FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Burova, E Hung, SC Chen, J Court, DL Zhou, JG Mogilnitskiy, G Gottesman, ME AF Burova, E Hung, SC Chen, J Court, DL Zhou, JG Mogilnitskiy, G Gottesman, ME TI Escherichia coli nusG mutations that block transcription termination by coliphage HK022 Nun protein SO MOLECULAR MICROBIOLOGY LA English DT Article ID RHO-DEPENDENT TERMINATION; ELONGATION-FACTOR; PHAGE-LAMBDA; IN-VITRO; BACTERIOPHAGE-LAMBDA; RNA-POLYMERASE; DNA-POLYMERASE; N-PROTEIN; ANTITERMINATION; MUTAGENESIS AB The Escherichia coli nusG gene product is required for transcription termination by phage HK022 Nun protein at the lambda nutR site in vivo. We show that it is also essential for Nun termination at lambda nutL. Three recessive missense nusG mutations have been isolated that inhibit termination by Nun at lambda nutR. The mutations are ineffective in a lambda pL nutL fusion, even when lambda nutR replaces lambda nutL. The mutant strains support lambda growth, indicating that lambda N antitermination activity is not impaired. Transcription arrest by Nun in vitro is stimulated by NusG protein at both lambda nutR and lambda nutL. Mutant NusG protein fails to enhance transcriptional arrest by Nun at either site. The mutant protein, like the wild-type protein, suppresses transcriptional pausing by RNA polymerase and stimulates Rho-dependent termination. These results imply that the role of NusG in Nun termination may be distinct from its roles in other transcription reactions. C1 Columbia Univ Coll Phys & Surg, Inst Canc Res, New York, NY 10032 USA. Columbia Univ Coll Phys & Surg, Dept Biochem & Mol Biophys, New York, NY 10032 USA. NCI, Lab Gene Regulat & Chromosome Biol, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. RP Gottesman, ME (reprint author), Columbia Univ Coll Phys & Surg, Inst Canc Res, 701 W 168th St, New York, NY 10032 USA. FU NIGMS NIH HHS [GM37219] NR 39 TC 23 Z9 23 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD MAR PY 1999 VL 31 IS 6 BP 1783 EP 1793 DI 10.1046/j.1365-2958.1999.01315.x PG 11 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 182RD UT WOS:000079511200016 PM 10209750 ER PT J AU Gao, WY Johns, DG Tanaka, M Mitsuya, H AF Gao, WY Johns, DG Tanaka, M Mitsuya, H TI Suppression of replication of multidrug-resistant HIV type 1 variants by combinations of thymidylate synthase inhibitors with zidovudine or stavudine SO MOLECULAR PHARMACOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; REVERSE-TRANSCRIPTASE; ENZYMATIC ASSAY; THERAPY; HYDROXYUREA; DIDANOSINE; MECHANISM; CELLS; 2',3'-DIDEOXYNUCLEOSIDES; TRIPHOSPHATES AB The replication of recombinant multidrug-resistant HIV-I clones modeled on clinically derived resistant HIV-I strains from patients receiving long-term combination therapy with zidovudine (AZT) plus 2',3'-dideoxycytidine was found to regain sensitivity to AZT and stavudine (D4T) as a consequence of a pharmacologically induced decrease in de novo dTMP synthesis. The host-cell system used was phytohemagglutinin-stimulated peripheral blood mononuclear cells; dTMP and dTTP depletion were induced by single exposures to a low level of the thymidylate synthase inhibitor 5-fluorouracil (5-FU) or its deoxynucleoside, 2'-deoxy-5-fluorouridine. The host-cell response to the latter was biphasic: a very rapid decrease in the rate of de novo dTMP formation and, consequently, in intracellular dTTP pools, followed by slower recovery in both indices over 3 to 24 h. With the additional presence of AZT or D4T, however, replication of the multidrug-resistant HIV-I strains remained inhibited, indicating dependence of HIV DNA chain termination by AZT-5'-monophosphate or 2',3'-didehydro-2',3'-dideoxythymidine-5'-monphosphate in these resistant strains on simultaneous inhibition of host-cell de novo synthesis of thymidine nucleotides. No effect on viability of control (uninfected) phytohemagglutinin-stimulated/peripheral blood mononuclear cells was noted on 6-day exposures to 5-FU or 2'-deoxy-5-fluorouridine alone or in combination with AZT or D4T, even at drug levels severalfold higher than those used in the viral inhibition studies. These studies may provide useful information for the potential clinical use of AZT/5-FU or D4T/5-FU combinations for the prevention or reversal of multidrug resistance associated with long-term dideoxynucleoside combination therapy. C1 NCI, Expt Retrovirol Sect, Med Branch, Div Clin Sci,NIH, Bethesda, MD 20892 USA. NCI, Med Chem Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Gao, WY (reprint author), NCI, Expt Retrovirol Sect, Med Branch, Div Clin Sci,NIH, Bldg 37,Room 5B22, Bethesda, MD 20892 USA. NR 26 TC 11 Z9 11 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD MAR PY 1999 VL 55 IS 3 BP 535 EP 540 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 173MK UT WOS:000078984200016 PM 10051538 ER PT J AU Koshiba, M Rosin, DL Hayashi, N Linden, J Sitkovsky, MV AF Koshiba, M Rosin, DL Hayashi, N Linden, J Sitkovsky, MV TI Patterns of A(2A) extracellular adenosine receptor expression in different functional subsets of human peripheral T cells. Flow cytometry studies with anti-A(2A) receptor monoclonal antibodies SO MOLECULAR PHARMACOLOGY LA English DT Article ID DEPENDENT PROTEIN-KINASE; TOXIC LYMPHOCYTES-T; PURINERGIC RECEPTOR; ADENYLATE-CYCLASE; IMMUNE-RESPONSE; ANTIGEN; ACTIVATION; ATP; PHARMACOLOGY; MACROPHAGES AB Signaling through A(2A) adenosine receptors (A(2A)R) regulates T lymphocyte expansion and modulates T cell receptor (TCR)mediated effector functions in vitro. To understand the role of A(2A)Rs in the regulation of immune response, we investigated the expression levels of this receptor in different functional lymphocyte subsets. Monoclonal anti-A(2A)R antibody was used to develop a flow cytometric assay to quantify the expression A(2A)Rs on lymphocytes. We report that detectable levels of expression of A(2A)Rs are much higher among T cells than B cells. More CD4(+) than CD8(+) T cells express A(2A)Rs, but activation of T cells increases A(2A)R expression, predominantly in CD8(+) T cells. No significant differences were found in the proportion of A(2A)R(+) cells between CD8(low) and CD8(high) T cells or between TCR/CD3(low) and TCR/CD3(high) T cells. Studies of T helper cell subsets (T(H)1 and T(H)2) reveal that lymphokine-producing cells are much more likely to express A(2A)Rs than are cells that do not produce lymphokines. These results suggest that A(2A)Rs are variably expressed on T cell subsets and may regulate cytokine production in activated T lymphocytes. C1 NIH, NIAID, Immunol Lab, Biochem & Immunopharmacol Sect, Bethesda, MD 20892 USA. Univ Virginia, Charlottesville, VA USA. RP Sitkovsky, MV (reprint author), NIH, NIAID, Immunol Lab, Biochem & Immunopharmacol Sect, Bldg 10,Room 11N311,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. EM mvsitkovsky@helix.nih.gov FU NHLBI NIH HHS [R01HL37942] NR 42 TC 103 Z9 107 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD MAR PY 1999 VL 55 IS 3 BP 614 EP 624 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 173MK UT WOS:000078984200025 PM 10051547 ER PT J AU Prolo, P Licinio, J AF Prolo, P Licinio, J TI Cytokines in affective disorders and schizophrenia: new clinical and genetic findings SO MOLECULAR PSYCHIATRY LA English DT Editorial Material ID CORTICOTROPIN-RELEASING HORMONE; NATURAL-KILLER-CELLS; MAJOR DEPRESSION; ATYPICAL DEPRESSION; STRESS; HYPOTHESIS AB This issue features articles by Anisman et al and by Katila et al indicating a role for IL-1 beta in mood disorders and schizophrenia respectively. These results raise the possibility that inflammatory mediators may contribute to the biology of psychiatric disorders. C1 NIMH, Clin Neuroendocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Prolo, P (reprint author), NIMH, Clin Neuroendocrinol Branch, NIH, Bldg 10-2D46,10 Ctr Dr,MSC 1284, Bethesda, MD 20892 USA. EM prolo@codon.nih.gov RI Licinio, Julio/L-4244-2013 OI Licinio, Julio/0000-0001-6905-5884 NR 26 TC 12 Z9 13 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD MAR PY 1999 VL 4 IS 2 BP 109 EP 111 DI 10.1038/sj.mp.4000523 PG 3 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 177WB UT WOS:000079233100002 PM 10208441 ER PT J AU Chen, R Karp, BI Goldstein, SR Bara-Jimenez, W Yaseen, Z Hallett, M AF Chen, R Karp, BI Goldstein, SR Bara-Jimenez, W Yaseen, Z Hallett, M TI Effect of muscle activity immediately after botulinum toxin injection for writer's cramp SO MOVEMENT DISORDERS LA English DT Article DE dystonia; botulinum toxin; treatment; writer's cramp; exercise; muscle strength ID CRANIAL-CERVICAL DYSTONIA; FOCAL HAND DYSTONIA; DOUBLE-BLIND; SPASMODIC TORTICOLLIS; HEMIFACIAL SPASM; A TOXIN; MOTOR; EXPERIENCE; MECHANISM; HUMANS AB Animal and human studies have shown that nerve stimulation enhances some effects of botulinum toxin (btx A) injection. Voluntary muscle activity might work similarly and would focus the effect of an injection into the active muscles. We studied the effects of exercise immediately after btx A injection in eight patients with writer's cramp with established response to btx A over two injection cycles with a single-blinded. randomized, crossover design. Immediately after the first study injection, they were randomly assigned to write continuously for 30 min or have their hand and forearm immobilized for 30 min. Following the second injection, they were assigned the alternate condition. Patients were assessed just before each injection, and at 2 weeks, 6 weeks, and 3 months post-injection. Assessment included objective strength testing, self-reported rating of benefit and weakness, and blinded evaluation of videotapes and writing samples of the patients writing a standard passage. Strength testing showed that the maximum weakness occurred at 2 weeks post-injection, but the benefit was maximum at 6 weeks post-injection. The "write" condition resulted in greater reduction in strength than the "rest" condition. Btx A treatment led to improvement in self-reported ratings, writer's cramp rating scale scores by blinded raters, and reduction in writing time, but the differences between the "write" and "rest" conditions were not significant. We conclude that voluntary muscle activity immediately after btx A injection leads to greater reduction in muscle strength. Our findings raise the possibility that voluntary muscle activation may allow reduction of btx A doses and favorably alter the balance of benefit and side effects of btx A injections. C1 NINDS, Human Motor Control Sect, Bethesda, MD 20892 USA. Univ Toronto, Toronto Hosp, Div Neurol, Toronto, ON, Canada. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, Bldg 10,Room 5N226,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. RI Chen, Robert/B-3899-2009 OI Chen, Robert/0000-0002-8371-8629 NR 34 TC 49 Z9 51 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD MAR PY 1999 VL 14 IS 2 BP 307 EP 312 DI 10.1002/1531-8257(199903)14:2<307::AID-MDS1016>3.0.CO;2-3 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 243LP UT WOS:000082999400016 PM 10091625 ER PT J AU Biragyn, A Tani, K Grimm, MC Weeks, S Kwak, LW AF Biragyn, A Tani, K Grimm, MC Weeks, S Kwak, LW TI Genetic fusion of chemokines to a self tumor antigen induces protective, T-cell dependent antitumor immunity SO NATURE BIOTECHNOLOGY LA English DT Article DE interferon inducible protein 10; monocyte chemotactic protein 3; chemokine fusion; antigen presenting cell targeting; idiotypic vaccine ID MONOCYTE CHEMOTACTIC PROTEIN-3; DNA IMMUNIZATION; LEUKOCYTE MIGRATION; LYMPHOMA; ANTIBODY; RECEPTOR; VACCINATION; ENDOCYTOSIS; VACCINES; BINDING AB We converted a model, syngeneic, nonimmunogenic tumor antigen into a vaccine by fusing it with a proinflammatory chemokine. Two chemokines, interferon inducible protein 10 and monocyte chemotactic protein 3, were fused to lymphoma Ig variable regions (sFv). The sFv-chemokine fusion proteins elicited chemotactic responses in vitro and induced inflammatory responses in vivo. Furthermore, in two independent models, vaccination with DNA constructs encoding the corresponding fusions generated superior protection against a large tumor challenge (20 times the minimum lethal dose), as compared with the best available protein vaccines. Immunity was not elicited by controls, including fusions with irrelevant sFv; fusions with a truncated chemokine that lacked receptor binding and chemotactic activity; mixtures of free chemokine and sFv proteins; or naked DNA plasmid vaccines encoding unlinked sFv and chemokine. The requirement for linkage of conformationally intact sFv and functionally active chemokine strongly suggested that the mechanism underlying these effects was the novel targeting of antigen presenting cells (APC) for chemokine receptor-mediated uptake of antigen, rather than the simple recruitment of APC to tumor by the chemokine. Finally, in addition to superior potency, these fusions were distinguished from lymphoma Ig fusions with granulocyte-macrophage colony-stimulating factor or other cytokines by their induction of critical effector T cells. C1 NCI, Dept Expt Transplantat & Immunol, Med Branch, Div Clin Sci, Bethesda, MD 20892 USA. NCI, Sci Applicat Int Corp, Frederick, MD 21702 USA. NCI, Mol Immunoregulat Lab, Frederick, MD 21702 USA. RP Kwak, LW (reprint author), NCI, Dept Expt Transplantat & Immunol, Med Branch, Div Clin Sci, Bethesda, MD 20892 USA. EM kwak@mail.ncifcrf.gov FU NCI NIH HHS [N01-CO-56000] NR 36 TC 212 Z9 223 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD MAR PY 1999 VL 17 IS 3 BP 253 EP 258 PG 6 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 173JM UT WOS:000078977500026 PM 10096292 ER PT J AU Suzuki, M Saxena, SK Boix, E Prill, RJ Vasandani, VM Ladner, JE Sung, C Youle, RJ AF Suzuki, M Saxena, SK Boix, E Prill, RJ Vasandani, VM Ladner, JE Sung, C Youle, RJ TI Engineering receptor-mediated cytotoxicity into human ribonucleases by steric blockade of inhibitor interaction SO NATURE BIOTECHNOLOGY LA English DT Article DE ribonuclease inhibitor; eosinophil-derived neurotoxin; site-directed mutagenesis; receptor-mediated endocytosis; immunotoxin ID EOSINOPHIL-DERIVED NEUROTOXIN; HUMAN PLACENTAL RIBONUCLEASE; BOVINE SEMINAL RIBONUCLEASE; TRANSFERRIN RECEPTOR; CATIONIC PROTEIN; SOLID TUMORS; MECHANISM; INVITRO; RNASE; ANGIOGENIN AB Several nonmammalian members of the RNase A superfamily exhibit anticancer activity that appears to correlate with resistance to the cytosolic ribonuclease inhibitor (RI). We mutated two human ribonucleases-pancreatic RNase (hRNAse) and eosinophil-derived neurotoxin (EDN)-to incorporate cysteine residues at putative sites of close contact to RI, but distant from the catalytic sites. Coupling of Cys89 of RNase and Cys87 of EDN to proteins at these sites via a thioether bond produced enzymatically active conjugates that were resistant to RI. To elicit cellular targeting as well as to block RI binding, transferrin was conjugated to a mutant human RNase, rhRNase(Gly89--->Cys) and a mutant EDN (Thr87-->Cys). The transferrin-rhRNase(Gly89-->Cys) thioether conjugate was 5000-fold more toxic to U251 cells than recombinant wild-type hRNase. In addition, transferrin-targeted EDN exhibited tumor cell toxicities similar to those of hRNase, Thus, we endowed two human RI-sensitive RNases with greater cytotoxicity by increasing their resistance to RI. This strategy has the potential to generate a novel set of recombinant human proteins useful for targeted therapy of cancer. C1 NINCDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Univ Maryland, Maryland Biotechnol Inst, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. Natl Inst Stand & Technol, Rockville, MD 20850 USA. NIH, Drug Delivery & Kinet Resource Bioengn & Phys Sci, Off Res Serv, Bethesda, MD 20892 USA. RP Youle, RJ (reprint author), NINCDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RI Boix, Ester/B-9038-2012; OI Boix, Ester/0000-0003-1790-2142; Saxena, Shailendra K/0000-0003-2856-4185 NR 31 TC 62 Z9 64 U1 0 U2 6 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD MAR PY 1999 VL 17 IS 3 BP 265 EP 270 PG 6 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 173JM UT WOS:000078977500028 PM 10096294 ER PT J AU Gong, YQ Krakow, D Marcelino, J Wilkin, D Chitayat, D Babul-Hirji, R Hudgins, L Cremers, CW Cremers, FPM Brunner, HG Reinker, K Rimoin, DL Cohn, DH Goodman, FR Reardon, W Patton, M Francomano, CA Warman, ML AF Gong, YQ Krakow, D Marcelino, J Wilkin, D Chitayat, D Babul-Hirji, R Hudgins, L Cremers, CW Cremers, FPM Brunner, HG Reinker, K Rimoin, DL Cohn, DH Goodman, FR Reardon, W Patton, M Francomano, CA Warman, ML TI Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis SO NATURE GENETICS LA English DT Article ID DELETION DEL(17) Q21.3Q23; SPEMANN ORGANIZER; XENOPUS; FOLLISTATIN; BINDING; PROTEIN; BMP-4; CDMP1 AB The secreted polypeptide noggin (encoded by the Nog gene) binds and inactivates members of the transforming growth factor beta superfamily of signalling proteins (TGF beta-FMs), such as BMP4 (ref. 1). By diffusing through extracellular matrices more efficiently than TGF beta-FMs, noggin may have a principal role in creating morphogenic gradients2. During mouse embryogenesis, Nog is expressed at multiple sites(3), including developing bones(4,5). Nog(-/-) mice die at birth from multiple defects that include bony fusion of the appendicular skeleton(3,4). We have identified five dominant human NOG mutations in unrelated families segregating proximal symphalangism (SYM1; OMIM 185800) and a de novo mutation in a patient with unaffected parents. We also found a dominant NOG mutation in a family segregating multiple synostoses syndrome (SYNS1; OMIM 186500); both SYM1 and SYNS1 have multiple joint fusion as their principal feature(6,7). All seven NOG mutations alter evolutionarily conserved amino CI acid residues. The findings reported here confirm that NOG is essential for joint formation and suggest that NOG requirements during skeletogenesis differ between species and between specific skeletal elements within species. C1 Case Western Reserve Univ, Dept Genet, Sch Med, Cleveland, OH 44106 USA. Case Western Reserve Univ, Ctr Human Genet, Sch Med, Cleveland, OH 44106 USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. Shandong Med Univ, Dept Genet, Jinan, Peoples R China. Cedars Sinai Med Ctr, Ahmanson Dept Pediat, Steven Spielberg Pediat Res Ctr, Burns & Allen Cedars Sinai Res Inst, Los Angeles, CA 90048 USA. Cedars Sinai Med Ctr, Dept Obstet, Los Angeles, CA 90048 USA. Cedars Sinai Med Ctr, Dept Gynecol, Los Angeles, CA 90048 USA. Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90024 USA. Natl Human Genome Res Inst, NIH, Bethesda, MD USA. Hosp Sick Children, Div Genet, Toronto, ON M5G 1X8, Canada. Childrens Hosp & Med Ctr, Div Med Genet, Washington, DC USA. Univ Nijmegen, Dept Otorhinolaryngol, Nijmegen, Netherlands. Univ Nijmegen, Dept Human Genet, Nijmegen, Netherlands. Shriners Hosp Crippled Children, Dept Orthoped, Honolulu, HI USA. Inst Child Hlth, Mothercare Unit Clin Genet & Fetal Med, London, England. St George Hosp, Sch Med, London, England. RP Warman, ML (reprint author), Case Western Reserve Univ, Dept Genet, Sch Med, Cleveland, OH 44106 USA. RI Brunner, Han/C-9928-2013; Cremers, Frans/A-5625-2014; Cremers, C.W.R.J./L-4254-2015 FU NIAMS NIH HHS [AR-43827]; NICHD NIH HHS [HD-01205, HD-22657] NR 24 TC 204 Z9 219 U1 1 U2 15 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 MAR PY 1999 VL 21 IS 3 BP 302 EP 304 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 173JR UT WOS:000078977900025 PM 10080184 ER PT J AU Buetow, KH Edmonson, MN Cassidy, AB AF Buetow, KH Edmonson, MN Cassidy, AB TI Reliable identification of large numbers of candidate SNPs from public EST data SO NATURE GENETICS LA English DT Article ID EXPRESSED SEQUENCE TAGS AB High-resolution genetic analysis of the human genome promises to provide insight into common disease susceptibility. To perform such analysis will require a collection of high-throughput, high-density analysis reagents. We have developed a polymorphism detection system that uses public-domain sequence data. This detection system is called the single nucleotide polyrmorphism pipeline (SNPpipeline). The analytic core of the SNPpipeline is composed of three components: PHRED, PHRAP and DEMIGLACE. PHRED and PHRAP are components of a sequence analysis suite developed to perform the semi-automated analysis required for large-scale genomes(1,2) (provided courtesy of P. Green). Using these informatics tools, which examine redundant raw expressed sequence tag (EST) data, we have identified more than 3,000 candidate single-nucleotide polyrmorphisms (SNPs). Empiric validation studies of a set of 192 candidates indicate that 82% identify variation in a sample of ten Centre d'Etudes Polymorphism Humain (CEPH) individuals. Our results suggest that existing sequence resources may serve as a valuable source for identifying genetic variation. C1 NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. RP Buetow, KH (reprint author), NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. NR 8 TC 198 Z9 219 U1 1 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 MAR PY 1999 VL 21 IS 3 BP 323 EP 325 DI 10.1038/6851 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 173JR UT WOS:000078977900030 PM 10080189 ER PT J AU McKay, RD AF McKay, RD TI Brain stem cells change their identity SO NATURE MEDICINE LA English DT Editorial Material ID ADULT MAMMALIAN FOREBRAIN; CENTRAL-NERVOUS-SYSTEM; MOUSE BRAIN; ZONE CELLS; DIFFERENTIATION; NEURONS; GENERATION; ASTROCYTES; EXPRESS; NESTIN C1 NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP McKay, RD (reprint author), NINDS, Mol Biol Lab, NIH, Bldg 36,Rm 5A29, Bethesda, MD 20892 USA. NR 25 TC 23 Z9 23 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD MAR PY 1999 VL 5 IS 3 BP 261 EP 262 DI 10.1038/6468 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 171FH UT WOS:000078851600021 PM 10086372 ER PT J AU Grivel, JC Margolis, LB AF Grivel, JC Margolis, LB TI CCR5- and CXCR4-tropic HIV-1 are equally cytopathic for their T-cell targets in human lymphoid tissue SO NATURE MEDICINE LA English DT Article ID CORECEPTOR USAGE; INFECTION; HISTOCULTURES; PHENOTYPE; TYPE-1 AB A rapid decline in T-cell counts and the progression to AIDS is often associated with a switch from CCR5-tropic (R5) HIV-1 to CXCR4-tropic (X4) HIV-1 or R5/X4 HIV-1 variants(1,2) Experimental infection with R5 HIV-1 causes less T-cell depletion than infection with X4 or R5/X4 variants in T-cell cultures(3), in ex vivo infected human lymphoid tissue(4,5) and in SCID/hu mice(6), despite similar replication levels. Experimental genetic changes in those sequences in gp120 that transform R5 HIV-1 variants into otherwise isogenic X4 viruses make them highly cytopathic(6,7). Thus, it is now believed that R5 variants are less cytopathic for T cells than are X4 variants. However, it is not known why CCR5-mediated HIV-1 infection does not lead to a massive CD4(+) T-cell depletion, as occurs in CXCR4-mediated HIV-1 infection. Here we demonstrate that R5 HIV-1 isolates are indeed highly cytopathic, but only for CCR5(+)/CD4(+) T cells. Because these cells constitute only a small fraction of CD4(+) T cells, their depletion does not substantially change the total CD4(+) T-cell count. These results may explain why the clinical stage of HIV disease correlates with viral tropism. C1 NICHHD, Lab Mol & Cellular Biophys, NIH, Bethesda, MD 20892 USA. RP Margolis, LB (reprint author), NICHHD, Lab Mol & Cellular Biophys, NIH, Bethesda, MD 20892 USA. NR 15 TC 134 Z9 135 U1 1 U2 2 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 MAR PY 1999 VL 5 IS 3 BP 344 EP 346 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 171FH UT WOS:000078851600043 PM 10086394 ER PT J AU Davenport, RW Thies, E Cohen, ML AF Davenport, RW Thies, E Cohen, ML TI Neuronal growth cone collapse triggers lateral extensions along trailing axons SO NATURE NEUROSCIENCE LA English DT Article ID RETINAL AXONS; RETINOTECTAL PROJECTION; TOPOGRAPHIC ORDER; CELLULAR-LOCALIZATION; TARGET RECOGNITION; DIRECTIONAL CUES; GUIDANCE CUES; IN-VITRO; GRADIENTS; MOLECULES AB Axonal outgrowth is generally thought to be controlled by direct interaction of the lead growth cone with guidance cues, and, in trailing axons, by fasciculation with pioneer fibers. Responses of axons and growth cones were examined as cultured retinal ganglion cell (RCC) axons encountered repellent cues. Either contact with cells expressing ephrins or mechanical probing increased the probability of lead growth cone retraction. Lateral extension of filopodia and lamellipodia hundreds of microns behind the lead growth cone was correlated with its collapse. Transmission electron microscopy showed that some of the lateral extensions originate from the pioneer axon, whereas others represent growth cones of defasciculating trailing axons. C1 NICHHD, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Davenport, RW (reprint author), Univ Maryland, Dept Biol, 1210 Zool Psychol Bldg, College Pk, MD 20742 USA. NR 42 TC 52 Z9 53 U1 1 U2 4 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 MAR PY 1999 VL 2 IS 3 BP 254 EP 259 DI 10.1038/6360 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 220TX UT WOS:000081684500013 PM 10195218 ER PT J AU Ingram, DK Jucker, M AF Ingram, DK Jucker, M TI Developing mouse models of aging: a consideration of strain differences in age-related behavioral and neural parameters SO NEUROBIOLOGY OF AGING LA English DT Article DE genetics; recombinant inbred strains; quantitative trait loci; learning; memory; motor performance; stereology; hippocampus; neurons; glia; synapse; aping; mouse ID QUANTITATIVE TRAIT LOCUS; AMYLOID PRECURSOR PROTEIN; RADIAL MAZE PERFORMANCE; TRANSGENIC MICE; C57BL/6 MICE; INBRED MICE; LIFE-SPAN; NEURODEGENERATIVE DISEASES; ALZHEIMERS-DISEASE; MOTOR-PERFORMANCE AB Increased interest is emerging for using mouse models to assess the genetics of brain aging and age-related neurodegenerative diseases. Despite this demand, relatively little information is available on aging in behavioral or neuromorphological parameters in various mouse strains that are being used to create transgenic and null mutant mice. We review several issues regarding selection of appropriate strains as follows: (1) Does the behavioral parameter exhibit a significant age by strain interaction? (2) Do the strains differ in lifespan? (3) Are there potential intervening variables, such as strain specific performance strategies or disease, in the behavioral task being investigated that would confound the desired conclusions'! (4) Does the behavioral difference have an underlying neural correlate? In this context we present a conceptual model pertaining to the selection of mouse strains and behavioral parameters for genetic analyses. We also review the importance of applying stereological techniques for determining age-related structural changes in the mouse brain as well as the potential value of a database that would catalog this information. Thus, our intention is to underscore the growing importance of mouse models of brain aging and the concomitant need for additional information about mouse aging in general. (C) 1999 Elsevier Science Inc, All rights reserved. C1 NIA, Ctr Gerontol Res, Lab Cellular & Mol Biol, Mol Physiol & Genet Sect,NIH, Baltimore, MD 21224 USA. Univ Basel, Dept Neuropathol, Inst Pathol, CH-4003 Basel, Switzerland. RP Ingram, DK (reprint author), NIA, Ctr Gerontol Res, Lab Cellular & Mol Biol, Mol Physiol & Genet Sect,NIH, 5600 Nathan Shock Lane, Baltimore, MD 21224 USA. NR 88 TC 50 Z9 56 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAR-APR PY 1999 VL 20 IS 2 BP 137 EP 145 DI 10.1016/S0197-4580(99)00033-0 PG 9 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 248JH UT WOS:000083271000007 PM 10537023 ER PT J AU Thies, B Truschke, E Morrison-Bogorad, M Hodes, RJ AF Thies, B Truschke, E Morrison-Bogorad, M Hodes, RJ TI Letter to the editor SO NEUROBIOLOGY OF AGING LA English DT Letter C1 Alzheimers Assoc, Potomac, MD 20854 USA. NIA, Program Neurosci, Bethesda, MD 20892 USA. NIA, Neuropsychol Aging Program, Bethesda, MD 20892 USA. RP Thies, B (reprint author), Alzheimers Assoc, Potomac, MD 20854 USA. NR 0 TC 2 Z9 2 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAR-APR PY 1999 VL 20 IS 2 BP 247 EP 247 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 248JH UT WOS:000083271000019 PM 10537034 ER PT J AU Chang, MCJ Bell, JM Purdon, AD Chikhale, EG Grange, E AF Chang, MCJ Bell, JM Purdon, AD Chikhale, EG Grange, E TI Dynamics of docosahexaenoic acid metabolism in the central nervous system: Lack of effect of chronic lithium treatment SO NEUROCHEMICAL RESEARCH LA English DT Article DE lithium; docosahexaenoate; arachidonate; palmitate; phospholipase A(2); phospholipids; fatty acids; acyl-CoA; brain; rat; in vivo incorporation; turnover; signal transduction ID CYTOSOLIC PHOSPHOLIPASE A(2); COENZYME-A ESTERS; BRAIN PHOSPHOLIPIDS; AXONAL REGENERATION; FATTY-ACIDS; SIGNAL-TRANSDUCTION; AWAKE RATS; SCHIZOPHRENIA; TURNOVER; NEURONS AB Using a method and model developed in our laboratory to quantitatively study brain phospholipid metabolism, in vivo rates of incorporation and turnover of docosahexaenoic acid in brain phospholipids were measured in awake rats. The results suggest that docosahexaenoate incorporation and turnover in brain phospholipids are more rapid than previously assumed and that this rapid turnover dilutes tracer specific activity in brain docoshexaenoyl-CoA pool due to release and recycling of unlabeled fatty acid from phospholipid metabolism. Fractional turnover rates for docosahexaenoate within phosphatidylinositol, choline glycerophospholipids, ethanolamine glycerophospholipids and phosphatidylserine were 17.7, 3.1, 1.2, and 0.2 %.h(-1), respectively. Chronic lithium treatment, at a brain level considered to be therapeutic in humans (0.6 mu mol.g(-1)), had no effect on turnover of docosahexaenoic acid in individual brain phospholipids. Consistent with previous studies from our laboratory that chronic lithium decreased the turnover of arachidonic acid within brain phospholipids by up to 80% and attenuated brain phospholipase A, activity, the lack of effect of lithium on docosahexaenoate recycling and turnover suggests that a target for lithium's action is an arachidonic acid-selective phospholipase A(2). C1 NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. RP Chang, MCJ (reprint author), NIA, Neurosci Lab, NIH, Bldg 10,Rm 6C103,10 Ctr Dr,MSC 1582, Bethesda, MD 20892 USA. NR 44 TC 72 Z9 72 U1 1 U2 3 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 MAR PY 1999 VL 24 IS 3 BP 399 EP 406 DI 10.1023/A:1020989701330 PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 161EB UT WOS:000078274800008 PM 10215514 ER PT J AU Lillrank, SM Lipska, BK Weinberger, DR Fredholm, BB Fuxe, K Ferre, S AF Lillrank, SM Lipska, BK Weinberger, DR Fredholm, BB Fuxe, K Ferre, S TI Adenosine and dopamine receptor antagonist binding in the rat ventral and dorsal striatum: lack of changes after a neonatal bilateral lesion of the ventral hippocampus SO NEUROCHEMISTRY INTERNATIONAL LA English DT Article ID H-3 RACLOPRIDE BINDING; FOS-LIKE IMMUNOREACTIVITY; POSTMORTEM BRAINS; A(2A) RECEPTORS; AUTORADIOGRAPHIC ANALYSIS; GUANINE-NUCLEOTIDES; PREPULSE INHIBITION; BASAL GANGLIA; ANIMAL-MODELS; SCHIZOPHRENIA AB There is experimental evidence from radioligand binding experiments for the existence of strong antagonistic interactions between different subtypes of adenosine and dopamine receptors in the striatum, mainly between adenosine Al and dopamine D-1 and between adenosine A(2A) and dopamine D-2 receptors. These interactions seem to be more powerful in the ventral compared to the dorsal striatum, which might have some implications for the treatment of schizophrenia. The binding characteristics of different dopamine and adenosine receptor subtypes were analysed in the different striatal compartments (dorsolateral striatum and shell and core of the nucleus accumbens), by performing saturation experiments with the dopamine DI receptor antagonist [I-125]SCH-23982. the dopamine D2-3 receptor antagonist [H-3]raclopride, the adenosine Al receptor antagonist [H-3]DPCPX and the adenosine A(2A) receptor antagonist [H-3]SCH 58261. The experiments were also performed in rats with a neonatal bilateral lesion of the ventral hippocampus (VH), a possible animal model of schizophrenia. Both dopamine D2-3 and adenosine A(2A) receptors follow a similar pattern, with a lower density of receptors (40%) in the shell of the nucleus accumbens compared with the dorsolateral caudate-putamen. A lower density of adenosine A(1) receptors (20%) was also found in the shell of the nucleus accumbens compared with the caudate-putamen. On the other hand, dopamine D-1 receptors showed a similar density in the different striatal compartments. Therefore, differences in receptor densities cannot explain the stronger interactions between adenosine and dopamine receptors found in the ventral, compared to the dorsal striatum. No statistical differences in the binding characteristics of any of the different adenosine and dopamine receptor antagonists used were found between sham-operated and V-H-lesioned rats. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden. NIMH, Clin Brain Disorders Branch, Washington, DC 20032 USA. Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden. RP Ferre, S (reprint author), Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden. RI Ferre, Sergi/K-6115-2014; Lipska, Barbara/E-4569-2017; OI Ferre, Sergi/0000-0002-1747-1779; Fuxe, Kjell/0000-0001-8491-4288 NR 57 TC 26 Z9 26 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0197-0186 J9 NEUROCHEM INT JI Neurochem. Int. PD MAR PY 1999 VL 34 IS 3 BP 235 EP 244 DI 10.1016/S0197-0186(99)00008-X PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 196TJ UT WOS:000080323400007 PM 10355490 ER PT J AU Albers, DS Weiss, SW Iadarola, MJ Standaert, DG AF Albers, DS Weiss, SW Iadarola, MJ Standaert, DG TI Immunohistochemical localization of N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor subunits in the substantia nigra pars compacta of the rat SO NEUROSCIENCE LA English DT Article DE dopamine; confocal microscopy; Parkinson's disease; basal ganglia; glutamate ID MIDBRAIN DOPAMINERGIC-NEURONS; HETEROMERIC NMDA RECEPTORS; DENSITY PROTEIN PSD-95; NITRIC-OXIDE SYNTHASE; GLUTAMATE-RECEPTOR; POSTSYNAPTIC DENSITY; ULTRASTRUCTURAL-LOCALIZATION; PARKINSONS-DISEASE; SPLICE VARIANTS; BASAL GANGLIA AB Ionotropic glutamate receptors in the substantia nigra pars compacta regulate the activity of dopamine neurons. We have used dual-label immunofluoresence and confocal laser microscopy to study the localization of subunits of two types of ionotropic receptors within the substantia nigra pars compacta of the rat. Immunostaining for N-methyl-D-aspartate receptor 1 and glutamate receptor 2/3 was prominent in the soma and proximal dendrites of all tyrosine hydroxylase-immunopositive cells, while only low amounts of N-methyl-D-aspartate receptor 2A and N-methyl-D-aspartate receptor 2B were present. Selective antibodies were used to determine the isoforms of N-methyl-D-aspartate receptor 1 present. Immunostaining for the N1, C1 and C2 variably spliced segments of N-methyl-D-aspartate receptor 1 were scarce in the substantia nigra pars compacta, while immunoreactivity for the alternative C2' terminus of N-methyl-D-aspartate receptor 1 was quite abundant. Staining for glutamate receptor 1 was heterogeneous; about half of the tyrosine hydroxylase immunopositive cells stained intensely, while the other half were immunonegative. The glutamate receptor 1-stained cells were concentrated in the ventral tier of the substantia nigra pars compacta. Glutamate receptor 4 was nor found in tyrosine hydroxylase-immunopositive cells within the substantia nigra pars compacta. Together, these data demonstrate that dopaminergic neurons in the substantia nigra pars compacta express primarily glutamate receptor 1, glutamate receptor 2/3 and,N-methyl-D-aspartate receptor 1 isoforms containing the alternative C2' terminus. (C) 1998 IBRO. Published by Elsevier Science Ltd. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Serv Neurol, Boston, MA 02114 USA. NIDR, Pain Neurosensory Mech Branch, NIH, Bethesda, MD 20892 USA. RP Standaert, DG (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Serv Neurol, Boston, MA 02114 USA. FU NINDS NIH HHS [NS34361, NS31579] NR 51 TC 46 Z9 46 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD MAR PY 1999 VL 89 IS 1 BP 209 EP 220 DI 10.1016/S0306-4522(98)00328-5 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 157XM UT WOS:000078087000019 PM 10051230 ER PT J AU Hansson, SR Mezey, E Hoffman, BJ AF Hansson, SR Mezey, E Hoffman, BJ TI Serotonin transporter messenger RNA expression in neural crest-derived structures and sensory pathways of the developing rat embryo SO NEUROSCIENCE LA English DT Review DE antidepressants; cocaine; in situ hybridization histochemistry; monoamines; neural crest cells; peripheral nervous system ID DENTATE GRANULE CELLS; VESICULAR MONOAMINE TRANSPORTER; ENTERIC NERVOUS-SYSTEM; GROWTH-FACTOR; MERKEL CELLS; TASTE-BUDS; FLUOXETINE PROZAC; NEUROTRANSMITTER TRANSPORTERS; CRANIOFACIAL MORPHOGENESIS; BIOGENIC-AMINES AB A growing body of evidence suggests that serotonin plays an important role in the early development of both neural and non-neural tissues from vertebrate and invertebrate species. Serotonin is removed from the extracellular space by the cocaine- and antidepressant-sensitive serotonin transporter, thereby limiting its action on receptors. In situ hybridization histochemistry was used to delineate serotonin transporter messenger RNA expression during rat embryonic development. Serotonin transporter messenger RNA was widely expressed beginning prior to organogenesis and throughout the second half of gestation. Strikingly, serotonin transporter messenger RNA nas detected in neural crest cells, some of which respond to serotonin iii vitro, and neural crest-derived tissues, such as autonomic ganglia, tooth primordia, adrenal medulla, chondrocytes and neuroepithelial cells, in the skin, heart, intestine and lung. Within the peripheral sensory pathways, two major cells types were serotonin transporter messenger RNA-positive: (i) sensory ganglionic neurons and (ii) neuroepithelial cells, which serve as targets for the outgrowing sensory neurons. Several sensory organs (cochlear and retinal ganglionic cells, taste buds, whisker and hair follicles) contained serotonin transporter messenger RNA by late gestation. The expression of serotonin transporter messenger RNA throughout the sensory pathways from central nervous system relay stations [Hansson S. R. et al. (1997) Neuroscience 83, 1185-1201; Lebrand C. ci iii. (1996) Neuron 17, 823-835] to sensory nerves and target organs as shown in tills study suggests that serotonin may regulate peripheral synaptogenesis, and thereby influence later processing of sensory stimuli. If the early detection of serotonin transporter messenger RNA in skin and gastrointestinal and airway epithelia correlates with protein activity, it may permit establishment of a serotonin concentration gradient across epithelia, either from serotonin in the amniotic fluid or from neuronal enteric serotonin, as a developmental cue. Our results demonstrating serotonin transporter messenger RNA in the craniofacial and cardiac areas identify this gene product as the transporter most likely responsible for the previously identified accumulation of serotonin in skin and tooth germ [Lauder J. M. and Zimmerman E. F. (1988) J. craniofac. Genet. devl Biol. 8, 265-276], and the fluoxetine-sensitive effects on craniofacial [Lauder J. M. et al. (1988) Development 102, 709-720; Shuey D. L. ct al. (1992) Teratology 46, 367-378; Shuey D. L. ei ui. (1993) Anat. Embryol., Berlin 187, 75-85] and cardiac [Kirby M. L. and Waldo K. L. (1995) Circulation Res. 77, 211-215; Yavarone M. S. L et al. (1993) Teratology 47, 573-584] malformations. Serotonin transporter messenger RNA was detected in several neural crest cell lineages and may be useful as an early marker for the sensory lineage in particular. The distribution of serotonin transporter messenger RNA in early development supports the hypothesis that serotonin may play a role in neural crest cell migration and differentiation [Lauder J. M. (1993) Trends Neurosci. 