD USA. Informat Management Serv Inc, Bethesda, MD USA. Univ Rouen, Sch Med, Dept Biostat, F-76821 Mt St Aignan, France. RP Costantino, JP (reprint author), 230 McKee Pl,Suite 403, Pittsburgh, PA 15213 USA. OI Anderson, Stewart/0000-0001-8948-0650 NR 17 TC 339 Z9 350 U1 0 U2 11 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 SEP 15 PY 1999 VL 91 IS 18 BP 1541 EP 1548 DI 10.1093/jnci/91.18.1541 PG 8 WC Oncology SC Oncology GA 237EB UT WOS:000082641400008 PM 10491430 ER PT J AU Yarbrough, WG Buckmire, RA Bessho, M Liu, ET AF Yarbrough, WG Buckmire, RA Bessho, M Liu, ET TI Biologic and biochemical analyses of p16(INK4a) mutations from primary tumors SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID CYCLIN-DEPENDENT KINASE-4; SQUAMOUS-CELL CARCINOMA; RETINOBLASTOMA-PROTEIN; FAMILIAL MELANOMA; SUPPRESSOR P16(INK4A); HUMAN CANCERS; P16; GENE; INHIBITORS; FREQUENCY AB Background: Point mutations in the tumor suppressor gene p16(INK4a) (also known as p16, CDKN2, MTS1, and INK4a) are found in many tumor types, Because the function of the products of these naturally occurring mutants has not been fully explored, we investigated the functional activities of a wide range of naturally occurring p16 mutant proteins. Methods: Sixteen cancer-associated p16 mutant proteins, resulting from missense mutations, were characterized for their ability to bind and inhibit the cyclin-dependent kinases (CDK4 and CDK6) and to induce cell cycle arrest in G(1) phase. Results/ Conclusions: Among 16 mutants analyzed, nine had detectable functional defects. Three mutants (D84V, D84G, and R87P) had defects in CDK binding, kinase inhibition, and cell cycle arrest. The corresponding mutations are located in the third ankyrin repeat in a highly conserved region believed to form the CDK binding cleft. Three mutants (P48L, D74N, and R87L) had defects in kinase inhibition and cell cycle arrest, Among the 10 mutants with normal CDK binding and inhibitory activity, three mutants (N71S, R80L, and H83Y) had defects only in their ability to induce cell cycle arrest. Thus, p16 mutant proteins that retain CDK4 and CDK6 binding may have more subtle functional defects, All nine mutations leading to functional impairments mapped to the central portion of the p16 protein. Ankyrin repeats II and III appear more critical to p16 function, and mutations in ankyrin repeats I and IV are less likely to disrupt p16 function. C1 Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Surg, Div Otolaryngol, Chapel Hill, NC 27599 USA. NCI, Div Clin Sci, Bethesda, MD 20892 USA. RP Yarbrough, WG (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Surg, Div Otolaryngol, CB 7295, Chapel Hill, NC 27599 USA. RI Liu, Edison/C-4141-2008 FU NCI NIH HHS [K08CA72968] NR 23 TC 28 Z9 29 U1 1 U2 1 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 SEP 15 PY 1999 VL 91 IS 18 BP 1569 EP 1574 DI 10.1093/jnci/91.18.1569 PG 6 WC Oncology SC Oncology GA 237EB UT WOS:000082641400012 PM 10491434 ER PT J AU Pozzo-Miller, LD Pivovarova, NB Connor, JA Reese, TS Andrews, SB AF Pozzo-Miller, LD Pivovarova, NB Connor, JA Reese, TS Andrews, SB TI Correlated measurements of free and total intracellular calcium concentration in central nervous system neurons SO MICROSCOPY RESEARCH AND TECHNIQUE LA English DT Article DE endoplasmic reticulum; mitochondria; Ca2+ imaging; electron probe X-ray microanalysis ID HIPPOCAMPAL PYRAMIDAL NEURONS; ORGANOTYPIC SLICE CULTURES; EXCITATORY AMINO-ACIDS; GATED CA2+ CHANNELS; ENDOPLASMIC-RETICULUM; DENDRITIC SPINES; MITOCHONDRIAL CALCIUM; SYNAPTIC DEVELOPMENT; PURKINJE-CELLS; CA1 AB Transient changes in the intracellular concentration of free calcium ([Ca-i(2+])) act as a trigger or modulator for a large number of important neuronal processes. Such transients can originate from voltage- or ligand-gated fluxes of Ca2+ into the cytoplasm from the extracellular space, or by ligand- or Ca2+-gated release from intracellular stores. Characterizing the sources and spatio-temporal patterns of [Ca2+](i) transients is critical for understanding the role of different neuronal compartments in dendritic integration and synaptic plasticity Optical imaging of fluorescent indicators sensitive to free Ca2+ is especially suited to studying such phenomena because this approach offers simultaneous monitoring of large regions of the dendritic tree in individual living central nervous system neurons. In contrast, energy-dispersive X-ray (EDX) microanalysis provides quantitative information on the amount and location of intracellular total, i.e., free plus bound, calcium (Ca) within specific subcellular dendritic compartments as a function of the activity state of the neuron. When optical measurements of [Ca2+](i) transients and parallel EDX measurements of Ca content are used in tandem, and correlated simultaneously with electrophysiological measurements of neuronal activity, the combined information provides a relatively general picture of spatio-temporal neuronal total Ca fluctuations. To illustrate the kinds of information available with this approach, we review here results from our ongoing work aimed at evaluating the role of various Ca uptake, release, sequestration, and extrusion mechanisms in the generation and termination of [Ca2+](i) transients in dendrites of pyramidal neurons in hippocampal slices during and after synaptic activity. Our observations support the long-standing speculation that the dendritic endoplasmic reticulum acts not only as an intracellular Ca2+ source that can be mobilized by a signal cascade originating at activated synapses, but also as a major intracellular Ca sink involved in active clearance mechanisms after voltage- and ligand-gated Ca2+ influx. (C) 1999 Wiley-Liss, Inc. C1 Univ Alabama Birmingham, Dept Neurobiol, Civitan Int Res Ctr, Birmingham, AL 35294 USA. NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. Univ New Mexico, Dept Neurosci, Albuquerque, NM 87131 USA. RP Univ Alabama Birmingham, Dept Neurobiol, Civitan Int Res Ctr, 429-A2,1719 6th Ave S, Birmingham, AL 35294 USA. EM pozzomiller@nrc.uab.edu FU NINDS NIH HHS [NS35644] NR 73 TC 17 Z9 17 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-910X EI 1097-0029 J9 MICROSC RES TECHNIQ JI Microsc. Res. Tech. PD SEP 15 PY 1999 VL 46 IS 6 BP 370 EP 379 DI 10.1002/(SICI)1097-0029(19990915)46:6<370::AID-JEMT5>3.0.CO;2-3 PG 10 WC Anatomy & Morphology; Biology; Microscopy SC Anatomy & Morphology; Life Sciences & Biomedicine - Other Topics; Microscopy GA 243CF UT WOS:000082979000005 PM 10504214 ER PT J AU Stierum, RH Dianov, GL Bohr, VA AF Stierum, RH Dianov, GL Bohr, VA TI Single-nucleotide patch base excision repair of uracil in DNA by mitochondrial protein extracts SO NUCLEIC ACIDS RESEARCH LA English DT Article ID XENOPUS-LAEVIS OOCYTES; HAMSTER OVARY CELLS; OXIDATIVE DAMAGE; POLYMERASE-GAMMA; MAMMALIAN-CELLS; SITE REPAIR; NUCLEAR-DNA; ENDONUCLEASE; IDENTIFICATION; GLYCOSYLASES AB Mammalian mitochondria contain several 16.5 kb circular DNAs (mtDNA) encoding electron transport chain proteins. Reactive oxygen species formed as byproducts from oxidative phosphorylation in these organelles can cause oxidative deamination of cytosine and lead to uracil in mtDNA, Upon mtDNA replication, these lesions, if unrepaired, can lead to mutations, Until recently, it was thought that there was no DNA repair in mitochondria, but lately there is evidence that some lesions are efficiently repaired in these organelles, In the study of nuclear DMA repair, the in vitro repair measurements in cell extracts have provided major insights into the mechanisms. The use of whole-cell extract based DNA repair methods has revealed that mammalian nuclear base excision repair (BER) diverges into two pathways: the single-nucleotide replacement and long patch repair mechanisms. Similar in vitro methods have not been available for the study of mitochondrial BER. We have established an in vitro DNA repair system supported by rat liver mitochondrial protein extract and DNA substrates containing a single uracil opposite to a guanine, Using this approach, we examined the repair pathways and the identity of the DNA polymerase involved in mitochondrial BER (mtBER), Employing restriction analysis of in vitro repaired DNA to map the repair patch size, we demonstrate that only one nucleotide is incorporated during the repair process, Thus, in contrast to BER in the nucleus, mtBER of uracil in DNA is solely accomplished by single-nucleotide replacement. C1 NIA, Genet Mol Lab, NIH, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Genet Mol Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 38 TC 55 Z9 57 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP 15 PY 1999 VL 27 IS 18 BP 3712 EP 3719 DI 10.1093/nar/27.18.3712 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 239QP UT WOS:000082781400012 PM 10471741 ER PT J AU Michal, CA Tycko, R AF Michal, CA Tycko, R TI Stray-field NMR imaging and wavelength dependence of optically pumped nuclear spin polarization in InP SO PHYSICAL REVIEW B LA English DT Article ID GAAS QUANTUM-WELLS; HIGH-PURITY GAAS; MAGNETIC-RESONANCE; GALLIUM-ARSENIDE; ELECTRONIC STATES; INDIUM-PHOSPHIDE; SEMICONDUCTORS; DYNAMICS; SHIFT; FE AB One-dimensional NMR imaging experiments with micron spatial resolution are used to investigate the penetration depth and excitation energy dependence of optical pumping in Fe-doped semi-insulating InP crystals in high magnetic field at low temperature. The depth profile of P-31 nuclear polarization revealed by NMR imaging is consistent with previous optical absorption measurements, while the efficiency of exciting nuclear polarization is found to be a complicated function of the excitation energy. This dependence is not explained by LO phonon emission by the photoexcited carriers. The optically pumped P-31 NMR signal exhibits a maximum intensity with excitation several meV below the band gap, but this maximum is shown to be due to the dramatically increased absorption length of below-gap radiation. The efficiency of exciting nuclear polarization drops off quickly below the gap, and is about 1/5 of its maximum value at the energy of greatest total NMR signal intensity. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Michal, CA (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. RI Michal, Carl/G-5288-2012 OI Michal, Carl/0000-0002-5764-3221 NR 53 TC 43 Z9 44 U1 0 U2 5 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1098-0121 EI 1550-235X J9 PHYS REV B JI Phys. Rev. B PD SEP 15 PY 1999 VL 60 IS 12 BP 8672 EP 8679 DI 10.1103/PhysRevB.60.8672 PG 8 WC Physics, Condensed Matter SC Physics GA 241EB UT WOS:000082868800048 ER PT J AU Ishima, R Freedberg, DI Wang, YX Louis, JM Torchia, DA AF Ishima, R Freedberg, DI Wang, YX Louis, JM Torchia, DA TI Flap opening and dimer-interface flexibility in the free and inhibitor-bound HIV protease, and their implications for function SO STRUCTURE LA English DT Article DE chemical exchange; dynamics; NMR; protein; relaxation ID VIRUS TYPE-1 PROTEASE; HUMAN-IMMUNODEFICIENCY; MOLECULAR-DYNAMICS; HUMAN-IMMUNODEFICIENCY-VIRUS-1 PROTEASE; RETROVIRAL PROTEASES; CRYSTAL-STRUCTURES; NMR-SPECTROSCOPY; CHEMICAL-SHIFT; TIME SCALES; RELAXATION AB Background: H-1 and N-15 transverse relaxation measurements on perdeuterated proteins are ideally suited for detecting backbone conformational fluctuations on the millisecond-microsecond timescale. The identification of conformational exchange on this timescale by measuring the relaxation of both H-1 and N-15 holds great promise for the elucidation of functionally relevant conformational changes in proteins. Results: We measured the transverse H-1 and N-15 relaxation rates of backbone amides of HIV-1 protease in its free and inhibitor-bound forms. An analysis of these rates, obtained as a function of the effective rotating frame field, provided information about the timescale of structural fluctuations in several regions of the protein. The flaps that cover the active site of the inhibitor-bound protein undergo significant changes of backbone (phi, psi) angles, on the 100 mu s timescale, in the free protein. In addition, the intermonomer beta-sheet interface of the bound form, which from protease structure studies appears to be rigid, was found to fluctuate on the millisecond timescale. Conclusions: We present a working model of the flap-opening mechanism in free HIV-1 protease which involves a transition from a semi-open to an open conformation that is facilitated by interaction of the Phe53 ring with the substrate. We also identify a surprising fluctuation of the beta-sheet intermonomer interface that suggests a structural requirement for maturation of the protease. Thus, slow conformational fluctuations identified by H-1 and N-15 transverse relaxation measurements can be related to the biological functions of proteins. C1 Natl Inst Dent & Cranofacial Res, Struct Mol Biol Unit, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Biophys Lab, Bethesda, MD 20892 USA. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Torchia, DA (reprint author), Natl Inst Dent & Cranofacial Res, Struct Mol Biol Unit, Bethesda, MD 20892 USA. EM torchia@yoda.nidr.nih.gov NR 53 TC 193 Z9 193 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD SEP 15 PY 1999 VL 7 IS 9 BP 1047 EP 1055 DI 10.1016/S0969-2126(99)80172-5 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 238BL UT WOS:000082691000007 PM 10508781 ER PT J AU Tjandra, N AF Tjandra, N TI Establishing a degree of order: obtaining high-resolution NMR structures from molecular alignment SO STRUCTURE WITH FOLDING & DESIGN LA English DT Article ID ORIENTED PHOSPHOLIPID MICELLES; LIQUID-CRYSTALLINE MEDIUM; PROTEIN-DNA COMPLEX; MAGNETIC ALIGNMENT; DIPOLAR COUPLINGS; CHEMICAL-SHIFTS; MACROMOLECULES; SPECTROSCOPY; INFORMATION; ANGLES C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Tjandra, N (reprint author), NHLBI, Biophys Chem Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 27 TC 24 Z9 27 U1 0 U2 6 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0969-2126 J9 STRUCT FOLD DES JI Struct. Fold. Des. PD SEP 15 PY 1999 VL 7 IS 9 BP R205 EP R211 DI 10.1016/S0969-2126(99)80167-1 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 238BL UT WOS:000082691000002 PM 10610262 ER PT J AU Villemagne, VL Wong, DF Yokoi, F Stephane, M Rice, KC Matecka, D Clough, DJ Dannals, RF Rothman, RB AF Villemagne, VL Wong, DF Yokoi, F Stephane, M Rice, KC Matecka, D Clough, DJ Dannals, RF Rothman, RB TI GBR12909 attenuates amphetamine-induced striatal dopamine release as measured by [C-11]raclopride continuous infusion PET scans SO SYNAPSE LA English DT Article DE neurochemical; methamphetamine; dopamine; amphetamine; PET; imaging ID C-11 RACLOPRIDE; NONHUMAN-PRIMATES; RAT-BRAIN; COCAINE; BINDING; INVIVO; HUMANS; MICRODIALYSIS; VOLUNTEERS; DEPENDENCE AB Major neurochemical effects of methamphetamine include release of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) via a carrier-mediated exchange mechanism. Preclinical research supports the hypothesis that elevations of mesolimbic DA mediate the addictive and reinforcing effects of methamphetamine and amphetamine. This hypothesis has not been adequately tested in humans. Previous in vivo rodent microdialysis demonstrated that the high affinity DA uptake inhibitor, GBR12909, attenuates cocaine- and amphetamine-induced increases in mesolimbic DA, The present study determined the ability of GBR12909 to attenuate amphetamine-induced increases in striatal DA as measured by [C-11]raclopride continuous infusion positron emission tomography (PET) scans in two Papio anubis baboons. [C-11]Raclopride was given in a continuous infusion paradigm resulting in a flat volume of distribution vs. time for up to 45 min postinjection. At that time, a 1.5 mg/kg amphetamine i.v, bolus was administered which caused a significant (30.3%) reduction in the volume of distribution (V-3") The percent reduction in the volume of distribution and, hence, a measure of the intrasynaptic DA release ranged between 22-41%. GBR12909 (1 mg/kg, slow i.v. infusion) was administered 90 min before the administration of the radiotracer. The comparison of the volume of distribution before and after administration of GBR12909 showed that GBR12909 inhibited amphetamine-induced DA release by 74%. These experiments suggest that GBR12909 is an important prototypical medication to test the hypothesis that stimulant-induced euphoria is mediated by DA and, if the DA hypothesis is correct, a potential treatment agent for cocaine and methamphetamine abuse, Furthermore, this quantitative approach demonstrates a way of testing various treatment medications, including other forms of GBR12909 such as a decanoate derivative. Synapse 33:268-273, 1999. (C) 1999 Wiley-Liss, Inc. C1 Johns Hopkins Med Inst, Dept Radiol, JHOC, Baltimore, MD 21287 USA. Johns Hopkins Med Inst, Dept Environm Hlth Sci, Baltimore, MD 21287 USA. Johns Hopkins Med Inst, Div Nucl Med, Baltimore, MD 21287 USA. Johns Hopkins Med Inst, Div Radiat Hlth Sci, Baltimore, MD 21287 USA. NIDDK, Med Chem Lab, NIH, Bethesda, MD 20892 USA. NIDA, Clin Psychopharmacol Sect, IRP, NIH, Baltimore, MD USA. RP Wong, DF (reprint author), Johns Hopkins Med Inst, Dept Radiol, JHOC, Room 3245,601 N Caroline St, Baltimore, MD 21287 USA. FU NIDA NIH HHS [DA11080, DA09482] NR 27 TC 46 Z9 47 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 0887-4476 J9 SYNAPSE JI Synapse PD SEP 15 PY 1999 VL 33 IS 4 BP 268 EP 273 DI 10.1002/(SICI)1098-2396(19990915)33:4<268::AID-SYN3>3.0.CO;2-W PG 6 WC Neurosciences SC Neurosciences & Neurology GA 221VN UT WOS:000081747800003 PM 10421707 ER PT J AU Cohen, RM Carson, RE Wyatt, RJ Doudet, DJ AF Cohen, RM Carson, RE Wyatt, RJ Doudet, DJ TI Opiate receptor avidity is reduced bilaterally in rhesus monkeys unilaterally lesioned with MPTP SO SYNAPSE LA English DT Article DE Parkinson's disease; neurodegeneration; positron emission tomography; basal ganglia; dopamine ID PARKINSONS-DISEASE PATIENTS; ENKEPHALIN GENE-EXPRESSION; DOPA-INDUCED DYSKINESIAS; EXCITATORY AMINO-ACID; RAT SUBSTANTIA-NIGRA; MESSENGER-RNA LEVELS; BASAL GANGLIA; MET-ENKEPHALIN; PRIMATE MODEL; HUMAN-BRAIN AB Opiate receptor avidity (unoccupied receptor density / the receptor dissociation constant), was measured in four animals with unilateral parkinsonian symptoms following MPTP ( 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) infusions into the internal carotid of one side, and nine normal controls with positron emission tomography (PET) and 6-deoxy-6-beta-[F-18] fluoronaltrexone (cyclofoxy, CF), a mu- and kappa-opiate receptor antagonist. PET studies of 6-[F-18] -L-fluoro-L-3,4-dihydroxyphenylalanine ([F-18]-DOPA) in these parkinsonian animals, although documenting the primarily unilateral nature of the lesion, also demonstrated a milder loss of dopaminergic on the side opposite the infusion. Opiate receptor avidity was found to be reduced by 20-34% in the caudate, anterior putamen, thalamus, and amygdala of these primarily unilaterally MPTP-exposed animals, bilaterally with no statistically significant differences between the two sides. The affected regions are the same as those previously demonstrated to have a 30-35% loss in clinically recovered bilaterally MPTP-lesioned animals. These findings confirm that the opiate pathway can change in response to modest decreases in basal ganglia dopamine innervation. Thus, opiate pathway adaptation is likely to contribute to the dynamic changes in basal ganglia circuits that forestall the initial clinical manifestations of Parkinson's disease. In addition, opiate pathway(s) may contribute to the treatment responsiveness and progression of the disease either directly through effects on basal ganglia function or indirectly through effects on basal ganglia plasticity. Synapse 33:282-288, 1999. (C) 1999 Wiley-Liss, Inc. C1 NIH, Cerebral Metab Lab, Bethesda, MD 20892 USA. NIH, PET Dept, Ctr Clin, Bethesda, MD 20892 USA. NIMH, Neuropsychiat Branch, Bethesda, MD 20892 USA. RP Cohen, RM (reprint author), NIH, Cerebral Metab Lab, Bldg 36,Room 1A05,36 Convent Dr,MSC 4030, Bethesda, MD 20892 USA. RI Carson, Richard/H-3250-2011 OI Carson, Richard/0000-0002-9338-7966 NR 64 TC 7 Z9 7 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 0887-4476 J9 SYNAPSE JI Synapse PD SEP 15 PY 1999 VL 33 IS 4 BP 282 EP 288 DI 10.1002/(SICI)1098-2396(19990915)33:4<282::AID-SYN5>3.0.CO;2-5 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 221VN UT WOS:000081747800005 PM 10421709 ER PT J AU LeBlanc, RA Pesnicak, L Godleski, M Straus, SE AF LeBlanc, RA Pesnicak, L Godleski, M Straus, SE TI Treatment of HSV-1 infection with immunoglobulin or acyclovir: Comparison of their effects on viral spread, latency, and reactivation SO VIROLOGY LA English DT Article ID HERPES-SIMPLEX VIRUS; PLACEBO-CONTROLLED TRIAL; GENITAL HERPES; ORAL ACYCLOVIR; DOUBLE-BLIND; TRIGEMINAL GANGLIA; ULTRAVIOLET-B; TYPE-1; ANTIBODY; NEURONS AB We compared immunoglobulin (IgG) and acyclovir (ACV) therapies on the establishment, maintenance, and reactivation from latency of HSV-1(McKrae) in a mouse ocular infection model. Mice were given one intraperitoneal (IP) dose of human IgG 24 h after infection (Day 1 p,i.) or ACV in the drinking water from Days 1 to 7 p.i. Both treatments allowed similar percentages of mice to survive the infection and decreased ocular virus shedding as compared with untreated controls. At most time points, there were no differences between IgG- and ACV-treated animals with respect to tissue virus titers or in the rates of virus reactivation during explant cocultivation. However, after ultraviolet exposure, HSV reactivated in 30% of ACV-treated mice compared with 90% of IgG-treated mice (P = 0.02). Also by quantitative PCR, we found more latent HSV-1 DNA copies in IgG-treated mice compared with those given ACV (P = 0.02). IgG treatment protects mice from HSV-1 infection essentially as well as ACV does. Nonetheless, it permits higher levels of latent infection and subsequent in vivo reactivation. These studies have implications for the mechanism by which IgG functions to attenuate HSV infections and for its potential value as a therapeutic agent in humans. C1 NIH, Med Virol Sect, Clin Invest Lab, Bethesda, MD 20892 USA. RP Straus, SE (reprint author), 10 Ctr Dr,Rm 11N228, Bethesda, MD 20892 USA. NR 30 TC 15 Z9 16 U1 0 U2 1 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 SEP 15 PY 1999 VL 262 IS 1 BP 230 EP 236 DI 10.1006/viro.1999.9891 PG 7 WC Virology SC Virology GA 240DY UT WOS:000082811700022 PM 10489356 ER PT J AU Yanagi, M Purcell, RH Emerson, SU Bukh, J AF Yanagi, M Purcell, RH Emerson, SU Bukh, J TI Hepatitis C virus: An infectious molecular clone of a second major genotype (2a) and lack of viability of intertypic 1a and 2a chimeras SO VIROLOGY LA English DT Article ID VIRAL DIARRHEA VIRUS; TICK-BORNE ENCEPHALITIS; DENGUE TYPE-4 VIRUSES; GENETIC ORGANIZATION; FLAVIVIRUS KUNJIN; E2-NS2 REGION; CDNA CLONE; RNA; SEQUENCE; GENOME AB Of the six major genotypes of hepatitis C virus (HCV), infectious cDNA clones of only genotype 1 have been reported. Here, we report the construction of an infectious cDNA clone representing a second major HCV genotype, genotype 2. This infectious clone (pJ6CF) encodes the consensus polyprotein of strain HC-J6(CH), genotype 2a. Its encoded polyprotein differs from those of the infectious clones of genotypes la and Ib by approximately 30%. Intertypic chimeric cDNA clones constructed from infectious clones of genotypes la and 2a of HCV were not infectious. RNA transcripts of four chimeras containing the 2a structural genes (C, E1, and 52) in the backbone of an infectious genotype 1a clone (pCV-H77C) were not viable in a chimpanzee regardless of whether p7 was from the 1a or 2a clone. However, the chimpanzee was subsequently infected with RNA transcripts of each of the two infectious parent clones, indicating that the inability of the chimeras to replicate was intrinsic to the clones and not the result of preexisting protective immune responses. C1 NIAID, NIH, LID, Hepatitis Viruses Sect, Bethesda, MD 20892 USA. NIAID, Mol Hepatitis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Bukh, J (reprint author), NIAID, NIH, LID, Hepatitis Viruses Sect, Bldg 7,Room 201,7 Ctr Dr,MSC 0740, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CO-56000]; NIAID NIH HHS [N01-AI-45180, N01-AI-52705] NR 52 TC 137 Z9 147 U1 1 U2 5 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 SEP 15 PY 1999 VL 262 IS 1 BP 250 EP 263 DI 10.1006/viro.1999.9889 PG 14 WC Virology SC Virology GA 240DY UT WOS:000082811700024 PM 10489358 ER PT J AU Xiao, B Singh, SP Nanduri, B Awasthi, YC Zimniak, P Ji, XH AF Xiao, B Singh, SP Nanduri, B Awasthi, YC Zimniak, P Ji, XH TI Crystal structure of a murine glutathione S-transferase in complex with a glutathione conjugate of 4-hydroxynon-2-enal in one subunit and glutathione in the other: Evidence of signaling across the dimer interface SO BIOCHEMISTRY LA English DT Article ID LIPID-PEROXIDATION PRODUCT; HETEROLOGOUS EXPRESSION; 3-DIMENSIONAL STRUCTURE; CELL-PROLIFERATION; OXIDATIVE STRESS; ACTIVE-SITE; ALDEHYDES; ENZYME; CDNA; 4-HYDROXYALKENALS AB mGSTA4-4, a murine glutathione S-transferase (GST) exhibiting high activity in conjugating the lipid peroxidation product 4-hydroxynon-2-enal (4-HNE) with glutathione (GSH), was crystallized in complex with the GSH conjugate of 4-HNE (GS-Hna). The structure has been solved at 2.6 Angstrom resolution, which reveals that the active site of one subunit of the dimeric enzyme binds GS-Hna, whereas the other binds GSH. A marked asymmetry between the two subunits is evident. Most noticeable are the differences in the conformation of arginine residues 69 and 15, In all GST structures published previously, the guanidino groups of R69 residues from both subunits stack at the dimer interface and are related by a (pseudo-) 2-fold axis. In the present structure of mGSTA4-4, however, the two R69 side chains point in opposite directions, although their guanidino groups remain in contact. In the subunit with bound GSH, R69 also interacts with R15, and the guanidino group of R15 points away from the active site, whereas in the subunit that binds GS-Hna, R15 pivots into the active site, which breaks its interaction with R69, According to our previous results [Nanduri et al. (1997) Arch. Biochem. Biophys. 335, 305-310], the availability of R15 in the active site assists the conjugation of 4-HNE with GSH. We propose a model for the catalytic mechanism of mGSTA4-4 in conjugating 4-HNE with GSH-i.e., the guanidino group of R15 is available in the active site of only one subunit at any given time and the stacked pair of R69 residues act as a switch that couples the concerted movement of the two R15 side chains. The alternate occupancy of 4-HNE in the two subunits has been confirmed by our kinetic analysis that shows the negative cooperativity of mGSTA4-4 for 4-HNE. Disruption of the signaling between the subunits by mutating the R69 residues released the negative cooperativity with 4-HNE. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. Univ Arkansas Med Sci, Dept Internal Med, Little Rock, AR 72205 USA. Univ Arkansas Med Sci, Dept Biochem & Mol Biol, Little Rock, AR 72205 USA. John L McClellan Mem Vet Hosp, Little Rock, AR 72205 USA. Univ Texas, Med Branch, Dept Human Biol Chem & Genet, Galveston, TX 77555 USA. RP Zimniak, P (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, POB B, Frederick, MD 21702 USA. RI Ji, Xinhua/C-9664-2012 OI Ji, Xinhua/0000-0001-6942-1514 FU NCI NIH HHS [CA27967]; NIEHS NIH HHS [ES07804] NR 55 TC 47 Z9 48 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 SEP 14 PY 1999 VL 38 IS 37 BP 11887 EP 11894 DI 10.1021/bi990468i PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 240PR UT WOS:000082834800004 PM 10508391 ER PT J AU Gakamsky, DM Boyd, LF Margulies, DH Davis, DM Strominger, JL Pecht, I AF Gakamsky, DM Boyd, LF Margulies, DH Davis, DM Strominger, JL Pecht, I TI An allosteric mechanism controls antigen presentation by the H-2K(b) complex SO BIOCHEMISTRY LA English DT Article ID SURFACE-PLASMON RESONANCE; CLASS-I MOLECULES; T-CELL RECEPTOR; PEPTIDE BINDING; CRYSTAL-STRUCTURE; MHC MOLECULES; BETA-2-MICROGLOBULIN; BETA(2)-MICROGLOBULIN; CONFORMATION; AFFINITY AB The mechanism of assembly/dissociation of a recombinant water-soluble class I major histocompatibility complex (MHC) H-2K(b) molecule was studied by a real-time fluorescence resonance energy transfer method. Like the H-2K(d) ternary complex [Gakamsky et al, (1996) Biochemistry, 35, 14841-14848], the interactions among the heavy chain, beta(2)-microglobulin (beta(2)m), and antigenic peptides were found to be controlled by an allosteric mechanism. Association of the heavy chain with beta(2)m increased peptide binding rate constants by more than 2 orders of magnitude and enhanced affinity of the heavy-chain molecule for peptides, Interaction of peptides with the heavy-chain binding site, in turn, increased markedly the affinity of the heavy chain for beta(2)m. Binding of peptide variants of the ovalbumin sequence (257-264) to the heavy chain/beta(2)m heterodimer was found to be a biphasic reaction. The fast phase was a second-order process with nearly the same rate constants as those of binding of peptides derived from the influenza virus nucleoprotein 147-155 to the H-2K(d) heavy chain/beta(2)m heterodimer [(3.0 +/- 1.0) x 10(-6) M-1 s(-1) at 37 degrees C]. The slow phase was a result of both the ternary complex assembly from the "free" heavy chain, beta(2)m, and peptide as well as an intramolecular conformational transition within the heavy chain/beta(2)m heterodimer to a peptide binding conformation. Biexponential kinetics of peptide or beta(2)m dissociation from the ternary complex were observed. They suggest that it can exist in two conformations. The rate constants of beta(2)m dissociation from the H-2K(b) ternary complex were, in the limits of experimental accuracy, independent of the structure of the bound peptide, though their affinities differed by an order of magnitude. Dissociation of peptides from the K-b heavy chain was always faster than from the ternary complexes, yet the heavy chain/peptide complexes were considerably more stable compared with their K-d/nucleoprotein peptide counterparts. C1 Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel. NIAID, Mol Biol Sect, NIH, Bethesda, MD 20892 USA. Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. RP Gakamsky, DM (reprint author), Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel. RI Gakamsky, Dmitry/H-6947-2013; Margulies, David/H-7089-2013; OI Margulies, David/0000-0001-8530-7375 NR 39 TC 22 Z9 23 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 SEP 14 PY 1999 VL 38 IS 37 BP 12165 EP 12173 DI 10.1021/bi9905821 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 240PR UT WOS:000082834800034 PM 10508421 ER PT J AU Leppala, JM Paunio, M Virtamo, J Fogelholm, R Albanes, D Taylor, PR Heinonen, OP AF Leppala, JM Paunio, M Virtamo, J Fogelholm, R Albanes, D Taylor, PR Heinonen, OP TI Alcohol consumption and stroke incidence in male smokers SO CIRCULATION LA English DT Article DE alcohol; blood pressure; HDL cholesterol; stroke ID HIGH-DENSITY-LIPOPROTEIN; CORONARY HEART-DISEASE; RISK-FACTORS; CIGARETTE-SMOKING; INTRACEREBRAL HEMORRHAGE; SUBARACHNOID HEMORRHAGE; ETHANOL INTOXICATION; BRAIN INFARCTION; ISCHEMIC STROKE; CHOLESTEROL AB Background-Studies on alcohol consumption and incidences of stroke subtypes have suggested distinct dose-response relationships. Blood pressure and HDL cholesterol mediate the effect of alcohol on coronary heart disease, but similar evidence on cerebrovascular diseases is not available. Methods and Results-We studied the risk of stroke in 26 556 male cigarette smokers 50 to 69 years of age without history of stroke. The men were categorized as nondrinkers, light (less than or equal to 24 g/d), moderate (25 to 60 g/d), or heavy (>60 g/d) drinkers. A total of 960 men suffered from incident stroke: 83 with subarachnoid and 95 with intracerebral hemorrhage, 733 with cerebral infarction, and 49 with unspecified stroke. The adjusted relative risk of subarachnoid hemorrhage was 1.0 in light drinkers, 1.3 in moderate drinkers, and 1.6 in heavy drinkers compared with nondrinkers. The respective relative risks of intracerebral hemorrhage were 0.8, 0.6, and 1.8; of cerebral infarction, 0.9, 1.2, and 1.5. Systolic blood pressure attenuated the effect of alcohol consumption in all subtypes of stroke, whereas HDL cholesterol strengthened the effect of alcohol in subarachnoid hemorrhage and cerebral infarction but attenuated the effect in intracerebral hemorrhage. Conclusions-Alcohol consumption may have a distinct dose-response relationship within each stroke subtype-linear in subarachnoid hemorrhage, U-shaped in intracerebral hemorrhage, and J-shaped in cerebral infarction-but further studies are warranted. Systolic blood pressure and HDL cholesterol seem to mediate the effect of alcohol on stroke incidence, but evidently additional mechanisms are involved. C1 Univ Helsinki, Dept Publ Hlth, FIN-00014 Helsinki, Finland. Univ Helsinki, Cent Hosp, Dept Clin Neurosci, Helsinki, Finland. Natl Canc Inst, Bethesda, MD USA. RP Leppala, JM (reprint author), Univ Helsinki, Dept Publ Hlth, POB 41,Mannerheimintie 172, FIN-00014 Helsinki, Finland. RI Albanes, Demetrius/B-9749-2015 FU NCI NIH HHS [N01-CN-45165] NR 42 TC 59 Z9 60 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 14 PY 1999 VL 100 IS 11 BP 1209 EP 1214 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 235FD UT WOS:000082528900012 PM 10484542 ER PT J AU Stern, MD AF Stern, MD TI Emergence of homeostasis and "noise imprinting" in an evolution model SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GENETIC ALGORITHMS; NETWORKS; COMPUTATION; AUTOMATA AB Homeostasis, the creation of a stabilized internal milieu, is ubiquitous in biological evolution, despite the entropic cost of excluding noise information from a region. The advantages of stability seem self evident, but the alternatives are not so clear. This issue was studied by means of numerical experiments on a simple evolution model: a population of Boolean network "'organisms" selected for performance of a curve-fitting task while subjected to noise. During evolution, noise sensitivity increased with fitness. Noise exclusion evolved spontaneously, but only if the noise was sufficiently unpredictable. Noise that was limited to one or a few stereotyped patterns caused symmetry breaking that prevented noise exclusion, Instead, the organisms incorporated the noise into their function at little cost in ultimate fitness and became totally noise dependent. This "noise imprinting" suggests caution when interpreting apparent adaptations seen in nature. If the noise was totally random from generation to generation, noise exclusion evolved reliably and irreversibly, but if the noise was correlated over several generations, maladaptive selection of noise-dependent traits could reverse noise exclusion, with catastrophic effect on population fitness. Noise entering the selection process rather than the organism had a different effect: adaptive evolution was totally abolished above a critical noise amplitude, in a manner resembling a thermodynamic phase transition. Evolutionary adaptation to noise involves the creation of a subsystem screened from noise information but increasingly vulnerable to its effects. Similar considerations may apply to information channeling in human cultural evolution. C1 NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM sternm@grc.nia.nih.gov FU NIAMS NIH HHS [AR41526] NR 28 TC 37 Z9 38 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 SEP 14 PY 1999 VL 96 IS 19 BP 10746 EP 10751 DI 10.1073/pnas.96.19.10746 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 235ZQ UT WOS:000082574100043 PM 10485897 ER PT J AU Cohen, SS Li, C Ding, LN Cao, YZ Pardee, AB Shevach, EM Cohen, DI AF Cohen, SS Li, C Ding, LN Cao, YZ Pardee, AB Shevach, EM Cohen, DI TI Pronounced acute immunosuppression in vivo mediated by HIV Tat challenge SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVATION-INDUCED APOPTOSIS; GP120 ENVELOPE GLYCOPROTEIN; PROGRAMMED CELL-DEATH; TRANSGENIC MICE; T-CELLS; FAS-LIGAND; PROTEIN; INFECTION; TYPE-1 AB HIV infection is accompanied by an early immune dysfunction limiting host control of virus and likely contributing to difficulties in achieving a successful vaccine against HIV. We report here that the HIV Tat protein is strongly immunosuppressive, both immediately after immunization of mice with soluble protein (sTat), and in seroconverting humans, and propose that Tat-induced suppression cripples immune surveillance to HIV infection. We show that macrophages are sensitive to sTat stimulation at concentrations 1,000-fold lower (500 pM) than T cells, and this stimulation is accompanied by the immunosuppressive induction of Fas ligand on the macrophage. T cell proliferative defects induced by sTat in vitro can be completely (at lower concentrations of sTat) or partially (at higher concentrations) reversed by antagonists to Fas/Fas ligand interaction. We further report a method to preserve immunogenicity while inactivating Tat immunosuppression through oxidation, which advances the use of oxidized Tat as a component of an anti-HIV vaccine. These observations define additional methods to study the immunosuppressive functions of sTat that now may be rapidly applied to primary isolates from individuals with differing clinical courses. Our Endings have immediate relevance for vaccine development, by describing and supporting a strategy that includes inactivated sTat in a multicomponent, anti-HIV vaccine. C1 Queens Coll, Bernard & Gloria Salick Ctr Mol & Cellular Biol, Flushing, NY 11367 USA. NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Rockefeller Univ, Aaron Diamond Res Ctr, New York, NY 10016 USA. RP Cohen, DI (reprint author), Queens Coll, Bernard & Gloria Salick Ctr Mol & Cellular Biol, Remsen Hall 117, Flushing, NY 11367 USA. NR 33 TC 85 Z9 85 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 SEP 14 PY 1999 VL 96 IS 19 BP 10842 EP 10847 DI 10.1073/pnas.96.19.10842 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 235ZQ UT WOS:000082574100059 PM 10485913 ER PT J AU Shapiro, MS Loose, MD Hamilton, SE Nathanson, NM Gomeza, J Wess, J Hille, B AF Shapiro, MS Loose, MD Hamilton, SE Nathanson, NM Gomeza, J Wess, J Hille, B TI Assignment of muscarinic receptor subtypes mediating G-protein modulation of Ca2+ channels by using knockout mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RAT SYMPATHETIC NEURONS; BETA-GAMMA-SUBUNITS; CALCIUM CHANNELS; N-TYPE; PERIPHERAL NEURONS; TARGETED DISRUPTION; VOLTAGE DEPENDENCE; CURRENT INHIBITION; GANGLION NEURONS; K+ CURRENT AB There are five known subtypes of muscarinic receptors (M-1-M-5) We have used knockout mice lacking the M-1, M-2, or M-4 receptors to determine which subtypes mediate modulation of voltage-gated Ca2+ channels in mouse sympathetic neurons. Muscarinic agonists modulate N- and L-type Ca2+ channels in these neurons through two distinct G-protein-mediated mechanisms. One pathway is fast and membrane-delimited and inhibits N- and P/Q-type channels by shifting their activation to more depolarized potentials. The other is slow and voltage-independent and uses a diffusible cytoplasmic messenger to inhibit both Ca2+ channel types. Using patch-clamp methods on acutely dissociated sympathetic neurons, we isolated each pathway by pharmacological and kinetic means and found that each one is nearly absent in a particular knockout mouse. The fast and voltage-dependent pathway is lacking in the M-2 receptor knockout mice; the slow and voltage-independent pathway is absent from the M-1 receptor knockout mice; and neither pathway is affected in the Mg receptor knockout mice. The knockout effects are clean and are apparently not accompanied by compensatory changes in other muscarinic receptors. C1 Univ Washington, Sch Med, Dept Physiol & Biophys, Seattle, WA 98195 USA. Univ Washington, Sch Med, Dept Pharmacol, Seattle, WA 98195 USA. Oberlin Coll, Neurosci Program, Oberlin, OH 44074 USA. NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Hille, B (reprint author), Univ Washington, Sch Med, Dept Physiol & Biophys, Box 357290, Seattle, WA 98195 USA. FU NIDA NIH HHS [DA11322, R01 DA011322]; NINDS NIH HHS [NS08174, NS26920, R01 NS008174, R01 NS026920, R37 NS008174] NR 52 TC 81 Z9 85 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 SEP 14 PY 1999 VL 96 IS 19 BP 10899 EP 10904 DI 10.1073/pnas.96.19.10899 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 235ZQ UT WOS:000082574100069 PM 10485923 ER PT J AU Floeter, MK Rothwell, JC AF Floeter, MK Rothwell, JC TI Releasing the brakes before pressing the gas pedal SO NEUROLOGY LA English DT Editorial Material ID TRANSCRANIAL MAGNETIC STIMULATION; HUMAN MOTOR CORTEX; CORTICOCORTICAL INHIBITION; EXCITABILITY C1 NINDS, EMG Sect, NIH, Bethesda, MD 20892 USA. RP Floeter, MK (reprint author), NINDS, EMG Sect, NIH, 10 Ctr Dr,MSC-1404, Bethesda, MD 20892 USA. OI Rothwell, John/0000-0003-1367-6467 NR 9 TC 44 Z9 44 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP 11 PY 1999 VL 53 IS 4 BP 664 EP 665 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 235BF UT WOS:000082518300002 PM 10489022 ER PT J AU Nash, TE Patronas, NJ AF Nash, TE Patronas, NJ TI Edema associated with calcified lesions in neurocysticercosis SO NEUROLOGY LA English DT Article DE cysticercosis; seizure; Taenia solium; MRI ID PARTIAL STATUS EPILEPTICUS; CEREBRAL CYSTICERCOSIS; EPILEPSY; SEIZURES AB Objective: To determine serial MRI and CT abnormalities around calcified cysts due to cysticercosis in previously treated patients during periods of seizure activity. Background: Some patients with calcified lesions due to cysticercosis have seizures. How and why seizures occur in this setting are unknown, Methods: Three patients with known, treated cysticercosis were studied prospectively by serial MRI and CT before, during, and after seizure activity. Results: All three patients demonstrated edema surrounding calcified lesions. Two of three patients had repeated episodes involving the same calcified lesions, and their symptoms corresponded to the location of the lesion. Enhancement was present in the lesions demonstrating edema, but was also present surrounding other nonsymptomatic calcified lesions. Conclusions: Perilesional edema surrounding calcified lesions due to cysticercosis occurs in some patients at the time of seizure activity. Repeated seizure episodes tend to be associated with the same lesions. Although the mechanisms involved are unknown, long-term antiseizure medication is likely indicated in these patients. Current evidence does not support the use of specific antiparasitic treatment in these patients. C1 NIAPD, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Nash, TE (reprint author), NIAPD, Parasit Dis Lab, NIH, Bldg 4,Room B1-06, Bethesda, MD 20892 USA. NR 26 TC 47 Z9 47 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP 11 PY 1999 VL 53 IS 4 BP 777 EP 781 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 235BF UT WOS:000082518300020 PM 10489040 ER PT J AU Sanchez-Pernaute, R Garcia-Segura, JM Alba, AD Viano, J de Yebenes, JG AF Sanchez-Pernaute, R Garcia-Segura, JM Alba, AD Viano, J de Yebenes, JG TI Clinical correlation of striatal H-1 MRS changes in Huntington's disease SO NEUROLOGY LA English DT Article DE proton MRS; Huntington's disease; striatum ID BASAL GANGLIA VOLUME; TRINUCLEOTIDE REPEAT LENGTH; ENERGY-METABOLISM; H-1-NMR SPECTROSCOPY; IMPAIRMENT; DYSFUNCTION; INCLUSIONS; PRIMATES; ATROPHY; ONSET AB Objective: To study the clinical significance of metabolic alterations as measured in vivo with proton MRS in the striatum of patients with Huntington's disease (HD). Methods: Localized, single-Troxel MRS was performed on the basal ganglia of 10 HD patients (4 presymptomatic gene carriers and 6 akinetic patients) and 5 age-matched healthy individuals. Metabolite quantification was pet-formed by referring the areas of the respective spectral peaks to that of water in the analyzed voxel. The spectroscopic findings were correlated with motor and cognitive performance in several specific tests and with the length of the CAG repeat expansion normalized for age. Results. N-acetylaspartate (NAA) and creatine were reduced markedly in both groups of patients, particularly in the advanced group (approximately 60%), but the decrease was also significant in presymptomatic patients (approximately 30%) whose motor and cognitive performances were within the normal range. Both metabolites correlated highly with the motor score of the Unified Hunting ton's Disease Rating Scale and with computed measurements of saccadic and tapping speed, Creatine reduction was also well correlated with performance in cognitive timed tasks and with the length of CAG expansion (r = -0.81). Conclusion: The creatine signal appears to be an interesting marker for progression in HD and could be useful in assessing therapeutic outcome, particularly during the initial stages when most clinical indices are still within the normal range. C1 Univ Autonoma Madrid, Fdn Jimenez Diaz, Dept Neurol, Madrid, Spain. Clin NS del Rosario, Neuroradiol Unit, Madrid, Spain. Univ Complutense Madrid, Fac Biol, Dept Biochem & Mol Biol, Madrid, Spain. RP Sanchez-Pernaute, R (reprint author), NINDS, Lab Mol Med & Neurosci, Bldg 36,Room 5W21 36,Convent Dr, Bethesda, MD 20892 USA. RI GARCIA-SEGURA, JUAN MANUEL/H-8215-2015 OI GARCIA-SEGURA, JUAN MANUEL/0000-0003-2616-8154 NR 40 TC 69 Z9 70 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP 11 PY 1999 VL 53 IS 4 BP 806 EP 812 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 235BF UT WOS:000082518300025 PM 10489045 ER PT J AU Anastos, K Kalish, LA Hessol, N Weiser, B Melnick, S Burns, D Delapenha, R DeHovitz, J Cohen, M Meyer, W Bremer, J Kovacs, A AF Anastos, K Kalish, LA Hessol, N Weiser, B Melnick, S Burns, D Delapenha, R DeHovitz, J Cohen, M Meyer, W Bremer, J Kovacs, A TI The relative value of CD4 cell count and quantitative HIV-1 RNA in predicting survival in HIV-1-infected women: results of the women's interagency HIV study SO AIDS LA English DT Article DE HIV; survival; women; HIV-1 RNA; CD4 cell count ID IMMUNODEFICIENCY-VIRUS TYPE-1; PLASMA VIRAL LOAD; LYMPHOCYTE COUNTS; CUBIC MILLIMETER; PROGNOSTIC VALUE; INFECTION; AIDS; DISEASE; MARKERS; PROGRESSION AB Objectives: To determine factors associated with survival and to assess the relative strength of CD4 cell count and HIV-1 RNA in predicting survival in a cohort of HIV 1-infected women. Design: Prospective cohort, enrolled during 1994-1995, with median follow-up of 29 months Results: Of 1769 HIV-infected women 252 died. In multivariate analyses, lower CD4 cell count, higher quantitative plasma HIV-1 RNA, and the presence of a self-reported AIDS-defining (Class C) condition were significantly associated with shorter survival: the relative hazard (RH) of dying was 1.17, 3.27, and 8.46, respectively for women with baseline CD4 cell count of 200-349, 50-199, and < 50 x 10(6) cells/l, compared with women with CD4 cell count of greater than or equal to 350 x 10(6) cells/l. Compared with women with HIV-1 RNA levels of < 4000 copies/ml plasma, the RH of dying for women with baseline quantitative HIV-1 RNA:measurements of 4000-20 000, 20 000-100 000, 100 000-500 000 and > 500 000 copies/ml, was 2.19, 2.17, 3.16, and 7.25, respectively. CD4 cell count had as strong a prognostic value as HIV-1 RNA level, particularly among participants with more advanced immunodeficiency. When the analysis was adjusted to eliminate the distortion created by having disproportionately sized strata of the categorized variables, the relative hazard of death associated with CD4 cell count became even larger in comparison with that for HIV-1 RNA. Eliminating from the analysis all follow up time during which participants could have received highly active antiretroviral therapy did not change these findings. Age was not a predictor of survival after adjustment for covariates. Conclusions: CD4 cell count and HIV-1 RNA had similar prognostic value in this cohort of HIV-1-infected women. Even in the presence of a low viral burden, a substantially decreased CD4 cell count remained a strong predictor of mortality. (C) 1999 Lippincott Williams & Wilkins. C1 Montefiore Med Ctr, Bronx, NY 10467 USA. New England Res Inst, Watertown, MA 02172 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. New York State Dept Hlth, Wadsworth Ctr, Albany, NY USA. NCI, Bethesda, MD 20892 USA. NICHHD, Bethesda, MD 20892 USA. Howard Univ, Sch Med, Washington, DC 20059 USA. SUNY Hlth Sci Ctr, Brooklyn, NY 11203 USA. Cook Cty Hosp, Chicago, IL 60612 USA. Quest Diagnost, Baltimore, MD USA. Rush Med Coll, Chicago, IL 60612 USA. Univ So Calif, Los Angeles, CA USA. RP Anastos, K (reprint author), Catholic Med Ctr Brooklyn & Queens Inc, Primary Care & Ambulatory Serv, 88-25 153rd St, Jamaica, NY 11432 USA. FU NIAID NIH HHS [U01-AI-31834, U01-AI-34994, U01-AI-35004] NR 41 TC 47 Z9 47 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 10 PY 1999 VL 13 IS 13 BP 1717 EP 1726 DI 10.1097/00002030-199909100-00016 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 236NF UT WOS:000082604900016 PM 10509574 ER PT J AU Agarwala, R Biesecker, LG Tomlin, JF Schaffer, AA AF Agarwala, R Biesecker, LG Tomlin, JF Schaffer, AA TI Towards a complete North American Anabaptist genealogy: A systematic approach to merging partially overlapping genealogy resources SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE autosomal recessive inheritance; Amish; Mennonite; consanguinity; inbreeding ID OLD ORDER AMISH; PEDIGREES AB Genetic studies on closed populations benefit from comprehensive, searchable genealogy resources. To support studies of Anabaptists, a computerized database has been developed that merges two large genealogy books, the "Fisher Family History" and the "Amish and Amish Mennonite Genealogies." The former is more current but the latter is more comprehensive for the 18th and 19th centuries. Therefore, the merger of the two books is significantly more useful than either book alone. We demonstrate the utility of the merged database with two results: an increase in inbreeding coefficients and the identification of parent-child relationships that do not exist in either book. Published 1999 Wiley-Liss, Inc.(dagger). C1 NHGRI, Inherited Dis Res Branch, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Genet Dis Res Branch, NIH, Bethesda, MD USA. NIH, Ctr Informat Technol, Computat Biosci & Engn Lab, Bethesda, MD USA. RP Biesecker, LG (reprint author), NHGRI, Inherited Dis Res Branch, NIH, 49 Convent Dr,Room 4A80, Bethesda, MD 20892 USA. RI Schaffer, Alejandro/F-2902-2012 NR 11 TC 23 Z9 23 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD SEP 10 PY 1999 VL 86 IS 2 BP 156 EP 161 DI 10.1002/(SICI)1096-8628(19990910)86:2<156::AID-AJMG13>3.0.CO;2-5 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 229HF UT WOS:000082186900013 PM 10449652 ER PT J AU Pedone, PV Pikaart, MJ Cerrato, F Vernucci, M Ungaro, P Bruni, CB Riccio, A AF Pedone, PV Pikaart, MJ Cerrato, F Vernucci, M Ungaro, P Bruni, CB Riccio, A TI Role of histone acetylation and DNA methylation in the maintenance of the imprinted expression of the H19 and Igf2 genes SO FEBS LETTERS LA English DT Article DE histone acetylation; DNA methylation; genomic imprinting; insulin-like growth factor-2; H19; histone deacetylase inhibitors ID FACTOR-II GENE; TRANSCRIPTIONAL REPRESSION; DEVELOPMENTAL CONTROL; CHROMATIN STRUCTURE; HUMAN CANCER; MOUSE; ALLELE; ACTIVATION; RELAXATION; RHABDOMYOSARCOMA AB H19 and Ig Igf2 are linked and reciprocally imprinted genes. We demonstrate that the histones associated with the paternally inherited and unexpressed H19 allele are less acetylated than those associated with the maternal expressed allele. Cell growth in the presence of inhibitors of either histone deacetylase or DNA methylation activated the silent Igf2 allele, whereas derepression of the silent H19 allele required combined inhibition of DNA methylation and histone deacetylation. Our results indicate that histone acetylation as well as DNA methylation contribute to the somatic maintenance of H19 and Igf2 imprinting and that silencing of the imprinted alleles of these two genes is maintained via distinct mechanisms. (C) 1999 Federation of European Biochemical Societies. C1 Univ Naples 2, Dipartimento Sci Ambientali, I-81100 Caserta, Italy. Univ Naples, Ctr Endocrinol & Oncol Sperimentale, CNR, Dipartimento Biol & Patol Cellulare & Mol, I-80131 Naples, Italy. NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Riccio, A (reprint author), Univ Naples 2, Dipartimento Sci Ambientali, Via Arena 22, I-81100 Caserta, Italy. RI Cerrato, Flavia/O-8315-2015; OI Cerrato, Flavia/0000-0003-3794-3021; Riccio, Andrea/0000-0001-7990-3576 NR 40 TC 59 Z9 61 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD SEP 10 PY 1999 VL 458 IS 1 BP 45 EP 50 DI 10.1016/S0014-5793(99)01124-2 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 236UH UT WOS:000082617200010 PM 10518931 ER PT J AU Jiang, H Takeda, K Lazarovici, P Katagiri, Y Yu, ZX Dickens, G Chabuk, A Liu, XW Ferrans, V Guroff, G AF Jiang, H Takeda, K Lazarovici, P Katagiri, Y Yu, ZX Dickens, G Chabuk, A Liu, XW Ferrans, V Guroff, G TI Nerve growth factor (NGF)-induced calcium influx and intracellular calcium mobilization in 3T3 cells expressing NGF receptors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AFFINITY NEUROTROPHIN RECEPTOR; FACTOR-INDUCED INCREASE; PC12 CELLS; SIGNAL-TRANSDUCTION; NEURONAL DIFFERENTIATION; RAT PHEOCHROMOCYTOMA; CHROMAFFIN CELLS; FIBER OUTGROWTH; TRK RECEPTORS; RELEASE AB The neurotrophins have been implicated in the acute regulation of synaptic plasticity. Neurotrophin-stimulated presynaptic calcium uptake appears to play a key role in this process. To understand the mechanism of neurotrophin-stimulated calcium uptake, the regulation of calcium uptake and intracellular mobilization by nerve growth factor (NGF) was investigated using NCH 3T3 cells stably transfected with either the high affinity NGF receptor p140(trk) (3T3-Trk) or the low affinity NGF receptor p75(NGFR) (3T3-p75). In 3T3-Trk cells, NGF increased both calcium uptake and intracellular calcium mobilization. In 3T3-p75 cells, NGF increased calcium uptake but not intracellular calcium mobilization. K-252a alone increased intracellular calcium in 3T3-Trk cells but not in 3T3-p75 cells. Nifedipine, an inhibitor of calcium uptake through L-type calcium channels, inhibited the action of NGF on both 3T3-Trk cells and 3T3-p75 cells, indicating that both p140(trk) and p75NGFR receptors are linked to nifedipine-sensitive L-type calcium channels. These studies show that either NGF receptor will support increases in intracellular calcium but that p140(trK) does so by increasing both uptake and mobilization, whereas p75NGFR does so by increasing uptake only. C1 NICHHD, Growth Factors Sect, NIH, Bethesda, MD 20892 USA. NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. RP Jiang, H (reprint author), Henry Ford Hlth Sci Ctr, William T Gossett Neurol Labs, 1 Ford Pl,4D Res, Detroit, MI 48202 USA. NR 57 TC 28 Z9 28 U1 2 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 10 PY 1999 VL 274 IS 37 BP 26209 EP 26216 DI 10.1074/jbc.274.37.26209 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 234DR UT WOS:000082469700040 PM 10473574 ER PT J AU Adam, L Bouvier, M Jones, TLZ AF Adam, L Bouvier, M Jones, TLZ TI Nitric oxide modulates beta(2)-adrenergic receptor palmitoylation and signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BETA-ADRENERGIC-RECEPTOR; HUMAN BETA-2-ADRENERGIC RECEPTOR; PROTEIN-ALPHA-SUBUNIT; MAMMALIAN HEART-RATE; SYNTHASE INHIBITION; MEMBRANE ATTACHMENT; BINDING; PHOSPHORYLATION; STIMULATION; ACTIVATION AB To determine whether nitric oxide (NO) modulates the beta-adrenergic signaling pathway, we treated cells expressing beta(2)-adrenergic receptors (beta(2)AR) with the NO donors, 3-morpholinosydnonimine (SIN-1) and 1,2,3,4-oxatriazolium,5-amino-3-(3-chloro-2-meth chloride and determined the intracellular production of cAMP after exposure to beta-adrenergic receptor agonists, cholera toxin and forskolin. NO significantly decreased the potency of the beta-adrenergic agonist, isoproterenol, to stimulate cAMP production without affecting the stimulatory action of forskolin and cholera toxin, which directly activate adenylyl cyclase and G(s), respectively. Treatment with the NO donor increased the guanyl nucleotide-sensitive high affinity constant for the agonist, isoproterenol, thus suggesting that it reduced functional coupling between the receptor and G(s). Stimulation of endogenous NO production by lipopolysaccharide in RAW 264.7 macrophages also caused a significant increase in the EC50 for isoproterenol-stimulated cAMP production. SIN-1 treatment also led to a reduction in both basal and isoproterenol-stimulated incorporation of [H-3]palmitate into the beta(2)AR. Signaling through the nonpalmitoylated, Gly(341)beta(2)AR mutant was unchanged by SIN-1 treatment. Given the link between beta(2)AR palmitoylation and its responsiveness to agonist, these results suggest that the primary action of NO was depalmitoylation of the beta(2)AR resulting in decreased signaling through the beta(2)AR. C1 NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. Univ Montreal, Dept Biochim, Montreal, PQ H3T 1J4, Canada. Univ Montreal, Grp Rech Syst Nerveux Autonome, Montreal, PQ H3T 1J4, Canada. RP Jones, TLZ (reprint author), NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RI Bouvier, Michel/H-2758-2014 OI Bouvier, Michel/0000-0003-1128-0100 NR 55 TC 69 Z9 70 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 SEP 10 PY 1999 VL 274 IS 37 BP 26337 EP 26343 DI 10.1074/jbc.274.37.26337 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 234DR UT WOS:000082469700056 PM 10473590 ER PT J AU Hildesheim, J Foster, RA Chamberlin, ME Vogel, JC AF Hildesheim, J Foster, RA Chamberlin, ME Vogel, JC TI Characterization of the regulatory domains of the human Skn-1a/Epoc-1/Oct-11 POU transcription factor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID REMOTE ENHANCER POSITION; DNA-BINDING; OCT2 TRANSACTIVATION; INSITU HYBRIDIZATION; CYTOKERATIN GENES; MAMMALIAN-CELLS; CROSS-LINKING; EXPRESSION; DIFFERENTIATION; ACTIVATION AB The Skn-1a POU transcription factor is primarily expressed in keratinocytes of murine embryonic and adult epidermis. Although some POU factors expressed in a tissue-specific manner are important for normal differentiation, the biological function of Skn-1a remains unknown. Previous in vitro studies indicate that Skn-1a has the ability to transactivate markers of keratinocyte differentiation. In this study, we have characterized Skn-1a's transactivation domain(s) and engineered a dominant negative protein that lacked this transactivation domain. Deletional analysis of the human homologue of Skn-1a with three target promoters revealed the presence of two functional domains: a primary C-terminal transactivation domain and a combined N-terminal inhibitory domain and transactivation domain. Skn-1a lacking the C-terminal region completely lost transactivation ability, irrespective of the promoter tested, and was able to block transactivation by normal Skn-1a in competition assays. Compared with full-length, Skn-1a lacking the N-terminal region demonstrated either increased transactivation (bovine cytokeratin 6 promoter), comparable transactivation (human papillomavirus type 1a long control region), or loss of transactivation (human papillomavirus type 18 long control region). The identification of a primary C-terminal transactivation domain enabled us to generate a dominant negative Skn-1a factor, which will be useful in the quest for a better understanding of this keratinocyte-specific gene regulator. C1 NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. NICHD, Cellular Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Vogel, JC (reprint author), NCI, Dermatol Branch, NIH, Bldg 10,Rm 12N238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. NR 51 TC 13 Z9 15 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 SEP 10 PY 1999 VL 274 IS 37 BP 26399 EP 26406 DI 10.1074/jbc.274.37.26399 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 234DR UT WOS:000082469700064 PM 10473598 ER PT J AU Han, B Fischbach, GD AF Han, B Fischbach, GD TI The release of acetylcholine receptor inducing activity (ARIA) from its transmembrane precursor in transfected fibroblasts SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUMOR-NECROSIS-FACTOR; NEU DIFFERENTIATION FACTOR; GROWTH-FACTOR; CELL-SURFACE; FACTOR-ALPHA; TGF-ALPHA; PROTEOLYTIC RELEASE; MOLECULAR-CLONING; MEMBRANE-PROTEINS; CYTOPLASMIC TAIL AB Acetylcholine receptor inducing activity (ARIA) is made by motoneurons and is released at the neuromuscular synapse to stimulate the synthesis of acetylcholine receptors by skeletal muscle. ARIA is derived from a transmembrane precursor (pro-ARIA) via proteolytic cleavage of the ectodomain. We studied requirements in the amino acid sequence at the cleavage site with various substitution and deletion mutations. Wild type (WT) and mutant proteins were transiently expressed in COS cells, and release of ARIA into the conditioned medium was measured by tyrosine phosphorylation of its receptor, p185, in L6 cells. Removal of all potential cleavage sites between the extracellular epidermal growth factor domain and the transmembrane domain by substitution and small deletions (<11 amino acid residues out of 21) did not significantly reduce ARIA release, whereas larger deletions abolished it. We propose that cleavage occurs independently of amino acid sequence at a short distance from the epidermal growth factor domain, unless sterically hindered by the nearby secondary structure. A mutant with shorter cytoplasmic domain ("c" isoform) released significantly less ARIA than the WT ("a" isoform), suggesting that the c isoform may be suitable for signaling through direct cell-cell contact. Alternatively, proteolytic conversion of the a isoform to the c isoform may rapidly down-regulate release of ARIA. C1 Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. RP Fischbach, GD (reprint author), NINDS, NIH, 31 Ctr Dr,Bldg 31,Rm 8A52, Bethesda, MD 20892 USA. FU NINDS NIH HHS [R01 NS18458] NR 43 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 SEP 10 PY 1999 VL 274 IS 37 BP 26407 EP 26415 DI 10.1074/jbc.274.37.26407 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 234DR UT WOS:000082469700065 PM 10473599 ER PT J AU Allerson, CR Cazzola, M Rouault, TA AF Allerson, CR Cazzola, M Rouault, TA TI Clinical severity and thermodynamic effects of iron-responsive element mutations in hereditary hyperferritinemia-cataract syndrome SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FERRITIN MESSENGER-RNA; L-SUBUNIT GENE; HUMAN-SERUM FERRITIN; BINDING PROTEIN; REGULATORY PROTEIN-2; METABOLISM; DEGRADATION; MISMATCHES; ACONITASE; DYNAMICS AB Hereditary hyperferritinemia-cataract syndrome (HHCS) is a novel genetic disorder characterized by elevated serum ferritin and early onset cataract formation. The excessive ferritin production in HHCS patients arises from aberrant regulation of L-ferritin translation caused by mutations within the iron-responsive element (IRE) of the L-ferritin transcript. IREs serve as binding sites for iron regulatory proteins (IRPs), iron-sensing proteins that regulate ferritin translation. Previous observations suggested that each unique HHCS mutation conferred a characteristic degree of hyperferritinemia and cataract severity in affected individuals. Here we have measured the in vitro affinity of the IRPs for the mutant IREs and correlated decreases in binding affinity with clinical severity. Thermodynamic analysis of these IREs has also revealed that although some HHCS mutations lead to changes in the stability and secondary structure of the IRE, others appear to disrupt IRP-IRE recognition with minimal effect on IRE stability. HHCS is a noteworthy example of a human genetic disorder that arises from mutations within a protein-binding site of an mRNA cis-acting element. Analysis of the effects of these mutations on the energetics of the RNA-protein interaction explains the phenotypic variabilities of the disease state. C1 NICHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. Univ Pavia, Sch Med, Dept Internal Med & Med Therapy, I-27100 Pavia, Italy. Univ Pavia, Sch Med, Dept Internal Med & Med Oncol, I-27100 Pavia, Italy. Policlin San Matteo, IRCCS, I-27100 Pavia, Italy. RP Rouault, TA (reprint author), NICHD, Cell Biol & Metab Branch, NIH, Bldg 18T,Rm 101,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 44 TC 66 Z9 68 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 10 PY 1999 VL 274 IS 37 BP 26439 EP 26447 DI 10.1074/jbc.274.37.26439 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 234DR UT WOS:000082469700069 PM 10473603 ER PT J AU Pengue, G Srivastava, AK Kere, J Schlessinger, D Durmowicz, MC AF Pengue, G Srivastava, AK Kere, J Schlessinger, D Durmowicz, MC TI Functional characterization of the promoter of the X-linked ectodermal dysplasia gene SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSCRIPTION FACTOR SP1; CPG ISLAND; EDA GENE; SYNERGISTIC ACTIVATION; ECTODYSPLASIN-A; BETA-CATENIN; PROTEINS SP1; BINDING; EXPRESSION; ELEMENTS AB Anhidrotic ectodermal dysplasia (EDA) is a disorder characterized by poor development of hair, teeth, and sweat glands, and results from lesions in the X-linked EDA gene. We have cloned a 1,6-kilobase 5'-flanking region of the human EDA gene and used it to analyze features of transcriptional regulation. Primer extension analysis located a single transcription initiation site 264 base pairs (bp) upstream of the translation start site. When the intact cloned fragment or truncated derivatives were placed upstream of a reporter luciferase gene and transfected into a series of cultured cells, expression comparable with that conferred by an SV40 promoter-enhancer was observed. The region lacks a TATA box sequence, and basal transcription from the unique start site is dependent on two binding sites for the Spl transcription factor. One site lies 38 bp 5' to the transcription start site, in a 71-bp sequence that is sufficient to support up to 35% of maximal transcription. The functional importance of the Sp1 sites was demonstrated when cotransfection of an Sp1expression vector transactivated the EDA promoter in the SL2 Drosophila cell line that otherwise lacks endogenous Sp1. Also, both Sp1 binding sites were active in footprinting and gel shift assays in the presence of either crude HeLa cell nuclear extract or purified Sp1 and lost activity when the binding sites were mutated. A second region involved in positive control was localized to a 40-bp sequence between -673 and -633 bp, This region activated an SV40 minimal promoter 4- to 5-fold in an orientation-independent manner and is thus inferred to contain an enhancer region. C1 NIA, Triad Technol Ctr, Genet Lab, Baltimore, MD 21224 USA. Univ Helsinki, Dept Med Genet, Haarman Inst, Helsinki 00014, Finland. Greenwood Genet Ctr, JC Self Res Inst Human Genet, Greenwood, SC 29646 USA. Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA. RP Durmowicz, MC (reprint author), NIA, Triad Technol Ctr, Genet Lab, Suite 4000,333 Cassell Dr, Baltimore, MD 21224 USA. RI Kere, Juha/A-9179-2008 OI Kere, Juha/0000-0003-1974-0271 NR 49 TC 8 Z9 8 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 10 PY 1999 VL 274 IS 37 BP 26477 EP 26484 DI 10.1074/jbc.274.37.26477 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 234DR UT WOS:000082469700074 PM 10473608 ER PT J AU Christenson, LK Johnson, PF McAllister, JM Strauss, JF AF Christenson, LK Johnson, PF McAllister, JM Strauss, JF TI CCAAT/enhancer-binding proteins regulate expression of the human steroidogenic acute regulatory protein (StAR) gene SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID C/EBP-BETA; TRANSCRIPTIONAL REGULATION; FOLLICULAR DEVELOPMENT; PROMOTER ACTIVITY; GRANULOSA-CELLS; DNA-BINDING; RAT OVARY; ALPHA; FACTOR-1; REGION AB Two putative CCAAT/enhancer-binding protein (C/EBP) response elements were identified in the proximal promoter of the human steroidogenic acute regulatory protein (StAR) gene, which encodes a key protein-regulating steroid hormone synthesis. Expression of C/EBP alpha and -beta increased StAR promoter activity in COS-l and HepG2 cells. Cotransfection of C/EBP alpha or -beta and steroidogenic factor 1, a transcription factor required for cAMP regulation of StAR expression, into COS-1 augmented 8-bromoadenosine 3':5'-cyclic monophosphate (8-Br-cAMP)-stimulated promoter activity. When the putative C/EBP response elements were mutated, individually or together, a pronounced decline in basal StAR promoter activity in human granulosa-lutein cells resulted, but the fold stimulation of promoter activity by 8-Br-cAMP was unaffected. Recombinant C/EBP alpha and -beta bound to the two identified sequences but not the mutated elements. Human granulosa-lutein cell nuclear extracts also bound these elements but not the mutated sequences. An antibody to C/EBP beta, but not C/EBP alpha, supershifted the nuclear protein complex associated with the more distal element. The complex formed by nuclear extracts with the proximal element was not supershifted by either antibody. Western blot analysis revealed the presence of C/EBPa and C/EBP beta in human granulosalutein cell nuclear extracts. C/EBP beta levels were up-regulated 3-fold by 8-Br-cAMP treatment. Our studies demonstrate a role for C/EBP beta as well as yet to be identified proteins, which can bind to C/EBP response elements, in the regulation of StAR gene expression and suggest a mechanism by which C/EBP beta participates in the cAMP regulation of StAR gene transcription. C1 Univ Penn, Ctr Res Reprod & Womens Hlth, Philadelphia, PA 19104 USA. NCI, Frederick Canc Res & Dev Ctr, Adv BioSci Labs, Basic Res Program, Frederick, MD 21702 USA. Penn State Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. RP Christenson, LK (reprint author), 1354 BRBII-III,421 Curie Blvd, Philadelphia, PA 19104 USA. RI Johnson, Peter/A-1940-2012; Christenson, Lane/G-6435-2013 OI Johnson, Peter/0000-0002-4145-4725; FU NICHD NIH HHS [HD06274, HD34449] NR 33 TC 82 Z9 81 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 SEP 10 PY 1999 VL 274 IS 37 BP 26591 EP 26598 DI 10.1074/jbc.274.37.26591 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 234DR UT WOS:000082469700090 PM 10473624 ER PT J AU Park, GT Morasso, MI AF Park, GT Morasso, MI TI Regulation of the Dlx3 homeobox gene upon differentiation of mouse keratinocytes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BOX-BINDING-PROTEINS; ETS TRANSCRIPTION FACTORS; DISTAL-LESS GENE; NF-Y; PROXIMAL PROMOTER; EPITHELIAL-CELLS; EPIDERMAL DIFFERENTIATION; MAMMALIAN EPIDERMIS; HOMEODOMAIN GENE; AP-1 ELEMENT AB The Distal-less Dlx3 homeodomain gene is expressed in terminally differentiated murine epidermal cells, and there is evidence to support an essential role as a transcriptional regulator of the terminal differentiation process in these cells. In an attempt to determine the factors that induce Dlx3 gene expression, we have cloned the 19-kilobase pair proximal region of murine gene and analyzed its cis-regulatory elements and potential trans-acting factors. The proximal region of the Dlx3 gene has a canonical TATA box and CCAAT box, and the transcription start site was located 205 base pairs upstream from the initiation of translation site. Serial deletion analysis showed that the region between -84 and -34 confers the maximal promoter activity both in undifferentiated and differentiated primary mouse keratinocytes. Gel retardation assays and mutational analysis demonstrated that the transcriptional regulator NF-Y (also referred to as CBF) binds to a CCAAT box motif within this region and is responsible for the majority of the Dlx3 promoter activity. In addition, an Sp1-binding site was located immediately upstream of transcription start site that acts as a positive regulatory element of the Dlx3 promoter, independent of the CCAAT box motif. Importantly, elements residing between +30 to +60 of the Dlx3 gene are responsible for the Ca2+-dependent induction of Dlx3 during keratinocyte differentiation. C1 NIAMS, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. RP Morasso, MI (reprint author), NIAMS, Skin Biol Lab, NIH, Bldg 6,Rm 134, Bethesda, MD 20892 USA. FU NIAMS NIH HHS [Z01 AR041124-06] NR 64 TC 31 Z9 33 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 SEP 10 PY 1999 VL 274 IS 37 BP 26599 EP 26608 DI 10.1074/jbc.274.37.26599 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 234DR UT WOS:000082469700091 PM 10473625 ER PT J AU Cao, XL Tian, Y Zhang, TY Li, X Ito, Y AF Cao, XL Tian, Y Zhang, TY Li, X Ito, Y TI Separation and purification of isoflavones from Pueraria lobata by high-speed counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Pueraria lobata; pharmaceutical analysis; plant materials; isoflavones; puerarins AB High-speed counter-current chromatography (HSCCC) was applied to the semipreparative separation and purification of puerarin and related isoflavones from a crude extract of Pueraria lobata. Analytical HSCCC was used for the preliminary selection of a suitable solvent system composed of ethyl acetate-n-butanol-water (2:1.3, v/v/v). Using the above solvent system the preparative HSCCC was successfully performed yielding six relatively pure isoflavones including puerarin from 80 mg of the crude extract in one-step separation. (C) 1999 Elsevier Science BN. All rights reserved. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. Beijing Inst New Technol Applicat, Beijing 100035, Peoples R China. Beijing Secondary Pharmaceut Factory Tradit Chine, Beijing 100010, Peoples R China. RP Ito, Y (reprint author), NHLBI, Biophys Chem Lab, NIH, Bldg 10,Room 7N322, Bethesda, MD 20892 USA. NR 6 TC 79 Z9 94 U1 3 U2 23 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD SEP 10 PY 1999 VL 855 IS 2 BP 709 EP 713 DI 10.1016/S0021-9673(99)00715-3 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 238YK UT WOS:000082742200027 PM 10519106 ER PT J AU Makarova, KS Grishin, NV AF Makarova, KS Grishin, NV TI The Zn-peptidase superfamily: Functional convergence after evolutionary divergence SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE protease; carboxypeptidase; aminopeptidase; aspartoacylase; succinylglutamate desuccinylase ID ARGININE SUCCINYLTRANSFERASE PATHWAY; CARBOXYPEPTIDASE-A; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; PSI-BLAST; PROTEIN; CLONING; FAMILY; AMINOPEPTIDASE; EXPRESSION AB Zn-dependent carboxypeptidases (ZnCP) cleave off the C-terminal amino acid residues from proteins and peptides. Here we describe a superfamily that unites classical ZnCP with other enzymes, most of which are known (or likely) to participate in metal-dependent peptide bond cleavage, but not necessarily in polypeptide substrates. It is demonstrated that aspartoacylase (ASP gene) and succinylglutamate desuccinylase (ASTE gene) are members of the ZnCP family. The Zn-binding site along with the structural core of the protein is shown to be conserved between ZnCP and another large family of hydrolases that includes mostly aminopeptidases (ZnAP). Both families (ZnCP and ZnAP) include not only proteases but also enzymes that perform N-deacylation, and enzymes that catalyze N-desuccinylation of amino acids. This is a result of functional convergence that apparently occurred after the divergence of the two families. (C) 1999 Academic Press. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Uniformed Serv Univ Hlth Sci, FE Hebert Sch Med, Dept Pathol, Bethesda, MD 20814 USA. RP Grishin, NV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. NR 32 TC 72 Z9 73 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 SEP 10 PY 1999 VL 292 IS 1 BP 11 EP 17 DI 10.1006/jmbi.1999.3059 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 234WB UT WOS:000082506400002 PM 10493853 ER PT J AU Xu, M Modarress, KJ Meeker, JEW Simons, SS AF Xu, M Modarress, KJ Meeker, JEW Simons, SS TI Steroid-induced conformational changes of rat glucocorticoid receptor cause altered trypsin cleavage of the putative helix 6 in the ligand binding domain SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE apo-glucocorticoid receptor; helix 6; meroreceptor; trypsin digestion ID HEAT-SHOCK-PROTEIN; HUMAN PROGESTERONE-RECEPTOR; TRANS-RETINOIC ACID; ESTROGEN-RECEPTOR; LIMITED PROTEOLYSIS; HORMONE-RECEPTOR; DEXAMETHASONE 21-MESYLATE; GENE-TRANSCRIPTION; ESTRADIOL-RECEPTOR; NUCLEAR RECEPTORS AB Steroid-induced changes in receptor protein conformation constitute a logical means of translating the variations in steroid structures into the observed array of whole cell biological activities. One conformational change in the rat glucocorticoid receptor (GR) can be readily discerned by following the ability of trypsin digestion to afford a 16-kDa fragment. This fragment is seen after proteolysis of steroid-free receptors but disappears in digests of either glucocorticoid- or antiglucocorticoid-bound receptors. The location of this cleavage site has now been located unambiguously as R651, in helix 6 of the ligand binding domain, by a combination of point mutagenesis, arginine specific protease digestion, and radiochemical sequencing. This 16-kDa species, corresponding to amino acids 652-795, was non-covalently associated with another, similar to 17-kDa species that was determined to be amino acids 518-651 after a comparison of co-immunoprecipitated fragments from wild type and two chimeric receptors. These assignments revise our earlier report of amino acids 537-673 being the 16-kDa fragment and suggest that sequences of the entire ligand binding domain are required for high affinity and specificity binding. This was supported by the observation that trypsin digestion of the steroid-free R651A mutant GR gave rise to the 30-kDa meroreceptor (amino acids 518-795), which displayed wild type affinity. This 30-kDa species is thus the smallest non-associated fragment of GR possessing wild type steroid binding affinity. This suggests that other GR regions do not influence steroid binding affinity. The above results are reminiscent of those observed for the estrogen receptor. However, unlike the estrogen receptor or the more closely related progesterone receptor, the precise proteolytic cleavage points of both the steroid-free and -bound GR fall within regions that are predicted, on the basis of X-ray crystal structures of related receptors, to be alpha-helical and resistant to proteolysis. Thus, the tertiary structure of the GR ligand binding domain may be distinctly different from that of estrogen and progesterone receptors. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 NIDDK, Steroid Hormones Sect, LMCB, NIH, Bethesda, MD 20892 USA. RP Simons, SS (reprint author), NIDDK, Steroid Hormones Sect, LMCB, NIH, Bethesda, MD 20892 USA. NR 82 TC 5 Z9 5 U1 1 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD SEP 10 PY 1999 VL 155 IS 1-2 BP 85 EP 100 DI 10.1016/S0303-7207(99)00110-0 PG 16 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 242BF UT WOS:000082917800010 PM 10580842 ER PT J AU Korach, KS AF Korach, KS TI Estrogen receptor knock-out mice: molecular and endocrine phenotypes SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Meeting Abstract C1 NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD SEP 10 PY 1999 VL 155 IS 1-2 MA 31 BP 162 EP 162 PG 1 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 242BF UT WOS:000082917800028 ER PT J AU Marshall, E AF Marshall, E TI View from the top of a biomedical empire SO SCIENCE LA English DT Editorial Material C1 NIH, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD SEP 10 PY 1999 VL 285 IS 5434 BP 1654 EP 1656 DI 10.1126/science.285.5434.1654 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 234EY UT WOS:000082472600008 ER PT J AU Ron, E Auvinen, A Alfandary, E Stovall, M Modan, B Werner, A AF Ron, E Auvinen, A Alfandary, E Stovall, M Modan, B Werner, A TI Cancer risk following radiotherapy for infertility or menstrual disorders SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID BREAST-CANCER; ENDOMETRIAL CANCER; FAMILY HISTORY; WOMEN; COHORT; DISEASE; HEALTH; IOWA AB A cohort of 968 Israeli women treated with radiotherapy for infertility was followed up for cancer incidence. The majority of the subjects were irradiated to both the ovaries and the pituitary gland. Mean doses to the brain, colon, ovary and bone marrow were 0.8, 0.6, 1.0 and 0.4 Gy, respectively. More than 10 years after radiation treatment, 60 cancers were observed compared with 74.5 expected based on national cancer incidence rates (standardized incidence ratio 0.81, 95% confidence interval 0.61-1.04), No statistically significant excess or deficit was seen for any individual type of cancer; however, a non-significant 60% increased risk of colon cancer was observed. Risk of colon cancer was higher among women with 2 or more treatments and increased with length of follow-up. A decreased risk of breast cancer was suggested. Neither age at exposure nor attained age modified subsequent cancer risk. No clear excess of any cancer site was observed among women at organ doses above the median compared with subjects at doses below the median, except a slight increase in colon cancer. No significant excess incidence of cancer was demonstrated in this small cohort of patients treated with radiotherapy for infertility, Our results are consistent with those from an earlier study of cancer mortality among women receiving radiotherapy for infertility conducted in New York City. Published 1999 Wiley-Liss, Inc.dagger. C1 NCI, Radiat Epidemiol Branch, Rockville, MD 20852 USA. Radiat Biol Lab, Helsinki, Finland. Chaim Sheba Med Ctr, Dept Clin Epidemiol, IL-52621 Tel Hashomer, Israel. Univ Texas, MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX USA. Chaim Sheba Med Ctr, Dept Oncol, IL-52621 Tel Hashomer, Israel. RP Ron, E (reprint author), NCI, Radiat Epidemiol Branch, 6120 Execut Blvd,Room EPN-408, Rockville, MD 20852 USA. OI Auvinen, Anssi/0000-0003-1125-4818 FU NCI NIH HHS [MAO-NO1-CP-51049] NR 26 TC 8 Z9 8 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 SEP 9 PY 1999 VL 82 IS 6 BP 795 EP 798 DI 10.1002/(SICI)1097-0215(19990909)82:6<795::AID-IJC4>3.0.CO;2-K PG 4 WC Oncology SC Oncology GA 227FU UT WOS:000082069000004 PM 10446443 ER PT J AU Touloumi, G Hatzakis, A Potouridov, I Milona, I Strarigos, J Katsambas, A Giraldo, G Beth-Giraldo, E Biggar, RJ Mueller, N Trichopoulos, D AF Touloumi, G Hatzakis, A Potouridov, I Milona, I Strarigos, J Katsambas, A Giraldo, G Beth-Giraldo, E Biggar, RJ Mueller, N Trichopoulos, D TI The role of immunosuppression and immune-activation in classic Kaposi's sarcoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID TAT PROTEIN; IMMUNODEFICIENCY; EPIDEMIOLOGY; CELLS; HUMAN-HERPESVIRUS-8; HERPESVIRUS; INFECTION; FEATURES; SYNERGY; AFRICAN AB Immunodeficiency and elevated levels of cytokines have been associated with the development of Kaposi's sarcoma (KS) lesions in patients with AIDS and iatrogenic immunodeficiency. However, their role in classic KS (CKS) is unclear. We measured peripheral blood cell levels, including T-cell subsets, as well as neopterin and beta(2)-microglobulin in 91 HIV-negative Greek patients with histologically confirmed CKS and in 107 controls matched for age and sex. CKS cases had slightly lower leukocyte counts (p = 0.08) and lymphocyte counts (p = 0.02). Although the percentage of CD4 and CD8 T-lymphocytes were not significantly different from controls (p = 0.10 and p = 0.45, respectively), CD4 T-lymphocytes were lower in cases than controls (812 cells/mu L and 1,009 cells/mu L, respectively; p = 0.01); part of this difference resulted from the lower lymphocyte counts (p 0.07 after adjusting for lymphocyte counts). However, neopterin and Pz-microglobulin were both considerably elevated [geometric mean (95% CI): 8.35 (7.27-9.73) nmol/L and 2,904 (2,479-3,401) mu g/L in cases and 5.86 (5.40-6.35) nmol/lL and 2,042 (1,880-2,218) mu g/L in controls, respectively]. We conclude that CKS patients are predominantly characterised by immune activation, although an element of minor immunosuppression may also be present. (C) 1999 Wiley-Liss, Inc. C1 Athens Med Sch, Dept Hyg & Epidemiol, GR-11527 Athens, Greece. Univ Athens Clin, Dept Dermatol & Venerol, Andreas Syngros Hosp, Athens, Greece. Inst Nazl Tumri Fond G Pascale, Dept Expt Oncol, Naples, Italy. Inst Nazl Tumri Fond G Pascale, AIDS Reference Ctr, Naples, Italy. NCI, Viral Epidemiol Branch, Bethesda, MD USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Hatzakis, A (reprint author), Athens Med Sch, Dept Hyg & Epidemiol, M Asias 75, GR-11527 Athens, Greece. FU NCI NIH HHS [R01 CA44578] NR 21 TC 28 Z9 30 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 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 9 PY 1999 VL 82 IS 6 BP 817 EP 821 DI 10.1002/(SICI)1097-0215(19990909)82:6<817::AID-IJC8>3.0.CO;2-7 PG 5 WC Oncology SC Oncology GA 227FU UT WOS:000082069000008 PM 10446447 ER PT J AU Wang, SM Liu, M Lewin, NE Lorenzo, PS Bhattacharrya, D Qiao, LX Kozikowski, AP Blumberg, PM AF Wang, SM Liu, M Lewin, NE Lorenzo, PS Bhattacharrya, D Qiao, LX Kozikowski, AP Blumberg, PM TI Probing the binding of indolactam-V to protein kinase C through site-directed mutagenesis and computational docking simulations SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CONFORMATIONALLY CONSTRAINED ANALOGS; PHORBOL ESTER BINDING; 5-DISUBSTITUTED TETRAHYDRO-2-FURANONE TEMPLATE; TUMOR PROMOTERS; SYNTHETIC ANALOGS; BIOLOGICAL EVALUATION; ACTIVE CONFORMATION; STRUCTURAL BASIS; TELEOCIDIN-B; DOMAIN AB Protein kinase C (PKC) comprises a family of ubiquitous enzymes transducing signals by the lipophilic second messenger sn-1,2-diacylglycerol (DAG). Teleocidin and its structurally simpler congener indolactam-V (ILV) bind to PKC with high affinity. In this paper, we report our computational docking studies on ILV binding to PKC using an automatic docking computer program, MCDOCK. In addition, we used site-directed mutagenesis to assess the quantitative contribution of crucial residues around the binding site of PKC to the binding affinity of ILV to PKC. On the basis of the docking studies, ILV binds to PKC in its cis-twist conformation and forms a number of optimal hydrogen bond interactions. In addition, the hydrophobic groups in ILV form "specific" hydrophobic interactions with side chains of a number of conserved hydrophobic residues in PKC. The predicted binding mode for ILV is entirely consistent with known structure-activity relationships and with our mutational analysis. Our mutational analysis establishes the quantitative contributions of a number of conserved residues to the binding of PKC to ILV. Taken together, our computational docking simulations and analysis by site-directed mutagenesis provide a clear understanding of the interaction between ILV and PKC and the structural basis for design of novel, high-affinity, and isozyme-selective PKC ligands. C1 Georgetown Univ, Med Ctr, Georgetown Inst Cognit & Computat Sci, Drug Discovery Program, Washington, DC 20007 USA. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Wang, SM (reprint author), Georgetown Univ, Med Ctr, Georgetown Inst Cognit & Computat Sci, Drug Discovery Program, Res Bldg,Room EP07,3700 Reservoir Rd, Washington, DC 20007 USA. RI Wang, Shaomeng/E-9686-2010 NR 50 TC 27 Z9 28 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 SEP 9 PY 1999 VL 42 IS 18 BP 3436 EP 3446 DI 10.1021/jm990129n PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 235HH UT WOS:000082535900003 PM 10479277 ER PT J AU Newman, AH Izenwasser, S Robarge, MJ Kline, RH AF Newman, AH Izenwasser, S Robarge, MJ Kline, RH TI CoMFA study of novel phenyl ring-substituted 3 alpha-(diphenylmethoxy)tropane analogues at the dopamine transporter SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID LIGAND-BINDING DOMAINS; FIELD ANALYSIS COMFA; ACID METHYL-ESTERS; UPTAKE INHIBITORS; KNOCKOUT MICE; COCAINE; QSAR; 3-ALPHA-TROPANE; HYPOTHESIS; MODELS AB A series of phenyl ring-substituted analogues of 3 alpha-(diphenylmethoxy)tropane (benztropine) has been prepared as novel probes for the dopamine transporter. Cross-validated comparative molecular field analysis (CoMFA) models of the binding domain on the dopamine transporter were constructed using 37 geometry-optimized structures of these compounds and their corresponding binding affinities (Ki values) for the displacement of [H-3]WIN 35,428 or potency of [H-3]dopamine uptake inhibition (IC50 values) in rat caudate putamen tissue. The most predictive model (q(2) = 0.78) correlated the steric component of CoMFA to the dependent variable of [H-3]WIN 35,428 binding affinities. A novel series of seven phenyl ring-substituted analogues of 3a-(diphenylmethoxy)tropane was prepared, and our best molecular model was used to accurately predict their binding affinities. This study is the first to provide a CoMFA model for this class of dopamine uptake inhibitors. This model represents an advancement in the design of novel dopamine transporter ligands, based on 3a-(diphenylmethoxy)tropane, and further substantiates structure-activity relationships that have previously been proposed for this class of compounds. This CoMFA model can now be used to predict the binding affinities of novel 3a-(diphenylmethoxy)tropane analogues at the dopamine transporter and will be useful in the design of molecular probes within this class of dopamine uptake inhibitors. C1 NIDA, Psychobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Newman, AH (reprint author), NIDA, Psychobiol Sect, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Izenwasser, Sari/G-9193-2012 NR 37 TC 31 Z9 31 U1 2 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 SEP 9 PY 1999 VL 42 IS 18 BP 3502 EP 3509 DI 10.1021/jm980701v PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 235HH UT WOS:000082535900009 PM 10479283 ER PT J AU Ananthan, S Kezar, HS Carter, RL Saini, SK Rice, KC Wells, JL Davis, P Xu, H Dersch, CM Bilsky, EJ Porreca, F Rothman, RB AF Ananthan, S Kezar, HS Carter, RL Saini, SK Rice, KC Wells, JL Davis, P Xu, H Dersch, CM Bilsky, EJ Porreca, F Rothman, RB TI Synthesis, opioid receptor binding, and biological activities of naltrexone-derived pyrido- and pyrimidomorphinans SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MESSAGE ADDRESS CONCEPT; PHARMACOLOGICAL CHARACTERIZATION; NALTRINDOLE 5'-ISOTHIOCYANATE; DIFFERENTIAL ANTAGONISM; MORPHINE-TOLERANCE; AGONIST; AFFINITY; DEPENDENCE; SUBTYPES; SELECTIVITY AB A series of pyrido- and pyrimidomorphinans (6a-h and 7a-g) were synthesized from naltrexone and evaluated for binding and biological activity at the opioid receptors. The unsubstituted pyridine 6a displayed high affinities at opioid delta, mu, and kappa receptors with Ki values of 0.78, 1.5, and 8.8 nM, respectively. Compound 6a was devoid of agonist activity in the mouse vas deferens (MVD) and guinea pig ileum (GPI) preparations but was found to display moderate to weak antagonist activity in the MVD and CPI with K-e values of 37 and 164 nM, respectively. The pyrimidomorphinans in general displayed lower binding potencies and 6 receptor binding selectivities than their pyridine counterparts. Incorporation of aryl groups as putative 6 address mimics on the pyrido- and pyrimidomorphinan framework gave ligands with significant differences in binding affinity and intrinsic activity. Attachment of a phenyl group at the 4'-position of 6a or the equivalent 6'-position of 7a led to dramatic reduction in binding potencies at all the three opioid receptors, indicating the existence of a somewhat similar steric constraint at the ligand binding sites of delta, mu, and kappa receptors. In contrast, the introduction of a phenyl group at the 6'-position of 6a did not cause any reduction in the binding affinity at the 6 receptor. In comparison to the unsubstituted pyridine 6a, the 5'-phenylpyridine 6c showed improvements in mu/delta and kappa/delta binding selectivity ratios as well as in the 6 antagonist potency in the MVD. Interestingly, introduction of a chlorine atom at the para position of the pendant 5'-phenyl group of 6c not only provided further improvements in 6 antagonist potency in the MVD but also shifted the intrinsic activity profile of sc from an antagonist to that of a mu agonist in the GPI. Compound Sd thus possesses the characteristics of a nonpeptide mu agonist/delta antagonist ligand with high affinity at the 6 receptor (Ki = 2.2 nM), high antagonist potency in the MVD (K-e, = 0.66 nM), and moderate agonist potency in the GPI (IC50 = 163 nM). Antinociceptive evaluations in mice showed that intracerebroventricular (icv) injections of 6d produced a partial agonist effect in the 55 degrees C tail-flick assay and a full agonist effect in the acetic acid writhing assay (A(50) = 7.5 nmol). No signs of overt toxicity were observed with this compound in the dose ranges tested. Moreover, repeated icy injections of an A(90) dose did not induce any significant development of antinociceptive tolerance in the acetic acid writhing assay. The potent 6 antagonist component of this mixed mu agonist/delta antagonist may be responsible for the diminished propensity to produce tolerance that this compound displays. C1 So Res Inst, Dept Organ Chem, Birmingham, AL 35255 USA. NIDA, Clin Psychopharmacol Sect, DIR, Baltimore, MD 21224 USA. NIDDKD, Med Chem Lab, NIH, Bethesda, MD 20892 USA. Univ No Colorado, Dept Biol Sci, Greeley, CO 80639 USA. Univ Arizona, Coll Med, Dept Pharmacol, Tucson, AZ 85724 USA. RP Ananthan, S (reprint author), So Res Inst, Dept Organ Chem, Birmingham, AL 35255 USA. FU NIDA NIH HHS [DA08883] NR 50 TC 58 Z9 59 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 9 PY 1999 VL 42 IS 18 BP 3527 EP 3538 DI 10.1021/jm990039i PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 235HH UT WOS:000082535900012 PM 10479286 ER PT J AU Chefer, SI Horti, AG Koren, AO Gundisch, D Links, JM Kurian, V Dannals, RF Mukhin, AG London, ED AF Chefer, SI Horti, AG Koren, AO Gundisch, D Links, JM Kurian, V Dannals, RF Mukhin, AG London, ED TI 2-[F-18]F-A-85380: a PET radioligand for alpha(4)beta(2) nicotinic acetylcholine receptors SO NEUROREPORT LA English DT Article DE 2-[F-18]F-A-85380; nicotinic acetylcholine receptor; positron emission tomography; radiotracer; receptor binding; rhesus monkey ID IN-VIVO; RADIOIODINATED ANALOG; EPIBATIDINE; BRAIN; BINDING; AFFINITY; SUBTYPE AB 2-[F-18]FLUORO-3-(2(S)-AZETIDINYMETHOXY)PYRIDINE (2[F-18]F-A-85380), a ligand for nicotinic acetylcholine receptors (nAChRs) was evaluated in an in vitro binding assay with membranes of rat brain and in vivo by PET in Rhesus monkey brain. The ligand has high affinity for alpha(4)beta(2) nAChRs (K-D=50pM), crosses the blood-brain barrier, and distributes in the monkey brain in a pattern consistent with that of alpha(4)beta(2) nAChRs. The specific/non-specific binding ratio increased steadily, reaching a value of 3.3 in the thalamus at 4 h. The specific binding of 2-[F-18]F-A-85380 Was reversed by cytisine. These results, in combination with the data demonstrating low toxicity of 2-[F-18]F-A-85380, indicate that this ligand shows promise for use with PET in human subjects. (C) 1999 Lippincott Williams & Wilkins. C1 Natl Inst Drug Abuse, Brain Imaging Ctr, Intramural Res Program, Baltimore, MD 21224 USA. Johns Hopkins Med Inst, Dept Radiol, Div Nucl Med, Baltimore, MD 21287 USA. RP London, ED (reprint author), Natl Inst Drug Abuse, Brain Imaging Ctr, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 22 TC 35 Z9 36 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD SEP 9 PY 1999 VL 10 IS 13 BP 2715 EP 2721 DI 10.1097/00001756-199909090-00005 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 237JV UT WOS:000082653400009 PM 10511429 ER PT J AU Khan, S Michaud, D Moody, TW Anisman, H Merali, Z AF Khan, S Michaud, D Moody, TW Anisman, H Merali, Z TI Effects of acute restraint stress on endogenous adrenomedullin levels SO NEUROREPORT LA English DT Article DE adrenomedullin; ACTH; homeostasis; HPA axis; restraint stress ID CONSCIOUS SHEEP; HYPOTENSIVE PEPTIDE; RAT ADRENOMEDULLIN; SEPTIC SHOCK; PLASMA; RESPONSES; CORTICOSTERONE; HYPERTENSION; TISSUE; AXIS AB ADRENOMEDULLIN (ADM) is a 52 amino acid peptide, with a potent hypotensive/vasodilatory action. Levels of ADM are significantly elevated in patients with hypertension, and it has been postulated that such stressor-related increases may serve a regulatory or protective function. The current study assessed the effects of acute restraint stress on ADM levels in regions of the brain, plasma and peripheral tissue including heart, lung and the adrenal glands of rats. This stressor, known to stimulate sympathetic activity as well as the hypothalamic-pituitary adrenal (HPA) axis, produced a significant increase in ADM levels in the pituitary gland, plasma and adrenal glands, all of which are key components of the HPA axis. The results suggest a regulatory and/or protective role for ADM in countering HPA activation following a variety of physiological and psychological stressors. (C) 1999 Lippincott Williams & Wilkins. C1 Univ Ottawa, Sch Psychol, Ottawa, ON K1N 6N5, Canada. Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON K1N 6N5, Canada. NCI, Rockville, MD USA. Carleton Univ, Inst Neurosci, Ottawa, ON K1S 5B6, Canada. RP Merali, Z (reprint author), Univ Ottawa, Sch Psychol, 11 Marie Curie,Vanier Hall Rm 214, Ottawa, ON K1N 6N5, Canada. NR 27 TC 17 Z9 23 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD SEP 9 PY 1999 VL 10 IS 13 BP 2829 EP 2833 DI 10.1097/00001756-199909090-00024 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 237JV UT WOS:000082653400028 PM 10511448 ER PT J AU Rosenstein, DL Lerner, D Cai, J AF Rosenstein, DL Lerner, D Cai, J TI More on the depressive effects of interferon alfa SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID CHRONIC VIRAL-HEPATITIS C1 NIMH, Bethesda, MD 20892 USA. RP Rosenstein, DL (reprint author), NIMH, Bethesda, MD 20892 USA. NR 6 TC 9 Z9 9 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 9 PY 1999 VL 341 IS 11 BP 849 EP 849 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 235GM UT WOS:000082534000021 PM 10490390 ER PT J AU Jeffers, M Vande Woude, GF AF Jeffers, M Vande Woude, GF TI Activating mutations in the Met receptor overcome the requirement for autophosphorylation of tyrosines crucial for wild type signaling SO ONCOGENE LA English DT Article DE mutant Met; signaling; autophosphorylation ID HEPATOCYTE GROWTH-FACTOR; FACTOR SCATTER FACTOR; KINASE RECEPTOR; PROTOONCOGENE PRODUCT; CELL-TRANSFORMATION; EPITHELIAL-CELLS; ONCOPROTEIN; MOTILITY; GRB2; SITE AB Mutations in Met have been identified in human cancer, and we have previously shown that these mutations deregulate the enzymatic activity of this tyrosine kinase receptor, thereby unleashing its oncogenic potential. Signal transduction via mild type Met has been shown to require the autophosphorylation of two tyrosine doublets; Y8,9 which functions to enhance enzymatic activity, and Y14,15 which provides docking sites for signaling molecules, and in the present investigation we examine the importance of these residues for signaling via mutationally activated Met. We find that activating mutations introduced into a membrane-spanning Met receptor circumvent the normally stringent requirement for Y8,9 phosphorylation, and do so in a largely ligand-dependent fashion. Similarly, activating mutations introduced into a constitutively dimerized cytoplasmic form of Met (i.e. Tpr-Met) facilitate its autophosphorylation and oncogenic activity in the absence of Y8,9 phosphorylation. We also find that activating mutations allow a membrane-spanning Met receptor to overcome the requirement for the Y14,15 phosphorylation in a manner which is largely ligand-independent, These findings support a model whereby activating mutations stabilize an active conformation of the Met kinase via a mechanism which can function independently of Y8,9 autophosphorylation and suggest that signaling via wild type Met and mutationally activated Met may proceed through distinct pathways. C1 NCI, Div Basic Sci, Natl Canc Inst, FCRDC, Ft Detrick, MD 21702 USA. NCI, ABL Basic Res Program, FCRDC, Ft Detrick, MD 21702 USA. RP Vande Woude, GF (reprint author), NCI, Div Basic Sci, Natl Canc Inst, FCRDC, Bldg 469,POB B, Ft Detrick, MD 21702 USA. NR 37 TC 16 Z9 16 U1 0 U2 1 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 9 PY 1999 VL 18 IS 36 BP 5120 EP 5125 DI 10.1038/sj.onc.1202902 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 234RA UT WOS:000082497100012 PM 10490849 ER PT J AU Weed, DL AF Weed, DL TI Higher standards for epidemiologic studies-replication prior to publication? SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. RP Weed, DL (reprint author), NCI, Bethesda, MD 20892 USA. NR 3 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 SEP 8 PY 1999 VL 282 IS 10 BP 937 EP 937 DI 10.1001/jama.282.10.937 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 231XD UT WOS:000082335900014 PM 10485668 ER PT J AU Bostom, AG Rosenberg, IH Silbershatz, H Jacques, PF Selhub, J D'Agostino, RB Wilson, PWF Wolf, PA AF Bostom, AG Rosenberg, IH Silbershatz, H Jacques, PF Selhub, J D'Agostino, RB Wilson, PWF Wolf, PA TI Nonfasting plasma total homocysteine levels and stroke incidence in elderly persons: The Framingham Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID VASCULAR-DISEASE; NATURAL-HISTORY; RISK FACTOR; HYPERHOMOCYSTEINEMIA; SERUM; HOMOCYSTINURIA; ADULTS AB Background: Total homocysteine levels are associated with arteriosclerotic outcomes. Objective: To determine whether total homocysteine levels predict incident stroke in elderly persons. Design: Prospective population-based cohort study with 9.9 years of follow-up. Setting: Framingham, Massachusetts. Patients: 1947 Framingham Study participants (1158 women and 789 men; mean age +/- SD, 70 +/- 7 years). Measurements: Baseline total homocysteine levels and 9.9-year stroke incidence. Results: The quartiles of nonfasting total homocysteine levels were as follows: quartile 1, 4.13 to 9.25 mu mol/L; quartile 2, 9.26 to 11.43 mu mol/L; quartite 3, 11.44 to 14.23 mu mol/L; quartile 4, 14.24 to 219.84 mu mol/L. During follow-up, 165 incident strokes occurred. In proportional hazards models adjusted for age, sex, systolic blood pressure, diabetes, smoking, and history of atrial fibrillation and coronary heart disease, relative risk (RR) estimates comparing quartile 1 with the other three quartiles were as follows: quartile 2 compared with quartile 1-RR, 1.32 (95% CI, 0.81 to 2.14); quartile 3 compared with quartile 1-RR, 1.44 (CI, 0.89 to 2.34); quartile 4 compared with quartile 1-RR, 1.82 (CI, 1.14 to 2.91). The linear trend across the quartiles was significant (P < 0.001). Conclusion: Nonfasting total homocysteine levels are an independent risk factor for incident stroke in elderly persons. C1 Tufts Univ, New England Med Ctr, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Brown Univ, Mem Hosp Rhode Isl, Providence, RI 02912 USA. NHLBI, Framingham Study, Framingham, MA 01701 USA. RP Rosenberg, IH (reprint author), Tufts Univ, New England Med Ctr, Jean Mayer USDA Human Nutr Res Ctr Aging, 711 Washington St, Boston, MA 02111 USA. FU NHLBI NIH HHS [R01-HL-40423-05, N01-HC-38038]; NINDS NIH HHS [2-RO1-NS-17950-17] NR 20 TC 272 Z9 285 U1 0 U2 3 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 SEP 7 PY 1999 VL 131 IS 5 BP 352 EP 355 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 234AC UT WOS:000082458500005 PM 10475888 ER PT J AU Huang, PL Sun, YT Chen, HC Kung, HF Huang, PL Lee-Huang, S AF Huang, PL Sun, YT Chen, HC Kung, HF Huang, PL Lee-Huang, S TI Proteolytic fragments of anti-HIV and anti-tumor proteins MAP30 and GAP31 are biologically active SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID POKEWEED ANTIVIRAL PROTEIN; RICIN-A-CHAIN; INHIBITION; ANGSTROM; GAP-31; DNA; REPLICATION; INFECTION; TYPE-1; MAP-30 AB We analyzed the structural and functional organization of anti-HIV and anti-tumor proteins MAP30 and GAP31 by limited proteolysis with endopeptidases Lys-C and Glu-C (V8), MAP30 and GAP31 are resistant to proteolytic digestion under conditions of as much as 5% (w/w) proteases. In the presence of 10% (w/w) protease, the central regions of the proteins are still. resistant to proteolysis, whereas the N- and C-termini are accessible. Peptide fragments were purified by FPLC on Superdex 75 columns, characterized by gel electrophoresis, identified by amino acid sequencing, and analyzed for anti-HIV, anti-tumor, and other biochemical activities. We report here that limited proteolysis yields biologically active fragments of both MAP30 and GAP31. These fragments are active against HIV-1 and tumor cells with EC(50)s in the sub-nanomolar ranges, 0.2-0.4 nM. At the dose levels used in the assays, little cytotoxicity to normal cells was observed. In addition, these fragments remain fully active in HIV-integrase inhibition and HIV-LTR topological inactivation, but not ribosome inactivation. These results demonstrate that the antiviral and anti-tumor activities of MAP30 and GAP31 are independent of ribosome inactivation activity. In addition, we demonstrate that portions of the N- and C-termini are not essential for antiviral and anti-tumor activities, but do appear to be required for ribosome inactivation. These results may provide novel strategies for rational design and targeted development of mimetic antiviral and anti-tumor therapeutics, (C) 1999 Academic Press. C1 NYU, Sch Med, Dept Biochem, New York, NY 10016 USA. Amer Biosci, New York, NY 10021 USA. NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. Univ Hong Kong, Inst Mol Biol, Hong Kong, Hong Kong. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Lee-Huang, S (reprint author), NYU, Sch Med, Dept Biochem, New York, NY 10016 USA. FU NIAID NIH HHS [R01 AI-31343] NR 28 TC 29 Z9 38 U1 0 U2 3 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 SEP 7 PY 1999 VL 262 IS 3 BP 615 EP 623 DI 10.1006/bbrc.1999.1213 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 235AH UT WOS:000082516200010 PM 10471373 ER PT J AU Borchers, C Tomer, KB AF Borchers, C Tomer, KB TI Characterization of the noncovalent complex of human immunodeficiency virus glycoprotein 120 with its cellular receptor CD4 by matrix-assisted laser desorption/ionization mass spectrometry SO BIOCHEMISTRY LA English DT Article ID TYPE-1 ENVELOPE GLYCOPROTEIN; PROTEIN COMPLEXES; GP120; AIDS; BINDING; ANTIBODIES; RETROVIRUS; INFECTION; CELLS; FORM AB The initial event in infection by the human immunodeficiency virus type 1 (HIV-1) is the interaction of the viral envelope glycoprotein (HIV-gp120) with its primary cellular receptor, the glycoprotein CD4. Molecular structure information about the HIV-gp120/CD4 complex can provide information relevant to an understanding of the basic processes occurring in HIV infection and to development of therapies that can inhibit AIDS. Previous studies by sugar gradient sedimentation of the interaction of HIV-gp120 with a cytoplasmic domain truncated soluble CD4 (sCD4) suggested that a one-to-one complex was formed. The stoichiometry, however, of the sCD4/HIV-gp120 complex remained to be confirmed by an independent method because (i) recent X-ray examination revealed dimerization of sCD4 and (ii) the low resolution and low accuracy of molecular weight determination by sugar gradient sedimentation can lead to artifactual data. Therefore, in this study matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) was used to determine the molecular mass of the complex of fully glycosylated HIV-gp120 and sCD4. A mass of 145 kDa was measured, which is exactly the sum of the molecular masses of one HIV-gp120 and one sCD4 molecule. Complexes of higher order of stoichiometry were not detected. Identical results were obtained by chemically cross-linking the HIV-gp120/sCD4 complex with subsequent analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and MALDI-MS. This study confirms the earlier suggestions of the stoichiometry of the sCD4/HIV-gp120 complex in solution and also demonstrates the potential of MALDI-MS in investigations of specific noncovalent complexes of glycoproteins. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Tomer, KB (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233,MD F0-03, Res Triangle Pk, NC 27709 USA. RI Tomer, Kenneth/E-8018-2013 NR 31 TC 37 Z9 40 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 SEP 7 PY 1999 VL 38 IS 36 BP 11734 EP 11740 DI 10.1021/bi990935w PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 239FC UT WOS:000082757300018 PM 10512629 ER PT J AU LaCour, TG Guo, CX Ma, SH Jeong, JU Boyd, MR Matsunaga, S Fusetani, N Fuchs, PL AF LaCour, TG Guo, CX Ma, SH Jeong, JU Boyd, MR Matsunaga, S Fusetani, N Fuchs, PL TI On topography and functionality in the B-D rings of cephalostatin cytotoxins SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID HEXACYCLIC STEROID UNIT; PYRAZINES; ANALOGS; ASSAY AB Analogues 12'beta-hydroxycephalostatin 1 (9), 7'-deoxyritterazine G (10), and 14-epi-7'-deoxyritterazine B (11) were prepared via our protocol for unsymmetrical pyrazine synthesis. Cytotoxicity against human tumors was also determined for the first time for ritterazines, with femtomolar potency and a high correlation to cephalostatins observed. The SAR of these and related. compounds provide insight into the importance of topography and certain chemical functionality in the B-D and B'-D' rings of cephalostatin type antineoplastics. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Univ Tokyo, Marine Biochem Lab, Bunkyo Ku, Tokyo 113, Japan. RP LaCour, TG (reprint author), Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. FU NCI NIH HHS [CA 60548] NR 24 TC 19 Z9 19 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD SEP 6 PY 1999 VL 9 IS 17 BP 2587 EP 2592 DI 10.1016/S0960-894X(99)00430-8 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 234GN UT WOS:000082476300027 PM 10498214 ER PT J AU Rogakou, EP Boon, C Redon, C Bonner, WM AF Rogakou, EP Boon, C Redon, C Bonner, WM TI Megabase chromatin domains involved in DNA double-strand breaks in vivo SO JOURNAL OF CELL BIOLOGY LA English DT Article DE ionizing radiation; histone H2AX; DNA double-strand breaks; phosphorylation; indirect immunofluorescence ID SACCHAROMYCES-CEREVISIAE; V(D)J RECOMBINATION; MAMMALIAN-CELLS; INDIAN MUNTJAC; REPAIR; RADIATION; MECHANISMS; PROTEIN AB The loss of chromosomal integrity from DNA double-strand breaks introduced into mammalian cells by ionizing radiation results in the specific phosphorylation of histone H2AX on serine residue 139, yielding a specific modified form named gamma-H2AX. An antibody prepared:to the unique region of human gamma-H2AX shows that H2AX homologues are phosphorylated not only in irradiated mammalian cells but also in irradiated cells from other species, including Xenopus laevis. Drosophila melanogaster, and Saccharomyces cerevisiae. The antibody reveals that gamma-H2AX appears as discrete nuclear foci within 1 min after exposure of cells to ionizing radiation, The numbers of these foci are comparable to the numbers of induced DNA double-strand breaks. When DNA double-strand breaks are introduced into specific partial nuclear volumes of cells by means of a pulsed microbeam laser, gamma-H2AX foci form at these sites. In mitotic cells from cultures exposed to nonlethal amounts of ionizing radiation, gamma-H2AX foci form band-like structures on chromosome arms and on the end of broken arms. These results offer direct visual confirmation that gamma-H2AX forms en masse at chromosomal sites of DNA double-strand breaks, The results further suggest the possible existence of units of higher order chromatin structure involved in monitoring DNA integrity. C1 NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Bonner, WM (reprint author), NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bldg 37,Rm 5D17, Bethesda, MD 20892 USA. NR 31 TC 1491 Z9 1529 U1 5 U2 41 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 SEP 6 PY 1999 VL 146 IS 5 BP 905 EP 915 DI 10.1083/jcb.146.5.905 PG 11 WC Cell Biology SC Cell Biology GA 234FV UT WOS:000082474600001 PM 10477747 ER PT J AU Wang, JM Oppenheim, JJ AF Wang, JM Oppenheim, JJ TI Interference with the signaling capacity of CC chemokine receptor 5 can compromise its role as an HIV-1 entry coreceptor in primary T lymphocytes SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Editorial Material ID PERTUSSIS TOXIN; ENVELOPE GLYCOPROTEIN; B-OLIGOMER; CXCR4; INFECTION; DESENSITIZATION; INHIBITION; GP120; CELLS; INTERNALIZATION C1 NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Div Basic Sci, Frederick, MD 21702 USA. RP Wang, JM (reprint author), NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Div Basic Sci, Bldg 560,Rm 31-40, Frederick, MD 21702 USA. NR 40 TC 11 Z9 13 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD SEP 6 PY 1999 VL 190 IS 5 BP 591 EP 595 DI 10.1084/jem.190.5.591 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 235GT UT WOS:000082534500001 PM 10477544 ER PT J AU Hartt, JK Barish, G Murphy, PM Gao, JL AF Hartt, JK Barish, G Murphy, PM Gao, JL TI N-formylpeptides induce two distinct concentration optima for mouse neutrophil chemotaxis by differential interaction with two N-formylpeptide receptor (FPR) subtypes: Molecular characterization of FPR2, a second mouse neutrophil FPR SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE chemoattractant; inflammation; neutrophil; G protein-coupled receptor; phagocyte ID FORMYL PEPTIDE RECEPTOR; FUNCTIONAL EXPRESSION; ACTIVATING PEPTIDE-2; GENE-CLUSTER; CDNA; CHEMOATTRACTANTS; IDENTIFICATION; DOMAINS AB The N-formylpeptide receptor (FPR) is a G protein-coupled receptor that mediates mammalian phagocyte chemotactic responses to bacterial N-formylpeptides. Here we show that a mouse gene named Fpr-rs2 encodes a second N-formylpeptide receptor subtype selective for neutrophils which we have provisionally named FPR2. The prototype N-formylpeptide fMLF induced calcium aux and chemotaxis in human embryonic kidney (HEK) 293 cells stably transfected with FPR2. The EC(50)s, similar to 5 mu M for calcium flux and chemotaxis, were similar to 100-fold greater than the corresponding values for mouse FPR-transfected HEK 293 cells. Consistent with this, fMLF induced two distinct concentration optima for chemotaxis of normal mouse neutrophils, but only the high concentration optimum for chemotaxis of neutrophils from FPR knockout mice. Based on these data, we hypothesize that high- and low-affinity N-formylpeptide receptors, FPR and FPR2, respectively, may function in vivo as a relay mediating neutrophil migration through the high and low concentration portions of N-formylpeptide gradients. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Gao, JL (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Rm 11N113, Bethesda, MD 20892 USA. NR 29 TC 85 Z9 87 U1 0 U2 5 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD SEP 6 PY 1999 VL 190 IS 5 BP 741 EP 747 DI 10.1084/jem.190.5.741 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 235GT UT WOS:000082534500015 PM 10477558 ER PT J AU Szabo, T Olah, Z Iadarola, MJ Blumberg, PM AF Szabo, T Olah, Z Iadarola, MJ Blumberg, PM TI Epidural resiniferatoxin induced prolonged regional analgesia to pain SO BRAIN RESEARCH LA English DT Article DE resiniferatoxin; capsaicin; vanilloid; VR1; nociception ID SPINAL-CORD; THERMAL-STIMULATION; VANILLOID RECEPTORS; CAPSAICIN RECEPTOR; RAT; DESENSITIZATION; HYPERALGESIA; MECHANISMS; MORPHINE; NEURONS AB Adequate treatment of cancer pain remains a significant clinical problem. To reduce side effects of treatment, intrathecal and epidural routes of administration have been used where appropriate to reduce the total dose of agent administered while achieving regional control. Resiniferatoxin (RTX), an ultrapotent capsaicin analog, gives long-term desensitization of nociception via C-fiber sensory neurons. We evaluate here the analgesic effect on rats of epidurally administered RTX, using latency of response to a thermal stimulus in unrestrained animals. Results were compared with those for systemically administered RTX. Vehicle or graded doses of RTX were injected subcutaneously (s.c.) or through an indwelling lumbar (L4) epidural catheter as a single dose. Both routes of application of RTX produced profound thermal analgesia, reaching a plateau within 4-6 h and showing no restoration of pain sensitivity over 7 days. Vehicle was without effect. For the epidural route, the effect was selective as expected for the targeted spinal cord region, whereas the subcutaneous administration of RTX had a generalized analgesic effect. At doses yielding a tripling of back paw withdrawal latency, epidural treatment was 25-fold more effective than the subcutaneous route of application. Consistent with the regional selectivity of the lumbar epidural route, the front paws showed no more effect than by systemic RTX treatment. Binding experiments with [H-3]RTX provided further evidence of the segmental desensitization induced by epidural RTX. We conclude that epidural administration of RTX at the lumbar spinal level produces profound, long-lasting, segmental analgesia to C-Fiber mediated pain in the rat. (C) 1999 Elsevier Science B.V. ALT rights reserved. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. NIDCR, Neuronal Gene Express Unit, NIH, Bethesda, MD 20892 USA. RP Blumberg, PM (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bldg 37,Rm 3A01 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 31 TC 29 Z9 31 U1 1 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 SEP 4 PY 1999 VL 840 IS 1-2 BP 92 EP 98 DI 10.1016/S0006-8993(99)01763-1 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 234GY UT WOS:000082477300010 PM 10517956 ER PT J AU Guay, LA Musoke, P Fleming, T Bagenda, D Allen, M Nakabiito, C Sherman, J Bakaki, P Ducar, C Deseyve, M Emel, L Mirochnick, M Fowler, MG Mofenson, L Miotti, P Dransfield, K Bray, D Mmiro, F Jackson, JB AF Guay, LA Musoke, P Fleming, T Bagenda, D Allen, M Nakabiito, C Sherman, J Bakaki, P Ducar, C Deseyve, M Emel, L Mirochnick, M Fowler, MG Mofenson, L Miotti, P Dransfield, K Bray, D Mmiro, F Jackson, JB TI Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVMET 012 randomised trial SO LANCET LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 AB Background The AIDS Clinical Trials Group protocol 076 zidovudine prophylaxis regimen for HIV-1-infected pregnant women and their babies has been associated with a significant decrease in vertical HIV-1 transmission in non-breastfeeding women in developed countries. We compared the safety and efficacy of short-course nevirapine or zidovudine during labour and the first week of life. Methods From November, 1997, to April, 1999, we enrolled 626 HIV-1-infected pregnant women at Mulago Hospital in Kampala, Uganda. We randomly assigned mothers nevirapine 200 mg orally at onset of labour and 2 mg/kg to babies within 72 h of birth, or zidovudine 600 mg orally to the mother at onset of labour and 300 mg every 3 h until delivery, and 4 mg/kg orally twice daily to babies for 7 days after birth. We tested babies for HIV-1 infection at birth, 6-8 weeks, and 14-16 weeks by HIV-1 RNA PCR. We assessed HIV-1 transmission and HIV-1-free survival with Kaplan-Meier analysis. Findings Nearly all babies (98.8%) were breastfed, and 95.6% were still breastfeeding at age 14-16 weeks. The estimated risks of HIV-1 transmission in the zidovudine and nevirapine groups were: 10.4% and 8.2% at birth (p=0.354); 21.3% and 11.9% by age 6-8 weeks (p=0.0027); and 25.1% and 13.1% by age 14-16 weeks (p=0.0006). The efficacy of nevirapine compared with zidovudine was 47% (95% CI 20-64) up to age 14-16 weeks. The two regimens were well tolerated and adverse events were similar in the two groups. Interpretation Nevirapine lowered the risk of HIV-1 transmission during the first 14-16 weeks of life by nearly 50% in a breastfeeding population. This simple and inexpensive regimen could decrease mother-to-child HIV-1 transmission in less-developed countries. C1 Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. Makerere Univ, Dept Paediat, Kampala, Uganda. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Fred Hutchinson Canc Res Ctr, HIVNET Stat Ctr, Seattle, WA 98104 USA. Makerere Univ, Dept Obstet & Gynaecol, Kampala, Uganda. Family Hlth Int, Durham, NC USA. NIAID, Div AIDS, NIH, Boston, MA USA. NICHD, Pediat Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD USA. Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA. Glaxo Wellcome, London, England. RP Jackson, JB (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Carnegie Bldg,Room 420,600 N Wolfe St, Baltimore, MD 21205 USA. FU NIAID NIH HHS [N01-AI-35173] NR 20 TC 1148 Z9 1170 U1 1 U2 37 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD SEP 4 PY 1999 VL 354 IS 9181 BP 795 EP 802 DI 10.1016/S0140-6736(99)80008-7 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 232ZH UT WOS:000082400700007 PM 10485720 ER PT J AU Li, A Prasad, A Mincemoyer, R Satorius, C Epstein, N Finkel, T Quyyumi, AA AF Li, A Prasad, A Mincemoyer, R Satorius, C Epstein, N Finkel, T Quyyumi, AA TI Relationship of the C242T p22phox gene polymorphism to angiographic coronary artery disease and endothelial function SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE coronary artery disease; endothelium; genes; oxidant stress ID VASCULAR SMOOTH-MUSCLE; NITRIC-OXIDE ACTIVITY; NEUTROPHIL CYTOCHROME-B; ANGIOTENSIN-II; NADPH OXIDASE; SUPEROXIDE ANION; LIGHT CHAIN; EXPRESSION; CELLS; HYPERCHOLESTEROLEMIA AB Patients with coronary artery disease (CAD) have impaired endothelial function in part due to an increase in vascular oxidant stress. p22phox, an essential component of the NADPH oxidase, is thought to play a critical role in the generation of superoxide anions in the vessel wall. The C242T polymorphism, located in the potential heme-binding site of the p22phox gene, has recently been reported to confer a protective effect on CAD risk in a Japanese study population. In a U.S. population of 252 patients (83% Caucasian) undergoing angiography for diagnosis of CAD, we investigated whether the C242T polymorphism was associated with the presence of CAD. In a subset of 142 patients, we studied whether the polymorphism manifests its potential protective effects through alteration of vascular endothelial function by measuring coronary epicardial and microvascular responses to intracoronary acetylcholine and sodium nitroprusside. Prevalence of the C242T allele was not different in 149 patients with CAD compared to 103 patients with angiographically normal coronary arteries (65.1% vs. 54.4%, P = 0.11), The C242T allele frequency in our population was nearly fourfold higher than reported previously in a Japanese population. There were also no significant differences in coronary epicardial or microvascular responses to acetylcholine or sodium nitroprusside between groups of patients with or without the C242T allele, In a U.S. population, the C242T polymorphism does not appear to confer protection from endothelial dysfunction or CAD. Am. J, Med, Genet, 86: 57-61, 1999, Published 1999 Wiley-Liss, Inc.dagger C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. RP Quyyumi, AA (reprint author), NHLBI, Cardiol Branch, NIH, 10 Ctr Dr,MSC 1650,Bldg 10,Room 7B-15, Bethesda, MD 20892 USA. NR 22 TC 64 Z9 67 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 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD SEP 3 PY 1999 VL 86 IS 1 BP 57 EP 61 DI 10.1002/(SICI)1096-8628(19990903)86:1<57::AID-AJMG11>3.0.CO;2-R PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 227CT UT WOS:000082061300011 PM 10440830 ER PT J AU Mills, JL Kirke, PN Molloy, AM Burke, H Conley, MR Lee, YJ Mayne, PD Weir, DG Scott, JM AF Mills, JL Kirke, PN Molloy, AM Burke, H Conley, MR Lee, YJ Mayne, PD Weir, DG Scott, JM TI Methylenetetrahydrofolate reductase thermolabile variant and oral clefts SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE cleft lip; cleft palate; genetic defect; folate; metabolic defect; birth defect ID FOLIC-ACID; OROFACIAL CLEFTS; SUPPLEMENTATION; DEFECTS; MULTIVITAMINS; PREVENTION; PREGNANCY; FOLATE; LIP AB Folic acid can prevent neural tube defects; in some cases the mechanism is probably a correction of a metabolic defect caused by thermolabile methylenetetrahydrofolate reductase (MTHFR) found in increased frequency in cases. It is less clear whether folic acid can prevent oral clefts, in part because it is not known whether thermolabile MTHFR is more common in those with oral clefts. This study examined the prevalence of the mutation (677 C-->T) that causes thermolabile MTHFR in subjects with oral clefts from a national Irish support group, and an anonymous control group randomly selected from a neonatal screening program covering all births in Ireland. Eighty-three of 848 control subjects were homozygous (TT) thermolabile MTHFR (9.8%). This defect was almost three times as common in the 27 subjects (25.9%) with isolated cleft palate (odds ratio 3.23, 95% confidence interval 1.32 -7.86, P = 0.02) and somewhat more common in the 66 subjects with cleft lip with or without cleft palate (15.2%, odds ratio 1.65, 95% confidence interval 0.81-3.35, P = 0.20). When the two groups with different etiologies were combined, the overall odds ratio was 2.06 (95% confidence interval 1.16-3.66, P = 0.02). In the Irish population homozygosity for the common folate-related polymorphism associated with thermolabile MTHFR is significantly more frequent in those with isolated cleft palate, and could be etiologically important. Am. J, Med. Genet, 86:71-74, 1999, Published 1999 Wiley-Liss, Inc.dagger C1 NICHD, Pediat Epidemiol Sect, Epidemiol Branch, DESPR,NIH, Bethesda, MD 20852 USA. Hlth Res Board, Dublin, Ireland. Univ Dublin Trinity Coll, Dept Clin Med, Dublin 2, Ireland. Univ Dublin Trinity Coll, Dept Biochem, Dublin 2, Ireland. Temple St Childrens Hosp, Dublin, Ireland. RP Mills, JL (reprint author), NICHD, Pediat Epidemiol Sect, Epidemiol Branch, DESPR,NIH, 6100 Execut Blvd,Room 7B03, Bethesda, MD 20852 USA. FU NICHD NIH HHS [N01-HD-2-3163] NR 18 TC 86 Z9 89 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 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD SEP 3 PY 1999 VL 86 IS 1 BP 71 EP 74 DI 10.1002/(SICI)1096-8628(19990903)86:1<71::AID-AJMG14>3.0.CO;2-Y PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 227CT UT WOS:000082061300014 PM 10440833 ER PT J AU Wang, NP Verna, L Hardy, S Zhu, Y Ma, KS Birrer, MJ Stemerman, MB AF Wang, NP Verna, L Hardy, S Zhu, Y Ma, KS Birrer, MJ Stemerman, MB TI c-Jun triggers apoptosis in human vascular endothelial cells SO CIRCULATION RESEARCH LA English DT Article DE c-Jun; adenovirus; endothelial cell; apoptosis; hydrogen peroxide ID NF-KAPPA-B; DOMINANT-NEGATIVE MUTANT; P53-INDEPENDENT APOPTOSIS; GENE-EXPRESSION; NITRIC-OXIDE; IN-VIVO; DEATH; AP-1; PATHWAY; FOS AB In endothelial cells (ECs), the transcription factor c-Jun is induced by a variety of stimuli that perturb EC function. To extend our understanding of the role of c-Jun in EC physiology, we have directed overexpression of c-Jun in human umbilical vein ECs by using a tetracycline-regulated adenoviral expression system. In this study, we report a novel observation using this system. Specific expression of c-dun is a sufficient trigger for ECs to undergo apoptosis, as demonstrated by a set of combined assays including an ELISA specific for histone-associated DNA fragmentation, DNA laddering, and TdT-mediated dUTP nick end labeling (TUNEL). Tetracycline can effectively shut off c-Jun overexpression and prevent EC apoptosis. Cleavage of poly(ADP-ribose) polymerase was also detected in ECs overexpressing c-Jun. Moreover, inhibitors of cysteine proteases blocked the apoptosis, suggesting a caspase-associated mechanism involved in proapoptotic effects of c-Jun. To gain further insight into the role of c-Jun as a pathophysiological regulator of EC death, TAM67, a dominant-negative mutant of c-Jun, was overexpressed in human umbilical vein ECs to abrogate endogenous cJun/activator protein-1 activation. H2O2-triggered apoptosis was largely attenuated in ECs overexpressing TAM67. Together, these results suggest that c-Jun, as a proapoptotic molecule. may play a role in mediating the cell death program in vascular endothelium. C1 Univ Calif Riverside, Div Biomed Sci, Riverside, CA 92521 USA. Chiron Corp, Emeryville, CA 94608 USA. NCI, Med Branch, NIH, Rockville, MD USA. RP Wang, NP (reprint author), Univ Calif Riverside, Div Biomed Sci, Riverside, CA 92521 USA. RI Wang, Nanping/G-1818-2011 FU NHLBI NIH HHS [HL 43023] NR 42 TC 66 Z9 67 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD SEP 3 PY 1999 VL 85 IS 5 BP 387 EP 393 PG 7 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 232DY UT WOS:000082352900001 PM 10473668 ER PT J AU Hahm, SH Eiden, LE AF Hahm, SH Eiden, LE TI Two separate cis-active elements of the vasoactive intestinal peptide gene mediate constitutive and inducible transcription by binding different sets of AP-1 proteins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CILIARY NEUROTROPHIC FACTOR; SCAVENGER RECEPTOR GENE; C-JUN; RAT-BRAIN; CHROMAFFIN CELLS; POLYPEPTIDE VIP; MESSENGER-RNA; KINASE; ACTIVATION; FOS AB Vasoactive intestinal peptide (VIP) gene expression is highly restricted throughout the neuroaxis and regulated by extracellular factors that activate tyrosine- or serine/threonine-directed protein kinase pathways. Cytokine, cyclic AMP, and tissue-specific response elements on the VIP gene have been characterized, Those mediating responsiveness to protein kinase C have not, The endogenous VIP gene and a 5.2-kilobase pair (kb) VIP-luciferase reporter gene, are up-regulated by phorbol 12-myristate 13-acetate (PMA) in SK-N-SH neuroblastoma cells. PMA stimulation was abolished by deletion of sequences at -1.37 to -1.28 or -1.28 to -0.904 kb, but not by removal of the single phorbol ester response element (TRE; TGACTCA) located at -2.25 kb. Mutation of sites at -1.32 or -1.20 that mediate neurotrophin responsiveness of the VIP gene (Symes, A., Lewis, S,, Corpus, L., Rajan, P., Hyman, S.E,, and Fink, J.S. (1994) Mol. Endocrinol. 8, 1750-1763) each reduced PMA induction in SK-N-SH cells by >50%, and double mutation abolished it. The two mutations also reduced basal VIP reporter gene transcription in SH-EP neuroblastoma cells expressing VIP constitutively. Both cis-active elements bound pre-existing AP-1 proteins in SH-EP- or PIMA-stimulated SK-N-SH cell nuclear extracts. The AP-1 complex at both sites contained a Fos-related protein with c-Jun in SH-EP cells and c-Fos with a Jun-related protein in SK-N-SH cells. Recruitment of combinatorially distinct AP-1 complexes to these elements may underlie cell type-specific regulation of the VIP gene. C1 NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Hahm, SH (reprint author), NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, 36 Convent Dr,MSC 4090,Bldg 36,Rm 2D10, Bethesda, MD 20892 USA. OI Eiden, Lee/0000-0001-7524-944X NR 35 TC 9 Z9 9 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 SEP 3 PY 1999 VL 274 IS 36 BP 25588 EP 25593 DI 10.1074/jbc.274.36.25588 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 235QN UT WOS:000082554200057 PM 10464293 ER PT J AU Ong, E Yeh, JC Ding, YL Hindsgaul, O Pedersen, LC Negishi, M Fukuda, M AF Ong, E Yeh, JC Ding, YL Hindsgaul, O Pedersen, LC Negishi, M Fukuda, M TI Structure and function of HNK-1 sulfotransferase - Identification of donor and acceptor binding sites by site-directed mutagenesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL-ADHESION MOLECULE; MYELIN-ASSOCIATED GLYCOPROTEIN; MONOCLONAL-ANTIBODY HNK-1; SULFATED GLUCURONIC-ACID; HEPARAN-SULFATE; CARBOHYDRATE EPITOPE; ESTROGEN SULFOTRANSFERASE; L2/HNK-1 CARBOHYDRATE; NERVOUS-SYSTEM; MUTATIONAL ANALYSIS AB HNK-1 glycan, sulfo-->3GlcA beta 1-->3Gal beta 1-->4GlcNAc-->R, is uniquely enriched in neural cells and natural killer cells and is thought to play important roles in cell-cell interaction. HNK-1 glycan synthesis is dependent on HNK-1 sulfotransferase (HNK-1ST), and cDNAs encoding human and rat HNK-1ST have been recently cloned. HNK-1ST belongs to the sulfotransferase gene family, which shares two homologous sequences in their catalytic domains. In the present study, we have individually mutated amino acid residues in these conserved sequences and determined how such mutations affect the binding to the donor substrate, adenosine 3'-phosphate 5'-phosphosulfate, and an acceptor. Mutations of Lys(128), Arg(189), Asp(190), Pro(191), and Ser(197) to Ala all abolished the enzymatic activity. When Lys(128) and Asp(190) were conservatively mutated to Arg and Glu, respectively, however, the mutated enzymes still maintained residual activity, and both mutant enzymes still bound to adenosine 3',5'-diphosphate-agarose. K128R and D190E mutant enzymes, on the other hand, exhibited reduced affinity to the acceptor as demonstrated by kinetic studies. These findings, together with those on the crystal structure of estrogen sulfotransferase and heparan sulfate N deacetylase/sulfotransferase, suggest that Lys(128) may be close to the 3-hydroxyl group of beta-glucuronic acid in a HNK-1 acceptor. In contrast, the effect by mutation at Asp(190) may be due to conformational change because this amino acid and Pro(191) reside in a transition of the secondary structure of the enzyme. These results indicate that conserved amino acid residues in HNK-1ST play roles in maintaining a functional conformation and are directly involved in binding to donor and acceptor substrates. C1 Burnham Inst, Glycobiol Program, Ctr Canc Res, La Jolla, CA 92037 USA. NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Fukuda, M (reprint author), Burnham Inst, Glycobiol Program, Ctr Canc Res, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. FU NCI NIH HHS [P01 CA71932, R01 CA33895] NR 49 TC 32 Z9 33 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 3 PY 1999 VL 274 IS 36 BP 25608 EP 25612 DI 10.1074/jbc.274.36.25608 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 235QN UT WOS:000082554200060 PM 10464296 ER PT J AU Rein, T Kobayashi, T Malott, M Leffak, M DePamphilis, ML AF Rein, T Kobayashi, T Malott, M Leffak, M DePamphilis, ML TI DNA methylation at mammalian replication origins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID C-MYC GENE; ESCHERICHIA-COLI CHROMOSOME; INACTIVE-X-CHROMOSOME; BINDING PROTEIN MECP2; HUMAN BLADDER-CANCER; XENOPUS EGG EXTRACT; CPG ISLAND PROMOTER; BETA-GLOBIN LOCUS; HELA-CELLS; INITIATION ZONE AB In Escherichia coli, DNA methylation regulates both origin usage and the time required to reassemble prereplication complexes at replication origins. In mammals, at least three replication origins are associated with a high density cluster of methylated CpG dinucleotides, and others whose methylation status has not yet been characterized have the potential to exhibit a similar DNA methylation pattern. One of these origins is found within the similar to 2-kilobase pair region upstream of the human c-myc gene that contains 86 CpGs. Application of the bisulfite method for detecting 5-methylcytosines at specific DNA sequences revealed that this region was not methylated in either total genomic DNA or newly synthesized DNA. Therefore, DNA methylation is not a universal component of mammalian replication origins, To determine whether or not DNA methylation plays a role in regulating the activity of origins that are methylated, the rate of remethylation and the effect of hypomethylation were determined at origin beta (ori-beta), downstream of the hamster DHFR gene. Remethylation at ori-beta did not begin until similar to 500 base pairs of DNA was synthesized, but it was then completed by the time that 4 kilobase pairs of DNA was synthesized (<3 min after release into S phase). Thus, DNA methylation cannot play a significant role in regulating reassembly of prereplication complexes in mammalian cells, as it does in E. coli, To determine whether or not DNA methylation plays any role in origin activity, hypomethylated hamster cells were examined for ori-beta activity. Cells that were >50% reduced in methylation at ori-beta no longer selectively activated ori-beta. Therefore, at some loci, DNA methylation either directly or indirectly determines where replication beans. C1 NICHD, NIH, Bethesda, MD 20892 USA. Max Planck Inst Psychiat, D-80804 Munich, Germany. Natl Inst Basic Biol, Okazaki, Aichi 444, Japan. Wright State Univ, Dept Biochem & Mol Biol, Dayton, OH 45435 USA. RP DePamphilis, ML (reprint author), NICHD, NIH, Bldg 6,Rm 416, Bethesda, MD 20892 USA. FU NIGMS NIH HHS [GM53819] NR 108 TC 38 Z9 39 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 SEP 3 PY 1999 VL 274 IS 36 BP 25792 EP 25800 DI 10.1074/jbc.274.36.25792 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 235QN UT WOS:000082554200082 PM 10464318 ER PT J AU Roche, KW Tu, JC Petralia, RS Xiao, B Wenthold, RJ Worley, PF AF Roche, KW Tu, JC Petralia, RS Xiao, B Wenthold, RJ Worley, PF TI Homer 1b regulates the trafficking of group I metabotropic glutamate receptors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CLIMBING FIBER SYNAPSES; POSTSYNAPTIC DENSITY; CLUSTERING ACTIVITY; GUANYLATE KINASES; PURKINJE-CELLS; MEMBRANE; PROTEINS; SUBUNITS; PARALLEL; PSD-95 AB The molecular basis for glutamate receptor trafficking to the plasma membrane is not understood. In the present study, we demonstrate that Homer 1b (H1b), a constitutively expressed splice form of the immediate early gene product Homer (now termed Homer 1a) regulates the trafficking and surface expression of group I metabotropic glutamate receptors, H1b inhibits surface expression of the metabotropic glutamate receptor mGluR5 in heterologous cells, causing mGluR5 to be retained in the endoplasmic reticulum (ER), In contrast, mGluR5 alone or mGluR5 coexpressed with Homer la successfully travels through the secretory pathway to the plasma membrane. In addition, point mutations that disrupt mGluR5 binding to H1b eliminate ER retention of mGluR5, demonstrating that H1b affects metabotropic receptor localization via a direct protein-protein interaction. Electron microscopic analysis reveals that the group I metabotropic receptor mGluR1a is significantly enriched in the ER of Purkinje cells, suggesting that a similar mechanism may exist in vivo. Because H1b is found in dendritic spines of neurons, local retention of metabotropic receptors within dendritic ER provides a potential mechanism for regulating synapse-specific expression of group I metabotropic glutamate receptors. C1 NIDCD, Neurochem Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Neurosci, Baltimore, MD 21205 USA. RP Roche, KW (reprint author), NIDCD, Neurochem Lab, NIH, Bldg 36,Rm 5D08, Bethesda, MD 20892 USA. OI Roche, Katherine/0000-0001-7282-6539 NR 29 TC 158 Z9 161 U1 0 U2 10 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 SEP 3 PY 1999 VL 274 IS 36 BP 25953 EP 25957 DI 10.1074/jbc.274.36.25953 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 235QN UT WOS:000082554200104 PM 10464340 ER PT J AU El-Kabbani, O Old, SE Ginell, SL Carper, DA AF El-Kabbani, O Old, SE Ginell, SL Carper, DA TI Aldose and aldehyde reductases: Structure-function studies on the coenzyme and inhibitor-binding sites SO MOLECULAR VISION LA English DT Article ID DIABETIC COMPLICATIONS; DIRECTED MUTAGENESIS; X-RAY; HOLOENZYME; MECHANISM; SPECIFICITY; SUBSTRATE; POCKET AB PURPOSE: To identify the structural features responsible for the differences in coenzyme and inhibitor specificities of aldose and aldehyde reductases. METHODS: The crystal structure of porcine aldehyde reductase in complex with NADPH and the aldose reductase inhibitor sorbinil was determined. The contribution of each amino acid lining the coenzyme-binding site to the binding of NADPH was calculated using the Discover package. In human aldose reductase, the role of the non-conserved Pro 216 (Ser in aldehyde reductase) in the binding of coenzyme was examined by site-directed mutagenesis. RESULTS: Sorbinil binds to the active site of aldehyde reductase and is hydrogen-bonded to Trp 22, Tyr 50, His 113, and the non-conserved Arg 312. Unlike tolrestat, the binding of sorbinil does not induce a change in the side chain conformation of Arg 312. Mutation of Pro 216 to Ser in aldose reductase makes the binding of coenzyme more similar to that of aldehyde reductase. CONCLUSIONS: The participation of non-conserved active site residues in the binding of inhibitors and the differences in the structural changes required for the binding to occur are responsible for the differences in the potency of inhibition of aldose and aldehyde reductases. We report that the non-conserved Pro 216 in aldose reductase contributes to the tight binding of NADPH. C1 Monash Univ, Victorian Coll Pharm, Dept Med Chem, Parkville, Vic 3052, Australia. NEI, NIH, Bethesda, MD USA. Argonne Natl Lab, Struct Biol Ctr, Argonne, IL 60439 USA. RP El-Kabbani, O (reprint author), Monash Univ, Victorian Coll Pharm, Dept Med Chem, Parkville Campus,381 Royal Parade, Parkville, Vic 3052, Australia. NR 25 TC 4 Z9 4 U1 0 U2 1 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD SEP 3 PY 1999 VL 5 IS 20 BP U1 EP U6 PG 6 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 240KG UT WOS:000082824700001 ER PT J AU Liepert, J Oreja-Guevara, C Cohen, LG Tegenthoff, M Hallett, M Malin, JP AF Liepert, J Oreja-Guevara, C Cohen, LG Tegenthoff, M Hallett, M Malin, JP TI Plasticity of cortical hand muscle representation in patients with hemifacial spasm SO NEUROSCIENCE LETTERS LA English DT Article DE plasticity; motor cortex; transcranial magnetic stimulation; mapping; hemifacial spasm; botulinum toxin ID TRANSCRANIAL MAGNETIC STIMULATION; HUMAN MOTOR CORTEX; PHANTOM-LIMB PAIN; REORGANIZATION; AMPUTATION; MODULATION; RESPONSES; MAPS AB To investigate interactions between face and hand representations in the human motor cortex, we studied patients with a hemifacial spasm before and after treatment with Botulinum toxin. Focal transcranial magnetic stimulation was used to assess the cortical motor output map of the abductor pollicis brevis muscle (APB) on both sides. Prior to therapy the representation of the APE ipsilateral to the facial muscle contractions (iAPB) was significantly smaller than on the contralateral side, Two weeks after successful therapy, the iAPB output area was significantly enlarged and expanded into the direction of the face representation. The results indicate activity dependent interactions between hand and face representations in the adult human motor cortex. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Jena, Dept Neurol, D-07743 Jena, Germany. Ruhr Univ Bochum, BG Kliniken Bergmannsheil, Dept Neurol, D-4630 Bochum, Germany. NIH, Human Cort Physiol Sect, Bethesda, MD 20892 USA. RP Liepert, J (reprint author), Univ Jena, Dept Neurol, Philosophenweg 3, D-07743 Jena, Germany. NR 20 TC 15 Z9 15 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD SEP 3 PY 1999 VL 272 IS 1 BP 33 EP 36 DI 10.1016/S0304-3940(99)00574-1 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 238CN UT WOS:000082693500009 PM 10507536 ER PT J AU Parascandola, M AF Parascandola, M TI The Nazi war on cancer SO TLS-THE TIMES LITERARY SUPPLEMENT LA English DT Book Review C1 NIH, Dept Clin Bioethics, Bethesda, MD 20892 USA. RP Parascandola, M (reprint author), NIH, Dept Clin Bioethics, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU TIMES SUPPLEMENTS LIMITED PI MARKET HARBOROUGH PA TOWER HOUSE, SOVEREIGN PARK, MARKET HARBOROUGH LE87 4JJ, ENGLAND SN 0307-661X J9 TLS-TIMES LIT SUPPL JI TLS-Times Lit. Suppl. PD SEP 3 PY 1999 IS 5031 BP 31 EP 31 PG 1 WC Humanities, Multidisciplinary SC Arts & Humanities - Other Topics GA 237KU UT WOS:000082656200056 ER PT J AU Le Roith, D AF Le Roith, D TI Tumor-induced hypoglycemia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Le Roith, D (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 10 TC 30 Z9 31 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 2 PY 1999 VL 341 IS 10 BP 757 EP 758 DI 10.1056/NEJM199909023411011 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 231DB UT WOS:000082291900011 PM 10471466 ER PT J AU Alper, O Hacker, NF Cho-Chung, YS AF Alper, O Hacker, NF Cho-Chung, YS TI Protein kinase A-I alpha subunit-directed antisense inhibition of ovarian cancer cell growth: crosstalk with tyrosine kinase signaling pathway SO ONCOGENE LA English DT Article DE protein kinase A; antisense; ovarian cancer; tyrosine kinase; EGF receptor ID REGULATORY SUBUNIT; CAMP; EXPRESSION; DIFFERENTIATION; OLIGODEOXYNUCLEOTIDE; TRANSFORMATION; ACTIVATION; RECEPTOR; SITE; FIBROBLASTS AB Expression of the RI alpha subunit of cAMP-dependent protein kinase type I is increased in human cancers in which an autocrine pathway for epidermal growth factor-related growth factors is activated. We have investigated the effect of sequence-specific inhibition of RI alpha gene expression on ovarian cancer cell growth. We report that RI alpha antisense treatment results in a reduction in RI alpha expression and protein kinase A type I, and inhibition of cell growth. The growth inhibition was accompanied by changes in cell morphology and appearance of apoptotic nuclei. In addition, EGF receptor, c-erbB-2 and c-erbB-3 levels were reduced, and the basal and EGF-stimulated mitogen-activated protein kinase activities were reduced. Protein kinase A type I and EGF receptor levels were also reduced in cells overexpressing EGF receptor antisense cDNA. These results suggest that the antisense depletion of RI alpha leads to blockade of both the serine-threonine kinase and the tyrosine kinase signaling pathways resulting in arrest of ovarian cancer cell growth. C1 NCI, Cellular Biochem Sect, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. Royal Hosp Women, Gynaecol Canc Ctr, Randwick, NSW 2031, Australia. RP Cho-Chung, YS (reprint author), NCI, Cellular Biochem Sect, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. NR 35 TC 25 Z9 26 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 2 PY 1999 VL 18 IS 35 BP 4999 EP 5004 DI 10.1038/sj.onc.1202830 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 231QQ UT WOS:000082321700013 PM 10490835 ER PT J AU da Costa, LT He, TC Yu, J Sparks, AB Morin, PJ Polyak, K Laken, S Vogelstein, B Kinzler, KW AF da Costa, LT He, TC Yu, J Sparks, AB Morin, PJ Polyak, K Laken, S Vogelstein, B Kinzler, KW TI CDX2 is mutated in a colorectal cancer with normal APC/beta-catenin signaling SO ONCOGENE LA English DT Article DE CDX2; APC; colorectal cancer; mutation; regulation ID TUMOR-SUPPRESSOR PROTEIN; APC GENE-PRODUCT; BETA-CATENIN; COLON-CARCINOMA; TUMORIGENESIS; ASSOCIATION; EXPRESSION; ACTIVATION; POLYPOSIS; MUTATIONS AB The majority of human colorectal cancers have elevated beta-catenin/TCF regulated transcription due to either inactivating mutations of the APC tumor suppressor gene or activating mutations of beta-catenin, Surprisingly, one commonly used colorectal cancer cell line was found to have intact APC and beta-catenin and no demonstrable beta-catenin/TCF regulated transcription. However, this line did possess a truncating mutation in one allele of CDX2, a gene whose inactivation has recently been shown to cause colon tumorigenesis in mice. Expression of CDX2 was found to be induced by restoring expression of wild type APC in a colorectal cancer cell line. These findings raise the intriguing possibility that CDX2 contributes to APC's tumor suppressive effects. C1 Johns Hopkins Oncol Ctr, Baltimore, MD 21231 USA. Johns Hopkins Univ, Program Human Genet & Mol Biol, Baltimore, MD 21231 USA. NIA, Biol Chem Lab, NIH, Baltimore, MD 21224 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Johns Hopkins Univ, Howard Hughes Med Inst, Baltimore, MD 20815 USA. RP Kinzler, KW (reprint author), Johns Hopkins Oncol Ctr, Baltimore, MD 21231 USA. FU NCI NIH HHS [CA57345]; NIGMS NIH HHS [GM07814] NR 27 TC 101 Z9 102 U1 0 U2 4 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 2 PY 1999 VL 18 IS 35 BP 5010 EP 5014 DI 10.1038/sj.onc.1202872 PG 5 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 231QQ UT WOS:000082321700015 PM 10490837 ER PT J AU Ellis, GB AF Ellis, GB TI Protecting the rights and welfare of human research subjects SO ACADEMIC MEDICINE LA English DT Article C1 NIH, Off Protect Res Risks, Rockville, MD USA. RP Ellis, GB (reprint author), NIH, Off Protect Res Risks, Rockville, MD USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU HANLEY & BELFUS INC PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD SEP PY 1999 VL 74 IS 9 BP 1008 EP 1009 DI 10.1097/00001888-199909000-00013 PG 2 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 236NR UT WOS:000082605900019 PM 10498093 ER PT J AU Bullitt, E Liu, A Aylward, SR Coffey, C Stone, J Mukherji, SK Muller, KE Pizer, SM AF Bullitt, E Liu, A Aylward, SR Coffey, C Stone, J Mukherji, SK Muller, KE Pizer, SM TI Registration of 3D cerebral vessels with 2D digital angiograms: Clinical evaluation SO ACADEMIC RADIOLOGY LA English DT Article DE angiography; blood vessels; DSA; interventional radiology; intracerebral vessels; MR angiography; registration ID X-RAY ANGIOGRAMS AB Rationale and Objectives. The purpose of this study was : to evaluate the accuracy and speed of a new, semiautomatic method of three-dimensional (3D)-two-dimensional (2D) vascular registration. This method should help guide endovascular procedures by allowing interpretion of each digital subtraction angiographic (DSA) image in terms of precreated, 3D vessel trees that contain "parent-child" connectivity information. Materials and Methods. Connected, 3D vessel trees were created from segmented magnetic resonance (MR) angiograms. Eleven total DSA images were registered with such trees by using both our method and the current standard (manual registration). The accuracy of each method was compared by using repeated-measures analysis of variance with correction for heterogeneity of variance to evaluate separation of curve pairs on the view plane. Subjective clinical comparisons of the two registration methods were evaluated with the sign test. Registration times were evaluated for both methods and also as a function of the error in the initial estimate of MR angiographic position. Results. The new registration method produced results that were numerically superior to those of manual registration (P < .001) and was subjectively judged to be as good as or better by clinical reviewers. Registration time with the new method was faster (P < .001). If the rotational error in the initial estimate of MR angiographic position is less than 10 degrees around each axis, the registration itself took only 1-2 minutes. Conclusion. This method is quicker than and produces results as good as or better than those of manual registration . This method should be able to calculate an initial registration matrix during endovascular embolization and adjust that matrix intermittenly with registration updates provided by automatic tracking systems. C1 Univ N Carolina, Div Neurosurg, Med Image Display & Anal Grp, Chapel Hill, NC 27599 USA. NIH, Bethesda, MD 20892 USA. RP Bullitt, E (reprint author), Univ N Carolina, Div Neurosurg, Med Image Display & Anal Grp, 148 Burnett Womack,CB 7060, Chapel Hill, NC 27599 USA. FU NCI NIH HHS [P01CA47982, R01CA67812] NR 10 TC 21 Z9 25 U1 0 U2 1 PU ASSOC UNIV RADIOLOGISTS PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523-2251 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD SEP PY 1999 VL 6 IS 9 BP 539 EP 546 DI 10.1016/S1076-6332(99)80432-2 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 296PV UT WOS:000086033600006 PM 10894063 ER PT J AU Bragg, DG Sullivan, DC Menkens, AE AF Bragg, DG Sullivan, DC Menkens, AE TI Radiologic sciences research in the next century: New national initiatives and evolving university and industrial relationships SO ACADEMIC RADIOLOGY LA English DT Article C1 NCI, Diagnost Imaging Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. Univ Utah, Dept Radiol, Salt Lake City, UT 84132 USA. RP Sullivan, DC (reprint author), NCI, Diagnost Imaging Program, Div Canc Treatment & Diag, NIH, Execut Pk N,Rm 800,6130 Execut Blvd, Bethesda, MD 20892 USA. NR 1 TC 1 Z9 1 U1 0 U2 0 PU ASSOC UNIV RADIOLOGISTS PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523-2251 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD SEP PY 1999 VL 6 IS 9 BP 552 EP 558 DI 10.1016/S1076-6332(99)80434-6 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 296PV UT WOS:000086033600008 PM 10894065 ER PT J AU Longenecker, K Read, P Derewenda, U Dauter, Z Liu, XP Garrard, S Walker, L Somlyo, AV Nakamoto, RK Somlyo, AP Derewenda, ZS AF Longenecker, K Read, P Derewenda, U Dauter, Z Liu, XP Garrard, S Walker, L Somlyo, AV Nakamoto, RK Somlyo, AP Derewenda, ZS TI How RhoGDI binds Rho SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID GDP-DISSOCIATION INHIBITOR; GTPASE-ACTIVATING-PROTEIN; SMOOTH-MUSCLE; CRYSTAL-STRUCTURE; NUCLEOTIDE EXCHANGE; CA2+ SENSITIZATION; ADP-RIBOSYLATION; CALCIUM SENSITIZATION; GDP/GTP EXCHANGE; MAST-CELLS AB Like all Rho (Ras homology) GTPases, RhoA functions as a molecular switch in cell signaling, alternating between GTP- and GDP-bound states, with its biologically inactive GDP-bound form maintained as a cytosolic complex with RhoGDI (guanine nucleotide-exchange inhibitor). The crystal structures of RhoA-GDP and of the C-terminal immunoglobulin-like domain of RhoGDI (residues 67-203) are known, but the mechanism by which the two proteins interact is not known. The functional human RhoA-RhoGDI complex has been expressed in yeast and crystallized (P6(5)22, unit-cell parameters a = b = 139, c = 253 Angstrom, two complexes in the asymmetric unit). Although diffraction from these crystals extends to 3.5 Angstrom and is highly anisotropic, the experimentally phased (MAD plus MIR) electron-density map was adequate to reveal the mutual disposition of the two molecules. The result was validated by molecular-replacement calculations when data were corrected for anisotropy. Furthermore, the N-terminus of RhoGDI (the region involved in inhibition of nucleotide exchange) can be identified in the electron-density map: it is bound to the switch I and switch II regions of RhoA, occluding an epitope which binds Db1-like nucleotide-exchange factors. The entrance of the hydrophobic pocket of RhoGDI is 25 Angstrom from the last residue in the RhoA model, with its C-terminus oriented to accommodate the geranylgeranyl group without conformational change in RhoA. C1 Univ Virginia, Hlth Sci Ctr, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22906 USA. NCI, Upton, NY 11973 USA. RP Derewenda, ZS (reprint author), Univ Virginia, Hlth Sci Ctr, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22906 USA. RI Walker, Lori/J-7098-2013 OI Walker, Lori/0000-0003-2556-8076 FU NHLBI NIH HHS [HL48807] NR 58 TC 57 Z9 60 U1 0 U2 2 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD SEP PY 1999 VL 55 BP 1503 EP 1515 DI 10.1107/S090744499900801X PN 9 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 238TK UT WOS:000082727800003 PM 10489445 ER PT J AU Chuaqui, R Cole, K Cuello, M Silva, M Quintana, ME Emmert-Buck, MR AF Chuaqui, R Cole, K Cuello, M Silva, M Quintana, ME Emmert-Buck, MR TI Analysis of mRNA quality in freshly prepared and archival Papanicolaou samples SO ACTA CYTOLOGICA LA English DT Article DE Papanicolaou smear; mRNA; gene expression; polymerase chain reaction ID MONOCLONAL-ANTIBODY B72.3; POLYMERASE CHAIN-REACTION; GENE-EXPRESSION PATTERNS; CERVICAL SMEARS; NEEDLE ASPIRATION; FLOW-CYTOMETRY; DNA ANALYSIS; BREAST; LESIONS; CANCER AB OBJECTIVE: To study the feasibility of utilizing mRNA recovered front cytologic Papanicolaou (Pay) specimens as a resource for gene expression studies of normal and diseased cells. STUDY DESIGN: To assess the effects of fixation on mRNA recovery and analysis, fresh Pay samples were processed by three separate methods: (1) routine cytologic fixation, (2) 70% ethanol fixation, and (3) air drying without fixation. One-week-old, 1-month-old, 1-year-old and 10-year-old samples were studied to determine the quality of mRNA in archival samples. mRNA quality was analyzed by RT-PCR for the HPRT gene, and by complete transcript amplification. Both heterogeneous (whole slide scrapes) and microdissected cell populations were studied. RESULTS: Reverse transcriptase-polymerase chain reaction (RT-PCR)for the hypoxanthine guanine phosphoribosil transferase gene teas positive in all fresh and archival samples and was not affected by fixative, processing methodology or microdissection. Complete transcript amplification followed by gel electrophoresis showed cDNA smears in all fresh samples with a maximum intensity between 1 and 2 kilobases (kb). Amplification of mRNA was Mot affected by fixation. Smaller cDNA smears were seen in archival specimens with a maximum intensity between 0.5 and 1.5 kb in both one-week-old and one-month-old samples. Smears of approximately 500 base pairs were observed in the 1-year-old and 10-year-old samples. Successful mRNA amplification was possible from microdissected cell populations. CONCLUSION: Messenger RNA recovery and analysis is possible from archival cytologic specimens, suggesting that they call serve as a useful template for RT-PCR analysis of individual genes as well as newly developing high-throughput gene expression methodologies, such as microarrays. Cytologic samples may be particularly useful for study of archival samples as well as diseases from which tissue samples amenable to mRNA-based studies are not available. C1 Catholic Univ Chile, Dept Pathol, Santiago, Chile. Catholic Univ Chile, Dept Obstet & Gynecol, Santiago, Chile. NCI, Pathogenet Unit, Pathol Lab, Bethesda, MD 20892 USA. RP Chuaqui, R (reprint author), Catholic Univ Chile, Hosp Clin, Dept Anat Patol, Marcoleta 367, Santiago, Chile. RI Cole, Kristina/M-3922-2015 NR 23 TC 9 Z9 12 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 0001-5547 J9 ACTA CYTOL JI Acta Cytol. PD SEP-OCT PY 1999 VL 43 IS 5 BP 831 EP 836 PG 6 WC Pathology SC Pathology GA 237DU UT WOS:000082640700015 PM 10518138 ER PT J AU Nelson, WL Hughes, HM Katz, B Searight, HR AF Nelson, WL Hughes, HM Katz, B Searight, HR TI Anorexic eating attitudes and behaviors of male and female college students SO ADOLESCENCE LA English DT Article ID SEXUAL ABUSE; NERVOSA; DISORDERS; BULIMIA; EPIDEMIOLOGY; POPULATIONS; PREVALENCE; ADJUSTMENT; PREVENTION; INVENTORY AB This study examined gender differences in eating attitudes and behaviors in a sample of 471 undergraduate college students. The prevalence of symptomatology indicative of anorexia was determined using the Eating Attitudes Test (EAT-26). In addition, the family climate, parent-child dynamics, and self-concept of students with and without maladaptive eating attitudes and behaviors were compared, and the relationship between eating attitudes/behaviors and current psychological distress was examined. Anorexic symptomatology was found for 20% of the females and 10% of the males. In general, students without symptomatic attitudes and behaviors had a more positive self-concept and reported less psychological distress than did those with eating disturbances. The findings suggest that eating problems may be more prevalent among males than previously estimated. C1 NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. St Louis Univ, Dept Psychol, St Louis, MO 63103 USA. St Louis Univ, Dept Res Methodol, St Louis, MO 63103 USA. So Illinois Univ, Dept Psychol, Edwardsville, IL 62026 USA. RP Nelson, WL (reprint author), NIAID, Div Aids, NIH, 6700-B Rockledge Dr,MSC-7628,Room 4112, Bethesda, MD 20892 USA. NR 44 TC 38 Z9 38 U1 2 U2 4 PU LIBRA PUBLISHERS INC PI SAN DIEGO PA 3089C CLAIREMONT DR SUITE 383, SAN DIEGO, CA 92117 USA SN 0001-8449 J9 ADOLESCENCE JI Adolescence PD FAL PY 1999 VL 34 IS 135 BP 621 EP 633 PG 13 WC Psychology, Developmental SC Psychology GA 269WE UT WOS:000084499900016 PM 10658869 ER PT J AU Cohen, SG Settipane, GA AF Cohen, SG Settipane, GA TI Max Samter, MD 1908-1999 - Obituary SO ALLERGY AND ASTHMA PROCEEDINGS LA English DT Biographical-Item C1 NIAID, Bethesda, MD 20892 USA. RP Cohen, SG (reprint author), NIAID, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU OCEAN SIDE PUBLICATIONS INC PI PROVIDENCE PA 95 PITMAN ST, PROVIDENCE, RI 02906 USA SN 1088-5412 J9 ALLERGY ASTHMA PROC JI Allergy Asthma Proc. PD SEP-OCT PY 1999 VL 20 IS 5 BP 329 EP 335 DI 10.2500/108854199778251997 PG 7 WC Allergy SC Allergy GA 253KF UT WOS:000083555200013 PM 10566103 ER PT J AU Jonas, WB AF Jonas, WB TI Do homeopathic nosodes protect against infection? An experimental test SO ALTERNATIVE THERAPIES IN HEALTH AND MEDICINE LA English DT Article AB Context For centuries, homeopathic practitioners have claimed that serially agitated dilutions of infectious agents (called "nosodes") are effective in the prevention of infectious disease. However, no rigorous tests of this claim have been performed. Objective To test whether a nosode of Francisella tularensis-infected tissue could protect from subsequent challenge with this pathogen in vivo. Design. Experimental laboratory test. Setting. A P3 containment laboratory at an infectious disease research facility Participants 142 male C3H/HeN specific, pathogen-free mice. Intervention Six levels of a nosode prepared from tularemia-infected tissue were produced All exposures were below the lowest level at which a classical vaccination response was expected. The nosode and dilutent control solutions were administered orally (.03 mL, 3 times per week)for 1 month before and after challenge. Animals were challenged with a potentially lethal nose (LD50 or LD75) Of F tularensis, then evaluated for time of death and total mortality. Main Outcome Measures Mortality and time to death. Results In a series of 15 trials (n=142), the tularemia nosode consistently produced increased mean times to death. All but 2 of 15 trials showed reduced time to death in the nosode group and decreased mortality compared with controls. Protection rates averaged 22% over controls compared to 100% protection by standard vaccination. Conclusions This study found partial protection from a nosode of tularemia in dilutions below those expected to have protective effects, but not as great as those produced by standard vaccination. If homeopathic nosodes can induce protection from infectious agents for which vaccination is currently unavailable, they may provide an interim method of reducing morbidity or mortality from such agents. C1 Uniformed Serv Univ Hlth Sci, Dept Family Med, Bethesda, MD 20814 USA. NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. RP Jonas, WB (reprint author), Uniformed Serv Univ Hlth Sci, Dept Family Med, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. NR 30 TC 16 Z9 16 U1 0 U2 0 PU INNOVISION COMMUNICATIONS PI ALISO VIEJO PA 101 COLUMBIA, ALISO VIEJO, CA 92656 USA SN 1078-6791 J9 ALTERN THER HEALTH M JI Altern. Ther. Health Med. PD SEP PY 1999 VL 5 IS 5 BP 36 EP 40 PG 5 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA 228GE UT WOS:000082128100010 PM 10484829 ER PT J AU Flack, JM Kvasnicka, JH Gardin, JM Gidding, SS Manolio, TA Jacobs, DR AF Flack, JM Kvasnicka, JH Gardin, JM Gidding, SS Manolio, TA Jacobs, DR CA CARDIA Investigators TI Anthropometric and physiologic correlates of mitral valve prolapse in a biethnic cohort of young adults: The CARDIA study SO AMERICAN HEART JOURNAL LA English DT Article ID PREVALENCE; DIAGNOSIS; CHILDREN; WOMEN; MEN AB Objective To describe the epidemiology of echocardiographic mitral valve prolapse (MVP) and its anthropometric, physiologic, and psychobehavioral correlates with a cross-sectional analysis at 4 urban clinical centers. Patients A biethnic, community-based sample of 4136 young (aged 23 to 35 years) adult participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study who had echocardiograms during their third examination between 1990 and 1991. Measurements Echocardiographic mitral valve prolapse, Doppler mitral regurgitation, blood pressure, anthropometry, and 4 psychobehavioral scales. Results Definite echocardiographic MVP prevalence was 0.6% overall and was similar across the 4 ethnicity/sex groups. Most participants (21 of 26, 80%) with definite echocardiographic MVP were unaware of their condition. Relative to persons with normal echocardiograms, those with echocardiographic MVP were taller (174.6 cm vs 171.0 cm, P < .01), leaner (26.7 mm vs 37.4 mm sum of triceps and subscapular skinfolds, P < .01), had lower body mass index (22.0 kg/m(2) vs 26.2 kg/m(2), P < .01), and more often has Doppler mitral regurgitation (34.8% vs 11.8%, P < .01). Women with echocardiographic MVP had higher ethnicity-adjusted hostility scores (19.9 vs 16.1, P < .05) than women with no MVP. Among 111 (2.7%) of 4136 participants reporting prior physician diagnosis of MVP, only 5 (0.45%) of 111 had definite echocardiographic MVP. Conclusions These data document a low prevalence of definite echocardiographic MVP and suggest a constellation of anthropometric, physiologic, and psychobehavioral characteristics in young adults with echocardiographic MVP. Most definite echocardiographic MVP diagnoses were discordant with self-reported MVP status, and false-positive diagnoses of echocardiographic MVP were made more often in women and whites. C1 Wayne State Univ, Harper Hosp,Med Ctr, Sch Med,Cardiovasc Epidemiol & Clin Applicat Prog, Div Endocrinol Metab & Hypertens,Dept Internal Me, Detroit, MI 48201 USA. John D Dingell Vet Adm Med Ctr, Detroit, MI USA. St Josephs Hosp, St Paul, MN USA. Univ Calif Irvine, Orange, CA 92668 USA. Northwestern Univ, Sch Med, Chicago, IL USA. NHLBI, Bethesda, MD 20892 USA. Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. RP Flack, JM (reprint author), Wayne State Univ, Harper Hosp,Med Ctr, Sch Med,Cardiovasc Epidemiol & Clin Applicat Prog, Div Endocrinol Metab & Hypertens,Dept Internal Me, 3990 John Rd,1 WS, Detroit, MI 48201 USA. FU NHLBI NIH HHS [N01-HV-48048, N01-HV-48047, N01-HV-48049] NR 25 TC 34 Z9 39 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 SEP PY 1999 VL 138 IS 3 BP 486 EP 492 DI 10.1016/S0002-8703(99)70151-1 PN 1 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 232ZW UT WOS:000082401900018 PM 10467199 ER PT J AU White, AD Rosamond, WD Chambless, LE Thomas, N Conwill, D Cooper, LS Folsom, AR AF White, AD Rosamond, WD Chambless, LE Thomas, N Conwill, D Cooper, LS Folsom, AR CA Atherosclerosis Risk Communities study inves TI Sex and race differences in short-term prognosis after acute coronary hear, disease events: The Atherosclerosis Risk In Communities (ARIC) study SO AMERICAN HEART JOURNAL LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; THROMBOLYTIC THERAPY; CASE-FATALITY; MONICA PROJECT; WOMEN; MORTALITY; MEN; GENDER; TRENDS; MINNESOTA AB Background Case fatality after myocardial infarction (MI) among patients admitted to the hospital may differ between men and women and blacks and whites. Furthermore, a different pattern of sex and race differences in case fatality may occur when coronary deaths outside the hospital are included in the analysis. The ARIC study provides community-based data to examine 28-day case fatality rates after coronary heart disease (CHD) events. Method and Results Surveillance of out-of-hospital CHD deaths and hospitalized MI was conducted in 4 U.S. communities from 1987 to 1993. Hospital discharges and death certificates were sampled, medical records abstracted, and interviews conducted with witnesses of out-of-hospital deaths. MI and out-of-hospital death classifications followed a standard algorithm. linkage of hospitalized Mis to fatality within 28 days ensured complete ascertainment of case fatality rate. Comorbidities and complications during hospital stay were compared to assess possible explanatory factors for differences in case fatality. Overall, age-adjusted 28-day case fatality (MI plus CHD) was higher in black men compared with white men (odds ratio 1.78, 95% confidence interval 1.4-2.2) and in black women compared with white women (odds ratio 1.5, 95% confidence interval 1.2-2.0). Although men had higher overall case fatality rates than did women, this difference was not statistically significant. After a hospitalized MI, 28-day case fatality rate was not statistically significantly different between men compared with women or blacks compared with whites. Conclusion Race and sex differences in case fatality after hospitalized MI were not evident in these data, although when out-of-hospital deaths were included, men and blacks were more likely than women and whites to die within 28 days of an acute cardiac event. A majority of deaths occurred before hospital admission, and additional study of possible reasons for these differences should be a priority. C1 Glaxo Wellcome Inc, Dept Epidemiol, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. Univ N Carolina, Sch Publ Hlth, Dept Biostat, Chapel Hill, NC USA. Bristol Myers Squibb, Biostat & Data Management, Wallingford, CT USA. Univ Mississippi, Med Ctr, Dept Prevent Med, Div Epidemiol, Jackson, MS 39216 USA. NHLBI, Bethesda, MD 20892 USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. RP White, AD (reprint author), Glaxo Wellcome Inc, Dept Epidemiol, 5 Moore Dr, Res Triangle Pk, NC 27709 USA. FU NHLBI NIH HHS [N01-HC-55016, N01-HC-55018, N01-HC-55015] NR 34 TC 24 Z9 24 U1 0 U2 1 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD SEP PY 1999 VL 138 IS 3 BP 540 EP 548 DI 10.1016/S0002-8703(99)70158-4 PN 1 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 232ZW UT WOS:000082401900025 PM 10467206 ER PT J AU Rywik, SL Manolio, TA Pajak, A Piotrowski, W Davis, CE Broda, GB Kawalec, E AF Rywik, SL Manolio, TA Pajak, A Piotrowski, W Davis, CE Broda, GB Kawalec, E TI Association of lipids and lipoprotein level with total mortality and mortality caused by cardiovascular and cancer diseases (Poland and United States Collaborative Study on Cardiovascular Epidemiology) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY HEART-DISEASE; SERUM-CHOLESTEROL; BLOOD CHOLESTEROL; RISK FACTOR; PRAVASTATIN; PREVENTION; PROGRAM; MEN AB This study evaluates the relation between total serum cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol, and subsequent total, cardiovascular, and cancer mortality. These data are from 4,946 US and 5,198 Polish men and women aged 35 to 64 years at baseline with mortality follow-up over 13 years. Total cholesterol showed a U-shaped or J-shaped relation to age-adjusted total and cancer mortality across all samples, with significance only in Polish women. The multivariable adjusted relative risk for total and cancer mortality was higher in the lowest cholesterol category only in Poland and significant only for cancer. Cardiovascular mortality was positively related to cholesterol, but only in Polish men and US women was mortality significantly higher in the highest versus the lowest cholesterol category. The multivariable adjusted relative risk of cardiovascular death wets greater in the highest versus the lowest cholesterol category, but this trend was significant only in the US. HDL cholesterol was inversely related to total (significant only in US men) and cardiovascular mortality (significant only in US and Polish men). A similar, but not significant, association of HDL cholesterol was found with cancer mortality. The multivariable adjusted relative risk of total mortality was inversely related to HDL cholesterol significant in both the US and Poland. The relative risk of cardiovascular mortality was significantly lower at higher HDL cholesterol levels in all samples. The relative risk of cancer mortality was highest and significant at the lowest HDL cholesterol level in the US and Poland. Elevated triglycerides were associated with increased risk of total and cardiovascular mortality, but this trend was significant only in the US. Cancer mortality was not significantly related to triglycerides. The present study indicates that in geographically and culturally diverse populations, the relation of lipids with cardiovascular mortality is similar. The relation with total and cancer mortality varies by country, gender, and lipids. This suggests that relations of total and cancer mortality with lipids or lipoproteins are weaker than associations with cardiovascular mortality. (C) 1999 by Excerpta Medica, Inc. C1 Stefan Cardinal Wyszynski Natl Inst Cardiol, Dept CVD Epidemiol & Prevent, Warsaw, Poland. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. Jagiellonian Univ, Coll Med, Inst Publ Hlth, Div Clin Epidemiol, Krakow, Poland. Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. RP Rywik, SL (reprint author), Univ N Carolina, Collaborat Studies Coordinating Ctr, 137 E Franklin St,Suite 203, Chapel Hill, NC 27514 USA. FU NHLBI NIH HHS [N01-HV-1-2243, N01-HV-59224, N01-HV-1-08112] NR 29 TC 24 Z9 25 U1 1 U2 5 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 SEP 1 PY 1999 VL 84 IS 5 BP 540 EP 548 DI 10.1016/S0002-9149(99)00374-4 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 229UK UT WOS:000082214000009 PM 10482152 ER PT J AU Zhou, YF Csako, G Grayston, JT Wang, SP Yu, ZX Shou, M Leon, M Epstein, SE AF Zhou, YF Csako, G Grayston, JT Wang, SP Yu, ZX Shou, M Leon, M Epstein, SE TI Lack of association of restenosis following coronary angioplasty with elevated C-reactive protein levels or seropositivity to Chlamydia pneumoniae SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID RISK; CYTOMEGALOVIRUS; INFLAMMATION; INFECTION; DISEASE; EVENTS AB Seventy-five consecutive patients undergoing directional coronary atherectomy were evaluated by measuring anti-Chlamydia immunoglobulin G and anticytomegalovirus immunoglobulin G antibodies, and serum levels of C-reactive proteins (before atherectomy). The results showed that although both Chlamydia infection and elevated C-reactive protein levels are associated with coronary artery disease and coronary artery disease events, neither of these appears to play a role in the development of restenosis. C1 Washington Hosp Ctr, Cardiovasc Res Fdn, Washington, DC 20010 USA. NHLBI, Cardiol Branch, Baltimore, MD USA. Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. RP Zhou, YF (reprint author), Washington Hosp Ctr, Cardiovasc Res Fdn, Suite 4B-1,110 Irving St, Washington, DC 20010 USA. NR 12 TC 47 Z9 48 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 SEP 1 PY 1999 VL 84 IS 5 BP 595 EP + DI 10.1016/S0002-9149(99)00386-0 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 229UK UT WOS:000082214000020 PM 10482163 ER PT J AU Schulz, LO Bennett, P Fox, C Ravussin, E AF Schulz, LO Bennett, P Fox, C Ravussin, E TI Genetically unknown foods or thrifty genes? Reply to R Baschetti SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Letter ID GENOTYPE C1 Univ Wisconsin, Dept Hlth Sci, Milwaukee, WI 53201 USA. NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Bethesda, MD USA. Bingham & Womens Hosp, Dept Internal Med, Boston, MA USA. Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. RP Schulz, LO (reprint author), Univ Wisconsin, Dept Hlth Sci, Milwaukee, WI 53201 USA. NR 6 TC 6 Z9 6 U1 0 U2 0 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP PY 1999 VL 70 IS 3 BP 421 EP 421 PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 231WM UT WOS:000082334500017 ER PT J AU Zheng, TZ Holford, TR Mayne, ST Ward, B Carter, D Owens, PH Dubrow, R Zahm, SH Boyle, P Archibeque, S Tessari, J AF Zheng, TZ Holford, TR Mayne, ST Ward, B Carter, D Owens, PH Dubrow, R Zahm, SH Boyle, P Archibeque, S Tessari, J TI DDE and DDT in breast adipose tissue and risk of female breast cancer SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE breast neoplasms; case-control studies; DDE; DDT ID ENVIRONMENTAL ORGANOCHLORINE EXPOSURE; POLYCHLORINATED BIPHENYL RESIDUES; SERUM; WOMEN; EPIDEMIOLOGY AB A case-control study was conducted in Connecticut from 1994 to 1997 to investigate the relation between dichlorodiphenyldichloroethane (DDE) and dichlorodiphenyltrichloroethane (DDT) exposure and breast cancer risk. Cases and controls were women aged 40-79 years, who had breast-related surgery at the Yale-New Haven Hospital and from whose surgical specimen the authors could obtain at least 0.4 g of breast adipose tissue for chemical analyses. A total of 304 incident breast cancer cases (including 62 in situ carcinomas) and 186 benign breast disease controls were recruited into the study. Tissue levels of DDE and DDT were measured using gas chromatography. Statistical significance for comparisons of mean levels of DDE and DDT was calculated using analysis of variance and rank sum tests. A logistic regression model was used to estimate the association and to control confounding. The age-adjusted geometric mean tissue level of DDE for cases (736.5 pob) was similar to that for the controls (784.1 ppb), DDT levels were also similar for cases (51.8 ppb) and controls (55.6 ppb), The adjusted odds ratio is 0.9 (95% confidence interval: 0.5, 1.5) for DDE and 0.8 (95% confidence interval: 0.5, 1.5) for DDT when the highest quartile was compared with the lowest. These results do not support an association between adipose tissue levels of DDE and DDT and breast cancer risk. C1 Yale Univ, Sch Med, New Haven, CT USA. Yale Canc Ctr, New Haven, CT USA. NCI, Bethesda, MD 20892 USA. European Inst Oncol, Milan, Italy. Colorado State Univ, Ft Collins, CO 80523 USA. RP Zheng, TZ (reprint author), 129 Church St,Suite 700, New Haven, CT 06510 USA. RI Boyle, Peter/A-4380-2014; Zahm, Shelia/B-5025-2015 OI Boyle, Peter/0000-0001-6251-0610; FU NCI NIH HHS [CA-62986] NR 29 TC 74 Z9 76 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 SEP 1 PY 1999 VL 150 IS 5 BP 453 EP 458 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 231DL UT WOS:000082292800004 PM 10472944 ER PT J AU Madigan, P Ziegler, RG Benichou, J Byrne, C Hoover, RN AF Madigan, P Ziegler, RG Benichou, J Byrne, C Hoover, RN TI Population attributable fraction estimation for established breast cancer risk factors: Considering the issues of high prevalence and unmodifiability SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter C1 NCI, Epidemiol & Biostat Program, Div Canc Etiol, Bethesda, MD 20892 USA. RP Madigan, P (reprint author), NCI, Epidemiol & Biostat Program, Div Canc Etiol, Bethesda, MD 20892 USA. RI Byrne, Celia/K-2964-2015 OI Byrne, Celia/0000-0001-8289-4252 NR 2 TC 2 Z9 2 U1 0 U2 2 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 SEP 1 PY 1999 VL 150 IS 5 BP 543 EP 543 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 231DL UT WOS:000082292800018 PM 10472956 ER PT J AU Keravich, DP Daniels, CE AF Keravich, DP Daniels, CE TI Challenges of thalidomide distribution in a hospital setting SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article; Proceedings Paper CT ASHP Midyear Clinical Meeting CY DEC 06-10, 1998 CL LAS VEGAS, NEVADA SP Amer Soc Hlth Syst Pharmacists DE administration; anti-infective agents; dispensing; drug distribution systems; erythema nodosum; patient information; patients; pharmacists, hospital; pharmacy, institutional, hospital; physicians; prescribing; regulations; thalidomide AB The various physician, patient, and pharmacy requirements for participation in the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.) program and procedures that institutions may implement in order to comply with these requirements are described. In 1998, FDA approved the marketing of thalidomide (Thalomid, Celgene). Because of the drug's known teratogenic effects, FDA tightly controls the distribution of thalidomide in the United States. To comply with FDA requirements, Celgene developed the S.T.E.P.S. oversight program, which includes registration of thalidomide prescribers and pharmacies that dispense thalidomide, extensive patient education about the risks associated with thalidomide, and a registry of ail patients receiving thalidomide. The S.T.E.P.S. program is considered part of the product label. The pharmacy requirements of the program were developed with a focus on a retail pharmacy practice model, which does not adequately reflect current hospital practice. The pharmacy department of the National Institutes of Health Clinical Center developed a model that adapts the S.T.E.P.S. program requirements to inpatient and outpatient institutional pharmacy practice. Procedures for registering patients and prescribers and dispensing thalidomide in the hospital setting were developed; the procedures were designed to meet the needs of both the inpatient and outpatient pharmacies and to comply with the requirements of the S.T.E.P.S. program. C1 NIH, Dept Pharm, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Daniels, CE (reprint author), NIH, Dept Pharm, Warren G Magnuson Clin Ctr, Bldg 10,Room 1N-257, Bethesda, MD 20892 USA. NR 1 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD SEP 1 PY 1999 VL 56 IS 17 BP 1721 EP 1725 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 232KL UT WOS:000082369900013 PM 10512502 ER PT J AU Grimbacher, B Schaffer, AA Holland, SM Davis, J Gallin, JI Malech, HL Atkinson, TP Belohradsky, BH Buckley, RH Cossu, F Espanol, T Garty, BZ Matamoros, N Myers, LA Nelson, RP Ochs, HD Renner, ED Wellinghausen, N Puck, JM AF Grimbacher, B Schaffer, AA Holland, SM Davis, J Gallin, JI Malech, HL Atkinson, TP Belohradsky, BH Buckley, RH Cossu, F Espanol, T Garty, BZ Matamoros, N Myers, LA Nelson, RP Ochs, HD Renner, ED Wellinghausen, N Puck, JM TI Genetic linkage of hyper-IgE syndrome to chromosome 4 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID INTERFERON-GAMMA PRODUCTION; INFECTION JOBS SYNDROME; HYPERIMMUNOGLOBULIN-E; INTERLEUKIN-4 RECEPTOR; T-CELLS; RECURRENT; DEFICIENCY; ASSOCIATION; CHEMOTAXIS AB The hyper-IgE syndrome (HIES) is a rare primary immunodeficiency characterized by recurrent skin abscesses, pneumonia, and highly elevated levels of serum IgE. HIES is now recognized as a multisystem disorder, with nonimmunologic abnormalities of the dentition, bones, and connective tissue. HIES can be transmitted as an autosomal dominant trait with variable expressivity. Nineteen kindreds with multiple cases of HIES were scored for clinical and laboratory findings and were genotyped with polymorphic markers in a candidate region on human chromosome 4. Linkage analysis showed a maximum two-point LOD score of 3.61 at recombination fraction of 0 with marker D4S428. Multipoint analysis and simulation testing confirmed that the proximal 4q region contains a disease locus for HIES. C1 Natl Human Genome Res Inst, Immunol Genet Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Med Genet Branch, NIH, Bethesda, MD 20892 USA. NIAID, Computat Biol Branch, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20892 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Univ Alabama, Dept Pediat, Birmingham, AL USA. Duke Univ, Med Ctr, Dept Pediat & Immunol, Durham, NC USA. Univ S Florida, All Childrens Hosp, Div Clin Immunol & Allergy, St Petersburg, FL 33701 USA. Univ Washington, Dept Pediat, Seattle, WA 98195 USA. Hosp Gen Valle Hebron, Immunol Unit, Barcelona, Spain. Hosp Son Dureta, Dept Immunol, Palma de Mallorca, Spain. Osped Microcitemico, Bone Marrow Transplant Unit, Cagliari, Italy. Tel Aviv Univ, Sackler Fac Med, Schneiders Children Med Ctr Israel, IL-69978 Tel Aviv, Israel. Univ Munich, Dr Von Haunerschen Kinderspital, Sect Infect Dis & Clin Immunol, D-80337 Munich, Germany. Univ Ulm, Sect Infect Dis & Clin Immunol, Ulm, Germany. RP Puck, JM (reprint author), Natl Human Genome Res Inst, Immunol Genet Sect, Genet & Mol Biol Branch, NIH, Bldg 49,Room 3A14,49 Convent Dr, Bethesda, MD 20892 USA. RI Schaffer, Alejandro/F-2902-2012 FU NICHD NIH HHS [HD17427] NR 46 TC 178 Z9 186 U1 0 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD SEP PY 1999 VL 65 IS 3 BP 735 EP 744 DI 10.1086/302547 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 233KQ UT WOS:000082426400018 PM 10441580 ER PT J AU Slaugenhaupt, SA Acierno, JS Helbling, LA Bove, C Goldin, E Bach, G Schiffmann, R Gusella, JF AF Slaugenhaupt, SA Acierno, JS Helbling, LA Bove, C Goldin, E Bach, G Schiffmann, R Gusella, JF TI Mapping of the mucolipidosis type IV gene to chromosome 19p and definition of founder haplotypes SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID MULTILOCUS LINKAGE ANALYSIS; ABNORMAL TRANSPORT; COMPUTATIONS AB Mucolipidosis type TV (MLIV) is a lysosomal storage disorder characterized by severe neurologic and ophthalmologic abnormalities. It is a rare autosomal recessive disease, and the majority of patients diagnosed, to date, are of Ashkenazi Jewish descent. We have mapped the MLIV gene to chromosome 19p13.2-13.3 by linkage analysis with 15 markers in 13 families. A maximum LOD score of 5.51 with no recombinants was observed with marker D19S873. Several markers in the linked interval also displayed significant linkage disequilibrium with the disorder. We constructed haplotypes in 26 Ashkenazi Jewish families and demonstrate the existence of two founder chromosomes in this population. The localization of MLIV to chromosome 13 will permit genetic prenatal diagnosis in affected families and will aid in the isolation of the disease gene. C1 Harvard Univ, Harvard Inst Human Genet, Sch Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Mol Neurogenet Unit, Charlestown, MA USA. NINDS, Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. Hadassah Univ Hosp, Dept Human Genet, IL-91120 Jerusalem, Israel. RP Slaugenhaupt, SA (reprint author), Harvard Univ, Harvard Inst Human Genet, Sch Med, HIM Bldg,Room 422,77 Ave Louis Pasteur, Boston, MA 02115 USA. FU NINDS NIH HHS [NS36326] NR 16 TC 57 Z9 59 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD SEP PY 1999 VL 65 IS 3 BP 773 EP 778 DI 10.1086/302549 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 233KQ UT WOS:000082426400023 PM 10441585 ER PT J AU Olsen, JH Mellemkjaer, L Gridley, G Brinton, L Johansen, C Kjaer, SK AF Olsen, JH Mellemkjaer, L Gridley, G Brinton, L Johansen, C Kjaer, SK TI Molar pregnancy and risk for cancer in women and their male partners SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE hydatidiform mole; maternal cancer; paternal cancer; gestational choriocarcinoma; cohort study ID GESTATIONAL TROPHOBLASTIC DISEASE; HYDATIDIFORM MOLE AB OBJECTIVE: It was our aim to evaluate the hypothesis that molar pregnancy is a marker of increased risk for cancer. STUDY DESIGN: This was a nationwide cohort study of 1520 women, identified from the Danish National Register of Patients, in whom a molar pregnancy was diagnosed during the period 1977-1992 and of 1295 male partners of these women, traced in the Danish Central Population Register. RESULTS: Linkage of the female roster with the Danish Cancer Registry through 1994 revealed 19 cases of gestational choriocarcinoma, whereas 0.04 was expected from the rates for the general population. Twenty cases of cancers of other types were observed with 24.9 expected (standardized incidence ratio, 0.8; 95% confidence interval, 0.5-1.2), but no specific type of cancer other than gestational choriocarcinoma occurred at a rate significantly different from that expected. Among the 1295 male partners notified in the Central Population Register, a total of 22 cancers were observed with 21.9 expected (standardized incidence ratio, 1.0; 95% confidence interval, 0.7-1.5). CONCLUSION: Molar pregnancy is not associated with an increased risk for cancer other than gestational carcinoma. C1 Danish Canc Soc, Inst Epidemiol, Res Dept 2, DK-2100 Copenhagen, Denmark. NCI, Biostat Branch, Bethesda, MD 20892 USA. NCI, Environm Epidemiol Branch, Bethesda, MD 20892 USA. RP Olsen, JH (reprint author), Danish Canc Soc, Inst Epidemiol, Res Dept 2, Strandblvd 49, DK-2100 Copenhagen, Denmark. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 FU NCI NIH HHS [N01-CP-85639-04] NR 25 TC 11 Z9 13 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 SEP PY 1999 VL 181 IS 3 BP 630 EP 634 DI 10.1016/S0002-9378(99)70504-1 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 237VN UT WOS:000082677400020 PM 10486475 ER PT J AU Vargas, JE Mudd, SH Waisbren, SE Levy, HL AF Vargas, JE Mudd, SH Waisbren, SE Levy, HL TI Maternal gamma-cystathionase deficiency: Absence of both teratogenic effects and pregnancy complications SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE inborn error of metabolism; pregnancy complications; gamma-cystathionase deficiency; cystathioninemia; cystathioninuria AB gamma-Cystathionase deficiency (cystathioninemia-cystathioninuria) is a disorder of the transsulfuration pathway characterized by the accumulation of cystathionine in blood and urine. There are probably no clinical consequences. However, maternal gamma-cystathionase deficiency has not been reported. We studied 2 pregnancies and the offspring of these pregnancies in a woman with the pyridoxine-nonresponsive form of the disorder. The outcomes were favorable, suggesting that maternal gamma-cystathionase deficiency may not be deleterious to the pregnant woman or the fetus. C1 Childrens Hosp, Div Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. NIMH, Lab Gen & Comparat Biochem, Bethesda, MD 20892 USA. RP Levy, HL (reprint author), Childrens Hosp, Div Genet, 300 Longwood Ave, Boston, MA 02115 USA. FU NICHD NIH HHS [N01-HD-2-3149] NR 3 TC 11 Z9 12 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 SEP PY 1999 VL 181 IS 3 BP 753 EP 755 DI 10.1016/S0002-9378(99)70525-9 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 237VN UT WOS:000082677400041 PM 10486496 ER PT J AU Catalano, PM Joffe, GM Levine, RJ AF Catalano, PM Joffe, GM Levine, RJ TI Insulin resistance and preeclampsia: Is there a relationship? Reply SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 Case Western Reserve Univ, Metrohlth Med Ctr, Dept Reprod Biol, Cleveland, OH 44109 USA. Lovelace Med Ctr, Dept Obstet & Gynecol, Albuquerque, NM 87108 USA. NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. RP Catalano, PM (reprint author), Case Western Reserve Univ, Metrohlth Med Ctr, Dept Reprod Biol, 2500 Metro Hlth Dr, Cleveland, OH 44109 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD SEP PY 1999 VL 181 IS 3 BP 769 EP 769 DI 10.1016/S0002-9378(99)70537-5 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 237VN UT WOS:000082677400053 ER PT J AU Parks, RA Danoff, JV AF Parks, RA Danoff, JV TI Motor performance changes in children testing positive for HIV over 2 years SO AMERICAN JOURNAL OF OCCUPATIONAL THERAPY LA English DT Article DE gross and fine motor skills; pediatrics ID IMMUNODEFICIENCY-VIRUS INFECTION; AIDS; THERAPY AB Objective. To determine the effect of HIV infection on the motor performance of children and preadolescents, the Bruininks-Oseretsky Test of Motor Proficiency (BOTMP) was administered to see whether performance scares (rdw and standard) would change with duration of the disease. Method. Thirty-four children and preadolescents were tested on the BOTMP at initial diagnosis of HIV positive and again at 6-month intervals over a 2-year period for a total of five test sessions. The participants' scores an the Cross, Fine, and Battery Composites, as well as eight individual subtests, were compared with those of children who were developing typically Results. Gross Composite and Battery Composite percentile scores were consistently I to 2 standard deviations below the means for the normal reference populations over the 2-year period. Fine Composite scores were closer than +.5 standard deviation to the mean for the normal reference population. Conclusion. Gross motor function was more impaired than fine motor function in this sample of children and preadolescents who were HIV positive, and this pattern was unchanged after 2 years of infection. The BOTMP can be useful bath to identify specific areas of motor deficits and to monitor changes in motor function over time after application of interventions. C1 NIH, Dept Rehabil Med, Occupat Therapy Sect, Bethesda, MD 20892 USA. NIH, Dept Rehabil Med, Phys Therapy Sect, Bethesda, MD 20892 USA. Howard Univ, Dept Phys Therapy, Washington, DC 20059 USA. RP Parks, RA (reprint author), NIH, Dept Rehabil Med, Occupat Therapy Sect, 10 Ctr Dr,MSC 1604, Bethesda, MD 20892 USA. NR 20 TC 9 Z9 10 U1 0 U2 0 PU AMER OCCUPATIONAL THERAPY ASSOC, INC PI BETHESDA PA 4720 MONTGOMERY LANE, BETHESDA, MD 20814-3425 USA SN 0272-9490 J9 AM J OCCUP THER JI Am. J. Occup. Ther. PD SEP-OCT PY 1999 VL 53 IS 5 BP 524 EP 528 PG 5 WC Rehabilitation SC Rehabilitation GA 237UV UT WOS:000082675200015 PM 10500862 ER PT J AU Chen, DS Lalwani, AK House, JW Choo, D AF Chen, DS Lalwani, AK House, JW Choo, D TI Aspergillus mastoiditis in acquired immunodeficiency syndrome SO AMERICAN JOURNAL OF OTOLOGY LA English DT Article DE Aspergillus fumigatus; mastoiditis; acquired immunodeficiency syndrome AB Objective: This study aimed to analyze the clinical presentation, diagnosis, management, and results of treatment in a series of three patients with acquired immunodeficiency syndrome (AIDS) in whom Aspergillus mastoiditis developed. This study also aimed to compare these aspects of Aspergillus mastoiditis in patients with AIDS with three additional cases present in the current literature. A classification system for fungal infections of the ear and temporal bone is proposed. Study Design: The study design was a retrospective case review. Setting: The study was conducted at multiple tertiary referral centers. Patients: Three individuals with diagnosed AIDS and mastoiditis resulting from culture-proven Aspergillus were studied. Intervention: Patients were treated with both medical and surgical methods including local and systemic antimicrobial/antifungal agents and mastoidectomy. Main Outcome Measures: These measures included return of facial nerve function, control/resolution of disease, and survival. Results:All three patients in this series initially presented with otalgia and otorrhea and intact facial nerve function. Facial nerve paresis developed in all patients between 5 and 12 weeks after initial symptoms. Paresis uniformly improved or resolved after mastoidectomy. Two patients treated with systemic antifungal therapy and prompt surgical debridement after development of facial palsy had full resolution of infection. One patient had full recovery of facial paresis and the other had partial recovery. The third patient was lost to follow-up after initial treatment with antimicrobials and surgery and died 3 months later without a clear etiology. Conclusions: Aspergillus mastoiditis is an unusual infection in patients with AIDS. Because of its rarity, fungal mastoiditis in immunocompromised individuals can result in a significant delay in diagnosis and treatment. The decision between conservative antimicrobial therapy and aggressive surgical treatment also can present a therapeutic challenge in the management of these life-threatening infections, especially in patients with existing immunodeficiency and illness. Early surgical debridement followed by antimicrobial therapy may be life preserving in this patient population. C1 Univ Calif San Francisco, Dept Otolaryngol Head & Neck Surg, Div Otol Neurol & Skull Base Surg, San Francisco, CA 94143 USA. House Ear Clin, Los Angeles, CA USA. NIDOCD, NIH, Bethesda, MD USA. RP Lalwani, AK (reprint author), Univ Calif San Francisco, Dept Otolaryngol Head & Neck Surg, Div Otol Neurol & Skull Base Surg, 400 Parnassus Ave,7th Floor, San Francisco, CA 94143 USA. NR 16 TC 15 Z9 15 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0192-9763 J9 AM J OTOL JI Am. J. Otol. PD SEP PY 1999 VL 20 IS 5 BP 561 EP 567 PG 7 WC Otorhinolaryngology SC Otorhinolaryngology GA 233HF UT WOS:000082420900001 PM 10503576 ER PT J AU Maniotis, AJ Folberg, R Hess, A Seftor, EA Gardner, LMG Pe'er, J Trent, JM Meltzer, PS Hendrix, MJC AF Maniotis, AJ Folberg, R Hess, A Seftor, EA Gardner, LMG Pe'er, J Trent, JM Meltzer, PS Hendrix, MJC TI Vascular channel formation by human melanoma cells in vivo and in vitro: Vasculogenic mimicry SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID UVEAL MALIGNANT-MELANOMA; CILIARY BODY MELANOMAS; 10 LARGEST NUCLEOLI; MICROCIRCULATION ARCHITECTURE; INTERMEDIATE FILAMENTS; CHOROIDAL MELANOMAS; HUMAN CYTOTROPHOBLASTS; ENDOVASCULAR INVASION; LASER OPHTHALMOSCOPY; EXTRACELLULAR-MATRIX AB Tissue sections from aggressive human intraocular (uveal) and metastatic cutaneous melanomas generally lack evidence of significant necrosis and contain patterned networks of interconnected loops of extracellular matrix. The matrix that forms these loops or networks may be solid or hollow. Red blood cells have been detected within the hollow channel components of this patterned matrix histologically, and these vascular channel networks have been detected in human tumors angiographically, Endothelial cells were not identified within these matrix-embedded channels by light microscopy, by transmission electron microscopy, or by using an immunohistochemical panel of endothelial cell markers (Factor VIII-related antigen, Ulex, CD31, CD34, and KDR[Flk-1]). Highly invasive primary and metastatic human melanoma cells formed patterned solid and hollow matrix channels (seen in tissue sections of aggressive primary and metastatic human melanomas) in three-dimensional cultures containing Matrigel or dilute Type I collagen, without endothelial cells or fibroblasts. These tumor cell-generated patterned channels conducted dye, highlighting looping patterns visualized angiographically in human tumors. Neither normal melanocytes nor poorly invasive melanoma cells generated these patterned channels in vitro under identical culture conditions, even after the addition of conditioned medium from metastatic pattern-forming melanoma cells, soluble growth factors, or regimes of hypoxia, Highly invasive and metastatic human melanoma cells, but clot poorly invasive melanoma cells, contracted and remodeled floating hydrated gels, providing a biomechanical explanation for the generation of microvessels in vitro. cDNA microarray analysis of highly invasive versus poorly invasive melanoma tumor cells confirmed a genetic reversion to a pluripotent embryonic-like genotype in the highly aggressive melanoma cells. These observations strongly suggest that aggressive melanoma cells may generate vascular channels that facilitate tumor perfusion independent of tumor angiogenesis. C1 Univ Iowa, Ctr Canc, Dept Anat, Iowa City, IA USA. Univ Iowa, Ctr Canc, Dept Cell Biol, Iowa City, IA USA. Univ Iowa, Coll Med, Dept Ophthalmol & Visual Sci, Iowa City, IA USA. Univ Iowa, Coll Med, Dept Pathol, Iowa City, IA USA. Hadassah Univ Hosp, Dept Ophthalmol, IL-91120 Jerusalem, Israel. Natl Human Genome Res Inst, Canc Genet Branch, NIH, Bethesda, MD USA. RP Hendrix, MJC (reprint author), Univ Iowa, Coll Med, Dept Anat & Cell Biol, Iowa City, IA 52242 USA. FU NCI NIH HHS [R01 CA59702, R01 CA059702, R01 CA80318]; NEI NIH HHS [R01 EY010457, R01 EY10457] NR 51 TC 919 Z9 1093 U1 13 U2 72 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD SEP PY 1999 VL 155 IS 3 BP 739 EP 752 DI 10.1016/S0002-9440(10)65173-5 PG 14 WC Pathology SC Pathology GA 235JD UT WOS:000082537800011 PM 10487832 ER PT J AU Lenfant, C AF Lenfant, C TI News from the National Heart, Lung, and Blood Institute SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Editorial Material C1 NHLBI, Bethesda, MD 20892 USA. RP Lenfant, C (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD SEP PY 1999 VL 277 IS 3 BP H855 EP H855 PG 1 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 231YE UT WOS:000082338300001 PM 10484403 ER PT J AU Pucci, ML Bao, Y Chan, B Itoh, S Lu, R Copeland, NG Gilbert, DJ Jenkins, NA Schuster, VL AF Pucci, ML Bao, Y Chan, B Itoh, S Lu, R Copeland, NG Gilbert, DJ Jenkins, NA Schuster, VL TI Cloning of mouse prostaglandin transporter PGT cDNA: species-specific substrate affinities SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE carrier proteins; biological transport; molecular cloning; interspecific mouse backcross mapping ID 7TH TRANSMEMBRANE DOMAIN; CARBOXYLIC-ACID GROUP; GENETIC-LINKAGE MAP; FUNCTIONAL INTERACTION; ARGININE RESIDUE; RECEPTOR; EXPRESSION; ORGANIZATION; SEQUENCES; AGONISTS AB We recently identified and/or cloned the PG transporter PGT in the rat (rPGT) (Kanai, N., R. Lu, J. A. Satriano, Y. Bao, A. W. Wolkoff, and V. L. Schuster, Science 268: 866-869, 1995) and the human (hPGT) (Lu, R., and V. L. Schuster, J. Clin. Invest. 98: 1142-1149, 1996). Here we have cloned and expressed the mouse PGT (mPGT) cDNA. The tissue distribution of mPGT mRNA expression is significantly more restricted than that of rPGT and hPGT mRNA. Although the deduced amino acid sequence of mPGT is similar to the rat (91% identity) and human (82% identity) homologues, it has three regions of dissimilarity: amino acids 128-163 and 283-298, and valine 610 and isoleucine 611 (predicted to lie within putative transmembrane span 12). Affinities of hPGT, rPGT, and mPGT for several PG substrates differed, with hPGT having the highest [low Michaelis constant (K-m)] and mPGT the lowest affinity. A chimeric protein, linking the N-terminal domain of mPGT with the C-terminal domain of hPGT, had affinity for PGE(2) indistinguishable from that of hPGT, indicating that the C-terminal domain dictates K-m. We mutagenized mouse valine 610 and isoleucine 611 to their corresponding human residues (methionine and glycine, respectively); however, these changes did not convert the inhibition constant of mPGT to that of hPGT. The mouse gene was localized to chromosome 9 in a region syntenic with the region of human chromosome 3 containing the hPGT gene. These studies highlight the species-dependence of tissue expression and function of PGT and lay the groundwork for the use of the mouse as a model system for the study of PGT function. C1 Yeshiva Univ Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Physiol & Biophys, Bronx, NY 10461 USA. Frederick Canc Res & Dev Ctr, Natl Canc Inst, ABL, Basic Res Program,Mammalian Genet Lab, Ft Detrick, MD 21702 USA. RP Schuster, VL (reprint author), Div Renal, Ullman 615,1300 Morris Pk Ave, Bronx, NY 10461 USA. EM schuster@aecom.yu.edu FU NIDDK NIH HHS [DK-49688, R01 DK049688] NR 35 TC 41 Z9 42 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD SEP PY 1999 VL 277 IS 3 BP R734 EP R741 PG 8 WC Physiology SC Physiology GA 231XN UT WOS:000082336800015 PM 10484490 ER PT J AU Kwon, TH Frokiaer, J Fernandez-Llama, P Knepper, MA Nielsen, S AF Kwon, TH Frokiaer, J Fernandez-Llama, P Knepper, MA Nielsen, S TI Reduced abundance of aquaporins in rats with bilateral ischemia-induced acute renal failure: prevention by alpha-MSH SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE acute tubular necrosis; alpha-melanocyte stimulating hormone; collecting duct; proximal tubule; urinary concentration mechanism ID MELANOCYTE-STIMULATING HORMONE; KIDNEY COLLECTING DUCT; WATER CHANNEL; NITRIC-OXIDE; INJURY; EXPRESSION; MEMBRANE; TUBULE; PERMEABILITY; PROTECTS AB We examined the effect of temporary renal ischemia (30 min or 60 min) and reperfusion (1 day or 5 days) on the expression of renal aquaporins (AQPs) and urinary concentration in rats with bilateral ischemia-induced acute renal failure (ARF). Next, we tested whether reducing ischemia/reperfusion (I/R) injury by treatment with or-melanocyte stimulating hormone (alpha-MSH) affects the expression of AQPs and urine output. Rats with ARF showed significant renal insufficiency, and urinary concentration was markedly impaired. In rats with mild ischemic injury (30 min), urine output increased significantly to a maximum at 48 h, and then nearly normalized within 5 days. Consistent with this, semiquantitative immunoblotting revealed that kidney AQP1 and AQP2 abundance was significantly decreased after 24 h to 30 +/- 5% and 40 +/- 11% (n = 8) of controls (n = 9), respectively (P < 0.05). Five days after ischemia, AQP2 abundance was not significantly decreased and urine output was normalized. In contrast, severe ischemic injury (60 min) resulted in a marked reduction in urine output at 24 h, despite a significant decrease in urine osmolality and solute-free water reabsorption, T(c)H(2)O. AQP1 and AQP2 abundance was markedly decreased to 51 +/- 5% and 31 +/- 9% (n = 10) of controls (n = 8) at 24 h (P ( 0.05). After 5 days, the rats developed gradually severe polyuria and had very low AQP2 and AQP1 levels [11 +/- 4% and 6 +/- 2% (n = 5) of controls (n = 8), respectively; P < 0.05]. A similar reduction was observed for AQP3. The reduction in AQP expression in the proximal tubule and inner medullary collecting duct was confirmed by immunocytochemistry. Next, we found that intravenous (alpha-MSH treatment of rats with ARF significantly reduced the ischemia-induced downregulation of renal AQPs and reduced the polyuria. In conclusion, the I/R injury is associated with markedly reduced expression of the collecting duct and proximal tubule AQPs, in association with an impairment of urinary concentration. Moreover, alpha-MSH treatment significantly prevented the reduction in expression of AQPs and renal functional defects. Thus decreased AQP expression is likely to contribute to the impairment in urinary concentration in the postischemic period. C1 Univ Aarhus, Dept Cell Biol, Inst Anat, DK-8000 Aarhus C, Denmark. Aarhus Univ Hosp, Dept Clin Physiol, DK-8000 Aarhus, Denmark. Aarhus Univ, Inst Expt Clin Res, DK-8000 Aarhus, Denmark. NHLBI, Kidney & Electrolyte Metab Lab, Bethesda, MD 20892 USA. RP Nielsen, S (reprint author), Univ Aarhus, Dept Cell Biol, Inst Anat, DK-8000 Aarhus C, Denmark. EM sn@ana.au.dk FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 53 TC 77 Z9 79 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD SEP PY 1999 VL 277 IS 3 BP F413 EP F427 PG 15 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 233BK UT WOS:000082405500013 PM 10484525 ER PT J AU Iwata, N Cowley, DS Radel, M Roy-Byrne, PP Goldman, D AF Iwata, N Cowley, DS Radel, M Roy-Byrne, PP Goldman, D TI Relationship between a GABA(A)alpha 6 Pro385Ser substitution and benzodiazepine sensitivity SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID SONS; ALCOHOLICS; RECEPTOR; DIAZEPAM; ABUSE AB Objective: In humans, interindividual variation in sensitivity to benzodiazepine drugs may correlate with behavioral variation, including vulnerability to disease states such as alcoholism. In the rat, variation in alcohol and benzodiazepine sensitivity has been correlated with an inherited variant of the GABA(A)alpha 6 receptor. The authors detected a Pro385Ser [1236C>T] amino acid substitution in the human GABA(A)alpha 6 that may influence alcohol sensitivity. In this pilot study, they evaluated the contribution of this polymorphism to benzodiazepine sensitivity. Method: Sensitivity to diazepam was assessed in 51 children of alcoholics by using two eye movement measures: peak saccadic velocity and average smooth pursuit gain. Association analysis was performed with saccadic velocity and smooth pursuit gain as dependent variables and comparing Pro385/Ser385 heterozygotes and Pro385/Pro385 homozygotes. Results: The Pro385Ser genotype was associated with less diazepam-induced impairment of saccadic velocity but not with smooth pursuit gain. Conclusions: The Pro385Ser genotype may play a role in benzodiazepine sensitivity and conditions, such as alcoholism, that may be correlated with this trait. C1 NIAAA, Neurogenet Lab, Bethesda, MD USA. Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. Univ Washington, Harborview Med Ctr, Seattle, WA 98104 USA. RP Iwata, N (reprint author), Fujita Hlth Univ, Sch Med, Dept Psychiat, Toyoake, Aichi 47011, Japan. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU NIAAA NIH HHS [AA-09635] NR 14 TC 48 Z9 51 U1 1 U2 1 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD SEP PY 1999 VL 156 IS 9 BP 1447 EP 1449 PG 3 WC Psychiatry SC Psychiatry GA 232FF UT WOS:000082359700025 PM 10484961 ER PT J AU Penninx, BWJH Leveille, S Ferrucci, L van Eijk, JTM Guralnik, JM AF Penninx, BWJH Leveille, S Ferrucci, L van Eijk, JTM Guralnik, JM TI Exploring the effect of depression on physical disability: Longitudinal evidence from the established populations for epidemiologic studies of the elderly SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID PRIMARY-CARE PATIENTS; CHRONIC DISEASES; IMMUNE-SYSTEM; LATER LIFE; SYMPTOMS; HEALTH; MACARTHUR; OUTCOMES; ANXIETY; ILLNESS AB Objectives. This study examined thr effect of depression on the incidence of physical disability and the role of confounding and explanatory variables in this relationship. Methods. A cohort of 6247 subjects 65 years and older who were initially free of disability ams followed up for 6 years. Baseline depression was assessed by the Center for Epidemiological Studies Depression Scale. Disability in mobility and disability in activities of daily living were measured annually. Results. Compared with the 5751 nondepressed subjects, the 496 depressed subjects had a relative risk (95% confidence interval) of 1.67 (1.44, 1.95) and 1.73 (1.54, 1.94) for incident disability in activities of daily living and mobility, respectively. Adjustment for sociodemographic characteristics and baseline chronic conditions reduced the risks to 1.39 (1.18. 1.63) and 1.45 (1.29, 1.93), respectively Less physical activity and fewer social contacts among depressed persons further explained part of their increased disability risk. Conclusions. Depression in older persons may increase the risk for incident disability. This excess risk is partly explained by depressed persons' decreased physical activity and social interaction. The role of other factors (e.g., biological mechanisms) should be examined. C1 NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. Free Univ Amsterdam, Inst Res Extramural Med, Amsterdam, Netherlands. Natl Res Inst, Geriatr Dept, Florence, Italy. RP Penninx, BWJH (reprint author), NIA, Epidemiol Demog & Biometry Program, 7201 Wisconsin Ave,Gateway Bldg,Suite 3C-309, Bethesda, MD 20892 USA. FU NIA NIH HHS [N01-AG-02107, N01-AG-02106, N01-AG-0215] NR 36 TC 319 Z9 326 U1 5 U2 16 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD SEP PY 1999 VL 89 IS 9 BP 1346 EP 1352 DI 10.2105/AJPH.89.9.1346 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 229UR UT WOS:000082214600009 PM 10474551 ER PT J AU Busse, W Elias, J Sheppard, D Banks-Schlegel, S AF Busse, W Elias, J Sheppard, D Banks-Schlegel, S TI Airway remodeling and repair SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material ID EPITHELIAL INTEGRINS; BASEMENT-MEMBRANE; CELL-ADHESION; MILD ASTHMA; INFLAMMATION; LUNG; HYPERREACTIVITY; EXPRESSION; INTERLEUKIN-5; PROLIFERATION C1 NHLBI, Div Lung Dis, Rockledge Ctr 2, Bethesda, MD 20892 USA. Univ Wisconsin, Dept Med, Madison, WI USA. Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. Univ Calif San Francisco, Sch Med, Lung Biol Ctr, San Francisco, CA USA. RP Banks-Schlegel, S (reprint author), NHLBI, Div Lung Dis, Rockledge Ctr 2, Suite 10018,6701 Rockledge Dr,MSC 7952, Bethesda, MD 20892 USA. NR 51 TC 161 Z9 168 U1 0 U2 1 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 SEP PY 1999 VL 160 IS 3 BP 1035 EP 1042 PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 236ND UT WOS:000082604700046 PM 10471638 ER PT J AU Matsumoto, Y Horiba, K Usuki, J Chu, SC Ferrans, VJ Moss, J AF Matsumoto, Y Horiba, K Usuki, J Chu, SC Ferrans, VJ Moss, J TI Markers of cell proliferation and expression of melanosomal antigen in lymphangioleiomyomatosis SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article ID PULMONARY LYMPHANGIOLEIOMYOMATOSIS; CLINICAL-APPLICATIONS; MELANOCYTE LINEAGE; HMB-45; LYMPHANGIOMYOMATOSIS; RECOGNIZES; TISSUE; TUMOR; LUNG; GENE AB Pulmonary lymphangioleiomyomatosis (LAM), a disease of young women, is characterized by proliferation of immature-appearing smooth-muscle cells (LAM cells) in the lungs and abdomen. LAM cells react with monoclonal antibody HMB45, which recognizes a 100-kD glycoprotein (gp100) originally found in human melanoma cells. We investigated the expression and the subcellular localization of gp100 in lung tissue from patients with LAM and in human melanoma cell lines (Malme-3M, A2058, and CHL-1), and the relationship between this expression and cellular proliferation. Binding sites for HMB45 antibody in melanoma and LAM cells were located in cytoplasmic granules resembling immature melanosomes. LAM cells reactive for proliferating-cell nuclear antigen (PCNA), a marker of cellular proliferation, were spindle-shaped, in contrast to the large, epithelioid cells reacting with HMB45 antibody. In accord with this finding, we observed an inverse relationship between the immunostaining for HMB45 antibody and PCNA in LAM and melanoma cells. Thus, LAM and melanoma cells are heterogeneous with respect to their stages of proliferation and their expression of melanoma antigens. PCNA-positive cells, which are more likely to be negative for reactivity with HMB45 antibody, may be more relevant to the progression of LAM than are HMB45-positive cells, which are the hallmark of LAM. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. RP Moss, J (reprint author), NHLBI, Pulm Crit Care Med Branch, NIH, Bldg 10,6D03,10 Ctr Dr, Bethesda, MD 20892 USA. NR 28 TC 77 Z9 79 U1 0 U2 0 PU AMER LUNG ASSOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD SEP PY 1999 VL 21 IS 3 BP 327 EP 336 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 237UQ UT WOS:000082674800007 PM 10460750 ER PT J AU Balducci, E Horiba, K Usuki, J Park, M Ferrans, VJ Moss, J AF Balducci, E Horiba, K Usuki, J Park, M Ferrans, VJ Moss, J TI Selective expression of RT6 superfamily in human bronchial epithelial cells SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article ID DEPENDENT ADP-RIBOSYLTRANSFERASE; RIBOSYLATING BACTERIAL TOXINS; DIFFERENTIATION MARKER RT6; SKELETAL-MUSCLE CELLS; PRONE BB RATS; T-CELLS; MOLECULAR CHARACTERIZATION; MESSENGER-RNA; SURFACE; NAD AB RT6 proteins are glycosylphosphatidylinositol (GPI)-linked alloantigens that are localized to cytotoxic T lymphocytes and that have nicotinamide adenine dinucleotide glycohydrolase and adenosine diphosphate (ADP)-ribosyltransferase activities. In view of the importance, of GPI-linked surface proteins in mediating interactions of cells with their milieu, and the varied functions of airway cells in inflammation, we undertook the present study to determine whether human homologues of the RT6 superfamily of ADP-ribosyltransferases (ART) are expressed in pulmonary epithelial cells. We hypothesized that these surface proteins or related family members may be present in cells that interact with inflammatory cells, and that they may thereby be involved in intercellular signaling. Using in situ analysis and Northern blot analysis, we identified ART1 messenger RNA (mRNA) in airway epithelial cells. As expected for GPI-anchored proteins, the localization of ART1 at the apical surface of ciliated epithelial cells was demonstrated by staining with polyclonal anti-ART1 antibody, and was confirmed by loss of this immunoreactivity after treatment with phosphatidylinositol-specific phospholipase C (PI-PLC), which selectively cleaves GPI anchors and releases proteins from the plasma membrane. Using in situ hybridization with specific ART3 and ART4 oligonucleotides, we also identified two additional members of the RT6 superfamily in epithelial cells. In accord with these findings, we identified ART3 and ART4 mRNAs through reverse transcription-polymerase chain reaction of polyadenine-positive RNA from human trachea. Interestingly, these proteins appeared to be preferentially localized to the airway epithelium. The localized expression of these members of the RT6 superfamily in human pulmonary epithelial cells may reflect a role for them in cell-cell signaling during immune responses within the airway. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. RP Moss, J (reprint author), NHLBI, Pulm Crit Care Med Branch, NIH, Bldg 10,6D05,10 Ctr Dr,MSC-1590, Bethesda, MD 20892 USA. NR 48 TC 14 Z9 15 U1 0 U2 0 PU AMER LUNG ASSOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD SEP PY 1999 VL 21 IS 3 BP 337 EP 346 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 237UQ UT WOS:000082674800008 PM 10460751 ER PT J AU Schatzberg, S Olby, N Steingold, S Keene, B Atkins, C Meurs, K Solomon, G Goedegebuure, SA Wilton, S Sharp, N AF Schatzberg, S Olby, N Steingold, S Keene, B Atkins, C Meurs, K Solomon, G Goedegebuure, SA Wilton, S Sharp, N TI A polymerase chain reaction screening strategy for the promoter of the canine dystrophin gene SO AMERICAN JOURNAL OF VETERINARY RESEARCH LA English DT Article ID DUCHENNE MUSCULAR-DYSTROPHY; IDIOPATHIC DILATED CARDIOMYOPATHY; MUSCLE-SPECIFIC PROMOTER; CONGESTIVE CARDIOMYOPATHY; SKELETAL-MUSCLE; MESSENGER-RNA; BRAIN; HEART; DOGS; IDENTIFICATION AB Objective:To develop a polymerase chain reaction (PCR) strategy to screen the dystrophin promoter(s) in dogs with cardiac and skeletal myopathies. Animals-9 Doberman Pinschers; 1 Dalmation, and ? Saint Bernard with dilated cardiomyopathy (DCM)1 Irish Terrier with muscular dystrophy; and 2 dystrophin-deficient German Shorthaired Pointers (GSHP). Procedure-For each of the 3 unique exons associated with the muscle (M), Purkinje (P), and cortical (C) promoters of the dystrophin gene, each first exon, and the M promoter plus its first exon, were amplified, cloned, and sequenced. The M dystrophin transcript was amplified by reverse transcriptase PCR from skeletal and cardiac muscle RNA of 1 Doberman Pinscher and from skeletal muscle RNA of 1 GSHP. Results-The M, P,and C first exons were amplified from all dogs except the 2 GSHP, which had a deletion encompassing-the entire M, P, and C dystrophin promoter region. The M transcript could not be amplified from muscles of-the GSHP, but was amplified from skeletal and cardiac muscle of the Doberman Pinscher. Sequencing of the product representing the M promoter and its first exon revealed no differences between clinically normal dogs and the Doberman' Pinscher with DCM. Conclusions and Clinical Relevance-We have ruled out a major rearrangement of the dystrophin promoter region as the universal cause of DCM in Doberman Pinschers or of Irish Terrier myopathy. Use of the strategy identified a large deletion of this region in muscle from the GSHP. C1 N Carolina State Univ, Coll Vet Med, Dept Compan Anim & Special Species Med, Raleigh, NC 27606 USA. Ohio State Univ, Dept Vet Clin Sci, Columbus, OH 43210 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Univ Utrecht, Fac Vet Med, Dept Pathol, Utrecht, Netherlands. Univ Western Australia, Queen Elizabeth II Med Ctr, Australian Neuromusc Res Inst, Nedlands, WA 6009, Australia. RP Schatzberg, S (reprint author), N Carolina State Univ, Coll Vet Med, Dept Compan Anim & Special Species Med, Raleigh, NC 27606 USA. NR 30 TC 5 Z9 5 U1 0 U2 2 PU AMER VETERINARY MEDICAL ASSOC PI SCHAUMBURG PA 1931 N MEACHAM RD SUITE 100, SCHAUMBURG, IL 60173-4360 USA SN 0002-9645 J9 AM J VET RES JI Am. J. Vet. Res. PD SEP PY 1999 VL 60 IS 9 BP 1040 EP 1046 PG 7 WC Veterinary Sciences SC Veterinary Sciences GA 233KE UT WOS:000082425400006 PM 10490068 ER PT J AU Wolffe, AP Shi, YB AF Wolffe, AP Shi, YB TI A hypothesis for the transcriptional control of amphibian metamorphosis by the thyroid hormone receptor SO AMERICAN ZOOLOGIST LA English DT Article; Proceedings Paper CT Symposium Evolution of the Steroid/Thyroid/Retinoic Acid Receptors, at the Annual Meeting of the Society-for-Integrative-and-Comparative Biology CY JAN 03-07, 1998 CL BOSTON, MASSACHUSETTS SP Soc Integrat & Comparat Biol ID HUMAN GLUCOCORTICOID RECEPTOR; RETINOIC ACID RECEPTORS; XENOPUS-LAEVIS; GENE-EXPRESSION; HISTONE ACETYLATION; VITELLOGENIN GENES; EXTRACELLULAR-MATRIX; ESTROGEN-RECEPTOR; TADPOLE INTESTINE; RESPONSE ELEMENT AB Amphibian metamorphosis is controlled by thyroid hormone and the thyroid hormone receptor. The thyroid hormone receptor functions as a master control factor that can both activate and repress genes in controlling the transformation of the larval tadpole to the adult frog. We have made use of the microinjection of both Xenopus laevis oocytes and embryos to investigate the molecular mechanisms involved in this regulation of transcription. We define three steps in the regulation of transcription by thyroid hormone receptor: the establishment of a repressive chromatin structure, disruption of chromatin and transcriptional activation. Our results also suggest that there are four major stages in the developmental control of gene expression during metamorphosis 1) Tissue and stage specific expression during embryonic development prior to tadpole hatching independent of thyroid hormone receptor, 2) The general repression of transcription of these genes by thyroid hormone receptor after tadpole hatching (stage 36), but prior to the production of thyroid hormone, which is first detectible in the circulating plasma around stage 55. 3) The activation of transcription dependent on thyroid hormone and receptor at metamorphosis (stages 55-66), 4) The acquisition of tissue specific and possibly thyroid hormone-independent patterns of gene activity. C1 NICHHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. RP Wolffe, AP (reprint author), NICHHD, Mol Embryol Lab, NIH, Bldg 18T,Rm 106, Bethesda, MD 20892 USA. NR 65 TC 6 Z9 6 U1 0 U2 0 PU AMER SOC ZOOLOGISTS PI LAWRENCE PA 1041 NEW HAMPSHIRE ST, LAWRENCE, KS 66044 USA SN 0003-1569 J9 AM ZOOL JI Am. Zool. PD SEP PY 1999 VL 39 IS 4 BP 807 EP 817 PG 11 WC Zoology SC Zoology GA 240CE UT WOS:000082807500011 ER PT J AU Byas-Smith, MG Bennett, GJ Gracely, RH Max, MB Robinovitz, E Dubner, R AF Byas-Smith, MG Bennett, GJ Gracely, RH Max, MB Robinovitz, E Dubner, R TI Tourniquet constriction exacerbates hyperalgesia-related pain induced by intradermal capsaicin injection SO ANESTHESIOLOGY LA English DT Article; Proceedings Paper CT Annual Scientific Meeting of the American-Pain-Society CY NOV 04, 1998 CL SAN DIEGO, CALIFORNIA SP Amer Pain Soc DE cutaneous blood now; ischemia; pain ID SUBSTANCE-P; SENSORY NEURONS; RAT; ISCHEMIA; SKIN; MECHANISMS; RELEASE; PROTONS; FIBERS AB Background When capsaicin is injected intradermally, hyperalgesia develops around the injection site. The authors observed that volunteers report painful sensations in the skin remote from the injection site during tourniquet constriction of the affected extremity. Methods: Each volunteer received an intradermal injection of capsaicin on the volar forearm, followed by intermittent tourniquet constriction of the extremity. In some participants, the tourniquet position was rotated between different sites on the upper extremities. Laser Doppler measurements were made in the skin to measure capillary blood now during pain magnification. Results: Hyperalgesia developed in the volunteers who were tested after the capsaicin injection. Blood now increased three times in the dermal capillaries remote from the injection site after capsaicin injection. The tourniquet-induced pain reached peak intensity soon after tourniquet inflation. Tourniquet constriction of the arm on the affected side reliably induced painful exacerbation in each person tested. The quality of the sensation was described as burning and extended across the arm in most volunteers. Only when pinprick hyperalgesia was detectable did the volunteers experience the diffuse, immediate pain sensation. The pain initiated by the tourniquet constriction likely is related to changes in skin capillary blood flow. Conclusions: Low cutaneous blood perfusion is related to the intensity of ongoing, spontaneous pain when secondary hyperalgesia is present. The specific trigger(s) have yet to be identified. C1 NIDR, Pain & Neurosensory Mechanisms Branch, Clin Measurement & Mechanisms Unit, NIH, Bethesda, MD 20892 USA. Emory Univ, Sch Med, Dept Anesthesiol, Atlanta, GA 30322 USA. RP Byas-Smith, MG (reprint author), Emory Univ Hosp, Dept Anesthesiol, Suite A 304,1364 Clifton Rd NE, Atlanta, GA 30322 USA. NR 20 TC 9 Z9 9 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD SEP PY 1999 VL 91 IS 3 BP 617 EP 625 DI 10.1097/00000542-199909000-00010 PG 9 WC Anesthesiology SC Anesthesiology GA 232KE UT WOS:000082369300005 PM 10485769 ER PT J AU Klein, HG AF Klein, HG TI Immunomodulatory aspects of transfusion - A once and future risk? SO ANESTHESIOLOGY LA English DT Article DE blood; immunology; leukoreduction; tolerance ID BLOOD-TRANSFUSIONS; CANCER RECURRENCE; METAANALYSIS; INFECTION; DISEASE C1 NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Klein, HG (reprint author), NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bldg 10,10 Ctr Dr,Room 1C-711, Bethesda, MD 20892 USA. NR 15 TC 102 Z9 107 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD SEP PY 1999 VL 91 IS 3 BP 861 EP 865 DI 10.1097/00000542-199909000-00040 PG 5 WC Anesthesiology SC Anesthesiology GA 232KE UT WOS:000082369300035 PM 10485799 ER PT J AU Kreuter, MW Strecher, VJ Glassman, B AF Kreuter, MW Strecher, VJ Glassman, B TI One size does not fit all: The case for tailoring print materials SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article ID SMOKING CESSATION; BEHAVIOR-CHANGE; SELF-EFFICACY; OLDER SMOKERS; HEALTH-CARE; MESSAGES; IMPACT; RECOMMENDATIONS; INTERVENTION; DEPENDENCE AB Printed health education materials frequently consist of mass-produced brochures, booklets, or pamphlets designed for a general population audience. Although this one-size-fits-all ap proach might be appropriate under certain circumstances and el en produce small changes at relatively modest costs, it cannot address the unique needs, interests, and concerns of different individuals. With the advent and dissemination of new communication technologies, our ability to collect information from individuals and provide feedback tailored to the specific information collected is not only possible, but practical. The purpose of this article is to: (a) distinguish between tailored print communication and other common communication-based approaches to health education and behavior change; (b) present a theoretical and public health rationale for tailoring health Information; and (c) describe the steps involved in creating and delivering tailored print communication programs. Studies suggest computer tailoring is a promising strategy for health education and behavior change. Practitioners and researchers should understand the approach and consider the possibilities it presents for enhancing their work in disease prevention. C1 St Louis Univ, Hlth Commun Res Lab, Dept Community Hlth, Sch Publ Hlth, St Louis, MO 63108 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Natl Canc Inst, Bethesda, MD 20892 USA. RP Kreuter, MW (reprint author), St Louis Univ, Hlth Commun Res Lab, Dept Community Hlth, Sch Publ Hlth, 321 Spring Ave, St Louis, MO 63108 USA. NR 61 TC 336 Z9 341 U1 0 U2 21 PU SOC BEHAVIORAL MEDICINE PI MIDDLETON PA 7611 ELMWOOD AVE, STE 201, MIDDLETON, WI 53562-3161 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD FAL PY 1999 VL 21 IS 4 BP 276 EP 283 DI 10.1007/BF02895958 PG 8 WC Psychology, Multidisciplinary SC Psychology GA 288LF UT WOS:000085563700002 PM 10721433 ER PT J AU Skinner, CS Campbell, MK Rimer, BK Curry, S Prochaska, JO AF Skinner, CS Campbell, MK Rimer, BK Curry, S Prochaska, JO TI How effective is tailored print communication? SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article ID SMOKING CESSATION; EXTRINSIC MOTIVATION; MESSAGES; MAMMOGRAPHY; INTERVENTIONS; BEHAVIOR; SETTINGS; PROGRAM AB This article reviews the "first generation" of tailored print communications studies ill the published literature, describing the purpose, theoretical framework, sample, research design, message type and source, outcomes measured, and findings of each. Eight studies compared tailored versus similar nontailored print, one compared tailored print versus an alternate intervention, and three included tailored print as one of several intervention components. Although studies varied by behavioral topic, type of tailoring, and mesurement of behavioral outcomes, several themes persist. Compared to their nontailored counterparts, tailored print communications have been consistently better remembered, read and perceived as relevant and/or credible. There is also evidence that tailored print communications are more effective for influencing health behaviors. Six of the eight tailored/nontailored comparisons found more behavior change among tailored than nontailored recipients. Tailored print communications have also demonstrated effectiveness as an adjunct to other intervention components such as self-help smoking cessation manuals. However; studies comparing tailored print communications with tailoring via other media such as telephone counseling have shown mixed results. Additional research is needed to assess whether the behavioral topic itself may make a difference in whether tailoring is appropriate and effective. C1 Duke Univ, Med Ctr, Durham, NC 27110 USA. Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC 27515 USA. Natl Canc Inst, Bethesda, MD 20892 USA. Univ Rhode Isl, Kingston, RI 02881 USA. RP Skinner, CS (reprint author), Duke Univ, Med Ctr, Trent Dr,Hanes House Room 177,Box 2949, Durham, NC 27110 USA. NR 33 TC 259 Z9 260 U1 1 U2 14 PU SOC BEHAVIORAL MEDICINE PI MIDDLETON PA 7611 ELMWOOD AVE, STE 201, MIDDLETON, WI 53562-3161 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD FAL PY 1999 VL 21 IS 4 BP 290 EP 298 DI 10.1007/BF02895960 PG 9 WC Psychology, Multidisciplinary SC Psychology GA 288LF UT WOS:000085563700004 PM 10721435 ER PT J AU Abrams, DB Mills, S Bulger, D AF Abrams, DB Mills, S Bulger, D TI Challenges and future directions for tailored communication research SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article ID SMOKING CESSATION; HEALTH-CARE; INTERVENTIONS; SMOKERS AB As informatics technology advances, a growing number of research trials on tailored communications provide an accumulation of promising evidence to support their efficacy These trials also reveal gaps and opportunities for future research. The scope and boundaries of tailoring must be redefined in terms of both new technology and the trade-offs between complexity, demand burden on participants, and the minimal information required for effective and efficient tailoring. Basic and methods research is needed to broaden theory, develop a common language, standardize measures, and isolate the kev mediating mechanisms that facilitate tailored communications. Applied research must consider more rigorous research designs for efficacy trials and conduct more effectiveness trials to investigate the mechanisms of technology transfer to enhance large-scale diffusion of tailored communications. The role of contextual variables needs to be examined as well as their interaction with different population groups, and also the channels, modes, and methods of tailored message delivery. Research is also needed on the feasibility of tailoring across clusters of multiple risk factors to identify the commonalities, differences, and interrelations among diverse behaviors. The potential cost-effectiveness of tailored communications must also be examined. No matter how efficacious, tailored communications delivered to large populations (i.e. mass-customization) will not make a public health impact unless proven to be practical and cost-efficient. C1 Brown Univ, Sch Med, Providence, RI 02912 USA. Natl Canc Inst, Bethesda, MD 20892 USA. MicroMass Commun Inc, Raleigh, NC 27606 USA. RP Abrams, DB (reprint author), Brown Univ, Miriam Hosp, Ctr Behav & Prevent Med, 164 Summit Ave,RISE Bldg, Providence, RI 02906 USA. FU NCI NIH HHS [CA38309]; NHLBI NIH HHS [HL32318]; NIAAA NIH HHS [AA11211] NR 43 TC 58 Z9 58 U1 0 U2 6 PU SOC BEHAVIORAL MEDICINE PI MIDDLETON PA 7611 ELMWOOD AVE, STE 201, MIDDLETON, WI 53562-3161 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD FAL PY 1999 VL 21 IS 4 BP 299 EP 306 DI 10.1007/BF02895961 PG 8 WC Psychology, Multidisciplinary SC Psychology GA 288LF UT WOS:000085563700005 PM 10721436 ER PT J AU Conant, K McArthur, JC Griffin, DE Sjulson, L Wahl, LM Irani, DN AF Conant, K McArthur, JC Griffin, DE Sjulson, L Wahl, LM Irani, DN TI Cerebrospinal fluid levels of MMP-2, 7, and 9 are elevated in association with human immunodeficiency virus dementia SO ANNALS OF NEUROLOGY LA English DT Article ID BLOOD-BRAIN-BARRIER; MATRIX METALLOPROTEINASE EXPRESSION; CENTRAL-NERVOUS-SYSTEM; MULTIPLE-SCLEROSIS; HIV-1 INFECTION; AIDS DEMENTIA; MONONUCLEAR PHAGOCYTES; NEURITE OUTGROWTH; SERINE PROTEASES; TYPE-1 INFECTION AB Pathological evidence suggests that alterations of the blood-brain barrier (BBB) may occur in association with human immunodeficiency virus (HN) dementia (HIVD). Increased BBB permeability could contribute to the development of dementia by facilitating the entry of activated and infected monocytes, as well as potentially toxic serum proteins, into the central nervous system. One mechanism by which BBB permeability may be altered is through increased activity of select matrix metalloproteinases (MMPs). In the present study, we examined the possibility that MMPs that target critical BBB proteins, including laminin, entactin, and collagen type IV, are elevated in the cerebrospinal fluid (CSF) of patients with HIVD. We also examined the possibility that such MMPs could be produced by brain-derived cells, and that MMP production by these cells might be increased by tumor necrosis factor-alpha, an inflammatory cytokine that is produced by HIV-infected monocytes/microglia and is elevated in HIVD. By using western blot and enzyme-linked immunosorbent assay, we observed that CSF levels of pro-MMP-2 and pro-MMP-7 were increased in association with HIVD, In addition, through the use of gelatin substrate zymography, a sensitive functional assay for MMP-2 and MMP-9, we observed that MMP-2 or pro-MMP-9 activity was more frequently detectable in the CSF of individuals with HIV dementia (9/16) than in the CSF from either nondemented seropositive (2/11) or seronegative (0/11) controls. Although the presence of MMPs in the serum could contribute to elevated levels in the CSF, we also show that brain-derived cells release MMP-2, 7, and 9, and that such release is increased after their stimulation with tumor necrosis factor-alpha. Together, these results suggest that elevated CSF levels of select MMPs may reflect immune activation within the central nervous system. They also suggest that further studies may be warranted to determine whether these proteins may play a role in the development of symptomatic neurological disease. C1 Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21218 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Mol Microbiol, Baltimore, MD USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Immunol, Baltimore, MD USA. Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. RP Conant, K (reprint author), Johns Hopkins Hosp, Dept Neurol, Meyer 6-109,600 N Wolfe St, Baltimore, MD 21287 USA. FU NCRR NIH HHS [RR00722]; NIAID NIH HHS [AI35042]; NINDS NIH HHS [NS26643] NR 61 TC 141 Z9 150 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD SEP PY 1999 VL 46 IS 3 BP 391 EP 398 DI 10.1002/1531-8249(199909)46:3<391::AID-ANA15>3.0.CO;2-0 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 232FJ UT WOS:000082360000015 PM 10482270 ER PT J AU Whitney, LW Becker, KG Tresser, NJ Caballero-Ramos, CI Munson, PJ Prabhu, VV Trent, JM McFarland, HF Biddison, WE AF Whitney, LW Becker, KG Tresser, NJ Caballero-Ramos, CI Munson, PJ Prabhu, VV Trent, JM McFarland, HF Biddison, WE TI Analysis of gene expression in multiple sclerosis lesions using cDNA microarrays SO ANNALS OF NEUROLOGY LA English DT Article ID CELLS; CHEMOKINES; PATTERNS; SYSTEM AB In multiple sclerosis (MS) patients, a coordinated attack of the immune system against the primary constituents of oligodendrocytes and/or the myelin sheath of oligodendrocytes results in the formation of lesions in the brain and spinal cord. Thus far, however, a limited number of genes that potentially contribute to lesion pathology have been identified. Using cDNA microarray technology, we have performed experiments on MS tissue monitoring the expression pattern of over 5,000 genes and compared the gene expression profile of normal white matter with that found in acute lesions from the brain of a single MS patient. Sixty-two differentially expressed genes were identified, including the Duffy chemokine receptor, interferon regulatory factor-2, and tumor necrosis factor alpha receptor-2 among others. Thus, cDNA microarray technology represents a powerful new tool for the identification of genes not previously associated with the MS disease process. C1 NINDS, Mol Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Canc Genet Branch, NIH, Bethesda, MD USA. RP Whitney, LW (reprint author), NINDS, Mol Immunol Sect, Neuroimmunol Branch, NIH, Bldg 10,Room 5B-16,10 Ctr Dr, Bethesda, MD 20892 USA. OI Becker, Kevin/0000-0002-6794-6656 NR 18 TC 180 Z9 184 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD SEP PY 1999 VL 46 IS 3 BP 425 EP 428 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 232FJ UT WOS:000082360000022 PM 10482277 ER PT J AU Ruggeri, B Ballatori, E Casali, P Tamburini, M Licitra, L Mencaglia, E Roila, F Cortesi, E Massidda, B Costantini, M De Angelis, V Ciccarese, G Mattei, A Valori, VM Lelli, G Nanni, L Romano, MP Di Maggio, G Morritti, MG Di Micco, C Palladino, MA Porrozzi, S De Angelis, V Ciccarese, G Milella, G Bruno, ML Basurto, C Locatelli, MC Valsecchi, R Zamparelli, G Pessi, A Molaro, O Luporini, G Giovanni, S Bertetto, O Donadio, M Fanchini, L Mistrangelo, M Bumma, C Parello, G Malacarne, P Donati, D Scapoli, D Ferrari, A Olmi, P Galardi, A Panichi, M Ruggiero, C Zironi, S Banzi, C Piccinini, L Campora, E Venturino, A Vincenti, M Gasco, M Marchioro, G Barbato, F Azzarello, G Vinante, O Sabbioni, R Nortilli, R Griso, C Cetto, L Aste, MG Pasqualucci, S Chierchi, MC Floris, C Barbieri, E Frezza, G Bunkeila, F Bonci, F Sarobba, MG Farris, A Sanna, G Ionta, MT Murru, R Mascia, MG Lopez, M Amodio, A Paoletti, G Timio, L Romano, M Amichetti, M Barni, S Ardizzoia, A Mandala, M Maxia, G Dessi, M Acito, L Giustini, L Casarini, MB Smerieri, F Riva, N Maltoni, M Antimi, M Bellini, V Boz, G Brema, F De Candis, D Polico, C Mandoliti, G Amendola, P Iacono, C Imperato, A Gelmi, S Giovanni, S Maluta, S Selvestrel, C Cognetti, F Barduagni, M Fusco, V Rossi, M Bracci, R Antognoli, S Mascia, V Farci, D Vitale, V Musi, M Grasso, F Nicodemo, M Cirillo, M Botta, M De Giovanni, D Giuliodori, L Silva, RR Martignetti, A Deplacido, S Domini, P Gareri, R Porcile, G Dalla Mola, A Ambrosini, G Casi, C Del Favero, A Pignata, S Ricchi, P Folco, U Castellana, MA Salvi, G Lionello, R Gaion, F Ronco, M Troccoli, G Ranuzzi, M Marchetti, P Montinari, F Fioretto, L Palmeri, S Sassi, M Carreca, I Cinieri, S Graiff, C Cariello, S Mantovani, G Lazzaro, B Spada, S Rosati, G De Marinis, F Gravina, A La Ciura, P Ognibeni, M Iannone, T Pusceddu, G Buffoli, A Marcellini, M AF Ruggeri, B Ballatori, E Casali, P Tamburini, M Licitra, L Mencaglia, E Roila, F Cortesi, E Massidda, B Costantini, M De Angelis, V Ciccarese, G Mattei, A Valori, VM Lelli, G Nanni, L Romano, MP Di Maggio, G Morritti, MG Di Micco, C Palladino, MA Porrozzi, S De Angelis, V Ciccarese, G Milella, G Bruno, ML Basurto, C Locatelli, MC Valsecchi, R Zamparelli, G Pessi, A Molaro, O Luporini, G Giovanni, S Bertetto, O Donadio, M Fanchini, L Mistrangelo, M Bumma, C Parello, G Malacarne, P Donati, D Scapoli, D Ferrari, A Olmi, P Galardi, A Panichi, M Ruggiero, C Zironi, S Banzi, C Piccinini, L Campora, E Venturino, A Vincenti, M Gasco, M Marchioro, G Barbato, F Azzarello, G Vinante, O Sabbioni, R Nortilli, R Griso, C Cetto, L Aste, MG Pasqualucci, S Chierchi, MC Floris, C Barbieri, E Frezza, G Bunkeila, F Bonci, F Sarobba, MG Farris, A Sanna, G Ionta, MT Murru, R Mascia, MG Lopez, M Amodio, A Paoletti, G Timio, L Romano, M Amichetti, M Barni, S Ardizzoia, A Mandala, M Maxia, G Dessi, M Acito, L Giustini, L Casarini, MB Smerieri, F Riva, N Maltoni, M Antimi, M Bellini, V Boz, G Brema, F De Candis, D Polico, C Mandoliti, G Amendola, P Iacono, C Imperato, A Gelmi, S Giovanni, S Maluta, S Selvestrel, C Cognetti, F Barduagni, M Fusco, V Rossi, M Bracci, R Antognoli, S Mascia, V Farci, D Vitale, V Musi, M Grasso, F Nicodemo, M Cirillo, M Botta, M De Giovanni, D Giuliodori, L Silva, RR Martignetti, A Deplacido, S Domini, P Gareri, R Porcile, G Dalla Mola, A Ambrosini, G Casi, C Del Favero, A Pignata, S Ricchi, P Folco, U Castellana, MA Salvi, G Lionello, R Gaion, F Ronco, M Troccoli, G Ranuzzi, M Marchetti, P Montinari, F Fioretto, L Palmeri, S Sassi, M Carreca, I Cinieri, S Graiff, C Cariello, S Mantovani, G Lazzaro, B Spada, S Rosati, G De Marinis, F Gravina, A La Ciura, P Ognibeni, M Iannone, T Pusceddu, G Buffoli, A Marcellini, M CA Italian Grp Evaluation Outcomes Onco TI Awareness of disease among Italian cancer patients: Is there a need for further improvement in patient information? SO ANNALS OF ONCOLOGY LA English DT Article DE awareness; neoplasms; psychology; quality of life; questionnaires; truth disclosure ID COMMUNICATION; DISCLOSURE; DIAGNOSIS; ATTITUDES; TELL AB Background: Studies are available showing that cancer patients in southern Europe may be less well informed about their disease than patients in northern Europe and North America. Patients and methods: In the framework of a survey aimed at exploring the meaning of quality of life for the Italian cancer patient, carried out all over Italy in a one-week time span on 6098 consecutive patients, two visual analogue scales evaluating severity and curability of disease were also submitted to the patients. Four patterns of patients' answers were defined: very easy/difficult-to-cure disease, and not-severe/severe disease. Multifactorial analyses were performed using logistic models for each of the four responses, assuming patient characteristics, time since diagnosis and disease extent as explanatory variables. Results: Only 26% of 2088 patients with disseminated disease believed it to be 'difficult to cure', while 39% felt it to be 'easy to cure'. In the same subgroup of patients, only 47% found their disease `severe'. Conclusions: Authors were impressed by these unexpected results, which are therefore reported separately from the overall analysis of data, aimed at exploring the quality of life domains for the Italian cancer patient. In fact, they would suggest a great lack of awareness of the severity and curability of their disease in a large group of unselected Italian cancer patients. This may depend on various factors, including cross-cultural ones, but could also be partly related to inadequacies in the process by which the Italian patient is informed, and this should be further investigated. C1 Univ Aquila, Dept Internal Med & Publ Hlth, Med Stat Unit, I-67100 Laquila, Italy. Ist Nazl Tumori, I-20133 Milan, Italy. Policlin Hosp, Div Med Oncol, Perugia, Italy. Univ La Sapienza, Div Med Oncol, Rome, Italy. Univ Cagliari, Dept Med Oncol, Cagliari, Italy. Natl Canc Inst, Genoa, Italy. Div Med Oncol, Foggia, Italy. S Carlo Borromeo Hosp, Div Med Oncol, Milan, Italy. S Giovanni AS Hosp, Div Med Oncol, Turin, Italy. Div Med Oncol, Ferrara, Italy. Careggi Univ, Radiotherapy Oncol Unit, Florence, Italy. Careggi Hosp, Radiotherapy Oncol Unit, Florence, Italy. Div Med Oncol, Modena, Italy. Ist Nazl Ric Canc, I-16132 Genoa, Italy. Div Med Oncol, Venice, Italy. Univ Verona, Dept Med Oncol, I-37100 Verona, Italy. Med Oncol Div 2, Cagliari, Italy. S Orsola Hosp, Radiotherapy Oncol Div, Bologna, Italy. S Chiara Hosp, Div Med Oncol, Pisa, Italy. Univ Sassari, Div Med Oncol, I-07100 Sassari, Italy. Univ Cagliari, Div Med Oncol, Cagliari, Italy. Regina Elena Hosp, Med Oncol Div 2, Rome, Italy. Radiotherapy Oncol Div, Trento, Italy. S Gerardo Hosp, Div Med Oncol, Milan, Italy. Radiotherapy Oncol Div, Cagliari, Italy. Med Oncol Serv, Fermo, Ascoli Piceno, Italy. Div Med Oncol, Mantova, Italy. Div Med Oncol, Forli, Italy. S Eugenio Hosp, Med Oncol Serv, Rome, Italy. Ctr Riferimento Oncol, Radiotherapy Oncol Div, I-33081 Aviano, Italy. S Paolo Hosp, Med Oncol Serv, Savona, Italy. Natl Canc Inst, Div Med Oncol, I-20133 Milan, Italy. Radiotherapy Oncol Div, Rovigo, Italy. Div Med Oncol, Ragusa, Italy. Div Med Oncol, Padua, Italy. S Giovanni & Paolo Hosp, Radiotherapy Oncol Div, Venice, Italy. Regina Elena Hosp, Div Med Oncol 1, Rome, Italy. Div Med Oncol, Alessandria, Italy. Univ Ancona, Div Med Oncol, Ancona, Italy. Med Oncol Div 3, Cagliari, Italy. Ist Nazl Ric Canc, Radiotherapy Oncol Div, I-16132 Genoa, Italy. Div Med Oncol, Aosta, Italy. Negrar Hosp, Div Med Oncol, Verona, Italy. S Spirito Hosp, Med Oncol Serv, Casale Monferrato, Alessandria, Italy. Med Oncol Serv, Ancona, Italy. Univ Naples Federico II, Dept Clin & Mol Oncol & Endocrinol, Naples, Italy. Univ La Sapienza, Dept Med Oncol, Rome, Italy. S Lazzaro Hosp, Med Oncol Ctr, Alba, Cuneo, Italy. S Chiara Hosp, Med Oncol Unit, Trento, Italy. Inst Internal Med & Oncol Sci, Perugia, Italy. Natl Canc Inst Pascale, Med Oncol Div B, Naples, Italy. S Corona Hosp, Med Oncol Serv, Pietra Ligure, Savona, Italy. S Filippo Neri Hosp, Div Med Oncol, Rome, Italy. Gemelli Hosp, Radiotherapy Oncol Ctr, Rome, Italy. Med Oncol Serv, Padua, Italy. Univ Bari, Policlin Hosp, Div Med Oncol, Bari, Italy. Regina Elena Hosp, Div Med Oncol, Rome, Italy. Univ Aquila, Med Oncol Serv, I-67100 Laquila, Italy. Ist Nazl Tumori, Div Med Oncol, I-20133 Milan, Italy. SM Annunziata Hosp, Med Oncol Serv, Florence, Italy. Univ Palermo, Inst Clin Med, Palermo, Italy. Med Oncol Serv, Perugia, Italy. Univ Palermo, Cattedra Med Oncol, Palermo, Italy. Div Internal Med, Francavilla Fontana, Brindisi, Italy. Div Med Oncol, Bolzano, Italy. Med Oncol Serv, Salerno, Italy. Univ Cagliari, Dept Internal Med Sci, Div Med Oncol, Cagliari, Italy. Med Ematol Div, Catanzaro, Italy. Clin Oncol, Catanzaro, Italy. Umberto I Hosp, Med Oncol Serv, Div Internal Med, Siracusa, Italy. Cardarelli Hosp, Div Med Oncol, Naples, Italy. S Camillo Forlanini Hosp, Pneumoncol Unit 5, Rome, Italy. Natl Canc Inst Pascale, Med Oncol Div A, Naples, Italy. S Croce Hosp, Med Oncol Ctr, Cuneo, Italy. Div Med Oncol, Ancona, Italy. Radiotherapy Oncol Div, Belluno, Italy. Binaghi Hosp, Pneumol Div 1, Cagliari, Italy. Radiotherapy Oncol Div, Udine, Italy. Div Med Oncol, Ancona, Italy. RP Ruggeri, B (reprint author), Univ Aquila, Dept Internal Med & Publ Hlth, Med Stat Unit, I-67100 Laquila, Italy. RI costantini, massimo/G-1443-2012; MATTEI, Antonella/M-6579-2016; Cognetti, Gaetana /P-1927-2015 OI MATTEI, Antonella/0000-0001-6420-8116; Cognetti, Gaetana /0000-0003-1371-9375 NR 18 TC 26 Z9 26 U1 2 U2 5 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 SEP PY 1999 VL 10 IS 9 BP 1095 EP 1100 PG 6 WC Oncology SC Oncology GA 239NN UT WOS:000082775000016 ER PT J AU Gnant, MFX Puhlmann, M Bartlett, DL Alexander, HR AF Gnant, MFX Puhlmann, M Bartlett, DL Alexander, HR TI Regional versus systemic delivery of recombinant vaccinia virus as suicide gene therapy for murine liver metastases SO ANNALS OF SURGERY LA English DT Article; Proceedings Paper CT 119th Annual Meeting of the American-Surgical-Association CY APR 15-17, 1999 CL SAN DIEGO, CALIFORNIA SP Amer Surg Assoc ID CYTOSINE DEAMINASE GENE; IN-VIVO; COLORECTAL-CARCINOMA; CARCINOEMBRYONIC ANTIGEN; COLON-CARCINOMA; CANCER-THERAPY; VECTORS; 5-FLUOROCYTOSINE; CELLS; IDENTIFICATION AB Objective Specific and efficient tumor-targeted gene delivery is the major goal for successful cancer gene therapy. Summary Background Data A recombinant thymidine kinase-deleted vaccinia virus (vv) encoding the firefly luciferase (luc) reporter gene or the prodrug converter gene cytosine deaminase (CD) was constructed. The authors compared the extent, duration, and pattern of transgene (luc) expression in vivo after portal venous, intraperitoneal, or intravenous virus administration and survival after treatment with the vv containing CD followed by the prodrug 5-fluorocytosine (5-FC) in a murine model of disseminated liver metastases from colon cancer. Methods Recombinant vv containing the luc transgene within the thymidine kinase locus was administered to mice with isolated liver metastases from an MC38 adenocarcinoma. Transgene expression was determined in tumor and organs at various time points. Tumor-bearing mice were treated with recombinant vv containing CD and 5-FC or with appropriate controls and followed for survival. Results Tumor-specific gene delivery was achieved irrespective of administration route, with gene expression in tumors increased by up to 100,000-fold compared with normal tissues. There was significantly increased transgene expression in tumor after portal venous or intraperitoneal virus administration (p = 0.001 vs. systemic). Treatment using a CD-expressing vv and systemic 5-FC resulted in a significant survival benefit in all treatment groups compared with controls (p < 0.007); there was no additional benefit for portal venous or intraperitoneal virus administration. Conclusions Suicide gene therapy using vv with the CD/5-FC system leads to tumor-specific gene expression and improved survival and can result in cure of established liver metastases. C1 NCI, Surg Metab Sect, Surg Branch, NIH, Bethesda, MD 20892 USA. Univ Vienna, Dept Surg, Vienna, Austria. Tech Univ Munich, Dept Surg, D-8000 Munich, Germany. RP Alexander, HR (reprint author), NCI, Surg Metab Sect, Surg Branch, NIH, Bldg 10,Rm 2B07,9000 Rockville Pike, Bethesda, MD 20892 USA. OI Gnant, Michael/0000-0003-1002-2118 NR 51 TC 27 Z9 29 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD SEP PY 1999 VL 230 IS 3 BP 352 EP 360 DI 10.1097/00000658-199909000-00008 PG 9 WC Surgery SC Surgery GA 234ZT UT WOS:000082514800015 PM 10493482 ER PT J AU Feldman, AL Alexander, HR Bartlett, DL Fraker, DL Libutti, SK AF Feldman, AL Alexander, HR Bartlett, DL Fraker, DL Libutti, SK TI Management of extremity recurrences after complete responses to isolated limb perfusion in patients with melanoma SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article DE complete response; limb perfusion; melanoma; melphalan; recurrence ID METASTATIC MELANOMA; MALIGNANT-MELANOMA; MELPHALAN AB Background: Despite high rates of complete responses (CRs) to isolated limb perfusion (ILP) for patients with in-transit melanoma (60% to 90%), extremity recurrences are common. We evaluated our experience with managing these recurrences to determine how best to treat these patients. Methods: Between April 1992 and April 1998, 72 patients experienced CRs after hyperthermic ILP using Melphalan, with (n = 46) or without (n = 26) tumor necrosis factor. Of these, 25 patients (35%) experienced initial recurrences in the extremities, and they form the basis of this study. Results: Three patients who underwent repeat ILP for treatment of their recurrences experienced a second CR and recurrence in the extremity (at 9, 15, and 16 months), allowing analysis of 28 cases. For 5 of 20 recurrences managed with excision, 2 of 6 managed with repeat lip, and 0 of 2 managed with systemic treatment, the patient was free of disease at the last follow-up examination (median follow-up period, 11 months). Conclusions: Isolated extremity recurrences after CRs to ILP occurred in 35% of patients. Initially, these could be managed successfully by excision or repeat lip for the majority of patients (92%). We recommend excision of small-volume recurrent disease, reserving repeat lip for patients with increasing numbers of lesions or increasing rapidity of in-field recurrences. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. Univ Penn, Dept Surg, Philadelphia, PA 19104 USA. RP Libutti, SK (reprint author), NCI, Surg Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RI Feldman, Andrew/D-5028-2012 NR 17 TC 24 Z9 24 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD SEP PY 1999 VL 6 IS 6 BP 562 EP 567 DI 10.1007/s10434-999-0562-x PG 6 WC Oncology; Surgery SC Oncology; Surgery GA 234FQ UT WOS:000082474200011 PM 10493624 ER PT J AU Park, BJ Alexander, HR Libutti, SK Wu, P Royalty, D Kranda, KC Bartlett, DL AF Park, BJ Alexander, HR Libutti, SK Wu, P Royalty, D Kranda, KC Bartlett, DL TI Treatment of primary peritoneal mesothelioma by continuous hyperthermic peritoneal perfusion (CHPP) SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article DE primary peritoneal mesothelioma; continuous hyperthermic peritoneal perfusion (CHPP); carcinomatosis; tumor necrosis factor; intraperitoneal cisplatin ID SYSTEMIC THIOSULFATE PROTECTION; LONG-TERM SURVIVAL; MALIGNANT MESOTHELIOMA; GASTRIC-CANCER; INTRAPERITONEAL CHEMOTHERAPY; MITOMYCIN-C; CISPLATIN; CARCINOMATOSIS; DISSEMINATION; PACLITAXEL AB Background: Primary peritoneal mesothelioma is a locally aggressive disease that is difficult to treat or even palliate. Continuous hyperthermic peritoneal perfusion (CHPP) with cisplatin (CDDP) allows uniform, high regional delivery of chemotherapeutics and hyperthermia to the peritoneal surface for the treatment of peritoneal tumors. This article summarizes the results of 18 patients with peritoneal mesothelioma treated with CHPP. Methods: From June 1993 through April 1998, 18 patients with primary peritoneal mesothelioma (13 male, 5 female; median age, 51 years) underwent surgical exploration and tumor debulking followed by a 90-minute CHPP with CDDP and hyperthermia as part of three consecutive phase I trials conducted at the National Cancer Institute. Seventeen of 18 patients had malignant peritoneal mesothelioma, 13 with associated ascites. One patient had a symptomatic, multiply recurrent, benign, cystic peritoneal mesothelioma. Three patients who had a recurrence after a prolonged progression-free interval (>6 months) after CHPP underwent re-treatment. CHPP parameters included median cisplatin dose of 530 mg (range, 187-816), perfusate volume 6.0 liter (range, 4-9), flow 1.5 liter/min (range, 1-2), intraperitoneal temperature 41 degrees C (range, 38.7-43.2), and central temperature 38.6 degrees C (range, 36.8-39.7). Results: Median follow-up after CHPP is 19 months (range, 2-56) with no operative or treatment-related mortality. Overall operative morbidity was 24% and included two patients with superficial wound infection and one patient each with atrial fibrillation, pancreatitis, fascial dehiscence, ileus, line sepsis, and clostridium difficile colitis. The major treatment-related toxicity was systemic renal toxicity at doses above what was defined as the maximum tolerated dose of cisplatin. Nine of 10 patients had resolution of their ascites postoperatively. Three patients who developed recurrent ascites (27, 22, and 10 months after initial treatment) were re-treated and had resolution of their ascites with ongoing responses at 24, 6, and 4 months after the second perfusion. The median progression-free survival was 26 months, and the overall 2-year survival was 80%. The median overall survival has not been reached. Conclusions: CHPP with cisplatin can be performed safely with no mortality and minimal morbidity. In selected patients, successful palliation in the abdomen and long-term survival, compared with historical controls, can be achieved with aggressive surgical debulking and CHPP. Re-treatment after initial response can result in a second long-term response. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Bartlett, DL (reprint author), NCI, Surg Branch, NIH, 10 Ctr Dr,Room B16, Bethesda, MD 20892 USA. NR 35 TC 100 Z9 105 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD SEP PY 1999 VL 6 IS 6 BP 582 EP 590 DI 10.1007/s10434-999-0582-6 PG 9 WC Oncology; Surgery SC Oncology; Surgery GA 234FQ UT WOS:000082474200015 PM 10493628 ER PT J AU Manzoli, L Billi, AM Faenza, I Matteucci, A Martelli, AM Peruzzi, D Falconi, M Rhee, SG Gilmour, RS Cocco, L AF Manzoli, L Billi, AM Faenza, I Matteucci, A Martelli, AM Peruzzi, D Falconi, M Rhee, SG Gilmour, RS Cocco, L TI Nuclear phospholipase C: A novel aspect of phosphoinositide signalling SO ANTICANCER RESEARCH LA English DT Article; Proceedings Paper CT 1st International Symposium on Disease Prevention by IP(6) and Other Rice Components CY JUN 08-09, 1998 CL KYOTO, JAPAN DE phospholipase C; nucleus; signalling ID PROTEIN-KINASE-C; SWISS 3T3 CELLS; INOSITOL LIPID CYCLE; GROWTH-FACTOR-I; FRIEND-CELLS; ERYTHROLEUKEMIA-CELLS; DNA-SYNTHESIS; S-PHASE; IGF-I; DIFFERENTIATION AB The role of polyphosphoinositides in cellular signalling is well known and recently it has also been shown that the nucleus is a site for both synthesis and hydrolysis of the phosphorylated forms of phosphatidylinositol. It has been demonstrated that phospholipase C specific for inositol lipids (PLC) is one of the main steps of the inositol lipid cycle. The PLC beta family, and especially type PL has given rise to considerable interest since, due to their common COOH-terminus they show nuclear localisation in addition to that at the plasma membrane. It is well established that an autonomous intranuclear inositide cycle exists, and that this cycle is endowed with conventional lipid kinases, phosphatases and PLCs. Among this latter the pr type undergoes stimulation or inhibition under different stimuli and this implicates the beta(1) isoform as a key enzyme for mitogen-activated cell growth as well as for differentiation. Indeed, both the overexpression and the down-regulation of PLC beta(1), by means of antisense mRNA, have demonstrated that PLC plays a role in the nuclear compartment. C1 Univ Bologna, Inst Human Anat, I-40126 Bologna, Italy. CNR, Inst Cytomorphol, I-40136 Bologna, Italy. Ist Rizzoli, Cell Biol Lab, I-40136 Bologna, Italy. Univ Trieste, Dept Human Morphol, I-34138 Trieste, Italy. NHLBI, Lab Cell Signalling, NIH, Bethesda, MD 20892 USA. Univ Auckland, Fac Med, Auckland, New Zealand. RP Cocco, L (reprint author), Univ Bologna, Inst Human Anat, Via Imerio 48, I-40126 Bologna, Italy. NR 40 TC 10 Z9 10 U1 0 U2 1 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDNTIOU-KALAMOU RD KAPANDRITI, POB 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD SEP-OCT PY 1999 VL 19 IS 5A BP 3753 EP 3756 PG 4 WC Oncology SC Oncology GA 260UZ UT WOS:000083973000024 PM 10625953 ER PT J AU Castiglione, F Sarotto, I Fontana, V Destefanis, M Venturino, A Ferro, S Cardaropoli, S Orengo, MA Porcile, G AF Castiglione, F Sarotto, I Fontana, V Destefanis, M Venturino, A Ferro, S Cardaropoli, S Orengo, MA Porcile, G TI Bcl2, p53 and clinical outcome in a series of 138 operable breast cancer patients SO ANTICANCER RESEARCH LA English DT Article DE breast cancer; p53 protein; bcl2 protein; prognostic factors; multivariate analysis ID TUMOR-SUPPRESSOR GENE; PROTEIN EXPRESSION; PROGNOSTIC FACTORS; CELL-DEATH; FOLLOW-UP; IN-VITRO; CARCINOMAS; APOPTOSIS; BAX; SURVIVAL AB Medical oncologists are increasingly interested in identifying reliable prognostic factors for breast cancer in order to distinguish subsets of breast cancer patients and to optimize therapeutic approaches. Among them, the p53 tumor studied, brit their role remains to be defined. Moreover the mechanism of action by which they affect cell kinetics has to be clarified, particularly with respect to the balance between breast cancer patients in order to verify the relationships of p53 and bcl2 proteins with better known clinicopathological features and their impact on the clinical outcomes of relapse-free survival (RFS) and overall survival (OS). Our data indicated a significant relationship between bcl2 expression and steroid receptor positive status, wild-type p53 and low proliferative index. Mutant p53 accumulation was found to be related to the absence of steroid receptors and high proliferation. Both were significant markers of better prognosis in univariate analysis. Multivariate analysis confirmed the favorable impact of bcl2 on both RFS and OS. On the contrary, we failed to observe any prognostic role for p53 status. We describe herein an independent favorable prognostic impact for patients with positive bcl2 expression that appears to be worthy of larger confirmatory study. On the contrary, our series seems to confirm the decreasing prognostic relevance of p53 in clinical practice. C1 Civ Hosp, Med Oncol Serv, Alba, Italy. Natl Canc Inst, IST, Dept Environm Epidemiol & Biostat, Genoa, Italy. Natl Canc Inst, IST, Liguria Canc Registry Sect, Genoa, Italy. RP Castiglione, F (reprint author), 21 Corso Piave, I-12051 Alba, Italy. OI Cardaropoli, Simona/0000-0002-8927-8900 NR 42 TC 25 Z9 25 U1 0 U2 0 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDNTIOU-KALAMOU RD KAPANDRITI, POB 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD SEP-OCT PY 1999 VL 19 IS 5C BP 4555 EP 4563 PG 9 WC Oncology SC Oncology GA 274LW UT WOS:000084768200034 PM 10650810 ER PT J AU Petraitiene, R Petraitis, V Groll, AH Candelario, M Sein, T Bell, R Lyman, CA McMillian, CL Bacher, J Walsh, TJ AF Petraitiene, R Petraitis, V Groll, AH Candelario, M Sein, T Bell, R Lyman, CA McMillian, CL Bacher, J Walsh, TJ TI Antifungal activity of LY303366, a novel echinocandin B, in experimental disseminated candidiasis in rabbits SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID IN-VITRO ACTIVITY; FUNGAL CELL-WALL; AMPHOTERICIN-B; CRYPTOCOCCUS-NEOFORMANS; MARROW TRANSPLANTATION; FLUCONAZOLE; ALBICANS; CANDIDEMIA; THERAPY; ASPERGILLUS AB The safety and antifungal activity of LY303366 (LY), a new broad-spectrum semisynthetic echinocandin, were studied against disseminated candidiasis in persistently neutropenic rabbits. In vitro time-kill assays demonstrated that LY has concentration-dependent fungicidal activity. The pharmacokinetics of LY in the plasma of nonneutropenic rabbits suggested a linear relationship between dose and area under the curve (AUC). The times spent above the MIC during the experimental dosing interval of 24 h were 4 h for LY at 0.1 mg/kg of body weight/day (LY0.1), 8 h for LY at 0.25 mg/kg/day (LY0.25), 12 h for LY at 0.5 mg/kg/day (LY0.5), and 20 h for LY at 1 mg/kg/day (LY1). Antifungal therapy was administered to infected rabbits for 10 days starting 24 h after the intravenous (i.v.) inoculation of Id Candida albicans blastoconidia. Study groups consisted of untreated controls (UCs) and animals treated with amphotericin B (AmB; 1 mg/kg/day i.v.), fluconazole (FLU; 10 mg/kg/day i.v.), and LY0.1, LY0.25, LY0.5, or LY1 i.v. Rabbits treated with LY0.5, LY1, AmB, and FLU had similarly significant clearance of C. albicans from the liver, spleen, Kidney, lung, vena cava, and brain in comparison to that for UCs. There was a dose-dependent clearance of C. albicans From tissues in response to LY. Among rabbits treated with LY0.1 there was a significant reduction of C. albicans only in the spleen. In animals treated with LY0.25 there was a significant reduction in all tissues but the brain. By comparison, LY0.5 and LY1 cleared all tissues, including the brain, of C. albicans. These in vivo findings were consistent with the results of in,vitro time-kill assays. A dose-dependent effect of altered cell wall morphology was observed among UCs and animals treated with LY0.1, and LY0.25, with a progressive transition from hyphal structure to disrupted yeast forms. Serum creatinine levels were higher and serum potassium levels were Lower in AmB-treated rabbits than in UCs and LY- and FLU-treated rabbits. LY0.5 and LY1 were well tolerated, displayed predictable pharmacokinetics in plasma, and had activities comparable to those of AmB and FLU in the treatment of disseminated candidiasis in persistently neutropenic rabbits. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NIH, Surg Serv, Vet Resources Program, Off Res Serv, Bethesda, MD 20892 USA. Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bldg 10,Rm 13N240,Ctr Dr, Bethesda, MD 20892 USA. NR 44 TC 75 Z9 76 U1 0 U2 2 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 SEP PY 1999 VL 43 IS 9 BP 2148 EP 2155 PG 8 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 233BM UT WOS:000082405700009 PM 10471556 ER PT J AU Lyman, CA Gonzalez, C Schneider, M Lee, J Walsh, TJ AF Lyman, CA Gonzalez, C Schneider, M Lee, J Walsh, TJ TI Effects of the hematoregulatory peptide SK&F 107647 alone and in combination with amphotericin B against disseminated candidiasis in persistently neutropenic rabbits SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID COLONY-STIMULATING FACTOR; FUNGAL INFECTION; SK-AND-F-107647; ALBICANS; THERAPY; MICE; FLUCONAZOLE; MODULATION; CYTOKINES AB The effects of the hematoregulatory peptide SK&F 107647 were examined in a persistently and profoundly neutropenic rabbit model of disseminated candidiasis in order to determine its potential to enhance resistance against infection and its role as an adjunct to conventional antifungal chemotherapy. In healthy animals, SK&F 107647 elicited a time-dependent increase in CD11b-positive monocytes and neutrophils, When administered to neutropenic rabbits infected with Candida albicans, no significant differences in the number of CFU per gram in any of the tissues tested compared with the number in untreated control rabbits were detected. However, when SK&F 107647 was administered in combination with low doses of amphotericin B, there was a significant reduction in organism burden in the lungs, liver, spleen, and kidneys compared with the burdens in the organs of untreated control animals and in the lungs and kidneys compared with the burdens in the lungs and kidneys of animals treated with amphotericin B alone. These data suggest a potential role for this peptide as adjunctive therapy in combination with conventional antifungal agents in the treatment of disseminated candidiasis in the setting of profound and persistent neutropenia. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. SmithKline Beecham, Dept Mol Virol & Host Def, Collegeville, PA 19426 USA. RP Lyman, CA (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bldg 10,Room 13N240, Bethesda, MD 20892 USA. NR 24 TC 5 Z9 5 U1 0 U2 0 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 SEP PY 1999 VL 43 IS 9 BP 2165 EP 2169 PG 5 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 233BM UT WOS:000082405700012 PM 10471559 ER PT J AU Xu, YY Ambudkar, I Yamagishi, H Swaim, W Walsh, TJ O'Connell, BC AF Xu, YY Ambudkar, I Yamagishi, H Swaim, W Walsh, TJ O'Connell, BC TI Histatin 3-mediated killing of Candida albicans: Effect of extracellular salt concentration on binding and internalization SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID HISTIDINE-RICH POLYPEPTIDES; HUMAN SALIVARY HISTATIN-5; PORPHYROMONAS-GINGIVALIS; HELICAL CONFORMATION; PROTEINS; VARIANTS; SEQUENCE; PEPTIDES AB Human saliva contains histidine-rich proteins, histatins, which have antifungal activity in vitro. The mechanism by which histatins are able to kill Candida albicans may have clinical significance but is currently unknown. Using radiolabeled histatin 3, we show that the protein binds to C. albicans spheroplasts in a manner that is dependent on time and concentration. Binding to the spheroplasts was saturable and could be competed with unlabeled histatin 3. A single histatin 3 binding site with a K-d = 5.1 mu M was detected. Histatin 3 binding resulted in potassium and magnesium efflux, predominantly within the first 30 min of incubation. Studies with fluorescent histatin 3 demonstrate that the protein is internalized by C. albicans and that translocation of histatin inside the cell is closely associated with cell death. Histatin binding, internalization, and cell death are accelerated in low-ionic-strength conditions. Indeed, a low extracellular salt concentration was essential for cell death to occur, even when histatin 3 was already bound to the cell. The interaction of histatin 3 with C. albicans, and subsequent cell death, is inhibited at low temperature. These results demonstrate that the candidacidal activity of histatin 3 is not due exclusively to binding at the cell surface but also involves subsequent interactions with the cell. C1 Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Cellular Imaging Core Facil, Bethesda, MD 20892 USA. NCI, Pediat Oncol Branch, Immunocompromised Host Sect, Bethesda, MD 20892 USA. RP O'Connell, BC (reprint author), Univ Dublin Trinity Coll, Sch Dent Sci, Dublin 2, Ireland. OI O'Connell, Brian/0000-0003-4529-7664 FU PHS HHS [ZO1-00675] NR 30 TC 50 Z9 50 U1 0 U2 0 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 SEP PY 1999 VL 43 IS 9 BP 2256 EP 2262 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 233BM UT WOS:000082405700028 PM 10471575 ER PT J AU Piscitelli, SC Spooner, K Baird, B Chow, AT Fowler, CL Williams, RR Natarajan, J Masur, H Walker, RE AF Piscitelli, SC Spooner, K Baird, B Chow, AT Fowler, CL Williams, RR Natarajan, J Masur, H Walker, RE TI Pharmacokinetics and safety of high-dose and extended-interval regimens of levofloxacin in human immunodeficiency virus-infected patients SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID MYCOBACTERIUM-TUBERCULOSIS; COMPLEX AB The pharmacokinetics of levofloxacin, administered in high doses and with extended dosing intervals, was studied in human immunodeficiency virus (HIV)-infected patients. Thirty patients received either 750 mg of the drug or a placebo once daily for 14 days, followed by 750 mg or 1,000 mg of the drug or a placebo three times weekly for an additional 14 days. Levofloxacin disposition was characterized by rapid oral absorption, with peak concentrations occurring approximately 1.5 h after dosing and elimination half-lives from 7.2 to 9.4 h. The overall incidence of any adverse effect was 70% (1,000 mg) to 95% (750 mg) for levofloxacin-treated patients and 71% for those taking the placebo. Levofloxacin pharmacokinetic parameters for HIV-infected patients were consistent with those observed in studies of healthy volunteers. C1 NIAID, Dept Pharm, Warren G Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NIAID, Dept Crit Care Med, Warren G Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RW Johnson Pharmaceut Res Inst, Raritan, NJ 08869 USA. RP Walker, RE (reprint author), NIAID, Dept Pharm, Warren G Magnuson Clin Ctr, NIH, Bldg 10,Rm 11C103,10 Ctr Dr,MSC 1880, Bethesda, MD 20892 USA. NR 12 TC 13 Z9 14 U1 1 U2 1 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 SEP PY 1999 VL 43 IS 9 BP 2323 EP 2327 PG 5 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 233BM UT WOS:000082405700044 PM 10471591 ER PT J AU Ramakrishnan, A Sadana, A AF Ramakrishnan, A Sadana, A TI Analyte-receptor binding kinetics for different types of biosensors - A fractal analysis SO APPLIED BIOCHEMISTRY AND BIOTECHNOLOGY LA English DT Article DE analyte-receptor binding; fractals; biosensors ID ANTIGEN-ANTIBODY BINDING; BIOMOLECULAR INTERACTION ANALYSIS; IMMOBILIZED ANTIBODY; MASS-TRANSPORT; EXTERNAL DIFFUSION; RATE COEFFICIENT; PROTEIN INTERACTIONS; OPTICAL BIOSENSOR; HYBRIDIZATION; LIMITATIONS AB A fractal analysis is presented for analyte-receptor binding kinetics for different types of biosensor applications. Data taken from the literature may be modeled using a single-fractal analysis, a single- and a dual-fractal analysis, or a dual-fractal analysis. The latter two methods represent a change in the binding mechanism as the reaction progresses on the surface. Predictive relationships developed for the binding rate coefficient as a function of the analyte concentration are of particular value since they provide a means by which the binding rate coefficients may be manipulated. Relationships are presented for the binding rate coefficients as a function of the fractal dimension D-f or the degree of heterogeneity that exists on the surface. When analyte-receptor binding is involved, an increase in the heterogeneity on the surface (increase in D-f) leads to an increase in the binding rate coefficient. It is suggested that an increase in the degree of heterogeneity on the surface leads to an increase in the turbulence on the surface owing to the irregularities on the surface. This turbulence promotes mixing, minimizes diffusional limitations, and leads subsequently to an increase in the binding rate coefficient. The binding rate coefficient is rather sensitive to the degree of heterogeneity, D-f, that exists on the biosensor surface. For example, the order of dependence on D-f1 is 7.25 for the binding rate coefficient k(1) for the binding of a Fab fragment of an antiparaquat monoclonal antibody in solution to an antigen in the form of a paraquat analog immobilized on a sensor surface. The predictive relationships presented for the binding rate coefficient and the fractal dimension as a function of the analyte concentration in solution provide further physical insights into the binding reactions on the surface, and should assist in enhancing biosensor performance. In general, the technique is applicable to other reactions occurring on different types of surfaces, such as cell-surface reactions. C1 Univ Mississippi, Dept Chem Engn, University, MS 38677 USA. NHLBI, Cardiol Branch, Bethesda, MD 20892 USA. RP Ramakrishnan, A (reprint author), Univ Mississippi, Dept Chem Engn, 230 Anderson Hall, University, MS 38677 USA. NR 50 TC 0 Z9 0 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0273-2289 J9 APPL BIOCHEM BIOTECH JI Appl. Biochem. Biotechnol. PD SEP PY 1999 VL 81 IS 3 BP 161 EP 179 DI 10.1385/ABAB:81:3:161 PG 19 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 271ZE UT WOS:000084624900003 PM 10652783 ER PT J AU Gorlatov, SN Stadtman, TC AF Gorlatov, SN Stadtman, TC TI Human selenium-dependent thioredoxin reductase from HeLa cells: Properties of forms with differing heparin affinities SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article ID LUNG ADENOCARCINOMA CELLS; HUMAN PLACENTA; PURIFICATION; DISULFIDE; BINDING; SELENOCYSTEINE; SELENOENZYME; MECHANISMS; INHIBITION; GOLD AB The TrxR1 form of thioredoxin reductase (TrxR) was the major form of the enzyme isolated from HeLa cells grown in a fermenter at 35 degrees C under controlled aeration conditions favorable to growth, nominally 30% of saturation of dissolved oxygen or 8 ml of oxygen in a liter of medium. This TrxR1 form was not retained on a heparin affinity matrix, it contained one selenium per subunit, was highly active catalytically, and showed strong cross-reactivity with anti-rat liver TrxR1 polyclonal antibodies. At higher aeration, 50% of saturation of dissolved oxygen or 12 ml of oxygen in a liter of medium, HeLa cell growth was slower and additional TrxR forms that bound to heparin were present in purified enzyme preparations. A minor component, TrxR2, the mitochondrial form of TrxR, was detected in the heparin-bound enzyme fraction. One enzyme form that contained less selenium (ca, 0.5 Se per TrxR subunit) was only about 50% as active with thioredoxin or 5,5'dithiobis(2-nitrobenzoic acid) as substrate. Cross-reactivity of this form with anti-rat liver TrxR1 polyclonal antibodies was very weak. The isoelectric point of the low Se enzyme, 5.85, was higher than that, 5.2-5.4, of normal Se content enzyme. Affinity of purified fully active TrxR1 to heparin could be induced by reduction with NADPH or tris-(2-carboxyethyl)phosphine (TCEP), Under anaerobic conditions there was complete retention of Se indicating that an enzyme conformation change effected by reduction was involved. The TCEP-reduced enzyme form was very oxygen labile and upon exposure to air both the Se content and catalytic activity decreased by about 50%, Addition of millimolar concentrations of NADPH or NADP(+) to the TCEP-reduced enzyme gave full protection from oxygen inactivation. TrxR1 exhibited weak peroxidase activity with H2O2 as substrate in the presence of an NADPH-generating system but this activity was unstable. Specific alkylation of the selenocysteine residue of TrxR1 which completely inhibits the NADPH-dependent reduction of disulfides also destroyed peroxidase activity. (C) 1999 Academic Press. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Stadtman, TC (reprint author), NHLBI, Biochem Lab, NIH, Bldg 3,Room 108,MSC-0320 Ctr Dr, Bethesda, MD 20892 USA. NR 29 TC 14 Z9 14 U1 1 U2 8 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD SEP 1 PY 1999 VL 369 IS 1 BP 133 EP 142 DI 10.1006/abbi.1999.1356 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 239DE UT WOS:000082752900015 PM 10462449 ER PT J AU Leverkus, M Schmidt, E Lazarova, Z Brocker, EB Yancey, KB Zillikens, D AF Leverkus, M Schmidt, E Lazarova, Z Brocker, EB Yancey, KB Zillikens, D TI Antiepiligrin cicatricial pemphigoid - An underdiagnosed entity within the spectrum of scarring autoimmune subepidermal bullous diseases? SO ARCHIVES OF DERMATOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the Arbeitsgemeinschaft Dermatologische Forschung CY FEB 20, 1999 CL BONN, GERMANY ID IGG AUTOANTIBODIES; SPLIT SKIN; EPILIGRIN; LAMININ-5; ANTIGEN; SPECIFICITY; DERMATOSES; CARCINOMA; SUBUNIT; PATIENT AB Background: Antiepiligrin cicatricial pemphigoid (AECP) is a chronic autoimmune subepidermal blistering disease characterized by autoantibodies to laminin 5 and clinical features of cicatricial pemphigoid. Only a few patients with AECP have been described to date. The aim of the present study was to analyze the relative frequency of AECP among patients with the clinical phenotype of cicatricial pemphigoid. Observations: Serum from 16 consecutive patients with the clinical phenotype of cicatricial pemphigoid were included in this study. Nine patients had circulating IgG autoantibodies by indirect immunofluorescence on sodium chloride-split skin; patients' IgG bound to the epidermal side (n = 2), dermal side (n = 5), or both sides (n = 2) of this test substrate. Interestingly, all 5 cases with dermal binding immunoprecipitated laminin 5 from extracts and media of cultured keratinocytes, and 4 of these serum samples reacted with the alpha 3 subunit of laminin 5 by immunoblotting. None of the patients with dermal binding of IgG demonstrated autoantibodies to type VII collagen. Conclusion: Our data suggest that, among patients with the clinical phenotype of cicatricial pemphigoid, AECP may be more frequent than previously assumed. C1 Univ Wurzburg, Dept Dermatol, Sch Med, D-97080 Wurzburg, Germany. NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Zillikens, D (reprint author), Univ Wurzburg, Dept Dermatol, Sch Med, Josef Schneider Str 2, D-97080 Wurzburg, Germany. RI Schmidt, Enno/C-4008-2009; Zillikens, Detlef/C-8572-2011 OI Schmidt, Enno/0000-0002-1206-8913; NR 34 TC 46 Z9 46 U1 0 U2 0 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 SEP PY 1999 VL 135 IS 9 BP 1091 EP 1098 DI 10.1001/archderm.135.9.1091 PG 8 WC Dermatology SC Dermatology GA 234KF UT WOS:000082483000009 PM 10490114 ER PT J AU Jeste, DV Alexopoulos, GS Bartels, SJ Cummings, JL Gallo, JJ Gottlieb, GL Halpain, MC Palmer, BW Patterson, TL Reynolds, CF Lebowitz, BD AF Jeste, DV Alexopoulos, GS Bartels, SJ Cummings, JL Gallo, JJ Gottlieb, GL Halpain, MC Palmer, BW Patterson, TL Reynolds, CF Lebowitz, BD TI Consensus statement on the upcoming crisis in geriatric mental health - Research agenda for the next 2 decades SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article; Proceedings Paper CT Workshop on the Future of Mental Health and Aging CY MAR 11, 1998 CL SAN DIEGO, CALIFORNIA ID PRIMARY-CARE PATIENTS; OLDER ADULTS; COMMUNITY POPULATION; ALZHEIMERS-DISEASE; LATER LIFE; DEPRESSION; SERVICES; PREVALENCE; SCHIZOPHRENIA; DEMENTIA AB It is anticipated that the number of people older than 65 years with psychiatric disorders in the United States will increase from about 4 million in 1970 to 15 million in 2030, The current health care system serves mentally ill older adults poorly and is unprepared to meet the upcoming crisis in geriatric mental health. We recommend the formulation of a 15- to :25-year plan for research on mental disorders in elderly persons. It should include studies of prevention, translation of findings from bench to bedside, large-scale intervention trials with meaningful outcome measures, and health services research. Innovative strategies are needed to formulate new conceptualizations of psychiatric disorders, especially those given scant attention in the past. New methods of clinical and research training involving specialists, primary care clinicians, and the lay public are warranted. C1 Univ Calif San Diego, San Diego, CA 92103 USA. VA San Diego Healthcare Syst, San Diego, CA USA. Cornell Univ, Med Ctr, White Plains, NY 10605 USA. Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Hanover, NH 03756 USA. Univ Calif Los Angeles, Los Angeles, CA USA. Johns Hopkins Univ, Baltimore, MD USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. NIMH, Rockville, MD 20857 USA. RP Jeste, DV (reprint author), Univ Calif San Diego, San Diego, CA 92103 USA. NR 64 TC 324 Z9 327 U1 7 U2 14 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD SEP PY 1999 VL 56 IS 9 BP 848 EP 853 DI 10.1001/archpsyc.56.9.848 PG 6 WC Psychiatry SC Psychiatry GA 232PK UT WOS:000082379000010 PM 12884891 ER PT J AU Klein, R Clegg, L Cooper, LS Hubbard, LD Klein, BEK King, WN Folsom, AR AF Klein, R Clegg, L Cooper, LS Hubbard, LD Klein, BEK King, WN Folsom, AR CA Atherosclerosis Risk Communities Study Investig TI Prevalence of age-related maculopathy in the atherosclerosis risk in communities study SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID BEAVER-DAM EYE; BLUE MOUNTAINS EYE; SENILE MACULAR DEGENERATION; ARTERY WALL THICKNESS; CARDIOVASCULAR-DISEASE; VISUAL-ACUITY; CAROTID ATHEROSCLEROSIS; RACIAL-DIFFERENCES; BLOOD-PRESSURE; POPULATION AB Objective: To describe the prevalence of age-related maculopathy (ARM) in blacks and whites and its relation to macrovascular disease and risk factors thereof in a population studied for cardiovascular disease risk factors and outcomes. Population: A biracial population of 11532 adults (ranging from 48-72 years of age; 8984 whites and 2548 blacks) living in 4 US communities (Forsyth County, North Carolina; the city of Jackson, Miss; selected suburbs of Minneapolis, Minn; and Washington County, Maryland) were examined during the interval from 1993 to 1995. Methods: Drusen and other lesions typical of ARM were identified by examining a 45 degrees color fundus photograph of 1 eye of each participant and classified by means of a modification of the Wisconsin Age-Related Maculopathy Grading System. Results: The overall prevalence of any ARM was lower in blacks (3.7%) than whites (5.6%). After controlling for age and sex, the odds ratio for any ARM in blacks compared with whites was 0.73 (95% confidence interval, 0.58-0.91; P =.006). Few associations between atherosclerosis and its risk factors and the presence of early ARM or its component lesions were found. After adjusting for age, race, and sex, carotid artery plaque (odds ratio, 1.77; 95% confidence interval, 1.18-2.65) and focal retinal arteriolar narrowing (odds ratio, 1.79, 95% confidence interval, 1.07-2.98) were associated with retinal pigment epithelial depigmentation. Conclusions: This population-based study documents the higher prevalence of early ARM in whites compared with blacks. Measures of atherosclerosis and its risk factors were generally unrelated to ARM and do not explain these racial differences. C1 Univ Wisconsin, Dept Ophthalmol & Visual Sci, Sch Med, Madison, WI 53705 USA. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN USA. RP Klein, R (reprint author), Univ Wisconsin, Dept Ophthalmol & Visual Sci, Sch Med, 610 N Walnut St,Room 460 WARF, Madison, WI 53705 USA. FU NEI NIH HHS [EY06594]; NHLBI NIH HHS [N01-HC-35125, N01-HC-35126] NR 55 TC 96 Z9 99 U1 0 U2 4 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 SEP PY 1999 VL 117 IS 9 BP 1203 EP 1210 PG 8 WC Ophthalmology SC Ophthalmology GA 234ZE UT WOS:000082513600011 PM 10496392 ER PT J AU Buggage, RR Velez, G Myers-Powell, B Shen, DF Whitcup, SM Chan, CC AF Buggage, RR Velez, G Myers-Powell, B Shen, DF Whitcup, SM Chan, CC TI Primary intraocular lymphoma with a low interleukin 10 to interleukin 6 ratio and heterogeneous IgH gene rearrangement SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID RETICULUM-CELL SARCOMA; NERVOUS-SYSTEM LYMPHOMA; ASSOCIATION AB Primary intraocular lymphoma is almost always a central nervous system B-cell nonHodgkin lymphoma. Primary intraocular lymphoma is commonly diagnosed by demonstrating lymphoma cells in the vitreous or cerebrospinal fluid. An interleukin (IL) 10 to IL-6 ratio greater than 1.0 in these fluids and the detection of immunoglobulin gene rearrangement are useful adjuncts in the diagnosis of primary intraocular lymphoma. We report a case of primary intraocular lymphoma diagnosed by chorioretinal biopsy in which no malignant cells were identified in the vitreous and in which the IL-10 to IL-6 ratio was less than 1.0. The detection of IgH gene rearrangement heterogeneity in the tumor cells by polymerase chain reaction, a high tumor mitotic figure rate, and the rapid onset of multiple brain lesions suggest an aggressive malignant neoplasm. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NEI, Clin Branch, NIH, Bethesda, MD 20892 USA. RP Buggage, RR (reprint author), NEI, Immunol Lab, NIH, 10 Ctr Dr,Bldg 10,Room 10N112, Bethesda, MD 20892 USA. NR 10 TC 35 Z9 37 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 SEP PY 1999 VL 117 IS 9 BP 1239 EP 1242 PG 4 WC Ophthalmology SC Ophthalmology GA 234ZE UT WOS:000082513600018 PM 10496399 ER PT J AU Zhang, GH Martinez, JR AF Zhang, GH Martinez, JR TI Effects of forskolin, dibutyryl cAMP and H89 on Ca2+ mobilization in submandibular salivary cells of newborn rats SO ARCHIVES OF ORAL BIOLOGY LA English DT Article DE forskolin; dibutyryl cAMP; H89; inositol 1,4,5-trisphosphate; Ca2+ mobilization; immature submandibular cells ID EARLY POSTNATAL RATS; AMP-DEPENDENT PHOSPHORYLATION; ADULT-RATS; CALCIUM MOBILIZATION; SIGNAL-TRANSDUCTION; INTRACELLULAR CA2+; PROTEIN-KINASE; ACINAR-CELLS; SECRETION; RECEPTOR AB The effects of substances which affect cAMP or the cAMP-dependent protein kinase (PKA) on the inositol 1,4,5-trisphosphate (IP3) and Ca2+ responses to acetylcholine or thapsigargin were investigated in submandibular gland cells of newborn rats. Exposure to forskolin, dibutyryl cAMP or the PKA inhibitor H89 did not affect the formation of IP3 or the release of Ca2+ from intracellular stores elicited by acetylcholine. However, the thapsigargin-induced Ca2+ release was reduced by dibutyryl cAMP and enhanced by H89 in immature cells. Ca2+ influx activated by acetylcholine and thapsigargin was additive in immature cells but not in mature cells, suggesting the presence of a separate Ca2+ entry pathway in immature cells. Moreover, the acetylcholine-stimulated Ca2+ influx was significantly potentiated by forskolin and dibutyrylcAMP, but not by H89 in immature cells. In contrast, the thapsigargin-activated Ca2+ influx was dramatically enhanced by H89, but not by forskolin and dibutyrylcAMP in these cells. This modulation of Ca2+ mobilization by the test substances is different from that observed in mature submandibular cells in which forskolin, dibutyrylcAMP and H89 affected both IP3 formation and Ca2+ release in response to acetylcholine. Therefore, these results suggest differences in the interaction between the cAMP-PKA and the phosphoinositide-Ca2+ signalling pathways of mature and immature salivary cells. The modulation of Ca2+ influx by the cAMP-PKA pathway in immature cells is likely to play a part in the maturation of salivary cells. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 Univ Texas, Hlth Sci Ctr, Dept Pediat, San Antonio, TX 78284 USA. NIDCR, Div Extramural Res, NIH, Bethesda, MD 20892 USA. RP Zhang, GH (reprint author), Univ Texas, Hlth Sci Ctr, Dept Pediat, 7703 Floyd Curl Dr, San Antonio, TX 78284 USA. FU NIDCR NIH HHS [DE09270, DE04897] NR 50 TC 6 Z9 11 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0003-9969 J9 ARCH ORAL BIOL JI Arch. Oral Biol. PD SEP PY 1999 VL 44 IS 9 BP 735 EP 744 DI 10.1016/S0003-9969(99)00065-5 PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 225EK UT WOS:000081945300004 PM 10471157 ER PT J AU Gladman, DD Urowitz, MB Esdaile, JM Hahn, BH Klippel, J Lahita, R Liang, MH Schur, P Petri, M Wallace, D AF Gladman, DD Urowitz, MB Esdaile, JM Hahn, BH Klippel, J Lahita, R Liang, MH Schur, P Petri, M Wallace, D TI Guidelines for referral and management of systemic lupus erythematosus in adults SO ARTHRITIS AND RHEUMATISM LA English DT Article ID ANTIPHOSPHOLIPID-ANTIBODY SYNDROME; LONG-TERM; AUTOIMMUNE THROMBOCYTOPENIA; EMERGING CONCEPTS; REVISED CRITERIA; CONTROLLED TRIAL; DAMAGE INDEX; RISK-FACTORS; DISEASE; NEPHRITIS C1 Amer Coll Rheumatol, Atlanta, GA 30345 USA. Toronto Hosp, Toronto, ON M5T 2S8, Canada. Univ Toronto, Toronto, ON, Canada. Vancouver Hosp, Vancouver, BC, Canada. Mary Pack Arthrit Ctr, Vancouver, BC, Canada. Univ Calif Los Angeles, Sch Med, Cedars Sinai Med Ctr, Los Angeles, CA USA. NIAMSD, NIH, Bethesda, MD 20892 USA. St Vincents Med Ctr, New York, NY USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. RP Gladman, DD (reprint author), Amer Coll Rheumatol, 1800 Century Pl,Suite 250, Atlanta, GA 30345 USA. NR 58 TC 79 Z9 86 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0004-3591 EI 1529-0131 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD SEP PY 1999 VL 42 IS 9 BP 1785 EP 1796 PG 12 WC Rheumatology SC Rheumatology GA 241YC UT WOS:000082910600001 ER PT J AU Tilley, BC Pillemer, SR Heyse, SP Li, SH Clegg, DO Alarcon, GS AF Tilley, BC Pillemer, SR Heyse, SP Li, SH Clegg, DO Alarcon, GS CA Mira Trial Grp TI Global statistical tests for comparing multiple outcomes in rheumatoid arthritis trials SO ARTHRITIS AND RHEUMATISM LA English DT Article ID CONTROLLED CLINICAL-TRIAL; DISEASE-ACTIVITY MEASURES; BINARY OUTCOMES; CORE SET; ENDPOINTS; PLACEBO; METHOTREXATE; MINOCYCLINE; IMPROVEMENT; PATIENT AB Objective, To evaluate global statistical tests (GSTs) of treatment effectiveness for rheumatoid arthritis (RA) trials measuring multiple outcomes. Methods. Using outcome measures from American College of Rheumatology (ACR) core set variables available in 3 RA trials, GSTs were calculated using the O'Brien ranking procedure and a procedure for binary data. GSTs take correlations among outcomes into account. Power calculations using 1 trial data set provide comparisons of GSTs and ACR criteria for improvement. Results. Spearman correlations among outcomes ranged from 0.21 to 0.73. Erythrocyte sedimentation rate had the lowest correlation with other outcomes in all 3 trials. Within a trial, joint swelling and joint tenderness or patient and physician assessment had the highest correlations, depending on the trial. Results were consistent with results using the ACR criteria, although the GST was more powerful. Conclusion. GSTs are a useful tool for comparing treatment effects across multiple clinically meaningful outcome measures, The GST allows easy inclusion of validated, reliable new measures that are not a part of ACR criteria, such as quality of life, and can be computed with or without selecting a cutoff point defining patient improvement. GSTs should be considered for rheumatic disease treatment trials. C1 Med Univ S Carolina, Dept Biometry & Epidemiol, Charleston, SC 29425 USA. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. NIAID, NIH, Bethesda, MD 20892 USA. Case Western Reserve Univ, Henry Ford Hlth Sci Ctr, Detroit, MI USA. Univ Utah, Salt Lake City, UT USA. Univ Alabama, Birmingham, AL USA. RP Tilley, BC (reprint author), Med Univ S Carolina, Dept Biometry & Epidemiol, 550 MUSC Complex,Suite 1148, Charleston, SC 29425 USA. FU NIAMS NIH HHS [N01-AR-1-2203, N01-AR-1-2202, N01-AR-1-2205] NR 31 TC 23 Z9 24 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 1999 VL 42 IS 9 BP 1879 EP 1888 DI 10.1002/1529-0131(199909)42:9<1879::AID-ANR12>3.0.CO;2-1 PG 10 WC Rheumatology SC Rheumatology GA 241YC UT WOS:000082910600012 PM 10513802 ER PT J AU Schumacher, HR Gerard, HC Arayssi, TK Pando, JA Branigan, PJ Saaibi, DL Hudson, AP AF Schumacher, HR Gerard, HC Arayssi, TK Pando, JA Branigan, PJ Saaibi, DL Hudson, AP TI Lower prevalence of Chlamydia pneumoniae DNA compared with Chlamydia trachomatis DNA in synovial tissue of arthritis patients SO ARTHRITIS AND RHEUMATISM LA English DT Article ID REACTIVE ARTHRITIS; FLUID; TWAR AB Objective. To assess the presence of Chlamydia pneumoniae DNA in the joints of patients with reactive arthritis (ReA) and other arthritides. Methods. DNA was prepared from synovial tissue (ST) and several synovial fluid (SF) samples from 188 patients with either ReA, undifferentiated oligoarthritis, or other forms of arthritis, and from 24 normal (non-arthritis) individuals. Preparations were screened using polymerase chain reaction (PCR) assays that independently targeted the C pneumoniae 16S ribosomal RNA and major outer membrane protein genes. Results. Twenty-seven of 212 ST samples (12.7%) were PCR positive for C pneumoniae DNA; 10 SF samples from these 27 patients were similarly positive. Among the PCR-positive patients, 3 had ReA, 2 had Reiter's syndrome, 7 had undifferentiated oligoarthritis, 4 had undifferentiated monarthritis, 6 had rheumatoid arthritis, and 5 had other forms of arthritis. No samples from normal control individuals were PCR positive. Conclusion. DNA of C pneumoniae is present in synovial specimens from some arthritis patients. The prevalence of this organism in the joints was lower than that of C trachomatis, and synovial presence of the organism was not associated with any distinct clinical syndrome. Widely disseminated nucleic acids such as those of C pneumoniae might have some role in the pathogenesis of several arthritides, since the organism was not found in the ST from normal control individuals. C1 Dept Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. NIAMSD, NIH, Bethesda, MD 20892 USA. Wayne State Univ, Sch Med, Detroit, MI USA. RP Schumacher, HR (reprint author), Dept Vet Affairs Med Ctr, Univ & Woodland Ave, Philadelphia, PA 19104 USA. OI Arayssi, Thurayya/0000-0003-2469-0272 FU NIAMS NIH HHS [AR-42541] NR 14 TC 60 Z9 63 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 1999 VL 42 IS 9 BP 1889 EP 1893 DI 10.1002/1529-0131(199909)42:9<1889::AID-ANR13>3.0.CO;2-W PG 5 WC Rheumatology SC Rheumatology GA 241YC UT WOS:000082910600013 PM 10513803 ER PT J AU Bennett, AJ Lesch, KP Heils, A Long, J Lorenz, JP Shoaf, SE Champoux, M Suomi, SJ Higley, JD AF Bennett, AJ Lesch, KP Heils, A Long, J Lorenz, JP Shoaf, SE Champoux, M Suomi, SJ Higley, JD TI Serotonin transporter gene variation and early rearing environment interact to affect CSF5-HIAA concentrations, aggressive behavior, and alcohol consumption in rhesus monkeys. SO BEHAVIOR GENETICS LA English DT Meeting Abstract C1 NIAAA, Bethesda, MD USA. Univ Wurzburg, Dept Psychiat, D-97080 Wurzburg, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 J9 BEHAV GENET JI Behav. Genet. PD SEP PY 1999 VL 29 IS 5 BP 349 EP 350 PG 2 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA 299CW UT WOS:000086179100011 ER PT J AU DuPree, MG Sirota, LA Hamer, DH AF DuPree, MG Sirota, LA Hamer, DH TI A genome screen for sexual orientation: Progress report. SO BEHAVIOR GENETICS LA English DT Meeting Abstract C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. Penn State Univ, Dept Anthropol, University Pk, PA 16802 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 J9 BEHAV GENET JI Behav. Genet. PD SEP PY 1999 VL 29 IS 5 BP 354 EP 354 PG 1 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA 299CW UT WOS:000086179100027 ER PT J AU Goldman, D Kittles, RA Bergen, AW Eggert, M Virkkunen, M Long, J AF Goldman, D Kittles, RA Bergen, AW Eggert, M Virkkunen, M Long, J TI Role of the Y chromosome in alcohol dependence and related personality traits: A cladistic analysis with eight-locus haplotypes in Finnish males. SO BEHAVIOR GENETICS LA English DT Meeting Abstract C1 NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 J9 BEHAV GENET JI Behav. Genet. PD SEP PY 1999 VL 29 IS 5 BP 356 EP 357 PG 2 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA 299CW UT WOS:000086179100038 ER PT J AU Higley, JD Bennett, A AF Higley, JD Bennett, A TI Impaired CNS serotonin functioning, excessive alcohol intake, and aggression: A nonhuman primate model of genetic and environmental influences. SO BEHAVIOR GENETICS LA English DT Meeting Abstract C1 NIAAA, Lab Clin Studies Primate Unit, Animal Ctr, NIH, Poolesville, MD 20837 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 J9 BEHAV GENET JI Behav. Genet. PD SEP PY 1999 VL 29 IS 5 BP 357 EP 358 PG 2 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA 299CW UT WOS:000086179100042 ER PT J AU Vanyukov, M Moss, HB Kaplan, BB Tarter, RE AF Vanyukov, M Moss, HB Kaplan, BB Tarter, RE TI Antisociality, substance dependence, and the DRD5 gene. SO BEHAVIOR GENETICS LA English DT Meeting Abstract C1 Univ Pittsburgh, Pittsburgh, PA 15213 USA. NIMH, Div Intramural Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 J9 BEHAV GENET JI Behav. Genet. PD SEP PY 1999 VL 29 IS 5 BP 372 EP 372 PG 1 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA 299CW UT WOS:000086179100101 ER PT J AU Epstein, DH Silverman, K Henningfield, JE Preston, KL AF Epstein, DH Silverman, K Henningfield, JE Preston, KL TI Low-dose oral cocaine in humans: acquisition of discrimination and time-course of effects SO BEHAVIOURAL PHARMACOLOGY LA English DT Article DE cocaine; humans; drug discrimination; oral administration; drug abuse ID ADMINISTERED COCAINE; INTRAVENOUS COCAINE; DEPRESSED-PATIENTS; PERFORMANCE; INTRANASAL; STIMULUS; CAFFEINE AB Seven cocaine-abusing volunteers were trained to discriminate 50 mg oral cocaine vs placebo across 50 2-h sessions. Discriminative, subjective and autonomic effects were assessed with a procedure developed for precise characterization of their acute time-course. Subjective effects of oral cocaine began 10-15 min post-drug, peaked at 40-50 min and took up to 100 min post drug to return nearly to baseline. Autonomic effects also began 10-15 min post-drug, peaked at 40-50 min and typically returned to baseline by 120 min post-drug; for most participants, peak heart rate and blood pressure remained within the range seen with placebo. Six out of seven participants acquired the discrimination (although this typically required 15-30 sessions, and there were some intriguing dissociations between the ability to discriminate oral cocaine from placebo and the ability to identify it as a stimulant). In most participants, oral cocaine produced increases in ratings of 'liking', 'alertness' and 'good effects', and in motor performance. Overall, the results support the sensitivity of the behavioral-testing procedure used, and show that 50 mg oral cocaine can serve as a discriminative stimulus in adult humans. (C) 1999 Lippincott Williams & Wilkins. C1 NIDA, IRP, Treatment Branch Clin Trials, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. RP Preston, KL (reprint author), NIDA, IRP, Treatment Branch Clin Trials, NIH, 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 34 TC 11 Z9 11 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD SEP PY 1999 VL 10 IS 5 BP 531 EP 542 PG 12 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 234GV UT WOS:000082477000011 PM 10780259 ER PT J AU Ferro-Flores, G Ramirez, FD Tendilla, JI Pimentel-Gonzalez, G Murphy, CA Melendez-Alafort, L Ascencio, JA Croft, BY AF Ferro-Flores, G Ramirez, FD Tendilla, JI Pimentel-Gonzalez, G Murphy, CA Melendez-Alafort, L Ascencio, JA Croft, BY TI Preparation and pharmacokinetics of samarium(III)-153-labeled DTPA-bis-biotin. Characterization and theoretical studies of the samarium(III)-152 conjugate SO BIOCONJUGATE CHEMISTRY LA English DT Article ID METAL-LIGAND INTERACTIONS; MONOCLONAL-ANTIBODY; COMPLEXES; AVIDIN; BIODISTRIBUTION; SYSTEM AB The complex(153)Sm(III)DTPA-bis-biotin was prepared with a 99% radiochemical purity and a specific activity of 370 MBq/mg employing a molar ratio of DTPA-bis-biotin/Sm from 2 to 4 at pH 8.0. In vitro studies demonstrated that the complex is stable after dilution in saline and in human serum. Avidity of labeled biotin for avidin was not affected by the labeling procedure. Pharmacokinetic data of Sm-153(III)DTPA-bis-biotin in normal mice showed that blood clearance is biexponential during the time interval from 0 to 24 h and that 3 h postinjection 92 +/- 4.32% of the dose is eliminated in the urine. To have further evidence which could sustain that Sm-153(III)DTPA-bis-biotin is stable in solution as a real coordination complex, Sm-152(III)DTPA-bis-biotin was obtained in macroscopic quantities and its characterization was done by IR, TGA, and conductivity measurements. The results indicated that the complex was chemically pure, where the Sm3+ ion is neutralized by three carboxylate groups of the DTPA-bis-biotin ligand and coordinated to it. Using the Force Field method followed by ab initio calculations, the DTPA-bis-biotin and the Sm(III)DTPA-bis-biotin molecules were done. Accordingly, the coordination sphere of Sm(III) was totally satisfied with nitrogen and oxygen donors; the best coordination number was 9. The conformation geometry of both compounds is presented. C1 Inst Nacl Invest Nucl, Mexico City 11801, DF, Mexico. Dept Quim, Salazar 52045, Estado Mexico, Mexico. Dept Fis Computac, Salazar 52045, Estado Mexico, Mexico. Inst Oncol & Radiobiol, Habana, Cuba. Inst Nacl Nutr Salvador Zubiran, Mexico City 14000, DF, Mexico. NIH, Rockville, MD USA. RP Ferro-Flores, G (reprint author), Inst Nacl Invest Nucl, Mexico City 11801, DF, Mexico. RI Croft, Barbara/D-1248-2013; Melendez-Alafort , Laura /B-8918-2013; OI Croft, Barbara/0000-0003-2544-150X; Melendez-Alafort , Laura /0000-0003-0701-3616; FERRO-FLORES, GUILLERMINA/0000-0003-0296-7605 NR 33 TC 19 Z9 19 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD SEP-OCT PY 1999 VL 10 IS 5 BP 726 EP 734 DI 10.1021/bc9900082 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 239RA UT WOS:000082782400004 PM 10502337 ER PT J AU Hrabie, JA Saavedra, JE Roller, PP Southan, GJ Keefer, LK AF Hrabie, JA Saavedra, JE Roller, PP Southan, GJ Keefer, LK TI Conversion of proteins to diazeniumdiolate-based nitric oxide donors SO BIOCONJUGATE CHEMISTRY LA English DT Article ID ALBUMIN AB Michael reaction of the methoxymethyl-protected monodiazeniumdiolate of piperazine (MOMPIPERAZI/NO) with 3-maleimidobutyric acid followed by its conversion to the N-hydroxy-succinimido ester produces a reagent capable of transferring the nitric oxide (NO)-donating diazeniumdiolate group to the terminal amines of the lysine residues contained in proteins. The reagent has been used to produce diazeniumdiolated bovine serum albumin (D-BSA) and diazeniumdiolated human serum albumin (D-HSA) containing 22 and 19 modified lysyl groups, respectively. Upon dissolution in pH 7.4 phosphate buffer at 37 degrees C, these albumin derivatives gradually released all of their contained NO (approximately 40 mol/mol of protein) with initial rates of about 30-40 pmol/min/mg and half-lives on the order of 3 weeks. This methodology is now available for use in exploiting the unique specific metabolic interactions of proteins to target NO therapy to specific physiological processes in vivo. C1 NCI, Frederick Canc Res & Dev Ctr, Chem Synth & Anal Lab, 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, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. NCI, Med Chem Lab, Bethesda, MD 20892 USA. RP Hrabie, JA (reprint author), NCI, Frederick Canc Res & Dev Ctr, Chem Synth & Anal Lab, Frederick, MD 21702 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU NCI NIH HHS [N01-CO-56000] NR 19 TC 25 Z9 25 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD SEP-OCT PY 1999 VL 10 IS 5 BP 838 EP 842 DI 10.1021/bc990035s PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 239RA UT WOS:000082782400018 PM 10502351 ER PT J AU Balmukhanov, BS Basenova, AT AF Balmukhanov, BS Basenova, AT TI Influences of potassium leakage on the reversible aggregation of human erythrocytes SO BIOFIZIKA LA Russian DT Article DE biorheology; erythrocytes; aggregation ID SUSPENSIONS AB Changes in the aggregation of human erythrocytes caused by polydextrane were studied under conditions influencing the rate of potassium leakage from cells to medium. It was shown that aggregation decreases as the leakage of potassium ions increases and is completely abolished at leakage rates higher than 2,5-3,0 mmol/l of erythrocytes per hour. The involvement of nonequilibrial electrokinetic phenomena in the inhibition of erythrocyte aggregation by ionic fluxes across erythrocyte surface is discussed. It is proposed that potassium leakage affects the erythrocyte sedimentation rate in clinical investigations. C1 Kazakhstan Natl Ctr Biotechnol, Stepnogorsk 474456, Akmolinskaya Ob, Kazakhstan. RP Balmukhanov, BS (reprint author), Kazakhstan Natl Ctr Biotechnol, Mikroraion 5,20A, Stepnogorsk 474456, Akmolinskaya Ob, Kazakhstan. NR 15 TC 1 Z9 1 U1 0 U2 1 PU MEZHDUNARODNAYA KNIGA PI MOSCOW PA 39 DIMITROVA UL., 113095 MOSCOW, RUSSIA SN 0006-3029 J9 BIOFIZIKA+ JI Biofizika PD SEP-OCT PY 1999 VL 44 IS 5 BP 898 EP 903 PG 6 WC Biophysics SC Biophysics GA 263TN UT WOS:000084141500016 PM 10624531 ER PT J AU Mori, C Allen, JW Dix, DJ Nakamura, N Fujioka, M Toshimori, K Eddy, EM AF Mori, C Allen, JW Dix, DJ Nakamura, N Fujioka, M Toshimori, K Eddy, EM TI Completion of meiosis is not always required for acrosome formation in HSP70-2 null mice SO BIOLOGY OF REPRODUCTION LA English DT Article ID GERM-CELL APOPTOSIS; ATM-DEFICIENT MICE; CHROMOSOME SYNAPSIS; DROSOPHILA SPERMATOGENESIS; SPERMATID DIFFERENTIATION; ATAXIA-TELANGIECTASIA; MEIOTIC PROPHASE; MURINE CYCLIN; MOUSE; GENE AB Hsp70-2 is a unique member of the mouse 70-kDa heat shock protein family that is synthesized during meiosis in spermatogenic cells. Germ cells in male mice homozygous for a targeted mutation in the Hsp70-2 gene (Hsp70-2(-/-)) arrest in development and undergo apoptosis at the end of the pachytene spermatocyte stage of meiotic prophase, However, cells with a putative acrosome were present occasionally in histological sections of the testes of juvenile and adult Hsp70-2(-/-) mice. This study verified that acrosomes were present and investigated the relationship between acrosome formation and the process of meiosis. Histochemistry with the periodic acid-Schiff procedure and immunostaining with monoclonal antibody MN7 verified that acrosomes were present in Hsp70-2(-/-) mice, and electron microscopy showed that some of these cells had condensing nuclei characteristic of step 8-9 spermatids. The frequency of acrosome-containing cells in Hsp70-2(-/-) mice was less than 0.01% of that in wild-type mice. Propidium iodide staining and cytophotometry indicated that the average DNA content of nuclei in MN7-positive cells in Hsp70-2(-/-) mice was usually about twice, or occasionally the same as, that of nuclei in round spermatids of wild-type mice. Meiotic metaphase I and II chromosome spreads were observed in spermatogenic cells from Hsp70-2(-/-) mice but at a much lower frequency than in wild-type mice. These results indicate that not all pachytene spermatocytes in Hsp70-2(-/-) mice arrest in meiosis, but they may divide once or sometimes twice and begin acrosome formation and nuclear condensation. This demonstrates that some aspects of spermatid development can occur without the completion of meiosis in mice, as has been reported recently for Drosophila. C1 Kyoto Univ, Fac Med, Dept Anat & Dev Biol, Kyoto 6068501, Japan. Kyoto Univ, Fac Med, Cent Lab Electron Microscopy, Kyoto 6068501, Japan. NIEHS, Gamete Biol Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. US EPA, Div Environm Carcinogenesis, Natl Hlth & Environ Effects Res Lab, Res Triangle Pk, NC 27711 USA. US EPA, Reprod Toxicol Div, Natl Hlth & Environ Effects Res Lab, Res Triangle Pk, NC 27711 USA. Miyazaki Med Coll, Dept Anat, Miyazaki 88916, Japan. RP Mori, C (reprint author), Kyoto Univ, Fac Med, Dept Anat & Dev Biol, Kyoto 6068501, Japan. NR 56 TC 16 Z9 16 U1 0 U2 0 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD SEP PY 1999 VL 61 IS 3 BP 813 EP 822 DI 10.1095/biolreprod61.3.813 PG 10 WC Reproductive Biology SC Reproductive Biology GA 229JE UT WOS:000082190000035 PM 10456862 ER PT J AU Weinberg, CR Umbach, DM AF Weinberg, CR Umbach, DM TI Using pooled exposure assessment to improve efficiency in case-control studies SO BIOMETRICS LA English DT Article DE biomarkers; case-central design; efficiency; group testing; pooling ID ESTIMATING PREVALENCE; DISEASE; MODELS; SEVESO; HIV AB Assays can be so expensive that interesting hypotheses become impractical to study epidemiologically. One need not, however, perform an assay for everyone providing a biological specimen. We propose pooling equal-volume aliquots from randomly grouped sets of cases and randomly grouped sets of controls, and then assaying the smaller number of pooled samples. If an effect modifier is of concern, the pooling can be done within strata defined by that variable. For covariates assessed on individuals (e.g., questionnaire data), set-based counterparts are calculated by adding the values for the individuals in each set. The pooling set then becomes the unit of statistical analysis. We show that, with appropriate specification of a set-based logistic model, standard software yields a valid estimated exposure odds ratio, provided the multiplicative formulation is correct. Pooling minimizes the depletion of irreplaceable biological specimens and can enable additional exposures to be studied economically. Statistical power suffers wry little compared with the usual, individual-based analysis. In settings where high assay costs constrain the number of people an investigator can afford to study, specimen pooling can make it possible to study more people and hence improve the study's statistical power with no increase in cost. C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Weinberg, CR (reprint author), NIEHS, Biostat Branch, MD A3-03,POB 12233, Res Triangle Pk, NC 27709 USA. NR 18 TC 57 Z9 57 U1 1 U2 4 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD SEP PY 1999 VL 55 IS 3 BP 718 EP 726 DI 10.1111/j.0006-341X.1999.00718.x PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 237XZ UT WOS:000082683000007 PM 11314998 ER PT J AU Follmann, DA Proschan, MA AF Follmann, DA Proschan, MA TI Valid inference in random effects meta-analysis SO BIOMETRICS LA English DT Article DE clinical trials; permutation test; randomization test; t-test ID CLINICAL-TRIALS; BLOOD-PRESSURE; METAANALYSIS AB The standard approach to inference for random effects meta-analysis relies on approximating the null distribution of a test statistic by a standard normal distribution. This approximation is asymptotic on k, the number of studies, and can be substantially in error in medical meta-analyses, which often have only a few studies. This paper proposes permutation and ad hoc methods for testing with the random effects model. Under the group permutation method, we randomly switch the treatment and control group labels in each trial. This idea is similar to using a permutation distribution for a community intervention trial where communities are randomized in pairs. The permutation method theoretically controls the type I error rate for typical meta-analyses scenarios. We also suggest two ad hoc procedures. Our first suggestion is to use a t-reference distribution with k - 1 degrees of freedom rather than a standard normal distribution for the usual random effects test statistic. We also investigate the use of a simple t-statistic on the reported treatment effects. C1 NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. RP Follmann, DA (reprint author), NHLBI, Off Biostat Res, 2 Rockledge Ctr MSC 7938, Bethesda, MD 20892 USA. NR 11 TC 49 Z9 50 U1 1 U2 5 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD SEP PY 1999 VL 55 IS 3 BP 732 EP 737 DI 10.1111/j.0006-341X.1999.00732.x PG 6 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 237XZ UT WOS:000082683000009 PM 11315000 ER PT J AU Pennello, GA Devesa, SS Gail, MH AF Pennello, GA Devesa, SS Gail, MH TI Using a mixed effects model to estimate geographic variation in cancer rates SO BIOMETRICS LA English DT Article DE delta method; maximum likelihood; method-of-moments; overdispersion; relative risk; standardized rates ID DISEASE AB Commonly used methods for depicting geographic Variation in cancer rates are based on rankings. They identify where the rates are high and low but do not indicate the magnitude of the rates nor their variability. Yet such measures of variability may be useful in suggesting which types of cancer warrant further analytic studies of localized risk factors. We consider a mixed effects model in which the logarithm of the mean Poisson rate is additive in fixed stratum effects (e.g., age effects) and in logarithms of random relative risk effects associated with geographic areas. These random effects are assumed to follow a gamma distribution with unit mean and variance 1/alpha, similar to Clayton and Kaldor (1987, Biometrics 43, 671-681). We present maximum likelihood and method-of-moments estimates with standard errors for inference on alpha(-1/2), the relative risk standard deviation (RRSD). The moment estimates rely an only the first two moments of the Poisson and gamma distributions but have larger standard errors than the maximum likelihood estimates. We compare these estimates with other measures of variability. Several examples suggest that the RRSD estimates have advantages compared to other measures of variability. C1 NCI, Biostat Branch, Bethesda, MD 20892 USA. RP Pennello, GA (reprint author), NCI, Biostat Branch, 6130 Execut Blvd,EPN 431, Bethesda, MD 20892 USA. NR 26 TC 5 Z9 7 U1 0 U2 0 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD SEP PY 1999 VL 55 IS 3 BP 774 EP 781 DI 10.1111/j.0006-341X.1999.00774.x PG 8 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 237XZ UT WOS:000082683000015 PM 11315006 ER PT J AU Follmann, DA Proschan, MA AF Follmann, DA Proschan, MA TI A simple permutation-type method for testing circular uniformity with correlated angular measurements SO BIOMETRICS LA English DT Article DE ancillary; conditionality principle; directional data; Kuiper test; Rayleigh test ID SEIZURE AB A simple method is provided for testing uniformity on the circle that allows dependence among repeated angular measurements on the same subject. Our null hypothesis is that the distribution of repeated angles is unaffected by rotation. This null can be evaluated with any test of uniformity by using a null reference distribution obtained by simulation, where each subject's vector of angles is rotated by a random amount. A new weighted version of the univariate Rayleigh test of circular uniformity is proposed. C1 NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. RP Follmann, DA (reprint author), NHLBI, Off Biostat Res, 2 Rockledge Ctr, Bethesda, MD 20892 USA. EM follmann@helix.nih.gov NR 15 TC 5 Z9 5 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X EI 1541-0420 J9 BIOMETRICS JI Biometrics PD SEP PY 1999 VL 55 IS 3 BP 782 EP 791 DI 10.1111/j.0006-341X.1999.00782.x PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 237XZ UT WOS:000082683000016 PM 11315007 ER PT J AU Clegg, LMX Cai, JW Sen, PK AF Clegg, LMX Cai, JW Sen, PK TI A marginal mixed baseline hazards model for multivariate failure time data SO BIOMETRICS LA English DT Article DE censoring; Cox regression; marginal hazards rate; martingale; multivariate failure times; semiparametric model; survival data ID REGRESSION-ANALYSIS; LIKELIHOOD; FRAILTY; EQUATIONS; SURVIVAL AB In multivariate failure time data analysis, a marginal regression modeling approach is often preferred to avoid assumptions on the dependence structure among correlated failure times. In this paper, a marginal mixed baseline hazards model is introduced. Estimating equations are proposed for the estimation of the marginal hazard ratio parameters. The proposed estimators are shown to be consistent and asymptotically Gaussian with a robust covariance matrix that can be consistently estimated. Simulation studies indicate the adequacy of the proposed methodology for practical sample sizes. The methodology is illustrated with a data set from the Framingham Heart Study. C1 NCI, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. RP Clegg, LMX (reprint author), NCI, NIH, 6130 Execut Blvd,MSC 7352, Bethesda, MD 20892 USA. EM lin_clegg@nih.gov FU NHLBI NIH HHS [R29 HL57444]; NIEHS NIH HHS [T32 ES07018] NR 20 TC 26 Z9 30 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD SEP PY 1999 VL 55 IS 3 BP 805 EP 812 DI 10.1111/j.0006-341X.1999.00805.x PG 8 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 237XZ UT WOS:000082683000019 PM 11315010 ER PT J AU Freidlin, B Podgor, MJ Gastwirth, JL AF Freidlin, B Podgor, MJ Gastwirth, JL TI Efficiency robust tests for survival or ordered categorical data SO BIOMETRICS LA English DT Article DE asymptotic relative efficiency; censored data; contingency tables; dose-response data; efficiency robustness; stratified data; survival analysis; weighted log-rank statistic. ID CONTINGENCY-TABLES; INDEPENDENCE AB The selection of a single method of analysis is problematic when the data could have been generated by one of several possible models. We examine the properties of two tests designed to have high power over a range of models. The first one, the maximum efficiency robust test (MERT), uses the linear combination of the optimal statistics for each model that maximizes the minimum efficiency. The second procedure, called the MX, uses the maximum of the optimal statistics. Both approaches yield efficiency robust procedures for survival analysis and ordinal categorical data. Guidelines for choosing between them are provided. C1 NCI, Biometr Res Branch, Bethesda, MD 20892 USA. NEI, Bethesda, MD 20892 USA. George Washington Univ, Dept Stat, Washington, DC 20052 USA. RP Freidlin, B (reprint author), NCI, Biometr Res Branch, Bethesda, MD 20892 USA. NR 14 TC 46 Z9 48 U1 0 U2 4 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD SEP PY 1999 VL 55 IS 3 BP 883 EP 886 PG 4 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 237XZ UT WOS:000082683000030 PM 11315021 ER PT J AU Dunson, DB Haseman, JK AF Dunson, DB Haseman, JK TI Modeling tumor onset and multiplicity using transition models with latent variables SO BIOMETRICS LA English DT Article DE EM algorithm; marginal analysis; transgenic mice; zero-inflated Poisson ID REGRESSION-MODELS; CARCINOGENS; LIKELIHOOD; BIOASSAYS; SERIES AB We describe a method for modeling carcinogenicity from animal studies where the data consist of counts of the number of tumors present over time. The research is motivated by applications to transgenic rodent studies, which have emerged as an alternative to chronic bioassays for screening possible carcinogens. In transgenic mouse studies, the endpoint of interest is frequently skin papilloma, with weekly examinations determining how many papillomas each animal has at a particular point in time. It is assumed that each animal has two unobservable latent variables at each time point. The first indicates whether or not the tumors are in a multiplying state and the second is the potential number of additional tumors if the tumors are in a multiplying state. The product of these variables follows a zero-inflated Poisson distribution, and the EM algorithm can be used to maximize the observed-data pseudo-likelihood, based on the latent variables. A generalized estimating equations robust variance estimator adjusts for dependency among outcomes within individual animals. The method is applied to testing for a dose-related trend in both tumor incidence and multiplicity in carcinogenicity studies. C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Dunson, DB (reprint author), NIEHS, Biostat Branch, POB 12233,MD A3-03, Res Triangle Pk, NC 27709 USA. NR 17 TC 16 Z9 16 U1 0 U2 2 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD SEP PY 1999 VL 55 IS 3 BP 965 EP 970 DI 10.1111/j.0006-341X.1999.00965.x PG 6 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 237XZ UT WOS:000082683000045 PM 11315036 ER PT J AU Wallqvist, A Lavoie, TA Chanatry, JA Covell, DG Carey, J AF Wallqvist, A Lavoie, TA Chanatry, JA Covell, DG Carey, J TI Cooperative folding units of Escherichia coli tryptophan repressor SO BIOPHYSICAL JOURNAL LA English DT Article ID MOLECULAR-DYNAMICS SIMULATION; DNA-BINDING PROTEIN; TRP REPRESSOR; HYDROGEN-EXCHANGE; 3-DIMENSIONAL STRUCTURE; CIRCULAR-DICHROISM; NATIVE PROTEINS; TROPONIN-C; APOREPRESSOR; INTERMEDIATE AB A previously published computational procedure was used to identify cooperative folding units within tryptophan repressor. The theoretical results predict the existence of distinct stable substructures in the protein chain for the monomer and the dimer. The predictions were compared with experimental data on structure and folding of the repressor and its proteolytic fragments and show excellent agreement for the dimeric form of the protein. The results suggest that the monomer, the structure of which is currently unknown, is likely to have a structure different from the one it has within the context of the highly intertwined dimer. Application of this method to the repressor monomer represents an extension of the computations into the realm of evaluating hypothetical structures such as those produced by threading. C1 Princeton Univ, Dept Chem, Princeton, NJ 08544 USA. NCI, Frederick Canc Res & Dev Ctr, Space Applicat Int Corp, Frederick, MD 21702 USA. RP Carey, J (reprint author), Princeton Univ, Dept Chem, Princeton, NJ 08544 USA. FU NIGMS NIH HHS [GM43558] NR 57 TC 4 Z9 4 U1 0 U2 0 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD SEP PY 1999 VL 77 IS 3 BP 1619 EP 1626 DI 10.1016/S0006-3495(99)77010-4 PG 8 WC Biophysics SC Biophysics GA 232AL UT WOS:000082343500041 PM 10465773 ER PT J AU Schriml, LM Padilla-Nash, HM Coleman, A Moen, P Nash, WG Menninger, J Jones, G Ried, T Dean, M AF Schriml, LM Padilla-Nash, HM Coleman, A Moen, P Nash, WG Menninger, J Jones, G Ried, T Dean, M TI Tyramide signal amplification (TSA)-FISH applied to mapping PCR-labeled probes less than 1 kb in size SO BIOTECHNIQUES LA English DT Article ID IN-SITU HYBRIDIZATION; C-MYC; LOCALIZATION; DEPOSITION AB Tyramide signal amplification (TSA)-FISH was used to map one mouse and two human DNA probes of less than 1 kb in size. The two human probes were 319 and 608 bp, and the mouse probe was 855 bp. Probes, made from PCR products, were labeled by incorporating biotin-11-dUTP (human) and biotin-16-dUTP (mouse) during PCR amplification. Signals were readily observed in both interphase and metaphase cells following TSA-FISH for all three genes, whereas conventional FISH experiments produced no signals. The two human ATP-binding cassette (ABC) genes, EST883227 (GenBank(R) Accession No. AA243820) and EST990006 (GenBank Accession No. AA348546), mapped to human chromosomes 7p21 and 17q25. The mouse gene, c-myc (exon 2) mapped to band D2 of mouse chromosome 15. These findings demonstrate the ability of this technique to map small probes (PCR products and expressed sequence tags) of less han 1 kb through highly increased signal amplification. C1 NCI, Lab Genom Divers, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NEN Life Sci Prod, Boston, MA USA. H&W Cytogenet Serv, Lovettsville, VA USA. RP Dean, M (reprint author), NCI, Lab Genom Divers, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RI Dean, Michael/G-8172-2012; OI Dean, Michael/0000-0003-2234-0631; Schriml, Lynn/0000-0001-8910-9851 FU NCI NIH HHS [N01-CO-56000] NR 19 TC 24 Z9 26 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 SEP PY 1999 VL 27 IS 3 BP 608 EP + PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 233VR UT WOS:000082448300027 PM 10489619 ER PT J AU Heerema, NA Sather, HN Sensel, MG Liu-Mares, W Lange, BJ Bostrom, BC Nachman, JB Steinherz, PG Hutchinson, R Gaynon, PS Arthur, DC Uckun, FM AF Heerema, NA Sather, HN Sensel, MG Liu-Mares, W Lange, BJ Bostrom, BC Nachman, JB Steinherz, PG Hutchinson, R Gaynon, PS Arthur, DC Uckun, FM TI Association of chromosome arm 9p abnormalities with adverse risk in childhood acute lymphoblastic leukemia: A report from the Children's Cancer Group SO BLOOD LA English DT Article ID ACUTE LYMPHOCYTIC-LEUKEMIA; LYMPHOMATOUS FEATURES; HOMOZYGOUS DELETION; INFANTS LESS; GENE; INTERFERON; PHENOTYPE; SURVIVAL; EXAMPLES; SUBGROUP AB Cytogenetic abnormalities of chromosome arm 9p occur frequently in children with acute lymphoblastic leukemia (ALL). We analyzed 201 such cases (11%) in 1,839 children with newly diagnosed ALL treated between 1989 and 1995 on risk-adjusted protocols of the Children's Cancer Group (CCG). The majority of patients (131; 65%) with a 9p abnormality were classified as higher risk. Nearly all patients had complex karyotypes; most cases had deletions of 9p, add/der(gp), a dicentric involving chromosome arm 9p, and/or balanced translocations and inversions involving 9p. Event-free survival (EFS) estimates at 6 years for patients with and without a 9p aberration were 61% (standard deviation [SD] = 5%) and 76% (SD = 2%; P < .0001). In addition, patients with a 9p abnormality had an increased cumulative incidence of both marrow (P = .04) and central nervous system (P = .0001) relapses. Overall survival also was significantly worse for patients with an abnormal 9p (P < .0001). These effects were most pronounced in standard-risk patients (age 1 to 9 years with white blood cell count <50,000/mu L): 6-year EFS of 61% (SD = 9%) versus 80% (SD = 2%; P < .0001). Also, a 9p aberration was an adverse risk factor for B-lineage, but not T-lineage patients. The effect of 9p status on EFS was attenuated, but maintained in a multivariate analysis of EFS after adjustment for Philadelphia chromosome status, age, white blood cell (WBC) count, sex, race, and ploidy group (P = .01). Thus, abnormalities of chromosome arm 9p identify a subgroup of standard-risk patients with increased risk of treatment failure. (C) 1999 by The American Society of Hematology. C1 Childrens Canc Grp, Grp Operat Ctr, Arcadia, CA 91066 USA. Hughes Inst, Dept Genet, St Paul, MN USA. Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. Childrens Hosp & Clin, Dept Hematol Oncol, Minneapolis, MN USA. Univ Chicago, Dept Pediat Hematol Oncol, Chicago, IL 60637 USA. Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10021 USA. Univ Michigan, Dept Pediat Hematol Oncol, Ann Arbor, MI 48109 USA. Childrens Hosp, Dept Pediat Hematol Oncol, Los Angeles, CA 90027 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. Childrens Canc Grp, ALL Biol Reference Lab, St Paul, MN USA. RP Heerema, NA (reprint author), Childrens Canc Grp, Grp Operat Ctr, POB 60012, Arcadia, CA 91066 USA. FU NCI NIH HHS [CA-13539, CA-60437, R25 CA092049] NR 40 TC 79 Z9 82 U1 2 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1200 19TH ST, NW, STE 300, WASHINGTON, DC 20036-2422 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 1 PY 1999 VL 94 IS 5 BP 1537 EP 1544 PG 8 WC Hematology SC Hematology GA 232AM UT WOS:000082343600005 PM 10477677 ER PT J AU Taylor, LS McVicar, DW AF Taylor, LS McVicar, DW TI Functional association of Fc epsilon RI gamma with Arginine(632) of paired immunoglobulin-like receptor (PIR)-A3 in murine macrophages SO BLOOD LA English DT Article ID CELL INHIBITORY RECEPTORS; CLASS-I MOLECULES; PERITONEAL-MACROPHAGES; INTERFERON-GAMMA; NK CELLS; V-RAF; FAMILY; LY-49D; ALPHA; STIMULATION AB Paired immunoglobulin-like receptors (PIR) are expressed on B cells and macrophages and include inhibitory and putative activating receptors referred to as PIR B and PIR-A, respectively. Although PIR-B's inhibitory pathway has been described, it is unknown whether PIR-A receptors can deliver activation signals to macrophages, and if so, through what mechanism. Here we use chimeric receptors to address the mechanisms of PIR-A signaling. Cotransfection of chimeric receptors comprised of the extracellular region of human CD4 and the transmembrane and cytoplasmic domains of murine PIR-A3 showed the ability of PIR-A3 to physically interact with the Fc epsilon Rl gamma chain in 293T cells. This interaction is dependent on Arg(632) within the PIR-A3 transmembrane domain. We also demonstrate PIR-A3 interaction with the endogenous Fc epsilon Rl gamma of the ANA-1 macrophage cell line, again in an Arg(632)-dependent manner. Furthermore, we show that crosslinking of these chimeric receptors synergizes with IFN-gamma in the production of nitric oxide. Our data are the first to show the potential of PIR-A3 to deliver activation signals to macrophages and establish its dependence on Arg632. These findings suggest that further study of the PIR-A receptors should be aggressively pursued toward a complete understanding of the intricate regulation of macrophage biology. This is a US government work. There are no restrictions on its use. C1 NCI, Frederick Canc Res & Dev Ctr, Expt Immunol Lab, Div Basic Sci, Frederick, MD 21702 USA. RP McVicar, DW (reprint author), NCI, Frederick Canc Res & Dev Ctr, Expt Immunol Lab, Div Basic Sci, Bldg 560,Room 31-93, Frederick, MD 21702 USA. RI McVicar, Daniel/G-1970-2015 NR 37 TC 27 Z9 28 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1200 19TH ST, NW, STE 300, WASHINGTON, DC 20036-2422 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 1 PY 1999 VL 94 IS 5 BP 1790 EP 1796 PG 7 WC Hematology SC Hematology GA 232AM UT WOS:000082343600033 PM 10477705 ER PT J AU Coates, RJ Uhler, RJ Hall, HI Potischman, N Brinton, LA Ballard-Barbash, R Gammon, MD Brogan, DR Daling, JR Malone, KE Schoenberg, JB Swanson, CA AF Coates, RJ Uhler, RJ Hall, HI Potischman, N Brinton, LA Ballard-Barbash, R Gammon, MD Brogan, DR Daling, JR Malone, KE Schoenberg, JB Swanson, CA TI Risk of breast cancer in young women in relation to body size and weight gain in adolescence and early adulthood SO BRITISH JOURNAL OF CANCER LA English DT Editorial Material DE breast neoplasms; weight gain; histological grade; neoplasm staging; adolescence; premenopause ID AGE 45 YEARS; MASS; HEIGHT; INDICATORS; INSULIN; LIFE AB Findings have been inconsistent on effects of adolescent body size and adult weight gain on risk of breast cancer in young women. These relations were examined in a population-based case control study of 1590 women less than 45 years of age newly diagnosed with breast cancer during 1990-1992 in three areas of the US and an age-matched control group of 1390 women. Height and weight were measured at interview and participants asked to recall information about earlier body size. Logistic regression was used to estimate the relative risk of breast cancer adjusted for other risk factors. Women who were either much heavier or lighter than average in adolescence or at age 20 were at reduced risk. Weight gain after age 20 resulted in reduced risk. but the effect was confined to early-stage and, more specifically, lower grade breast cancer. Neither the risk reduction nor the variation by breast cancer stage or grade was explained by the method of cancer detection or by prior mammography history. These findings suggest that relations between breast cancer risk in young women and body weight at different ages is complex and that the risk reduction with adult weight gain is confined to less aggressive cancers. C1 Ctr Dis Control & Prevent, Div Canc Prevent & Control, CDC, Atlanta, GA 30341 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Columbia Univ, Sch Publ Hlth, Div Epidemiol, New York, NY 10032 USA. Emory Univ, Dept Biostat, Atlanta, GA 30322 USA. Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. New Jersey Dept Hlth & Senior Serv, Canc Epidemiol Program, Trenton, NJ 08652 USA. RP Coates, RJ (reprint author), Ctr Dis Control & Prevent, Div Canc Prevent & Control, CDC, K-55,4770 Buford Highway NE, Atlanta, GA 30341 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 FU NCI NIH HHS [N01-CP-95604, N01-CP-95671, N01-CP-95672] NR 47 TC 40 Z9 43 U1 2 U2 3 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD SEP PY 1999 VL 81 IS 1 BP 167 EP 174 DI 10.1038/sj.bjc.6690667 PG 8 WC Oncology SC Oncology GA 230RB UT WOS:000082263200027 PM 10487629 ER PT J AU Groves, FD Gridley, G Wacholder, S Shu, XO Robison, LL Neglia, JP Linet, MS AF Groves, FD Gridley, G Wacholder, S Shu, XO Robison, LL Neglia, JP Linet, MS TI Infant vaccinations and risk of childhood acute lymphoblastic leukaemia in the USA SO BRITISH JOURNAL OF CANCER LA English DT Editorial Material DE acute lymphoblastic leukaemia; Haemophilus influenzae; vaccination; children ID B DISEASE; LEUKEMIA; CANCER AB Previous studies have suggested that infant vaccinations may reduce the risk of subsequent childhood leukaemia. Vaccination histories were compared in 439 children (ages 0-14) diagnosed with acute lymphoblastic leukaemia (ALL) in nine Midwestern and Mid-Atlantic states (USA) between 1 January 1989 and 30 June 1993 and 439 controls selected by random-digit dialing and individually matched to cases on age, race and telephone exchange. Among matched pairs, similar proportions of cases and controls had received at least one dose of oral poliovirus (98%), diphtheria-tetanus-pertussis (97%), and measles-mumps-rubella (90%) vaccines. Only 47% of cases and 53% of controls had received any Haemophilus influenzae type b (Hib) vaccine (relative risk (RR) = 0.73; 95% confidence interval (CI) 0.50-1.06). Although similar proportions of cases (12%) and controls (11%) received the polysaccharide Hib vaccine (RR = 1.13; 95% CI 0.64-1.98), more controls (41%) than cases (35%) received the conjugate Hib vaccine (RR = 0.57; 95% CI 0.36-0.89). Although we found no relationship between most infant vaccinations and subsequent risk of childhood ALL, our findings suggest that infants receiving the conjugate Hib vaccine may be at reduced risk of subsequent childhood acute lymphoblastic leukemia. Further studies are needed to confirm this association and, if confirmed, to elucidate the underlying mechanism. C1 NCI, Descript Studies Sect, Biostat Branch,Div Canc Epidemiol & Genet, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. Univ Minnesota, Sch Med, Dept Pediat, Minneapolis, MN 55455 USA. RP Groves, FD (reprint author), NCI, Descript Studies Sect, Biostat Branch,Div Canc Epidemiol & Genet, Epidemiol & Biostat Program, Evecut Plaza S,Room 8089,6120 Execut Blvd,MSC 724, Bethesda, MD 20892 USA. NR 17 TC 25 Z9 25 U1 1 U2 4 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 SEP PY 1999 VL 81 IS 1 BP 175 EP 178 DI 10.1038/sj.bjc.6690668 PG 4 WC Oncology SC Oncology GA 230RB UT WOS:000082263200028 PM 10487630 ER PT J AU Szallasi, A Szabo, T Biro, T Modarres, S Blumberg, PM Krause, JE Cortright, DN Appendino, G AF Szallasi, A Szabo, T Biro, T Modarres, S Blumberg, PM Krause, JE Cortright, DN Appendino, G TI Resiniferatoxin-type phorboid vanilloids display capsaicin-like selectivity at native vanilloid receptors on rat DRG neurons and at the cloned vanilloid receptor VR1 SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE phorbol 12,13-didecanoate 20-homovanillate; phorboid vanilloids; capsaicin-type vanilloid pharmacology; [H-3]-resiniferatoxin binding; capsaicin; native vanilloid receptors; vanilloid receptor subtype 1 (VR1); VR1-transfected CHO cells ID ROOT GANGLION MEMBRANES; POSITIVE COOPERATIVITY; BINDING; ANALOGS; 20-HOMOVANILLATE; MECHANISMS; INSIGHTS; CELLS AB 1 Although the cloned rat vanilloid receptor VRI appears to account for both receptor binding and calcium uptake, the identification of vanilloids selective for one or the other response is of importance because these ligands may induce distinct patterns of biological activities. 2 Phorbol 12,13-didecanoate 20-homovanillate (PDDNV) evoked Ca-45(2+)-uptake by rat dorsal root ganglion neurons (expressing native vanilloid receptors) in culture with an EC50 of 70 nM but inhibited [H-3]-resiniferatoxin (RTX) binding to rat dorsal root ganglion membranes with a much lower potency (K-i > 10,000 nM). This difference in potencies represents a more than 100 fold selectivity for capsaicin-type pharmacology. 3 Ca-45(2+) influx by PDDHV was fully inhibited by the competitive vanilloid receptor antagonist capsazepine, consistent with the calcium uptake occurring via vanilloid receptors. 4 PDDHV induced calcium mobilization in CHO cells transfected with the cloned rat vanilloid receptor VRI with an EC50, of 125 nhl and inhibited [H-3]-RTX binding to these cells with an estimated K-i of 10,000 nhl. By contrast, PDDHV failed to evoke a measurable calcium response in non-transfected CHO cells, confirming its action through VRI. 5 We conclude that PDDHV is two orders of magnitude more potent for inducing calcium uptake than for inhibiting RTX binding at vanilloid receptors, making this novel vanilloid a ligand selective for capsaicin-type pharmacology. These results emphasize the importance of monitoring multiple endpoints for evaluation of vanilloid receptor structure-activity relations. Furthermore, PDDHV now provides a tool to explore the biological correlates of capsaicin-type vanilloid pharmacology. C1 NCI, Bethesda, MD 20892 USA. Neurogen Corp, Branford, CT USA. Univ Turin, Dipartimento Sci & Tecnol Farmaco, Turin, Italy. RP Szallasi, A (reprint author), St Louis Univ, Sch Med, Dept Pathol, 1402 S Grand Blvd, St Louis, MO 63104 USA. RI Appendino, Giovanni/O-4832-2015 OI Appendino, Giovanni/0000-0002-4170-9919 NR 28 TC 46 Z9 47 U1 0 U2 4 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD SEP PY 1999 VL 128 IS 2 BP 428 EP 434 DI 10.1038/sj.bjp.0702810 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 239ZJ UT WOS:000082800600021 PM 10510454 ER PT J AU Partonen, T Haukka, J Virtamo, J Taylor, PR Lonnqvist, J AF Partonen, T Haukka, J Virtamo, J Taylor, PR Lonnqvist, J TI Association of low serum total cholesterol with major depression and suicide SO BRITISH JOURNAL OF PSYCHIATRY LA English DT Article ID MEN; INSTRUMENTS AB Background It has been suggested that low serum total cholesterol is associated with an increased risk of suicide. Aims To study the association between serum total cholesterol, depression and suicide using versatile, prospective data. Method A total of 29 133 men aged 50-69 years were followed up for 5-8 years. Baseline blood samples were analysed for serum total and high-density lipoprotein cholesterol concentrations. Self-reported depression was recorded, data on hospital treatments due to depressive disorders were derived from the National Hospital Discharge Register and deaths from suicide were identified from death certificates. Results Low serum total cholesterol was associated with low mood and subsequently a heightened risk of hospital treatment due to major depressive disorder and of death from suicide. Conclusions Our results suggest that low serum total cholesterol appears to be associated with low mood and thus to predict its serious consequences. Declaration of interest Atrial contract (N01-CN-45165) with the National Cancer Institute. C1 Natl Publ Hlth Inst, Dept Mental Hlth & Alcohol Res, FIN-00300 Helsinki, Finland. Natl Publ Hlth Inst, Dept Nutr, FIN-00300 Helsinki, Finland. NCI, Div Clin Sci, Bethesda, MD 20892 USA. RP Partonen, T (reprint author), Natl Publ Hlth Inst, Dept Mental Hlth & Alcohol Res, Mannerheimintie 166, FIN-00300 Helsinki, Finland. RI Partonen, Timo/G-1105-2012; Haukka, Jari/G-1484-2014 OI Partonen, Timo/0000-0003-1951-2455; Haukka, Jari/0000-0003-1450-6208 FU NCI NIH HHS [N01-CN-45165] NR 15 TC 137 Z9 140 U1 0 U2 8 PU ROYAL COLLEGE OF PSYCHIATRISTS PI LONDON PA BRITISH JOURNAL OF PSYCHIATRY 17 BELGRAVE SQUARE, LONDON SW1X 8PG, ENGLAND SN 0007-1250 J9 BRIT J PSYCHIAT JI Br. J. Psychiatry PD SEP PY 1999 VL 175 BP 259 EP 262 DI 10.1192/bjp.175.3.259 PG 4 WC Psychiatry SC Psychiatry GA 232PM UT WOS:000082379200011 PM 10645328 ER PT J AU Sudakov, SK Terebilina, NN Medvedeva, OF Rusakova, IV Goldberg, SR AF Sudakov, SK Terebilina, NN Medvedeva, OF Rusakova, IV Goldberg, SR TI Brain contents of substance P, diazepam-binding inhibitor, and neuropeptide Y in high- and low-anxiety inbred rats during stress SO BULLETIN OF EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Article DE anxiety; substance P; diazepam-binding inhibitor; neuropeptide Y; stress; inbred rats AB The content of substance P in the hippocampus, hypothalamus, and midbrain of WAG/G rats surpassed these in Fischer-344 rats. After a 15-min stay in a shuttle box, the level of substance P in the hypothalamus and especially in the hippocampus decreased only in WAG/G rats. The content of diazepam-binding inhibitor in the hippocampus and midbrain of WAG/G rats was higher than in Fischer-344 rats, Stress increased the content of diazepam-binding inhibitor only in Fischer-344 rats. Midbrain content of neuropeptide Y in intact and stressed WAG/G rats was significantly lower than in Fischer-344 rats. There were no interstrain differences in the initial hypothalamic levels of neuropeptide Y between WAG/G and Fischer-344 rats, However, 15-min stress in the shuttle box increased hypothalamic content of neuropeptide Y only in Fischer-344 rats. Thus, high-anxiety rats are characterized by a low density of benzodiazepine receptors, decreased levels of substance P and diazepam-binding inhibitor, and high brain content of neuropeptide Y. C1 Russian Minist Hlth, Lab Attract Neurobiol, Moscow, Russia. Russian Minist Hlth, Lab Biochem, Inst Drug Abuse, Moscow, Russia. NIDA, Dept Preclin Pharmacol, Amer Natl Inst Hlth, Baltimore, MD USA. OI Sudakov, Sergey/0000-0002-9485-3439 NR 9 TC 0 Z9 0 U1 0 U2 0 PU CONSULTANTS BUREAU PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0007-4888 J9 B EXP BIOL MED+ JI Bull. Exp. Biol. Med. PD SEP PY 1999 VL 128 IS 9 BP 879 EP 881 DI 10.1007/BF02438072 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 305NC UT WOS:000086545800002 ER PT J AU De Vries, G Sherman, A Zhu, HR AF De Vries, G Sherman, A Zhu, HR TI Diffusively coupled bursters: Effects of cell heterogeneity (vol 60, pg 1167, 1998) SO BULLETIN OF MATHEMATICAL BIOLOGY LA English DT Correction C1 NIDDK, Math Res Branch, NIH, Bethesda, MD 20892 USA. HSIU RONG ZHU, Phoenix, AZ 85048 USA. RP De Vries, G (reprint author), NIDDK, Math Res Branch, NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0092-8240 J9 B MATH BIOL JI Bull. Math. Biol. PD SEP PY 1999 VL 61 IS 5 BP 1017 EP 1017 DI 10.1006/bulm.1999.0125 PG 1 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 245CV UT WOS:000083089400011 ER PT J AU Meldrum, M AF Meldrum, M TI Inventing pain medicine: From the laboratory to the clinic. SO BULLETIN OF THE HISTORY OF MEDICINE LA English DT Book Review C1 NIH, Bethesda, MD 20892 USA. RP Meldrum, M (reprint author), NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4319 USA SN 0007-5140 J9 B HIST MED JI Bull. Hist. Med. PD FAL PY 1999 VL 73 IS 3 BP 534 EP 536 DI 10.1353/bhm.1999.0125 PG 3 WC Health Care Sciences & Services; History & Philosophy Of Science SC Health Care Sciences & Services; History & Philosophy of Science GA 235TP UT WOS:000082558900038 ER PT J AU Shu, XO Stewart, P Wen, WQ Han, DH Potter, JD Buckley, JD Heineman, E Robison, LL AF Shu, XO Stewart, P Wen, WQ Han, DH Potter, JD Buckley, JD Heineman, E Robison, LL TI Parental occupational exposure to hydrocarbons and risk of acute lymphocytic leukemia in offspring SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CHILDHOOD-CANCER; INFANT LEUKEMIA; CHILDREN; BIRTH; TIME AB Parental exposure to hydrocarbons at work has been suggested to increase the risk of childhood leukemia. Evidence, however, is not entirely consistent. Very few studies have evaluated the potential parental occupational hazards by exposure time windows. The Children's Cancer Group recently completed a large-scale case-control study involving 1842 acute lymphocytic leukemia (ALL) cases and 1986 matched controls. The study examined the association of self-reported occupational exposure to various hydrocarbons among parents with risk of childhood ALL by exposure time window, immunophenotype of ALL, and age at diagnosis. We found that maternal exposure to solvents [odds ratio (OR), 1.8; 95% confidence interval (CI), 1.3-2.5] and paints or thinners (OR, 1.6; 95% CI, 1.2-2.2) during the preconception period (OR, 1.6; 95% CI, 1.1-2.3) and during pregnancy (OR, 1.7; 95% CI, 1.2-2.3) and to plastic materials during the postnatal period (OR, 2.2; 95% CI, 1.0-4.7) were related to an increased risk of childhood ALL, A positive association between ALL and paternal exposure to plastic materials during the preconception period was also found (OR, 1.4; 95% CI, 1.0-1.9), The ALL risk associated with parental exposures to hydrocarbons did not vary greatly with immunophenotype of ALL. These results suggest that the effect of parental occupational exposure to hydrocarbons on offspring may depend on the type of hydrocarbon and the timing of the exposure. C1 Univ Minnesota, Dept Pediat, Div Pediat Epidemiol & Clin Res, Minneapolis, MN 55454 USA. NCI, Occupat Epidemiol Branch, Div Canc Etiol & Genet, Bethesda, MD 20892 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. Univ So Calif, Sch Med, Los Angeles, CA 91066 USA. RP Shu, XO (reprint author), Childrens Canc Grp, POB 60012, Arcadia, CA 91066 USA. OI Potter, John/0000-0001-5439-1500 FU NCI NIH HHS [CA 48051] NR 28 TC 73 Z9 73 U1 1 U2 4 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 SEP PY 1999 VL 8 IS 9 BP 783 EP 791 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 236CK UT WOS:000082580500007 PM 10498397 ER PT J AU Liang, JC Ning, Y Wang, RY Padilla-Nash, HM Schrock, E Soenksen, D Nagarajan, L Ried, T AF Liang, JC Ning, Y Wang, RY Padilla-Nash, HM Schrock, E Soenksen, D Nagarajan, L Ried, T TI Spectral karyotypic study of the HL-60 cell line: Detection of complex rearrangements involving chromosomes 5, 7, and 16 and delineation of critical region of deletion on 5q31.1 SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID LEUKEMIA; PATIENT AB Interstitial deletions of the q arm of chromosome 5 have been associated with acute myelogenous leukemia (AML); therefore, accurate identification of rearrangements of this chromosome in a model cell line, HL-60, is important for understanding the critical genes involved in this disease. In this study, we employed a newly developed technology termed spectral karyotyping to delineate chromosomal rearrangements in this cell line. Our study revealed a derivative of chromosome 7 that resulted from translocations of chromosome arms 5q and 26q to 7q; that is, der(7)t(5;7)(?;q?)t(5;16)(?;q?). Interestingly, both chromosomes 5 and 7 were also involved in translocations with chromosome 16 in der(16) t(5;16)(q?;q?22 similar to 24) and der(16)t(7;16)(?;q?22 similar to 24), respectively. Other notable chromosomal abnormalities that were not previously reported in the HL-60 included an insertion of chromosome 8 in the q arm of chromosome 11, a translocation between chromosomes 9 and 14, and a translocation between chromosomes 14 and 15. In an attempt to define the loss of the 5q31.1 region in HL-60, we performed fluorescence in situ hybridization analysis by utilizing bacterial artificial chromosomes BAC1 and BAC2 that spanned the IL9 and EGR1 gene interval, which was previously shown to be a critical region of loss in AML. We showed that a copy of both BAC1 (spanning the D5S399 locus) and BAC2 (spanning the D5S393 locus centromeric to BAC1) were present in the normal chromosome 5,;but a second copy of BAC1 was lost and a second copy of BAC2 was inserted in the der(16)t(7;16) chromosome. Thus, not only was this study the first to use the new 24-color karyotyping technique to identify several novel chromosomal rearrangements in HL-60, but it also narrowed the 5q31.1 critical region of deletion to the region represented by BAC1. (C) Elsevier Science Inc., 1999. All rights reserved. C1 Univ Texas, MD Anderson Canc Ctr, Div Lab Med, Sect Cytogenet, Houston, TX 77054 USA. Univ Texas, MD Anderson Canc Ctr, Dept Mol Hematol & Therapy, Div Med, Houston, TX 77054 USA. NIH, Natl Human Genome Res Inst, Genome Technol Branch, Bethesda, MD 20892 USA. Appl Spectral Imaging Inc, Carlsbad, CA USA. RP Liang, JC (reprint author), Univ Texas, MD Anderson Canc Ctr, Div Lab Med, Sect Cytogenet, Box 37,8515 Fannin, Houston, TX 77054 USA. FU NCI NIH HHS [CA55164, CA66982] NR 13 TC 20 Z9 21 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0165-4608 J9 CANCER GENET CYTOGEN JI Cancer Genet. Cytogenet. PD SEP PY 1999 VL 113 IS 2 BP 105 EP 109 DI 10.1016/S0165-4608(99)00030-8 PG 5 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 232RF UT WOS:000082383200001 PM 10484974 ER PT J AU Libutti, SK Choyke, P Carrasquillo, JA Bacharach, S Neumann, RD AF Libutti, SK Choyke, P Carrasquillo, JA Bacharach, S Neumann, RD TI Monitoring responses to antiangiogenic agents using noninvasive imaging tests SO CANCER JOURNAL FROM SCIENTIFIC AMERICAN LA English DT Article ID TUMOR BLOOD-FLOW; POSITRON EMISSION TOMOGRAPHY; CARBOGEN-INDUCED CHANGES; MAGNETIC-RESONANCE; MICROVESSEL DENSITY; BREAST-LESIONS; ENHANCED MRI; ANGIOGENESIS; PET; CANCER C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Nucl Med, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Radiol, Bethesda, MD 20892 USA. RP Libutti, SK (reprint author), NCI, Surg Branch, NIH, Bldg 10,Room 2B07,10 Ctr Dr, Bethesda, MD 20892 USA. RI Carrasquillo, Jorge/E-7120-2010; OI Carrasquillo, Jorge/0000-0002-8513-5734 NR 37 TC 23 Z9 23 U1 0 U2 0 PU SCI AMERICAN INC PI NEW YORK PA 415 MADISON AVE, NEW YORK, NY 10017 USA SN 1081-4442 J9 CANCER J SCI AM JI Cancer J. Sci. Am. PD SEP-OCT PY 1999 VL 5 IS 5 BP 252 EP 256 PG 5 WC Oncology SC Oncology GA 247CL UT WOS:000083203000001 PM 10526663 ER PT J AU Touloukian, CE Rosenberg, SA AF Touloukian, CE Rosenberg, SA TI A survey of treatments used in patients with metastatic melanoma: Analysis of 189 patients referred to the National Cancer Institute SO CANCER JOURNAL FROM SCIENTIFIC AMERICAN LA English DT Article DE melanoma; metastatic disease; systemic treatment; clinical protocol; chemotherapy ID MALIGNANT-MELANOMA; COMPLETE RESPONSES AB BACKGROUND Few effective treatments exist for patients with metastatic melanoma. The United States Food and Drug Administration has approved the use of interferon alfa-2b after the resection of locoregional disease, and dacarbazine or interleukin-2 for the treatment of patients with metastatic melanoma beyond the locoregional area, although many additional agents and combinations of agents are currently in use. METHODS Between January 1997 and June 1998, the Surgery Branch of the National Cancer Institute conducted a prospective analysis of 226 consecutive patients with metastatic melanoma referred for protocol evaluation, The previous systemic treatments these patients received both before and after the development of metastatic disease were tabulated, along with the association of these treatments with formal institutional protocols, Only the identity of the agents and not the dose or the schedule of treatments was considered in this analysis. Complete information could be obtained from 189 of the 226 patients. RESULTS Of the 189 patients evaluated for this study, 135 (71%) received some form of systemic therapy before referral to the National Cancer Institute, Before the development of metastatic disease, 80 patients were administered 25 different systemic treatments, including 23 different agents. After the development of metastatic disease, 53 patients were administered 57 different systemic and regional treatments, including 37 different agents. After the resection of all metastatic sites, 23 patients were administered nine different systemic adjuvant treatments. Overall, 78 different systemic treatments were administered to these patients. The majority of treatments in each group were not associated with formal institutional protocols. CONCLUSIONS This study has demonstrated that a large number of agents and different combinations of agents are currently being administered to patients before and after the development of metastatic melanoma, and frequently not within the context of an approved institutional protocol. These results indicate a need for more formal evaluation of treatments in prospective protocols and greater standardization of the treatment of patients with melanoma. C1 NCI, Surg Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Touloukian, CE (reprint author), NCI, Surg Branch, Div Clin Sci, NIH, Bldg 10,Room 2B46,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 11 TC 4 Z9 4 U1 0 U2 0 PU SCI AMERICAN INC PI NEW YORK PA 415 MADISON AVE, NEW YORK, NY 10017 USA SN 1081-4442 J9 CANCER J SCI AM JI Cancer J. Sci. Am. PD SEP-OCT PY 1999 VL 5 IS 5 BP 269 EP 274 PG 6 WC Oncology SC Oncology GA 247CL UT WOS:000083203000005 PM 10526667 ER PT J AU Totsuka, Y Ushiyama, H Ishihara, J Sinha, R Goto, S Sugimura, T Wakabayashi, K AF Totsuka, Y Ushiyama, H Ishihara, J Sinha, R Goto, S Sugimura, T Wakabayashi, K TI Quantification of the co-mutagenic beta-carbolines, norharman and harman, in cigarette smoke condensates and cooked foods SO CANCER LETTERS LA English DT Article; Proceedings Paper CT 7th International Conference on Carcinogenic and Mutagenic N-Substituted Aryl Compounds CY NOV 04-06, 1998 CL NAGOYA, JAPAN DE norharman; harman; cigarette smoke; cooked food ID HETEROCYCLIC AMINE CONTENT; VARYING DEGREES; PRODUCTS; DONENESS; URINE; BEEF AB Co-mutagenic beta-carbolines, such as norharman and harman, were quantified in mainstream and sidestream smoke condensates of six Japanese brands of cigarettes; and also in 13 kinds of cooked foods, using a combination of blue cotton treatment and HPLC. Norharman and harman were detected in all the cigarette smoke condensate samples. Their levels in the mainstream smoke case were 900-4240 ng per cigarette for norharman, and 360-2240 ng for harman, and in sidestream smoke, 4130-8990 ng for norharman and 2100-3000 ng for harman. These beta-carbolines were also found to be present in all the cooked food samples, at levels of 2.39-795 ng for norharman and 0.62-377 ng for harman per gram of cooked food. The observed concentrations are much higher than those found for mutagenic and carcinogenic heterocyclic amines (HCAs), suggesting that humans are exposed to norharman and harman in daily life to a larger extent than to HCAs. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 Natl Canc Ctr, Res Inst, Canc Prevent Div, Chuo Ku, Tokyo 1040045, Japan. Tokyo Metropolitan Res Lab Publ Hlth, Div Food Hyg, Shinjuku Ku, Tokyo 1690073, Japan. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Natl Inst Publ Hlth, Dept Community Environm Sci, Minato Ku, Tokyo 1088638, Japan. RP Wakabayashi, K (reprint author), Natl Canc Ctr, Res Inst, Canc Prevent Div, Chuo Ku, 1-1 Tsukiji 5 Chome, Tokyo 1040045, Japan. RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 NR 17 TC 83 Z9 85 U1 0 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD SEP 1 PY 1999 VL 143 IS 2 BP 139 EP 143 DI 10.1016/S0304-3835(99)00143-3 PG 5 WC Oncology SC Oncology GA 234QH UT WOS:000082495500009 PM 10503893 ER PT J AU Stillwell, WG Turesky, RJ Sinha, R Skipper, PL Tannenbaum, SR AF Stillwell, WG Turesky, RJ Sinha, R Skipper, PL Tannenbaum, SR TI Biomonitoring of heterocyclic aromatic amine metabolites in human urine SO CANCER LETTERS LA English DT Article; Proceedings Paper CT 7th International Conference on Carcinogenic and Mutagenic N-Substituted Aryl Compounds CY NOV 04-06, 1998 CL NAGOYA, JAPAN DE biomonitoring; human urine; heterocyclic aromatic amines; food mutagens; biotransformation ID CYTOCHROME P4501A2; FRIED MEAT; 2-AMINO-3,8-DIMETHYLIMIDAZO<4,5-F>QUINOXALINE; EXCRETION; 2-AMINO-1-METHYL-6-PHENYLIMIDAZO<4,5-B>PYRIDINE; EXPOSURE; MEIQX AB Human exposure to heterocyclic aromatic amines such as MeIQx (2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline) may be monitored by measuring the levels of the heterocyclic aromatic amine in urine. In order to investigate the contribution of N-oxidation to the metabolism of MeIQx in vivo, we developed a biomonitoring procedure for the analysis and quantification of the N-2-glucuronide conjugate of 2-hydroxyamino-3,8-dimethylimidazo[4,5-f]quinoxaline in human urine. Subjects (n = 66) in the dietary study ingested a uniform diet of cooked meat containing known amounts of MeIQx, and urine was collected after consumption of the test meal. A method based on solid-phase extraction and immunoaffinity separation was used to isolate N-2-(beta-1-glucosiduronyl)-2-hydroxyamino-3,8-dimethylimidazo[4,5-f]quinoxaline and its stable isotope-labeled internal standard from urine. The isolated conjugate was converted to the deaminated product 2-hydroxy-3,8-dimethylimidazo[4,5-f]quinoxaline by treatment with acetic acid under moderate heating. 2-Hydroxy-3,8-dimethylimidazo[4,5-f]quinoxaline and the [H-2(3)]methyl analog were derivatized to form the corresponding 3,5-bis(trifluoromethyl)benzyl ether derivatives and quantified by capillary gas chromatography-negative ion chemical ionization mass spectrometry employing selected ion monitoring procedures. The amounts of N-2-(beta-1-glucosiduronyl)-2-hydroxyamino-3,8-dimethylimidazo[4,5-f]quinoxaline recovered in urine collected 0-12 h after the test meal accounted for 2.2-17.1% of the ingested dose, with a median value of 9.5%. The variability in the proportion of the dose excreted among the subjects may be reflective of several factors, including interindividual variation in the enzymic activity of CYP1A2 and/or conjugation reactions of the N-hydroxylamine metabolite with N-glucuronosyltransferase(s). (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 MIT, Div Bioengn & Environm Hlth, Cambridge, MA 02139 USA. Nestec Ltd, Nestle Res Ctr, CH-1000 Lausanne 26, Switzerland. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. MIT, Dept Chem, Cambridge, MA 02139 USA. RP Tannenbaum, SR (reprint author), MIT, Div Bioengn & Environm Hlth, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 FU NIEHS NIH HHS [ES05622] NR 14 TC 29 Z9 29 U1 2 U2 8 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD SEP 1 PY 1999 VL 143 IS 2 BP 145 EP 148 DI 10.1016/S0304-3835(99)00144-5 PG 4 WC Oncology SC Oncology GA 234QH UT WOS:000082495500010 PM 10503894 ER PT J AU Sinha, R Rothman, N AF Sinha, R Rothman, N TI Role of well-done, grilled red meat, heterocyclic amines (HCAs) in the etiology of human cancer SO CANCER LETTERS LA English DT Article; Proceedings Paper CT 7th International Conference on Carcinogenic and Mutagenic N-Substituted Aryl Compounds CY NOV 04-06, 1998 CL NAGOYA, JAPAN DE heterocyclic amine; epidemiology; red meat; cooking; doneness; questionnaire ID COLORECTAL-CANCER; VARYING DEGREES; RISK; FOOD; CARCINOGEN; PRODUCTS; URUGUAY; CHICKEN; PHIP AB High-temperature cooking techniques and doneness level of red meat are linked to cancer of various sites, particularly colorectal cancer. In a colorectal adenoma study, we found an elevated risk for red meat consumption that was mainly due to an association with well-done/very well-done red meat. High-temperature cooking methods (i.e. grilling) were also associated with increased risk. We are currently using an HCA database linked to this questionnaire to estimate MeIQx, DiMeIQx and PhIP consumption and determine their association with risk of colorectal adenoma. Similar results on red meat doneness and fried meat were found in a case-control study of lung cancer. Thus, initial positive findings are stimulating the development of a more refined questionnaire instrument and its validation using food diaries, 24-h recalls, biomarkers of internal dose and direct food measurements. Furthermore, the use of these exposure assessment approaches are being used in large prospective studies world wide and should help clarify the role of doneness, cooking practices and pyrolysis products in the etiology of human cancer. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Sinha, R (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Room 7028,6120 Execut Blvd, Bethesda, MD 20892 USA. RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 NR 20 TC 56 Z9 56 U1 1 U2 8 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD SEP 1 PY 1999 VL 143 IS 2 BP 189 EP 194 DI 10.1016/S0304-3835(99)00123-8 PG 6 WC Oncology SC Oncology GA 234QH UT WOS:000082495500018 PM 10503902 ER PT J AU Gonzalez, FJ Kimura, S AF Gonzalez, FJ Kimura, S TI Role of gene knockout mice in understanding the mechanisms of chemical toxicity and carcinogenesis SO CANCER LETTERS LA English DT Article; Proceedings Paper CT 7th International Conference on Carcinogenic and Mutagenic N-Substituted Aryl Compounds CY NOV 04-06, 1998 CL NAGOYA, JAPAN DE knockout mice; P450; carcinogenesis ID AROMATIC HYDROCARBON METABOLISM; EPOXIDE HYDROLASE; ACETAMINOPHEN HEPATOTOXICITY; INDUCIBLE CYTOCHROME-P450; DRUG OXIDATION; DT-DIAPHORASE; CELL-LINE; RAT; ACTIVATION; EXPRESSION AB Most chemical carcinogens require metabolic activation to electrophilic metabolites that are capable of binding to DNA and causing gene mutation. Carcinogen metabolism is carried out by large groups of xenobiotic-metabolizing enzymes that include the phase I cytochromes P450 (P450) and phase II enzymes that include various transferases. During the past 10 years, considerable attention has been focused on the role of P450s in human cancer susceptibility. Polymorphisms in expression of P450s and transferases exist in humans and these might render increased susceptibility or resistance to cancer. Thus it is important to understanding how P450s participate in the carcinogenesis process and to determine if they are indeed the rate limiting and critical interface between the chemical and its biological activity. Since there are marked species differences in expressions and catalytic activities of the multiple P450 forms that activate carcinogens, this validation process becomes especially difficult. To address the role of P450s in whole animal carcinogenesis, mice were produced that lack the P450s known to catalyze carcinogen activation. Mouse lines having disruption of genes encoding P450s CYP1A2, CYP2E1, and CYP1B1 were developed by use of gene disruption in empbryonic stem cells. Mice lacking expression of microsomal epoxide hydrolase and NADPH:quinone oxidoreductase were also made. These mice exhibit no grossly abnormal phenotypes, suggesting that the xenobiotic-metabolizing enzymes have no critical roles in mammalian development and physiological homeostasis. This explains the occurrence of polymorphisms in humans and other mammalian species. However, these null mice do show differences in sensitivities to acute chemical toxicities, thus establishing the importance of xenobiotic metabolism in activation pathways that lead to cell death. Rodent bioassays using null mice and known genotoxic carcinogens should establish whether these enzymes are required for carcinogenesis in an intact animal model. These studies will also provide a framework for the production of transgenic mice and carcinogen bioassay protocols that may be more predictive for identifying human carcinogens and validate the molecular epidemiology studies ongoing in humans that seek to establish a role for polymorphisms in cancer risk. (C) 1999 Published by Elsevier Science Ireland Ltd. C1 NCI, NIH, Bethesda, MD 20892 USA. RP Gonzalez, FJ (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 43 TC 26 Z9 30 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD SEP 1 PY 1999 VL 143 IS 2 BP 199 EP 204 DI 10.1016/S0304-3835(99)00125-1 PG 6 WC Oncology SC Oncology GA 234QH UT WOS:000082495500020 PM 10503904 ER PT J AU Snyderwine, EG AF Snyderwine, EG TI Mammary gland carcinogenesis by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in rats: possible mechanisms SO CANCER LETTERS LA English DT Article; Proceedings Paper CT 7th International Conference on Carcinogenic and Mutagenic N-Substituted Aryl Compounds CY NOV 04-06, 1998 CL NAGOYA, JAPAN DE diet; breast cancer; heterocyclic amine; PhIP; rat; mammary gland; high fat level ID SPRAGUE-DAWLEY RATS; HETEROCYCLIC AMINES; BREAST-CANCER; DIETARY-FAT; COOKED FOODS; PHIP AB 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic amine derived from cooked meat. Mammary gland cancer can be induced in female Sprague-Dawley rats by administration of several oral doses of PhIP. The mechanism of mammary gland carcinogenesis by PhIP in this rat model is not fully understood but appears to involve several factors. One factor is the formation of PhIP-DNA adducts in the mammary gland after metabolic activation of PhIP. Possible target cell populations include the epithelial cells of the mammary gland terminal end buds (TEBs), putative sites of origin of carcinomas. Another factor involved in the mammary carcinogenicity of PhIP may be an increased proliferation in epithelial cells of the TEBs which occurs after a carcinogenic dose of PhIP is administered. This proliferation would be likely to enhance the fixation of mutations from PhIP-DNA adducts in target cells and facilitate the initiation of carcinogenesis. PhIP exposure also transiently inhibits the development of the mammary gland by retarding the differentiation of TEBs to alveolar buds and lobules. As a consequence, more TEBs are available for neoplastic transformation. Recent studies in rats have also shown that PhIP increases the levels of serum prolactin, a well-recognized promoter of mammary gland cancer, which may further explain the targeting of PhIP to the mammary gland. The results to date indicate that PhIP has multiple effects on the mammary gland and hormone status in rats that could potentially play a role in its ability to induce mammary gland cancer. (C) 1999 Published by Elsevier Science Ireland Ltd. All rights reserved. C1 NCI, Expt Carcinogenesis Lab, Chem Carcinogenesis Sect, Bethesda, MD 20892 USA. RP Snyderwine, EG (reprint author), NCI, Expt Carcinogenesis Lab, Chem Carcinogenesis Sect, Bethesda, MD 20892 USA. NR 22 TC 24 Z9 24 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD SEP 1 PY 1999 VL 143 IS 2 BP 211 EP 215 DI 10.1016/S0304-3835(99)00127-5 PG 5 WC Oncology SC Oncology GA 234QH UT WOS:000082495500022 PM 10503906 ER PT J AU Masumura, K Matsui, K Yamada, M Horiguchi, M Ishida, K Watanabe, M Ueda, O Suzuki, H Kanke, Y Tindalle, KR Wakabayashi, K Sofuni, T Nohmi, T AF Masumura, K Matsui, K Yamada, M Horiguchi, M Ishida, K Watanabe, M Ueda, O Suzuki, H Kanke, Y Tindalle, KR Wakabayashi, K Sofuni, T Nohmi, T TI Mutagenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the new gpt Delta transgenic mouse SO CANCER LETTERS LA English DT Article; Proceedings Paper CT 7th International Conference on Carcinogenic and Mutagenic N-Substituted Aryl Compounds CY NOV 04-06, 1998 CL NAGOYA, JAPAN DE PhIP; gender difference; organ specificity; transgenic mouse gpt Delta; 6-thioguanine slection; Spi(-) selection ID HETEROCYCLIC AMINES; COOKED FOODS AB Gender differences and organ specificity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced mutagenesis were examined with the new gpt Delta transgenic mouse (T. Nohmi, M. Katoh, H. Suzuki, M. Matsui, M. Yamada, M. Watanabe, M. Suzuki, N. Horiya, O. Ueda, T. Shibuya, H. Ikeda, T. Sofuni, A new transgenic mouse mutagenesis test system using Spi(-) and 6-thioguanine selections (Environ. Mel. Mutagen. 28 (1996) 465-470). In this mouse model, two distinct selections are employed to efficiently detect different types of mutations, i.e 6-thioguanine (6-TG) selection for point mutations and Spi(-) selection for deletions, respectively. In both selections, the highest mutant frequencies were observed in colon, followed by in spleen and liver. No increases in mutations were observed in testis, brain and bone marrow in PhIP-treated male mice. No significant differences in 6-TG and Spi- mutant frequencies were observed in colon and liver between male and female treated mice. The correlation between PhIP-induced mutagenesis and carcinogenesis in colon is discussed. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 Natl Inst Hlth Sci, Div Genet & Mutagenesis, Setagaya Ku, Tokyo 1588501, Japan. Tokyo Univ Agr, Div Bioregulat Studies, Setagaya Ku, Tokyo 1568502, Japan. Natl Canc Ctr, Res Inst, Div Canc Prevent, Chuo Ku, Tokyo 104, Japan. Chugai Pharmaceut Co Ltd, Exploratory Res Lab, Fuji Gotemba Res Lab, Shizuoka 412, Japan. NIEHS, Lab Environm Carcinogenesis & Mutagenesis, NIH, Res Triangle Pk, NC 27709 USA. RP Nohmi, T (reprint author), Natl Inst Hlth Sci, Div Genet & Mutagenesis, Setagaya Ku, Tokyo 1588501, Japan. NR 10 TC 28 Z9 28 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD SEP 1 PY 1999 VL 143 IS 2 BP 241 EP 244 DI 10.1016/S0304-3835(99)00132-9 PG 4 WC Oncology SC Oncology GA 234QH UT WOS:000082495500027 PM 10503911 ER PT J AU Thorgeirsson, SS Ryu, DY Weidner, V Snyderwine, EG AF Thorgeirsson, SS Ryu, DY Weidner, V Snyderwine, EG TI Carcinogenicity and mutagenicity of heterocyclic amines in transgenic mouse models SO CANCER LETTERS LA English DT Article; Proceedings Paper CT 7th International Conference on Carcinogenic and Mutagenic N-Substituted Aryl Compounds CY NOV 04-06, 1998 CL NAGOYA, JAPAN DE transgenic mouse models; heterocyclic amines; carcinogenicity; mutagenicity ID GROWTH-FACTOR-ALPHA; LIVER EPITHELIAL-CELLS; EXPRESSING C-MYC; MICE; OVEREXPRESSION; TUMORIGENESIS AB Double transgenic mice bearing fusion genes consisting of mouse albumin enhancer/promoter-mouse c-myc cDNA and mouse metallothionein1 promoter-human TGF alpha cDNA were generated to investigate the interaction of these genes in hepatic oncogenesis and to provide a general paradigm for characterizing both the interaction of nuclear oncogenes and growth factors in tumorigenesis. In addition, these mice provide an experimental model to test how environmental chemicals might interact with the c-myc and TGF alpha transgenes during the neoplastic process. Treatment of the double transgenic mice with both genotoxic agents such as diethylnitrosamine and 2-amino-3-methylimidazo-[4,5-f]quinoline (IQ) as well as the tumor promoter phenobarbital greatly accelerated the neoplastic process. To investigate the role of mutagenesis in the carcinogenic process, 2-amino-3,8-dimethyl-imidazo [4,5-f]quinoxaline (MeIQx) induced mutagenesis and hepatocarcinogenicity was examined in C57BL/lacZ (Muta(TM)Mice) and double transgenic c-myc/lacZ mice that carry the lacZ mutation reporter gene. The MelQx hepatocarcinogenicity was associated with an increase in in vivo mutagenicity as scored by mutations in the lacZ reporter gene. These results suggest that transgenic mouse models may provide important tools for testing both the carcinogenic potential of environmental chemicals and the interaction/cooperation of these compounds with specific genes during the neoplastic process. (C) 1999 Published by Elsevier Science Ireland Ltd. C1 NCI, Div Basic Sci, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Thorgeirsson, SS (reprint author), NCI, Div Basic Sci, Expt Carcinogenesis Lab, NIH, Bldg 37,Room 3C28,37 Convent Dr,MSC4255, Bethesda, MD 20892 USA. NR 10 TC 1 Z9 2 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD SEP 1 PY 1999 VL 143 IS 2 BP 245 EP 247 DI 10.1016/S0304-3835(99)00133-0 PG 3 WC Oncology SC Oncology GA 234QH UT WOS:000082495500028 PM 10503912 ER PT J AU Greenwald, P AF Greenwald, P TI Clinical trials in cancer prevention SO CANCER LETTERS LA English DT Meeting Abstract C1 NCI, Div Canc Prevent, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD SEP PY 1999 VL 143 SU 1 BP S30 EP S30 PG 1 WC Oncology SC Oncology GA 243LX UT WOS:000083000300015 ER PT J AU Kang, MH Figg, WD Dahut, W AF Kang, MH Figg, WD Dahut, W TI Taxanes in hormone-refractory prostate cancer SO CANCER PRACTICE LA English DT Editorial Material ID PHASE-II TRIAL; ESTRAMUSTINE; CHEMOTHERAPY; CARCINOMA C1 NCI, Med Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Kang, MH (reprint author), NCI, Med Branch, Div Clin Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 19 TC 8 Z9 8 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1065-4704 J9 CANCER PRACT JI Cancer Pract. PD SEP-OCT PY 1999 VL 7 IS 5 BP 270 EP 272 DI 10.1046/j.1523-5394.1999.75005.x PG 3 WC Oncology; Health Care Sciences & Services; Nursing SC Oncology; Health Care Sciences & Services; Nursing GA 235LU UT WOS:000082543800015 PM 10687598 ER PT J AU Hagiwara, K McMenamin, MG Miura, K Harris, CC AF Hagiwara, K McMenamin, MG Miura, K Harris, CC TI Mutational analysis of the p63/p73L/p51/p40/CUSP/KET gene in human cancer cell lines using intronic primers SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-BETA; P53 HOMOLOG; CLONING; MICE; P73 AB After the identification of p73, a second homologue of the human p53 tumor suppressor gene has been reported and named p63/p73L/p51/p40/CUSP/KET. We have investigated the hypotheses that: (a) p63 is mutated in diverse types of human cancers; and (b) p63 functions in the same pathway as p53 and p73 in the process of carcinogenesis; therefore, mutations in these three genes would be mutually exclusive, We have analyzed the genomic structure of the p63 gene and have performed mutational analyses on 54 human cell lines using intronic primers nanking each exon. We have confirmed that the human p63 open reading frame encodes the same length of protein as murine p63 that was initially reported to be 39 amino acids longer than human p63. By mutational analysis, we have shown that DLD1 and SKOV3 cells have either heterozygous mutations or polymorphisms in the putative DNA binding domain of p63. In these cell lines, p63 is biallelically expressed. We conclude that mutations in the p63 gene are rare in human cell lines. The fact that DLD1 is abnormal for both p63 and p53 genes suggests that they may not be involved in the same tumor suppressor pathway. C1 NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, NIH, Bldg 37,Room 2C01,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. NR 22 TC 106 Z9 109 U1 0 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 SEP 1 PY 1999 VL 59 IS 17 BP 4165 EP 4169 PG 5 WC Oncology SC Oncology GA 232PY UT WOS:000082380200003 PM 10485447 ER PT J AU Izzotti, A Camoirano, A Cartiglia, C Grubbs, CJ Lubet, RA Kelloff, GJ De Flora, S AF Izzotti, A Camoirano, A Cartiglia, C Grubbs, CJ Lubet, RA Kelloff, GJ De Flora, S TI Patterns of DNA adduct formation in liver and mammary epithelial cells of rats treated with 7,12-dimethylbenz(a)anthracene, and selective effects of chemopreventive agents SO CANCER RESEARCH LA English DT Article ID BUTYLATED HYDROXYTOLUENE; DIETARY SELENITE; INHIBITION; TUMORIGENESIS; INVIVO; 7,12-DIMETHYLBENZANTHRACENE; TUMORS; 7,12-DIMETHYLBENZANTHRACENE; CARCINOGENESIS; SENSITIVITY AB 7,12-Dimethylbenz(a)anthracene (DMBA) is a prototype carcinogen that induces a high yield of mammary tumors in rats after a single feeding. We investigated the induction and chemoprevention of DNA adducts in female Sprague Dawley rats receiving DMBA by gavage according to a variety of treatment schedules. The patterns of P-32-postlabeled DNA adducts in liver and mammary epithelial cells were similar to those produced by the in vitro reaction of metabolically activated DMBA with calf thymus DNA. There was a high and statistically significant correlation between dose of DMBA administered to rats (0, 0.6, 2.4, and 12 mg/kg body weight) and levels of DNA adducts in both types of cells. The regression lines relating DMBA doses to total DNA adduct levels were significantly divergent and crossed at 1.5 mg/kg body weight, indicating that, at lower doses, the formation of DNA adducts is more intense in target mammary cells, whereas at higher doses, DNA adduct levels are more elevated in liver cells, presumably due to the greater metabolic capacity of this organ. When the rats were sacrificed 7 days rather than 2 days after DMBA administration, DNA adduct levels were approximately halved in both liver and mammary cells. The observed patterns can be interpreted based on toxicokinetic factors, local and distant metabolism, removal of DNA adducts by excision repair, and cell proliferation rate. Of three chemopreventive agents given with the diet to rats treated with 12 mg of DMBA, 5,6-benzoflavone (1650 ppm) was the most effective, inhibiting DNA adduct formation in liver and mammary cells by 96.5 and 83.5%, respectively. Feeding of 1,2-dithiole-3-thione (600 ppm) inhibited this biomarker by 68.5 and 50.2%, whereas butyl hydroxyanisole (BHA; 5000 ppm) showed a significant inhibition in the liver (46.5%) but: was ineffective in mammary cells (29.0%, not significant). These data correlate nicely with the results of a parallel study in which 5,6-benzoflavone, 1,2-dithiole-3-thione, and BHA inhibited formation of hemoglobin adducts by 80.0, 44.0, and 0%, respectively; the incidence of mammary tumors by 82.4, 47.1, and 5.9%, respectively; and their multiplicity by 92.6, 80.0, and 7.4%, respectively. Therefore, biomarkers of biologically effective dose are highly predictive of the efficacy of chemopreventive agents in the DMBA rat mammary model. The selective inhibition by BHA of DNA adducts in the liver but not in mammary cells is consistent with the finding that this phenolic antioxidant stimulated phase II activities in the liver but not in the mammary gland (L. L. Song et at, manuscript in preparation). In any case, the broad-spectrum inducer 5,6-BF appears to be more effective than the two monofunctional phase II inducers, presumably because an enhanced activation of DMBA to reactive metabolites is coordinated with their blocking, detoxification, and excretion. C1 Univ Genoa, Dept Hlth Sci, Sect Hyg & Prevent Med, I-16132 Genoa, Italy. Univ Alabama, Chemoprevent Ctr, Birmingham, AL 35294 USA. NCI, Rockville, MD 20892 USA. RP De Flora, S (reprint author), Univ Genoa, Dept Hlth Sci, Sect Hyg & Prevent Med, Via A Pastore 1, I-16132 Genoa, Italy. OI izzotti, alberto/0000-0002-8588-0347 FU NCI NIH HHS [N01-CN-75008] NR 36 TC 47 Z9 47 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 SEP 1 PY 1999 VL 59 IS 17 BP 4285 EP 4290 PG 6 WC Oncology SC Oncology GA 232PY UT WOS:000082380200029 PM 10485473 ER PT J AU Sinha, R Chow, WH Kulldorff, M Denobile, J Butler, J Garcia-Closas, M Weil, R Hoover, RN Rothman, N AF Sinha, R Chow, WH Kulldorff, M Denobile, J Butler, J Garcia-Closas, M Weil, R Hoover, RN Rothman, N TI Well-done, grilled red meat increases the risk of colorectal adenomas SO CANCER RESEARCH LA English DT Article ID HETEROCYCLIC AMINE CONTENT; VARYING DEGREES; CANCER; BEEF; FOODS AB Red meat or meat-cooking methods such as frying and doneness level have been associated with an increased risk of colorectal and other cancers. It is unclear whether it is red meat intake or the way it is cooked that is involved in the etiology of colorectal cancer. To address this issue, we developed an extensive food frequency questionnaire module that collects information on meat-cooking techniques as well as the level of doneness for individual meat items and used it in a study of colorectal adenomas, known precursors of colorectal cancer. A case-control study of colorectal adenomas was conducted at the National Naval Medical Center (Bethesda, MD) between April 1994 and September 1996. All cases (n = 146) were diagnosed with colorectal adenomas at sigmoidoscopy or colonoscopy and histologically confirmed. Controls (n = 228) were screened with sigmoidoscopy and found not to have colorectal adenomas. The subjects completed a food frequency questionnaire and answered detailed questions on meat-cooking practices. We used frequency and portion size to estimate grams of meat consumed per day for total meat as well as for meat subgroups defined by cooking methods and doneness levels. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression, adjusted for age, gender, total caloric intake, reason for screening (routine or other), and several established risk factors for colorectal adenomas or cancer, including the use of nonsteroidal anti-inflammatory drugs, physical activity, and pack-gears of cigarette smoking. There was an increased risk of 11% per 10 g/day (or 2.5 oz/week) of reported red meat consumption (OR, 1.11; CI, 1.03-1.19). The increased risk was mainly associated with well-done/very well-done red meat, with an excess risk of 29% per 10 g/day (OR, 1.29; CI, 1.08-1.54) versus an excess of 10% per 10 g/day (OR, 1.10; CI, 0.96-1.26) for consumption of rare/medium red meat. High-temperature cooking methods were also associated with increased risk; 26% per 10 g/day (OR, 1.26; CI, 1.06-1.50) of grilled red meat and 15% per 10 g/day (OR, 1.15; CI, 0.97-1.36) of pan-fried red meat consumption. There was an increased risk of colorectal adenomas associated with higher intake of red meat, most of which was due to the subgroup of red meat that was cooked until well done/very well done and/or by high-temperature cooking techniques, such as grilling. These results are consistent with the hypothesis that carcinogenic compounds formed by high-temperature cooking techniques, such as heterocyclic amines and polycyclic aromatic hydrocarbons, may contribute to the risk of developing colorectal tumors. C1 NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. NCI, Div Canc Prevent, NIH, Rockville, MD 20852 USA. Natl Naval Med Ctr, Bethesda, MD 20889 USA. RP Sinha, R (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Execut Plaza S,Room 7028,6120 Execut Blvd, Rockville, MD 20852 USA. RI Kulldorff, Martin/H-4282-2011; Garcia-Closas, Montserrat /F-3871-2015; Sinha, Rashmi/G-7446-2015; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Sinha, Rashmi/0000-0002-2466-7462; Kulldorff, Martin/0000-0002-5284-2993 NR 26 TC 142 Z9 145 U1 0 U2 7 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 SEP 1 PY 1999 VL 59 IS 17 BP 4320 EP 4324 PG 5 WC Oncology SC Oncology GA 232PY UT WOS:000082380200035 PM 10485479 ER PT J AU Joshi, B Li, L Taffe, BG Zhu, ZY Wahl, S Tian, H Ben-Josef, E Taylor, JD Porter, AT Tang, DG AF Joshi, B Li, L Taffe, BG Zhu, ZY Wahl, S Tian, H Ben-Josef, E Taylor, JD Porter, AT Tang, DG TI Apoptosis induction by a novel anti-prostate cancer compound, BMD188 (a fatty acid-containing hydroxamic acid), requires the mitochondrial respiratory chain SO CANCER RESEARCH LA English DT Article ID CERAMIDE-INDUCED APOPTOSIS; PROGRAMMED CELL-DEATH; CYTOCHROME-C RELEASE; PERMEABILITY TRANSITION; HYDROGEN-PEROXIDE; ARACHIDONATE LIPOXYGENASES; GENERATION; NECROSIS; PROTEASE; OXYGEN AB We recently developed a class of novel anti-prostate cancer compounds, cyclic hydroxamates that elicit a potent apoptotic response in many tumor cells cultured in vitro (D.G. Tang et at, Biochem. Biophys. Res. Commun., 242: 380-384, 1998). The lead compound, termed BMD188, induces programmed cell death in a variety of prostate cancer cells in vitro as well as in vivo (L. Li et al., Anticancer Res., 19: 51-70, 1999). BMD188 kills androgen-independent prostate cancer cells as well as prostate cancer cells with a multidrug-resistance phenotype. The apoptotic effect of BMD188 in prostate cancer tells does not depend on cell cycle, p53 status, or its purported target, arachidonate 12-lipoxygenase, but does require caspase activation and seems to involve mitochondria. To synthesize more specific and effective anti-prostate cancer hydroxamic acid compounds, it is important to understand their mechanism(s) of action. In the present study, we studied the role of mitochondrial respiratory chain (MRC) in BMD188-induced apoptosis in androgen-independent prostate cancer PC3 cells and compared its effect with that of staurosporine (STS), a widely used apoptosis inducer. Several lines of evidence indicate that BMD188-induced cell death depends on MRC: (a) the death could be significantly inhibited by several complex-specific respiration inhibitors; (b) respiration-deficient rho(o) cells were more resistant than wild-type parent cells to apoptosis induction by BMD188; and (c) BMD188 induced a rapid increase in reactive oxygen species in mitochondria, an up-regulation of cytochrome c oxidase subunits, a biphasic alteration (i.e., an early hyperpolarization, followed by later hypopolarization) in the mitochondrial membrane potential (Delta psi(m)), dramatic changes in mitochondrial morphology and distribution prior to caspase activation, and an abnormal proliferation of mitochondria at the ultrastructural level. By contrast, STS-induced PC3 apoptosis seemed not to depend on MRC. Taken together, the data suggest that the MRC represents a functional target for anti-prostate cancer hydroxamates. C1 Wayne State Univ, Biomide Labs, Detroit, MI 48202 USA. Wayne State Univ, Dept Radiat Oncol, Detroit, MI 48202 USA. Wayne State Univ, Dept Occupat & Environm Hlth Sci, Detroit, MI 48202 USA. Wayne State Univ, Dept Chem, Detroit, MI 48202 USA. Wayne State Univ, Dept Biol Sci, Detroit, MI 48202 USA. Barbara Ann Karmanos Canc Inst, Detroit, MI 48201 USA. Wayne State Univ, Harper Hosp, Gershenson Radiat Oncol Ctr, Detroit, MI 48201 USA. NIDR, NIH, Bethesda, MD 20892 USA. RP Tang, DG (reprint author), UCL, MRC, Mol Cell Biol Lab, Gower St, London WC1E 6BT, England. EM d.tang@ucl.ac.uk FU NCI NIH HHS [CA72256] NR 65 TC 63 Z9 64 U1 0 U2 8 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 SEP 1 PY 1999 VL 59 IS 17 BP 4343 EP 4355 PG 13 WC Oncology SC Oncology GA 232PY UT WOS:000082380200038 PM 10485482 ER PT J AU Jacob, K Webber, M Benayahu, D Kleinman, HK AF Jacob, K Webber, M Benayahu, D Kleinman, HK TI Osteonectin promotes prostate cancer cell migration and invasion: A possible mechanism for metastasis to bone SO CANCER RESEARCH LA English DT Article ID BASEMENT-MEMBRANE; EXTRACELLULAR-MATRIX; INSITU HYBRIDIZATION; ENDOTHELIAL-CELLS; MALIGNANT-CELLS; TUMOR-CELLS; SPARC; LINES; EXPRESSION; TISSUES AB The mechanism underlying the "organ-specific" metastasis of prostate cancer cells to the bane is still poorly understood. It is not clear whether the cells only invade the bone and proliferate there or whether they invade many tissues but survive mainly in the bone ("seed and soil"). Extracts from various organs were used as chemoattractants in the irt vitro chemotaxis and invasion assays, Results show that, in comparison with extracts of other tissues, bone extracts promote a 2- to 4-fold increase in chemotaxis by human prostate epithelial cells and a 4-fold increase in the invasive ability of human prostate carcinoma cells. The purified active factor from bone and from marrow stromal-cell-conditioned medium is a low glycosylated osteonectin that specifically promotes the invasive ability of bone-metastasizing prostate land breast) cancer cells but not that of non-bone-metastasizing tumor cells. It does not stimulate the growth of prostate cancer cells irt vitro or in vivo. Because osteonectin specifically enhances matrix metalloprotease activity in prostate and breast cancer cells land not in other tumor cell types), we conclude that prostate cancer cell metastasis to the bone is, in part, mediated by the ability of osteonectin to promote migration, protease activity, and invasion. C1 NIDR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. Michigan State Univ, Dept Zool, E Lansing, MI 48824 USA. Michigan State Univ, Dept Med, E Lansing, MI 48824 USA. Tel Aviv Univ, Sackler Sch Med, Dept Cell Biol & Histol, IL-69978 Tel Aviv, Israel. RP Kleinman, HK (reprint author), NIDR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bldg 30,Room 433,30 Convent Dr, Bethesda, MD 20892 USA. NR 38 TC 149 Z9 158 U1 0 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 SEP 1 PY 1999 VL 59 IS 17 BP 4453 EP 4457 PG 5 WC Oncology SC Oncology GA 232PY UT WOS:000082380200053 PM 10485497 ER PT J AU Wei, SJC Chang, RL Merkler, KA Gwynne, M Cui, XX Murthy, B Huang, MT Xie, JG Lu, YP Lou, YR Jerina, DM Conney, AH AF Wei, SJC Chang, RL Merkler, KA Gwynne, M Cui, XX Murthy, B Huang, MT Xie, JG Lu, YP Lou, YR Jerina, DM Conney, AH TI Dose-dependent mutation profile in the c-Ha-ras proto-oncogene of skin tumors in mice initiated with benzo[a]pyrene SO CARCINOGENESIS LA English DT Article ID POLYCYCLIC AROMATIC-HYDROCARBONS; GROWTH-FACTOR-ALPHA; GUANINE PHOSPHORIBOSYLTRANSFERASE GENE; POLYMERASE CHAIN-REACTION; HUMAN LYMPHOCYTES-T; HAMSTER V-79 CELLS; MOUSE SKIN; DNA-ADDUCTS; (+)-ANTI-DIOL EPOXIDE; MUTAGENIC SPECIFICITY AB Female CD-1 mice were treated topically with a low (25-50 nmol) or high (800 nmol) dose of benzo[a]pyrene (BP) or acetone vehicle, followed by 5 nmol 12-O-tetradecanoylphorbol 13-acetate (TPA) twice a week for 26 weeks. Selective UV radiation fractionation followed by PCR methods were used to analyze histologically defined subsets of cells (similar to 100-200 cells) on formalin-fixed, paraffin-embedded and H&E stained microscope sections. DNA samples from normal-appearing, hyperplastic or tumor regions from the skin of animals from each treatment group were isolated and amplified by PCR with c-Ha-ras-specific primers. Single-strand conformation polymorphism (SSCP) analyses were performed on both exon 1 and 2 products from each sample. DNA extracted from each aberrant band of SSCP analyses was amplified by PCR for further sequence analysis. The data indicate that c-Ha-ras mutations can be detected in normal-looking and hyperplastic epidermal cells as well as in tumor cells obtained from mice initiated with BP and promoted with TPA, The frequencies of c-Ha-ras mutations for normal-looking, hyperplastic and tumor samples were 3/20 (15%), 8/17 (47%) and 58/68 (85%), respectively, for the low dose group and 8/18 (44%), 10/20 (50%) and 64/86 (74%), respectively, for the high dose group. These observations indicate that there were no dose dependencies in the mutation frequencies for normal-looking, hyperplastic and tumor samples. For combined high dose and low dose samples, differences in mutation frequencies of the c-Ha-ras gene between the normal-looking, hyperplastic and tumor samples were highly significant (P < 0.0001, Fisher's exact test). All mutations detected were located at codons 12, 13 and 61 of the c-Ha-ras gene. With the numbers in parentheses indicating the nucleotide position in the coding sequence of the c-Ha-ras proto-oncogene, the distributions of mutations for G-->A (35), G-->T (35), G-->C (37), G-->T (38), C-->A (181), A-->T (182) and A-->G (182) in the low dose tumors were 5, 2, 11, 74, 0, 7 and 2%, respectively, and the distribution of mutations in tumors from animals treated with a high dose of BP were 3, 7, 13, 61, 15, 1 and 0%, respectively. Differences in the global mutation spectra (site and kind of all mutations) for the c-Ha-ras gene between the high and low dose group tumors were statistically significant (P < 0.004, Fisher's exact test) and the major difference between these two groups was C-->A (181) base substitutions. In summary, our data indicate that: (i) 79% of the BP/TPA skin tumors in CD-1 mice had c-Ha-ras mutations for the combined data for high dose and low dose tumors; (ii) the major mutations detected in BP/TPA skin tumors were G-->T transversions; (iii) the global mutation profile in the c-Ha-ras proto-oncogene in skin tumors obtained after initiation with a low dose of BP was different from that obtained after initiation with a high dose of BP. C1 Rutgers State Univ, Coll Pharm, Dept Biol Chem, Canc Res Lab, Piscataway, NJ 08854 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Wei, SJC (reprint author), Rutgers State Univ, Coll Pharm, Dept Biol Chem, Canc Res Lab, 164 Frelinghuysen Rd, Piscataway, NJ 08854 USA. FU NCI NIH HHS [CA49756] NR 58 TC 23 Z9 24 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD SEP PY 1999 VL 20 IS 9 BP 1689 EP 1696 DI 10.1093/carcin/20.9.1689 PG 8 WC Oncology SC Oncology GA 232RA UT WOS:000082382700005 PM 10469612 ER PT J AU Lunn, RM Bell, DA Mohler, JL Taylor, JA AF Lunn, RM Bell, DA Mohler, JL Taylor, JA TI Prostate cancer risk and polymorphism in 17 hydroxylase (CYP17) and steroid reductase (SRD5A2) SO CARCINOGENESIS LA English DT Article ID ANDROGEN RECEPTOR GENE; VITAMIN-D-RECEPTOR; AFRICAN-AMERICANS; SERUM ANDROGENS; BREAST-CANCER; UNITED-STATES; 5-ALPHA-REDUCTASE; ASSOCIATION; PHENOTYPE; GENOTYPE AB Prostate cancer is the most common malignancy in males and is the second most common cause of cancer mortality in American men, Polymorphisms have been identified in two genes, the 17-hydroxylase cytochrome P450 gene (CYP17) and the steroid 5-reductase type II gene (SRD5A2) that are involved with androgen biosynthesis and metabolism. The CYP17 A2 allele contains a T-->C transition in the 5' promoter region that creates an additional Spl-type (CCACC box) promoter site. The SRD5A2 valine to leucine (V89L) polymorphism has been correlated with lower dihydroxytestosterone levels. We tested genotypes in 108 prostate cases and 167 controls along with samples (n = 340) from several different ethnic groups. The CYP17 A2 allele (combined A1/A2 and A2/A2 genotypes) occurred at a higher frequency in Caucasian patients with prostate cancer (70%) than in Caucasian clinical control urology patients (57%), suggesting that the A2 allele may convey increased risk for prostate cancer [odds ratio (OR) = 1.7, 95% confidence interval (CI) = 1.0-3.0]. Blacks and Caucasians had a similar frequency of the A2 genotype (16 and 17%, respectively) while Taiwanese had the highest frequency (27%), The SRD5A2 leucine genotype was most frequent in Taiwanese (28%), intermediate in Caucasians (8.5%) and lowest in Blacks (2.5%), Genotypes having a SRD5A2 leucine allele were somewhat more common in prostate cancer cases (56%) than in controls (49%) (OR = 1.4, 95% CI = 0.8-2.2) but this difference was not significant. These results support the hypothesis that some allelic variants of genes involved in androgen biosynthesis and metabolism may be associated with prostate cancer risk. C1 NIEHS, Lab Computat Biol & Risk Assessment, Res Triangle Pk, NC 27709 USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dept Surg, Div Urol, Chapel Hill, NC USA. RP Taylor, JA (reprint author), NIEHS, Mol & Genet Epidemiol Sect, POB 12233,Mail Drop A3-05, Res Triangle Pk, NC 27709 USA. OI taylor, jack/0000-0001-5303-6398 NR 36 TC 156 Z9 161 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD SEP PY 1999 VL 20 IS 9 BP 1727 EP 1731 DI 10.1093/carcin/20.9.1727 PG 5 WC Oncology SC Oncology GA 232RA UT WOS:000082382700010 PM 10469617 ER PT J AU Salnikow, K An, WG Melillo, G Blagosklonny, MV Costa, M AF Salnikow, K An, WG Melillo, G Blagosklonny, MV Costa, M TI Nickel-induced transformation shifts the balance between HIF-1 and p53 transcription factors SO CARCINOGENESIS LA English DT Article ID HYPOXIA-INDUCIBLE FACTOR-1; ENDOTHELIAL GROWTH-FACTOR; TUMORIGENIC PHENOTYPE; ERYTHROPOIETIN GENE; FACTOR 1-ALPHA; SOLID TUMORS; CELLS; PROTEIN; EXPRESSION; CARCINOGENESIS AB Nickel (Ni) compounds are potent carcinogens and can induce malignant transformation of rodent and human cells. In an attempt to unravel the molecular mechanisms of Ni-induced transformation we investigated transcriptional activity of hypoxia-inducible factor (HIF-1) and p53 tumor suppressor protein in Ni-transformed cells, We demonstrated that the activity of HIF-1-responsive promoters was increased in Ni-transformed rodent cells resulting in the increased ratio between HIF-1- and p53-stimulated transcription. To further elucidate the roles of HIF-1 and p53 in Ni-induced transformation we used human osteosarcoma (HOS) cells and a Ni-transformed derivative, SA-8 cells. Since non-functional p53 was expressed in both HOS and SA-8 cells, acute Ni treatment induced HIF-1 alpha protein and HIF-1-dependent transcription without affecting p53. In MCF-7 and A549, human cancer cells with the wild-type p53, both functional p53 and HIF-1 alpha proteins accumulated following exposure to Ni, The induction of HIF-1 alpha and wild-type p53 by Ni was detected after 6 h and was most pronounced by 24 h, These results suggest that acute Ni treatment causes accumulation of HIF-1 alpha protein and simultaneous accumulation of wild-type, but not mutant, p53. We suggest that the induction of hypoxia-like conditions in Ni-treated cells with subsequent selection for increased HIF-1-dependent transcription is involved in Ni-induced carcinogenesis. C1 NYU Med Ctr, Nelson Inst Environm Med, New York, NY 10016 USA. NYU Med Ctr, Kaplan Comprehens Canc Ctr, New York, NY 10016 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. RP Salnikow, K (reprint author), NYU Med Ctr, Nelson Inst Environm Med, New York, NY 10016 USA. RI costa, max/H-1754-2012 FU NCI NIH HHS [CA16037]; NIEHS NIH HHS [ES000260, ES05512] NR 45 TC 101 Z9 105 U1 2 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD SEP PY 1999 VL 20 IS 9 BP 1819 EP 1823 DI 10.1093/carcin/20.9.1819 PG 5 WC Oncology SC Oncology GA 232RA UT WOS:000082382700022 PM 10469629 ER PT J AU Kimura, S Kawabe, M Ward, JM Morishima, H Kadlubar, FF Hammons, GJ Fernandez-Salguero, P Gonzalez, FJ AF Kimura, S Kawabe, M Ward, JM Morishima, H Kadlubar, FF Hammons, GJ Fernandez-Salguero, P Gonzalez, FJ TI CYP1A2 is not the primary enzyme responsible for 4-aminobiphenyl-induced hepatocarcinogenesis in mice SO CARCINOGENESIS LA English DT Article ID METABOLIC-ACTIVATION; CYTOCHROME P4501A2; AROMATIC-AMINES; N-OXIDATION; LIVER; 2-AMINO-1-METHYL-6-PHENYLIMIDAZO<4,5-B>PYRIDINE; CARCINOGENESIS; CAFFEINE; ADDUCTS; BIOTRANSFORMATION AB 4-Aminobiphenyl (4-ABP), a potent carcinogen in rodents (liver cancer) and human (bladder cancer), is found as an environmental contaminant and in tobacco smoke. Hemoglobin adducts and lung DNA adducts of 3-ABP are found in tobacco smokers. In vitro metabolism studies with human and rat liver microsomes have shown that CYP1A2 is primarily responsible for catalyzing N-hydroxylation, the initial step in the metabolic activation of 4-ABP, To determine whether this P450 is a rate limiting pathway for hepatocarcinogenesis, CYP1A2-null mice were analyzed at 16 months of age and were compared with wild-type mice in their response to 4-ABP using the neonatal mouse bioassay and two different doses of the carcinogen. Overall differences in incidences of hepatocellular adenoma, carcinoma and preneoplastic foci were not significant between either genotypes or 4-ABP doses used, whereas small, but significant, differences were found for specific types of foci, These results suggest that while CYP1A2 levels may not be rate limiting for 4-ABP metabolism to produce tumors and foci, it may modulate the induction process of some types of liver foci in either a positive or negative manner. In vitro studies using CYP1A2-null and wild-type mouse liver microsomes revealed that CYP1A2 is not the sole P450 required for 4-ABP N-hydroxylation and that another, yet to be identified, P450 is likely to be involved. C1 NCI, Met Lab, NIH, Bethesda, MD 20892 USA. NCI, Vet & Tumor Pathol Sect, Anim Sci Branch, Frederick, MD 21702 USA. Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Kimura, S (reprint author), NCI, Met Lab, NIH, Bldg 37,Room 3E-24, Bethesda, MD 20892 USA. EM shioko@helix.nih.gov OI Fernandez-Salguero, Pedro M./0000-0003-2839-5027 NR 27 TC 53 Z9 54 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD SEP PY 1999 VL 20 IS 9 BP 1825 EP 1830 DI 10.1093/carcin/20.9.1825 PG 6 WC Oncology SC Oncology GA 232RA UT WOS:000082382700023 PM 10469630 ER PT J AU Smaili, SS Russell, JT AF Smaili, SS Russell, JT TI Permeability transition pore regulates both mitochondrial membrane potential and agonist-evoked Ca2+ signals in oligodendrocyte progenitors SO CELL CALCIUM LA English DT Article ID ENDOPLASMIC-RETICULUM; CALCIUM OSCILLATIONS; RELEASE SITES; CELL-DEATH; WAVES; ASTROCYTES; RESPONSES; NEURONS; DEPOLARIZATION; MODULATION AB In this study, we investigated the importance of mitochondrial permeability transition pore (PTP) in agonist-evoked cytosolic Ca2+ ([Ca2+](c)) signals in oligodendrocyte progenitor cells (OP cells). We measured transmembrane potential across the mitochondrial inner membrane (Delta Psi(m)) and [Ca2+](c) in the immediate vicinity simultaneously using tetramethylrhodamine ethyl ester (TMRE) and calcium green respectively. Stimulation of OP cells with methacholine evoked robust [Ca2+](c) signals in approximately 80% of cells which were either oscillatory or showed a peak followed by a plateau. Elevations in [Ca2+](c) induced by supramaximal concentrations of the agonist (> 200 mu M) were accompanied by changes in Delta Psi(m) in 33-42% of the total mitochondria investigated. The mitochondria that responded either depolarized (26-29%), hyperpolarized (7-13%) or showed no change (58-67%). Thus, of the responsive mitochondria, most (70%) depolarized during agonist-evoked [Ca2+](c) signals. Blockade of PTP with cyclosporin A (CSA) reduced the number of mitochondria that depolarized with a corresponding increase in the number that hyperpolarized. In addition, CSA or its analogue methyl valine-4- CSA (MeVal-CSA), reduced the frequency of agonist-evoked global [Ca2+](c) oscillations. In resting cells, CSA (63%) and MeVal-CSA (77%) hyperpolarized a majority of the mitochondria suggesting that PTP is constitutively active and may show flickering openings. Such hyperpolarizations were not mimicked by either cyclosporine H or verapamil and were inhibited by Ru360, which blocks the mitochondrial uniporter. This observation suggested that in resting cells, Ca2+ ions might redistribute between cytosol and mitochondrial matrix through the uniporter and the PTP. Taken together, these data suggest that PTP may play an important role in regulating Delta Psi(m) and local [Ca2+](c) signals during agonist stimulation in OP cells. (C) Harcourt Publishers Ltd 1999. C1 NICHD, Sect Cell Biol & Signal Transduct, LCMN, NIH, Bethesda, MD 20892 USA. Univ Fed Sao Paulo, Dept Farmacol, Sao Paulo, Brazil. RP Smaili, SS (reprint author), NICHD, Sect Cell Biol & Signal Transduct, LCMN, NIH, Bldg 49,Rm 5A78,49 Convent Dr,MSC 4495, Bethesda, MD 20892 USA. NR 52 TC 62 Z9 62 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 0143-4160 J9 CELL CALCIUM JI Cell Calcium PD SEP-OCT PY 1999 VL 26 IS 3-4 BP 121 EP 130 DI 10.1054/ceca.1999.0061 PG 10 WC Cell Biology SC Cell Biology GA 253FU UT WOS:000083546500005 PM 10598276 ER PT J AU Steinert, PM Candi, E Tarcsa, E Marekov, LN Sette, M Paci, M Ciani, B Guerrieri, P Melino, G AF Steinert, PM Candi, E Tarcsa, E Marekov, LN Sette, M Paci, M Ciani, B Guerrieri, P Melino, G TI Transglutaminase crosslinking and structural studies of the human small proline rich 3 protein SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE barrier function; cell envelope; circular dichroism; epithelia; nuclear magnetic resonance; small proline-rich proteins; skin; transglutaminase; cross-linking ID CORNIFIED CELL-ENVELOPE; HUMAN EPIDERMAL-KERATINOCYTES; DIFFERENTIAL EXPRESSION; HELICAL CONFORMATION; SUBSTRATE PROPERTIES; HUMAN LORICRIN; FAMILY; SPECTROSCOPY; EPITHELIA; SEQUENCE AB The cell envelope (CE) is a vital structure for barrier function in terminally differentiated dead stratified squamous epithelia, It is assembled by transglutaminase (TGase) cross-linking of several proteins, including SPR3 in certain specialized epithelia normally subjected to mechanical trauma. We have expressed recombinant human SPR3 in order to study its cross-linking properties, It serves as a complete substrate for, and is cross-linked at similar efficiencies by, the three enzymes (TGases 1, 2 and 3) that are widely expressed in many epithelia, Multiple adjacent glutamines (4, 5, 16, 17, 18, 19 and 167) and lysines (6, 21, 164, 166 and 168) of only head and tail domain sequences are used for cross-linking. However, each enzyme preferentially uses certain residues on the head domain, Moreover, our in vitro data suggest a defined temporal order of cross-linking of SPR3 in vivo: It is first cross-linked by TGase 3 into short intra- and inter-chain oligomers which are later further cross-linked to the CE by TGase 1, To investigate the absence of cross-linking in the central domain (e.g. lysine in position 2 of each of the 16 repeats) we performed structural studies on recombinant SPR3 and on a synthetic peptide containing three repeats of the central domain. 2D H-l NMR spectroscopy, TOCSY and POESY, shows strong and medium intensity NOEs connectivities along the amino acid sequence with one weak long range NOE contact between Thr and Cys of subsequent repeats. Distance geometry computation on the basis of intensities of NOEs found generated 50 compatible structures grouped in three main families differing by the number of H-bonds, These measurements were repeated at different concentrations of trifluoroethanol (TFE) water mixture, an alpha-helical promoting solvent, in order to check the stability of the conformations determined; no changes were observed up to 50% TFE in solution. Also temperature changes did not produce any variation in the POESY spectrum in the same condition as above, The NMR and circular dichroism data strongly indicate the presence of an ordered (not alpha-helix nor beta-sheet) highly flexible structure in the eight amino acids repetitive units of SPR3, confirming the prediction of one possible beta-turn per each repeating unit, Thus, biochemical and biophysical data, strongly support SPR3 to function as a flexible cross-bridging protein to provide tensile strength or rigidity to the CE of the stratified squamous epithelia in which it is expressed. C1 Univ Roma Tor Vergata, IRCCS, Biochem Lab,Ist Dermopat Immacolata, Dept Expt Med & Biochem Sci, I-00133 Rome, Italy. NIAMSD, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Roma Tor Vergata, Dept Chem Sci & Technol, I-00173 Rome, Italy. RP Melino, G (reprint author), Univ Roma Tor Vergata, IRCCS, Biochem Lab,Ist Dermopat Immacolata, Dept Expt Med & Biochem Sci, Room D26-F153,Via Tor Vergata 135, I-00133 Rome, Italy. RI Ciani, Barbara/A-1679-2012 OI Ciani, Barbara/0000-0001-7223-4154 NR 60 TC 36 Z9 36 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD SEP PY 1999 VL 6 IS 9 BP 916 EP 930 DI 10.1038/sj.cdd.4400568 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 242UC UT WOS:000082959200013 PM 10510474 ER PT J AU Lerga, A Crespo, P Berciano, M Delgado, MD Canelles, M Cales, C Richard, C Ceballos, E Gutierrez, P Ajenjo, N Gutkind, S Leon, J AF Lerga, A Crespo, P Berciano, M Delgado, MD Canelles, M Cales, C Richard, C Ceballos, E Gutierrez, P Ajenjo, N Gutkind, S Leon, J TI Regulation of c-Myc and Max in megakaryocytic and monocytic-macrophagic differentiation of K562 cells induced by protein kinase C modifiers: c-Myc is down-regulated but does not inhibit differentiation SO CELL GROWTH & DIFFERENTIATION LA English DT Article ID MYELOID-LEUKEMIA CELLS; INDUCED TERMINAL DIFFERENTIATION; HUMAN ERYTHROLEUKEMIA-CELLS; ERYTHROID-DIFFERENTIATION; GENE-EXPRESSION; DNA-BINDING; NEGATIVE AUTOREGULATION; HEMATOPOIETIC-CELLS; PROLIFERATION; GROWTH AB We have studied the regulation and role of c-Myc and Max in the differentiation pathways induced in K562 cells by 12-O-tetradecanoyl phorbol-13 acetate (TPA) and staurosporine, an activator and inhibitor, respectively, of protein kinase C (PKC), We found that staurosporine induced megakaryocytic differentiation, as revealed by the cellular ultrastructure, platelet formation, and DNA endoreduplicatian. In contrast, TPA induced a differentiated phenotype that more closely resembled that of the monocyte-macrophage lineage. c-myc expression was down-regulated in K562 differentiated by both TPA and staurosporine, whereas max expression did not change in either case. Although PKC enzymatic activity was low in cells terminally differentiated with TPA and staurosporine, inhibition of PKC activity by itself did not induce c-myc down-regulation. We conclude that the c-myc gene is switched off as a consequence of the differentiation process triggered by these drugs in a manner independent from PKC, Ectopic overexpression of c-Myc in K562 cells did not affect the monocytic-macrophagic and megakaryocytic differentiation, indicating that c-Myc suppression is not required for these processes in K562, Similarly, both differentiation pathways were not affected by Max overexpression or by concomitant overexpression of c-Myc and Max. This result is in contrast with the inhibition of erythroid differentiation of K562 exerted by c-Myc, suggesting divergent roles for c-Myc/Max, depending on the differentiation pathway. C1 CSIC, Ctr Invest Biol, Unidad Asociada, Dept Mol Biol,Grp Biol Mol Canc, Santander, Spain. Univ Cantabria, Dept Anat & Biol Celular, Santander, Spain. Hosp Univ Marques de Valdecilla, Hematol Serv, Santander, Spain. Univ Autonoma Madrid, Dept Bioquim, Madrid, Spain. NIDR, NIH, Bethesda, MD 20892 USA. RP Leon, J (reprint author), Fac Med, Dept Mol Biol, Santander 39011, Spain. RI Gutkind, J. Silvio/A-1053-2009; Crespo, Piero/M-3273-2014 OI Crespo, Piero/0000-0003-2825-7783 NR 70 TC 22 Z9 22 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1044-9523 J9 CELL GROWTH DIFFER JI Cell Growth Differ. PD SEP PY 1999 VL 10 IS 9 BP 639 EP 654 PG 16 WC Cell Biology SC Cell Biology GA 240UC UT WOS:000082842800005 PM 10511314 ER PT J AU Moncman, CL Wang, K AF Moncman, CL Wang, K TI Functional dissection of nebulette demonstrates actin binding of nebulin-like repeats and Z-line targeting of SH3 and linker domains SO CELL MOTILITY AND THE CYTOSKELETON LA English DT Article DE green fluorescent protein; cardiac muscle; myofibrillogenesis; nebulin; cytoskeleton ID SKELETAL-MUSCLE SARCOMERE; RANDOM PEPTIDE LIBRARIES; FIBER-LIKE STRUCTURES; STRIATED-MUSCLE; ALPHA-ACTININ; SACCHAROMYCES-CEREVISIAE; MONOCLONAL-ANTIBODIES; NASCENT MYOFIBRILS; CARDIAC MYOCYTES; PTK2 CELLS AB Nebulette, a 107 kDa protein associated with the I-Z-I complex of cardiac myofibrils, may play an important role in the assembly of the Z-line. Determination of the complete primary structure of 1011 residue human fetal nebulette, reveals a four-domain layout similar to skeletal muscle nebulin: a short N-terminal domain, followed by 22 nebulin-like repeats that are Linked to a C-terminal Src homology 3 (SH3) domain via a short linker domain. To elucidate the mechanisms of assembly for nebulette in the Z-line, the complete coding sequence or fusions of nebulette domains with green fluorescent protein (GFP) were expressed in cardiomyocytes and fibroblasts. The complete protein localized to Z-lines in cardiac cells and to dense bodies in nonmuscle cells. The GFP-repeat domain forms bundles that are associated with actin filaments in both cell types and disrupts the microfilament network. In contrast, the GFP-repeat plus linker shows limited interaction with dense bodies in nonmuscle cells and the Z-lines of cardiomyocytes. Interestingly, the tagged linker or SH3 is diffusely distributed in nonmuscle cells, but localizes to the Z-lines in cardiomyocytes. Supporting the cellular localization work, recombinant nebulette fragments bind to actin, tropomyosin, and alpha-actinin in in vitro binding assays. These results suggest the repeat domain contains actin binding functions and that the linker domain may target this interaction to Z-lines and dense bodies. Our data also indicate that the linker and SH3 domains can distinguish between dense bodies and Z-lines, suggesting that the ligands for their interactions are specific to these muscular substructures. (C) 1999 Wiley-Liss. Inc. C1 Univ Texas, Dept Chem & Biochem, Austin, TX 78712 USA. RP Wang, K (reprint author), NIAMSD, Phys Biol Lab, NIH, Bldg 6 Rm 401, Bethesda, MD 20892 USA. FU NIAMS NIH HHS [AR43514] NR 65 TC 43 Z9 44 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0886-1544 J9 CELL MOTIL CYTOSKEL JI Cell Motil. Cytoskeleton PD SEP PY 1999 VL 44 IS 1 BP 1 EP 22 DI 10.1002/(SICI)1097-0169(199909)44:1<1::AID-CM1>3.0.CO;2-8 PG 22 WC Cell Biology SC Cell Biology GA 232DG UT WOS:000082350000001 PM 10470015 ER PT J AU Duesbery, NS Vande Woude, GF AF Duesbery, NS Vande Woude, GF TI Anthrax toxins SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE anthrax; mitogen-activated protein kinases; bacterial pathogens; edema factor; lethal factor ID ACTIVATED PROTEIN-KINASE; DEPENDENT ADENYLATE-CYCLASE; SIGNAL-TRANSDUCTION PATHWAY; GERMINAL VESICLE BREAKDOWN; XENOPUS-OOCYTE MATURATION; MAMMALIAN SOMATIC-CELLS; LETHAL FACTOR GENE; CYCLIC-AMP LEVELS; BACILLUS-ANTHRACIS; MAP-KINASE AB Though its lethal effects were ascribed to an exotoxin almost half a century ago, the pathogenesis of anthrax has yet to be satisfactorily explained. Subsequent work has led to the molecular identification and enzymatic characterization of three proteins that constitute two anthrax toxins. Protective antigen binds an as yet unknown cell receptor and mediates the entry of the other two components to the cytoplasm via the endosomal pathway. Edema factor, so named for its ability to induce edema, is a Ca2+ /calmodulin-dependent adenylate cyclase. Lethal factor, the dominant virulence factor associated with the toxin, proteolytically inactivates mitogen-activated protein kinase kinases, key players in signal transduction. We describe the fascinating work that has led to these discoveries End discuss their relevance to our understanding of the pathogenesis of anthrax. C1 NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. RP Vande Woude, GF (reprint author), NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, POB B, Frederick, MD 21702 USA. OI DUESBERY, NICK/0000-0002-4258-5655 NR 134 TC 53 Z9 58 U1 1 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 SEP PY 1999 VL 55 IS 12 BP 1599 EP 1609 DI 10.1007/s000180050399 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 242YV UT WOS:000082971200010 PM 10526577 ER PT J AU Hackstadt, T Scidmore-Carlson, MA Shaw, EI Fischer, ER AF Hackstadt, T Scidmore-Carlson, MA Shaw, EI Fischer, ER TI The Chlamydia trachomatis IncA protein is required for homotypic vesicle fusion SO CELLULAR MICROBIOLOGY LA English DT Article ID OUTER-MEMBRANE PROTEIN; INCLUSION MEMBRANE; ELECTRON-MICROSCOPY; CULTURED-CELLS; INFECTED-CELLS; HELA-CELLS; HOST-CELLS; PSITTACI; IDENTIFICATION; GENE AB Chlamydiae replicate within an intracellular vacuole, termed an inclusion, that is non-fusogenic with vesicles of the endosomal or lysosomal compartments. Instead, the inclusion appears to intersect an exocytic pathway from which chlamydiae intercept sphingomyelin en route from the Golgi apparatus to the plasma membrane. Chlamydial protein synthesis is required to establish this interaction. In an effort to identify those chlamydial proteins controlling vesicle fusion, we have prepared polyclonal antibodies against several Chlamydia trachomatis inclusion membrane proteins. Microinjection of polyclonal antibodies against three C. trachomatis inclusion membrane proteins, IncA, F and G, into the cytosol of cells infected with C. trachomatis demonstrates reactivity with antigens on the cytoplasmic face of the inclusion membrane, without apparent inhibition of chlamydial multiplication. Microinjection of antibodies against the C. trachomatis IncA protein, however, results in the development of an aberrant multilobed inclusion structure remarkably similar to that of C. psittaci GPIC. These results suggest that the C. trachomatis IncA protein is involved in homotypic vesicle fusion and/or septation of the inclusion membrane that is believed to accompany bacterial cell division in C. psittaci. This proposal is corroborated by the expression of C. trachomatis and C. psittaci IncA in a yeast two-hybrid system to demonstrate C. trachomatis, but not C. psittaci, IncA interactions. Despite the inhibition of homotypic fusion of C. trachomatis inclusions, fusion of sphingomyelin-containing vesicles with the inclusion was not suppressed. C1 NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. NIAID, Microscopy Branch, NIH, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Hackstadt, T (reprint author), NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. NR 37 TC 138 Z9 145 U1 1 U2 9 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 1462-5814 J9 CELL MICROBIOL JI Cell Microbiol. PD SEP PY 1999 VL 1 IS 2 BP 119 EP 130 DI 10.1046/j.1462-5822.1999.00012.x PG 12 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA 343HC UT WOS:000088695100004 PM 11207546 ER PT J AU Merrill, RM Henson, DE Barnes, M AF Merrill, RM Henson, DE Barnes, M TI Conditional survival among patients with carcinoma of the lung SO CHEST LA English DT Article DE annual hazards; conditional survival; lung neoplasms; observed survival; outcome ID CANCER AB Objective: One- and 5-year probabilities of survival or death change once a patient has already survived greater than or equal to 1 year after diagnosis. The current paper reports these probabilities for lung cancer patients according to histologic subtype, stage, and age at diagnosis. Methods: Cumulative observed survival rates were calculated and compared among 95,283 patients with histologically confirmed lung cancer (diagnosed from 1983 to 1992 and followed through 1995) by the life-table method using population-based tumor registries participating in the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute, On the basis of the cumulative survival estimates, we derived the probability of death in the next year, conditioned on having already survived to the start of the year (annual hazards), and the probability of survival conditioned on having already survived greater than or equal to 1 year (conditional survival), These rates were reported according to histologic subtype, stage, and age groups. Results: At the time of diagnosis, annual hazard rates differ greatly among histologic subtypes. However, by 5 years after diagnosis, the rates become similar. Bronchioloalveolar carcinoma displays the lowest annual hazards and small-cell carcinoma displays the highest annual hazards, Stage-age subcategories within histologic subtypes continue to show large differences in annual hazard rates. Five-year conditional survival probabilities are also reported, providing survival information that is consistent to that obtained from the annual hazards. Conclusions: One- and 5-year prognosis for lung cancer patients is influenced by years already survived and histology, stage, and age at diagnosis. Annual hazards and conditional survival provides useful and more relevant information than conventional survival estimates for patients and their physicians. These statistics can be directly obtained from cumulative survival estimates and should be more widely reported. C1 Brigham Young Univ, Dept Hlth Sci, Coll Hlth & Human Performance, Provo, UT 84602 USA. Univ Utah, Coll Med, Dept Family & Prevent Med, Div Epidemiol, Salt Lake City, UT USA. NCI, Div Canc Prevent, Canc Biomarkers Res Grp, Rockville, MD USA. RP Merrill, RM (reprint author), Brigham Young Univ, Dept Hlth Sci, Coll Hlth & Human Performance, 213 RB, Provo, UT 84602 USA. NR 16 TC 74 Z9 78 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 SEP PY 1999 VL 116 IS 3 BP 697 EP 703 DI 10.1378/chest.116.3.697 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 234GJ UT WOS:000082475900020 PM 10492274 ER PT J AU Stewart, GR Boussinesq, M Coulson, T Elson, L Nutman, T Bradley, JE AF Stewart, GR Boussinesq, M Coulson, T Elson, L Nutman, T Bradley, JE TI Onchocerciasis modulates the immune response to mycobacterial antigens SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE Onchocerca volvulus; helminth; mycobacterium; PPD; immune response ID T-CELL CLONES; SCHISTOSOMA-MANSONI; CYTOKINE RESPONSES; PARASITE ANTIGEN; BRUGIA-MALAYI; TUBERCULOSIS; INFECTION; HELMINTH; PROFILES; RESPONSIVENESS AB Chronic helminth infection induces a type-2 cellular immune response. Tn contrast to this, mycobacterial infections commonly induce a type-1 immune response which is considered protective. Type-2 responses and diminished type-1 responses to mycobacteria have been previously correlated with active infection states such as pulmonary tuberculosis and lepromatous leprosy. The present study examines the immune responses of children exposed to both the helminth parasite Onchocerca volvulus and the mycobacterial infections, Mycobacterium tuberculosis and M. leprae. Proliferation of peripheral blood mononuclear cells (PBMC) and production of IL-4 in response to both helminth and mycobacterial antigen (PPD) decreased dramatically with increasing microfilarial (MF) density. Although interferon-gamma (IFN-gamma) production strongly correlated with cellular proliferation, it was surprisingly not related to MF density for either antigen. IL-4 production in response to helminth antigen and PPD increased with ascending children's age. IFN-gamma and cellular proliferation to PPD were not related to age, but in response to helminth antigen were significantly higher in children of age 9-12 years than children of either the younger age group (5-8 years) or the older group (13-16 years). Thus, there was a MF density-related down-regulation of cellular responsiveness and age-related skewing toward type 2 which was paralleled in response to both the helminth antigen and PPD. This parasite-induced immunomodulation of the response to mycobacteria correlates with a previous report of doubled incidence of lepromatous leprosy in onchocerciasis hyperendemic regions. Moreover, this demonstration that helminth infection in humans can modulate the immune response to a concurrent infection or immunological challenge is of critical importance to future vaccination strategies. C1 Univ Salford, Dept Biol Sci, Salford M5 4WT, Lancs, England. Univ London Sch Pharm, Dept Biol, London, England. Imperial Coll Sch Med, London, England. Antenne Orstom Aupres Ctr Pasteur, Yaounde, Cameroon. Zool Soc London, Inst Zool, London NW1 4RY, England. NIAID, NIH, Bethesda, MD 20892 USA. RP Bradley, JE (reprint author), Univ Salford, Dept Biol Sci, Salford M5 4WT, Lancs, England. RI Boussinesq, Michel/J-7256-2016; OI Boussinesq, Michel/0000-0001-6312-0681; Bradley, Janette/0000-0003-3973-7977; Coulson, Tim/0000-0001-9371-9003 NR 40 TC 89 Z9 90 U1 0 U2 4 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0009-9104 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD SEP PY 1999 VL 117 IS 3 BP 517 EP 523 PG 7 WC Immunology SC Immunology GA 237VR UT WOS:000082677700016 PM 10469056 ER PT J AU Pai-Scherf, LH Villa, J Pearson, D Watson, T Liu, E Willingham, MC Pastan, I AF Pai-Scherf, LH Villa, J Pearson, D Watson, T Liu, E Willingham, MC Pastan, I TI Hepatotoxicity in cancer patients receiving erb-38, a recombinant immunotoxin that targets the erbB2 receptor SO CLINICAL CANCER RESEARCH LA English DT Article ID THERAPY; PROTOONCOGENE; STABILIZATION; EXPRESSION; EXOTOXIN AB To exploit overexpression of erbB2 in human cancers, we constructed a single-chain immunotoxin (erb-38) that contains the Fv portion of monoclonal antibody e23 fused to a truncated form of Pseudomonas exotoxin A. In a Phase I study, five breast cancer patients and one esophageal cancer patient received three doses of erb-38 at 1.0 and 2.0 mu g/kg, Hepatotoxicity was observed in all patients. Immunohistochemistry showed the presence of erbB2 on hepatocytes explaining the liver toxicity of erb-38, We suggest that targeting of tumors with antibodies to erbB2 armed with radioisotopes or other toxic agents may result in unexpected organ toxicities due to erbB2 on normal cells. C1 NCI, Mol Biol Lab, NIH, Div Basic Sci, Bethesda, MD 20892 USA. NCI, Lab Mol Signaling & Oncogenesis, NIH, Bethesda, MD 20892 USA. NCI, Med Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. Wake Forest Univ, Dept Pathol, Winston Salem, NC 27157 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, NIH, Div Basic Sci, 37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. NR 15 TC 77 Z9 78 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP PY 1999 VL 5 IS 9 BP 2311 EP 2315 PG 5 WC Oncology SC Oncology GA 236DN UT WOS:000082583100006 PM 10499598 ER PT J AU Bauer, KS Figg, WD Hamilton, JM Jones, EC Premkumar, A Steinberg, SM Dyer, V Linehan, WM Pluda, JM Reed, E AF Bauer, KS Figg, WD Hamilton, JM Jones, EC Premkumar, A Steinberg, SM Dyer, V Linehan, WM Pluda, JM Reed, E TI A pharmacokinetically guided phase II study of carboxyamido-triazole in androgen-independent prostate cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID MEDIATED SIGNAL-TRANSDUCTION; CALCIUM INFLUX INHIBITOR; CELL-LINES; L651582 AB We conducted a Phase II clinical trial of the antiproliferative, antimetastatic, and antiangiogenic agent carboxyamido-triazole (CAI), using pharmacokinetic assessment to guide drug dosing. Fifteen patients who had stage D2 androgen-independent prostate cancer with soft tissue metastases were enrolled. Because CAI previously had been shown to decrease prostate-specific antigen secretion in vitro, this marker was not used to assess disease status. The dose of CAI used in this study was calculated so that plasma steady-state maximum concentrations between 2.0 and 5.0 mu g/ml would be maintained. Following the initial dosage adjustment, 93% (14 of 15) of patients were within the predicted range. Fourteen of 15 patients were evaluable for response. All of the 14 evaluable patients demonstrated progressive disease at similar to 2 months. Twelve patients progressed by computed tomography and or bone scan at 2 months, whereas two patients demonstrated clinical progression at 1.5 and 2 months. One patient was removed from study at 6 weeks due to grade II peripheral neuropathy lasting >1 month. Although no clinical responses were noted, a 27.7% decrease in serum vascular endothelial growth factor concentration was observed. CAI does not possess clinical activity in patients with androgen-independent prostate cancer and soft tissue metastases, Pharmacokinetically guided dosing, although found to be feasible using a Bayesian approach, was not found to be of practical benefit. Although plasma CAI concentrations were maintained within the designated range, grade III toxicity requiring drug discontinuation was still observed. C1 NCI, Med Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Div Clin Sci, NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. NIH, Dept Radiol, Ctr Clin, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Med Branch, Div Clin Sci, NIH, Bldg 10,Room 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 13 TC 46 Z9 46 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP PY 1999 VL 5 IS 9 BP 2324 EP 2329 PG 6 WC Oncology SC Oncology GA 236DN UT WOS:000082583100008 PM 10499600 ER PT J AU Conry, RM Khazaeli, MB Saleh, MN Allen, KO Barlow, DL Moore, SE Craig, D Arani, RB Schlom, J LoBuglio, AF AF Conry, RM Khazaeli, MB Saleh, MN Allen, KO Barlow, DL Moore, SE Craig, D Arani, RB Schlom, J LoBuglio, AF TI Phase I trial of a recombinant vaccinia virus encoding carcinoembryonic antigen in metastatic adenocarcinoma: comparison of intradermal versus subcutaneous administration SO CLINICAL CANCER RESEARCH LA English DT Article ID COSTIMULATORY MOLECULE B7; ANTITUMOR-ACTIVITY; IMMUNE-RESPONSES; GENE; INHIBITION; GENERATION; ADMIXTURE; EPITOPES; CEA AB The principal objectives of this trial were twofold: (a) to examine the safety and relative efficacy of intradermal needle injection versus s.c. jet administration of a carcinoembryonic antigen (CEA)-encoding recombinant vaccinia virus (rV-CEA) over a limited dose range and (b) to evaluate CEA-specific immune responses or antitumor effects induced by rV-CEA vaccination. Patients were randomly as signed to one of two groups, depending upon the technique of vaccine administration, All 20 patients received two doses of 10(7) or 10(8) pfu of rV-CEA at a 4-week interval. Toxicity was limited to modest local inflammation at the inoculation site as well as low-grade fever and increased fatigue, each affecting fewer than 20% of the patients. No evidence of CEA-specific lymphoproliferation, interleukin 2 release, delayed-type hypersensitivity, or antibody response was observed. Thus, the efficacy comparison between the two administration techniques was based upon the induction of immune responses to the vaccinia virus vector. Both techniques induced vaccinia-specific lymphoproliferation, interleukin 2 release, and antibody responses of comparable magnitude and frequency as well as protected 80% of patients against pustule formation following vaccinia scarification, Thus, there is no compelling reason to recommend one administration technique over the other based upon toxicity or efficacy, We have selected s.c. jet injection for subsequent trials of rV-CEA based on the ability to accommodate larger injection volumes, enhanced standardization between clinicians, and avoidance of needles that could transmit the vaccine or blood-borne pathogens to health care workers, We recommend use of 10(8) pfu doses for subsequent trials of recombinant vaccinia virus vaccines based upon the favorable toxicity profile and more consistent local pustule formation indicative of an adequate inoculation of live virus. No objective clinical responses to the rV-CEA vaccine were observed among this population of patients with widely metastatic adenocarcinoma. C1 Univ Alabama, Ctr Comprehens Canc, Birmingham, AL 35294 USA. NCI, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. RP Conry, RM (reprint author), Univ Alabama, Ctr Comprehens Canc, 1824 6th Ave,WTI 263, Birmingham, AL 35294 USA. NR 19 TC 65 Z9 66 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP PY 1999 VL 5 IS 9 BP 2330 EP 2337 PG 8 WC Oncology SC Oncology GA 236DN UT WOS:000082583100009 PM 10499601 ER PT J AU Bergan, RC Reed, E Myers, CE Headlee, D Brawley, O Cho, HK Figg, WD Tompkins, A Linehan, WM Kohler, D Steinberg, SM Blagosklonny, MV AF Bergan, RC Reed, E Myers, CE Headlee, D Brawley, O Cho, HK Figg, WD Tompkins, A Linehan, WM Kohler, D Steinberg, SM Blagosklonny, MV TI A phase II study of high-dose tamoxifen in patients with hormone-refractory prostate cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-BETA; PROTEIN-KINASE-C; FUNCTIONAL LIVING INDEX; FOCAL ADHESION KINASE; CELL-LINES; IN-VITRO; TRANSFORMING GROWTH-FACTOR-BETA-1; METASTATIC CARCINOMA; MALIGNANT GLIOMA; CLINICAL-TRIALS AB Micromolar concentrations of tamoxifen inhibit the activity of protein kinase C and were recently shown to inhibit prostate cancer cell growth in preclinical studies. Because micromolar concentrations can be attained with high-dose therapy, the clinical activity of high-dose tamoxifen was evaluated in patients with metastatic adenocarcinoma of the prostate. Between December 1993 and February 1997, 30 patients with hormone-refractory metastatic adenocarcinoma of the prostate were continuously administered tamoxifen at 160 mg/m(2)/day, Therapy was continued until disease progression. All study patients had failed prior treatment with combined androgen blockade, had castrate levels of testosterone, and were heavily pretreated, having received a median of three prior regimens, The average steady-state plasma concentration of tamoxifen was 2.96 +/- 1.32 mu M (mean +/- SD), Grade 3 neurotoxicity was observed in 29 % of patients and was rapidly reversible and readily managed with dose modification. Otherwise, grade 3 toxicities were rare, One partial response (80% decline in prostate-specific antigen) was observed (3.3%), whereas disease stabilization was observed in six patients (20%), for a combined partial response/stable disease response rate of 23%. Median time to progression was 2.1 months, and median survival time was 10.5 months. High-dose tamoxifen therapy was well tolerated and associated with micromolar concentrations of tamoxifen in human plasma, and it demonstrated activity, albeit limited, in a heavily pretreated patient cohort,vith hormone-refractory prostate cancer. These findings suggest that further investigation of the role of protein kinase C modulation in prostate cancer is warranted. C1 NCI, Med Branch, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Branch, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. Univ Virginia, Dept Med, Charlottesville, VA 22908 USA. RP Bergan, RC (reprint author), Northwestern Univ, Sch Med, Div Hematol Oncol, Olson Pavil 8524,710 N Fairbanks, Chicago, IL 60611 USA. RI Figg Sr, William/M-2411-2016 NR 42 TC 70 Z9 70 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP PY 1999 VL 5 IS 9 BP 2366 EP 2373 PG 8 WC Oncology SC Oncology GA 236DN UT WOS:000082583100014 PM 10499606 ER PT J AU Grem, JL Sorensen, JM Cullen, E Takimoto, CH Steinberg, SM Chen, AP Hamilton, JM Arbuck, SG McAtee, N Lawrence, D Goldspiel, B Johnston, PG Allegra, CJ AF Grem, JL Sorensen, JM Cullen, E Takimoto, CH Steinberg, SM Chen, AP Hamilton, JM Arbuck, SG McAtee, N Lawrence, D Goldspiel, B Johnston, PG Allegra, CJ TI A phase I study of raltitrexed, an antifolate thymidylate synthase inhibitor, in adult patients with advanced solid tumors SO CLINICAL CANCER RESEARCH LA English DT Article ID ADVANCED COLORECTAL-CANCER; FOLYLPOLYGLUTAMATE SYNTHETASE-ACTIVITY; EPITHELIAL OVARIAN-CANCER; ADVANCED BREAST-CANCER; ORAL FOLIC-ACID; N-10-PROPARGYL-5,8-DIDEAZAFOLIC ACID; ZD1694 TOMUDEX; HEPATOCELLULAR-CARCINOMA; ORMAPLATIN TETRAPLATIN; POTENT INHIBITOR AB The purpose of this study was to perform a Phase I trial of raltitrexed, a selective inhibitor of thymidylate synthase, and to determine the pharmacokinetic and toxicity profiles as a function of raltitrexed dose, Fifty patients with advanced solid tumors and good performance status were treated with raltitrexed as a 15-min i.v. infusion every 3 weeks, at doses escalating from 0.6 to 4.5 mg/m(2). Asthenia, neutropenia, and hepatic toxicity were the most common dose-limiting toxicities in this largely pretreated patient population, but they occurred during the initial cycle in only one of nine patients treated with 4.0 mg/m(2) and in two of nine patients treated with 4.5 mg/m2. Only 2 of 13 patients treated with 3.5 mg/m(2) ultimately experienced unacceptable toxicity after three and seven cycles, compared with 42 and 56% of patients receiving 4.0 and 4.5 mg/m(2) after medians of three and two cycles, respectively. The maximum raltitrexed plasma concentration and the area under the plasma concentration-time curve increased in proportion to dose. Raltitrexed clearance was independent of dose and was associated with the estimated creatinine clearance. Asthenia, neutropenia, and hepatic transaminitis were dose-related and tended to occur more frequently when patients received three or more cycles of therapy. A 3-week treatment interval was feasible in the majority of patients at all doses. Although 4.0 mg/m(2) appeared to be a safe starting dose in this pretreated patient population, about half who received two or more courses ultimately experienced dose-limiting toxicity. A dose of 3.5 mg/m(2) was well tolerated in most patients. C1 NCI, Med Branch, Natl Naval Med Ctr, Bethesda, MD 20889 USA. NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. Natl Naval Med Ctr, Dept Radiol, Bethesda, MD 20889 USA. Uniformed Serv Univ Hlth Sci, Dept Radiol & Nucl Med, Bethesda, MD 20889 USA. WG Magnusen Clin Ctr, Dept Pharm, Bethesda, MD 20892 USA. RP Grem, JL (reprint author), NCI, Med Branch, Natl Naval Med Ctr, 8901 Wisconsin Ave,Bldg 8,Room 5101, Bethesda, MD 20889 USA. NR 61 TC 12 Z9 12 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP PY 1999 VL 5 IS 9 BP 2381 EP 2391 PG 11 WC Oncology SC Oncology GA 236DN UT WOS:000082583100016 PM 10499608 ER PT J AU Shapiro, JD Harold, N Takimoto, C Hamilton, JM Vaughn, D Chen, A Steinberg, SM Liewehr, D Allegra, C Monahan, B Lash, A Grollman, F Flemming, D Behan, K Johnston, PG Haller, D Quinn, M Morrison, G Grem, JL AF Shapiro, JD Harold, N Takimoto, C Hamilton, JM Vaughn, D Chen, A Steinberg, SM Liewehr, D Allegra, C Monahan, B Lash, A Grollman, F Flemming, D Behan, K Johnston, PG Haller, D Quinn, M Morrison, G Grem, JL TI A pilot study of interferon alpha-2a, fluorouracil, and leucovorin given with granulocyte-macrophage colony stimulating factor in advanced gastrointestinal adenocarcinoma SO CLINICAL CANCER RESEARCH LA English DT Article ID ADVANCED COLORECTAL-CANCER; THYMIDYLATE SYNTHASE EXPRESSION; COOPERATIVE-ONCOLOGY-GROUP; INFUSION FLUOROURACIL; RANDOMIZED TRIAL; CARCINOMA CELLS; TUMOR RESPONSE; FOLINIC ACID; 5-FLUOROURACIL; CHEMOTHERAPY AB We reported previously that the addition of recombinant Escherichia coli human granulocyte-macrophage colony stimulating factor (GM-CSF) to a 5-fluorouracil (5-FU) and leucovorin (LV) regimen seemed to ameliorate diarrhea and permit increased S-FU dose intensity (J, L. Grem et at, J. Clin, Oncol., 12: 560-568, 1994), We then tested the effect of GM-CSF given with a more toxic regimen of 5-FU/LV/ IFN-alpha (IFN alpha-2a), Thirty-one patients with a good performance status and no prior chemotherapy for systemic disease received IFN alpha-2a (5 MU/m(2) s.c., days 1-7), 5-FU (370 mg/m(2) i.v., days 2-6), LV (500 mg/m(2) i.v., days 2-6), and GM-CSF (Saccharomyces cerevisiae 250 mu g/m(2) s.c,, days 7-18) every 3 weeks. Toxicities and 5-FU dose intensity were compared with that observed in our prior Phase II trial with 5-FU/LV/IFN alpha-2a (J. L. Grem et al., J. Clin. Oncol., 11: 1737-1745, 1993), In comparison with the prior Phase II study, the WBC and granulocyte nadirs in the present trial were significantly higher. When trends in toxicity grades for all cycles were compared, stratifying for 5-FU dose, the incidence and severity of mucositis, skin rash, WBC toxicity, and granulocyte toxicity were significantly lower in the present trial, whereas nausea/vomiting and fatigue were significantly worse. The delivered 5-FU dose intensity for all cycles of therapy appeared to be significantly higher in the present trial. Six of 28 evaluable patients had a partial response (21.4%), and 13 (46%) had stable disease for greater than or equal to 12 weeks. Despite treatment-related toxicity, patient quality of life did not worsen during the study, No correlation was observed between thymidylate synthase content in primary tumor specimens and response, time to treatment failure, or survival The addition of GM-CSF appeared to decrease the severity of leukopenia, granulocytopenia, mucositis, and skin rash when compared with our prior experience with this regimen of 5-FU/LV/IFN alpha-2a, at the cost of greater nausea/vomiting and fatigue. The potential impact of increased 5-FU dose intensity on clinical response, however, remains to be determined. C1 NCI, Med Branch, Natl Naval Med Ctr, Div Clin Sci, Bethesda, MD 20889 USA. Univ Penn, Ctr Canc, Dept Med Oncol, Philadelphia, PA 19104 USA. Natl Naval Med Ctr, Dept Internal Med, Bethesda, MD 20889 USA. NCI, Biostat & Data Management Sect, Off Director, Div Clin Sci, Bethesda, MD 20892 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. Natl Naval Med Ctr, Dept Radiol, Bethesda, MD 20889 USA. RP Grem, JL (reprint author), NCI, Med Branch, Natl Naval Med Ctr, Div Clin Sci, 8901 Wisconsin Ave,Bldg 8,Room 5101, Bethesda, MD 20889 USA. OI Lash, Alex/0000-0003-3787-1590 NR 44 TC 5 Z9 7 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP PY 1999 VL 5 IS 9 BP 2399 EP 2408 PG 10 WC Oncology SC Oncology GA 236DN UT WOS:000082583100018 PM 10499610 ER PT J AU van Golen, KL Davies, S Wu, ZF Wang, YF Bucana, CD Root, H Chandrasekharappa, S Strawderman, M Ethier, SP Merajver, SD AF van Golen, KL Davies, S Wu, ZF Wang, YF Bucana, CD Root, H Chandrasekharappa, S Strawderman, M Ethier, SP Merajver, SD TI A novel putative low-affinity insulin-like growth factor-binding protein, LIBC (lost in inflammatory breast cancer), and RhoC GTPase correlate with the inflammatory breast cancer phenotype SO CLINICAL CANCER RESEARCH LA English DT Article ID MAMMARY EPITHELIAL-CELLS; RNA HYBRIDIZATION TECHNIQUE; EUKARYOTIC MESSENGER-RNA; DIFFERENTIAL DISPLAY; GENE-EXPRESSION; FACTOR RECEPTOR; HUMAN HOMOLOG; CARCINOMA; DISEASE; PROGRESSION AB Inflammatory breast cancer is a rapidly growing, distinct form of locally advanced breast cancer that carries a guarded prognosis. To identify the genes that contribute to this aggressive phenotype, we compared under- and overexpressed sequences in an inflammatory breast tumor cell line with those of actively replicating normal human mammary epithelial cell lines using differential display. Of the 17 transcripts isolated and characterized from these experiments, overexpression of RhoC GTPase and loss of expression of a novel gene on 6q22, LIBC (lost in inflammatory breast cancer), were highly correlated (P < 0.0095 and P < 0.0013, respectively) with the inflammatory phenotype when a panel of archival inflammatory breast cancers was compared with noninflammatory stage III breast cancers by in situ hybridization. This study suggests two new molecular markers specific for inflammatory breast cancer. C1 Univ Michigan, Ctr Canc, Dept Internal Med, Div Hematol & Oncol, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. Univ Texas, MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. RP Merajver, SD (reprint author), Univ Michigan, Ctr Canc, Dept Internal Med, Div Hematol & Oncol, 7217 CCGC,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. FU NCI NIH HHS [5T32 CA09537-16] NR 51 TC 183 Z9 186 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP PY 1999 VL 5 IS 9 BP 2511 EP 2519 PG 9 WC Oncology SC Oncology GA 236DN UT WOS:000082583100035 PM 10499627 ER PT J AU Frucht, H Jensen, RT Dexter, D Yang, WL Xiao, YH AF Frucht, H Jensen, RT Dexter, D Yang, WL Xiao, YH TI Human colon cancer cell proliferation mediated by the M-3 muscarinic cholinergic receptor SO CLINICAL CANCER RESEARCH LA English DT Article ID HUMAN-BREAST CANCER; COLORECTAL-CANCER; ACETYLCHOLINE-RECEPTOR; BINDING-PROPERTIES; GROWTH-REGULATION; EXPRESSION; ACTIVATION; INHIBITOR; AUTOCRINE; CARCINOMA AB We have demonstrated previously cell surface receptors for gastrointestinal peptides on 10 human colon cancer cell lines, Because most of the cells studied bind muscarinic cholinergic agonists, we undertook the determination of the cholinergic receptor subtype expressed by human colon cancer cells, as well as the biological function of these receptors, and more specifically, the effect on cell proliferation. me used radiolabeled ligand binding, PCR, calcium mobilization, and cellular proliferation studies. The present study demonstrates a muscarinic cholinergic receptor having two classes of binding site for carbamylcholine. Analysis demonstrated 2499 +/- 153 binding sites/cell, of which 75% had a high affinity for carbamylcholine (K-d 55 mu M), and 25% had a low affinity (K-d 0.33 mM). N-Methylscopolamine, a receptor antagonist, recognized only one binding site having high affinity (K-d 0.20 nM). The number of muscarinic cholinergic binding sites/cell found on colon cancer cells is 50% of the number of receptors found on guinea pig chief cells in physiological conditions. Specific cholinergic receptor antagonists inhibit binding in the following order of potency: N-methylscopolamine > 4-DAMP much greater than pirenzipine > AFDX116, This order of potency pharmacologically classifies the receptor as an M-3 subtype, Receptor expression, studied by reverse transcription-PCR, correlates with the binding data. Specifically, cell lines that exhibit binding, abundantly expressed the M-3 receptor subtype, whereas cell lines that do not exhibit binding for muscarinic cholinergic agonists did not abundantly express the M, receptor. Agonist activation of the M, receptor on these cells resulted in intracellular calcium mobilization, The dose-response curve of calcium mobilization suggests that there are spare receptors on these cells. Signal transduction can be inhibited by receptor antagonists in the same order of potency in which the binding is inhibited. Exogenous agonist added to the cells in culture induces significant cell proliferation. These results demonstrate a muscarinic cholinergic receptor of the M-3 subtype on human colon cancer cells. This receptor Induces intracellular calcium mobilization and mediates cell proliferation. The data suggest that there are spare receptors present, and that there may be enhanced intracellular signal activation in response to receptor binding. C1 Fox Chase Canc Ctr, Div Oncol Gastroenterol, Philadelphia, PA 19111 USA. NIH, Digest Dis Branch, Bethesda, MD 20892 USA. RP Frucht, H (reprint author), Fox Chase Canc Ctr, Div Oncol Gastroenterol, 7701 Burholme Ave, Philadelphia, PA 19111 USA. FU NCI NIH HHS [CA70335] NR 40 TC 72 Z9 74 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP PY 1999 VL 5 IS 9 BP 2532 EP 2539 PG 8 WC Oncology SC Oncology GA 236DN UT WOS:000082583100038 PM 10499630 ER PT J AU Archer, GE Sampson, JH Lorimer, IAJ McLendon, RE Kuan, CT Friedman, AH Friedman, HS Pastan, IH Bigner, DD AF Archer, GE Sampson, JH Lorimer, IAJ McLendon, RE Kuan, CT Friedman, AH Friedman, HS Pastan, IH Bigner, DD TI Regional treatment of epidermal growth factor receptor vIII-expressing neoplastic meningitis with a single-chain immunotoxin, MR-1 SO CLINICAL CANCER RESEARCH LA English DT Article ID RAT MODEL; CARCINOMATOUS MENINGITIS; RECOMBINANT IMMUNOTOXINS; TUMORS; EGFRVIII; MICE AB The incidence of neoplastic meningitis is on the rise. Neoplastic meningitis can result from a direct seeding of the neuraxis by primary brain tumors or by hematogeneous spread of systemic solid tumors, A frequent genetic alteration in primary brain tumors such as gliomas is an in-frame deletion in the epidermal growth factor receptor (EGFR) gene EGFRvIII, which brings together what were normally distant polypeptide sequences in the intact receptor. A novel glycine is formed at the fusion junction, resulting in a unique and tumor-specific target, By using phage display, we have isolated a single-chain antibody specific for the EGFRvIII mutation and expressed it with a modified form of the Pseudomonas exotoxin to form the immunotoxin MR1scFvPE38KDEL (MR-1). The multiple dose toxicity and therapeutic efficacy of MR-1 immunotoxin were tested in an athymic rat model of neoplastic meningitis. The maximally tolerated doses in non-tumor-bearing rats were three doses of 3 mu g each. For therapeutic studies, the target was a neoplastic meningitis induced by intrathecal inoculation of the EGFRvIII-expressing human glioma U87MG.Delta EGFR. A dose escalation study compared the survival of three equal doses of 1, 2, and 3 mu g of MR-1 immunotoxin with saline or 3 mu g of the control immunotoxin specific for the interleukin 2 receptor, anti-Tac, All animals treated with three doses of saline or 3 mu g of anti-Tac died, with median survival of 7 and 10 days, respectively, There were 75% (six of eight) long-term survivors In the group treated with three doses of 1 mu g and 57% (four of seven) long-term survivors in the groups treated with three doses of either 2 or 3 mu g of MR-1 immunotoxin. None of the MR-1 Immunotoxin-treated groups reached median survival by the termination of the study at 53 days. Therefore, median survival,vas estimated to be >53 days, resulting in an estimated increase in median survival of >657% compared with saline and 430% versus anti-Tac, Compartmental therapy with three doses of 2 mu g of MR-1 immunotoxin is effective in the treatment of EGFRvIII expressing neoplastic meningitis. This dose was found to have no clinical or histopathological effects on non-tumor-bearing animals. MR-1 immunotoxin is, therefore, considered specific and safe within its therapeutic window. Phase I clinical trials for tumors Invading the Intrathecal space that express the EGFRvIII target should be initiated. C1 Duke Univ, Med Ctr, Dept Surg Neurosurg, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Pathol, Preuss Lab Brain Tumor Res, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA. Duke Univ, Med Ctr, Durham, NC 27710 USA. Ottawa Reg Canc Ctr, Ottawa, ON K1H 8L6, Canada. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Bigner, DD (reprint author), Duke Univ, Med Ctr, Dept Pathol, Preuss Lab Brain Tumor Res, Durham, NC 27710 USA. FU NCI NIH HHS [CA11898]; NINDS NIH HHS [NS20023] NR 23 TC 42 Z9 45 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP PY 1999 VL 5 IS 9 BP 2646 EP 2652 PG 7 WC Oncology SC Oncology GA 236DN UT WOS:000082583100052 PM 10499644 ER PT J AU Wu, YY Delgado, RM Sunderland, T Csako, G AF Wu, YY Delgado, RM Sunderland, T Csako, G TI Detection of a deletion polymorphism of the human alpha(2)-macroglobulin gene (A2M-2) by a semi-automated PCR-single-stranded conformational polymorphism method SO CLINICAL CHEMISTRY LA English DT Letter ID BETA-AMYLOID PEPTIDE; ALZHEIMER-DISEASE; FIBRIL FORMATION; PROTEIN; ALPHA-2-MACROGLOBULIN C1 NIMH, Dept Clin Pathol, Warren G Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NIMH, Geriatr Psychol Branch, NIH, Bethesda, MD 20892 USA. RP Csako, G (reprint author), NIMH, Dept Clin Pathol, Warren G Magnuson Clin Ctr, NIH, Bldg 10,Rm 2C-407, Bethesda, MD 20892 USA. NR 11 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD SEP PY 1999 VL 45 IS 9 BP 1572 EP 1573 PG 2 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 232QU UT WOS:000082382100027 PM 10471666 ER PT J AU Irony, I Cutler, GB AF Irony, I Cutler, GB TI Effect of carbenoxolone on the plasma renin activity and hypothalamic-pituitary-adrenal axis in congenital adrenal hyperplasia due to 21-hydroxylase deficiency SO CLINICAL ENDOCRINOLOGY LA English DT Article ID APPARENT MINERALOCORTICOID EXCESS; 11-BETA-HYDROXYSTEROID DEHYDROGENASE; GLUCOCORTICOID RECEPTOR; PERIPHERAL METABOLISM; CORTISOL; LOCALIZATION; TISSUE; RAT; SODIUM AB OBJECTIVE To test the hypothesis that carbenoxolone, an inhibitor of 11 beta-hydroxysteroid dehydrogenase, might augment the ACTH-suppressing and mineralocorticoid activities of hydrocortisone without a corresponding increase in peripheral hydrocortisone effects, we assessed the effects of carbenoxolone in patients with congenital adrenal hyperplasia. DESIGN AND PATIENTS Six patients with classic 21-hydroxylase deficiency (5 salt-losing, 1 nonsalt-losing) were enrolled in this study. The study protocol involved 3 treatment periods (except for patient 3): phase 1, hydrocortisone and fludrocortisone; phase 2, hydrocortisone, fludrocortisone and carbenoxolone; phase 3, hydrocortisone and carbenoxolone. Patient 3 was not treated with fludrocortisone at baseline, so she participated only in phase 1 (hydrocortisone only) and phase 2 (hydrocortisone and carbenoxolone). Hydrocortisone and fludrocortisone dosages were kept the same during the study except for the discontinuation of fludrocortisone during phase 3. MEASUREMENTS Plasma adrenal androgens or their precursors (androstenedione, 17-hydroxyprogesterone, and testosterone, and urine pregnanetriol); plasma cortisol, cortisol-binding globulin, ACTH, apparent cortisol metabolic clearance, 24-h urine 17-hydroxysteroids, and urine free cortisol; mineralocorticoid activity, as measured by plasma renin activity, body weight, plasma potassium, and mean blood pressure; fasting insulin/glucose ratio, protein balance, % eosinophils in peripheral blood, and total urine pyridinoline and deoxypyridinoline; TRH stimulation of TSH and pyridostigmine/GHRH stimulation of growth hormone. RESULTS Compared to phase 1, the addition of carbenoxolone (with or without concurrent fludrocortisone administration) produced statistically significant decreases of 20-50% in mean plasma 17-hydroxyprogesterone, androstenedione, and renin activity. Since carbenoxolone also decreased the apparent metabolic clearance rate of cortisol by 20%, other measures of systemic glucocorticoid activity were examined. Carbenoxolone did not produce a cushingoid appearance or increase body weight, blood pressure, blood glucose or plasma insulin levels. Carbenoxolone also did not suppress stimulated GH levels, but did decrease TRH-stimulated TSH levels by approximately 20% (P < 0.05). CONCLUSION Carbenoxolone can augment the adrenal androgen-suppressing activity of hydrocortisone in patients with 21-hydroxylase deficiency. These observations support the hypothesis that selective inhibition of enzymes that metabolize cortisol may lead to new approaches to improve the treatment of congenital adrenal hyperplasia. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Irony, I (reprint author), Suburban Primary Care Phys, 5225 Pooks Hill Rd 1, Bethesda, MD 20814 USA. NR 27 TC 7 Z9 7 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0300-0664 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD SEP PY 1999 VL 51 IS 3 BP 285 EP 291 DI 10.1046/j.1365-2265.1999.00818.x PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 236WN UT WOS:000082622400006 PM 10469007 ER PT J AU Yamano, S Atkinson, JC Baum, BJ Fox, PC AF Yamano, S Atkinson, JC Baum, BJ Fox, PC TI Salivary gland cytokine expression in NOD and normal BALB/c mice SO CLINICAL IMMUNOLOGY LA English DT Article DE Sjogren's syndrome; NOD mouse; salivary gland; cytokine; autoimmunity ID MESSENGER-RNA EXPRESSION; T-CELL CLONES; TUMOR-NECROSIS-FACTOR; PRIMARY SJOGRENS-SYNDROME; AUTOIMMUNE SIALADENITIS; LYMPHOCYTIC INFILTRATION; FACTOR-ALPHA; MOUSE MODEL; IMMUNE; IMMUNOGLOBULIN AB The autoimmune diabetes-prone nonobese diabetic (NOD) mouse develops a chronic lymphocytic infiltration of endocrine and exocrine glands. The objectives of this study were to characterize the salivary immune infiltration and cytokine expression of NOD mice and compare these findings to those of normal BALB/c mice. A decline in salivary flow rates in NOD mice began between 8 and 12 weeks of age. At this same time lymphocytic foci are detectable in the salivary glands. Lymphocytic infiltration in the salivary glands of NOD mice increased with age and simultaneously salivary function declined. No lymphocytic infiltration was seen in BALB/c salivary tissues. Messenger RNA expression of several inflammatory cytokines, including interleukin-1 beta (IL-1 beta), IL-2, IL-10, interferon-gamma, and tumor necrosis factor-cu was detected in the submandibular glands of both NOD and BALB/c mice by the reverse transcription polymerase chain reaction. IL-4 synthesis was also present in some tissues. Immunohistochemical analysis demonstrated the intense expression of inflammatory cytokines within lymphocytic infiltrates and epithelial cells of all NOD mice. Minimal expression of the same cytokines was detected only occasionally in BALB/c tissues stained in parallel. These results demonstrate cytokine expression in the salivary glands of normal mice and suggest that the overexpression of these inflammatory cytokines is likely involved in the development and progression of the organ-localized autoimmunity in the salivary glands of NOD mice. C1 NIDCR, GTTB, NIH, Bethesda, MD 20892 USA. RP Baum, BJ (reprint author), NIDCR, GTTB, NIH, Bldg 10,Room 1N113,10 Ctr Dr,MSC 1190, Bethesda, MD 20892 USA. OI Yamano, Seiichi/0000-0003-2056-4359 NR 54 TC 57 Z9 59 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD SEP PY 1999 VL 92 IS 3 BP 265 EP 275 DI 10.1006/clim.1999.4759 PG 11 WC Immunology SC Immunology GA 239JB UT WOS:000082764000006 PM 10479531 ER PT J AU Kaplan, JE Janoff, EN Masur, H AF Kaplan, JE Janoff, EN Masur, H TI Do bacterial pneumonia and Pneumocystis carinii pneumonia accelerate progression of human immunodeficiency virus disease? Editorial response SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID IMMUNE ACTIVATION; HIV-1 INFECTION; T-CELLS; PNEUMOCOCCAL DISEASE; UNITED-STATES; AIDS PATIENTS; RISK-FACTORS; REPLICATION; PROPHYLAXIS; LOAD C1 Ctr Dis Control & Prevent, Div AIDS STD, Atlanta, GA 30333 USA. Ctr Dis Control & Prevent, TB Lab Res, Atlanta, GA 30333 USA. Ctr Dis Control & Prevent, Div HIV AIDS Prevent Surveillance & Epidemiol, Atlanta, GA 30333 USA. Univ Minnesota, Sch Med, Div Infect Dis, Minneapolis, MN 55455 USA. Vet Affairs Med Ctr, Minneapolis, MN USA. NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Kaplan, JE (reprint author), Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Mailstop G-29,1600 Clifton Rd, Atlanta, GA 30333 USA. FU NHLBI NIH HHS [HL57880]; NIAID NIH HHS [AI39445] NR 38 TC 7 Z9 7 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP PY 1999 VL 29 IS 3 BP 544 EP 546 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 238GY UT WOS:000082703600013 PM 10530444 ER PT J AU Klion, AD Horton, J Nutman, TB AF Klion, AD Horton, J Nutman, TB TI Albendazole therapy for loiasis refractory to diethylcarbamazine treatment SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID IVERMECTIN TREATMENT; DOUBLE-BLIND; LOA-LOA; FILARIASIS; EFFICACY; TRIAL AB Although diethylcarbamazine is curative in similar to 60% of patients who acquire loiasis as long-term visitors to an endemic area, some individuals continue to have signs and symptoms of infection despite multiple courses of diethylcarbamazine. On the basis of a study of albendazole treatment of loiasis in microfilaremic patients that suggested a macrofilaricidal effect of the drug, we treated three patients who had symptomatic loiasis refractory to more than four courses of diethylcarbamazine with albendazole. At the time of treatment, ail patients had persistent symptoms despite decreasing titers of antifilarial antibodies and normal eosinophil counts. Symptoms resolved in all three patients following albendazole therapy. In one patient, nonspecific symptoms recurred 2 years later, but unlike her symptoms before albendazole therapy, they were not accompanied by the appearance of subcutaneous nodules containing adult worms. The other two patients have been symptom-free in the 8 years after albendazole treatment. In summary, albendazole may be useful for the treatment of loiasis when diethylcarbamazine is ineffective or cannot be used. C1 NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. SmithKline Beecham, Brentford, England. RP Klion, AD (reprint author), NIH, Parasit Dis Lab, Bldg 4,Room 126, Bethesda, MD 20892 USA. OI Klion, Amy/0000-0002-4986-5326 NR 13 TC 16 Z9 16 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP PY 1999 VL 29 IS 3 BP 680 EP 682 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 238GY UT WOS:000082703600036 PM 10530467 ER PT J AU Roberts, RL Roytburd, LA Newman, JD AF Roberts, RL Roytburd, LA Newman, JD TI Puzzle feeders and gum feeders as environmental enrichment for common marmosets SO CONTEMPORARY TOPICS IN LABORATORY ANIMAL SCIENCE LA English DT Article ID JACCHUS AB Common marmosets (Callithrix jacchus jacchus) are highly social New World monkeys that consume a principally gummivorous and insectivorous diet. We examined the efficacy of two types of foraging devices, Puzzle-Feeders(TM) and gum feeders, as environmental enrichment for marmosets housed singly (n = 16) or in sibling (n = 4) and heterosexual (n = 8) pairs. In experiment 1, marmosets were exposed to each of the two types of foraging devices for three hours, once per week for two weeks. Thirty-minute observations were conducted at the beginning and end of each exposure period. Marmosets in all housing conditions experienced significant reductions in the frequency of stereotyped pacing and significantly less time sitting still while exposed to the foraging devices. Marmosets experienced significantly lower levels of feeder use and significantly more time sitting still at the end of the three-hour exposure than at the beginning. Marmosets that were singly or sibling housed used the devices the most and had the largest reductions in time spent sitting still during enrichment, In experiment 2, singly housed marmosets were given two types of gum feeders, a wooden and a Gumabone(TM) gum feeder, each for a week-long period. Thirty-minute observations were conducted three times per week immediately after loading the feeders with fresh gum, The wooden gum feeders were heavily gouged during the week-long exposure, although significantly less use of both types of gum feeders was observed on the third and fifth days. These results indicated that marmosets in variable social housing conditions can benefit from environmental enrichment additional to social housing, and that foraging enrichment promotes increased non-stereotyped movement and decreased pacing in this species. C1 NICHHD, Comparat Ethol Lab, Poolesville, MD 20837 USA. RP Roberts, RL (reprint author), NICHHD, Comparat Ethol Lab, POB 529, Poolesville, MD 20837 USA. NR 9 TC 10 Z9 10 U1 2 U2 8 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1060-0558 J9 CONTEMP TOP LAB ANIM JI Contemp. Top. Lab. Anim. Sci. PD SEP PY 1999 VL 38 IS 5 BP 27 EP 31 PG 5 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 246QA UT WOS:000083174600005 PM 12086412 ER PT J AU Gladwin, MT Slonim, A Landucci, DL Gutierrez, DC Cunnion, RE AF Gladwin, MT Slonim, A Landucci, DL Gutierrez, DC Cunnion, RE TI Cannulation of the internal jugular vein: Is postprocedural chest radiography always necessary? SO CRITICAL CARE MEDICINE LA English DT Article DE central venous catheter; catheterization; radiology; complications; pneumothorax; radiographic decision rule ID CENTRAL VENOUS CATHETERS; MULTICENTER TRIAL; COMPLICATIONS; INJURIES AB Objectives: To determine whether clinical features can be used in a decision rule to prospectively identify a subgroup of internal jugular catheter placements that are correctly positioned and free from mechanical complications, thus obviating the need for routine postprocedural chest radiographs in selected patients. Design: Prospective cohort study. Setting: Tertiary care teaching hospital. Patients: A total of 107 consecutive patients who presented to our catheter service for internal jugular catheter insertion because of clinical indications between November 1995 and April 1996. Exclusion criteria were mechanical ventilation, an altered mental status, an age of <15 years, and a height of <152 cm. interventions. Right or left internal jugular vein catheter placement followed by a postprocedural chest radiograph. Measurements: The operating physician completed a detailed questionnaire for each catheter insertion, designed to detect potential complications and to predict the necessity, or lack of necessity, for a postprocedural chest radiograph. The questionnaire documented patient characteristics, the number of needle passes, difficulty establishing access, operator experience, poor anatomical landmarks, number of previous catheter placements, resistance to wire or catheter advancement, resistance to aspiration of blood or flushing of the catheter ports, sensations in the ear, chest, or arm, and development of signs or symptoms suggestive of pneumothorax. After catheter insertion, chest radiographs were obtained to assess for mechanical complications and malpositioned catheters. Main Results: In 46 cases, the decision rule predicted either a complication or a malposition and, thus, the need for a chest radiograph. In 61 cases, neither was predicted (no chest radiograph was needed). Radiographs confirmed one complication (pneumothorax) and 15 catheter tip malpositions (nine in the right atrium and six in the right axillary vein). Among the 46 cases predicted to have a potential complication or malposition, there were one actual complication (pneumothorax) and six actual malpositions (three axillary vein malpositions and three right atrial malpositions). The positive predictive value of this decision rule is 15%. Among the 61 cases predicted to he free from complications or malpositions and not to require a postprocedural chest radiograph, there were nine unexpected malpositions (three axillary vein malpositions and six right atrial malpositions). The negative predictive value is 85%. The overall sensitivity of the decision rule for detecting complications and malpositions is 44%, and the specificity is 55%. Conclusions:ln experienced hands, internal jugular venous catheterization is a safe procedure. However, the incidence of axillary vein or right atrial catheter malposition is 14%, and clinical factors alone will not reliably identity malpositioned catheters. Chest radiographs are necessary to ensure correct internal jugular catheter position. C1 NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Gladwin, MT (reprint author), NIH, Dept Crit Care Med, Bldg 10,Room 7D43,10 Ctr Dr, Bethesda, MD 20892 USA. NR 18 TC 52 Z9 55 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD SEP PY 1999 VL 27 IS 9 BP 1819 EP 1823 DI 10.1097/00003246-199909000-00019 PG 5 WC Critical Care Medicine SC General & Internal Medicine GA 238VZ UT WOS:000082736300019 PM 10507604 ER PT J AU Danis, M Federman, D Fins, JJ Fox, E Kastenbaum, B Lanken, PN Long, K Lowenstein, E Lynn, J Rouse, F Tulsky, J AF Danis, M Federman, D Fins, JJ Fox, E Kastenbaum, B Lanken, PN Long, K Lowenstein, E Lynn, J Rouse, F Tulsky, J TI Incorporating palliative care into critical care education: Principles, challenges, and opportunities SO CRITICAL CARE MEDICINE LA English DT Article DE intensive care; death; palliative care; medical education; consensus; life-sustaining treatment; cardiopulmonary resuscitation; opportunities; barriers; principles; skills; goals ID HOPELESSLY ILL PATIENTS; LIFE-SUPPORT; PHYSICIANS RESPONSIBILITY; MEDICAL FUTILITY; DECISION-MAKING; MANAGEMENT; WITHDRAWAL; MORTALITY; FAMILY; ETHICS AB Objective: To identify the goals and methods for medical education about end-of-life care in the intensive care unit (ICU). Data Sources and Study Selection: A status report on palliative care, a summary report of recent research on palliative care education, articles in the medical literature on end-of-life care acid critical care, and expert opinion were considered. Data Extraction: A working group, including specialists in critical care, palliative care, medical ethics, consumer advocacy, and communications, was convened at the "Medical Education for Care Near the End of Life National Consensus Conference." A modified nominal group process was used to develop a consensus, Data Synthesis: In the ICU, life and death decisions are often made in a crisis mode or in the face of uncertainty, and may necessitate the withholding and withdrawal of life-supporting technologies. Because critical illness often diminishes the capacity of patients to make decisions, clinicians must often make decisions in conjunction with surrogates, rather than with patients. Discontinuity of care can threaten trusting relationships, and cultural diversity can have a particularly powerful impact on choices for care. In the face of these realities, it is possible and appropriate to give compassionate palliative care to dying patients and their families in the ICU. Conclusions: Teaching care of the dying in the ICU should emphasize the following: a) the goals of care should guide the use of technology; b) understanding of prognostication and treatment withholding and withdrawal is essential; c) effective communication and trusting relationships are crucial to good care; d) cultural differences should be acknowledged and respected; and e) the delivery of excellent palliative care is appropriate and necessary when patients die in the ICU. C1 NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. Cornell Univ, Coll Med, Ithaca, NY 14853 USA. Arizona State Univ, Tempe, AZ 85287 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. George Washington Univ, Ctr Improve Care Dying, Washington, DC 20052 USA. Duke Univ, Med Ctr, Durham, NC 27706 USA. RP Danis, M (reprint author), NIH, Dept Clin Bioeth, Bldg 10,Rm 1C118,MSC 1156, Bethesda, MD 20892 USA. NR 58 TC 95 Z9 99 U1 5 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD SEP PY 1999 VL 27 IS 9 BP 2005 EP 2013 DI 10.1097/00003246-199909000-00047 PG 9 WC Critical Care Medicine SC General & Internal Medicine GA 238VZ UT WOS:000082736300047 PM 10507632 ER PT J AU Nishanian, E AF Nishanian, E TI Can epidural anesthesia change the mortality rate of tetanus? SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE tetanus; epidural; epidural infection; long-term use; sympathetic; hypertension ID NERVOUS-SYSTEM DYSFUNCTION; UNITED-STATES; MANAGEMENT C1 NIH, Bethesda, MD 20892 USA. RP Nishanian, E (reprint author), NIH, Bldg 10,Room 7D43,10 Ctr Dr, Bethesda, MD 20892 USA. NR 15 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD SEP PY 1999 VL 27 IS 9 BP 2025 EP 2026 DI 10.1097/00003246-199909000-00053 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 238VZ UT WOS:000082736300053 PM 10507637 ER PT J AU Richiert, DM Ireland, ME AF Richiert, DM Ireland, ME TI Matrix metalloproteinase secretion is stimulated by TGF-beta in cultured lens epithelial cells SO CURRENT EYE RESEARCH LA English DT Article DE matrix metalloproteinase; transforming growth factor beta (TGF-beta); plasminogen activator; zymography; lens epithelial cells ID GROWTH-FACTOR-BETA; HUMAN PROGELATINASE-A; PLASMINOGEN-ACTIVATOR; MACROMOLECULAR ORGANIZATION; INTERSTITIAL COLLAGENASE; AQUEOUS-HUMOR; EXPRESSION; CAPSULE; LOCALIZATION; INHIBITORS AB Purpose. To determine if TGF-beta regulates the expression of metalloproteinases in chick lens annular pad cells. Methods. The activity of secreted matrix metalloproteinases was examined with gelatin zymography in primary cultures exposed to TGF-beta. Results. Metalloproteinases with electrophoretic mobilities corresponding to MMP2 and MMP9 were tentatively identified. Activated, processed forms of the two metalloproteinases were also observed. Plasminogen activators potentially capable of initiating metalloproteinase cascades were concomitantly elicited. Metalloproteinase secretion was shown to be specific for TGF-beta stimulation and independent of substrate composition. Conclusions. These results indicate that TGF-beta-mediated processes could be responsible for localized lens capsular heterogeneity, establishing a substrate suitable for cell migration or the release of matrix-bound factors which influence the terminal differentiation of lens cells. C1 Wayne State Univ, Sch Med, Dept Cell Biol & Anat, Detroit, MI 48201 USA. RP Richiert, DM (reprint author), NEI, Lab Mechanisms Ocular Dis, NIH, Bldg 6 Room 228, Bethesda, MD 20892 USA. FU NEI NIH HHS [EY09346, EY04068] NR 46 TC 26 Z9 26 U1 0 U2 1 PU SWETS ZEITLINGER PUBLISHERS PI LISSE PA P O BOX 825, 2160 SZ LISSE, NETHERLANDS SN 0271-3683 J9 CURR EYE RES JI Curr. Eye Res. PD SEP PY 1999 VL 19 IS 3 BP 269 EP 275 DI 10.1076/ceyr.19.3.269.5316 PG 7 WC Ophthalmology SC Ophthalmology GA 248BD UT WOS:000083254700011 PM 10487967 ER PT J AU Acampora, D Merlo, GR Paleari, L Zerega, B Postiglione, MP Mantero, S Bober, E Barbieri, O Simeone, A Levi, G AF Acampora, D Merlo, GR Paleari, L Zerega, B Postiglione, MP Mantero, S Bober, E Barbieri, O Simeone, A Levi, G TI Craniofacial, vestibular and bone defects in mice lacking the Distal-less-related gene Dlx5 SO DEVELOPMENT LA English DT Article DE homeobox; Dlx5; gene disruption; craniofacial; inner ear; periosteal bone; mouse ID NEURAL CREST CELLS; MOUSE EMBRYO; INNER-EAR; OSTEOBLAST DIFFERENTIATION; EXPRESSION DEFINES; BRANCHIAL ARCHES; HOMEOBOX GENES; FOREBRAIN; FAMILY; TRANSCRIPTION AB The Dlx5 gene encodes a Distal-less-related DNA-binding homeobox protein first expressed during early embryonic development in anterior regions of the mouse embryo, In later developmental stages, it appears in the branchial arches, the otic and olfactory placodes and their derivatives, in restricted brain regions, in all extending appendages and in all developing bones. We have created a null allele of the mouse Dlx5 gene by replacing exons I and II with the E, coli lacZ gene. Heterozygous mice appear normal. beta-galactosidase activity in Dlx5(+/-) embryos and newborn animals reproduces the known pattern of expression of the gene. Homozygous mutants die shortly after birth with a swollen abdomen. They present a complex phenotype characterised by craniofacial abnormalities affecting derivatives of the first four branchial arches, severe malformations of the vestibular organ, a delayed ossification of the roof of the skull and abnormal osteogenesis. No obvious defect was observed in the patterning of limbs and other appendages. The defects observed in Dlx5(-/-) mutant animals suggest multiple and independent roles of this gene in the patterning of the branchial arches, in the morphogenesis of the vestibular organ and in osteoblast differentiation. C1 CNR, Int Inst Genet & Biophys, I-80125 Naples, Italy. Natl Canc Inst, IST, Adv Biotechnol Ctr, Mol Biol Lab, I-16132 Genoa, Italy. Museum Natl Hist Nat, CNRS, URA 90, Lab Physiol Gen & Comparee, F-75015 Paris, France. Tech Univ Braunschweig, Dept Mol & Cellular Biol, D-38106 Braunschweig, Germany. Univ Genoa, Dept Oncol Genet & Biol, Genoa, Italy. RP Simeone, A (reprint author), CNR, Int Inst Genet & Biophys, Via Marconi 10, I-80125 Naples, Italy. RI Barbieri, Ottavia/E-8768-2011; Levi, Giovanni/B-4416-2013; Acampora, Dario/C-2156-2013; OI Mantero, Stefano/0000-0003-0608-2724 FU Telethon [D.037, D.076] NR 40 TC 278 Z9 284 U1 0 U2 16 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD SEP PY 1999 VL 126 IS 17 BP 3795 EP 3809 PG 15 WC Developmental Biology SC Developmental Biology GA 239WP UT WOS:000082793200008 PM 10433909 ER PT J AU Rankin, T Talbot, P Lee, E Dean, J AF Rankin, T Talbot, P Lee, E Dean, J TI Abnormal zonae pellucidae in mice lacking ZP1 result in early embryonic loss SO DEVELOPMENT LA English DT Article DE zona pellucida; fertility; Zp1 null mutant mice; embryonic loss; pre-implantation development ID SPERM RECEPTOR ACTIVITY; EGG VITELLINE ENVELOPE; STRUCTURAL-ANALYSIS; MOLECULAR-CLONING; ACROSOME REACTION; GENE-EXPRESSION; MONOCLONAL-ANTIBODIES; GAMETE INTERACTIONS; PRECURSOR PROTEIN; XENOPUS-LAEVIS AB All vertebrates have an egg shell that surrounds ovulated eggs and plays critical roles in gamete recognition. This extracellular matrix is known as the zona pellucida in eutherian mammals and consists of three glycoproteins, ZP1, ZP2 and ZP3 in the mouse. To investigate the role of ZP1 in fertilization and early development, we have used targeted mutagenesis in embryonic stem cells to create mouse lines (Zp1(tm/tm)) lacking ZP1. Although a zona pellucida composed of ZP2 and ZP3 was formed around growing Zp1(tm/tm) oocytes, the matrix was more loosely organized than zonae around normal oocytes. In some Zp1 null follicles, this structural abnormality resulted in ectopic clusters of granulosa cells, lodged between the zona matrix and the oolemma, that perturbed normal folliculogenesis, Comparable numbers of eggs were ovulated from Zp1 null females and normal females following hormonal stimulation. However, after mating with males, fewer two-cell embryos were recovered from Zp1 null females, and their litters were significantly smaller than those produced by normal mice. Therefore, although mouse ZP1 is not essential for sperm binding or fertilization, it is required for the structural integrity of the zona pellucida to minimize precocious hatching and reduced fecundity. C1 NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. NICHD, Lab Mammalian Genes, NIH, Bethesda, MD 20892 USA. RP Rankin, T (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. NR 59 TC 137 Z9 145 U1 0 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD SEP PY 1999 VL 126 IS 17 BP 3847 EP 3855 PG 9 WC Developmental Biology SC Developmental Biology GA 239WP UT WOS:000082793200012 PM 10433913 ER PT J AU Mozer, BA Easwarachandran, K AF Mozer, BA Easwarachandran, K TI Pattern formation in the absence of cell proliferation: Tissue-specific regulation of cell cycle progression by string (stg) during Drosophila eye development SO DEVELOPMENTAL BIOLOGY LA English DT Article DE eye development; cell cycle; string (stg); cdc25; Drop (Dr); Drosophila ID CDC25 MITOTIC INDUCER; MORPHOGENETIC FURROW; PRONEURAL CLUSTERS; CDK REGULATION; FISSION YEAST; DNA-DAMAGE; S-PHASE; MITOSIS; RETINA; GENE AB During Drosophila eye development, the posterior-to-anterior movement of the morphogenetic furrow coordinates cell cycle progression with the early events of pattern formation. The cdc25 phosphatase string (stg) has been proposed to contribute to the synchronization of retinal precursors anterior to the furrow by driving cells in G(2) through mitosis and into a subsequent G(1). Genetic and molecular analysis of Drop (Dr) mutations suggests that they represent novel cis-regulatory alleles of stg that inactivate expression in eye. Retinal precursors anterior to the furrow lacking stg arrest in G(2) and fail to enter mitosis, while cells within the furrow accumulate high levels of cyclins A and B. Although G(2)-arrested cells initiate normal pattern formation, the absence of sfg results in retinal patterning defects due to the recruitment of extra photoreceptor cells. These results demonstrate a requirement for stg in cell cycle regulation and cell fate determination during eye development. C1 NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Mozer, BA (reprint author), NINDS, Mol Biol Lab, NIH, Bldg 36,Room 3D02, Bethesda, MD 20892 USA. NR 63 TC 13 Z9 13 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD SEP 1 PY 1999 VL 213 IS 1 BP 54 EP 69 DI 10.1006/dbio.1999.9350 PG 16 WC Developmental Biology SC Developmental Biology GA 233HR UT WOS:000082421900004 PM 10452846 ER PT J AU Ceccarelli, E McGrew, MJ Nguyen, T Grieshammer, U Horgan, D Hughes, SH Rosenthal, N AF Ceccarelli, E McGrew, MJ Nguyen, T Grieshammer, U Horgan, D Hughes, SH Rosenthal, N TI An E box comprises a positional sensor for regional differences in skeletal muscle gene expression and methylation SO DEVELOPMENTAL BIOLOGY LA English DT Article ID LIGHT-CHAIN GENE; ROSTROCAUDAL POSITION; TRANSGENE EXPRESSION; CARDIAC-MUSCLE; MLC1/3 LOCUS; DNA-BINDING; ENHANCER; ELEMENTS; TRANSCRIPTION; GRADIENT AB To dissect the molecular mechanisms conferring positional information in skeletal muscles, we characterized the control elements responsible for the positionally restricted expression patterns of a muscle-specific transgene reporter, driven by regulatory sequences from the MLC1/3 locus. These sequences have previously been shown to generate graded transgene expression in the segmented axial muscles and their myotomal precursors, fortuitously marking their positional address. An evolutionarily conserved E box in the MLC enhancer core, not recognized by MyoD, is a target for a nuclear protein complex, present in a variety of tissues, which includes Hox proteins and Zbu1, a DNA-binding member of the SW12/SNF2 gene family. Mutation of this E box in the MLC enhancer has only a modest positive effect on linked CAT gene expression in transfected muscle cells, but when introduced into transgenic mice the same mutation elevates CAT transgene expression in skeletal muscles, specifically releasing the rostral restriction on MLC-CAT transgene expression in the segmented axial musculature. Increased transgene activity resulting from the E box mutation in the MLC enhancer correlates with reduced DNA methylation of the distal transgenic MLC1 promoter as well as in the enhancer itself. These results identify an E box and the proteins that bind to it as a positional sensor responsible for regional differences in axial skeletal muscle gene expression and accessibility. (C) 1999 Academic Press. C1 Massachusetts Gen Hosp E, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. NCI, Frederick Canc Res Program, ABL Basic Res Program, Frederick, MD 21702 USA. RP Rosenthal, N (reprint author), Massachusetts Gen Hosp E, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. FU NCI NIH HHS [N01-CO-74101]; NIAMS NIH HHS [R01AR41926] NR 41 TC 23 Z9 26 U1 0 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD SEP 1 PY 1999 VL 213 IS 1 BP 217 EP 229 DI 10.1006/dbio.1999.9345 PG 13 WC Developmental Biology SC Developmental Biology GA 233HR UT WOS:000082421900017 PM 10452859 ER PT J AU Schmidt, LA Fox, NA Schulkin, J Gold, PW AF Schmidt, LA Fox, NA Schulkin, J Gold, PW TI Behavioral and psychophysiological correlates of self-presentation in temperamentally shy children SO DEVELOPMENTAL PSYCHOBIOLOGY LA English DT Article; Proceedings Paper CT 1997 Biennial Meeting of the Society-of-Research-in-Child-Development CY MAR-APR -, 1997 CL WASHINGTON, D.C. SP Soc Res Child Dev DE cardiac vagal tone; children; frontal EEG activity; heart rate; salivary cortisol; self-presentation; shyness; startle eyeblink response ID FEAR-POTENTIATED STARTLE; AMYGDALA CENTRAL NUCLEUS; FRONTAL ACTIVATION; CONDITIONED FEAR; ACOUSTIC STARTLE; ADULTS SHYNESS; YOUNG-ADULTS; EMOTION; RESPONSES; ASYMMETRY AB We examined temporal changes in behavior, regional brain electrical activity (EEG), heart rate, cardiac vagal tone, the startle eyeblink response, and salivary cortisol during a task designed to elicit self-presentation anxiety in a group of 7-year-olds, some of whom were classified as temperamentally shy. We found that temperamentally shy children displayed a significantly greater increase in anxious behavior, a greater increase in right, but not left frontal EEG activity, and a greater increase in heart rate as the task became more demanding compared with their nonshy counterparts. However, the results failed to reveal any significant group differences on the startle eyeblink and salivary cortisol measures. The present findings extend our prior work, in which we found distinct patterns of psychophysiological activity on baseline measures, to differences on psychophysiological measures collected concurrently during a socially evaluative situation in temperamentally shy children. (C) 1999 John Wiley & Sons, Inc. C1 McMaster Univ, Dept Psychol, Hamilton, ON L8S 4K1, Canada. Univ Maryland, Inst Child Study, College Pk, MD 20742 USA. NIMH, Clin Neuroendocrinol Branch, Behav Neurosci Unit, Bethesda, MD 20892 USA. NIMH, Clin Neuroendocrinol Branch, Neuroendocrine Immunol & Behav Unit, Bethesda, MD 20892 USA. RP Schmidt, LA (reprint author), McMaster Univ, Dept Psychol, Hamilton, ON L8S 4K1, Canada. FU NICHD NIH HHS [HD 17899] NR 67 TC 111 Z9 113 U1 5 U2 16 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0012-1630 J9 DEV PSYCHOBIOL JI Dev. Psychobiol. PD SEP PY 1999 VL 35 IS 2 BP 119 EP 135 DI 10.1002/(SICI)1098-2302(199909)35:2<119::AID-DEV5>3.3.CO;2-7 PG 17 WC Developmental Biology; Psychology SC Developmental Biology; Psychology GA 231ZX UT WOS:000082342200005 PM 10461126 ER PT J AU Young, SK Fox, NA Zahn-Waxler, C AF Young, SK Fox, NA Zahn-Waxler, C TI The relations between temperament and empathy in 2-year-olds SO DEVELOPMENTAL PSYCHOLOGY LA English DT Article ID PRESCHOOL-CHILDREN; BEHAVIOR; DISTRESS; SHYNESS; INFANT; SOCIABILITY; REACTIVITY; ORIGINS; NEWBORN AB The role of infant and toddler temperament in the prediction of empathy in 2-year-old children was examined. Assessments of temperament included reactivity and affect observed at 4 months of age, as well as inhibition at Age 2. Empathy was measured in 2-year-old children's responses to simulations of distress performed by their mothers and by an unfamiliar person. Children showed relatively more concern for the mother's distress, but they were also responsive to unfamiliar victims. Infants who were unreactive and showed little affect also showed less empathy toward the unfamiliar adult almost 2 years later. Inhibition toward an unfamiliar adult (but not toward the mother) at 2 years of age was negatively related to empathy. Inhibited temperament may thus have a major impact on young children's empathy in unfamiliar contexts. Findings also highlight the need to consider early underarousal as another dimension of temperament that may dampen expressions of empathic concern. C1 Univ Maryland, Inst Child Study, College Pk, MD 20742 USA. NIMH, Bethesda, MD 20892 USA. RP Fox, NA (reprint author), Univ Maryland, Inst Child Study, College Pk, MD 20742 USA. FU NICHD NIH HHS [HD 17899] NR 43 TC 74 Z9 75 U1 2 U2 19 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0012-1649 J9 DEV PSYCHOL JI Dev. Psychol. PD SEP PY 1999 VL 35 IS 5 BP 1189 EP 1197 DI 10.1037//0012-1649.35.5.1189 PG 9 WC Psychology, Developmental SC Psychology GA 233HT UT WOS:000082422000002 PM 10493645 ER PT J AU Appelbaum, M Batten, DA Belsky, J Booth, C Bradley, R Brownell, CA Burchinal, M Caldwell, B Campbell, SB Clarke-Stewart, A Cox, M Friedman, SL Hirsh-Pasek, K Huston, A Knoke, B Marshall, N McCartney, K O'Brien, M Owen, MT Phillips, D Pianta, R Spieker, S Vandell, DL Weinraub, M AF Appelbaum, M Batten, DA Belsky, J Booth, C Bradley, R Brownell, CA Burchinal, M Caldwell, B Campbell, SB Clarke-Stewart, A Cox, M Friedman, SL Hirsh-Pasek, K Huston, A Knoke, B Marshall, N McCartney, K O'Brien, M Owen, MT Phillips, D Pianta, R Spieker, S Vandell, DL Weinraub, M CA NICHD Early Child Care Res Network TI Chronicity of maternal depressive symptoms, maternal sensitivity, and child functioning at 36 months SO DEVELOPMENTAL PSYCHOLOGY LA English DT Article ID POSTNATAL DEPRESSION; INFANT ATTACHMENT; YOUNG-CHILDREN; MOTHERS; COMPETENCE; IMPACT; 2-YEAR-OLDS; 3-YEAR-OLDS; STRATEGIES; DISTRESS AB Women (N = 1,215) and their infants were followed from birth, and maternal reports of depressive symptoms were obtained at 1, 6, 15, 24, and 36 months. Women who never reported symptoms of depression were compared with those who reported symptoms sometimes or chronically. Women with chronic symptoms of depression were the least sensitive when observed playing with their children from infancy through 36 months. Children whose mothers reported feeling depressed performed more poorly on measures of cognitive-Linguistic functioning and were rated as less cooperative and more problematic at 36 months. Depression-group differences in school readiness and verbal comprehension were accounted for by maternal sensitivity.; Depression-group differences in expressive language and ratings of cooperation were moderated by maternal sensitivity; maternal sensitivity predicted better outcomes more noticeably among children whose mothers reported feeling depressed. C1 NICHD, Publ Informat & Commun Branch, Bethesda, MD 20892 USA. Vanderbilt Univ, Bowling Green, KY 42101 USA. Penn State Univ, University Pk, PA 16802 USA. Univ Washington, Seattle, WA 98195 USA. Univ Arkansas, Little Rock, AR 72204 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Univ Calif Irvine, Irvine, CA 92717 USA. Univ N Carolina, Chapel Hill, NC 27514 USA. Temple Univ, Philadelphia, PA 19122 USA. Univ Texas, Austin, TX 78712 USA. Wellesley Coll, Wellesley, MA 02181 USA. Univ New Hampshire, Durham, NH 03824 USA. Univ Kansas, Lawrence, KS 66045 USA. Univ Texas, Dallas, TX 75230 USA. Univ Wisconsin, Madison, WI 53706 USA. RP Appelbaum, M (reprint author), NICHD, Publ Informat & Commun Branch, Bldg 31,2A32,31 Ctr Dr,MSC 2425, Bethesda, MD 20892 USA. RI Marshall, Nancy/C-3428-2012 NR 55 TC 273 Z9 275 U1 7 U2 39 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0012-1649 J9 DEV PSYCHOL JI Dev. Psychol. PD SEP PY 1999 VL 35 IS 5 BP 1297 EP 1310 PG 14 WC Psychology, Developmental SC Psychology GA 233HT UT WOS:000082422000012 ER PT J AU Chae, HZ Kim, HJ Kang, SW Rhee, SG AF Chae, HZ Kim, HJ Kang, SW Rhee, SG TI Characterization of three isoforms of mammalian peroxiredoxin that reduce peroxides in the presence of thioredoxin SO DIABETES RESEARCH AND CLINICAL PRACTICE LA English DT Article; Proceedings Paper CT 1st International Symposium on Free Radicals and Vascular Biology of Diabetes CY SEP 20-21, 1997 CL SEOUL, SOUTH KOREA DE antioxidant enzyme; thioredoxin-dependent peroxidase; peroxiredoxin; hydrogen peroxide; mitochondria ID ALKYL HYDROPEROXIDE REDUCTASE; THIOL-SPECIFIC ANTIOXIDANT; MOUSE OSTEOBLASTIC CELLS; NECROSIS-FACTOR-ALPHA; HYDROGEN-PEROXIDE; TRANSFORMING GROWTH-FACTOR-BETA-1; SACCHAROMYCES-CEREVISIAE; GLUTATHIONE-PEROXIDASE; SALMONELLA-TYPHIMURIUM; SIGNAL-TRANSDUCTION AB A peroxidase from yeast that reduces H2O2 with the use of electrons provided by thioredoxin (Trx) together with homologs from a wide variety of species constitute the peroxiredoxin (Prx) family of proteins. Twelve mammalian Prx members have been previously identified in association with various cellular functions apparently unrelated to peroxidase activity. These mammalian proteins have now been divided into three distinct types, Prx I, II, and III, on the basis of their deduced amino acid sequences and immunological reactivity. With the use of recombinant proteins, Prx I, II, and III have now been shown to possess peroxidase activity and to rely on Tm as a source of reducing equivalents. None of the three proteins exhibited peroxidase activity in the presence of glutaredoxin. All three enzymes showed similar kinetic properties: the V-max was 6-13 mu mol/min per mg at 37 degrees C, the K-m for Trx was 3-6 mu M, and the K-m for H2O2 was < 20 mu M. Immunoblot analysis of various rat tissues and cultured cells indicated that most cell types contain the three Prx isoforms, the sum of which amounts to similar to 1-10 mu g per milligram of soluble protein. Pm. I and II are cytosolic proteins, whereas Pm. III is localized in mitochondria. These results suggest that, together with glutathione peroxidase and catalase, Prx enzymes likely play an important role in eliminating peroxides generated during metabolism as well as during stimulation of cell surface receptors. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. Chonnam Natl Univ, Coll Sci, Dept Biol, Kwangju 500757, South Korea. Yonsei Univ, Sch Med, Young Dong Hosp, Dept Internal Med,Pulm Branch, Seoul 14692, South Korea. RP Rhee, SG (reprint author), NHLBI, Lab Cell Signaling, NIH, Bldg 3,Room 122, Bethesda, MD 20892 USA. NR 42 TC 227 Z9 242 U1 1 U2 18 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0168-8227 J9 DIABETES RES CLIN PR JI Diabetes Res. Clin. Pract. PD SEP PY 1999 VL 45 IS 2-3 BP 101 EP 112 DI 10.1016/S0168-8227(99)00037-6 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 240KY UT WOS:000082826200004 PM 10588361 ER PT J AU Huang, SN Fischer, SH O'Shaughnessy, E Gill, VJ Masur, H Kovacs, JA AF Huang, SN Fischer, SH O'Shaughnessy, E Gill, VJ Masur, H Kovacs, JA TI Development of a PCR assay for diagnosis of Pneumocystis carinii pneumonia based on amplification of the multicopy major surface glycoprotein gene family SO DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE LA English DT Article; Proceedings Paper CT 36th Annual Meeting of the Infectious-Diseases-Society-of-America CY NOV 12-15, 1998 CL DENVER, COLORADO SP Infectious Dis Soc Amer ID POLYMERASE CHAIN-REACTION; DNA AMPLIFICATION; RESPIRATORY SPECIMENS; SPUTUM SAMPLES; RIBOSOMAL-RNA; INFECTION; PRODUCTS AB We have evaluate a PCR technique using primers based on Pneumocystis carinii major surface glycoprotein (MSG) genes, a multicopy gene family, for utility in detection of P. carinii in BAL and oropharyngeal samples obtained from immunosuppressed patients. These primers were able to detect P. carinii DNA in as little as 16 fg of genomic DNA. PCR using MSG primers detected P. carinii DNA in 7 smear-positive BAL samples (100% sensitivity, and found no P. carinii DNA in 12 smear-negative BAL samples (100% specificity. Mitochondrial ribosomal RNA (mrRNA)primers, commonly used in PCR studies of PCP, defected P. carinii in six of seven positive samples (85.7% sensitivity) and none of 12 were negative samples (100% specificity). Diagnosis of PCP by amplification of 81 oropharyngeal samples using MSG primers had a 50% sensitivity (4/8) and 96% specificity (70/73). PCR with mrRNA primers was 37.5% sensitive (3/8) and 100% specific (73/73). All three false positive MSG results showed a very low intensity on Southern hybridization. PCR using MSG gene primers should prove valuable in the diagnosis of PCP. (C) 1999 Elsevier Science Inc. C1 NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Clin Pathol, Microbiol Serv, Bethesda, MD 20892 USA. RP Kovacs, JA (reprint author), Bldg 10,Room 7D43,MSC 1662, Bethesda, MD 20892 USA. NR 28 TC 28 Z9 30 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0732-8893 J9 DIAGN MICR INFEC DIS JI Diagn. Microbiol. Infect. Dis. PD SEP PY 1999 VL 35 IS 1 BP 27 EP 32 DI 10.1016/S0732-8893(99)00050-4 PG 6 WC Infectious Diseases; Microbiology SC Infectious Diseases; Microbiology GA 240LA UT WOS:000082826400005 PM 10529878 ER PT J AU Eissele, R Anlauf, M Schafer, MKH Eiden, LE Arnold, R Weihe, E AF Eissele, R Anlauf, M Schafer, MKH Eiden, LE Arnold, R Weihe, E TI Expression of vesicular monoamine transporters in endocrine hyperplasia and endocrine tumors of the oxyntic stomach SO DIGESTION LA English DT Article DE vesicular monoamine transporter; chronic atrophic gastritis; Zollinger-Ellison syndrome; gastric carcinoid; neuroendocrine carcinoma ID ZOLLINGER-ELLISON SYNDROME; GASTRIC CARCINOID-TUMORS; CELL HYPERPLASIA; RAT STOMACH; ECL CELLS; HISTAMINE TRANSPORTER; PERNICIOUS-ANEMIA; AMINE TRANSPORTER; NERVOUS-SYSTEM; ACHLORHYDRIA AB Background: Gastric enterochromaffin-like (ECL) cells selectively express the vesicular monoamine transporter (VMAT) VMAT2, and enterochromaffin (EC) cells the VMAT1 isoform. Aims: We investigated whether VMAT isoform selection indicates the origin of endocrine hyperplasia and neoplasia from oxyntic ECL or EC cells and may be of prognostic significance in different types of gastric carcinoids. Methods: Tissue from patients with chronic atrophic gastritis (CAG), Zollinger-Ellison-syndrome (ZES), gastric carcinoids and neuroendocrine carcinoma (NEC) was investigated by immunohistology and in situ hybridization. Results: Endocrine cells forming diffuse, linear, and micronodular hyperplasia in CAG and ZES, as well as oxyntic microcarcinoids expressed both VMAT2 and chromogranin A (CgA) but neither VMAT1 nor serotonin. In five of six sporadic carcinoids VMAT2 and CgA but not VMAT1 were detected. One carcinoid was copositive for VMAT1 and serotonin but negative for VMAT2. Electron microscopy confirmed the VMAT2-positive tumors as ECLoma and the VMAT1 -immunoreactive carcinoid as EComa. Conclusions: VMAT2 and VMAT1 are reliable markers for differentiation of gastric endocrine hyperplasia and neoplasia from ECL and EC cells, respectively. The significance of VMAT2 and VMAT1 as prognostic markers lies in the relatively poor prognosis for EComa compared to ECLoma, characterized by VMAT2 positivity. The absence of both VMAT2 and VMAT1 in NEC may indicate poor prognosis. C1 Univ Marburg, Dept Mol Neuroimmunol, Inst Anat & Cell Biol, D-35033 Marburg, Germany. Univ Marburg, Dept Gastroenterol & Endocrinol, D-35033 Marburg, Germany. NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. RP Weihe, E (reprint author), Univ Marburg, Dept Mol Neuroimmunol, Inst Anat & Cell Biol, D-35033 Marburg, Germany. OI Eiden, Lee/0000-0001-7524-944X NR 50 TC 43 Z9 44 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0012-2823 J9 DIGESTION JI Digestion PD SEP-OCT PY 1999 VL 60 IS 5 BP 428 EP 439 DI 10.1159/000007688 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 233VN UT WOS:000082459900003 PM 10473967 ER PT J AU Vonderhaar, BK AF Vonderhaar, BK TI Prolactin involvement in breast cancer SO ENDOCRINE-RELATED CANCER LA English DT Review ID PROTEIN-KINASE-C; MOUSE MAMMARY-GLAND; RAT LYMPHOMA-CELLS; CAPILLARY ENDOTHELIAL-CELLS; MESSENGER-RIBONUCLEIC-ACID; POLYMERASE CHAIN-REACTION; FIBROBLAST GROWTH-FACTOR; REGULATORY FACTOR-I; ATHYMIC NUDE-MICE; SIGNAL-TRANSDUCTION AB Normal development and differentiation of the mammary gland are profoundly influenced by prolactin (PRL). In rodent mammary cancer PRL plays a well defined role, but its role in human breast cancer has not been appreciated until recently. It is now clear that breast tissue, both normal and malignant, is a significant source of extrapituitary PRL. Thus an autocrine/paracrine role of PRL in human breast cancer may be invoked. Both PRL and PRL receptor mRNA are expressed in the vast majority of breast cancer biopsies independent of estrogen and progesterone receptor status, An autocrine/paracrine PRL acting in human breast cancer requires that this hormone's action be blocked at the cellular level, as opposed to suppressing the synthesis and secretion of pituitary PRL. Mutants of PRL or human growth hormone are being explored which act as selective PRL antagonists. In addition, tamoxifen has been shown to act locally at the target tissue by binding directly to the PRL receptor and thus inhibiting PRL's action. These strategies may have clinical relevance in treating PRL-responsive human breast cancer. C1 NCI, Mol & Cellular Endocrinol Sect, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. RP Vonderhaar, BK (reprint author), NCI, Mol & Cellular Endocrinol Sect, Tumor Immunol & Biol Lab, NIH, 10 Ctr Dr,Bldg 10,Room 5B47, Bethesda, MD 20892 USA. NR 158 TC 104 Z9 107 U1 1 U2 1 PU SOC ENDOCRINOLOGY PI BRISTOL PA 17/18 THE COURTYARD, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4NQ, ENGLAND SN 1351-0088 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD SEP PY 1999 VL 6 IS 3 BP 389 EP 404 DI 10.1677/erc.0.0060389 PG 16 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 234CA UT WOS:000082465600004 PM 10516853 ER PT J AU Fairey, ER Edmunds, JSG Deamer-Melia, NJ Glasgow, H Johnson, FM Moeller, PR Burkholder, JM Ramsdell, JS AF Fairey, ER Edmunds, JSG Deamer-Melia, NJ Glasgow, H Johnson, FM Moeller, PR Burkholder, JM Ramsdell, JS TI Reporter gene assay for fish-killing activity produced by Pfiesteria piscicida SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE assay; c-fos; GH(4)C(1); Pfiesteria piscicida; pituitary; toxin ID DOMOIC ACID; DINOFLAGELLATE; BREVETOXINS; CIGUATOXINS; SAXITOXINS; SURVIVAL; EXPOSURE; TOXIN AB Collaborative studies were performed to develop a functional assay for fish-killing activity produced by P. fiesteria piscicida. Eight cell lines were used to screen organic fractions and residual water fraction by using a 3-[4,5-dimethylthiazol-(2-4)]-diphenyltetrazolium bromide cytotoxicity assay. Diethyl ether and a residual water fraction were cytotoxic to several cell lines including rat pituitary (GH(4)C(1)) cells. Residual water as well as preextracted culture water containing P. piscicida cells induced c-fos-luciferase expressed in GH(4)C(1) cells with a rapid time course of induction and sensitive detection. The reporter gene assay detected activity in toxic isolates of P. piscicida from several North Carolina estuaries in 1997 and 1998 and may also be suitable for detecting toxic activity in human and animal serum. C1 Natl Ocean Serv, NOAA, Ctr Coastal Environm Hlth & Biomol Res, Marine Biotoxins Program, Charleston, SC 29412 USA. N Carolina State Univ, Dept Bot, Raleigh, NC 27695 USA. NIEHS, Intramural Res Program, Res Triangle Pk, NC 27709 USA. NIEHS, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Ramsdell, JS (reprint author), Natl Ocean Serv, NOAA, Ctr Coastal Environm Hlth & Biomol Res, Marine Biotoxins Program, 219 Ft Johnson Rd, Charleston, SC 29412 USA. NR 17 TC 53 Z9 55 U1 0 U2 2 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD SEP PY 1999 VL 107 IS 9 BP 711 EP 714 DI 10.2307/3434655 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 236BT UT WOS:000082578900021 PM 10464070 ER PT J AU Guo, YLL Yu, ML Hsu, CC Rogan, WJ AF Guo, YLL Yu, ML Hsu, CC Rogan, WJ TI Chloracne, goiter, arthritis, and anemia after polychlorinated biphenyl poisoning: 14-year follow-up of the Taiwan Yucheng cohort SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE acneform eruptions; food intoxication; PCBs; polychlorinated biphenyls; skin manifestations; thyroid gland ID BLOOD; DIBENZOFURANS; MORTALITY; EXPOSURE; DISEASE; DIOXIN; PCDFS; PCBS; OIL AB In 1979, a mass poisoning involving 2,000 people occurred in central Taiwan from ingestion of cooking oil contaminated by polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs). We studied the prevalence of medical conditions in the exposed individuals and in a neighborhood control group. Starting with a registry of the exposed individuals from 1983, we updated the addresses of exposed individuals and identified a control group matched for age, sex, and neighborhood in 1979. In 1993, individuals 30 years of age or older were interviewed by telephone. We obtained usable information from 795 exposed subjects and 693 control subjects. Lifetime prevalence of chloracne, abnormal nails, hyperkeratosis, skin allergy, goiter, headache, gum pigmentation, and broken teeth were observed more frequently in the PCB/PCDF-exposed men and women. The exposed women reported anemia 2,3 times more frequently than controls. The exposed men reported arthritis and herniated intervertebral disks 4.1 and 2.9 times, respectively, more frequently than controls. There was no difference in reported prevalences of other medical conditions. We conclude that Taiwanese people exposed to high le,els of PCBs and PCDFs reported more frequent medical problems, including skin diseases, goiter, anemia, and joint and spine diseases. C1 Natl Cheng Kung Univ, Coll Med, Tainan 70101, Taiwan. Tainan City Hosp, Tainan, Taiwan. NIEHS, Res Triangle Pk, NC 27709 USA. RP Yu, ML (reprint author), Natl Cheng Kung Univ, Coll Med, 138 Sheng Li Rd, Tainan 70101, Taiwan. RI Rogan, Walter/I-6034-2012; OI Rogan, Walter/0000-0002-9302-0160; GUO, Yue Leon/0000-0002-8530-4809 NR 26 TC 60 Z9 66 U1 2 U2 6 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD SEP PY 1999 VL 107 IS 9 BP 715 EP 719 DI 10.2307/3434656 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 236BT UT WOS:000082578900022 PM 10464071 ER PT J AU McConnell, R Berhane, K Gilliland, F London, SJ Vora, H Avol, E Gauderman, WJ Margolis, HG Lurmann, F Thomas, DC Peters, JM AF McConnell, R Berhane, K Gilliland, F London, SJ Vora, H Avol, E Gauderman, WJ Margolis, HG Lurmann, F Thomas, DC Peters, JM TI Air pollution and bronchitic symptoms in Southern California children with asthma SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE air pollution; asthma; bronchitis; children; respiratory tract ID PEAK EXPIRATORY FLOW; RESPIRATORY HEALTH; MEXICO-CITY; INHALABLE PARTICLES; AMERICAN CHILDREN; CHILDHOOD ASTHMA; OZONE EXPOSURE; POLLUTANTS; VISITS AB The association of air pollution with the prevalence of chronic lower respiratory tract symptoms among children with a history of asthma or related symptoms was examined in a cross-sectional study. Parents of a total of 3,676 fourth, seventh, and tenth graders from classrooms in 12 communities in Southern California completed questionnaires that characterized the children's histories of respiratory illness and associated risk factors. The prevalences of bronchitis, chronic phlegm, and chronic cough were investigated among children with a history of asthma, wheeze without diagnosed asthma, and neither wheeze nor asthma. Average ambient annual exposure to ozone, particulate matter (PM10 and PM2.5; less than or equal to 10 mu m and < 2.5 mu m in aerodynamic diameter, respectively), acid vapor, and nitrogen dioxide (NO2) was estimated from monitoring stations in each community. Positive associations between air pollution and bronchitis and phlegm were observed only among children with asthma. As PM10 increased across communities, there was a corresponding increase in the risk per interquartile range of bronchitis [odds ratio (OR) 1.4/19 mu g/m(3); 95% confidence interval (CI), 1.1-1.8). Increased prevalence of phlegm was significantly associated with increasing exposure to all ambient pollutants except ozone. The strongest association was for NO2, based on relative risk per interquartile range in the 12 communities (OR 2.7/24 ppb; CI, 1.4-5.3). The results suggest that children with a prior diagnosis of asthma are more likely to develop persistent lower respiratory tract symptoms when exposed to air pollution in Southern California. C1 Univ So Calif, Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Seonoma Technol Inc, Petaluma, CA USA. Calif Air Resources Board, Sacramento, CA USA. RP McConnell, R (reprint author), Univ So Calif, Sch Med, Dept Prevent Med, 1540 Alcazar St,CHP 236, Los Angeles, CA 90033 USA. OI London, Stephanie/0000-0003-4911-5290 FU NIEHS NIH HHS [5P30ES07048-02] NR 25 TC 139 Z9 143 U1 0 U2 12 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD SEP PY 1999 VL 107 IS 9 BP 757 EP 760 DI 10.2307/3434662 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 236BT UT WOS:000082578900028 PM 10464077 ER PT J AU Zahm, SH AF Zahm, SH TI Childhood leukemia and pesticides SO EPIDEMIOLOGY LA English DT Editorial Material ID CANCER C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. RP Zahm, SH (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 8074, Rockville, MD 20892 USA. RI Zahm, Shelia/B-5025-2015 NR 10 TC 7 Z9 8 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD SEP PY 1999 VL 10 IS 5 BP 473 EP 475 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 227HV UT WOS:000082075800002 PM 10468417 ER PT J AU Boross, P Bagossi, P Copeland, TD Oroszlan, S Louis, JM Tozser, J AF Boross, P Bagossi, P Copeland, TD Oroszlan, S Louis, JM Tozser, J TI Effect of substrate residues on the P2 ' preference of retroviral proteinases SO EUROPEAN JOURNAL OF BIOCHEMISTRY LA English DT Article DE HIV proteinase; retroviral proteinases; retropepsins; oligopeptide substrates; substrate specificity ID HUMAN-IMMUNODEFICIENCY-VIRUS; PROTEASE CLEAVAGE SITES; HIV-1 PROTEASE; TYPE-2 PROTEASE; ACTIVE-SITE; AMINO-ACID; SPECIFICITY; GAG; INHIBITOR; SUBSITES AB The substrate sequence requirements for preference toward P2 ' Glu residue by human immunodeficiency virus type 1 (HIV-l) proteinase were studied in both the matrix protein/ capsid protein (MA/CA) and CA/p2 cleavage site sequence contexts. These sequences represent typical type 1 (-aromatic*Pro-) and type 2 (-hydrophobic* hydrophobic-) cleavage site sequences, respectively. While in the type 1 sequence context, the preference for P2 ' Glu over Ile or Gin was found to be strongly dependent on the ionic strength and the residues being outside the P2-P2 ' region of the substrate, it remained preferable in the type 2 substrates when typical type 1 substrate sequence residues were substituted into the outside regions. The pH profile of the specificity constants suggested a lower pH optimum for substrates having P2 ' Glu in contrast to those having uncharged residues, in both sequence contexts. The very low frequency of P2 ' Glu in naturally occurring retroviral cleavage sites of various retroviruses including equine infectious anemia virus (EIAV) and murine leukemia virus (MuLV) suggests that such a residue may not have a general regulatory role in the retroviral life cycle. In fact, unlike HN-I and HIV-2, EIAV and MuLV proteinases do not favor P2 ' Glu in either the MA/CA or CA/p2 sequence contexts. C1 Debrecen Univ Med, Sch Med, Dept Biochem & Mol Biol, H-4012 Debrecen, Hungary. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Special Program Prot Chem, Frederick, MD USA. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Mol Virol & Carcinogenesis Lab, Frederick, MD USA. NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Tozser, J (reprint author), Debrecen Univ Med, Sch Med, Dept Biochem & Mol Biol, POB 6, H-4012 Debrecen, Hungary. EM tozser@indi.biochem.dote.hu RI Tozser, Jozsef/A-7840-2008; OI Tozser, Jozsef/0000-0003-0274-0056; Tozser, Jozsef/0000-0001-5076-8729 NR 43 TC 24 Z9 24 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2956 J9 EUR J BIOCHEM JI Eur. J. Biochem. PD SEP PY 1999 VL 264 IS 3 BP 921 EP 929 DI 10.1046/j.1432-1327.1999.00687.x PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 238GC UT WOS:000082701700031 PM 10491141 ER PT J AU Borresen-Dale, AL Hahnemann, J Hammerstrom, L Kleinerman, R Kaarianen, H Laake, K Olsen, JH Sankila, R Tretli, S Tucker, M AF Borresen-Dale, AL Hahnemann, J Hammerstrom, L Kleinerman, R Kaarianen, H Laake, K Olsen, JH Sankila, R Tretli, S Tucker, M TI The role of ATM gene in cancer predisposition SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 Norwegian Radium Hosp, Dept Genet, Oslo, Norway. John F Kennedy Inst, DK-2600 Glostrup, Denmark. Karolinska Inst, Div Clin Immunol, Huddinge, Sweden. NIH, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. Family Fed Finland, Dept Med Genet, Helsinki, Finland. RI Tucker, Margaret/B-4297-2015 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 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 1999 VL 35 SU 4 MA 1214 BP S302 EP S302 DI 10.1016/S0959-8049(99)81633-5 PG 1 WC Oncology SC Oncology GA 244UC UT WOS:000083068301198 ER PT J AU Schultze-Mosgau, A Treeck, O Koshimizu, T Arora, KK Stojilkovic, SS Diedrich, K Ortmann, O AF Schultze-Mosgau, A Treeck, O Koshimizu, T Arora, KK Stojilkovic, SS Diedrich, K Ortmann, O TI Identification, characterization and signal transduction of P2Y(2) receptors in human ovarian cancer cell lines and ovarian cancer tissues SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 Univ Lubeck, Dept Obstet Gynecol, D-2400 Lubeck, Germany. Univ Lubeck, Dept Mol Med, D-2400 Lubeck, Germany. NICHD, Endo Reprod Res Branch, 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 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 1999 VL 35 SU 4 MA 911 BP S232 EP S232 DI 10.1016/S0959-8049(99)81331-8 PG 1 WC Oncology SC Oncology GA 244UC UT WOS:000083068300896 ER PT J AU Widemann, BC Balis, FM Reaman, GH Sato, J O'Brien, M Krailo, M Lowery, C Adamson, PC AF Widemann, BC Balis, FM Reaman, GH Sato, J O'Brien, M Krailo, M Lowery, C Adamson, PC TI Pediatric phase I trial and pharmacokinetic study of 'Tomudex' (Ralitrexed) SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. Childrens Canc Grp, Arcadia, CA USA. Zeneca Pharmaceut, Wilmington, DE USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 1999 VL 35 SU 4 MA 1152 BP S287 EP S287 DI 10.1016/S0959-8049(99)81572-X PG 1 WC Oncology SC Oncology GA 244UC UT WOS:000083068301137 ER PT J AU Mandishona, EM Moyo, VM Gordeuk, VR Khumalo, H Saungweme, T Gangaidzo, IT Gomo, ZAR Rouault, T MacPhail, AP AF Mandishona, EM Moyo, VM Gordeuk, VR Khumalo, H Saungweme, T Gangaidzo, IT Gomo, ZAR Rouault, T MacPhail, AP TI A traditional beverage prevents iron deficiency in African women of child bearing age SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE iron deficiency; nutritional anaemia; dietary iron ID ABSORPTION; OVERLOAD AB Objective: To determine if a traditional item in the diet might he useful in preventing iran deficiency in African women of child-bearing age. Design: In a prospective study, the inn status of women who did and did net drink traditional beer high in iron and folic acid, was compared. Iron status was determined by a combination of haemoglobin, serum ferritin and transferrin saturation. Setting: The study was conducted amongst rural villagers in the Murchwa and Zaka districts of Zimbabwe and in Mpumalanga province. South Africa. Subjects: 112 women aged between 12 and 50 y from a population of 425 rural people participating in on-going family genetic studies. Results: Women who consumed traditional beer had significantly higher serum ferritin concentrations and transferrin saturations compared to non-drinkers (P = 0.0001 and 0.03 respectively). Iron deficiency anaemia was not present in drinkers but the prevalence in non-drinkers was 13%. Forty seven percent of the non-drinkers and only 14% of the drinkers had evidence of iran deficiency (P = 0.002). Six (21%) of the drinkers and none of the non-drinkers had evidence of iron overload (transferrin saturation > 55% and serum ferritin > 400 ug/l). Conclusion: We conclude that the consumption of traditional beer, rich in iron, protects women against iron deficiency. While the use of an alcoholic beverage is not ideal, our findings suggest that indigenous cultural practices might be successfully employed or adapted for promoting iron nutrition. C1 Univ Witwatersrand, Dept Med, ZA-2001 Johannesburg, South Africa. Univ Zimbabwe, Dept Med, Harare, Zimbabwe. George Washington Univ, Med Ctr, Dept Med, Washington, DC 20037 USA. NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. RP MacPhail, AP (reprint author), Univ Witwatersrand, Sch Med, Dept Med, 7 York Rd, ZA-2193 Parktown, South Africa. FU NICHD NIH HHS [1-HD 3-3196] NR 26 TC 7 Z9 7 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0954-3007 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD SEP PY 1999 VL 53 IS 9 BP 722 EP 725 DI 10.1038/sj.ejcn.1600840 PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 236TP UT WOS:000082615000009 PM 10509769 ER PT J AU Saab, NH Donkor, IO Rodriguez, L Kador, PF Miller, DD AF Saab, NH Donkor, IO Rodriguez, L Kador, PF Miller, DD TI Phenylsulfonylnitromethanes as potent irreversible inhibitors of aldose reductase SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE aldose reductase; diabetic complication; phenylsulphonyl-nitromethane; irreversible inhibitors; aldose reductase inhibitors ID SITE; EXPRESSION; RAT AB Aldose reductase (AR) inhibition provides a viable pharmacologically direct mode for the treatment of diabetic complications. We have synthesized a series of N-4 substituted analogues (15-21) of the known aldose reductase inhibitor phenyl-sulfonylnitromethane. The compounds are potent inhibitors of AR with IC(50)s between 0.01 and 0.19 mu M Some of the compounds are also potent affinity labels for AR. Compound 19 exhibits the highest and almost complete irreversible inhibition of AR known to date. (C) 1999 Editions scientifiques et medicales Elsevier SAS. C1 Univ Tennessee, Dept Pharmaceut Sci, Memphis, TN 38163 USA. NEI, Lab Ocular Therapeut, NIH, Bethesda, MD 20892 USA. RP Miller, DD (reprint author), Univ Tennessee, Dept Pharmaceut Sci, Memphis, TN 38163 USA. NR 17 TC 7 Z9 7 U1 0 U2 0 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS CEDEX 15 PA 23 RUE LINOIS, 75724 PARIS CEDEX 15, FRANCE SN 0223-5234 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD SEP PY 1999 VL 34 IS 9 BP 745 EP 751 DI 10.1016/S0223-5234(99)00219-6 PG 7 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 248JG UT WOS:000083270900007 ER PT J AU Immisch, I Bandmann, O Quintern, J Straube, A AF Immisch, I Bandmann, O Quintern, J Straube, A TI Different postural reaction patterns for expected and unexpected perturbations in patients with idiopathic Parkinson's disease and other parkinsonian syndromes SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Article DE Parkinsonism; Parkinson's disease; posture; postural reactions; balance; predicted perturbation; unpredicted perturbation; tilt platform ID LOWER-BODY; REFLEXES; ADJUSTMENTS AB Different postural reaction patterns after predictable and unpredictable perturbations during free stance were studied in 8 patients with idiopathic Parkinson's disease (iPD), in 4 patients with other parkinsonian syndromes (PS) and in 5 healthy controls. First, the amplitude of leaning maximally backward and forward was measured (condition I). Secondly, the body equilibrium was disturbed by self-paced, predictable, rapid arm elevations (condition II) and by sudden unpredictable toe-down and toe-up rotations of a supporting platform (condition III). Patients with PS particularly had difficulties in regaining body equilibrium after unexpected perturbations, In controls and patients with PS, unpredictable disturbances were better compensated in toe-down than in toe-up direction, whereas the opposite was true for patients with iPD, These results correspond to the fact that patients,vith PS had a specific leaning-backward impairment and patients with iPD, a leaning-forward impairment. The authors conclude that the differences in postural stability between patients with iPD and PS are caused by different pathophysiological mechanisms. These differences in postural stability could serve as an additional tool for differential diagnosis. fur J Neurol 6:549-554 (C) 1999 Lippincott Williams & Wilkins. C1 Univ Munich, Klinikum Grosshadern, Dept Neurol, Munich, Germany. Univ Marburg, Dept Neurol, Marburg, Germany. RP Immisch, I (reprint author), NINDS, NIH, Bldg 10,Room 5N234,10 Ctr Dr,MSC 1430, Bethesda, MD 20892 USA. NR 14 TC 1 Z9 1 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 1351-5101 J9 EUR J NEUROL JI Eur. J. Neurol. PD SEP PY 1999 VL 6 IS 5 BP 549 EP 554 DI 10.1046/j.1468-1331.1999.650549.x PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 236BU UT WOS:000082579000003 PM 10457387 ER PT J AU Krause, BJ Horwitz, B Taylor, JG Schmidt, D Mottaghy, FM Herzog, H Halsband, U Muller-Gartner, HW AF Krause, BJ Horwitz, B Taylor, JG Schmidt, D Mottaghy, FM Herzog, H Halsband, U Muller-Gartner, HW TI Network analysis in episodic encoding and retrieval of word-pair associates: a PET study SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE episodic memory; network analysis; paired word associates; positron emission tomography; structural equation modelling ID POSITRON-EMISSION-TOMOGRAPHY; WORKING-MEMORY TASKS; LONG-TERM-MEMORY; HIPPOCAMPAL-FORMATION; PREFRONTAL CORTEX; FRONTAL-CORTEX; VERBAL MEMORY; RHESUS-MONKEY; FUNCTIONAL INTERACTIONS; CORTICAL AFFERENTS AB The involvement of distributed brain regions in declarative memory has been hypothesized based on studies with verbal memory tasks. To characterize episodic declarative memory function further, 14 right-handed volunteers performed a visual verbal learning task using paired word associates. The volunteers underwent positron emission tomography. (15)O-butanol was used as a tracer of regional cerebral blood flow (rCBF). Inter-regional functional interactions were assessed based on within-task, across-subject interregional rCBF correlations. Anatomical connections between brain areas were based on known anatomy. Structural equation modelling was used to calculate the path coefficients representing the magnitudes of the functional influences of each area on the ones to which it is connected by anatomical pathways. The encoding and the retrieval network elicit similarities in a general manner but also differences. Strong functional linkages involving visual integration areas, parahippocampal regions, left precuneus and cingulate gyrus were found in both encoding and retrieval; the functional linkages between posterior regions and prefrontal regions were more closely linked during encoding, whereas functional linkages between the left parahippocampal region and posterior cingulate as well as extrastriate areas and posterior cingulate gyrus were stronger during retrieval. In conclusion, these findings support the idea of a global bihemispheric, asymmetric encoding/retrieval network subserving episodic declarative memory. Our results further underline the role of the precuneus in episodic memory, not only during retrieval but also during encoding. C1 Univ Dusseldorf Hosp, Dept Nucl Med, D-40225 Dusseldorf, Germany. Forschungszentrum Julich, Res Ctr, Dept Nucl Med, D-52425 Julich, Germany. NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. Forschungszentrum Julich, Res Ctr, Inst Med IME, D-52425 Julich, Germany. Univ Tubingen, Inst Med Psychol & Behav Neurobiol, D-72074 Tubingen, Germany. RP Krause, BJ (reprint author), Univ Dusseldorf Hosp, Dept Nucl Med, Moorenstr 5, D-40225 Dusseldorf, Germany. EM j.b.krause@fz-juelich.de NR 65 TC 46 Z9 47 U1 1 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD SEP PY 1999 VL 11 IS 9 BP 3293 EP 3301 DI 10.1046/j.1460-9568.1999.00723.x PG 9 WC Neurosciences SC Neurosciences & Neurology GA 243NU UT WOS:000083004800030 PM 10510193 ER PT J AU Heinz, A Jones, D Weinberger, DR Hommer, D AF Heinz, A Jones, D Weinberger, DR Hommer, D TI Serotonin transporter availability in alcoholics and non-human primates - [I-123]beta-CIT SPECT studies SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 Ruhr Univ Bochum Hosp, Dept Neurol, Bochum, Germany. NIH, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6997 J9 EUR J NUCL MED JI Eur. J. Nucl. Med. PD SEP PY 1999 VL 26 IS 9 MA OS46 BP 972 EP 972 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 236TF UT WOS:000082614100048 ER PT J AU Takashima, H Tsujihata, M Kishikawa, M Freed, WJ AF Takashima, H Tsujihata, M Kishikawa, M Freed, WJ TI Bromocriptine protects dopaminergic neurons from levodopa-induced toxicity by stimulating D-2 receptors SO EXPERIMENTAL NEUROLOGY LA English DT Article; Proceedings Paper CT 2nd Conference of Cellular and Molecular Treatments of Neurological Diseases (CMT) CY OCT, 1998 CL CAMBRIDGE, MASSACHUSETTS DE dopaminergic neurons; levodopa; neurotoxicity; neuroprotection; bromocriptine; D-2 receptor; D-2 agonist ID PARKINSONS-DISEASE; L-DOPA; SUBSTANTIA-NIGRA; FOLLOW-UP; MESENCEPHALIC CULTURES; OXIDIZED GLUTATHIONE; IRON CONTENT; SERUM-FREE; IN-VITRO; NEUROTOXICITY AB Neuroprotective properties of bromocriptine, a D-2 receptor agonist, were investigated using the in vitro neurotoxicity of levodopa for dopaminergic neurons from rat embryonic ventral mesencephalon. Levodopa, when added to the culture medium, showed toxicity which was specific for dopaminergic neurons. Bromocriptine was found to protect dopaminergic neurons from levodopa toxicity. Another D-2 agonist, 2-(N-phenethyl-N-propyl-amino-5-hydroxytetralin, showed similar protective effects. The neuroprotective effect of bromocriptine was inhibited by supplementation of the culture medium with sulpiride, a D-2 antagonist, or by D-2 receptor knockdown with an antisense oligonucleotide. Dopaminergic neurons treated with levodopa showed an increase in free radicals. These data suggest that neuroprotective properties of bromocriptine seen in this cellular model of neurotoxicity are dependent on dopamine D-2 autoreceptor binding and that levodopa toxicity may be related to increased free radical generation in dopaminergic neurons. (C) 1999 Academic Press. C1 Nagasaki Kita Hosp, Neurol Sect, Nagasaki 8528061, Japan. Aichi Human Serv Ctr, Dept Morphol, Aichi 4800392, Japan. NIDA, IRP, Baltimore, MD 21224 USA. RP Takashima, H (reprint author), Nagasaki Kita Hosp, Neurol Sect, Nagasaki 8528061, Japan. NR 58 TC 37 Z9 39 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD SEP PY 1999 VL 159 IS 1 BP 98 EP 104 DI 10.1006/exnr.1999.7122 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 237FM UT WOS:000082644700009 PM 10486178 ER PT J AU Bachrach, CA Newcomer, S AF Bachrach, CA Newcomer, S TI Intended pregnancies and unintended pregnancies: Distinct categories or opposite ends of a continuum? SO FAMILY PLANNING PERSPECTIVES LA English DT Article C1 NICHHD, Demog & Behav Sci Branch, Washington, DC USA. RP Bachrach, CA (reprint author), NICHHD, Demog & Behav Sci Branch, Washington, DC USA. NR 4 TC 92 Z9 94 U1 1 U2 6 PU ALAN GUTTMACHER INST PI NEW YORK PA 120 WALL STREET, NEW YORK, NY 10005 USA SN 0014-7354 J9 FAM PLANN PERSPECT JI Fam. Plann. Perspect. PD SEP-OCT PY 1999 VL 31 IS 5 BP 251 EP 252 DI 10.2307/2991577 PG 2 WC Demography; Family Studies SC Demography; Family Studies GA 241FT UT WOS:000082872600010 PM 10723654 ER PT J AU Hahn, SM Sullivan, FJ DeLuca, AM Bacher, JD Liebmann, J Krishna, MC Coffin, D Mitchell, JB AF Hahn, SM Sullivan, FJ DeLuca, AM Bacher, JD Liebmann, J Krishna, MC Coffin, D Mitchell, JB TI Hemodynamic effect of the nitroxide superoxide dismutase mimics SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE hypotension; nitroxides; SOD mimics; swine; nitric oxide; free radical ID NITRIC-OXIDE; ENDOTHELIAL DYSFUNCTION; ANION PRODUCTION; SPIN TRAPS; MECHANISM; TEMPOL; HYPERTENSION; DAMAGE; MODEL; CELLS AB Reactive oxygen species play critical roles in a number of physiologic and pathologic processes. Nitroxides are stable free radical compounds that possess superoxide dismutase (SOD) mimetic activity and have been shown to protect against the toxicity of reactive oxygen species in vitro and in vivo. Tempol, a cell-permeable hydrophilic nitroxide, protects against oxidative stress and also is an in vitro and in vivo radioprotector. In the course of evaluating the pharmacology and toxicity of the nitroxides, Tempol and another nitroxide, 3-carbamoyl-PROXYL (3-CP), were administered intravenously in various concentrations to miniature swine. Tempol caused dose-related hypotension accompanied by reflex tachycardia and increased skin temperature. Invasive hemodynamic monitoring with Swan Ganz catheterization (SGC) confirmed the potent vasodilative effect of Tempol. However, 3-CP had no effect on porcine blood pressure. The hemodynamic effects of Tempol and 3-CP are discussed in the context of differential catalytic rate constants for superoxide disumation that may impact systemic nitric oxide (NO) levels and lead to vasodilation. These findings are consistent with a role for the superoxide ion in the modulation of blood pressure and have potential implications for the systemic use of nitroxides. (C) 1999 Elsevier Science Inc. C1 NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. NCI, Vet Resources Program, Natl Ctr Res Resources, NIH, Bethesda, MD 20892 USA. Hosp Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. RP Mitchell, JB (reprint author), NCI, Radiat Biol Branch, NIH, Bldg 10,Rm B3B69,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 27 TC 57 Z9 57 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD SEP PY 1999 VL 27 IS 5-6 BP 529 EP 535 DI 10.1016/S0891-5849(99)00099-4 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 234RK UT WOS:000082498000006 PM 10490272 ER PT J AU Ward, SM Ordog, T Bayguinov, JR Horowitz, B Epperson, A Shen, LY Westphal, H Sanders, KM AF Ward, SM Ordog, T Bayguinov, JR Horowitz, B Epperson, A Shen, LY Westphal, H Sanders, KM TI Development of interstitial cells of Cajal and pacemaking in mice lacking enteric nerves SO GASTROENTEROLOGY LA English DT Article ID MURINE GASTROINTESTINAL-TRACT; KIT-DEPENDENT DEVELOPMENT; CANINE PROXIMAL COLON; MOUSE SMALL-INTESTINE; C-KIT; HIRSCHSPRUNGS-DISEASE; ELECTRICAL RHYTHMICITY; INHIBITORY NEUROTRANSMISSION; NERVOUS-SYSTEM; GROWTH-FACTOR AB Background & Aims: Development of interstitial cells of Cajal (ICC) requires signaling via Kit receptors. Kit is activated by stem cell factor (SCF), but the source of SCF in the bowel wall is unclear and controversy exists about whether enteric neurons express the SCF required for ICC development. Methods: Glial cell line-derived neurotrophic factor (GDNF) knockout mice, which lack enteric neurons throughout most of the gut, were used to determine whether neurons are necessary for ICC development. ICC distributions were determined with Kit immunofluorescence, and function of ICC was determined by intracellular electrical recording. Results: ICC were normally distributed throughout the gastrointestinal tracts of GDNF-/- mice. Intracellular recordings from aganglionic gastrointestinal muscles showed normal slow wave activity at birth in the stomach and small intestine. Slow waves developed normally in aganglionic segments of small bowel placed into organ culture at birth quantitative polymerase chain reaction showed similar expression of SCF in the muscles of animals with and without enteric neurons. Expression of SCF was demonstrated in isolated intestinal smooth muscle cells. Conclusions: These data suggest that enteric neurons are not required for the development of functional ICC. The circular smooth muscle layer, which develops before ICC, may be the source of SCF required for ICC development. C1 Univ Nevada, Sch Med, Dept Physiol & Cell Biol, Reno, NV 89557 USA. NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Ward, SM (reprint author), Univ Nevada, Sch Med, Dept Physiol & Cell Biol, Reno, NV 89557 USA. FU NIDDK NIH HHS [DK40569, DK41315] NR 39 TC 81 Z9 87 U1 0 U2 10 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD SEP PY 1999 VL 117 IS 3 BP 584 EP 594 DI 10.1016/S0016-5085(99)70451-8 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 230QF UT WOS:000082261300016 PM 10464134 ER PT J AU Everhart, JE Khare, M Hill, M Maure, KR AF Everhart, JE Khare, M Hill, M Maure, KR TI Prevalence and ethnic differences in gallbladder disease in the United States SO GASTROENTEROLOGY LA English DT Article ID GALLSTONE DISEASE; MEXICAN-AMERICANS; DANISH POPULATION; CHOLESTEROL CHOLELITHIASIS; HISPANIC POPULATIONS; PHYSICAL-ACTIVITY; RISK-FACTORS; WOMEN; WEIGHT; EPIDEMIOLOGY AB Background & Aims: Gallbladder disease is one of the most common conditions in the United States, but its true prevalence is unknown. A national population-based survey was performed to determine the age, sex, and ethnic distribution of gallbladder disease in the United States. Methods: The third National Health and Nutrition Examination Survey (NHANES III) conducted gallbladder ultrasonography among a representative U.S. sample of more than 14,000 persons. The diagnosis of gallbladder disease by detection of gallstones or cholecystectomy was made with-excellent reproducibility. Results: An estimated 6.3 million men and 14.2 million women aged 20-74 years had gallbladder disease. Age-standardized prevalence was similar for non-Hispanic white (8.6%) and Mexican American (8.9%) men, and both were higher than non-Hispanic black men (5.3%). These relationships persisted with multivariate adjustment. Among women, age-adjusted prevalence was highest for Mexican Americans (26.7%) followed by non-Hispanic whites (16.6%) and non-Hispanic blacks (13.9%). Among women, multivariate adjustment reduced the risk of gallbladder disease for both Mexican Americans and non-Hispanic blacks compared with non-Hispanic whites. Conclusions: More than 20 million persons have gallbladder disease in the United States. Ethnic differences in gallbladder disease prevalence differed according to sex and were only partly explained by known risk factors. C1 NIDDKD, Div Digest Dis & Nutr, Bethesda, MD 20892 USA. George Washington Univ, Washington, DC USA. Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. RP Everhart, JE (reprint author), NIDDKD, Div Digest Dis & Nutr, Natcher Bldg,Room 6AN-12J,45 Ctr Dr, Bethesda, MD 20892 USA. NR 39 TC 299 Z9 308 U1 2 U2 8 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD SEP PY 1999 VL 117 IS 3 BP 632 EP 639 DI 10.1016/S0016-5085(99)70456-7 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 230QF UT WOS:000082261300021 PM 10464139 ER PT J AU Lewis, EW Rudo, TJ Rahman, MA John, S Chu, JL Heinze, AW Howard, BH Engleka, KA AF Lewis, EW Rudo, TJ Rahman, MA John, S Chu, JL Heinze, AW Howard, BH Engleka, KA TI Endothelial cell DNA transfer and expression using Petri dish electroporation and the nonreplicating vaccinia virus/T7 RNA polymerase hybrid system SO GENE THERAPY LA English DT Article DE endothelial cell; vaccinia virus; electroporation; transfection; expression ID GREEN-FLUORESCENT PROTEIN; EFFICIENT GENE-TRANSFER; MAMMALIAN-CELLS; MOLECULAR-CLONING; IN-VIVO; SEQUENCE; MICE; PURIFICATION; OPTIMIZATION; INFLUENZA AB The nonreplicating vaccinia virus MVA/T7 RNA polymerase hybrid system was tested with Petri dish electroporation for ectopic gene expression in human umbilical vein endothelial cells (HUVECs). A range of voltages (150-450 V), pulse times (10-40ms), DNA concentrations (0-20 mu g/ml) and infection levels (0-15 multiplicities of infection) were tested for effects on T7 promoter-directed chloramphenicol acetyltransferase (CAT7) activity after MVA/T7RP infection. MVA/T7RP-directed expression was transient and at least 10 000-fold in excess of nonviral, cytomegalovirus enhancer-directed expression. Use of a Petri dish electrode with the MVA/T7RP system showed increased viability compared with a cuvette electrode. Overexpression of interleukin-e alpha subunit (IL2R alpha) protein followed by anti-IL2R alpha-directed magnetic immunoaffinity cell sorting allowed isolation of the transfected population. The high fidelity of cellular sorting was shown by segregation of CAT activity in the IL2R alpha-sorted population after transfection of T7 promoter-directed bicistronic IL2R alpha/CAT DNA. Expression of a panel of proteins including the fluorophore green fluorescent protein as defected by fluorescence microscopy and p21(cip1), p27(idp1), pp60(c-src) FGF-1, pRb, p107 and pRb2/p130 proteins was also achieved. Thus, use of the nonreplicating vaccinia virus/T7 RNA polymerase expression system with Petri dish electroporation is feasible for certain applications for the manipulation of HUVECs by gene transfer. C1 Thomas Jefferson Univ, Jefferson Med Coll, Dept Physiol, Philadelphia, PA 19107 USA. NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. RP Engleka, KA (reprint author), Thomas Jefferson Univ, Jefferson Med Coll, Dept Physiol, 1020 Locust St, Philadelphia, PA 19107 USA. NR 46 TC 2 Z9 2 U1 0 U2 1 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD SEP PY 1999 VL 6 IS 9 BP 1617 EP 1625 DI 10.1038/sj.gt.3300977 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 236KP UT WOS:000082599000016 PM 10490772 ER PT J AU Lopez, J Cuesta, N Cuttitta, F Martinez, A AF Lopez, J Cuesta, N Cuttitta, F Martinez, A TI Adrenomedullin in nonmammalian vertebrate pancreas: An immunocytochemical study SO GENERAL AND COMPARATIVE ENDOCRINOLOGY LA English DT Article DE adrenomedullin; endocrine cells; pancreas; nonmammalian vertebrates; Carcharhinus plumbeus; Onchorhynchus mykiss; Necturus maculosus; Xenopus laevis; Anolis sagrei; Gecko gecko; Gallus gallus ID CHICKEN ENDOCRINE PANCREAS; AMINO-ACID DECARBOXYLASE; HYPOTENSIVE PEPTIDE; INSULIN-SECRETION; NEUROPEPTIDE-Y; PULMONARY TUMORS; GROWTH-FACTOR; HUMAN LUNG; PP-CELLS; POLYPEPTIDE AB Adrenomedullin (AM) immunoreactive cells have been identified, by immunocytochemical methods, in the endocrine pancreas of seven nonmammalian vertebrate species, belonging to the cartilaginous and bony fish, amphibian, reptilian, and bird classes. The frequency and distribution of the pancreatic AM cells vary among the different animals. In most species, these cells are found scattered mainly among the exocrine component, with a few present in the islet-like structures. The distribution of AM cells in both fish species and Xenopus shows an inverse pattern, since almost every AM cell is located in the islets. In addition, the colocalization of AM with other classical pancreatic peptide immunoreactivities has been analyzed. In numerous cells, AM immunoreactivity did not colocalize with the other hormones, suggesting that AM-producing cells might constitute a new endocrine cell type in the pancreas of many species. Nevertheless, in other cells a species-specific pattern of colocalizations with insulin, somatostatin, glucagon, and pancreatic polypeptide was found, indicating that complex interactions among all these hormones may occur. In conclusion, AM represents a new regulatory peptide of the endocrine nonmammalian vertebrate pancreas, which is possibly involved in the modulation of insulin secretion and other pancreatic Functions. C1 Univ Autonoma Madrid, Fac Sci, Dept Biol, Cell Biol Unit, Madrid, Spain. NCI, Dept Cell & Canc Biol, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Lopez, J (reprint author), Univ Autonoma Madrid, Fac Sci, Dept Biol, Cell Biol Unit, Madrid, Spain. RI Cuesta, Natalia/C-1358-2012; Martinez, Alfredo/A-3077-2013; Cuesta, Natalia/J-7761-2015 OI Martinez, Alfredo/0000-0003-4882-4044; Cuesta, Natalia/0000-0003-0809-2934 FU NIDDK NIH HHS [DK41301] NR 60 TC 31 Z9 31 U1 0 U2 6 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0016-6480 J9 GEN COMP ENDOCR JI Gen. Comp. Endocrinol. PD SEP PY 1999 VL 115 IS 3 BP 309 EP 322 DI 10.1006/gcen.1999.7335 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 236KY UT WOS:000082599800001 PM 10480982 ER PT J AU Woodgate, R AF Woodgate, R TI A plethora of lesion-replicating DNA polymerases SO GENES & DEVELOPMENT LA English DT Article ID XERODERMA-PIGMENTOSUM VARIANT; SOS-INDUCED MUTAGENESIS; ESCHERICHIA-COLI DINB; SACCHAROMYCES-CEREVISIAE; UV MUTAGENESIS; THYMINE DIMER; RECA PROTEIN; GENE; REPAIR; HOMOLOG C1 NICHHD, Sect DNA Replicat Repair & Mutagenesis, NIH, Bethesda, MD 20892 USA. RP Woodgate, R (reprint author), NICHHD, Sect DNA Replicat Repair & Mutagenesis, NIH, Bethesda, MD 20892 USA. NR 36 TC 223 Z9 224 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 SEP 1 PY 1999 VL 13 IS 17 BP 2191 EP 2195 DI 10.1101/gad.13.17.2191 PG 5 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 237GK UT WOS:000082647200001 PM 10485842 ER PT J AU Peterson, RJ Goldman, D Long, JC AF Peterson, RJ Goldman, D Long, JC TI Effects of worldwide population subdivision on ALDH2 linkage disequilibrium SO GENOME RESEARCH LA English DT Article ID MODERN HUMANS; GAMETIC DISEQUILIBRIUM; DIASTROPHIC DYSPLASIA; HAPLOTYPE ANALYSIS; GENETIC DRIFT; LOCUS; EVOLUTION; LIKELIHOOD; DIVERGENCE; ALGORITHM AB The effect of human population subdivision on linkage disequilibrium has previously been studied for unlinked genes. However, no study has focused on closely linked polymorphisms or formally partitioned linkage disequilibrium within and among worldwide populations. With an emphasis on population subdivision, the goal of this paper is to investigate the causes of linkage disequilibrium in ALDH2, the gene that encodes aldehyde dehydrogenase 2. Haplotypes for 756 people from 17 populations across five continents were estimated by maximum-likelihood From genotypes at six closely linked ALDH2, nucleotide substitutions. Linkage disequilibrium was partitioned into three components: within populations, among populations within continents, and among continents. It was Found that; population subdivision among continents had a larger and more disparate effect on linkage disequilibrium than subdivision among local populations. Further, linkage disequilibrium did not increase with population divergence-as predicted by a simple model. Rather, the patterns of linkage disequilibrium were complicated because of the interplay of a near absence of recombination, the linkage disequilibrium that existed prior to the divergence of modern humans, subsequent mutation, population subdivision, random genetic drift, and perhaps natural selection. These results suggest that simple models may not well predict patterns of linkage disequilibrium in human populations. C1 NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Penn State Univ, Dept Anthropol, University Pk, PA 16802 USA. RP Peterson, RJ (reprint author), NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 42 TC 33 Z9 39 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD SEP PY 1999 VL 9 IS 9 BP 844 EP 852 DI 10.1101/gr.9.9.844 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 242ND UT WOS:000082946400007 PM 10508843 ER PT J AU Nakashima, H Grahovac, MJ Mazzarella, R Fujiwara, H Kitchen, JR Threat, TA Ko, MSH AF Nakashima, H Grahovac, MJ Mazzarella, R Fujiwara, H Kitchen, JR Threat, TA Ko, MSH TI Two novel mouse genes-Nubp2, mapped to the t-complex on chromosome 17, and Nubp1, mapped to chromosome 16 - Establish a new gene family of nucleotide-binding proteins in eukaryotes SO GENOMICS LA English DT Article ID ATP-BINDING; SEQUENCE; GENOME; EXPRESSION; PCR; TRANSCRIPTS; SUPERFAMILY; ALIGNMENT; DATABASE; HOMOLOGY AB Two novel mouse genes and one novel human gene that define distinctive eukaryotic nucleotide-binding proteins (NUBP) and are related to the mrp gene of prokaryotes are characterized. Phylogenetic analyses of the genes, encoding a short form (Nubp2) and a long form (Nubp1) of NUBP, clearly establish them as a new NUBP/MRP gene family that is well conserved throughout phylogeny. In addition to conserved ATP/GTP-binding motifs A (P-loop) and A', members of this family share at least two highly conserved sequence motifs, NUBP/MRP motifs alpha and beta. Only one type of NUBP/MRP gene has been observed thus far in prokaryotes, but there are two types in eukaryotes. One group includes mouse Nubp1, human NBP, yeast NBP35, and Caenorhabditis elegans F10G8.6 and is characterized by a unique N-terminal sequence with four cysteine residues that is lacking in the other group, which includes mouse Nubp2, human NUBP2, and yeast YIA3w. Northern blot analyses of the two mouse genes show distinctive patterns consistent with this classification. Mouse Nubp2 is mapped to the t-complex region of mouse Chromosome 17, whereas Nubp1 is mapped to the proximal region of mouse Chromosome 16. Interestingly, both regions are syntenic with human chromosome 16p13.1-p13.3, suggesting that a chromosomal breakage between Nubp2 and Nubp1 probably occurred during the evolution of mouse chromosomes. (C) 1999 Academic Press. C1 NIA, Genet Lab, Dev Genom & Aging Sect, NIH, Baltimore, MD 21224 USA. Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48202 USA. Washington Univ, Inst Biomed Comp, St Louis, MO 63110 USA. RP Ko, MSH (reprint author), NIA, Genet Lab, Dev Genom & Aging Sect, NIH, 333 Cassell Dr,TRIAD,Suite 4000, Baltimore, MD 21224 USA. RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 FU NICHD NIH HHS [1R01HD32243] NR 37 TC 11 Z9 14 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 SEP 1 PY 1999 VL 60 IS 2 BP 152 EP 160 DI 10.1006/geno.1999.5898 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 239KU UT WOS:000082767900005 PM 10486206 ER PT J AU Zhang, K Kniazeva, M Hutchinson, A Han, M Dean, M Allikmets, R AF Zhang, K Kniazeva, M Hutchinson, A Han, M Dean, M Allikmets, R TI The ABCR gene in recessive and dominant Stargardt diseases: A genetic pathway in macular degeneration SO GENOMICS LA English DT Article ID DYSTROPHY; MAPS AB Stargardt disease (STGD) is a juvenile-onset macular dystrophy and can be inherited in an autosomal recessive or in an autosomal dominant manner. Genes involved in dominant STDG have been mapped to human chromosomes 13q (STGD2) and 6q (STGD3), Here, we identify a new kindred with dominant STGD and demonstrate genetic linkage to the STGD3 locus. Because of a more severe macular degeneration phenotype of one of the patients in this family, the gene responsible for the recessive STGD1, ABCR, was analyzed for sequence variants in all family members. One allele of the ABCR gene was shown to carry a stop codon-generating mutation (R152X) in three family members, including the one patient who had inherited also the dominant gene. A grandparent of that patient with the same ABCR mutation developed age-related macular degeneration (AMD), consistent with our earlier observation that some variants in the ABCR gene may increase susceptibility to AMD in the heterozygous state. Based on these results, we propose that there is a common genetic pathway in macular degeneration that includes genes for both recessive and dominant STGD. (C) 1999 Academic Press. C1 Columbia Univ, Dept Ophthalmol, New York, NY 10032 USA. NCI, Frederick Canc Res & Dev Ctr, Lab Genom Divers, Frederick, MD 21702 USA. Columbia Univ, Dept Pathol, New York, NY 10032 USA. Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA. Univ Colorado, Howard Hughes Med Inst, Boulder, CO 80309 USA. Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21287 USA. RP Allikmets, R (reprint author), Columbia Univ, Dept Ophthalmol, Eye Res Addit,2nd Floor,630 W 168th st, New York, NY 10032 USA. RI Dean, Michael/G-8172-2012; Kniazeva, Marina/D-4085-2012 OI Dean, Michael/0000-0003-2234-0631; NR 10 TC 33 Z9 37 U1 0 U2 2 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 SEP 1 PY 1999 VL 60 IS 2 BP 234 EP 237 DI 10.1006/geno.1999.5896 PG 4 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 239KU UT WOS:000082767900014 PM 10486215 ER PT J AU Pras, E Pras, E Kreiss, Y Frishberg, Y Prosen, L Aksentijevich, I Kastner, DL AF Pras, E Pras, E Kreiss, Y Frishberg, Y Prosen, L Aksentijevich, I Kastner, DL TI Refined mapping of the CSNU3 gene to a 1.8-Mb region on chromosome 19q13.1 using historical recombinants in libyan Jewish cystinuria patients SO GENOMICS LA English DT Article ID PHYSICAL MAP; HUMAN-CHROMOSOME-19; JEWS AB Cystinuria is a genetic disease manifested by the development of kidney stones. In some patients, the disease is caused by mutations in the SLC3A1 gene located on chromosome 2p, In others, the disease is caused by a gene that maps to chromosome 19q, but has not yet been cloned. Cystinuria is very common among Jews of Libyan ancestry living in Israel. Previously we have shown that the disease-causing gene in Libyan Jews maps to an 8-cM interval on chromosome 19q between the markers D19S409 and D19S208. Several markers from chromosome 19q showed strong linkage disequilibrium, and a specific haplotype was found in more than half of the carrier chromosomes. In this study we have analyzed Libyan Jewish cystinuria families with eight markers from within the interval containing the gene. Seven of these markers showed significant linkage disequilibrium, A common haplotype was found in 16 of the 17 carrier chromosomes. Analysis of historical recombinants placed the gene in a 1.8-Mb interval between the markers D19S430 and D19S874. Two segments of the historical carrier chromosome used to calculate the mutation's age revealed that the disease-causing mutation was introduced into this population 7-16 generations ago. (C) 1999 Academic Press. C1 Chaim Sheba Med Ctr, Inst Human Genet, IL-52621 Tel Hashomer, Israel. Chaim Sheba Med Ctr, Dept Med C, IL-52621 Tel Hashomer, Israel. Sapir Med Ctr, Dept Ophthalmol, IL-44281 Kefar Sava, Israel. Shaare Zedek Med Ctr, Div Pediat Nephrol, IL-91031 Jerusalem, Israel. Med Coll Wisconsin, Dept Psychiat, Milwaukee, WI 53226 USA. Med Coll Wisconsin, Dept Family Med, Milwaukee, WI 53226 USA. NIAMSD, Arthritis & Rheumat Branch, NIH, Bethesda, MD 20892 USA. RP Pras, E (reprint author), Chaim Sheba Med Ctr, Inst Human Genet, IL-52621 Tel Hashomer, Israel. EM epras@cc.tau.ac.il; epras@cc.tau.ac.il NR 9 TC 9 Z9 9 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD SEP 1 PY 1999 VL 60 IS 2 BP 248 EP 250 DI 10.1006/geno.1999.5917 PG 3 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 239KU UT WOS:000082767900018 PM 10486219 ER PT J AU Breidert, M Miehlke, S Glasow, A Orban, Z Stolte, M Ehninger, G Bayerdorffer, E Halm, U Haidan, A Bontstein, SR AF Breidert, M Miehlke, S Glasow, A Orban, Z Stolte, M Ehninger, G Bayerdorffer, E Halm, U Haidan, A Bontstein, SR TI Leptin and its receptor in normal human gastric mucosa and in Helicobacter pylori-associated gastritis SO GUT LA English DT Meeting Abstract C1 TU Hosp Dresden, Dept Med 1, Dresden, Germany. Univ Leipzig, Dept Intern Med 2 & 3, D-7010 Leipzig, Germany. Klinikum Bayreuth, Inst Pathol, Bayreuth, Germany. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 J9 GUT JI Gut PD SEP PY 1999 VL 45 SU 3 BP A52 EP A52 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 234DN UT WOS:000082469400172 ER PT J AU Nyan, D Welch, A Dubois, A Coleman, W AF Nyan, D Welch, A Dubois, A Coleman, W TI Development of a non-invasive method for the antemortem detection of Helicobacter pylori infection in mice SO GUT LA English DT Meeting Abstract C1 NIDDKD, NIH, Bethesda, MD 20892 USA. Diagnon Corp, Rockville, MD USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 J9 GUT JI Gut PD SEP PY 1999 VL 45 SU 3 BP A65 EP A65 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 234DN UT WOS:000082469400211 ER PT J AU Cornelison, TL Trimble, EL Kosary, CL AF Cornelison, TL Trimble, EL Kosary, CL TI SEER data, corpus uteri cancer: Treatment trends versus survival for FIGO stage 11, 1988-1994 SO GYNECOLOGIC ONCOLOGY LA English DT Article DE SEER; corpus uteri cancer; adenocarcinoma; FIGO II; radical hysterectomy; survival ID II ENDOMETRIAL CARCINOMA; CERVICAL INVOLVEMENT; PROGNOSTIC FACTORS; SURGICAL-TREATMENT; ADENOCARCINOMA; MANAGEMENT; RADIATION; SURGERY AB Objective. 1998 Surveillance, Epidemiology, and End Results (SEER) data estimate an 83.1% 5-year survival rate for corpus uteri adenocarcinoma FIGO stage II. The SEER data were evaluated to determine whether primary treatment differences using simple hysterectomy or radical hysterectomy, with or without radiation, altered disease survival. Materials and Methods. SEER incidence data for FIGO II uterine corpus cancer of adenocarcinoma histology from 1988 to 1994 were stratified by hysterectomy type (simple versus radical) and whether radiation was given. Survival rates were calculated using a relative survival method and are expressed as percentages. Statistical analysis was done using a Z test. Results. The 5-year cumulative survival rate for patients with stage II uterine corpus adenocarcinoma who received surgery alone as primary therapy was 84.36% with simple hysterectomy and 92.96% with radical hysterectomy (P < 0.05). Survival for patients who received combination radiation and surgery as primary therapy was 82.77% with simple hysterectomy and 88.02% with radical hysterectomy (P < 0.05). Pelvic and para-aortic nodes were negative. There was no significant survival difference for radiation versus no radiation in either surgical group. Conclusion. Radical hysterectomy is associated with better survival when compared to simple hysterectomy for FIGO LI corpus uteri adenocarcinoma. C1 NCI, Div Canc Prevent, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Johns Hopkins Hosp, Dept Obstet & Gynecol, Div Gynecol Oncol, Baltimore, MD 21287 USA. Johns Hopkins Med Inst, Baltimore, MD 21287 USA. RP Cornelison, TL (reprint author), NCI, Div Canc Prevent, Bethesda, MD 20892 USA. NR 30 TC 44 Z9 46 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD SEP PY 1999 VL 74 IS 3 BP 350 EP 355 DI 10.1006/gyno.1999.5501 PG 6 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 238JX UT WOS:000082708100005 PM 10479492 ER PT J AU Parens, E Asch, A AF Parens, E Asch, A TI The disability rights critique of prenatal genetic testing - Reflections and recommendations SO HASTINGS CENTER REPORT LA English DT Article ID DIAGNOSIS; CHILDREN; AUTONOMY; MOTHERS C1 Hastings Ctr, Adjunct Associate Educ, Garrison, NY USA. George Washington Univ, Washington, DC USA. New England Med Ctr, Boston, MA 02111 USA. NIH, Natl Ctr Human Genome Res, Bethesda, MD 20892 USA. Univ Utah, Salt Lake City, UT USA. Univ Oregon, Eugene, OR 97403 USA. CUNY, Grad Sch & Univ Ctr, New York, NY USA. SUNY Stony Brook, Stony Brook, NY 11794 USA. Natl Ctr Educ Restruct & Inclus, New York, NY USA. Univ Tennessee, Knoxville, TN USA. Amer Med Assoc, Eth Inst, Chicago, IL 60610 USA. Univ N Carolina, Chapel Hill, NC USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. Beth Israel Med Ctr, New York, NY 10003 USA. New England Med Ctr, Boston, MA 02111 USA. NYU, New York, NY USA. Wprld Inst Disabil, Oakland, CA USA. SUNY Albany, Albany, NY 12222 USA. Eunice Kennedy Shriver Ctr Mental Retardat Inc, Waltham, MA 02154 USA. RP Parens, E (reprint author), Hastings Ctr, Adjunct Associate Educ, Garrison, NY USA. NR 68 TC 1 Z9 1 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0093-0334 J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD SEP-OCT PY 1999 VL 29 IS 5 PG 24 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA 250HA UT WOS:000083381900012 ER PT J AU Norquist, G Hyman, SE AF Norquist, G Hyman, SE TI Advances in understanding and treating mental illness: Implications for policy SO HEALTH AFFAIRS LA English DT Article ID ASSERTIVE COMMUNITY TREATMENT; SUBSTANCE-ABUSE SERVICES; PRIMARY-CARE; MEDICAL OUTCOMES; DOUBLE-BLIND; DEPRESSION; DISORDERS; SCHIZOPHRENIA; MANAGEMENT; THERAPY AB Mental illnesses have a significant impact on public health and contribute to a substantial part of the disability of the general population. Recent research on understanding and treating such illnesses has produced data that can inform policymakers about how to improve the condition of persons who suffer from these illnesses. This paper discusses how this re search can be used to inform policy decisions regarding the allocation of community treatment resources and what research is still needed. C1 NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90024 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Norquist, G (reprint author), NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. NR 53 TC 20 Z9 20 U1 1 U2 2 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD SEP-OCT PY 1999 VL 18 IS 5 BP 32 EP 47 DI 10.1377/hlthaff.18.5.32 PG 16 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 237GE UT WOS:000082646600004 PM 10495590 ER PT J AU Feldman, S AF Feldman, S TI Strangers in the night: Research and managed mental health care SO HEALTH AFFAIRS LA English DT Article C1 United Behav Hlth, San Francisco, CA USA. NIMH, Staff Coll, Bethesda, MD 20892 USA. NIMH, Natl Community Mental Hlth Program, Bethesda, MD 20892 USA. NIMH, Appl Serv Res Program, Bethesda, MD 20892 USA. RP Feldman, S (reprint author), United Behav Hlth, San Francisco, CA USA. NR 4 TC 12 Z9 12 U1 0 U2 0 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD SEP-OCT PY 1999 VL 18 IS 5 BP 48 EP 51 DI 10.1377/hlthaff.18.5.48 PG 4 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 237GE UT WOS:000082646600005 PM 10495591 ER PT J AU Lubin, JH AF Lubin, JH TI Response to Cohen's comments on the Lubin rejoinder SO HEALTH PHYSICS LA English DT Letter ID RESIDENTIAL RADON EXPOSURE; LUNG-CANCER; RISK C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 8 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD SEP PY 1999 VL 77 IS 3 BP 330 EP 332 PG 3 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 226FN UT WOS:000082009800014 PM 10456507 ER PT J AU Peterson, AB Hall, T AF Peterson, AB Hall, T TI Nursing challenge: Caring for a patient with complex, multiple complications SO HEART & LUNG LA English DT Editorial Material C1 NIH, Dept Nursing, Bethesda, MD 20892 USA. RP Peterson, AB (reprint author), NIH, Dept Nursing, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0147-9563 J9 HEART LUNG JI Heart Lung PD SEP-OCT PY 1999 VL 28 IS 5 BP 373 EP 376 DI 10.1053/hl.1999.v28.a100954 PG 4 WC Cardiac & Cardiovascular Systems; Nursing; Respiratory System SC Cardiovascular System & Cardiology; Nursing; Respiratory System GA 237VL UT WOS:000082677200009 PM 10486455 ER PT J AU Ogata, N Cote, PJ Zanetti, AR Miller, RH Shapiro, M Gerin, J Purcell, RH AF Ogata, N Cote, PJ Zanetti, AR Miller, RH Shapiro, M Gerin, J Purcell, RH TI Licensed recombinant hepatitis B vaccines protect chimpanzees against infection with the prototype surface gene mutant of hepatitis B virus SO HEPATOLOGY LA English DT Article ID IMMUNE GLOBULIN PROPHYLAXIS; POLYMERASE CHAIN-REACTION; INDUCED ESCAPE MUTANT; S-GENE; MOLECULAR EPIDEMIOLOGY; LIVER-TRANSPLANTATION; CARRIER STATE; IMMUNOLOGICAL ANALYSIS; MONOCLONAL-ANTIBODY; ACTIVE IMMUNIZATION AB The emergence in vaccinated individuals of hepatitis B virus (HBV) mutants with amino acid substitutions within the a determinant of the surface protein has raised the possibility that such variants represent neutralization escape mutants, We previously demonstrated that one such mutant HBV, strain AS, with an arginine substituted for glycine at surface gene codon 145, was infectious and pathogenic in seronegative chimpanzees. In the present study, the protective efficacy of licensed hepatitis B vaccines was evaluated against challenge with this mutant virus, Four chimpanzees were immunized with 1 of 2 licensed recombinant hepatitis B vaccines. Shortly after the chimpanzees developed antibodies to hepatitis B surface antigen (anti-HBs), they were challenged intravenously with mutant HBV strain AS. Two unvaccinated chimpanzees served as positive controls. The 4 vaccinated chimpanzees did not develop evidence of HBV infection or hepatitis during 2 years following virus challenge. In contrast, the 2 unvaccinated chimpanzees developed HBV infection and hepatitis. Serum anti-HBs in the vaccinated chimpanzees reacted not only with wild-type surface antigen, but also with mutant surface antigen by competition enzyme-linked immunosorbent assay (ELISA), Thus, immunization of chimpanzees with licensed recombinant hepatitis B vaccines stimulates anti-HBs that is broadly reactive and affords protection against infection with a surface gene mutant of HBV, suggesting that properly immunized individuals are not at significant risk of infection with this prototype variant strain of HBV. C1 NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Toyama Med & Pharmaceut Univ, Dept Clin & Lab Med, Toyama, Japan. Georgetown Univ, Ctr Med, Div Mol Virol & Immunol, Rockville, MD USA. Univ Milan, Inst Virol, Milan, Italy. NIAID, Target Intervent Branch, Div Aids, Bethesda, MD 20892 USA. Bioqual Inc, Rockville, MD USA. RP Purcell, RH (reprint author), NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, 7 Ctr Dr,MSC 0740, Bethesda, MD 20892 USA. FU NIAID NIH HHS [N01-AI-52705, N01-AI-45180, N01-AI-22394-1028] NR 86 TC 75 Z9 80 U1 1 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD SEP PY 1999 VL 30 IS 3 BP 779 EP 786 DI 10.1002/hep.510300309 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 230PL UT WOS:000082259500025 PM 10462386 ER PT J AU Reddy, KR Hoofnagle, JH Tong, MJ Lee, WM Pockros, P Heathcote, EJ Albert, D Joh, T AF Reddy, KR Hoofnagle, JH Tong, MJ Lee, WM Pockros, P Heathcote, EJ Albert, D Joh, T CA Consensus Interferon Study Grp TI Racial differences in responses to therapy with interferon in chronic hepatitis C SO HEPATOLOGY LA English DT Article ID SENSITIVITY-DETERMINING REGION; AMINO-ACID SUBSTITUTIONS; NON-B-HEPATITIS; CONTROLLED TRIAL; CONSENSUS INTERFERON; VIRUS-INFECTION; VIRAL-HEPATITIS; ALPHA THERAPY; FOLLOW-UP; 5A GENE AB The likelihood of a sustained response to a course of interferon in patients with chronic hepatitis C correlates with several clinical and viral factors, including age, viral genotype and initial levels of hepatitis C virus (HCV) RNA in serum. The role of race and ethnicity has not been assessed. We evaluated the association of race with response to interferon in a large randomized, controlled trial using either consensus interferon (9 mu g) or interferon alfa-2b (3 million units) given three times weekly for 24 weeks. African-American patients participating in the study were similar to white patients in mean age (43 vs. 42 years) and baseline levels of HCV RNA (3.6 vs. 3.0 million copies/mL) but had lower rates of cirrhosis (5% vs. 12%) and more frequently had viral genotype 1 (88% vs. 66%: P =.004). Most strikingly, the rates of end-of-treatment and sustained virological responses were lower among the 40 African-American patients (5% and 2%) than among the 380 white patients (33% and 12%) (P =.04 and .07). Rates of response among Hispanic and Asian-American patients were not statistically different than non-Hispanic white patients. Median viral levels decreased by week 24 of therapy by 2.5 logs in white patients (from 3.0 to 0.012 million copies/mL) but by only 0.5 logs among African-American patients (from 3.6 to 1.8 million copies/mL). Thus, there are marked racial differences in virological responses to interferon in hepatitis C that must be considered in assessing trials of interferon therapy and in counseling patients regarding treatment. The differences in response rates are as yet unexplained. C1 NIDDKD, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. Univ Miami, Miami, FL 33152 USA. Huntington Mem Hosp, Pasadena, CA USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Scripps Clin, La Jolla, CA USA. Univ Toronto, Toronto, ON, Canada. Amgen Inc, Boulder, CO USA. Amgen Inc, Thousand Oaks, CA 91320 USA. RP NIDDKD, Div Digest Dis & Nutr, NIH, Bldg 31,Room 9A23, Bethesda, MD 20892 USA. EM HoofnagleJ@extra.niddk.nih.gov NR 39 TC 219 Z9 221 U1 0 U2 2 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD SEP PY 1999 VL 30 IS 3 BP 787 EP 793 DI 10.1002/hep.510300319 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 230PL UT WOS:000082259500026 PM 10462387 ER PT J AU Torpy, DJ Bornstein, SR Taylor, W Tauchnitz, R Gordon, RD AF Torpy, DJ Bornstein, SR Taylor, W Tauchnitz, R Gordon, RD TI Leptin levels are suppressed in primary aldosteronism SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE leptin; aldosterone; hypertension; adrenalectomy; potassium ID PLASMA LEPTIN; INSULIN SENSITIVITY; SECRETION; GLUCOSE AB Primary aldosteronism is associated with hypertension secondary to salt and water retention, hypokalemia and impaired insulin secretion with glucose intolerance in some patients. The secretion of leptin, a hormone produced by adipocytes, may be altered by reduced insulin secretion in primary aldosteronism. We measured plasma leptin approximately 3 months before and 3 months after curing of primary aldosteronism in 18 patients (12 male, 6 female, body mass index 29.1 +/- 4.4, mean +/- SD). Patients were treated by unilateral laparoscopic adrenalectomy to remove an aldosterone-producing adenoma. There was a 46% postoperative increase in plasma leptin concentrations from 6.65 +/- 0.81 to 9.68 +/- 1.50 ng/ml (P = 0.004), despite a non-significant fall in body mass index. Plasma leptin was noted to increase after adrenalectomy in 16 of the 18 patients. The patients also had improved blood pressure and a significant increase in plasma potassium post-operatively. It is proposed that increased insulin secretory capacity associated with correction of negative potassium balance may account for the increase in plasma leptin after curing primary aldosteronism. Further studies are indicated to identify the mechanism of plasma leptin suppression in primary aldosteronism. C1 Univ Queensland, Dept Med, Greenslopes Hosp, Hypertens Unit, Brisbane, Qld 4120, Australia. NIH, Dev Endocrinol Branch, Bethesda, MD 20892 USA. Univ Leipzig, Dept Med, D-7010 Leipzig, Germany. RP Torpy, DJ (reprint author), Univ Queensland, Dept Med, Greenslopes Hosp, Hypertens Unit, Newdegate St, Brisbane, Qld 4120, Australia. RI Gordon, Richard/K-2555-2012 NR 17 TC 22 Z9 24 U1 0 U2 0 PU GEORG THIEME VERLAG PI STUTTGART PA P O BOX 30 11 20, D-70451 STUTTGART, GERMANY SN 0018-5043 J9 HORM METAB RES JI Horm. Metab. Res. PD SEP PY 1999 VL 31 IS 9 BP 533 EP 536 DI 10.1055/s-2007-978789 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 254VZ UT WOS:000083634000008 PM 10569256 ER PT J AU Nyska, A Maronpot, RR Ghanayem, BI AF Nyska, A Maronpot, RR Ghanayem, BI TI Ocular thrombosis and retinal degeneration induced in female F344 rats by 2-butoxyethanol SO HUMAN & EXPERIMENTAL TOXICOLOGY LA English DT Article DE rat; ethylene glycol monobutyl ether; retina; thrombosis ID MONOBUTYL ETHER 2-BUTOXYETHANOL; HEMOLYTIC-ANEMIA; TOXICITY; ALCOHOL AB 2-butoxyethanol, used extensively for domestic and industrial purposes, was tested in our experiments for its potential to cause damage to female rat ocular tissues. Female rats were previously found to be particularly sensitive to 2-butoxyethanol. A group of eight female F344 rats (2 - 3 months old) were exposed by gavage to 250 mg of 2-butoxyethanol/kg b.w. per day for 3 consecutive days and sacrificed 24 h after the last dose. Eight female rats received the dosing vehicle (water) and served as controls. At necropsy, petechial hemorrhages were noted on the sclera. Microscopic examination revealed treatment-related effects in the eyes, in addition to other known effects of BE exposure such as disseminated thrombosis and necrosis and infarction in various organs. The spectrum of histopathological changes noted in the eyes included hemorrhages localized in the posterior layers of time retina, leading to photoreceptor degeneration. Thrombi were identified in ciliary processes and limbal blood vessels. Histological changes suggestive of the retinal ischemic-infarctive process were also noted. Possible pathogenic mechanisms of 2-butoxyethanol-induced retinopathy are discussed. C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Nyska, A (reprint author), NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 23 TC 15 Z9 16 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0144-5952 J9 HUM EXP TOXICOL JI Hum. Exp. Toxicol. PD SEP PY 1999 VL 18 IS 9 BP 577 EP 582 DI 10.1191/096032799678845070 PG 6 WC Toxicology SC Toxicology GA 247QL UT WOS:000083231400006 PM 10523872 ER PT J AU Licht, T Aran, JM Goldenberg, SK Vieira, WD Gottesman, MM Pastan, I AF Licht, T Aran, JM Goldenberg, SK Vieira, WD Gottesman, MM Pastan, I TI Retroviral transfer of human MDR1 gene to hematopoietic cells: Effects of drug selection and of transcript splicing on expression of encoded P-glycoprotein SO HUMAN GENE THERAPY LA English DT Article ID MULTIDRUG-RESISTANCE GENE; BONE-MARROW CELLS; ADENOSINE-DEAMINASE GENE; PROGENITOR CELLS; STEM-CELLS; TRANSPLANTED MICE; SELECTABLE MARKER; MEDIATED TRANSFER; TRANSGENIC MICE; PRECURSOR CELLS AB Protection of hematopoietic cells of patients undergoing anticancer chemotherapy by MDR1 gene transfer is currently being studied in clinical trials. From animal studies, it has been suggested that aberrant splicing. due to cryptic donor and acceptor sites in the MDR1 cDNA could be a major reason for failure to obtain high-level expression of P-glycoprotein in bone marrow. We investigated effects of drug selection on protein expression levels and on splicing of MDR1 transcripts in murine bone marrow cells (BMCs) in vitro. To this end, retroviruses were generated through an identical plasmid, pHaMDR1/A, introduced into different packaging cells. GP + E86- but not PA317-derived producer cells were found to express truncated in addition to full-length message. In BMCs transduced with GP + E86-derived viruses, both messages were increased after treatment with colchicine or daunomycin. Similar results were obtained with NIH 3T3 fibroblasts. However, transduced and drug-selected BMCs displayed the spliced transcript even if the respective PA317-derived producer cells contained no truncated RNA as detected in transduced NIH 3T3 fibroblasts, Short-term drug selection in BMCs transduced with either ecotropic or amphotropic retroviruses resulted in a striking increase in P-glycoprotein expression. Thus, aberrant splicing failed to abrogate P-glycoprotein expression in BMCs, We also studied a vector in which MDR1 was coexpressed with glucocerebrosidase, using an internal ribosomal entry site. Although chemoprotection was less efficient than with pHaMDR1/A, augmentation of protein expression was observed at low selecting drug concentrations. Our study shows that drug selection can partially compensate for inefficient transduction of hematopoietic cells, and may help to develop strategies by which unstable expression of transduced genes can be overcome. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37,Room 4E16,37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. NR 50 TC 12 Z9 15 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD SEP 1 PY 1999 VL 10 IS 13 BP 2173 EP 2185 DI 10.1089/10430349950017167 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 237PD UT WOS:000082664500009 PM 10498249 ER PT J AU Vendola, K Zhou, J Wang, J Bondy, CA AF Vendola, K Zhou, J Wang, J Bondy, CA TI Androgens promote insulin-like growth factor-I and insulin-like growth factor-I receptor gene expression in the primate ovary SO HUMAN REPRODUCTION LA English DT Article DE folliculogenesis; granulosa cells; PCOS; testosterone; theca ID MESSENGER RIBONUCLEIC-ACIDS; IGF-I; GRANULOSA-CELLS; MALE-TRANSSEXUALS; TREATED FEMALE; RAT UTERUS; LOCALIZATION; TESTOSTERONE; ESTROGEN; SYSTEM AB It has recently been shown that androgens increase the growth of immature follicles in the primate ovary. In the present study the effect of androgens on ovarian insulinlike growth factor I(IGF-I) and IGF-I receptor gene expression was investigated. The study groups included five follicular phase, placebo-treated controls, and four testosterone- and three dihydrotestosterone (DHT)-treated rhesus monkeys. The treatment period was 5 days. Both testosterone and DHT treatment resulted in significant, 3-4-fold increases in IGF-I mRNA concentration in granulosa, thecal and interstitial compartments. Likewise, both androgens induced significant increases in the amount of IGF-I receptor mRNA, most notably in thecal cells and less markedly in granulosa and interstitium (P < 0.05). These changes in amounts of IGF system mRNA were documented in growing follicles up to the small antral (less than or equal to 1 mm diameter) stage. Larger follicles were too few in number for significant comparisons. By contrast, amounts of ovarian insulin receptor mRNA were not appreciably altered by androgen treatment. These data suggest that IGP-I and its cognate receptor may mediate androgen-induced ovarian follicular and thecal-interstitial growth. C1 NICHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Bondy, CA (reprint author), NICHD, Dev Endocrinol Branch, NIH, Bg 10,Rm 10N262,10 Ctr Dr 1862, Bethesda, MD 20892 USA. NR 36 TC 106 Z9 113 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD SEP PY 1999 VL 14 IS 9 BP 2328 EP 2332 DI 10.1093/humrep/14.9.2328 PG 5 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 235VY UT WOS:000082564300030 PM 10469704 ER PT J AU Domanski, MJ Davis, BR Pfeffer, MA Kastantin, M Mitchell, GF AF Domanski, MJ Davis, BR Pfeffer, MA Kastantin, M Mitchell, GF TI Isolated systolic hypertension - Prognostic information provided by pulse pressure SO HYPERTENSION LA English DT Article DE pulse pressure; stroke; hypertension; elderly; compliance ID DIASTOLIC BLOOD-PRESSURE; INTIMA-MEDIA THICKNESS; MYOCARDIAL-INFARCTION; ARTERIAL STIFFNESS; CARDIOVASCULAR MORTALITY; CAROTID STENOSIS; OLDER ADULTS; RISK FACTOR; ATHEROSCLEROSIS; DISTENSIBILITY AB Increased arterial stiffness results in increased characteristic impedance of the aorta and increased pulse wave velocity, which increases systolic and pulse pressures, An association between increased pulse pressure and adverse cardiovascular events has been found in normotensive and hypertensive patient populations. Increased pulse pressure has also been associated with thickening of the carotid intima and media. However, the relationship between pulse pressure and stroke has not previously been evaluated. In this study, we examined the hypothesis that pulse pressure is an independent predictor of stroke in elderly patients with systolic hypertension entered in the Systolic Hypertension in the Elderly Program. Differences in baseline characteristics were examined by tertiles of pulse pressure. The independent prognostic value of pulse pressure and mean arterial pressure for predicting either stroke or total mortality was assessed with Cox proportional hazards models that included pulse pressure, mean arterial pressure, and other variables that were significant on univariate analysis. This analysis demonstrated an 11% increase in stroke risk and a 16% increase in risk of all-cause mortality for each 10-mm Hg increase in pulse pressure. Each IO-mm Hg increase in mean arterial pressure was independently associated with a 20% increase in the risk of stroke and a 14% increase in the risk of all-cause mortality. These data provide strong evidence of an association of increased conduit vessel stiffness, as indicated by increased pulse pressure, with stroke and total mortality, independent of the effects of mean arterial pressure, in elderly patients with isolated systolic hypertension. C1 NHLBI, Clin Trials Grp, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. Univ Texas, Sch Publ Hlth, Houston, TX USA. Cardiovasc Engn Inc, Dover, MA USA. RP Domanski, MJ (reprint author), NHLBI, Clin Trials Grp, 6701 Rockledge Dr,RM 8146, Bethesda, MD 20892 USA. RI Kastantin, Mark/C-7519-2011 OI Kastantin, Mark/0000-0003-1766-8747 NR 43 TC 226 Z9 254 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD SEP PY 1999 VL 34 IS 3 BP 375 EP 380 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 239JU UT WOS:000082765600003 PM 10489379 ER PT J AU Lloyd-Jones, DM Evans, JC Larson, MG O'Donnell, CJ Levy, D AF Lloyd-Jones, DM Evans, JC Larson, MG O'Donnell, CJ Levy, D TI Differential impact of systolic and diastolic blood pressure level on JNC-VI staging SO HYPERTENSION LA English DT Article DE hypertension, detection and control; risk factors; epidemiology; guidelines ID CORONARY HEART-DISEASE; HYPERTENSION; FRAMINGHAM; PLACEBO AB The sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure classifies blood pressure into stages on the basis of both systolic (SBP) and diastolic (DBP) blood pressure levels. When a disparity exists between SEP and DBP stages, patients are classified into the higher stage ("up-staged"). We evaluated the effect of disparate levels of SEP and DBP on blood pressure staging and eligibility for therapy. We examined 4962 Framingham Heart Study subjects between 1990 and 1995 and determined blood pressure stages on the basis of SEP alone, DBP alone, or both. After the exclusion of subjects on antihypertensive therapy (n=1306), 3656 subjects (mean age 58+/-13 years; 55% women) were eligible. In this sample, 64.6% of subjects had congruent stages of SEP and DBP, 31.6% were up-staged on the basis of SEP, and 3.8% on the basis of DBP; thus, SEP alone correctly classified JNC-VI stage in approximate to 96% (64.6% +31.6%) of the subjects. Among subjects >60 years of age, SEP alone correctly classified 99% of subjects; in those less than or equal to 60 years old, SEP alone correctly classified 95%. Of 1488 subjects with high-normal blood pressure or hypertension, who were potentially eligible for drug therapy, 13.0% had congruent elevations of SEP and DBP, 77.7% were up-staged on the basis of SEP, and 9.3% were up-staged on the basis of DBP; SEP alone correctly classified 91%, whereas DBP alone correctly classified only 22%. SEP elevation out of proportion to DBP is common in middle-aged and older persons. SEP appears to play a greater role in the determination of JNC-VI blood pressure stage and eligibility for therapy. Given these results, combined with evidence from hypertension treatment trials, future guidelines might consider a greater role for SEP than for DBP in determining the presence of hypertension, risk of cardiovascular events, eligibility for therapy, and benefits of treatment. C1 NHLBI, Framingham Heart Study, NIH, Framingham, MA 01702 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Cardiol Div, Boston, MA 02114 USA. Boston Univ, Sch Med, Div Epidemiol & Prevent Med, Boston, MA 02118 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, NIH, 5 Thurber St, Framingham, MA 01702 USA. RI Lloyd-Jones, Donald/C-5899-2009 FU NHLBI NIH HHS [N01-HC-38038] NR 24 TC 84 Z9 88 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD SEP PY 1999 VL 34 IS 3 BP 381 EP 385 PG 5 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 239JU UT WOS:000082765600004 PM 10489380 ER PT J AU Moore, TJ Vollmer, WM Appel, LJ Sacks, FM Svetkey, LP Vogt, TM Conlin, PR Simons-Morton, DG Carter-Edwards, L Harsha, DW AF Moore, TJ Vollmer, WM Appel, LJ Sacks, FM Svetkey, LP Vogt, TM Conlin, PR Simons-Morton, DG Carter-Edwards, L Harsha, DW CA DASH Collaborative Res Grp TI Effect of dietary patterns on ambulatory blood pressure - Results from the Dietary Approaches to Stop Hypertension (DASH) Trial SO HYPERTENSION LA English DT Article DE blood pressure monitoring, ambulatory; nutrition; diet; blood pressure ID NORMOTENSIVE MEN; SALT RESTRICTION; CLINICAL-TRIALS; EXERCISE; FAILURE; DISEASE; RHYTHM AB We measured ambulatory blood pressure (ABP) in 354 participants in the Dietary Approaches to Stop Hypertension (DASH) Trial to determine the effect of dietary treatment on ABP (24-hour, day and night) and to assess participants' acceptance of and compliance with the ABP monitoring (ABPM) technique, After a 3-week run-in period on a control "typical" American diet, subjects (diastolic blood pressure [BP], 80 to 95 mm Hg; systolic BP, <160 mm Hg; mean age, 45 years) were randomly assigned to 1 of 3 diets for an 8-week intervention period: a continuation of the control diet; a diet rich in fruits and vegetables; and a "combination" diet: that emphasized fruits, vegetables, and low-fat dairy products. We measured ABP at the end of the run-in and intervention periods. Both the fruit/vegetable and combination diets lowered 24-hour ABP significantly compared with the control diet (P<0.0001 for systolic and diastolic pressures on both diets: control diet, -0.2/+0.1 mm Hg; fruit/vegetable diet, -3.2/-1.9 mm Hg; combination diet, -4.6/-2.6 mm Hg). The combination diet lowered pressure during both day and night. Hypertensive subjects had a significantly greater response than normotensives to the combination diet (24-hour ABP, -10.1/-5.5 versus -2.3/-1.6 mm Hg, respectively). After correction for the control diet responses, the magnitude of BP lowering was not significantly different whether measured by ABPM or random-zero sphygmomanometry. Participant acceptance of ABPM was excellent: only 1 participant refused to wear the ABP monitor, and 7 subjects (2%) provided incomplete recordings. These results demonstrate that the DASH combination diet provides significant round-the-clock reduction in BP, especially in hypertensive participants:. C1 Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Merck & Co Inc, Westwood, MA USA. Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. Duke Univ, Med Ctr, Duke Hypertens Ctr, Durham, NC USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. Pennington Biomed Res Ctr, Baton Rouge, LA USA. Kaiser Permanente Ctr Hlth Res, Honolulu, HI USA. RP Moore, TJ (reprint author), Suite 365,690 Canton St, Westwood, MA 02090 USA. FU NHLBI NIH HHS [HL-50968, HL-50972, HL-50981] NR 23 TC 70 Z9 71 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD SEP PY 1999 VL 34 IS 3 BP 472 EP 477 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 239JU UT WOS:000082765600020 PM 10489396 ER PT J AU Brigger, P Muller, F Illgner, K Unser, M AF Brigger, P Muller, F Illgner, K Unser, M TI Centered pyramids SO IEEE TRANSACTIONS ON IMAGE PROCESSING LA English DT Article DE Haar pyramid; multiresolution decomposition; multiscale processing; pyramids ID SPLINE FILTERS; SEGMENTATION; L(2) AB Quadtree-like pyramids have the advantage of resulting in a multiresolution representation where each pyramid node has four unambiguous parents. Such a centered topology guarantees a clearly defined up-projection of labels. This concept has been successfully and extensively used in applications of contour detection, object recognition and segmentation. Unfortunately, the quadtree-like type of pyramid has poor approximation powers because of the employed piecewise-constant image model. This paper deals with the construction of improved centered image pyramids in terms of general approximation functions. The advantages of the centered topology such a symmetry, consistent boundary conditions and accurate up-projection of labels are combined with a more faithful image representation at coarser pyramid levels. We start by introducing a general framework for the design of least squares pyramids using the standard filtering and decimation tools. We give the most general explicit formulas for the computation of the filter coefficients by any (well behaving) approximation function in both the continuous (L-2) and the discrete (l(2)) norm. We then define centered pyramids and provide the filter coefficients for odd spline approximation functions. Finally, we compare the centered pyramid to the ordinary one and highlight some applications. C1 NIH, Natl Ctr Res Resources, Biomed Engn & Instrumentat Program, Bethesda, MD 20892 USA. Aachen Univ Technol, D-52056 Aachen, Germany. Texas Instruments Inc, DSPS R&D Ctr, Dallas, TX 75265 USA. Swiss Fed Inst Technol, Biomed Imaging Grp, CH-1015 Lausanne, Switzerland. RP Brigger, P (reprint author), ImageMinds, Greenwich, CT 06830 USA. RI Unser, Michael/A-1550-2008 NR 26 TC 15 Z9 15 U1 0 U2 3 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017-2394 USA SN 1057-7149 J9 IEEE T IMAGE PROCESS JI IEEE Trans. Image Process. PD SEP PY 1999 VL 8 IS 9 BP 1254 EP 1264 DI 10.1109/83.784437 PG 11 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic SC Computer Science; Engineering GA 231AB UT WOS:000082282900009 PM 18267542 ER PT J AU Pham, DL Prince, JL AF Pham, DL Prince, JL TI Adaptive fuzzy segmentation of magnetic resonance images SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE clustering methods; fuzzy sets; image segmentation; magnetic resonance imaging ID MR-IMAGES; INTENSITY NONUNIFORMITY; CLUSTERING ALGORITHMS; BRAIN IMAGES; GRAY-MATTER; MIXTURES; WHITE AB An algorithm is presented for the fuzzy segmentation of two-dimensional (2-D) and three-dimensional (3-D) multispectral magnetic resonance (MR) images that have been corrupted by intensity inhomogeneities, also known as shading artifacts. The algorithm is an extension of the 2-D adaptive fuzzy C-means algorithm (2-D AFCM) presented in previous work by the authors, This algorithm models the intensity inhomogeneities as a gain field that causes image intensities to smoothly and slowly vary through the image space. It iteratively adapts to the intensity inhomogeneities and is completely automated. In this paper, we fully generalize 2-D AFCM to three-dimensional (3-D) multispectral images. Because of the potential size of 3-D image data, we also describe a new faster multigrid-based algorithm for its implementation. We show, using simulated MR data, that 3-D AFCM yields lower error rates than both the standard fuzzy C-means (FCM) algorithm and two other competing methods, when segmenting corrupted images. Its efficacy is further demonstrated using real 3-D scalar and multispectral MR brain images. C1 Johns Hopkins Univ, Dept Elect & Comp Engn, Image Anal & Commun Lab, Baltimore, MD 21218 USA. Johns Hopkins Univ, Image Anal & Commun Lab, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. NIA, Lab Personal & Cognit, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Prince, JL (reprint author), Johns Hopkins Univ, Dept Elect & Comp Engn, Image Anal & Commun Lab, Baltimore, MD 21218 USA. RI Prince, Jerry/A-3281-2010 OI Prince, Jerry/0000-0002-6553-0876 FU NINDS NIH HHS [1RO1NS37747-01] NR 39 TC 482 Z9 507 U1 3 U2 18 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017-2394 USA SN 0278-0062 J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD SEP PY 1999 VL 18 IS 9 BP 737 EP 752 DI 10.1109/42.802752 PG 16 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 255UW UT WOS:000083689400001 PM 10571379 ER PT J AU Dittel, BN Stefanova, I Germain, RN Janeway, CA AF Dittel, BN Stefanova, I Germain, RN Janeway, CA TI Cross-antagonism of a T cell clone expressing two distinct T cell receptors SO IMMUNITY LA English DT Article ID PROTEIN-TYROSINE KINASE; PEPTIDE-MHC COMPLEXES; ANTIGEN RECEPTOR; SIGNAL-TRANSDUCTION; ZETA-PHOSPHORYLATION; PARTIAL AGONISTS; ACTIVATION; TCR; LIGANDS; ZAP-70 AB Inhibition of T cell activation can be mediated by analogs of the original antigenic peptide (TCR antagonists). Here, a T cell clone expressing two distinct TCR was used to investigate whether such inhibition involves an active mechanism by examining whether an antagonist for one TCR could influence responses stimulated by the other TCR engaging its agonist. Our results demonstrate functional cross-inhibition under these conditions involving the ability of antagonist: TCR interactions to diminish Lck enzymatic activity associated with the agonist-recognizing second TCR, apparently through enhancement of SHP-1 association with these receptors. Our findings reveal that inhibition of cellular responses by antagonists arises at least in part from active negative regulation of proximal TCR signaling and identify elements of the biochemical process. C1 Yale Univ, Sch Med, Immunobiol Sect, New Haven, CT 06510 USA. Howard Hughes Med Inst, New Haven, CT 06510 USA. NIAID, Lymphocyte Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Dittel, BN (reprint author), Yale Univ, Sch Med, Immunobiol Sect, 333 Cedar St, New Haven, CT 06510 USA. FU NIAID NIH HHS [AI/AR36529] NR 50 TC 79 Z9 80 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD SEP PY 1999 VL 11 IS 3 BP 289 EP 298 DI 10.1016/S1074-7613(00)80104-1 PG 10 WC Immunology SC Immunology GA 242BN UT WOS:000082918500004 PM 10514007 ER PT J AU Aringer, M Frucht, DM O'Shea, JJ AF Aringer, M Frucht, DM O'Shea, JJ TI Interleukin/interferon signaling - A 1999 perspective SO IMMUNOLOGIST LA English DT Review ID SEVERE COMBINED IMMUNODEFICIENCY; INTERFERON-GAMMA-RECEPTOR; GERMINAL-CENTER FORMATION; NECROSIS-FACTOR-ALPHA; IFN-GAMMA; INTERLEUKIN-2 RECEPTOR; TARGETED DISRUPTION; IL-2 RECEPTOR; T-LYMPHOCYTES; SELECTIVE EXPRESSION AB The molecular understanding of cytokine signaling has recently advanced due to new information on knockout animals and patients with mutations, as well as the discovery of inhibitory proteins. Here, Martin Aringer, David M. Frucht, and John J, O'Shea discuss the developments, focusing on the receptors for interferon-gamma, IL-2, IL-4, and IL-12. C1 Univ Vienna, Dept Rheumatol Internal Med 3, A-1090 Vienna, Austria. NIAMSD, Lymphocyte Biol Sect, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. RP Aringer, M (reprint author), Univ Vienna, Dept Rheumatol Internal Med 3, Waehringer Guertel 18-20, A-1090 Vienna, Austria. NR 103 TC 2 Z9 2 U1 0 U2 0 PU HOGREFE & HUBER PUBLISHERS PI KIRKLAND PA PO BOX 2487, KIRKLAND, WA 98083-2487 USA SN 1192-5612 J9 IMMUNOLOGIST JI Immunologist PD SEP-OCT PY 1999 VL 7 IS 5 BP 139 EP 146 PG 8 WC Immunology SC Immunology GA 262BY UT WOS:000084046800002 ER PT J AU Ashwell, JD D'Oro, U AF Ashwell, JD D'Oro, U TI CD45 and Src-family kinases: and now for something completely different SO IMMUNOLOGY TODAY LA English DT Editorial Material ID PROTEIN-TYROSINE-PHOSPHATASE; T-CELL RECEPTOR; LEUKOCYTE-COMMON ANTIGEN; PHOSPHOTYROSINE PHOSPHATASE; THYMOCYTE DEVELOPMENT; NEGATIVE REGULATION; ENZYME-ACTIVITY; LYMPHOCYTES-T; C ACTIVATION; B-CELLS AB How does the CD45 tyrosine phosphatase regulate Src-family kinase activity in vivo? Here, Jonathan Ashwell and Ugo D'Oro discuss evidence that, contrary to the widely accepted model, CD45 can actually inhibit the activity of some Src-family kinases by dephosphorylating the positive regulatory tyrosine in the activation loop of the catalytic region. C1 NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. RP Ashwell, JD (reprint author), NCI, Lab Immune Cell Biol, NIH, Bldg 10,Room 1B-40,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 63 TC 79 Z9 81 U1 0 U2 3 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 SEP PY 1999 VL 20 IS 9 BP 412 EP 416 DI 10.1016/S0167-5699(99)01505-4 PG 5 WC Immunology SC Immunology GA 230ZB UT WOS:000082280600007 PM 10462741 ER PT J AU Choi, Y Chuang, LF Lam, KM Kung, HF Wang, JM Osburn, BI Chuang, RY AF Choi, Y Chuang, LF Lam, KM Kung, HF Wang, JM Osburn, BI Chuang, RY TI Inhibition of chemokine-induced chemotaxis of monkey leukocytes by mu-opioid receptor agonists SO IN VIVO LA English DT Article DE chemotaxis; monkey leukocytes; chemokines; opioids ID MORPHINE-SULFATE; GENE-EXPRESSION; OPIATE RECEPTOR; LYMPHOCYTES; CLONING; BRAIN AB It is recognized that chemotaxis and phagocytosis constitute the first line of defense in the immune system, and chemokines function mainly as chemoattractants for phagocytic cells, recruiting monocytes and neutrophils from the blood to sites of infection. In this study, chemotaxis of monkey leukocytes was evaluated using human chemokines IL-8 (interleukin-8), MIP-I beta and RANTES as the chemoattractants, and the effects of mu-opioid receptor agonists, morphine, DAMGO, methadone and endomorphine, on the efficiency of chemotaxis were examined. It was found that human chemokines sewed well as chemoattractants for monkey leukocytes, and similar to the human system, chemokine-induced chemotaxis of monkey leukocytes was inhibited in the presence of mu-opioid receptor agonists. The inhibition could be reversed by naloxone, a specific mu-opioid receptor antagoinst. These studies further support the value of the monkey model for drug abuse studies in humans, as well as suggest that opioids such as morphine may alter immune functions through mu-opioid receptors on leukocytes. C1 Univ Calif Davis, Sch Med, Dept Med Pharmacol & Toxicol, Davis, CA 95616 USA. Univ Calif Davis, Dept Populat Hlth & Reprod, Davis, CA 95616 USA. Univ Calif Davis, Dept Vet Pathol Microbiol & Immunol, Davis, CA 95616 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD USA. RP Chuang, RY (reprint author), Univ Calif Davis, Sch Med, Dept Med Pharmacol & Toxicol, Davis, CA 95616 USA. FU NIDA NIH HHS [DA 05901, DA 10433] NR 18 TC 29 Z9 29 U1 0 U2 2 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDNTIOU-KALAMOU RD KAPANDRITI, POB 22, ATHENS 19014, GREECE SN 0258-851X J9 IN VIVO JI In Vivo PD SEP-OCT PY 1999 VL 13 IS 5 BP 389 EP 396 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 276FV UT WOS:000084865700003 PM 10654191 ER PT J AU Duensing, TD Wing, JS van Putten, JPM AF Duensing, TD Wing, JS van Putten, JPM TI Sulfated polysaccharide-directed recruitment of mammalian host proteins: a novel strategy in microbial pathogenesis SO INFECTION AND IMMUNITY LA English DT Article ID SERUM SPREADING FACTOR; EPITHELIAL-CELLS; NEISSERIA-GONORRHOEAE; HEPARAN-SULFATE; PROTEOGLYCAN RECEPTORS; STREPTOCOCCUS-PYOGENES; INTEGRIN RECEPTORS; VITRONECTIN BINDS; ADHERENCE; INVASION AB Fundamental to the virulence of microbial pathogens is their capacity for adaptation and survival within variable, and often hostile, environments encountered in the host. We describe a novel, extragenomic mechanism of surface modulation which may amplify the adaptive and pathogenic potential of numerous bacterial species, including Staphylococcus, Yersinia, and pathogenic Neisseria species, as well as Helicobacter pylori and Streptococcus pyogenes. The mechanism involves specific bacterial recruitment of heparin, glycosaminoglycans, or related sulfated polysaccharides, which in turn serve as universal binding sites for a diverse array of mammalian heparin binding proteins, including adhesive glycoproteins (vitronectin and fibronectin), inflammatory (MCP-3, PF-4, and MIP-1 alpha) and immunomodulatory (gamma interferon) intermediates, and fibroblast growth factor, This strategy impacts key aspects of microbial pathogenicity as exemplified by increased bacterial invasion of epithelial cells and inhibition of chemokine-induced chemotaxis, Our findings illustrate a previously unrecognized form of parasitism that complements classical virulence strategies encoded within the microbial genome. C1 NIAID, Rocky Mt Labs, Microbial Struct & Funct Lab, NIH, Hamilton, MT 59840 USA. RP NIAID, Rocky Mt Labs, Microbial Struct & Funct Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM jos_van_putten@nih.gov OI van Putten, Jos/0000-0002-4126-8172 NR 46 TC 68 Z9 71 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD SEP PY 1999 VL 67 IS 9 BP 4463 EP 4468 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 228LU UT WOS:000082138600021 PM 10456887 ER PT J AU Sreenath, TL Cho, A MacDougall, M Kulkarni, AB AF Sreenath, TL Cho, A MacDougall, M Kulkarni, AB TI Spatial and temporal activity of the dentin sialophosphoprotein gene promoter: differential regulation in odontoblasts and ameloblasts SO INTERNATIONAL JOURNAL OF DEVELOPMENTAL BIOLOGY LA English DT Article DE transgene; dentinogenesis; teeth; gene expression; DSPP ID SIALOPROTEIN DSP; MAMMALIAN TOOTH; EXPRESSION; PHOSPHOPROTEIN; HUMAN-CHROMOSOME-4; ORGANIZATION; COLLAGEN; CELLS AB Dentin sialoprotein and dentin phosphoprotein are non-collagenous proteins that are cleavage products of dentin sialophosphoprotein (DSPP). Although these two protein products are believed to have a crucial role in the process of tooth mineralization, their precise biological functions and the molecular mechanisms of gene regulation are not clearly understood. To understand such functions, we have developed a transgenic mouse model expressing a reporter gene (lacZ) under the control of similar to 6 kb upstream sequences of Dspp. The transgenic fusion protein was designed to reside within the cells to facilitate the precise identification of cell type and developmental stages at wh ich the Dspp-lacZ gene is expressed. The results presented in th is report demonstrate: (a) the 6 kb upstream sequences of Dspp have the necessary regulatory elements to direct the tissue specific expression of the transgene similar to endogenous Dspp, (b) both odontoblasts and ameloblasts exhibit transgene expression in a differentiation dependent manner, and (c) a differential regulation of the transgene in odontoblasts and ameloblasts occurs during tooth development and mineralization. C1 NIDCR, Funct Genom Unit, NIH, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. RP Kulkarni, AB (reprint author), NIDCR, Funct Genom Unit, NIH, Bldg 30,Room 529,30 Convent Dr, Bethesda, MD 20892 USA. FU NIDCR NIH HHS [DE 11658, 1Z01DE00698-1] NR 34 TC 27 Z9 27 U1 0 U2 0 PU UNIV BASQUE COUNTRY PRESS PI BILBAO PA POST BOX 1397, E-48080 BILBAO, SPAIN SN 0214-6282 J9 INT J DEV BIOL JI Int. J. Dev. Biol. PD SEP PY 1999 VL 43 IS 6 BP 509 EP 516 PG 8 WC Developmental Biology SC Developmental Biology GA 257GG UT WOS:000083773700005 PM 10610024 ER PT J AU Schrauwen, P Troost, FJ Xia, J Ravussin, E Saris, WHM AF Schrauwen, P Troost, FJ Xia, J Ravussin, E Saris, WHM TI Skeletal muscle UCP2 and UCP3 expression in trained and untrained male subjects SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE UCP gene expression; energy expenditure; endurance training ID RESTING METABOLIC-RATE; UNCOUPLING PROTEIN HOMOLOG; INDUCED THERMOGENESIS; ENERGY-EXPENDITURE; ADIPOSE-TISSUE; EXERCISE; GENE; MEDIATOR; OBESITY AB OBJECTIVE: The new uncoupling proteins, UCP2 and UCP3, are thought to play a role in energy efficiency in humans. Endurance training has been suggested to have effects on resting metabolic rate and energy efficiency, We therefore determined UCP2 and UCP3 mRNA levels in skeletal muscle of trained and untrained male subjects. METHODS: Using reverse transcription-polymerase chain reaction (RT-PCR), expression of UCP2, UCP3L and UCP3S mRNA were measured in muscle biopsies from the quadriceps femoris in eight trained (23.9 +/- 1.6 y; 70.6 +/- 3.1 kg; 14 +/- 3% body fat; maximal power output (W-max): 5.6 +/- 0.4 W/kg; mean +/- s.d.) and 10 lean, untrained (22.1 +/- 2.9 y; 72.0 +/- 7.9 kg; 18 +/- 4% body fat; W-max: 3.9 +/- 0.4 W/kg; mean +/- s.d.) subjects. In six of the trained subjects, UCP2 and UCP3 mRNA were measured before and after an exercise bout to exhaustion. To correct for differences in mitochondrial content, levels of UCP2 and UCP3 mRNA were expressed relative to cytochrome-b, a marker of mitochondrial content. RESULTS: Acute exercise had no effect on the expression of UCP3L or UCP3S, but in five out of six subjects UCP2 expression decreased after exercise, although the difference was not statistically significant (P = 0.11). Trained subjects had significantly reduced mRNA levels of UCP3L (P = 0.028) and UCP3S (P = 0.031), VO2max expressed per kg of fat-free mass was negatively correlated with UCP3L (r = -0.61, P = 0.009) and UCP3S (r = -0.52, P = 0.028). Mechanical efficiency correlated negatively with UCP3L (r = -0.56, P = 0.019), UCP3S (r = -0.47, P = 0.048) and tended to correlate with UCP2 (r = -0.46, P = 0.06). CONCLUSION: The lower levels of UCP3 mRNA in trained subjects and the inverse relationship of UCP3 expression and mechanical efficiency suggest that exercise training produces an adaptive physiological response in skeletal muscle improving mechanical efficiency. C1 Maastricht Univ, Dept Human Biol, NL-6200 MD Maastricht, Netherlands. NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. RP Schrauwen, P (reprint author), Maastricht Univ, Dept Human Biol, POB 616, NL-6200 MD Maastricht, Netherlands. RI Troost, Freddy/B-2782-2015 NR 26 TC 63 Z9 65 U1 0 U2 1 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD SEP PY 1999 VL 23 IS 9 BP 966 EP 972 DI 10.1038/sj.ijo.0801026 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 233WB UT WOS:000082449200009 PM 10490803 ER PT J AU Buggage, RR Whitcup, SM Nussenblatt, RB Chan, CC AF Buggage, RR Whitcup, SM Nussenblatt, RB Chan, CC TI Using interleukin 10 to interleukin 6 ratio to distinguish primacy intraocular lymphoma and uveitis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Letter ID FLUID C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Buggage, RR (reprint author), NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NR 4 TC 30 Z9 30 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 SEP PY 1999 VL 40 IS 10 BP 2462 EP 2462 PG 1 WC Ophthalmology SC Ophthalmology GA 230EX UT WOS:000082239800043 PM 10476821 ER PT J AU Le Roith, D Karas, M Yakar, S Qu, BH Wu, YP Blakesley, VA AF Le Roith, D Karas, M Yakar, S Qu, BH Wu, YP Blakesley, VA TI The role of the insulin-like growth factors in cancer SO ISRAEL MEDICAL ASSOCIATION JOURNAL LA English DT Review DE insulin-like growth factors; cancer; diabetes mellitus; oncogenes; tumorigenesis ID FACTOR-I RECEPTOR; HORMONE-RELEASING HORMONE; IGF-I; PHOSPHATIDYLINOSITOL 3'-KINASE; TYROSINE PHOSPHORYLATION; SIGNAL-TRANSDUCTION; BINDING-PROTEINS; C-CRK; GENE; EXPRESSION C1 NIDDKD, Mol Cell Endocrine Branch, MSC, NIH, Bethesda, MD 20892 USA. RP Le Roith, D (reprint author), NIDDKD, Mol Cell Endocrine Branch, MSC, NIH, Room 8D12,Bldg 10, Bethesda, MD 20892 USA. NR 44 TC 11 Z9 11 U1 0 U2 0 PU ISRAEL MEDICAL ASSOC JOURNAL PI RAMAT GAN PA 2 TWIN TOWERS, 11TH FL, 35 JABOTINSKY ST, PO BOX 3604, RAMAT GAN 52136, ISRAEL SN 1565-1088 J9 ISRAEL MED ASSOC J JI Isr. Med. Assoc. J. PD SEP PY 1999 VL 1 IS 1 BP 25 EP 30 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 305BC UT WOS:000086518100013 PM 11370118 ER PT J AU Lubaki, NM Shepherd, ME Brookmeyer, RS Hon, H Quinn, TC Kashamuka, M Johnson, M Gottle, R Devers, J Lederman, HM Bollinger, RC AF Lubaki, NM Shepherd, ME Brookmeyer, RS Hon, H Quinn, TC Kashamuka, M Johnson, M Gottle, R Devers, J Lederman, HM Bollinger, RC TI HIV-1-specific cytolytic T-lymphocyte activity correlates with lower viral load, higher CD4 count, and CD8(+)CD38(-)DR(-) phenotype: Comparison of statistical methods for measurement SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article; Proceedings Paper CT 12th International Conference on AIDS CY JUN-JUL -, 1998 CL GENEVA, SWITZERLAND DE cytolytic T lymphocytes; viral load; CD4 count; CD8(+)CD38(-)DR(-); HIV ID HUMAN-IMMUNODEFICIENCY-VIRUS; LONGITUDINAL DATA-ANALYSIS; HIV TYPE-1 INFECTION; DISEASE PROGRESSION; CLONAL ANALYSIS; CELL RESPONSES; PLASMA; RNA; SEROCONVERSION; QUANTITATION AB Objectives: The objective of this study was to use novel statistical methods to determine the correlation between HIV-1-specific cytolytic T-lymphocyte (CTL) activity and HIV-1 plasma viral load, in a blinded study of HIV-infected patients at various stages of clinical disease. Methods: Peripheral blood mononuclear cells (PBMC) were collected and stored at enrollment and 2 weeks later, from 15 HIV-infected individuals who were receiving stable antiretroviral therapy for the previous 6 weeks and during the study period. HIV-1-specific CTL activity was measured using an antigen-specific PBMC in vitro stimulation method. Measurements of plasma viral load, as well as CD4(+) and CD8(+) T lymphocytes expressing T-cell activation markers (DR and CD38) were also performed at each time point. CTL activity was quantified using three separate statistical methods: area under the net HIV-specific lysis curve (AUC), lytic units (LU20), and linear regression (LR) of net HIV-specific lysis. Results: HIV-1 nef-, pol- and gag-specific CTL activity (AUC method) was significantly higher in subjects with a plasma viral load less than or equal to 30,000 RNA copies/ml, than in those with viral load >30,000 RNA copies/ml. When plasma viral load was analyzed as a continuous variable, there was a strong correlation between higher CTL activity and lower viral load for nef(r(2) = .77; p < .001), pol (r(2) = .63; p < .001) and gag (r(2) = 0.75; p < .001) targets by the AUG, but not for the LU20 analysis. Using the LR analysis, which is less dependent on in vitro PBMC growth than the AUC analysis, an independent association was demonstrated between nef- and gag-specific CTL activity and lower viral load. Measurement of CTL activity was also significantly correlated with a higher percentage of circulating CD8(+)DR(-)CD38(-) T lymphocytes. Conclusions: In this blinded study using an in vitro stimulation of frozen PBMC, higher HIV-1 nef-, pol-, and gag-specific CTL activity correlated with lower plasma viral load, particularly in patients with a CD4 count <500 cells/mm(3). Two new statistical methods for estimating CTL activity, AUC and LR analyses, were superior to the standard lytic unit (LU20) method for demonstrating this correlation. These data also demonstrated that higher circulating CD8(+) T lymphocytes with a DR(-)CD38(-) phenotype, correlate with a lower plasma viral and load and higher HIV-specific CTL activity. This suggests that lymphocytes with this double-negative phenotype may include circulating HIV-specific CD8(+) CTL. C1 Johns Hopkins Univ, Sch Med, Div Infect Dis, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Biostat, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. NIAID, NIH, Baltimore, MD 21205 USA. RP Bollinger, RC (reprint author), Johns Hopkins Univ, Sch Med, Div Infect Dis, Dept Med, Ross 1159,720 Rutland Ave, Baltimore, MD 21205 USA. FU NIAID NIH HHS [U01AI27668] NR 27 TC 20 Z9 21 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-9450 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. PD SEP 1 PY 1999 VL 22 IS 1 BP 19 EP 30 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 245TV UT WOS:000083125000003 PM 10534143 ER PT J AU Nguyen, GT Carrington, M Beeler, JA Dean, M Aledort, LM Blatt, PM Cohen, AR DiMichele, D Eyster, ME Kessler, CM Konkle, B Leissinger, C Luban, N O'Brien, SJ Goedert, JJ O'Brien, TR AF Nguyen, GT Carrington, M Beeler, JA Dean, M Aledort, LM Blatt, PM Cohen, AR DiMichele, D Eyster, ME Kessler, CM Konkle, B Leissinger, C Luban, N O'Brien, SJ Goedert, JJ O'Brien, TR TI Phenotypic expressions of CCR5-Delta 32/Delta 32 homozygosity SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE AIDS; CCR5; chemokine; chemokine; receptors; epidemiology; genetics; HIV-1; hemophilia; hepatitis C virus; hypertension; lymphocytes; therapy ID HUMAN IMMUNODEFICIENCY VIRUS; HIV-1 INFECTION; CHEMOKINE RECEPTORS; DISEASE PROGRESSION; DELETION ALLELE; CCR5; RESISTANCE; AIDS; GENE; CORECEPTOR AB Objective: As blockade of CC-chemokine receptor 5 (CCR5) has been proposed as therapy for HIV-1, we examined whether the CCR5-Delta 32/Delta 32 homozygous genotype has phenotypic expressions other than those related to HIV-1. Design: Study subjects were white homosexual men or men with hemophilia who were not infected with HIV-1. In this study, 15 CCR5-Delta 32/Delta 32 homozygotes were compared with 201 CCR5 wild-type (+/+) subjects for a wide range of clinical conditions and laboratory assay results ascertained during prospective cohort studies and routine clinical care. CCR5-Delta 32 genotype was determined by polymerase chain reaction, followed by single-stranded conformational polymorphism analysis. Results: Hypertension and conditions attributable to hemophilia were the only diagnoses frequently found in clinical records of CCR5-Delta 32/Delta 32 study subjects. Based on blood pressure measurement and treatment history, CCR5-Delta 32/Delta 32 homozygotes had a 2.8-fold higher prevalence of hypertension than age-matched CCR5-+/+ study subjects (95% confidence interval [CI], 1.2-6.4; p = .01); none of the homozygotes had severe hypertension. Hematologic measures were generally similar across the genotypes, but total lymphocyte counts were similar to 20% higher in CCR5-Delta 32/Delta 32 study subjects than in CCR5-+/+ study subjects (p < .05). Among patients with hemophilia who were infected with hepatitis C virus (HCV), mean alanine aminotransferase levels were 117% higher among CCR5-Delta 32/Delta 32 homozygotes (p < .05), but serum HCV levels did not differ by CCR5-Delta 32 genotype. CCR5-Delta 32/Delta 32 homozygous study subjects had a lower prevalence of antibodies to measles virus than those with other genotypes, but this association was not confirmed in a group of blood donors. The prevalence of antibodies to nine other common viruses, HBV, and HCV was not related to CCR5 genotype. Conclusions: CCR5-Delta 32/Delta 32 homozygotes are generally similar to wild-type persons. Confirmatory investigations are required to determine whether hypertension, increased lymphocyte counts, and higher hepatic enzyme levels in the presence of HCV infection represent true phenotypic expressions of this genotype. CCR5-Delta 32/Delta 32 homozygosity does not provide broad protection against viral infections. C1 US Dept HHS, Viral Epidemiol Branch, NCI, Rockville, MD 20852 USA. NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Frederick, MD USA. US FDA, Div Viral Prod, Bethesda, MD 20014 USA. NCI, Lab Genomic Divers, Frederick, MD 21701 USA. Mt Sinai Med Ctr, Hemophilia Ctr, New York, NY 10029 USA. Christiana Hosp, Delaware Clin & Lab Phys, Newark, DE USA. Childrens Hosp Philadelphia, Hemophilia Ctr, Dept Hematol, Philadelphia, PA 19104 USA. Cornell Univ, Med Ctr, New York Hosp, Dept Pediat Hematol Oncol, New York, NY 10021 USA. Penn State Univ, Milton S Hershey Med Ctr, Sch Med, Div Hematol Oncol, Hershey, PA 17033 USA. Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. Thomas Jefferson Univ Hosp, Cardeza Fdn Hemophilia Ctr, Philadelphia, PA 19107 USA. Tulane Univ, Sch Med, Hematol Oncol Sect, New Orleans, LA 70112 USA. Childrens Hosp, Natl Med Ctr, Dept Hematol Oncol, Hemophilia Ctr, Washington, DC 20010 USA. RP O'Brien, TR (reprint author), US Dept HHS, Viral Epidemiol Branch, NCI, 6120 Execut Blvd 8016, Rockville, MD 20852 USA. RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 FU NCI NIH HHS [N01-CP-33002, N01-CP-40521] NR 39 TC 46 Z9 47 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-9450 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. PD SEP 1 PY 1999 VL 22 IS 1 BP 75 EP 82 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 245TV UT WOS:000083125000010 PM 10534150 ER PT J AU Mekori, YA Metcalfe, DD AF Mekori, YA Metcalfe, DD TI Mast cell-T cell interactions SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE mast cell; T cell; adhesion; antigen presentation; chemotaxis; cytokines; degranulation; migration ID FC-EPSILON-RI; MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA; INTERCELLULAR-ADHESION MOLECULE-1; LYMPHOCYTE CHEMOATTRACTANT FACTOR; MESSENGER-RNA EXPRESSION; CYTOKINE PRODUCTION; LEUKOCYTE ADHESION; ENDOTHELIAL-CELLS; IGE SYNTHESIS; IN-VIVO AB In addition to being a major effector cell in the elicitation of allergic inflammation, mast cells have been found to be activated in various T cell-mediated inflammatory processes and to reside in close physical proximity to T cells, Such observations and the wide spectrum of mediators produced and secreted by mast cells have led investigators to propose a functional relationship between these 2 cell populations. Indeed, mast cell activation has been reported to induce T-cell migration either directly by the release of chemotactic factors, such as lymphotactin or IL-16, or indirectly by the induction of adhesion molecule expression on endothelial cells, Mast cells are also able to present antigens to T cells, resulting in their activation in either an MHC class I- or class II-restricted and costimulatory molecule-dependent fashion. Adhesion molecule-dependent intercellular contact or MHC class II cognate interactions between T cells and mast cells result in the release of both granule-associated mediators and cytokines from the latter, Also, T cell-derived mediators, such as beta-chemokines, directly induce mast cell degranulation, On the other hand, mast cell-derived cytokines, such as IL-4, have been found to polarize T cells to preferentially differentiate into the T-H2 subset. Thus T cell-mast fell interactions are bidirectional, fulfilling regulatory and/or modulatory roles affecting various aspects of the immune response. C1 Tel Aviv Univ, Sackler Sch Med, Kefar Sava, Israel. NIAID, Lab Allerg Dis, NIH, Bethesda, MD USA. Meir Hosp, Dept Med B, Allergy Clin Immunol Unit, IL-44281 Kefar Sava, Israel. RP Mekori, YA (reprint author), Meir Hosp, Dept Med B, Allergy Clin Immunol Unit, IL-44281 Kefar Sava, Israel. NR 67 TC 157 Z9 161 U1 2 U2 5 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD SEP PY 1999 VL 104 IS 3 BP 517 EP 523 DI 10.1016/S0091-6749(99)70316-7 PN 1 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA 241EP UT WOS:000082870000008 PM 10482820 ER PT J AU Preston, KL Huestis, MA Wong, CJ Umbricht, A Goldberger, BA Cone, EJ AF Preston, KL Huestis, MA Wong, CJ Umbricht, A Goldberger, BA Cone, EJ TI Monitoring cocaine use in substance-abuse-treatment patients by sweat and urine testing SO JOURNAL OF ANALYTICAL TOXICOLOGY LA English DT Article ID HAIR; METHAMPHETAMINE; METABOLITE; PATCH C1 Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD 21224 USA. Univ Vermont, Dept Psychol, Burlington, VT 05405 USA. Univ Florida, Coll Med, Dept Pathol Immunol & Lab Med, Gainesville, FL USA. RP Preston, KL (reprint author), Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD 21224 USA. RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 NR 27 TC 41 Z9 42 U1 1 U2 7 PU PRESTON PUBLICATIONS INC PI NILES PA 7800 MERRIMAC AVE PO BOX 48312, NILES, IL 60648 USA SN 0146-4760 J9 J ANAL TOXICOL JI J. Anal. Toxicol. PD SEP PY 1999 VL 23 IS 5 BP 313 EP 322 PG 10 WC Chemistry, Analytical; Toxicology SC Chemistry; Toxicology GA 232CV UT WOS:000082348900003 PM 10488917 ER PT J AU Matteson, DM Shen, DF Chan, CC AF Matteson, DM Shen, DF Chan, CC TI Inhibition of experimental melanin protein-induced uveitis (EMIU) by targeting nitric oxide via phosphatidylcholine-specific phospholipase C SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE apoptosis; experimental melanin protein-induced uveitis (EMIU); nitric oxide synthase (NOS); phosphatidylcholine-specific phospholipase C (PC-PLC); tricyclodecan-9-yl-xanthogenate (D609) ID AUTOIMMUNE ANTERIOR UVEITIS; ENDOTOXIN-INDUCED UVEITIS; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; RETINAL-PIGMENT EPITHELIUM; SYNTHASE EXPRESSION; INDUCED APOPTOSIS; DEATH FACTOR; FAS LIGAND; KAPPA-B; INDUCTION AB Experimental melanin protein-induced uveitis (EMIU) is an autoimmune uveitis induced by immunization with uveal melanin protein. Fas and FasL enhancement is reported in rats with EMIU. Tricyclodecan-9-yl-xanthogenate (D609), a specific inhibitor of phosphatidylcholine-specific phospholipase C, inhibits inducible nitric oxide synthase (iNOS) induction. In two independent experiments, 35 Lewis rats with EMIU received either D609 or PBS daily. The eyes and draining lymph nodes were collected for histology, analyses of nitrite, peroxide, and superoxide dismutase, Fas and FasL immunochemistry, in situ hybridization for iNOS mRNA and in situ apoptosis detection at the peak of the disease. Both experiments showed significant inhibition of EMIU by D609. Decreases in nitrite and peroxide, increase of superoxide dismutase and lower expressions of iNOS mRNA were found in D609-treated, as compared to PBS-treated eyes. There was mild enhancement of Fas and FasL in the eyes and lymph nodes of D609-injected animals. DNA fragmentation was increased in the lymph nodes of D609-treated rats. We conclude that iNOS activation is responsible for NO production in eyes with EMIU. The suppressive effect of D609 on EMIU may result from scavenging NO and activating apoptosis previously inhibited by NO along with other anti-inflammatory effects. (C) 1999 Academic Press. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Chan, CC (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Rm 10N103,10 Ctr Dr, Bethesda, MD 20892 USA. NR 42 TC 10 Z9 10 U1 0 U2 0 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 J9 J AUTOIMMUN JI J. Autoimmun. PD SEP PY 1999 VL 13 IS 2 BP 197 EP 204 DI 10.1006/jaut.1999.0319 PG 8 WC Immunology SC Immunology GA 234FP UT WOS:000082474100003 PM 10479388 ER PT J AU Kataeva, I Li, XL Chen, HZ Choi, SK Ljungdahl, LG AF Kataeva, I Li, XL Chen, HZ Choi, SK Ljungdahl, LG TI Cloning and sequence analysis of a new cellulase gene encoding CelK, a major cellulosome component of Clostridium thermocellum: Evidence for gene duplication and recombination SO JOURNAL OF BACTERIOLOGY LA English DT Article ID INTEGRATING PROTEIN CIPA; ESCHERICHIA-COLI; BINDING DOMAIN; SCAFFOLDING PROTEIN; LIMITED PROTEOLYSIS; ENDOGLUCANASE CELD; TRICHODERMA-REESEI; CELLULOMONAS-FIMI; EXPRESSION; COMPLEX AB The cellulolytic and hemicellulolytic complex of Clostridium thermocellum, termed cellulosome, consists of up to 26 polypeptides, of which at least 17 have been sequenced. They include 12 cellulases, 3 xylanases, 1 lichenase, and CipA, a scaffolding polypeptide. me report here a new cellulase gene, celK, coding for CelK, a 98-kDa major component of the cellulosome. The gene has an open reading frame (ORF) of 2,685 nucleotides coding for a polypeptide of 895 amino acid residues with a calculated mass of 100,552 Da. A signal peptide of 27 amino acid residues is cut off during secretion, resulting in a mature enzyme of 97,572 Da. The nucleotide sequence is highly similar to that of cbhA (V.V. Zverlov et al., J. Bacteriol. 180:3091-3099, 1998), having an ORF of 3,690 bp coding for the 1,230-amino-acid-residue CbhA of the same bacterium. Homologous regions of the two genes are 86.5 and 84.3% identical without deletion or insertion on the nucleotide and amino acid levels, respectively. Both have domain structures consisting of a signal peptide, a family IV cellulose binding domain (CBD), a family 9 glycosyl hydrolase domain, and a dockerin domain. A striking distinction between the two polypeptides is that there is a 330-amino-acid insertion in CbhA between the catalytic domain and the dockerin domain containing a fibronectin type 3-like domain and family III CBD. This insertion, missing in CelK, is responsible for the size difference between CelK and CbhA Upstream and downstream flanking sequences of the two genes show no homology. The data indicate that celK and cbhA in the genome of C. thermocellum have evolved through gene duplication and recombination of domain coding sequences. celK without a dockerin domain was expressed in Escherichia coli and purified. The enzyme had pH and temperature optima at 6.0 and 65 degrees C, respectively. It hydrolyzed p-nitrophenyl-beta-D-cellobioside with a K-m and a V-max of 1.67 mu M and 15.1 U/mg, respectively. Cellobiose was a strong inhibitor of CelK activity, with a K-i of 0.29 mM. The enzyme was thermostable, after 200 h of incubation at 60 degrees C, 97% of the original activity remained. Properties of the enzyme indicated that it is a cellobiohydrolase. C1 Univ Georgia, Dept Biochem & Mol Biol, Athens, GA 30602 USA. Univ Georgia, Ctr Biol Resource Recovery, Athens, GA 30602 USA. NICHHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. RP Ljungdahl, LG (reprint author), Univ Georgia, Dept Biochem & Mol Biol, A214 Life Sci Bldg, Athens, GA 30602 USA. NR 51 TC 51 Z9 55 U1 1 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD SEP PY 1999 VL 181 IS 17 BP 5288 EP 5295 PG 8 WC Microbiology SC Microbiology GA 231PB UT WOS:000082318000020 PM 10464199 ER PT J AU Resnekov, O AF Resnekov, O TI Role of the sporulation protein BofA, in regulating activation of the Bacillus subtilis developmental transcription factor sigma(K) SO JOURNAL OF BACTERIOLOGY LA English DT Article ID GENE-EXPRESSION; RNA-POLYMERASE; PROTEOLYTIC ACTIVATION; MOTHER-CELL; FTSH GENE; PRO-SIGMA(K); MUTATIONS AB During sporulation, the Bacillus subtilis transcription factor sigma(K) is activated by regulated proteolytic processing. I have used a system that facilitates the analysis of the contributions of a modified form of the processing enzyme, SpoIVFB-GFP, and the regulatory proteins BofA and SpoIVFA to the conversion of pro-sigma(K) to sigma(K). The results show that in the presence of BofA, SpoIVFA levels increase by greater than 20-fold, SpoIVFA is substantially stabilized, and pro-sigma(K) processing is inhibited. In addition, enhanced accumulation of the SpoNFA protein in the absence of BofA (achieved through the use of an ftsH null mutation) substantially inhibits pro-sigma(K) processing. These results suggest that during growth, increased accumulation of the SponIVFA protein inhibits the activity of SpoIVFB-GFP and regulates the activation of sigma(K). C1 NICHHD, Sect Microbial Genet, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Resnekov, O (reprint author), NICHHD, Sect Microbial Genet, Mol Genet Lab, NIH, Bldg 6B-304,6 Ctr Ctr Dr,MSC 2785, Bethesda, MD 20892 USA. NR 30 TC 13 Z9 16 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD SEP PY 1999 VL 181 IS 17 BP 5384 EP 5388 PG 5 WC Microbiology SC Microbiology GA 231PB UT WOS:000082318000031 PM 10464210 ER PT J AU Chang, YC Kwon-Chung, KJ AF Chang, YC Kwon-Chung, KJ TI Isolation, characterization, and localization of a capsule-associated gene, CAP10, of Cryptococcus neoformans SO JOURNAL OF BACTERIOLOGY LA English DT Article ID GREEN-FLUORESCENT PROTEIN; VIRULENCE; MUTATIONS; MUTANTS; TRANSFORMATION; URA5 AB Cryptacoccus neoformans is a pathogenic fungus which most commonly affects the central nervous system and causes fatal meningoencephalitis primarily in patients with AIDS. This fungus produces a thick extracellular polysaccharide capsule which is well recognized as a virulence factor. Here, we describe the isolation and characterization of a novel gene, CAP10, which is required for capsule formation. Complementation of the acapsular cap10 mutant produced an encapsulated strain and the deletion of CAP10 from a wild strain resulted in an acapsular phenotype. The molecular mass of the hemagglutinin epitope-tagged Cap10p is about 73 kDa, which is similar to the size predicted from sequence analysis. When CRP10 was fused with a hybrid green fluorescent protein construct, the fluorescence signals appeared as patches in the cytoplasm. Using a reporter gene construct, we found that CAP10 was expressed at high levels in late-stationary-phase cells. In addition, we found that the expression levels of CAP10 are modulated by the transcriptional factor STE12 alpha. Deletion of STE12 alpha! downregulated the expression levels of CAP10 while overexpression of STE12 alpha upregulated the expression levels of CAP10. Animal model studies indicate that deletion of the CAP10 gene results in the loss of virulence, and complementation of the acapsular phenotype of cap10 restores virulence. Thus, CAP10 is required for capsule formation and virulence. C1 NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Kwon-Chung, KJ (reprint author), NIAID, Clin Invest Lab, NIH, Bldg 10,Room 11C304, Bethesda, MD 20892 USA. NR 31 TC 113 Z9 129 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD SEP PY 1999 VL 181 IS 18 BP 5636 EP 5643 PG 8 WC Microbiology SC Microbiology GA 235GV UT WOS:000082534700012 PM 10482503 ER PT J AU Bai, YW AF Bai, YW TI Equilibrium amide hydrogen exchange and protein folding kinetics SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE EX1 and EX2 exchange behaviors; hydrogen exchange; protein dynamics; protein folding kinetics; protein folding pathway ID MOLECULAR CHAPERONES GROEL; INTERMEDIATE; NMR; STABILITY; SECB AB The classical Linderstrom-Lang hydrogen exchange (HX) model is extended to describe the relationship between the HX behaviors (EX1 and EX2) and protein folding kinetics for the amide protons that can only exchange by global unfolding in a three-state system including native (N), intermediate (I), and unfolded (U) states. For these slowly exchanging amide protons, it is shown that the existence of an intermediate (I) has no effect on the HX behavior in an off-pathway three-state system (I <----> U <----> N). On the other hand, in an on-pathway three-state system (U <----> I <----> N), the existence of a stable folding intermediate has profound effect on the HX behavior. It is shown that fast refolding from the unfolded state to the stable intermediate state alone does not guarantee EX2 behavior. The rate of refolding from the intermediate state to the native state also plays a crucial role in determining whether EX1 or EX2 behavior should occur. This is mainly due to the fact that only amide protons in the native state are observed in the hydrogen exchange experiment. These new concepts suggest that caution needs to be taken if one tries to derive the kinetic events of protein folding from equilibrium hydrogen exchange experiments. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Bai, YW (reprint author), NCI, Biochem Lab, NIH, Bldg 37,Rm 4A-01, Bethesda, MD 20892 USA. NR 18 TC 9 Z9 9 U1 0 U2 2 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD SEP PY 1999 VL 15 IS 1 BP 65 EP 70 DI 10.1023/A:1008316430724 PG 6 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 237HT UT WOS:000082650300006 PM 10549134 ER PT J AU Li, DW DeRose, EF London, RE AF Li, DW DeRose, EF London, RE TI The inter-ligand Overhauser effect: A powerful new NMR approach for mapping structural relationships of macromolecular ligands SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE ILOE; inter-ligand Overhauser effect; ternary complex; transferred NOE; TRNOE ID TRANSFER-NOE EXPERIMENTS; LACTATE-DEHYDROGENASE; MAGNETIC-RESONANCE; SPIN-DIFFUSION; RELAXATION; CONFORMATIONS; RESOLUTION; PROTEINS; SPECTRA; RATES AB NMR experiments that transfer conformational information from the bound to the uncomplexed state via exchange have been utilized for many years. It is demonstrated here that inter-ligand NOEs ('ILOEs'), which exist in ternary complexes with enzymes or other macromolecular receptors, can be transferred via exchange to pairs of uncomplexed ligands. This approach is illustrated by studies of glycolate + NAD(+) in the presence of porcine heart lactate dehydrogenase, and by glucose-6-phosphate + NADPH in the presence of L. mesenteroides glucose-6-phosphate dehydrogenase. This strategy opens up a general methodology for exploring the active sites of enzymes and for the development of artificial ligands which can function as inhibitors, or more generally as modifiers of protein function. C1 NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Li, DW (reprint author), NIEHS, Struct Biol Lab, MR-1,Box 12233, Res Triangle Pk, NC 27709 USA. NR 28 TC 47 Z9 50 U1 1 U2 10 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD SEP PY 1999 VL 15 IS 1 BP 71 EP 76 DI 10.1023/A:1008360208627 PG 6 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 237HT UT WOS:000082650300007 PM 10549135 ER PT J AU Marcus, R Holloway, L Wells, B Greendale, G James, MK Wasilauskas, C Kelaghan, J AF Marcus, R Holloway, L Wells, B Greendale, G James, MK Wasilauskas, C Kelaghan, J TI The relationship of biochemical markers of bone turnover to bone density changes in postmenopausal women: Results from the postmenopausal estrogen/progestin interventions (PEPI) trial SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article ID HORMONE REPLACEMENT THERAPY; BIOLOGICAL VARIABILITY; MINERAL DENSITY; ELDERLY WOMEN; ESTROGEN; PREDICT AB We assessed the associations of eight bone turnover markers (BTMs), with baseline and 1-year percentage changes in lumbar spine and hip bone mineral density (BMD) of 293 postmenopausal women undergoing treatment with hormone replacement therapy (HRT) or placebo using squared correlation coefficients (R-2). In 239 women assigned to treatment with estrogen alone or with with estrogen plus progestins (active treatment), mean percentage changes for all markers decreased significantly and remained below baseline values through 3 years of study, whereas mean percentage changes for 54 women assigned to the placebo group showed no significant change from baseline in any marker. At baseline, age and body mass index (BMI) together accounted for 16% and 25% of the variance in spine and hip BMD, respectively. The telopeptide resorption marker, cross-linked N-telopeptide of type I collagen (NTX), alone accounted for 12% and 8% of variance, respectively. Another telopeptide, carboxyterminal telopeptide of type I collagen (Crosslaps), accounted for 8% and 7% of variance, respectively. A bone-specific alkaline phosphatase (BALP-2) accounted for 8% of variance at the spine and 5% at the hip. No other marker accounted for more than 5% of total variance at either site; adding either baseline NTX, Crosslaps, or BAP-2 to regressions containing age and BMI increased R-2 values at the spine and hip to about 22% and 28%, respectively. In the placebo group, baseline spine BMD accounted for 4% of the variance in 1-year spine BMD percentage change, whereas baseline values for age and BMI accounted for 1% and 0% of the variance, respectively; none of the three accounted for more than 0% of hip BMD percentage change; Crosslaps and NTX contributed 5% and 4% to the variance in 1-year spine BMD percentage change, but other markers accounted for < 2% of variance at the spine. At the hip, another BALP (BALP-1) accounted for 4% of variance, but no other baseline marker except NTX accounted for more than 1% of variance. In the active treatment group, baseline values for age, BMI, and spine BMD together accounted for 13% of the percentage change in spine BMD and for 4% of the BMD change at the hip. No individual or pair of baseline markers significantly enhanced these R-2 values, but addition of 1-year percentage changes in some individual markers did significantly increase it. The largest R-2 value was obtained by adding the percentage change in BALP-2, which increased the R-2 in spine BMD percentage change to 20% and that at the hip to 8%. Adding baseline and change variables for an eight markers to the regression increased R-2 to 28% at the spine and 12% at the hip. Restricting the set of analyses to individuals who suppressed marker activity beyond the precision error for the measurement did not improve R(2)s for the regressions. When baseline marker values were stratified into quartiles, only NTX and osteocalcin showed significant relationships between quartile and change in spine BMD, and these did not reach significance at the hip. When the 1-year change in markers was stratified into quartiles, significant relationships with percentage change in spine BMD were observed only for BALP phosphatases. We conclude that BTMs are not a surrogate for BMD to identify women,vith low bone mass and that they offer little useful information for predicting BMD changes for individual untreated or HRT-treated postmenopausal women. C1 Vet Affairs Med Ctr, GRECC 182B, Palo Alto, CA 94304 USA. Stanford Univ, Dept Med, Palo Alto, CA 94304 USA. Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Biostat Sect, Winston Salem, NC 27109 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. NICHHD, Contracept & Reprod Hlth Branch, NIH, Bethesda, MD 20892 USA. RP Marcus, R (reprint author), Vet Affairs Med Ctr, GRECC 182B, 3801 Miranda Ave, Palo Alto, CA 94304 USA. NR 15 TC 86 Z9 87 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 IS 9 BP 1583 EP 1595 DI 10.1359/jbmr.1999.14.9.1583 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 230XB UT WOS:000082276000015 PM 10469288 ER PT J AU Barsony, J Prufer, K Lin, GC AF Barsony, J Prufer, K Lin, GC TI Ligand-dependent targeting of vitamin D receptors to the centrosome. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA 1072 BP S150 EP S150 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347100074 ER PT J AU Bernardini, S Teti, A Marino, M Korach, KK Wetsel, WC Faraggiana, T Spera, G Migliaccio, S AF Bernardini, S Teti, A Marino, M Korach, KK Wetsel, WC Faraggiana, T Spera, G Migliaccio, S TI Specific protein kinase C isoforms modulate differentiation and hormonal responsiveness in osteoblast-like cells. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Duke Univ, Depy Psych, Durham, NC 27706 USA. NIEHS, LRDT, Res Triangle Pk, NC 27709 USA. Univ Aquila, Dept Expt Med, I-67100 Laquila, Italy. Rome 3 Univ, Dept Phys, Rome, Italy. Univ La Sapienza, Dept Histol & Embryol, Rome, Italy. Univ La Sapienza, Dept Physiopat Med, Rome, Italy. Univ La Sapienza, Dept Expt Med, Rome, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA F141 BP S239 EP S239 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347100428 ER PT J AU Burton, DW Tu, S Gujral, A Patel, JA Terkeltaub, RA Rhim, JS Deftos, LJ AF Burton, DW Tu, S Gujral, A Patel, JA Terkeltaub, RA Rhim, JS Deftos, LJ TI Intracellular (intracrine), non-PTH/PTHrP receptor mediated effects of PTHrP on prostate cancer cell growth. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 San Diego Vet Affairs Med Ctr, La Jolla, CA USA. Univ Calif San Diego, La Jolla, CA 92093 USA. NCI, NIH, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA F403 BP S290 EP S290 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347100629 ER PT J AU Chen, L Deng, CX AF Chen, L Deng, CX TI Ser365Cys mutation in mouse fibroblast growth factor receptor-3 causes severe dwarfism. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 NIDDK, GDDB, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA T055 BP S190 EP S190 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347100230 ER PT J AU Chen, XD Xu, T Young, M AF Chen, XD Xu, T Young, M TI Age-related osteoporosis in biglycan deficient mice is related to a defect in bone marrow stromal cells. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. Osiris Therapeut Inc, Osteoporosis, Baltimore, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA 1003 BP S133 EP S133 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347100005 ER PT J AU Collins, MT Bianco, P Wientroub, S Mankani, MH Feuillan, P Spiegel, AM Jones, J Robey, PG AF Collins, MT Bianco, P Wientroub, S Mankani, MH Feuillan, P Spiegel, AM Jones, J Robey, PG TI Renal abnormalities in fibrous dysplasia of bone: A fanconi-like syndrome. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 NIDCR, NIH, Bethesda, MD USA. Univ Aquila, I-67100 Laquila, Italy. Tel Aviv Univ, IL-69978 Tel Aviv, Israel. NICHD, NIH, Bethesda, MD USA. NIDDK, NIH, Bethesda, MD USA. NIH, CC, Bethesda, MD 20892 USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA SU068 BP S448 EP S448 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347101258 ER PT J AU Corsi, A Bianco, P Fisher, LW Chen, XD Xu, T Iozza, RV Danialson, KG Robey, PG Young, MF AF Corsi, A Bianco, P Fisher, LW Chen, XD Xu, T Iozza, RV Danialson, KG Robey, PG Young, MF TI Biglycan and decorin deficiency interferes with collagen assembly and structure and results in diverse ehlers-danlos like phenotypes. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Univ Aquila, I-67100 Laquila, Italy. NIDCR, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA 1005 BP S134 EP S134 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347100007 ER PT J AU Cui, L Ma, YF Jee, WSS Zhou, H Yao, W Setterberg, R Liang, CT AF Cui, L Ma, YF Jee, WSS Zhou, H Yao, W Setterberg, R Liang, CT TI Prostaglandin E2 mainly induced modeling-dependent bone gain in aged male rats. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Univ Utah, Div Radiobiol, Salt Lake City, UT 84112 USA. NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA SA019 BP S313 EP S313 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347100721 ER PT J AU Derubeis, AR Dieudonne, SC Kim, IS Kuznetsov, SA Robey, PG Young, MF AF Derubeis, AR Dieudonne, SC Kim, IS Kuznetsov, SA Robey, PG Young, MF TI beta ig-h3: A matrix protein important in bone formation?. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 NIH, CSDB, Bethesda, MD 20892 USA. Kyungpook Natl Univ, Taegu 702701, South Korea. RI Robey, Pamela/H-1429-2011; Kim, In-San/D-3956-2017 OI Robey, Pamela/0000-0002-5316-5576; NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA SU040 BP S441 EP S441 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347101230 ER PT J AU Fedarko, NS Fisher, LW AF Fedarko, NS Fisher, LW TI Bone sialoprotein in serum is predominantly masked by a serum protein: Unmasking shows BSP is elevated in osteotropic cancer patient sera. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 NIDCR, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA SA053 BP S322 EP S322 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347100755 ER PT J AU Fedarko, NS Fohr, B Young, MF Fisher, LW AF Fedarko, NS Fohr, B Young, MF Fisher, LW TI Integrins and factor H mediate bone sialoprotein's and osteopontin's protective properties in complement attack on susceptible cancer cells. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 NIDCR, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA T024 BP S187 EP S187 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347100221 ER PT J AU Fohr, B Torchia, DA Fedarko, NS Young, MF Fisher, LW AF Fohr, B Torchia, DA Fedarko, NS Young, MF Fisher, LW TI Recombinant human bone sialoprotein and osteopontin: Structure-function studies including solving their structures in solution by NMR. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 NIDCR, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. NIDCR, Struct Mol Biol Unit, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA SA012 BP S311 EP S311 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347100714 ER PT J AU Forlino, A Porter, FD Marini, JC AF Forlino, A Porter, FD Marini, JC TI Knock-in mouse reproducing human "brittle bone" disorder (Osteogenesis imperfecta) displays undermineralized, disorganized bone matrix and variable phenotype. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 NICHD, NIH, Bethesda, MD USA. RI Forlino, Antonella/H-5385-2015 OI Forlino, Antonella/0000-0002-6385-1182 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA 1045 BP S144 EP S144 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347100047 ER PT J AU Heegaard, AM Young, MF Jensen, K AF Heegaard, AM Young, MF Jensen, K TI Transforming growth factor beta activation of the human biglycan promoter involves several responsive elements. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Ctr Clin & Basic Res, Dept Basic Res, DK-2750 Ballerup, Denmark. NIDCR, Craniofacial & Skeletal Dis Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA F441 BP S298 EP S298 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347100662 ER PT J AU Huang, DC Papavasiliou, V Rhim, J Kremer, R AF Huang, DC Papavasiliou, V Rhim, J Kremer, R TI Targeted disruption of the 25-hydroxyvitamin D-3 1 alpha-hydroxylase gene in a Ras-transformed human keratinocyte cell line: Evidence for an autocrine growth regulatory function of 1 alpha, 25-dihydroxyvitamin D-3 in vitro and in vivo. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Royal Victoria Hosp, Dept Med, Montreal, PQ H3A 1A1, Canada. McGill Univ, Dept Med, Montreal, PQ, Canada. NIH, Cell Biol & Res Ctr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA 1033 BP S141 EP S141 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347100035 ER PT J AU Jensen, K Xu, T Pedersen, BJ Young, MF Heegaard, AM AF Jensen, K Xu, T Pedersen, BJ Young, MF Heegaard, AM TI Uncoupled bone resorption in biglycan deficient mice. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Ctr Clin & Basic Res, Dept Basic Res, Ballerup, Denmark. NIDCR, Craniofacial & Skeletal Dis Branch, Bethesda, MD USA. Osteometer Biotech AS, Herlev, Denmark. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA F022 BP S218 EP S218 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347100343 ER PT J AU Johnson, DC Collins, MT Kuznetsov, SA Majolagbe, A Riminucci, M Bianco, P Robey, PG AF Johnson, DC Collins, MT Kuznetsov, SA Majolagbe, A Riminucci, M Bianco, P Robey, PG TI Proliferation of human bone marrow stromal cells derived from patients with activating Gs alpha mutations. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 NIDCR, NIH, Bethesda, MD USA. Univ Aquila, Dipartimento Med Sperimentale, I-67100 Laquila, Italy. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA F053 BP S224 EP S224 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347100365 ER PT J AU Kiel, DP Harris, T Visser, M Hannan, MT Wilson, PWF AF Kiel, DP Harris, T Visser, M Hannan, MT Wilson, PWF TI Leptin and bone mineral density (BMD) in older men and women. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Vrije Univ Amsterdam, Amsterdam, Netherlands. NCI, Bethesda, MD 20892 USA. Hebrew Rehabil Ctr Aged, Boston, MA 02131 USA. Harvard Univ, Sch Med, Framingham, MA USA. NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA SU475 BP S550 EP S550 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347101665 ER PT J AU Kiel, DP Rosen, C Dawson-Hughes, MT Hannan, MT McLean, RR Krueqer, K Gagnon, D Wilson, PWF Visser, M Langlois, J AF Kiel, DP Rosen, C Dawson-Hughes, MT Hannan, MT McLean, RR Krueqer, K Gagnon, D Wilson, PWF Visser, M Langlois, J TI Insulin-like growth factor binding proteins (IGFBPs) and bone mineral density (BMD) in elderly persons. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Hebrew Rehabil Ctr Aged, Boston, MA 02131 USA. Harvard Univ, Sch Med, Framingham, MA USA. St Joseph Hosp, Bangor, ME USA. Tufts Univ, HNRC, Boston, MA 02111 USA. CDC, NHLBI, Atlanta, GA 30333 USA. Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. Vrije Univ Amsterdam, Amsterdam, Netherlands. Loma Linda Univ, Loma Linda, CA 92350 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA SA312 BP S386 EP S386 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347101013 ER PT J AU Kim, YS Burns, AL Goldsmith, PK Heppner, C Park, SY Chandrasekharappa, SC Collins, FS Spiegel, AM Marx, SJ AF Kim, YS Burns, AL Goldsmith, PK Heppner, C Park, SY Chandrasekharappa, SC Collins, FS Spiegel, AM Marx, SJ TI Stable overexpression of the MEN1 gene suppresses tumorigenicity of RAS-transformed cells. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 NIDDK, Metab Dis Branch, Bethesda, MD USA. NHGRI, Genet & Mol Biol Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA 1187 BP S179 EP S179 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347100189 ER PT J AU Kuznetsov, SA Mankani, MH Collins, MT Robey, PG AF Kuznetsov, SA Mankani, MH Collins, MT Robey, PG TI Effects of serum on in vitro and in vivo properties of human bone marrow stromal cells. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 NIH, NIDCR, CSDB, Bethesda, MD 20892 USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA SA185 BP S355 EP S355 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347100886 ER PT J AU Lang, T Cauley, J Li, J Scherzinger, A Tylavsky, F Nevitt, M Harris, T AF Lang, T Cauley, J Li, J Scherzinger, A Tylavsky, F Nevitt, M Harris, T TI The effect of abdominal fat and muscle on vertebral bone mineral density (BMD). SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Colorado, Denver, CO 80202 USA. Univ Tennessee, Memphis, TN USA. NIA, Washington, DC USA. RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA 1108 BP S159 EP S159 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347100110 ER PT J AU Lethbridge-Cejku, M Tobin, JD Creamer, P Roy, TA Scott, WW Hochberg, MC AF Lethbridge-Cejku, M Tobin, JD Creamer, P Roy, TA Scott, WW Hochberg, MC TI Higher spine bone mineral density (BMD), but not hip BMD, is associated with increased risk for incident knee osteoarthritis (OA): Data from the Baltimore Longitudinal Study of Aging (BLSA). SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Univ Maryland, Sch Med, Baltimore, MD 21201 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Johns Hopkins Univ, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA SU134 BP S465 EP S465 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347101324 ER PT J AU Lyles, KW Pieper, CF Tobin, JD Newton, RA Tracy, RP AF Lyles, KW Pieper, CF Tobin, JD Newton, RA Tracy, RP TI Paget's disease of bone causes elevated C-reactive protein levels. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 Vet Adm Med Ctr, GRECC, Durham, NC USA. Duke Univ, Med Ctr, Durham, NC USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Univ Vermont, Burtington, VT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA SU432 BP S539 EP S539 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347101622 ER PT J AU Mankani, MH Kuznetsov, SA Fowler, BO Robey, PG AF Mankani, MH Kuznetsov, SA Fowler, BO Robey, PG TI In vivo bone formation by human bone marrow stromal cells: Effect of carrier particle size. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract C1 NIH, NIDCR, CSDB, Bethesda, MD 20892 USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI DURHAM PA PO BOX 2759, DURHAM, NC 27715-2759 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 1999 VL 14 SU 1 MA SA189 BP S356 EP S356 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 232CA UT WOS:000082347100890 ER EF