16,233-240], and that the morphogenetic actions of serotonin may be regulated by transport. The striking pattern of serotonin transporter messenger RNA throughout developing sensory pathways suggests that serotonin may play a role in establishing patterns of connectivity critical to processing sensory stimuli. As a target for drugs, such as cocaine, amphetamine derivatives and antidepressants, expression of serotonin transporter during development may reflect critical periods of vulnerability for fetal drug exposure. The widespread distribution of serotonin transporter messenger RNA during ontogeny suggests a previously unappreciated rule of serotonin in diverse physiological systems during embryonic development. (C) 1998 IBRO. Published by Elsevier Science Ltd. C1 NIMH, Lab Cellular & Mol Regulat, Unit Mol Pharmacol, Bethesda, MD 20892 USA. NINDS, Basic Neurosci Program, Bethesda, MD 20892 USA. RP Hoffman, BJ (reprint author), Lilly Corp Ctr, Lilly Res Labs, Drop Code 0510, Indianapolis, IN 46285 USA. NR 114 TC 53 Z9 54 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD MAR PY 1999 VL 89 IS 1 BP 243 EP 265 DI 10.1016/S0306-4522(98)00281-4 PG 23 WC Neurosciences SC Neurosciences & Neurology GA 157XM UT WOS:000078087000022 PM 10051233 ER PT J AU Keefe, KA Gerfen, CR AF Keefe, KA Gerfen, CR TI Local infusion of the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione does not block D-1 dopamine receptor-mediated increases in immediate early gene expression in the dopamine-depleted striatum SO NEUROSCIENCE LA English DT Article DE glutamate; c-fos; zif268; SKF 38393; in situ hybridization; tetrodotoxin ID PREPRODYNORPHIN MESSENGER-RNA; EXCITATORY AMINO-ACIDS; C-FOS INDUCTION; RAT STRIATUM; EXTRACELLULAR DOPAMINE; NEURONS INVITRO; NMDA RECEPTORS; PHENOTYPICAL CHARACTERIZATION; CORTICOSTRIATAL AFFERENTS; INVIVO MICRODIALYSIS AB Administration of selective agonists of D-1 dopamine receptors increases immediate early gene expression in striatal neurons, a response which is particularly robust in the dopamine-depleted striatum. Although interactions between dopamine and glutamate receptor-mediated responses in striatal neurons have been demonstrated in a number of experimental paradigms, our previous findings indicate that N-methyl-D-aspartate antagonists do not block D-1 receptor-mediated induction of immediate early genes in the dopamine-depleted striatum. In the present study, we therefore examined interactions between D-1 dopamine receptors and the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole- subtypes of glutamate receptor by determining whether striatal infusion of the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole(-)4(-)propionate/kainate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione would block D, receptor-mediated induction of the immediate early genes c-fos and zif268 in the dopamine-depleted striatum. Striatal infusion of 6-cyano-7-nitroquinoxaline-2,3-dione (1 mM) completely blocked (+/-)alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate-induced c-Sos and zif268 expression. However, 6-cyano-7-nitroquinoxaline-2,3-dione (1 mu M-1 mM) did not significantly affect induction of c-Sos and zif268 by D-1 receptor stimulation (SKF 38393, 2 mg/kg, i.p.) in the dopamine-depleted striatum. To more generally block excitatory input, tetrodotoxin (10 mu M) was infused into the striatum of rats receiving a D-1 agonist. Local infusion of tetrodotoxin had minimal effect on induction of c-fos and zif268 in the dopamine-depleted striatum. In contrast, tetrodotoxin abolished induction of c-fos and zif268 messenger RNAs by the D-2 antagonist eticlopride (0.5 mg/kg, i.p.) in both intact rats and dopamine-depleted rats receiving continuous D-2 agonist treatment (quinpirole, 0.5 mg/kg/day). The results indicate that D-1 receptor-mediated induction of immediate early genes in the dopamine-depleted striatum occurs by mechanisms that are independent of excitatory input through (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors. C1 NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. RP Gerfen, CR (reprint author), NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. NR 66 TC 8 Z9 8 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD MAR PY 1999 VL 89 IS 2 BP 491 EP 504 DI 10.1016/S0306-4522(98)00327-3 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 160BB UT WOS:000078209500018 PM 10077330 ER PT J AU Neuwelt, EA Abbott, NJ Drewes, L Smith, QR Couraud, PO Chiocca, EA Audus, KL Greig, NH Doolittle, ND AF Neuwelt, EA Abbott, NJ Drewes, L Smith, QR Couraud, PO Chiocca, EA Audus, KL Greig, NH Doolittle, ND TI Cerebrovascular biology and the various neural barriers: Challenges and future directions SO NEUROSURGERY LA English DT Article DE blood-brain barrier; cerebrovascular biology; neural barriers ID CENTRAL-NERVOUS-SYSTEM; MOLECULAR NEUROSURGERY; GENE-THERAPY; PATHWAYS; REALITY AB DESPITE MAJOR ADVANCES in neuroscience, potential therapeutic options for the treatment of central nervous system diseases often cannot be optimized secondary to the presence of the blood-brain barrier (BBB). During the next decade of inquiry, it is crucial that basic science and clinical research that is focused on overcoming the BBB, to optimize delivery to the central nervous system, be identified and supported as a priority topic. For this reason, the third international Cerebrovascular Biology and Blood-Brain Barrier Conference was convened in March 1998 in Gleneden Beach, OR. This meeting brought together basic science and clinical researchers from around the world to analyze BBB function and to discuss delivery of effective agents to the central nervous system for treatment of brain disease. This report summarizes the information presented at the meeting and the discussions that ensued. The current state of knowledge, obstacles to further understanding the BBB, and research priorities are identified. C1 Oregon Hlth Sci Univ, Portland, OR 97201 USA. Univ London Kings Coll, London WC2R 2LS, England. Univ Minnesota, Duluth, MN 55812 USA. Texas Tech Univ, Hlth Sci Ctr, Amarillo, TX USA. Inst Cochin Genet Mol, F-75014 Paris, France. Massachusetts Gen Hosp, Charlestown, MA USA. Univ Kansas, Lawrence, KS 66045 USA. NIA, Bethesda, MD 20892 USA. RP Neuwelt, EA (reprint author), Oregon Hlth Sci Univ, 3181 Sw Sam Jackson Pk Rd L603, Portland, OR 97201 USA. NR 5 TC 29 Z9 30 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD MAR PY 1999 VL 44 IS 3 BP 604 EP 608 DI 10.1097/00006123-199903000-00095 PG 5 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 168WQ UT WOS:000078716500087 PM 10069598 ER PT J AU Aravind, L Walker, DR Koonin, EV AF Aravind, L Walker, DR Koonin, EV TI Conserved domains in DNA repair proteins and evolution of repair systems SO NUCLEIC ACIDS RESEARCH LA English DT Review ID NUCLEOTIDE EXCISION-REPAIR; D-XYLOSE ISOMERASE; ESCHERICHIA-COLI; SACCHAROMYCES-CEREVISIAE; XERODERMA-PIGMENTOSUM; CRYSTAL-STRUCTURE; GENE ENCODES; ACTIVE-SITE; EXONUCLEASE ACTIVITY; (A)BC EXCINUCLEASE AB A detailed analysis of protein domains involved in DNA repair was performed by comparing the sequences of the repair proteins from two well-studied model organism, the bacterium Escherichia coli and yeast Saccharomyces cerevisiae, to the entire sets of protein sequences encoded in completely sequenced genomes of bacteria, archaea and eukaryotes. Previously uncharacterized conserved domains involved in repair were identified, namely four families of nucleases and a family of eukaryotic repair proteins related to the proliferating cell nuclear antigen. In addition, a number of previously undetected occurrences of known conserved domains were detected; for example, a modified helix-hairpin-helix nucleic acid-binding domain in archaeal and eukaryotic RecA homologs. There is a limited repertoire of conserved domains, primarily ATPases and nucleases, nucleic acid-binding domains and adaptor (protein-protein interaction) domains that comprise the repair machinery in all cells, but very few of the repair proteins are represented by orthologs with conserved domain architecture across the three superkingdoms of life. Both the external environment of an organism and the internal environment of the cell, such as the chromatin superstructure in eukaryotes, seem to have a profound effect on the layout of the repair systems. Another factor that apparently has made a major contribution to the composition of the repair machinery is horizontal gene transfer, particularly the invasion of eukaryotic genomes by organellar genes, but also a number of likely transfer events between trends in the evolution of repair proteins were noticed; in particular, multiple, independent fusions of helicase and nuclease domains, and independent inactivation of enzymatic domains that apparently retain adaptor or regulatory functions. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Texas A&M Univ, Dept Biol, College Stn, TX USA. Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov NR 152 TC 380 Z9 386 U1 1 U2 26 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 MAR 1 PY 1999 VL 27 IS 5 BP 1223 EP 1242 DI 10.1093/nar/27.5.1223 PG 20 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 173QB UT WOS:000078990300001 PM 9973609 ER PT J AU Dianov, G Bischoff, C Sunesen, M Bohr, VA AF Dianov, G Bischoff, C Sunesen, M Bohr, VA TI Repair of 8-oxoguanine in DNA is deficient in Cockayne syndrome group B cells SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RNA-POLYMERASE-II; TRANSCRIPTION-COUPLED REPAIR; EXCISION-REPAIR; DAMAGE; GLYCOSYLASE; DEFECT; STRAND; GENE AB The incision of the 8-oxoguanine in DNA by normal and Cockayne Syndrome (CS) cell extracts has been investigated. The incision in extracts derived from CS cells was similar to 50% of the incision level compared with extracts prepared from normal cells. In contrast, the incision rate of uracil and thymine glycol was not defective in CS cells. The deficiency in 8-oxoguanine incision was also demonstrated in a CS family. Whereas the proband had markedly less incision compared with the normal siblings, the parents had intermediate levels. The low level of 8-oxoguanine-DNA glycosyl;ase in CS extracts correlates with the reduced expression of the 8-oxoguanine-DNA glycosylase gene (hOGG1) in CS cells, Both the levels of expression of the hOGG1 gene and the incision of 8-oxoguanine in DNA increased markedly after transfection of CS-B cells with the CSB gene. We suggest that the CSB mutation leads to deficient transcription of the hOGG1 gene and thus to deficient repair of 8-oxoguanine in DNA. C1 NIA, Genet Mol Lab, NIH, Baltimore, MD 21224 USA. Univ Aarhus, Inst Mol & Struct Biol, Aarhus, Denmark. RP Bohr, VA (reprint author), NIA, Genet Mol Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 25 TC 98 Z9 99 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR 1 PY 1999 VL 27 IS 5 BP 1365 EP 1368 DI 10.1093/nar/27.5.1365 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 173QB UT WOS:000078990300019 PM 9973627 ER PT J AU Sparks, SM AF Sparks, SM TI Untitled SO NURSING OUTLOOK LA English DT Letter C1 Natl Lib Med, Div Extramural Programs, Bethesda, MD 20209 USA. RP Sparks, SM (reprint author), Natl Lib Med, Div Extramural Programs, Bethesda, MD 20209 USA. NR 1 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 0029-6554 J9 NURS OUTLOOK JI Nurs. Outlook PD MAR-APR PY 1999 VL 47 IS 2 BP 95 EP 95 DI 10.1016/S0029-6554(99)90081-7 PG 1 WC Nursing SC Nursing GA 189LD UT WOS:000079905500014 ER PT J AU Schwarz, K Foltz, CM AF Schwarz, K Foltz, CM TI Selenium as an integral part of Factor 3 against dietary necrotic liver degeneration (Reprinted from Journal of the American Chemistry Society, vol 79, pg 3292, 1957) SO NUTRITION LA English DT Reprint C1 Natl Inst Arthritis & Metab Dis, US Dept Hlth Educ & Welfare, NIH, Bethesda, MD 20892 USA. RP Schwarz, K (reprint author), Natl Inst Arthritis & Metab Dis, US Dept Hlth Educ & Welfare, NIH, Bethesda, MD 20892 USA. NR 13 TC 9 Z9 9 U1 1 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0899-9007 J9 NUTRITION JI Nutrition PD MAR PY 1999 VL 15 IS 3 BP 255 EP 255 PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 178TF UT WOS:000079282000019 PM 10408880 ER PT J AU Mennuti, MT Thomson, E Press, N AF Mennuti, MT Thomson, E Press, N TI Screening for cystic fibrosis carrier state SO OBSTETRICS AND GYNECOLOGY LA English DT Editorial Material AB Carrier screening for cystic fibrosis as part of reproductive health care, including prenatal care, is not the standard of practice at this time. However, a recent National Institutes of Health Consensus Development Conference recommended that cystic fibrosis carrier screening should be offered to adults with a family history of cystic fibrosis, partners of individuals with cystic fibrosis, couples planning a pregnancy, and couples seeking prenatal testing. A workshop convened to discuss the implementation of these recommendations concluded that several issues must be resolved before these recommendations can be implemented. This commentary reviews the discussions that occurred and the conclusions that were reached at this workshop. Some of the subjects considered by the workshop participants were: the goals and outcomes of carrier screening; the continuum from making a test available to offering that test; to whom, when, and how cystic fibrosis testing should be offered; laboratory practice and quality assurance; provider and patient education; and insurance issues. The workshop participants concluded that those populations to whom carrier screening should be offered might include individuals and couples in high-risk groups who seek preconception counseling, infertility care, or prenatal care. High-risk groups include individuals of: white northern European or of Ashkenazi-Jewish descent, those whose partners have cystic fibrosis, and those with a family history of cystic fibrosis. Before screening can be offered systematically to these individuals or couples, practice guidelines, educational materials for providers and patients, informed-consent protocols, and laboratory standards for testing must be developed. (C) 1999 by The American College of Obstetricians and Gynecologists. C1 Univ Penn, Med Ctr, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90024 USA. RP Mennuti, MT (reprint author), Univ Penn, Med Ctr, Dept Obstet & Gynecol, 3400 Spruce St, Philadelphia, PA 19104 USA. EM mmennuti@obgyn.upenn.edu NR 11 TC 21 Z9 21 U1 0 U2 0 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 MAR PY 1999 VL 93 IS 3 BP 456 EP 461 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 171RA UT WOS:000078876600030 PM 10075000 ER PT J AU Smith, R AF Smith, R TI Therapy for early-stage colorectal cancer - The Peeters/Haller article reviewed SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID CARCINOMA C1 Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. RP Smith, R (reprint author), Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. NR 7 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 MAR PY 1999 VL 13 IS 3 BP 320 EP 321 PG 2 WC Oncology SC Oncology GA 368QA UT WOS:000090127900007 ER PT J AU Kaplan, RS Smiley, JK Cheson, BD AF Kaplan, RS Smiley, JK Cheson, BD TI Clinical trials referral resource - Multicenter trials of therapies for adult brain tumors SO ONCOLOGY-NEW YORK LA English DT Article C1 NCI, Bethesda, MD 20892 USA. RP Kaplan, RS (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 MAR PY 1999 VL 13 IS 3 BP 376 EP + PG 3 WC Oncology SC Oncology GA 368QA UT WOS:000090127900016 PM 10204156 ER PT J AU Okamoto, A Woodworth, CD Yen, K Chung, J Isonishi, S Nikaido, T Kiyokawa, T Seo, H Kitahara, Y Ochiai, K Ochiai, K Tanaka, T AF Okamoto, A Woodworth, CD Yen, K Chung, J Isonishi, S Nikaido, T Kiyokawa, T Seo, H Kitahara, Y Ochiai, K Ochiai, K Tanaka, T TI Combination therapy with podophyllin and vidarabine for human papillomavirus positive cervical intraepithelial neoplasia SO ONCOLOGY REPORTS LA English DT Article DE cervical cancer of uterus; cervical intraepithelial neoplasia; DNA polymerase inhibitor; apoptosis; PCR-RFLP ID EPITHELIAL-CELLS; KERATINOCYTES; DIFFERENTIATION; APOPTOSIS; PROLIFERATION; INFECTION; CARCINOMA; CANCER; LINES; ACID AB Our aim was to establish an effective non-surgical treatment for cervical intraepithelial neoplasia (CIN) through inactivation of human papillomavirus (HPV), the major etiological agent for this disease. We show that vidarabine,a DNA polymerase inhibitor, suppressed growth and HPV gene expression in human cervical keratinocytes immortalized by HPV or in cervical cancer cell lines. Expression of HPV-16 E6 and E7 proteins in normal cervical keratinocytes sensitized cells to apoptosis in the presence of podophyllin or vidarabine. We applied vidarabine ointment and/or podophyllin to cervical epithelium in 28 cases of GIN I-II to evaluate the therapeutic effectiveness of these agents. Go-application of vidarabine and podophyllin in six treatments caused regression of lesions cytologically and histologically, and disappearance of HPV-16 or -18 DNA in 17 of 21 (81%) women. Our results suggest that the combination of vidarabine and podophyllin therapy is an effective non-surgical treatment for HPV-positive GIN. C1 Jikei Univ, Sch Med, Dept Obstet, Minato Ku, Tokyo 1050003, Japan. Jikei Univ, Sch Med, Dept Gynecol, Minato Ku, Tokyo 105003, Japan. Jikei Univ, Sch Med, Dept Gene Therapy,Inst DNA Med, Minato Ku, Tokyo 105003, Japan. Jikei Univ, Sch Med, Dept Pathol, Minato Ku, Tokyo 1050003, Japan. NCI, Biol Lab, NIH, Bethesda, MD 20892 USA. RP Tanaka, T (reprint author), Jikei Univ, Sch Med, Dept Obstet, Minato Ku, Nishi Shinbashi 3-25-8, Tokyo 1050003, Japan. NR 25 TC 10 Z9 10 U1 0 U2 0 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1021-335X J9 ONCOL REP JI Oncol. Rep. PD MAR-APR PY 1999 VL 6 IS 2 BP 269 EP 276 PG 8 WC Oncology SC Oncology GA 168WJ UT WOS:000078715900004 PM 10022988 ER PT J AU Sanguineti, G Corvo, R AF Sanguineti, G Corvo, R TI Treatment of nasopharyngeal carcinoma: State of the art and new perspectives (Review) SO ONCOLOGY REPORTS LA English DT Review DE nasopharyngeal carcinoma; radiotherapy; chemotherapy; prognostic factors ID SQUAMOUS-CELL-CARCINOMA; EPSTEIN-BARR-VIRUS; LYMPH-NODE METASTASES; THERAPY ONCOLOGY GROUP; RADIATION-THERAPY; LOCAL-CONTROL; PROGNOSTIC FACTORS; MEGAVOLTAGE IRRADIATION; INDUCTION CHEMOTHERAPY; COMPUTED-TOMOGRAPHY AB The role of radiotherapy and the current strategies to improve outcome in nasopharyngeal carcinoma are reviewed. Emphasis is on the factors, which may provide a more accurate selection of patients for more aggressive treatments. Clinical data suggest that local failure and distant metastases are separate events. Thus, strategies to optimize one of them are not expected to impact significantly on the other. Patients with advanced T stage disease, cranial nerve palsy, bulky primary lesions and well differentiated tumors may benefit from more local aggressive treatment. These include higher dose radiotherapy throughout conformal 3D radiotherapy and brachytherapy. Altered fractionation schedules and concomitant chemotherapy may also enhance the results obtained by conventional external beam radiotherapy. Patients with advanced neck disease and/or low neck nodes are candidates for additional systemic treatments as well. The role of technical innovations in radiotherapy delivery and that of altered fractionation schedules are unknown, even if results from phase II studies are promising. Regarding chemotherapy, 'first generation trials' have shown some impact of chemotherapy on outcome. However, additional testing is needed in order to improve the therapeutic index and validate its rationale. C1 Natl Canc Inst, Dept Radiat Oncol, I-16132 Genoa, Italy. RP Sanguineti, G (reprint author), Ist Nazl Ric Canc, Serv Oncol Radioterap, Largo Rosanna Benzi 10, I-16132 Genoa, Italy. NR 116 TC 9 Z9 9 U1 0 U2 0 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1021-335X J9 ONCOL REP JI Oncol. Rep. PD MAR-APR PY 1999 VL 6 IS 2 BP 377 EP 391 PG 15 WC Oncology SC Oncology GA 168WJ UT WOS:000078715900025 PM 10023009 ER PT J AU Mogil, JS Wilson, SG Bon, K Lee, SE Chung, K Raber, P Pieper, JO Hain, HS Belknap, JK Hubert, L Elmer, GI Chung, JM Devor, M AF Mogil, JS Wilson, SG Bon, K Lee, SE Chung, K Raber, P Pieper, JO Hain, HS Belknap, JK Hubert, L Elmer, GI Chung, JM Devor, M TI Heritability of nociception I: Responses of 11 inbred mouse strains on 12 measures of nociception SO PAIN LA English DT Review DE algesiometry; inbred strains; mouse genetics; pain models; strain differences ID MORPHINE-INDUCED ANALGESIA; NEUROPATHIC PAIN; FORMALIN TEST; MICE LACKING; EXPERIMENTAL-MODEL; RECEPTOR GENE; RATS; SENSITIVITY; BEHAVIOR; LOCI AB It is generally acknowledged that humans display highly variable sensitivity to pain, including variable responses to identical injuries or pathologies, The possible contribution of genetic factors has, however, been largely overlooked. An emerging rodent literature documents the importance of genotype in mediating basal nociceptive sensitivity, in establishing a predisposition to neuropathic pain following neural injury, and in determining sensitivity to pharmacological agents and endogenous antinociception. One clear finding from these studies is that the effect of genotype is at least partially specific to the nociceptive assay being considered. In this report we begin to systematically describe and characterize genetic variability of nociception in a mammalian species, Mus musculus. We tested 11 readily-available inbred mouse strains (129/J, A/J, AKR/J, BALB/cJ, C3H/HeJ, C57BL/6J, C58/J, CBA/J, DBA/2J, RIIIS/J and SM/J) using 12 common measures of nociception. These included assays for thermal nociception (hot plate, Hargreaves' test, tail withdrawal), mechanical nociception (von Frey filaments), chemical nociception (abdominal constriction, carrageenan, formalin), and neuropathic pain (autotomy, Chung model peripheral nerve injury). We demonstrate the existence of clear strain differences in each assay, with 1.2 to 54-fold ranges of sensitivity. All nociceptive assays display moderate-to-high heritability (h(2) = 0.30-0.76) and mediation by a limited number of apparent genetic loci. Data comparing inbred strains have considerable utility as a tool for understanding the genetics of nociception, and a particular relevance to transgenic studies. (C) 1999 international Association for the Study of Pain. Published by Elsevier Science B.V. C1 Univ Illinois, Dept Psychol, Champaign, IL 61820 USA. Univ Illinois, Neurosci Program, Champaign, IL 61820 USA. Univ Texas, Med Branch, Inst Marine Biomed, Galveston, TX 77555 USA. Univ Texas, Med Branch, Dept Anat & Neurosci, Galveston, TX 77555 USA. Hebrew Univ Jerusalem, Inst Life Sci, Dept Cell & Anim Biol, IL-91904 Jerusalem, Israel. NIDA, Behav Neurosci Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Oregon Hlth Sci Univ, Dept Behav Neurosci, Portland, OR 97201 USA. Oregon Hlth Sci Univ, VA Med Ctr, Portland, OR 97201 USA. Univ Maryland Baltimore Cty, Sch Med, Dept Psychiat, Maryland Psychiat Res Ctr, Baltimore, MD 21228 USA. RP Mogil, JS (reprint author), Univ Illinois, Dept Psychol, 603 E Daniel St, Champaign, IL 61820 USA. EM jmogil@s.psych.uiuc.edu FU NIAAA NIH HHS [P60 AA010760]; NIDA NIH HHS [DA11394, DA11888]; NINDS NIH HHS [NS35057] NR 110 TC 417 Z9 423 U1 4 U2 22 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD MAR PY 1999 VL 80 IS 1-2 BP 67 EP 82 DI 10.1016/S0304-3959(98)00197-3 PG 16 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 180GW UT WOS:000079378600008 PM 10204719 ER PT J AU Mogil, JS Wilson, SG Bon, K Lee, SE Chung, K Raber, P Pieper, JO Hain, HS Belknap, JK Hubert, L Elmer, GI Chung, JM Devor, M AF Mogil, JS Wilson, SG Bon, K Lee, SE Chung, K Raber, P Pieper, JO Hain, HS Belknap, JK Hubert, L Elmer, GI Chung, JM Devor, M TI Heritability of nociception II. 'Types' of nociception revealed by genetic correlation analysis SO PAIN LA English DT Article DE algesiometry; inbred strains; mouse genetics; pain models; strain differences ID MIDBRAIN PERIAQUEDUCTAL GRAY; VENTRO-BASAL THALAMUS; AMINO-ACID RECEPTORS; 3 PAIN TESTS; NEUROPATHIC PAIN; THERMAL STIMULI; C-FOS; HYPERALGESIC-INFLAMMATION; MECHANICAL HYPERALGESIA; NEUROGENIC HYPERALGESIA AB Clinical pain syndromes, and experimental assays of nociception, are differentially affected by manipulations such as drug administration and exposure to environmental stress. This suggests that there are different 'types' of pain, We exploited genetic differences among inbred strains of mice in an attempt to define these primary 'types'; that is, to identify the fundamental parameters of pain processing. Eleven randomly-chosen inbred mouse strains were tested for their basal sensitivity on I? common measures of nociception, These measures provided for a range of different nociceptive dimensions including noxious stimulus modality, location, duration and etiology, among others. Since individual members of inbred strains are identical at all genetic loci, the observation of correlated strain means in any given pair of nociceptive assays is an index of genetic correlation between these assays, and hence an indication of common physiological mediation, Obtained correlation matrices were subjected to multivariate analyses to identify constellations of nociceptive assays with common genetic mediation. This analysis revealed three major clusters of nociception: (1) baseline thermal nociception, (2) spontaneously emitted responses to chemical stimuli, and (3) baseline mechanical sensitivity and cutaneous hypersensitivity. Many other nociceptive parameters that might a priori have been considered closely related proved to bt:genetically divergent. (C) 1999 International Association for the Study of Pain. Published by Elsevier Science B.V. C1 Univ Illinois, Dept Psychol, Champaign, IL 61820 USA. Univ Illinois, Neurosci Program, Champaign, IL 61820 USA. Univ Texas, Med Branch, Inst Marine Biomed, Galveston, TX 77555 USA. Univ Texas, Med Branch, Dept Anat & Neurosci, Galveston, TX 77555 USA. Hebrew Univ Jerusalem, Inst Life Sci, Dept Cell & Anim Biol, IL-91904 Jerusalem, Israel. NIDA, Behav Neurosci Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Oregon Hlth Sci Univ, Dept Behav Neurosci, Portland, OR 97201 USA. Oregon Hlth Sci Univ, VA Med Ctr, Portland, OR 97201 USA. Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Catonsville, MD 21228 USA. RP Mogil, JS (reprint author), Univ Illinois, Dept Psychol, 603 E Daniel St, Champaign, IL 61820 USA. EM jmogil@s.psych.uiuc.edu FU NIAAA NIH HHS [P60 AA010760]; NIDA NIH HHS [DA11888, DA11394]; NINDS NIH HHS [NS35057] NR 66 TC 171 Z9 174 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD MAR PY 1999 VL 80 IS 1-2 BP 83 EP 93 DI 10.1016/S0304-3959(98)00196-1 PG 11 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 180GW UT WOS:000079378600009 PM 10204720 ER PT J AU Fang, Q Sun, YY El-Gabalawy, H Cai, W Ko, L Chin, H Arayssi, T Schumacher, HR Williams, WV AF Fang, Q Sun, YY El-Gabalawy, H Cai, W Ko, L Chin, H Arayssi, T Schumacher, HR Williams, WV TI Synovial T cell receptor heterogeneity in early arthritis SO PATHOBIOLOGY LA English DT Article DE rheumatoid arthritis; reactive arthritis; undifferentiated arthritis; synovial tissue; T cell receptors; single-stranded conformational polymorphism ID COLLAGEN-INDUCED ARTHRITIS; HEAT-SHOCK-PROTEIN; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MAJOR HISTOCOMPATIBILITY COMPLEX; MYELIN BASIC-PROTEIN; V-ALPHA DOMAIN; RHEUMATOID-ARTHRITIS; BETA-CHAIN; ANTIGEN RECEPTOR; RESTRICTED HETEROGENEITY AB Rheumatoid arthritis (RA) has been postulated to result from a synovial immune response to an unidentified antigen(s), which should be mirrored by the T cell response. Here we investigate the T cell receptor (TCR) repertoire in the synovial tissue of patients with arthritis of early to moderate duration. We developed a nested polymerase chain reaction (PCR) technique to examine the TCR repertoire of small biopsy specimens, and show that the method is highly sensitive. We apply this technique to synovial biopsies obtained from the knee joints of patients with early to moderate duration arthritis (average duration of arthritis 1 year, range 0.02-2.75 years). We examined biopsies from 5 normal individuals, 32 RA patients, 7 patients with seronegative spondyloarthropathy (Sp), and 12 patients with undifferentiated arthritis (UA). TCR message was detectable in 4/5 normals, 15/32 RA, 5/7 Sp, and 8/11 UA biopsies, with sampling error likely accounting for most negative biopsies. The average numbers of TCR V beta s detected per TCR-positive biopsy were 5.0 +/- 3.7 for normals, 12.7 +/- 8.4 for RA, 18.0 +/- 7.4 for Sp patients, and 14.4 +/- 10.2 for UA. Examination of TCR messages by single-stranded conformational polymorphism analysis showed similar proportions of dominant clones in the normals compared with the patients with inflammatory arthritis. Sequence analysis was performed on 33 dominant clones from 16 patients. Sequence alignment of the third hypervariable regions showed some evidence of disease-specific sequence clustering for Sp, while some RA sequences showed similarity to previously described motifs. These data indicate greater TCR heterogeneity in early Sp and UA compared with normal synovium. Disease-specific TCR sequences may occur in early RA and Sp. C1 Univ Penn, Sch Med, Dept Med, Div Rheumatol, Philadelphia, PA 19104 USA. SmithKline Beecham Pharmaceut, Dept Clin Pharmacol, Philadelphia, PA 19104 USA. Vet Affairs Med Ctr, Philadelphia, PA USA. NIAMSD, NIH, Bethesda, MD 20892 USA. RP Williams, WV (reprint author), SmithKline Beecham Pharmaceut, Dept Clin Pharmacol, 51 N 39th St,Andrew Mutch Bldg, Philadelphia, PA 19104 USA. EM William_V_Williams@sbphrd.com OI Arayssi, Thurayya/0000-0003-2469-0272 NR 67 TC 1 Z9 3 U1 0 U2 2 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1015-2008 J9 PATHOBIOLOGY JI Pathobiology PD MAR-APR PY 1999 VL 67 IS 2 BP 59 EP 74 DI 10.1159/000028053 PG 16 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 172TM UT WOS:000078940800001 PM 10023134 ER PT J AU Aros, S Cassorla, F Torres, C Henriquez, C Iniguez, G Fuentes, A Mena, M Klebanoff, M Mills, J AF Aros, S Cassorla, F Torres, C Henriquez, C Iniguez, G Fuentes, A Mena, M Klebanoff, M Mills, J TI Clinical features and growth factors in infants exposed to alcohol in ureto. SO PEDIATRIC RESEARCH LA English DT Meeting Abstract C1 Univ Chile, IDIMI, Santiago, Chile. NICHD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD MAR PY 1999 VL 45 IS 3 MA 15 BP 439 EP 439 DI 10.1203/00006450-199903000-00038 PG 1 WC Pediatrics SC Pediatrics GA 172EU UT WOS:000078911000039 ER PT J AU Long, RM AF Long, RM TI News from the National Institute of General Medical Sciences (NIGMS) SO PHARMACEUTICAL RESEARCH LA English DT Article C1 NIGMS, Pharmacol & Physiol Sci Branch, Div Pharmacol Physiol & Biol Chem, NIH, Bethesda, MD 20892 USA. RP Long, RM (reprint author), NIGMS, Pharmacol & Physiol Sci Branch, Div Pharmacol Physiol & Biol Chem, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU 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 MAR PY 1999 VL 16 IS 3 BP 339 EP 341 PG 3 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 182FQ UT WOS:000079472600001 ER PT J AU Carrozza, V Csako, G Yanovski, JA Skarulis, MC Nieman, L Wesley, R Pucino, F AF Carrozza, V Csako, G Yanovski, JA Skarulis, MC Nieman, L Wesley, R Pucino, F TI Levothyroxine replacement therapy in central hypothyroidism: A practice report SO PHARMACOTHERAPY LA English DT Article ID L-THYROXINE THERAPY; BINDING GLOBULIN; BONE-DENSITY; HYPERTHYROIDISM; THYROTOXICOSIS; HUMANS AB Because of lack of well-documented laboratory criteria, we assessed the usefulness of measuring free thyroxine (FT4) levels for monitoring levothyroxine replacement therapy in patients with central hypothyroidism. This consisted of a retrospective review from 1991-1997 of patient profiles extracted into a Macintosh 4th Dimension data base from the medical information system at a tertiary care biomedical research facility. Information was also retrieved from medical records of 135 ambulatory patients treated by 42 endocrinology practitioners, and 52 ambulatory patients treated by 20 endocrinology practitioners for central and primary hypothyroidism, respectively. Patient profiles were reviewed for most recent thyroid function test results and levothyroxine dosing information. Of 112 (83%) patients with central hypothyroidism who had FT4 levels within the laboratory's reference interval, only 2 had a dosage change. The FT4 concentration was concordant with physician-assessed thyroid status in 65 (82%) of 79 patients (95% CI 72-90, p<0.02) for whom clinical assessment was available in medical records. Thyrotropin, total thyroxine, and triiodothyronine levels were not significantly associated with clinical status (p>0.12) in patients with central hypothyroidism. Despite similar demographic and levothyroxine dosing profiles, patients with central hypothyroidism had significantly lower serum FT4 and thyrotropin concentrations than those with primary hypothyroidism. The appropriateness of levothyroxine replacement therapy in most patients with central hypothyroidism is reflected by a normal FT4 concentration measured with a valid assay. Whether midnormal or upper normal values are necessary for optimal therapy, and whether the therapeutic goal should be different in children than in adults, require prospective studies with independent, objective assessment of thyroid status. C1 NICHHD, Dept Pharm, NIH, Bethesda, MD 20892 USA. NICHHD, Dept Clin Pathol, NIH, Bethesda, MD 20892 USA. NICHHD, Warren G Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Off Director, NIH, Bethesda, MD 20892 USA. NIDDKD, Div Intramural, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. RP Carrozza, V (reprint author), NICHHD, Dept Pharm, NIH, Bldg 10,Room 1N-257,10 Ctr Dr, Bethesda, MD 20892 USA. NR 25 TC 17 Z9 18 U1 0 U2 0 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER BOX 806 171 HARRISON AVE, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD MAR PY 1999 VL 19 IS 3 BP 349 EP 355 DI 10.1592/phco.19.4.349.30940 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 173PQ UT WOS:000078989300010 PM 10221374 ER PT J AU Link, A Zaharevitz, DW Kunick, C AF Link, A Zaharevitz, DW Kunick, C TI Antitumor pyrido[3,2-d][1]benzazepines: Synthesis and in vitro activity of thiophene analogs SO PHARMAZIE LA English DT Article ID NATIONAL-CANCER-INSTITUTE; TUMOR-CELL-LINES; DRUG DISCOVERY; DIVERSE PANEL; SCREEN; PHARMACOLOGY; CYTOTOXICITY; PROGRAM AB The bioisosteric replacement of benzene elements in the antitumor lead structures 2 and 3 led to the thienyl substituted 5H-pyrido[3,2-d][1]benzazepin-6(7H)-ones 8a and 8b, the analogous thiolactams 4a and 4b, and the 4H-pyrido[2,3-d]thieno[3,2-b]azepines 11 and 12 which represent a novel heterocyclic scaffold. The in vitro evaluation of 4a in a cell line based screening revealed a noteworthy antitumor activity and a remarkable selectivity for renal tumor cell lines. The cell line selectivity pattern of 4a differs distinctly from the pattern displayed by standard antitumor agents. C1 Univ Hamburg, Inst Pharm, D-20146 Hamburg, Germany. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Kunick, C (reprint author), Univ Hamburg, Inst Pharm, Bundesstr 45, D-20146 Hamburg, Germany. RI Link, Andreas/H-5067-2013 OI Link, Andreas/0000-0003-1262-6636 NR 18 TC 10 Z9 10 U1 0 U2 1 PU GOVI-VERLAG GMBH PI ESCHBORN PA PHARMAZEUTISCHER VERLAG GINNHEIMER STRASSE 26, D-65760 ESCHBORN, GERMANY SN 0031-7144 J9 PHARMAZIE JI Pharmazie PD MAR PY 1999 VL 54 IS 3 BP 163 EP 166 PG 4 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 179JY UT WOS:000079324600001 PM 10192102 ER PT J AU Motten, AG Martinez, LJ Holt, N Sik, RH Reszka, K Chignell, CF Tonnesen, HH Roberts, JE AF Motten, AG Martinez, LJ Holt, N Sik, RH Reszka, K Chignell, CF Tonnesen, HH Roberts, JE TI Photophysical studies on antimalarial drugs SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID BIOLOGICALLY-ACTIVE COMPOUNDS; PHOTOCHEMICAL STABILITY; IN-VITRO; PHOTOREACTIVITY; SENSITIZATION; METABOLITES; CHLOROQUINE; PRIMAQUINE; RESONANCE; SOLVENTS AB Most drugs used in the treatment of malaria produce phototoxic side effects in both the skin and the eye. Cutaneous and ocular effects that may be caused by light include changes in skin pigmentation, corneal opacity, cataract formation and other visual disturbances including irreversible retinal damage (retinopathy) leading to blindness. The mechanism for these reactions in humans is unknown. We irradiated a number of antimalarial drugs (amodiaquine, chloroquine, hydroxychloroquine, mefloquine, primaquine and quinacrine) with light (lambda > 300 mn) and conducted electron paramagnetic resonance (EPR) and laser hash photolysis studies to determine the possible active intermediates produced. Each antimalarial drug produced at least one EPR adduct with the spin-trap 5,5-dimethyl-1-pyrroline N-oxide in benzene: super-oxide/hydroperoxyl adducts (chloroquine, mefloquine, quinacrine, amodiaquine and quinine), carbon-centered radical adducts (all but primaquine), or a nitrogen-centered radical adduct only (primaquine). fn ethanol all drugs except primaquine produced some superoxide/hydroperoxyl adduct, with quinine, quinacrine, and hydroxychloroquine also producing the ethoxyl adduct. As detected with flash photolysis and steady-state techniques, mefloquine, quinine, amodiquine and a photoproduct of quinacrine produced singlet oxygen (cp, 0.38; phi( Delta) = 0.36; phi(Delta), = 0.011; phi(Delta), = 0.013 in D2O, pD7), but only primaquine quenched singlet oxygen efficiently (2.6 x 10(8) M-1 s(-1) in D2O, pD7), Because malaria is a disease most prevalent in regions of high light intensity, protective measures (clothing, sunblock, sunglasses or eye wraps) should be recommended when administering antimalarial drugs. C1 NIEHS, Mol Biophys Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Oslo, Dept Pharmaceut, N-0316 Oslo, Norway. Fordham Univ, Div Sci & Math, New York, NY 10023 USA. RP Chignell, CF (reprint author), NIEHS, Mol Biophys Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM chignell@niehs.nih.gov NR 35 TC 35 Z9 36 U1 0 U2 7 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 MAR PY 1999 VL 69 IS 3 BP 282 EP 287 DI 10.1562/0031-8655(1999)069<0282:PSOAD>2.3.CO;2 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 175GA UT WOS:000079084000005 PM 10089818 ER PT J AU Riess, J Bicout, D Duguet, T Magyar, P AF Riess, J Bicout, D Duguet, T Magyar, P TI Increase of quantum Hall plateau width by electron-phonon interaction SO PHYSICA B LA English DT Article; Proceedings Paper CT 9th International Conference on Phonon Scattering in Condensed Matter (PHONONS 98) CY JUL 26-31, 1998 CL LANCASTER, ENGLAND SP Engn & Phys Sci Res Council, European Commiss, Int Union Pure & Appl Phys, US Army European Res Off, Lancaster Univ Dept Phys, Inst Phys, European Phys Soc DE quantum Hall effect; electron-phonon interaction; plateau widths ID SYSTEMS AB We perform model calculations which illustrate the role of electron-phonon interaction in the integer quantum Hall effect. We show that electron-phonon interaction can generate electron velocities which contribute to the formation of the quantized plateaus of sigma(xy). In systems which contain insulating states (typical quantum Hall samples) the fraction of this kind of velocities is small. This leads to slightly larger plateaus of sigma(xy) compared to those of the dissipative conductivity. Experimentally, this difference has been known for a long time, but remained unexplained so far. In the special case where the substrate potential has no spatial fluctuations in the direction of the macroscopic electric field, all states are conducting and the dissipative conductivity vanishes only close to the band edges. Nevertheless, the calculated Hall conductivity shows surprisingly broad quantized plateaus, which hers ape entirely generated by electron-phonon interaction. Our results show that dissipation must not necessarily vanish in the Hall plateau regime, contrary to a widespread belief. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Univ Grenoble 1, Ctr Rech Tres Basses Temp, CNRS, F-38042 Grenoble 9, France. NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Riess, J (reprint author), Univ Grenoble 1, Ctr Rech Tres Basses Temp, CNRS, BP 166, F-38042 Grenoble 9, France. NR 11 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0921-4526 J9 PHYSICA B JI Physica B PD MAR PY 1999 VL 263 BP 199 EP 201 DI 10.1016/S0921-4526(98)01334-9 PG 3 WC Physics, Condensed Matter SC Physics GA 180AN UT WOS:000079362700053 ER PT J AU Bicout, DJ Berezhkovskii, AM Szabo, A Weiss, GH AF Bicout, DJ Berezhkovskii, AM Szabo, A Weiss, GH TI First-passage times in phase space for the strong collision model SO PHYSICAL REVIEW E LA English DT Article AB We consider the dynamics in phase space in which particles follow Newtonian trajectories that are randomly interrupted by collisions which equilibrate both the velocity and position of the particles. Collisions are assumed to be statistically independent events of zero duration and the intercollision rime is a random variable with a negative exponential distribution. For this model, we derive an analytical expression for the Laplace transform of the survival probability and quadrature expressions for mean first-passage times. [S1063-651X(99)01103-4]. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NIH, Ctr Informat Technol, Math & Stat Comp Lab, Bethesda, MD 20892 USA. LY Karpov Phys Chem Res Inst, Moscow 103064, Russia. RP Bicout, DJ (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5,Room 136, Bethesda, MD 20892 USA. RI Szabo, Attila/H-3867-2012 NR 8 TC 7 Z9 7 U1 2 U2 5 PU AMERICAN PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1063-651X J9 PHYS REV E JI Phys. Rev. E PD MAR PY 1999 VL 59 IS 3 BP 3702 EP 3705 DI 10.1103/PhysRevE.59.3702 PN B PG 4 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 177WF UT WOS:000079233500074 ER PT J AU Leshner, AI Koob, GF AF Leshner, AI Koob, GF TI Drugs of abuse and the brain SO PROCEEDINGS OF THE ASSOCIATION OF AMERICAN PHYSICIANS LA English DT Article DE addiction; corticotropin-releasing factor (CRF); dopamine; relapse; reward; vulnerability ID CORTICOTROPIN-RELEASING FACTOR; RAT NUCLEUS-ACCUMBENS; ALCOHOL DEPENDENCE; MOLECULAR MECHANISMS; INTRAVENOUS COCAINE; OPIATE WITHDRAWAL; REWARD SYSTEM; MICE LACKING; DOPAMINE; ADDICTION AB New insights into our understanding of drug abuse and addiction have revealed that the desire to use drugs and the process of addiction depend on effects on brain function. Drugs of abuse have been hypothesized to produce their rewarding effects by neuropharmacological actions on a common brain reward circuit called the extended amygdala. The extended amygdala involves the mesolimbic dopamine system and specific subregions of the basal forebrain, such as the shell of the nucleus accumbens, the bed nucleus of the stria terminalis, and the central nucleus of the amygdala. The psychomotor stimulants cocaine and amphetamine activate the mesolimbic dopamine system; opiates activate opioid peptide receptors within and independent of the mesolimbic dopamine system. Sedative hypnotics alter multiple neurotransmitter systems in this circuitry, including: 1) gamma aminobutyric acid; 2) dopamine; 3) serotonin;;1) glutamate; and 5) opioid peptides. Nicotine and tetrahydrocannabinol both activate mesolimbic dopamine function and possibly opioid peptide systems in this circuitry. Repeated and prolonged drug abuse leads to compulsive use, and the mechanism for this transition involves, at the behavioral level, a progressive dysregulation of brain reward circuitry and a recruitment of brain stress systems such as corticotropin-releasing factor. The molecular mechanisms of signal transduction in these systems are a likely target for residual changes in that they convey allostatic changes in reward set point, which lead to vulnerability to relapse. C1 Scripps Res Inst, Dept Neuropharmacol, La Jolla, CA 92037 USA. NIDA, NIH, Rockville, MD USA. RP Koob, GF (reprint author), Scripps Res Inst, Dept Neuropharmacol, CVN-7,10550 N Torrey Pines Rd, La Jolla, CA 92037 USA. RI koob, george/P-8791-2016 FU NIDA NIH HHS [DA04043, DA04398, DA08467] NR 83 TC 139 Z9 141 U1 1 U2 13 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1081-650X J9 P ASSOC AM PHYSICIAN JI Proc. Assoc. Am. Phys. PD MAR-APR PY 1999 VL 111 IS 2 BP 99 EP 108 DI 10.1046/j.1525-1381.1999.09218.x PG 10 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 178FG UT WOS:000079255100002 PM 10220804 ER PT J AU Zakhari, S Gordis, E AF Zakhari, S Gordis, E TI Moderate drinking and cardiovascular health SO PROCEEDINGS OF THE ASSOCIATION OF AMERICAN PHYSICIANS LA English DT Article DE atherogenesis; cell signaling; coronary artery disease; fibrinolysis; moderate alcohol consumption; plasminogen activators ID HIGH-DENSITY-LIPOPROTEIN; CORONARY HEART-DISEASE; ESTER TRANSFER PROTEIN; LECITHIN-CHOLESTEROL ACYLTRANSFERASE; ISCHEMIA-REPERFUSION INJURY; CHRONIC ALCOHOL-CONSUMPTION; RED WINE CONSUMPTION; MYOCARDIAL-INFARCTION; HDL CHOLESTEROL; RISK-FACTORS AB Moderate alcohol consumption (1-2 drinks a day) can be beneficial in reducing the risk of coronary artery disease. This article focuses on cellular and molecular mechanisms underlying the beneficial effect of moderate drinking, including increased plasma high-density lipoprotein levels, changes in cellular signaling, reduction in platelet function, stimulation of fibrinolysis, and reduction in ischemia-reperfusion injury. While moderate drinking may be protective against coronary artery disease for some individuals, populations such as pregnant women and individuals who are about to operate motor vehicles or heavy machinery should not drink alcoholic beverages. People with family histories of alcoholism should exercise extreme caution in their decision to drink. C1 NIAAA, Div Basic Res, Bethesda, MD 20892 USA. RP Zakhari, S (reprint author), NIAAA, Div Basic Res, 6000 Execut Blvd,Suite 402, Bethesda, MD 20892 USA. NR 85 TC 12 Z9 12 U1 1 U2 4 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1081-650X J9 P ASSOC AM PHYSICIAN JI Proc. Assoc. Am. Phys. PD MAR-APR PY 1999 VL 111 IS 2 BP 148 EP 158 DI 10.1046/j.1525-1381.1999.09250.x PG 11 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 178FG UT WOS:000079255100008 PM 10220810 ER PT J AU Figg, WD Blumenfeld, JR AF Figg, WD Blumenfeld, JR TI Are we making an impact on prostate cancer? SO PROSTATE CANCER AND PROSTATIC DISEASES LA English DT Article DE prostate cancer; epidemiology; mortality rate; publication rate; peer-reviewed articles C1 NCI, Med Branch, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Med Branch, Bldg 10,Room 5 A01,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1365-7852 J9 PROSTATE CANCER P D JI Prostate Cancer Prostatic Dis. PD MAR PY 1999 VL 2 IS 2 BP 60 EP 61 PG 2 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 204GE UT WOS:000080755100003 ER PT J AU Sampaleanu, LM Davidson, AR Graham, C Wistow, GJ Howell, PL AF Sampaleanu, LM Davidson, AR Graham, C Wistow, GJ Howell, PL TI Domain exchange experiments in duck delta-crystallins: Functional and evolutionary implications SO PROTEIN SCIENCE LA English DT Article DE accessible surface area; argininosuccinate lyase; duck delta crystallin; protein folding; thermal stability ID ARGININOSUCCINATE LYASE ACTIVITY; ESCHERICHIA-COLI; EYE LENS; EQUILIBRIUM DENATURATION; STRUCTURAL PROTEIN; GENE RECRUITMENT; FUMARASE-C; ENZYME; EXPRESSION; SITE AB delta-Crystallin, the major soluble protein component of the avian and reptilian eye lens, is homologous to the urea cycle enzyme argininosuccinate lyase (ASL). In duck lenses there are two delta crystallins, denoted delta 1 and delta 2. Duck delta 2 is both a major structural protein of the lens and also the duck orthologue of ASL, an example of gene recruitment. Although 94% identical to delta 2/ASL in the amino acid sequence, delta 1 is enzymatically inactive. A series of hybrid proteins have been constructed to assess the role of each structural domain in the enzymatic mechanism. Five chimeras-221, 122, 121, 211, and 112, where the three numbers correspond to the three structural domains and the value of 1 or 2 represents the protein of origin, delta 1 or delta 2, respectively-were constructed and thermodynamically and kinetically analyzed. The kinetic analysis indicates that only domain 1 is crucial for restoring ASL activity to delta 1 crystallin, and that amino acid substitutions in domain 2 may play a role in substrate binding. These results confirm the hypothesis that only one domain, domain I, is responsible for the loss of catalytic activity in delta 1. The thermodynamic characterization of human ASL (hASL) and duck delta 1 and delta 2 indicate that delta crystallins are slightly less stable than hASL, with the delta 1 being the least stable. The Delta Gs of unfolding are 57.25, 63.13, and 70.71 kcal mol(-1) for delta 1, delta 2, and hASL, respectively. This result was unexpected, and we speculate that delta crystallins have adapted to their structural role by adopting a slightly less stable conformation that might allow for enhanced protein-protein and protein-solvent interactions. C1 Hosp Sick Children, Res Inst, Div Biochem Res, Toronto, ON M5G 1X8, Canada. Univ Toronto, Fac Med, Dept Biochem, Toronto, ON M5S 1A8, Canada. Univ Toronto, Fac Med, Dept Mol & Med Genet, Toronto, ON M5S 1A8, Canada. NEI, Sect Mol Struct & Funct, NIH, Bethesda, MD 20892 USA. RP Howell, PL (reprint author), Hosp Sick Children, Res Inst, Div Biochem Res, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM howell@sickkids.on.ca NR 59 TC 9 Z9 9 U1 1 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD MAR PY 1999 VL 8 IS 3 BP 529 EP 537 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 174HH UT WOS:000079028300007 PM 10091655 ER PT J AU Teplyakov, A Obmolova, G Badet-Denisot, MA Badet, B AF Teplyakov, A Obmolova, G Badet-Denisot, MA Badet, B TI The mechanism of sugar phosphate isomerization by glucosamine 6-phosphate synthase SO PROTEIN SCIENCE LA English DT Article DE aldose-ketose isomerase; catalytic mechanism; crystal structure; glucosamine 6-phosphate synthase ID COLI GLUCOSAMINE-6-PHOSPHATE SYNTHASE; D-XYLOSE ISOMERASE; ESCHERICHIA-COLI; FRUCTOSE 6-PHOSPHATE; SUBSTRATE; GLUTAMINE; BINDING; SITE; INTERCONVERSION; CATALYSIS AB Glucosamine 6-phosphate synthase converts fructose-6P into glucosamine-6P or glucose-6P depending on the presence or absence of glutamine. The isomerase activity is associated with a 40-kDa C-terminal domain, which has already been characterized crystallographically. Now the three-dimensional structures of the complexes with the reaction product glucose-6P and with the transition state analog 2-amino-2-deoxyglucitol-6P have been determined. Glucose-6P binds in a cyclic form whereas 2-amino-2-deoxyglucitol-6P is in an extended conformation. The information on ligand-protein interactions observed in the crystal structures together with the isotope exchange and site-directed mutagenesis data allow us to propose a mechanism of the isomerase activity of glucosamine-6P synthase. The sugar phosphate isomerization involves a ring opening step catalyzed by His504 and an enolization step with Glu488 catalyzing the hydrogen transfer from C1 to C2 of the substrate. The enediol intermediate is stabilized by a helix dipole and the epsilon-amino group of Lys603. Lys485 may play a role in deprotonating the hydroxyl O1 of the intermediate. C1 NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. CNRS, Inst Chim Subst Nat, F-91198 Gif Sur Yvette, France. RP Teplyakov, A (reprint author), NIDDK, Genet & Biochem Branch, NIH, Bldg 10,Rm 9D17,10 Ctr Dr, Bethesda, MD 20892 USA. NR 29 TC 62 Z9 67 U1 2 U2 12 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD MAR PY 1999 VL 8 IS 3 BP 596 EP 602 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 174HH UT WOS:000079028300014 PM 10091662 ER PT J AU Lipska, BK Khaing, ZZ Weinberger, DR AF Lipska, BK Khaing, ZZ Weinberger, DR TI Neonatal hippocampal damage in the rat: A heuristic model of schizophrenia SO PSYCHIATRIC ANNALS LA English DT Article ID CORTICAL DEVELOPMENT; ANIMAL-MODEL; LESIONS; HYPERRESPONSIVENESS; ABNORMALITIES; DISTURBANCES; HALOPERIDOL; AMPHETAMINE; NEURONS; STRESS C1 NIMH, IRP, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. RP Lipska, BK (reprint author), NIMH, IRP, Clin Brain Disorders Branch, Bldg 9,Rm 1N 124B, Bethesda, MD 20892 USA. RI Lipska, Barbara/E-4569-2017 NR 43 TC 4 Z9 4 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD MAR PY 1999 VL 29 IS 3 BP 157 EP 160 PG 4 WC Psychiatry SC Psychiatry GA 176HA UT WOS:000079144600009 ER PT J AU Sirota, LA Greenberg, BD Murphy, DL Hamer, DH AF Sirota, LA Greenberg, BD Murphy, DL Hamer, DH TI Non-linear association between the serotonin transporter promoter polymorphism and neuroticism: a caution against using extreme samples to identify quantitative trait loci SO PSYCHIATRIC GENETICS LA English DT Article ID BIPOLAR AFFECTIVE-DISORDER; OBSESSIVE-COMPULSIVE DISORDER; FUNCTIONAL POLYMORPHISM; GENE POLYMORPHISMS; PANIC DISORDER; 5-HTT GENE; SIB PAIRS; LINKAGE; SUSCEPTIBILITY; DISEQUILIBRIUM C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. NR 31 TC 26 Z9 26 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8829 J9 PSYCHIATR GENET JI Psychiatr. Genet. PD MAR PY 1999 VL 9 IS 1 BP 35 EP 38 DI 10.1097/00041444-199903000-00006 PG 4 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA 199HH UT WOS:000080474800006 PM 10335550 ER PT J AU Taber, MT Crawley, JN AF Taber, MT Crawley, JN TI Galanin attenuates the effects of scopolamine but not exposure to a novel environment on acetylcholine release in the rat ventral hippocampus SO PSYCHOBIOLOGY LA English DT Article ID ALZHEIMERS-DISEASE; PHOSPHOINOSITIDE TURNOVER; NUCLEUS-ACCUMBENS; IMPULSE FLOW; IN-VIVO; INCREASES; MEMORY; IMMUNOREACTIVITY; INNERVATION; STIMULATION AB In vivo microdialysis was used to measure the effects of galanin on extracellular acetylcholine concentrations in the ventral hippocampus of rats produced by exposure to a novel environment or scopolamine. The novel environment produced a significant increase in acetylcholine release, to 58% above baseline. This effect was insensitive to pretreatment with galanin (5 mu g, i.c.v.) or the peptidergic galanin receptor antagonist M40 (16 mu g, i.c.v.). In contrast, galanin strongly attenuated the increase in acetylcholine release produced by scopolamine (0.3 mg/kg, s.c.). These results indicate that galanin differentially affects the increases in acetylcholine neurotransmission produced by a pharmacological and an environmental stimulus. C1 NIMH, Bethesda, MD 20892 USA. RP Crawley, JN (reprint author), NIH, Bldg 10,Room 4D11,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 32 TC 3 Z9 3 U1 0 U2 0 PU PSYCHONOMIC SOC INC PI AUSTIN PA 1710 FORTVIEW RD, AUSTIN, TX 78704 USA SN 0889-6313 J9 PSYCHOBIOLOGY JI Psychobiology PD MAR PY 1999 VL 27 IS 1 BP 57 EP 62 PG 6 WC Psychology; Psychology, Multidisciplinary SC Psychology GA 191VN UT WOS:000080042400005 ER PT J AU Levin, JR Neumann, E AF Levin, JR Neumann, E TI Testing for predicted patterns: When interest in the whole is greater than in some of its parts SO PSYCHOLOGICAL METHODS LA English DT Article ID SELECTIVE ATTENTION; INHIBITION; RESEARCHERS; POWERFUL AB This article provides a general rationale and step-by-step procedures for statistically assessing a theory-based or predicted pattern in a set of K > 2 means. A coherent hypothesis-testing strategy that incorporates Type I error and power considerations is an integral part of the process. Some specific advantages that are conferred by predicted pattern testing, relative to commonly adopted alternatives, include its (a) scientific parsimony; (b) precision, with respect to getting to the heart of a researcher's hypothesis; (c) sensitivity, as reflected by greater statistical power and which includes applicability to experimental factors associated with small "piecewise" effects; and (d) ability to lend varying degrees of statistical support to a researcher's hypothesis. Both a hypothetical example and a published application of predicted pattern testing are provided to demonstrate its use and usefulness. C1 Univ Wisconsin, Dept Educ Psychol, Madison, WI 53706 USA. NIMH, Sect Socioenvironm Studies, Bethesda, MD 20892 USA. RP Levin, JR (reprint author), Univ Wisconsin, Dept Educ Psychol, 1025 W Johnson St, Madison, WI 53706 USA. NR 30 TC 25 Z9 25 U1 0 U2 1 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1082-989X J9 PSYCHOL METHODS JI Psychol. Methods PD MAR PY 1999 VL 4 IS 1 BP 44 EP 57 DI 10.1037//1082-989X.4.1.44 PG 14 WC Psychology, Multidisciplinary SC Psychology GA 175GE UT WOS:000079084400003 ER PT J AU Shoaib, M Swanner, LS Yasar, S Goldberg, SR AF Shoaib, M Swanner, LS Yasar, S Goldberg, SR TI Chronic caffeine exposure potentiates nicotine self administration in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE caffeine; nicotine self-administration; rat ID INDUCED DOPAMINE RELEASE; LOCOMOTOR-ACTIVITY; NUCLEUS-ACCUMBENS; COCAINE; BRAIN; ADENOSINE; STIMULATION; METHYLXANTHINES; REINFORCEMENT; AMPHETAMINE AB The prevalence of tobacco smoking and coffee drinking place nicotine and caffeine among the most used licit drugs in many societies and their consumption is often characterised by concurrent use. The pharmacological basis for any putative interaction between these drugs remains unclear. Epidemiological reports support anecdotal evidence, which suggests that smokers consume caffeine to enhance the euphoric effects of nicotine. The aim of the present experiment was to examine effects of chronic exposure to caffeine on responding maintained by nicotine. Sprague-Dawley rats consuming caffeine (approximately 150-180 mg/kg per day) in their drinking water for 7 days prior to the beginning and throughout behavioural testing acquired intravenous nicotine self-administration (0.03 mg/kg per infusion) more rapidly than did controls. In a cross-over design, exclusion of caffeine brought levels of nicotine self-administration back to baseline, while adding caffeine to the drinking water of control rats increased responding maintained by nicotine over 90%. These findings strongly suggest that caffeine can potentiate the reinforcing properties of nicotine, thus highlighting the importance of environmental factors in shaping and maintaining tobacco smoking. C1 NIDA, Preclin Pharmacol Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Div Geriatr Med & Gerontol, Baltimore, MD 21224 USA. RP Shoaib, M (reprint author), NIDA, Preclin Pharmacol Lab, Intramural Res Program, NIH, POB 5180, Baltimore, MD 21224 USA. EM spjumos@iop.bpmf.ac.uk NR 42 TC 56 Z9 56 U1 2 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 MAR PY 1999 VL 142 IS 4 BP 327 EP 333 DI 10.1007/s002130050896 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 184NT UT WOS:000079618800001 PM 10229056 ER PT J AU Barber, JP Luborsky, L Crits-Christoph, P Thase, ME Weiss, R Frank, A Onken, L Gallop, R AF Barber, JP Luborsky, L Crits-Christoph, P Thase, ME Weiss, R Frank, A Onken, L Gallop, R TI Therapeutic alliance as a predictor of outcome in treatment of cocaine dependence SO PSYCHOTHERAPY RESEARCH LA English DT Article ID NATIONAL-INSTITUTE; DEPRESSION; PSYCHOTHERAPY; DETERMINANTS AB Cocaine dependent outpatients (N = 252) were randomly assigned to one of three individual treatments (cognitive, dynamic therapy, or drug counseling) as part of the training phase of the National Institute of Drug Abuse Cocaine Collaborative Treatment Study. Patients and therapists completed the Helping Alliance (HAq-II) and the California Alliance Scale (CALPAS), which documented generally high alliance. Although patient reports of the alliance did not predict outcome on drug related measures at the sixth month assessment, it did at the one month assessment. Alliance, however, predicted improvement in depressive symptoms at six months. Overall, therapist ratings of the alliance were less often predictive of outcome than patient ratings. Results were similar across the completer and the intent-to-treat samples. The CALPAS, but-not the HAq-II, predicted attrition. There was preliminary evidence that higher alliance predicted more change in depressive symptoms in patients who remained for a longer time in treatment than for those who remained for a shorter time in treatment. C1 Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. Western Psychiat Inst & Clin, Pittsburgh, PA 15261 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. NIDA, Lexington, KY 40853 USA. Univ Penn, Sch Med, Ctr Psychotherapy Res, Philadelphia, PA 19104 USA. RP Barber, JP (reprint author), Univ Penn, Sch Med, Dept Psychiat, Room 704,3600 Market St, Philadelphia, PA 19104 USA. NR 35 TC 79 Z9 80 U1 1 U2 8 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 1050-3307 J9 PSYCHOTHER RES JI Psychother. Res. PD SPR PY 1999 VL 9 IS 1 BP 54 EP 73 DI 10.1080/10503309912331332591 PG 20 WC Psychology, Clinical SC Psychology GA 185MC UT WOS:000079671900004 ER PT J AU Janowsky, EC Lester, GE Weinberg, CR Millikan, RC Schildkraut, JM Garrett, PA Hulka, BS AF Janowsky, Esther C. Lester, Gayle E. Weinberg, Clarice R. Millikan, Robert C. Schildkraut, Joellen M. Garrett, Peter A. Hulka, Barbara S. TI Association between low levels of 1,25-dihydroxyvitamin D and breast cancer risk SO PUBLIC HEALTH NUTRITION LA English DT Article DE Vitamin D; 1,25; dihydroxyvitamin D; Breast cancer epidemiology AB Objective: To determine if blood levels of 25- hydroxyvitamin D ( 25- D) or its active metabolite, 1,25- dihydroxyvitamin D ( 1,25- D), are lower in women at the time of first diagnosis of breast cancer than in comparable women without breast cancer. Design: This was a clinic- based case- control study with controls frequency- matched to cases on race, age, clinic and month of blood drawing. Setting: University- based breast referral clinics. Subjects: One hundred and fifty- six women with histologically documented adenocarcinoma of the breast and 184 breast clinic controls. Results: There were significant mean differences in 1,25- D levels ( pmol ml - 1) between breast cancer cases and controls; white cases had lower 1,25- D levels than white controls ( mean difference6SE: - 11.0860.76), and black cases had higher 1,25- D levels than black controls ( mean difference6SE: 4.5462.14), although the number of black women in the study was small. After adjustment for age, assay batch, month of blood draw, clinic and sample storage time, the odds ratio ( 95% confidence interval, CI) for lowest relative to highest quartile was 5.2 ( 95% CI 2.1, 12.8) for white cases and controls. The association in white women was stronger in women above the median age of 54 than in younger women, 4.7 ( 95% CI 2.1, 10.2) vs. 1.5 ( 95% CI 0.7, 3.0). There were no case- control differences in 25- D levels in either group. Conclusions: These data are consistent with a protective effect of 1,25- D for breast cancer in white women. C1 [Janowsky, Esther C.; Millikan, Robert C.; Garrett, Peter A.; Hulka, Barbara S.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Lester, Gayle E.] Univ N Carolina, Dept Orthoped Surg, Chapel Hill, NC 27599 USA. [Weinberg, Clarice R.] NIEHS, Res Triangle Pk, NC 27709 USA. [Schildkraut, Joellen M.] Duke Univ, Med Ctr, Off Canc Prevent & Control, Durham, NC 27710 USA. RP Janowsky, EC (reprint author), Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. EM esther_janowsky@unc.edu FU Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill [NC 27599]; Department of Defense DAMD [17-94-J-4344] FX This research was supported by an intramural grant from the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, and by the Department of Defense DAMD 17-94-J-4344. The content of the information does not necessarily reflect the position or the policy of the government and no official endorsement should be inferred. We would like to thank David Ontjes for reviewing an earlier version of this manuscript. NR 48 TC 101 Z9 105 U1 1 U2 3 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 1368-9800 EI 1475-2727 J9 PUBLIC HEALTH NUTR JI Public Health Nutr. PD MAR PY 1999 VL 2 IS 3 BP 283 EP 291 PG 9 WC Public, Environmental & Occupational Health; Nutrition & Dietetics SC Public, Environmental & Occupational Health; Nutrition & Dietetics GA V32XT UT WOS:000208984600009 PM 10512563 ER PT J AU Forman, MR Zhang, J Nebeling, L Yao, SX Slesinski, MJ Qiao, YL Ross, S Keith, S Maher, M Giffin, C Barrett, M Taylor, PR Graubard, BI AF Forman, M. R. Zhang, J. Nebeling, L. Yao, S-X Slesinski, M. J. Qiao, Y-L Ross, S. Keith, S. Maher, M. Giffin, C. Barrett, M. Taylor, P. R. Graubard, B. I. TI Relative validity of a food frequency questionnaire among tin miners in China: 1992/93 and 1995/96 diet validation studies SO PUBLIC HEALTH NUTRITION LA English DT Article DE Diet validation; Food frequency; China AB Objective: Diet validation research was conducted to compare the respondents' reporting of dietary intake in a food frequency questionnaire (FFQ) with intake reported in food recalls. Because the population received annual salary increments that could modify food intake, diet validation studies (DVSs) were conducted during two time intervals. Design: A 99-item FFQ was administered by an interviewer twice in a 1-year interval, and responses to each FFQ item were compared with 28 days of interviewer-administered food recalls that were collected in four 1-week intervals during each season of 1992/93. The second validation study in 1995/96 had a similar design to the earlier one. Setting: A prospective cohort study of lung cancer among tin miners in China was initiated in 1992, with dietary and other risk factors updated annually. Subjects: Among a cohort of high risk tin miners for lung cancer, two different samples (n = 141 in 1992/93, and n 113 in 1995/96) for each diet validation study were randomly selected from four mine units, that were representative of all worker units. Results: Miners reported a significantly higher average frequency of intake of foods in the food recalls than the FFQ, with few exceptions. Deattenuated Pearson correlation coefficients of the frequency of food intake between the FFQ and food recalls were in the range of -0.40 to 0.72 in both studies, with higher positive correlations for beverages and cereal staples than for animal protein sources, vegetables, fruits and legumes. The percentage of individuals with exact agreement in the extreme quartiles of intake in the food recalls and FFQ ranged from 0 to 100% in both studies. Conclusions: Among Chinese miners, the range in correlations between the food recalls and the FFQ were due to: (i) market availability of foods during the food recall weeks compared to their annual reported intake in the FFQ; (ii) cultural perception of time; and (iii) differences in how the intake of mixed dishes and their multi-ingredient foods were reported in the recalls vs. the FFQ. The range in the percentage of agreement in the same quartiles and the changes in food intake over time may have implications for the analysis of the diet-disease relationship in this cohort. C1 [Forman, M. R.; Ross, S.; Maher, M.; Taylor, P. R.] NCI, Canc Prevent Studies Branch, Div Clin Sci, Bethesda, MD 20892 USA. [Zhang, J.; Yao, S-X] Yunnan Tin Mine Corp, Labor Protect Inst, Gejiu, Yunnan, Peoples R China. [Nebeling, L.] NCI, Div Canc Control & Populat Studies, Bethesda, MD 20892 USA. [Slesinski, M. J.] Westat Corp, Rockville, MD 20850 USA. [Qiao, Y-L] Chinese Acad Med Sci, Inst Canc, Dept Canc Epidemiol, Beijing 100021, Peoples R China. [Keith, S.; Giffin, C.; Barrett, M.] Informat Management Sci, Silver Spring, MD 20904 USA. [Graubard, B. I.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Forman, MR (reprint author), NCI, Canc Prevent Studies Branch, Div Clin Sci, Bethesda, MD 20892 USA. EM mf63p@nih.gov RI Qiao, You-Lin/B-4139-2012 OI Qiao, You-Lin/0000-0001-6380-0871 NR 22 TC 11 Z9 12 U1 1 U2 2 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 1368-9800 EI 1475-2727 J9 PUBLIC HEALTH NUTR JI Public Health Nutr. PD MAR PY 1999 VL 2 IS 3 BP 301 EP 315 DI 10.1017/S1368980099000403 PG 15 WC Public, Environmental & Occupational Health; Nutrition & Dietetics SC Public, Environmental & Occupational Health; Nutrition & Dietetics GA V32XT UT WOS:000208984600011 PM 10512565 ER PT J AU Martling, U Mattsson, A Travis, LB Holm, LE Hall, P AF Martling, U Mattsson, A Travis, LB Holm, LE Hall, P TI Mortality after long-term exposure to radioactive thorotrast: A forty-year follow-up survey in Sweden SO RADIATION RESEARCH LA English DT Article ID BREAST-CANCER PATIENTS; ANKYLOSING-SPONDYLITIS; RADIATION TREATMENT; BOMB SURVIVORS; RADIOTHERAPY; DAMAGE; RISK; THORIUM; TRENDS; TRIAL AB To evaluate temporal patterns of cause-specific mortality after long-term exposure to the alpha-particle-emitting contrast medium Thorotrast, we investigated a cohort consisting of 693 Swedish patients with neurological disorders who received Thorotrast during cerebral angiography, with follow-up ending in 1993, Standardized mortality ratios (SMRs) were calculated as the ratio of observed cases in the cohort to expected cases in the general population, Persons exposed to Thorotrast had significant excesses of all causes of death (SMR = 2.8; 95% CI 2.5-3.0), with similar increases noted for men and women. The largest risks were observed for deaths from hematological causes (SMR = 16.4; n = 8), cerebrovascular diseases (SMR = 10.1; n = 18), gastrointestinal disorders including liver cirrhosis (SMR = 5.2; n = 36), and tumors (SMR = 4.7; n = 187), There was a significant decrease in SMR with time since injection for cerebrovascular and circulatory diseases, indicative of the impact of underlying neurological disorders. In contrast, the SMR increased significantly with time for tumors and gastrointestinal diseases, suggestive of a detrimental effect of cumulative radiation dose. A significant dose-response relationship was found for all causes of death and malignant tumors among all age groups, and since SMR increased with time for the latter category, this is consistent with an effect of cumulative radiation exposure on cancer development. However, the findings should be treated with caution, since selection bias may have influenced some of the results. (C) 1999 by Radiation Research Society. C1 Karolinska Univ Hosp, Radiumhemmet, Dept Canc Epidemiol, S-17176 Stockholm, Sweden. NCI, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. Swedish Radiat Protect Inst, Stockholm, Sweden. RP Martling, U (reprint author), Karolinska Univ Hosp, Radiumhemmet, Dept Canc Epidemiol, S-17176 Stockholm, Sweden. FU NCI NIH HHS [N01-CP-33059-01] NR 48 TC 12 Z9 13 U1 0 U2 1 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 MAR PY 1999 VL 151 IS 3 BP 293 EP 299 DI 10.2307/3579941 PG 7 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 172NX UT WOS:000078931600008 PM 10073667 ER PT J AU Alderson, PO Chen, DCP Fleishman, MJ Hoh, CK Kim, CK Lee, VW Mellins, RB Miller, JH Moore, WH Peavy, HH Shah, A Treves, ST AF Alderson, PO Chen, DCP Fleishman, MJ Hoh, CK Kim, CK Lee, VW Mellins, RB Miller, JH Moore, WH Peavy, HH Shah, A Treves, ST CA Pediat Pulm Cardiovascular Complications Vertic TI Radioaerosol scintigraphy in infants and children born to mothers with HIV disease SO RADIOLOGY LA English DT Article DE acquired immunodeficiency syndrome (AIDS); lung, diseases; lung, radionuclide studies; lung, ventilation ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; TC-99M-DTPA; LUNG AB PURPOSE: To determine the usefulness of technetium 99m diethyltriaminepentacetic acid (DTPA) radioaerosol inhalation-clearance scintigraphy for early detection of pulmonary complications of human immunodeficiency virus (HIV) disease in children. MATERIALS AND METHODS: A total of 301 studies were performed in 132 HIV-positive children (group 1; mean age, 46.6 months). In children born to HIV-positive mothers (group 2), 273 studies were performed in 160 children who eventually were proved to be HIV negative (mean age, 10.3 months), and 80 studies were performed in 47 HIV-positive children (mean age, 15.6 months). Radioaerosol studies were performed by using commercially available radioaerosol nebulizers. Pulmonary clearance half-time was measured by using conventional gamma camera computer systems. Radioaerosol results were correlated with indexes of pulmonary health and function. RESULTS: The HIV-negative, group 2 children had a mean radioaerosol clearance half-time (58.1 minutes; 162 studies in 108 children) similar to that reported in healthy adults. Group 1 children with pulmonary involvement exhibited a faster mean clearance half-time (28.6 minutes) than did children without evidence of pulmonary involvement from either group 1 or group 2 (P < .05). A faster pulmonary clearance rate did not simply reflect the presence of chest disease that also was detectable on radiographs (P = .3). CONCLUSION: Quantitative DTPA radioaerosol clearance studies may provide useful information about pulmonary involvement in selected children with HIV disease. C1 Columbia Presbyterian Med Ctr, Dept Radiol, New York, NY 10032 USA. Columbia Presbyterian Med Ctr, Dept Pediat, New York, NY 10032 USA. Univ So Calif, Dept Radiol, Ctr Med, Los Angeles, CA 90089 USA. Univ Calif Los Angeles, Ctr Med, Dept Radiol, Los Angeles, CA 90024 USA. Mt Sinai Med Ctr, Dept Radiol, New York, NY USA. Sch Med, New York, NY USA. Boston City Hosp, Dept Radiol, Boston, MA 02118 USA. Childrens Hosp, Dept Radiol, Los Angeles, CA 90027 USA. Texas Childrens Hosp, Dept Radiol, Houston, TX 77030 USA. NHLBI, Div Lung Dis, Bethesda, MD 20892 USA. Cleveland Clin, Dept Biostat & Epidemiol, Cleveland, OH USA. Harvard Univ, Sch Med, Div Nucl Med, Childrens Hosp, Boston, MA USA. RP Alderson, PO (reprint author), Columbia Presbyterian Med Ctr, Dept Radiol, 622 W 168th St, New York, NY 10032 USA. FU NCRR NIH HHS [RR-00188]; NHLBI NIH HHS [N01-HR-96043, N01-HR-96037] NR 21 TC 2 Z9 2 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMER PI EASTON PA 20TH AND NORTHAMPTON STS, EASTON, PA 18042 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD MAR PY 1999 VL 210 IS 3 BP 815 EP 822 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 170FW UT WOS:000078796500035 PM 10207486 ER PT J AU Levy, LM Gaither, CC AF Levy, LM Gaither, CC TI MRI of dynamic cord deformation and CSF flow: Effects of tethering and compression, and visualization with vector fields SO RIVISTA DI NEURORADIOLOGIA LA English DT Article DE CSF; MRI; functional MRI ID CEREBROSPINAL-FLUID FLOW; SPINAL-CORD; MOTION AB The purpose of this study is to evaluate the spatial-temporal characteristics of spinal cord motion and CSF flow in normal subjects and in cases involving cord compression or tethering and cystic diseases using MRI. MR examinations were conducted in healthy subjects as well as in patients with spinal cord compression, spinal stenosis, myelopathy, cord atrophy, syringomyelia and cystic diseases. Gradient and spin echo phase contrast sequences were used to determine pulsatile motion of the CSF and spinal cord. A new method of displaying the spatial distribution of velocities in the spinal cord and CSF as a vector field superimposed over the corresponding anatomical images was implemented to directly visualize the two dimensional spatial-temporal characteristics of cord motion and CSF flow. C1 NINDS, NIH, Bethesda, MD 20892 USA. NHLBI, NIH, Bethesda, MD 20892 USA. NR 8 TC 0 Z9 0 U1 0 U2 1 PU EDIZIONI CENTAURO PI BOLOGNA PA VIA DEL PRATELLO, 8, 40122 BOLOGNA, ITALY SN 1120-9976 J9 RIV NEURORADIOL JI Riv. Neuroradiol. PD MAR PY 1999 VL 12 SU 2 BP 215 EP 216 PG 2 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 192PG UT WOS:000080087100057 ER PT J AU Allen, J AF Allen, J TI Stirred, not shaken SO SCIENCES-NEW YORK LA English DT Letter C1 NIAAA, Rockville, MD 20852 USA. RP Allen, J (reprint author), NIAAA, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 E 63RD ST, NEW YORK, NY 10021 USA SN 0036-861X J9 SCIENCES JI Sci.-New York PD MAR-APR PY 1999 VL 39 IS 2 BP 3 EP + PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 174QE UT WOS:000079045300004 ER PT J AU Briggs, JP AF Briggs, JP TI Gender matters in renal research: A National Institutes of Health perspective SO SEMINARS IN NEPHROLOGY LA English DT Review C1 NIDDKD, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. RP Briggs, JP (reprint author), NIDDK, Div Kidney Urol & Hematol, NIH, Bldg 31,Room 9A17,31 Ctr Dr,MSC 2560, Bethesda, MD 20892 USA. RI Briggs, Josephine/B-9394-2009 OI Briggs, Josephine/0000-0003-0798-1190 NR 4 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 0270-9295 J9 SEMIN NEPHROL JI Semin. Nephrol. PD MAR PY 1999 VL 19 IS 2 BP 105 EP 108 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 175KE UT WOS:000079091700005 PM 10192241 ER PT J AU Macaluso, M Artz, L Kelaghan, J Austin, H Fleenor, M Hook, EW AF Macaluso, M Artz, L Kelaghan, J Austin, H Fleenor, M Hook, EW TI Prospective study of barrier contraception for the prevention of sexually transmitted diseases study design and general characteristics of the study group SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CHLAMYDIA-TRACHOMATIS; IN-VITRO; SPERMICIDE NONOXYNOL-9; NEISSERIA-GONORRHOEAE; CHEMICAL BARRIERS; VENEREAL-DISEASE; CLINICAL-TRIAL; INFECTION; CONDOM AB Background and Objectives: The AIDS epidemic has brought barrier contraceptives to the forefront of public health research. A comprehensive evaluation of the efficacy of barrier contraceptive use in preventing sexually transmitted diseases (STDs), including AIDS, is necessary to inform both potential users and public health policy makers. This study was undertaken to evaluate the efficacy of condoms and vaginal spermicide products, used alone or in combination, in preventing gonorrhea and chlamydia among women attending an STD clinic. Goal of this Study: To describe the general characteristics of the study group and its follow-up experience. Study Design: Women who met the eligibility criteria were invited to participate. The initial visit included an interview, a behavioral intervention promoting barrier methods, a physical examination, and instructions to complete a sexual diary. Participants received free barrier contraceptives and returned for six monthly follow-up visits. Design Results: Participants (n = 1,122) were low income, single (74%) black (89%) women with a median age of 24, The behavioral intervention led to the use of barrier protection in more than 70% of reported acts of vaginal intercourse. Barriers were used consistently (100% of sexual acts) during 51% of the months of follow-up, A total of 148 cases of gonorrhea (28 per 1,000 months) and 122 cases of chlamydia infection (23 cases per 1,000 months) were diagnosed during follow-up. Conclusion: This Study represents a practical solution to a complex set of design considerations. The study protocol was successful in promoting consistent and proper use of barrier methods. C1 Univ Alabama, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. NICHHD, Contracept & Reprod Hlth Branch, Bethesda, MD 20892 USA. Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. Jefferson Cty Dept Hlth, Birmingham, AL USA. Univ Alabama, Sch Med, Dept Med, Div Infect Dis, Birmingham, AL USA. RP Macaluso, M (reprint author), MJH 108,UAB Stn, Birmingham, AL 35294 USA. RI Macaluso, Maurizio/J-2076-2015 OI Macaluso, Maurizio/0000-0002-2977-9690 FU NICHD NIH HHS [N01-HD-1-3135] NR 50 TC 23 Z9 24 U1 0 U2 0 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 MAR PY 1999 VL 26 IS 3 BP 127 EP 136 DI 10.1097/00007435-199903000-00002 PG 10 WC Infectious Diseases SC Infectious Diseases GA 173WR UT WOS:000079003200002 PM 10100769 ER PT J AU Greenblatt, RM Bacchetti, P Barkan, S Augenbraun, M Silver, S Delapenha, R Garcia, P Mathur, U Miotti, P Burns, D AF Greenblatt, RM Bacchetti, P Barkan, S Augenbraun, M Silver, S Delapenha, R Garcia, P Mathur, U Miotti, P Burns, D CA WIHS Collaborative Study Grp TI Lower genital tract infections among HIV-infected and high-risk uninfected women - Findings of the Women's Interagency HIV Study (WIHS) SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; SEXUALLY-TRANSMITTED DISEASES; HUMAN PAPILLOMAVIRUS INFECTION; CRACK COCAINE USE; BACTERIAL VAGINOSIS; SEROPOSITIVE WOMEN; HERPES; ASSOCIATION; MEN; ABNORMALITIES AB Background and Objectives: Few comparisons of factors associated with sexually transmitted diseases (STDs) and HIV are available for representative samples of American women. Goal of the Study: To compare factors associated with STDs in a large sample of women infected with HIV and women not infected with HIV. Study Design: A cross-sectional analysis of STDs in 2,058 women seropositive (HIV+) for HIV and 567 women seronegative (HIV-) for HIV. Results: HIV+ women were more likely than HIV- women to report previous STDs, with the exceptions of chlamydia and bacterial vaginosis. Both HIV status and CD4 lymphocyte count were associated with evidence of genital ulcerations, warts, and vaginal candidiasis (p < 0.001 for all). HIV- women were more apt to report recent vaginal intercourse (p < 0,001), a factor that was independently associated with the occurrence of bacterial and protozoan infections. CD4 lymphocyte depletion was the factor most closely associated with the expression of chronic viral infections. Conclusions: In this North American cohort, HIV+ women were more likely than HIV- women to report previous genital tract infections and symptoms. However, the HIV+ women reported less recent sexual activity and few gonococcal or chlamydial infections. C1 Univ Calif San Francisco, Dept Med, Div Infect Dis, San Francisco, CA 94143 USA. New England Res Inst, Watertown, MA 02172 USA. SUNY Brooklyn, New York, NY USA. George Washington Univ, Washington, DC USA. Howard Univ, Washington, DC 20059 USA. Northwestern Univ, Chicago, IL 60611 USA. Beth Israel Med Ctr, New York, NY 10003 USA. NIAID, Bethesda, MD 20892 USA. NICHHD, Bethesda, MD 20892 USA. RP Greenblatt, RM (reprint author), Univ Calif San Francisco, Dept Med, Div Infect Dis, Box 1352, San Francisco, CA 94143 USA. FU NIAID NIH HHS [U01-AI-31834, U01-AI-34994, U01-AI-35004] NR 38 TC 52 Z9 55 U1 2 U2 2 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 MAR PY 1999 VL 26 IS 3 BP 143 EP 151 DI 10.1097/00007435-199903000-00004 PG 9 WC Infectious Diseases SC Infectious Diseases GA 173WR UT WOS:000079003200004 PM 10100771 ER PT J AU Popescu, NC AF Popescu, NC TI Sister chromatid exchange formation in mammalian cells is modulated by deoxyribonucleotide pool imbalance SO SOMATIC CELL AND MOLECULAR GENETICS LA English DT Article ID SYRIAN-HAMSTER CELLS; BLOOM-SYNDROME CELLS; BROMODEOXYURIDINE MUTAGENESIS; TRIPHOSPHATE POOLS; VERTEBRATE CELLS; DNA; GENE; TRANSFORMATION; THYMIDINE; DEOXYCYTIDINE AB The formation of sister chromatid exchanges (SEC) is closely related to DNA replication which is dependent on the proper balance of deoxyribonucleic triphosphates. Since DNA precursor imbalances can influence DNA metabolism, the relationship between 5-bromodeoxyuridine (Br-dUrd)-induction of SCE and nucleotide pool imbalance was examined in Syrian hamster fetal cells (HFC) and mouse 3T6 cell line. In exponentially growing HFC, deoxyadenosine and deoxyguanosine stimulated the formation of SCE, while deoxycytidine (dCyd) prevented the dose dependent increase of SCE caused by BrdUrd. Cell growth inhibition produced by amino acid deprivation resulted in a significant increase in SCE as compared to exponentially growing cultures. This SCE enhancement was reduced by dCyd in HFC and did not occur in mouse 3T6 clone deficient in deoxycytidine deaminase. The modulation of SCE by DNA precursors is consistent with the induction of BrdUrd mutagenesis in mammalian cells and raises the possibility that common DNA changes are responsible for the induction of SCE and mutation in mammalian cells. C1 NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Popescu, NC (reprint author), NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. NR 39 TC 6 Z9 6 U1 0 U2 0 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0740-7750 J9 SOMAT CELL MOLEC GEN JI Somat.Cell Mol.Genet. PD MAR PY 1999 VL 25 IS 2 BP 101 EP 108 DI 10.1023/B:SCAM.0000007145.65508.d0 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity GA 400TK UT WOS:000166887600005 PM 11225054 ER PT J AU Rao, PN Acosta, CK Cessac, JW Bahr, ML Kim, HK AF Rao, PN Acosta, CK Cessac, JW Bahr, ML Kim, HK TI Synthesis of N-desmethyl derivatives of 17 alpha-acetoxy-11 beta(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione and mifepristone - Substrates for the synthesis of radioligands SO STEROIDS LA English DT Article; Proceedings Paper CT 10th International Congress on Hormonal Steroids CY JUN 17-21, 1998 CL QUEBEC CITY, CANADA DE steroids; synthesis; N-desmethyl; CDB-2914; mifepristone; radioligands AB The syntheses of N-desmethyl derivatives of CDB-2914 and the mono-N-desmethyl derivative of Mifepristone are described. We also describe the use of the mono-desmethyl derivatives as substrates for the synthesis of N-tritomethyl derivatives of CDB-2914 and Mifepristone with high specific activity (ca. 80 Ci/mmol), which serve as radioligands for radioimmunoassay. (C) 1999 Elsevier Science Inc. All rights reserved. C1 SW Fdn Biomed Res, Dept Organ Chem, San Antonio, TX 78245 USA. NICHHD, NIH, Bethesda, MD 20892 USA. RP Rao, PN (reprint author), SW Fdn Biomed Res, Dept Organ Chem, San Antonio, TX 78245 USA. FU NICHD NIH HHS [N01-HD-1-3137, N01-HD-6-3255] NR 9 TC 6 Z9 6 U1 0 U2 2 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 MAR PY 1999 VL 64 IS 3 BP 205 EP 212 DI 10.1016/S0039-128X(98)00086-5 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 209BJ UT WOS:000081027200004 PM 10400381 ER PT J AU Yeh, SY AF Yeh, SY TI N-tert-butyl-alpha-phenylnitrone protects against 3,4-methylenedioxymethamphetamine-induced depletion of serotonin in rats SO SYNAPSE LA English DT Article DE 3,4-ethylenedioxymethamphetamine; MDMA; 3,4-methylenedioxyamphetamine; neurotoxicity; N-tert-butyl-alpha-phenylnitrone; PBN; ethanol; hydroxyl radicals; superoxide radicals ID METHYLENEDIOXYMETHAMPHETAMINE MDMA; BODY-TEMPERATURE; TRANSGENIC MICE; METHYLENEDIOXYMETHYLAMPHETAMINE MDMA; 3,4-METHYLENEDIOXYAMPHETAMINE MDA; METHYLENEDIOXYAMPHETAMINE MDA; P-CHLOROAMPHETAMINE; RHESUS-MONKEYS; NEUROTOXICITY; BRAIN AB The present study examined the effect of N-tert-butyl-alpha-phenylnitrone (PBN) on 3,4-methylenedioxmathamphetamine (MDMA)-induced depletion of serotonin in the CNS. Rats were treated with two concurrent injections of MDMA. (20 mg/kg, s.c.), PEN (50-400 mg/kg dissolved in ethanol, 50 mg/ml of 25% ethanol, i.p.), saline or 25% ethanol, alone or in combination, 6 h apart, and sacrificed 5 days later. Rectal temperature was measured prior to and hourly following the drug injection for 5 h. Monoamine levels in the tissue were measured by HPLC. Density of the 5-HT transporters was assayed by [H-3]paroxetine binding. Rectal temperature of rats increased after MDMA, decreased after PEN, ethanol, PEN plus ethanol, and MDMA plus ethanol, and was not significantly altered after MDMA plus PEN. Levels of 5-HT and 5-HIAA in the frontal cortex, hippocampus, striatum, and brain stem of rats decreased significantly after MDMA or MDMA plus ethanol, but not after MDMA plus PEN, PEN plus ethanol (PBN dissolved in ethanol), or ethanol as compared to the saline controls. Levels of 5-HT and 5-HIAA in the brain tissues of rats treated with MDMA plus PEN were elevated as compared to those treated with MDMA plus saline. Similar results were observed in the density of 5-HT transporters in the frontal cortex and hippocampus. These results indicate that scavenging of free radicals of MDMA metabolites or reactive oxygen species by PEN and with lowering of body temperature protected against MDMA-induced depletion of serotonin transmitter. Synapse 31:169-177, 1999. Published 1999 Wiley-Liss, Inc.dagger. C1 NIDA, Addict Res Ctr, Mol Neuropsychiat Sect,Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Yeh, SY (reprint author), NIDA, Addict Res Ctr, Mol Neuropsychiat Sect,Intramural Res Program, NIH, POB 5180, Baltimore, MD 21224 USA. NR 40 TC 30 Z9 30 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 0887-4476 J9 SYNAPSE JI Synapse PD MAR 1 PY 1999 VL 31 IS 3 BP 169 EP 177 DI 10.1002/(SICI)1098-2396(19990301)31:3<169::AID-SYN1>3.0.CO;2-N PG 9 WC Neurosciences SC Neurosciences & Neurology GA 160LX UT WOS:000078233100001 PM 10029234 ER PT J AU Pozzi, S Longo, A Ferrara, GB AF Pozzi, S Longo, A Ferrara, GB TI HLA-B locus sequence-based typing SO TISSUE ANTIGENS LA English DT Article DE HLA-B; PCR; sequence-based typing ID PRIMERS PCR-SSP; ALLELES; DNA; TRANSPLANTATION; AMPLIFICATION; POLYMORPHISM; GENES AB We describe an approach for HLA-B high-resolution typing. A single locus-specific amplification generates a l-kb fragment useful for direct sequencing. Four internal primers are necessary for exon 2 and 3 cycle-sequencing in both directions. Fluorescent dye-labelled nucleotides are incorporated during cycle-sequencing and reaction products are analyzed in an automated DNA sequencer. At present, software programs allow automatic assignment of exon 2 only; analysis of exon 3 is not automatic. In the future, the development of more sophisticated software will improve allele assignment. The approach described in this work offers a precise and efficient identification of known allele sequences and at the same time can differentiate new alleles, Furthermore, it may be applied as a model for the development of similar molecular typing approaches for other polymorphic HLA loci. C1 Adv Biotechnol Ctr, IST, Natl Canc Inst, I-16132 Genoa, Italy. RP Ferrara, GB (reprint author), Adv Biotechnol Ctr, Immunogenet Lab, Lgo R Benzi 10, I-16132 Genoa, Italy. EM ferrara@sirio.cba.unige.it NR 29 TC 60 Z9 73 U1 0 U2 3 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD MAR PY 1999 VL 53 IS 3 BP 275 EP 281 DI 10.1034/j.1399-0039.1999.530308.x PG 7 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 177QM UT WOS:000079222100008 PM 10203021 ER PT J AU Chhabra, RS Maronpot, RM Bucher, JR Haseman, JK Toft, JD Hejtmancik, MR AF Chhabra, RS Maronpot, RM Bucher, JR Haseman, JK Toft, JD Hejtmancik, MR TI Toxicology and carcinogenesis studies of pentachlorophenol in rats SO TOXICOLOGICAL SCIENCES LA English DT Article DE pentachlorophenol; mesothelioma; nasal tumors; liver toxicity; pentachlorophenol carcinogenicity ID OXIDATIVE DNA-DAMAGE; TETRACHLORO-P-HYDROQUINONE; B6C3F1 MICE; TESTS; LIVER; 8-HYDROXY-2-DEOXYGUANOSINE; SURVIVAL AB Pentachlorophenol (PCP) has been used as an herbicide, algaecide, defoliant, wood preservative, germicide, fungicide, and molluscicide. A 28-day toxicity study of PCP in F344/N rats of both sexes was conducted to select dose levels for a carcinogenicity study. Groups of 10 male and 10 female rats were given 0, 200, 400, 800, 1600, or 3200 ppm PCP in feed for 28 days. The incidences of minimal to mild hepatocyte degeneration in males and females exposed to 400 ppm or greater and the incidences of centrilobular hepatocyte hypertrophy in the 3200-ppm groups were increased. For carcinogenicity studies, groups of 50 male and 50 female F344/N rats were fed diets containing 200, 400, or 600 PCP for 2 years. A stop-exposure group of 60 male and 60 female rats received 1000 ppm of PCP in feed for 52 weeks and control feed thereafter for the remainder of the 2-year studies; 10 male and 10 female rats were evaluated at 7 months. Survival of 600-ppm males was significantly greater than that of the controls; survival of all other exposed groups was similar to that of the control groups. Mean body weights of the 400- and 600-ppm groups were generally less than those of the controls throughout the studies. There was no evidence of carcinogenic activity of PCP in male or female rats fed diets containing 200, 400, or 600 ppm for 2 years. Stop-exposure study males and females regained a transitory body weight reduction by the end of the 2 year study, and males had better survival than the controls. At a 7-month interim evaluation, the incidences of centrilobular hypertrophy in stop-exposure males and females exceeded those in the controls. At 2 years, malignant mesothelioma originating from the tunica vaginalis was present in 9 1000-ppm males and 1 control male (p = 0.014). Nasal squamous cell carcinomas were present in five 1000-ppm males and 1 control male. This incidence was not significantly increased but exceeded the historical control range (0-4%). Based on the increased incidences of mesotheliomas and nasal tumors, there was some evidence of carcinogenic activity of PCP in male rats given a diet containing 1000 ppm for 1 year followed by control diet for 1 year. There was no evidence of PCP carcinogenic activity in stop-exposure female rats. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Battelle Labs, Columbus, OH 43201 USA. RP Chhabra, RS (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 31 TC 36 Z9 42 U1 2 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD MAR PY 1999 VL 48 IS 1 BP 14 EP 20 DI 10.1093/toxsci/48.1.14 PG 7 WC Toxicology SC Toxicology GA 251PV UT WOS:000083454800003 PM 10330679 ER PT J AU Mahler, JF Price, HC O'Connor, RW Wilson, RE Eldridge, SR Moorman, MP Morgan, DL AF Mahler, JF Price, HC O'Connor, RW Wilson, RE Eldridge, SR Moorman, MP Morgan, DL TI Characterization of hepatocellular resistance and susceptibility to styrene toxicity in B6C3F1 mice SO TOXICOLOGICAL SCIENCES LA English DT Article DE mouse; styrene; hepatotoxicity; cell cycle; regeneration ID NUCLEAR ANTIGEN PCNA; INHALATION TOXICITY; CELL-PROLIFERATION; RAT HEPATOCYTES; PEROXISOME PROLIFERATOR; CARBON-TETRACHLORIDE; DNA-SYNTHESIS; LIVER; PLOIDY; STYRENE-7,8-OXIDE AB Short-term inhalation exposure of B6C3F1 mice to styrene causes necrosis of centrilobular (CL) hepatocytes. However, in spite of continued exposure, the necrotic parenchyma is rapidly regenerated, indicating resistance by regenerated cells to styrene toxicity. These studies were conducted to test the hypothesis that resistance to repeated styrene exposure is due to sustained cell proliferation, with production of hepatocytes that have reduced metabolic capacity. Male mice were exposed to air or 500 ppm styrene (6 h/day); hepatotoxicity was evaluated by microscopic examination, serum liver enzyme levels, and bromodeoxyuridine (BrdU)-labeling index (LI). Metabolism was assessed by measurement of blood styrene and styrene oxide. Both single and repeated exposures to styrene resulted in mortality by Day 2; in mice that survived, there was CL necrosis with elevated BrdU LI at Day 6, and complete restoration of the necrotic parenchyma by Day 15. The BrdU LI in mice given a single exposure had returned to control levels by Day 15. Re-exposure of these mice on Day 15 resulted in additional mortality and hepatocellular necrosis, indicating that regenerated CL cells were again susceptible to the cytolethal effect of styrene following a 14-day recovery. However, in mice repeatedly exposed to styrene for 14 days, the BrdU LI remained significantly increased on Day 15, with preferential labeling of CL hepatocytes with enlarged nuclei (karyomegaly). If repeated exposures were followed by a 10-day recovery period, CL karyomegaly persisted, but the BrdU LI returned to control level and CL hepatocytes became susceptible again to styrene toxicity, as demonstrated by additional mortality and acute necrosis after a challenge exposure. These findings indicated a requirement for continued styrene exposure and DNA synthesis in order to maintain this resistant phenotype. Analyses of proliferating-cell nuclear-antigen (PCNA) labeling were conducted to further characterize the cell cycle kinetics of these hepatocytes. The proportion of cells in S-phase was increased by repeated exposure. However, PCNA analysis also revealed an even larger increase in the G1 cell compartment with repeated exposures, without a concurrent increase in G2 phase or in mitotic cell numbers. These data indicate that resistance to styrene-induced necrosis under conditions of repeated exposure is not due to sustained cell turnover and production of new, metabolically inactive cells, but rather is due to some other, as yet unknown, protective phenotype of the regenerated cells. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Pathol Associates Inc, Res Triangle Pk, NC 27709 USA. Mantech Environm Technol Inc, Res Triangle Pk, NC 27709 USA. RP Morgan, DL (reprint author), NIEHS, Mail Stop IF-00,POB 12233, Res Triangle Pk, NC 27709 USA. NR 37 TC 2 Z9 3 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD MAR PY 1999 VL 48 IS 1 BP 123 EP 133 DI 10.1093/toxsci/48.1.123 PG 11 WC Toxicology SC Toxicology GA 251PV UT WOS:000083454800016 PM 10330692 ER PT J AU Langston, MM Procter, JL Cipolone, KM Stroncek, DF AF Langston, MM Procter, JL Cipolone, KM Stroncek, DF TI Evaluation of the gel system for ABO grouping and D typing SO TRANSFUSION LA English DT Article AB BACKGROUND: The gel agglutination assay has been approved by the Food and Drug Administration as an alternative to the tube assay for the detection of red cell antibodies. It has also been approved recently by the Food and Drug Administration for ABO blood grouping and D typing. STUDY DESIGN AND METHODS: Tube and gel agglutination assays were compared for ABO grouping and D typing of 100 donor and 100 patient specimens. ABO grouping of 14 specimens of known ABO groups and D typing of 10 specimens with weak D were also compared. When antigen typing or isohemagglutinin results differed, gel testing was repeated by the use of modified incubation times, reagent or specimen volumes, and red cell concentrations. RESULTS: ABO grouping and D typing in all patient and donor specimens concurred. B isohemagglutinins were not detected in seven group A specimens. Six of seven discrepancies were resolved when gel tests were incubated at room temperature with increased serum or plasma volume. Weak D was detected in all 10 specimens tested by both assays. When weak A and/or B were tested with monoclonal antibody reagents, the correct phenotypes were identified in 9 specimens by gel assay and in 10 by tube assay. Using human antisera, 6 specimens were correctly phenotyped by gel assay and 7 by tube assay. CONCLUSION: The gel assay performed as well as the tube assay in detection of A, B, and D, but the tube assay was slightly better at detecting B isohemagglutinins. The gel assay can be used in place of the tube assay far ABO blood grouping and D typing. C1 NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. RP Langston, MM (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. NR 8 TC 24 Z9 36 U1 0 U2 2 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD MAR PY 1999 VL 39 IS 3 BP 300 EP 305 DI 10.1046/j.1537-2995.1999.39399219288.x PG 6 WC Hematology SC Hematology GA 178HD UT WOS:000079259400012 PM 10204594 ER PT J AU Stroncek, DF Clay, ME Jaszcz, W Lennon, S Smith, J McCullough, J AF Stroncek, DF Clay, ME Jaszcz, W Lennon, S Smith, J McCullough, J TI Collection of two peripheral blood stem cell concentrates from healthy donors SO TRANSFUSION MEDICINE LA English DT Article DE allogeneic transplants; granulocyte colony stimulating factor; peripheral blood stem cells ID COLONY-STIMULATING FACTOR; PROGENITOR CELLS; ALLOGENEIC TRANSPLANTATION; G-CSF; HEMATOLOGIC MALIGNANCIES; FILGRASTIM MOBILIZATION; MARROW TRANSPLANTATION; APHERESIS; VOLUNTEERS; COUNTS AB When peripheral blood stem cell (PBSC) concentrates are used for allogeneic transplants, two or more apheresis procedures must often be performed. To determine how many cells could be collected from healthy people by two back-to-back apheresis procedures and what effect these collections would have on donors, we gave 19 healthy people 5 mu g kg(-1) day(-1) and 21 people 10 mu g kg(-1) day(-1) of granulocyte colony stimulating factor, filgrastim, for 5 days. We then collected two PBSC concentrates, one on day 5 and one on day 6. A third group of six people was given filgrastim 10 mu g kg(-1) day(-1) for 5 days but had no PBSC concentrates collected. PBSC concentrate cell counts and donor cell counts, symptoms, and blood chemistries were assessed for up to 1 year. On day 5, three times more CD34+ cells were collected from donors given 10 mu g kg(-1) day(-1) than those given 5 mu g kg(-1) day(-1) (P = 0.009) but on day 6 the quantity of cells collected was the same (P = 0.23). The total number of CD34+ cells collected was two times greater in donors given the higher dose of filgrastim (median = 579 x 10(6); range = 174-1639 x 10(6) compared to 237 x 10(6); 103-1670 x 10(6) P = 0.061), Platelet counts fell after each PBSC concentrate collection, but there were no differences between the two groups of donors in platelet counts measured immediately after each collection. The platelet counts also fell in people who did not donate PBSC concentrates. The lowest counts in all three groups of people also occurred on day 10, In PBSC donors given 10 mu g kg(-1) day(-1) of filgrastim the absolute neutrophil count (ANC) fell below premobilization counts an day 14, In donors given 5 mu g kg(-1) day(-1) the ANC fell below premobilization counts on days 21, 28 and 49. CD34+ cell counts were significantly lower than premobilization counts on days 14 and 28 in donors given 10 mu g kg(-1) day(-1) of filgrastim and on day 14 in those given 5 mu g kg(-1) day(-1). No decrease in neutrophil or CD34+ cell counts occurred after filgrastim was given in the people who did not donate PBSC concentrates. The incidence of symptoms was similar in both groups of PBSC concentrate donors, except that those given 10 mu g kg(-1) day(-1) were more than twice as likely to experience myalgias as those receiving the lower dose (P = 0.029). Several blood chemistries changed. Levels of alkaline phosphatase, LDH, SGPT, SGOT, uric acid and sodium increased. Levels of bilirubin, total protein, potassium, calcium and chloride decreased. In conclusion, twice as many CD34+ cells were collected from donors given 10 mu g kg(-1) day(-1) of filgrastim. Platelet, neutrophil and CD34+ cell counts fell after the PBSC concentrate collections. The fall in platelet counts was due to both the collection and the administration of filgrastim. The falls in neutrophil and CD34+ cell counts were due to the loss of haematpoietic progenitor cells in the PBSC concentrates. Allogeneic PBSC concentrate donors should be given 10 mu g kg(-1) day(-1) of filgrastim, and if possible only one component should be collected in order to avoid thrombocytopenia. C1 NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. Univ Minnesota, Sch Med, Dept Pathol & Lab Med, Minneapolis, MN 55455 USA. RP Stroncek, DF (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, 10 Ctr Dr,MSC 1184,Bldg 10,Room 1C711, Bethesda, MD 20892 USA. NR 23 TC 20 Z9 21 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0958-7578 J9 TRANSFUSION MED JI Transfus. Med. PD MAR PY 1999 VL 9 IS 1 BP 37 EP 50 PG 14 WC Hematology SC Hematology GA 180VK UT WOS:000079405700005 PM 10216904 ER PT J AU Horwitz, B Tagamets, MA McIntosh, AR AF Horwitz, B Tagamets, MA McIntosh, AR TI Neural modeling, functional brain imaging, and cognition SO TRENDS IN COGNITIVE SCIENCES LA English DT Review ID PRINCIPAL-COMPONENT ANALYSIS; WORKING-MEMORY; PREFRONTAL CORTEX; DATA SETS; PET; PATHWAYS; SYSTEM; IMAGES; OBJECT; TASK AB The richness and complexity of data sets acquired from PET or fMRI studies of human cognition have not been exploited until recently by computational neuronal modeling methods. In this article, two neural-modeling approaches for use with functional brain imaging data are described. One, which uses structural equation modeling, estimates the functional strengths of the anatomical connections between various brain regions during specific cognitive tasks. The second employs large-scale neural modeling to relate functional neuroimaging signals in multiple, interconnected brain regions to the underlying neurobiological time-varying activities in each region. Delayed match-to-sample (visual working memory for form) tasks are used to illustrate these models. C1 NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Sch Med, Georgetown Inst Cognit & Computat Sci, Washington, DC USA. Univ Toronto, Baycrest Ctr Geriat Care, Rotman Res Inst, Toronto, ON, Canada. RP Horwitz, B (reprint author), NIA, Neurosci Lab, NIH, Bldg 10,Rm 6C414,9000 Rockville Pike, Bethesda, MD 20892 USA. EM horwitz@helix.nih.gov RI McIntosh, Anthony/G-4955-2011; OI McIntosh, Anthony/0000-0002-1784-5662 NR 72 TC 148 Z9 150 U1 2 U2 8 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 MAR PY 1999 VL 3 IS 3 BP 91 EP 98 DI 10.1016/S1364-6613(99)01282-6 PG 8 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 173QT UT WOS:000078991800003 ER PT J AU De Luca, F Baron, J AF De Luca, F Baron, J TI Control of bone growth by fibroblast growth factors SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID PLATE CHONDROCYTES; FACTOR RECEPTOR-3; FACTOR-BETA; CROUZON-SYNDROME; PROTEOGLYCAN SYNTHESIS; TRANSMEMBRANE DOMAIN; CELL-PROLIFERATION; FGF RECEPTOR-1; DNA-SYNTHESIS; FACTOR-II AB Fibroblast growth factors (FGFs) and their receptors (FGFRs) negatively regulate longitudinal bone growth. Activating FGFR3 mutations impair growth, causing human skeletal dysplasias, whereas inactivating mutations stimulate growth. Systemic administration of FGF-2 to mice stimulates bone growth at low doses but inhibits growth at high doses. In organ culture, FGF-2 inhibits growth by decreasing growth plate chondrocyte proliferation, hypertrophy and cartilage matrix synthesis. Local FGF-2 infusion accelerates ossification of growth plate cartilage. Thus, FGFs may regulate both growth plate chondrogenesis and ossification. C1 Univ Maryland, Sch Med, Div Pediat Endocrinol, Baltimore, MD 21202 USA. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP De Luca, F (reprint author), Univ Maryland, Sch Med, Div Pediat Endocrinol, Baltimore, MD 21202 USA. NR 44 TC 40 Z9 40 U1 1 U2 3 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 MAR PY 1999 VL 10 IS 2 BP 61 EP 65 DI 10.1016/S1043-2760(98)00120-9 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 214LQ UT WOS:000081329800004 ER PT J AU Gasior, M Carter, RB Witkin, JM AF Gasior, M Carter, RB Witkin, JM TI Neuroactive steroids: potential therapeutic use in neurological and psychiatric disorders SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID GAMMA-AMINOBUTYRIC-ACID; GABA(A) RECEPTOR; ANXIOLYTIC ACTIVITY; ULTRASONIC VOCALIZATIONS; ANTICONVULSANT ACTIVITY; REDUCED METABOLITES; ETHANOL WITHDRAWAL; HIGH-AFFINITY; MICE; NEUROSTEROIDS AB Neuroactive steroids are a novel class of positive allosteric modulators of the GABA, receptor. Although neuroactive steroids are endogenous neuronal modulators, synthetic entities with improved oral bioavailability have recently been developed. These compounds demonstrate efficacy as anticonvulsants against a range of convulsant stimuli and demonstrate anti-epileptogenic activity in a kindling model of epilepsy. Efficacy has also been reported in preclinical models of anxiety, insomnia, migraine and drug dependence. Clinical evidence to date is generally supportive of these findings and indicates that neuroactive steroids are generally well tolerated. Taken as a whole, current data suggest that neuroactive steroids could have a future role in clinical practice. In this article, Maciej Gasior, Richard Carter and Jeffrey Within review preclinical and clinical evidence that forms the basis for predicting the potential therapeutic application of neuroactive steroids. C1 CoCensys Inc, Irvine, CA 92618 USA. NIDA, Drug Dev Grp, Behav Neurosci Branch, NIH, Baltimore, MD 21224 USA. NR 65 TC 168 Z9 170 U1 0 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD MAR PY 1999 VL 20 IS 3 BP 107 EP 112 DI 10.1016/S0165-6147(99)01318-8 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 180ZN UT WOS:000079416300004 PM 10203866 ER PT J AU Orenstein, JM Wahl, SM AF Orenstein, JM Wahl, SM TI The macrophage origin of the HIV-expressing multinucleated giant cells in hyperplastic tonsils and adenoids SO ULTRASTRUCTURAL PATHOLOGY LA English DT Article DE adenoid; dendritic cells; HIV; Langerhans' cells; Langhans' cell; macrophages; multinucleated giant cells; tonsils ID HUMAN-IMMUNODEFICIENCY-VIRUS; DENDRITIC LANGERHANS CELLS; VIRAL REPLICATION; LYMPHOID-TISSUES; IN-VITRO; PRODUCTIVE INFECTION; PERIPHERAL-BLOOD; PROGENITOR CELLS; NASOPHARYNGEAL; DEPLETION AB Replication and storage of virus are characteristic features of hyperplastic lymphoid tissues in HIV infection. In opportunistic infections, HIV is synthesized by phagocytic mononuclear and Langhans'-type multinucleated macrophages that coexpress the dendritic cell-associated S-100 and p55 antigens. However, similar cells in hyperplastic tonsils and adenoids from HIV+ individuals were alternatively identified as macrophages or, on the basis of the same S-100 and p55 staining, as dendritic cells. To consider establishing the role of these HIV-rich cells in HIV disease, it is important to reconcile this apparent discrepancy in identity. Hyperplastic tonsils and adenoid specimens were analyzed by HIV RNA in situ hybridization (ISH), light and transmission electron microscopy (TEM), and immunohistochemistry (IHC) (HIV Gag p24 protein, S-100, p55, CD68, HAM56, lysozyme, alpha-1-anti-trypsin, and alpha-1-anti-chymotrypsin). In HIV+ pediatric and adult surgical specimens (n = 11), the giant cells and their mononuclear counterpart were positive for both macrophage and p55 and S-100 IHC markers. In addition, TEM, p24 IHC, and ISH showed HIV expression by cells with typical features of macrophages. Furthermore, these cells were not unique to HIV+ specimens, being seen in 20% of hyperplastic T&A surgical specimens (n = 57) lacking HIV as well as in several types of granulomatous processes, such as sarcoidosis. These cells appear to represent an activated phenotype that can develop independent of HIV, but that may represent a viral host in HIV-infected individuals. Thus, the giant and mononuclear cells that produce striking amounts of HIV in tonsils and adenoids are of macrophage origin, yet, as in opportunistic infections, share dendritic cell-associated antigens, reflecting a common CD34(+) bone marrow progenitor. C1 George Washington Univ, Med Ctr, Dept Pathol, Washington, DC 20037 USA. NIDR, NIH, Oral Infect & Immun Branch, Bethesda, MD USA. RP Orenstein, JM (reprint author), George Washington Univ, Med Ctr, Dept Pathol, 2300 Eye St NW,Ross 502, Washington, DC 20037 USA. FU NIDCR NIH HHS [DE 12585] NR 43 TC 26 Z9 26 U1 0 U2 1 PU HEMISPHERE PUBL CORP PI BRISTOL PA 1900 FROST ROAD, SUITE 101, BRISTOL, PA 19007-1598 USA SN 0191-3123 J9 ULTRASTRUCT PATHOL JI Ultrastruct. Pathol. PD MAR-APR PY 1999 VL 23 IS 2 BP 79 EP 91 PG 13 WC Microscopy; Pathology SC Microscopy; Pathology GA 192KU UT WOS:000080078500002 PM 10369102 ER PT J AU Walther, MM Lyne, JC Libutti, SK Linehan, WM AF Walther, MM Lyne, JC Libutti, SK Linehan, WM TI Laparoscopic cytoreductive nephrectomy as preparation for administration of systemic interleukin-2 in the treatment of metastatic renal cell carcinoma: A pilot study SO UROLOGY LA English DT Article ID RADICAL NEPHRECTOMY; PORT SITE; EXPERIENCE; SURGERY; THERAPY AB Objectives. Cytoreductive nephrectomy is commonly performed in patients with metastatic renal cell carcinoma before systemic interleukin-2 (IL-2) therapy. Open nephrectomy is associated with prolonged recovery during which metastatic disease can progress. The feasibility of laparoscopic cytoreductive surgery in these patients with large renal tumors was examined. The role of tumor morcellation in reducing the recovery period and allowing earlier treatment with IL-2 was investigated. Methods, Patients with metastatic renal cancer underwent either open nephrectomy (group 1, n = 19) or laparoscopic cytoreductive nephrectomy (n = 11; 6 with tumor morcellation [group 2], 5 with removal of the tumor through a small incision [group 3]). The three groups were compared to evaluate relative recovery, suitability for treatment with IL-2, and laparoscopic port site seeding. Results. A group of 19 patients underwent open nephrectomy (group 1). Eleven patients with a median tumor volume of 377 cm(3) (median tumor diameter 9 cm) underwent laparoscopic cytoreductive nephrectomy. Six of these patients underwent tumor morcellation (group 2) and 5 underwent laparoscopic assisted nephrectomy (group 3). There was no difference in patient age, sex, sites of metastatic disease, ECOG status, size of renal tumor, or surgical complication rates among groups. Patients whose tumor was morcellated had reduced postoperative parenteral narcotic requirements and were discharged sooner than patients undergoing open cytoreductive nephrectomy. Time to treatment with IL-2 was shortest in the morcellation group (median time to treatment 37 days). No port site seeding was observed. Conclusions. Laparoscopic cytoreductive nephrectomy in patients with bulky renal disease is a safe procedure in selected patients. This pilot study demonstrated a significant association of laparoscopic tumor morcellation with less postoperative pain, faster time to discharge, and shorter time to treatment with IL-2. A randomized study is warranted to determine the role of laparoscopic cytoreductive nephrectomy with tumor morcellation. C1 NCI, Urol Oncol Branch, Div Canc Serv, NIH, Bethesda, MD 20898 USA. NCI, Surg Branch, NIH, Bethesda, MD 20898 USA. RP Walther, MM (reprint author), NCI, Urol Oncol Branch, Div Canc Serv, NIH, 9000 Rockville Pike,Bldg 10,Room 2b-43,10 Ctr Dr, Bethesda, MD 20898 USA. NR 16 TC 101 Z9 101 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD MAR PY 1999 VL 53 IS 3 BP 496 EP 501 DI 10.1016/S0090-4295(98)00562-7 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 177DW UT WOS:000079193000010 PM 10096373 ER PT J AU Platte, P Westhof, B Klein, C Pugh, EW Wilson, AF Pirke, KM Stunkard, AJ AF Platte, P Westhof, B Klein, C Pugh, EW Wilson, AF Pirke, KM Stunkard, AJ TI Obesity among Old Order Amish - Environment or genes? SO VERHALTENSTHERAPIE LA German DT Meeting Abstract C1 Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Natl Human Genome Res Inst, Baltimore, MD USA. Univ Trier, D-54290 Trier, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1016-6262 J9 VERHALTENSTHERAPIE JI Verhaltenstherapie PD MAR PY 1999 VL 9 SU 1 BP 61 EP 61 PG 1 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 189AB UT WOS:000079881000180 ER PT J AU Carlson, BA Kwon, SY Chamorro, M Oroszlan, S Hatfield, DL Lee, BJ AF Carlson, BA Kwon, SY Chamorro, M Oroszlan, S Hatfield, DL Lee, BJ TI Transfer RNA modification status influences retroviral ribosomal frameshifting SO VIROLOGY LA English DT Article ID ESCHERICHIA-COLI; TRANSLATION; EXPRESSION; ANTICODON; PSEUDOKNOT; PROTEIN; SIGNAL; VIRUS; SITE; BASE AB The possibility of whether tRNAs with and without a highly modified base in their anticodon loop may influence the level of retroviral ribosomal frameshifting was examined. Rabbit reticulocyte lysates were programmed with mRNA encoding UUU or AAC at the frameshift site and the corresponding Phe tRNA with or without the highly modified wyebutoxine (Y) base on the 3' side of its anticodon or Asn tRNA with or without the highly modified queuine (Q) base in the wobble position of its anticodon added. Phe and Asn tRNAs without the Y or Q base, respectively, stimulated the level of frameshifting, suggesting that the frameshift event is influenced by tRNA modification status. In addition, when AAU occurred immediately upstream of UUU as the penultimate frameshift site codon, addition of tRNA(Asn) without the Q base reduced the stimulatory effect of tRNA(Phe) without the Y base, whereas addition of tRNA(Asn) with the Q base did not alter the stimulatory effect. The addition of tRNA(Asn) without the Q base and tRNA(Phe) with the Y base inhibited frameshifting. The latter studies suggest an interplay between the tRNAs decoded at the penulimate frameshift and frameshift site codons that is also influenced by tRNA modification status. These data may be intrepreted as indicating that a hypomodified isoacceptor modulates frameshifting in an upward manner when utilized at the frameshift site codon, but modulates frameshifting in a downward manner when utilized at the penultimate frameshift site codon. (C) 1999 Academic Press. C1 NCI, Sect Mol Biol Selenium, Basic Res Lab, NIH, Bethesda, MD 20892 USA. NCI, Varmus Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Seoul Natl Univ, Inst Mol Biol & Genet, Genet Mol Lab, Seoul 151742, South Korea. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. RP Lee, BJ (reprint author), NCI, Sect Mol Biol Selenium, Basic Res Lab, NIH, Bethesda, MD 20892 USA. EM imbglmg@plaza.snu.ac.kr RI Kwon, So Yeon/M-5625-2014 OI Kwon, So Yeon/0000-0002-8490-9101 NR 27 TC 47 Z9 48 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 MAR 1 PY 1999 VL 255 IS 1 BP 2 EP 8 DI 10.1006/viro.1998.9569 PG 7 WC Virology SC Virology GA 174DB UT WOS:000079017900002 PM 10049815 ER PT J AU Zhou, HB Weinberg, CR AF Zhou, HB Weinberg, CR TI Potential for bias in estimating human fecundability parameters: A comparison of statistical models SO STATISTICS IN MEDICINE LA English DT Article ID EM ALGORITHM; CONCEPTION; INTERCOURSE; PROBABILITY; OVULATION; BABY; SEX AB Fecundability studies, where couples attempting pregnancy subject to 'failure' (conception) one time in each menstrual cycle, present a natural discrete failure-time scenario. Because the biologic capacity to conceive varies among couples in the population, a complication arises in choosing a method of analysis, related to the fact that the maximum follow-up time can vary from study to study, and follow-up time could potentially have different effects on parameters based on different approaches to modelling. Traditional development in fertility studies has been based on an implicit assumption that binary outcomes for different menstrual cycles are mutually independent. We contrast traditional models to a random effects model where cycle viability is modelled as subject-specific, We clarify the interpretations for different parameters from different models. We show that the traditional approach yields some regression parameters that depend on follow-up time, limiting the generalizability of inferences based on this analytic approach. By contrast, the subject-specific model consistently estimates parameters of interest, if the underlying distribution is properly specified. Data from a fecundability study carried out in North Carolina serves to illustrate these points. Copyright (C) 1999 John Wiley & Sons, Ltd. C1 Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Zhou, HB (reprint author), Univ N Carolina, Dept Biostat, CB 7400, Chapel Hill, NC 27599 USA. NR 14 TC 14 Z9 15 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD FEB 28 PY 1999 VL 18 IS 4 BP 411 EP 422 DI 10.1002/(SICI)1097-0258(19990228)18:4<411::AID-SIM26>3.0.CO;2-M PG 12 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 164FC UT WOS:000078451500005 PM 10070683 ER PT J AU Oh, JD Russell, DS Vaughan, CL Chase, TN AF Oh, JD Russell, DS Vaughan, CL Chase, TN TI Enhanced tyrosine phosphorylation of striatal NMDA receptor subunits: effect of dopaminergic denervation and L-DOPA administration (vol 813, pg 150, 1998) SO BRAIN RESEARCH LA English DT Correction C1 NIH, Expt Therapeut Branch, Inst Neurol Disorders & Stroke, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Neurol & Psychiat, New Haven, CT 06508 USA. RP Chase, TN (reprint author), NIH, Expt Therapeut Branch, Inst Neurol Disorders & Stroke, Bldg 10,Rm 5C103,Rm 5C211,90900 Rockville Pike, Bethesda, MD 20892 USA. NR 1 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD FEB 27 PY 1999 VL 820 IS 1-2 BP 117 EP 117 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 175JJ UT WOS:000079089700015 ER PT J AU Benfield, MR Herrin, J Feld, L Rose, S Stablein, D Tejani, A AF Benfield, MR Herrin, J Feld, L Rose, S Stablein, D Tejani, A TI Safety of kidney biopsy in pediatric transplantation - A report of the controlled clinical trials in pediatric transplantation trial of induction therapy study group SO TRANSPLANTATION LA English DT Article ID PERCUTANEOUS RENAL BIOPSY; COMPLICATIONS; CHILDREN; EFFICACY; OUTCOMES; GUN AB Background, Historically, young children undergoing renal transplantation have lower allograft survival than adults, and potential causes of this are being addressed by the North American Pediatric Renal Transplant Cooperative Study through the National Institutes of Health-sponsored study Cooperative Clinical Trials in Pediatric Transplantation. Included in this study is evaluation of surveillance renal biopsies (SB) and clinically indicated biopsies (CB). Few data exist in children to identify the risk involved with renal transplant biopsies. Methods. Questionnaires were mailed to 21 participating centers asking for descriptions of adverse events associated with kidney biopsies, with choices limited to none, gross hematuria, perinephric hematoma, and other. Further clinical details were obtained from review of medical records of all patients with reported adverse events. Data were collected from 19 centers on 126 patients. Results. Eighty-six patients had undergone 212 biopsies (75 SB and 137 CB). Nine biopsy-related adverse events were reported (4.2%): three SE (4.0%) and six CB (4.4%). Gross hematuria was reported in six patients (2.8%): two SE (2.7%) and four CB (2.9%). A perinephric hematoma was reported in one patient. Two patients with intraperitoneal kidneys developed significant bleeding after biopsy and required transfusions and surgical exploration. No patient lost kidney function or required nephrectomy after biopsy. No difference was noted in adverse events between SE at day 5 or 12 versus CB. Conclusion. Evaluation of transplanted kidney tissue may provide important information for the care of the transplantation patient. This analysis suggests that transplanted kidney biopsies can be performed with minimal risks in pediatric patients. C1 Univ Alabama, Birmingham, AL USA. Childrens Hosp, Boston, MA 02115 USA. Childrens Hosp, Buffalo, NY 14222 USA. NIAID, NIH, New York, NY USA. EMMES Corp, New York, NY USA. New York Med Coll, New York, NY USA. RP Tejani, A (reprint author), NAPRTCS, Suite 10,19 Bradhurst Ave, Hawthorne, NY 10532 USA. FU NIAID NIH HHS [AI37206] NR 16 TC 39 Z9 44 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 FEB 27 PY 1999 VL 67 IS 4 BP 544 EP 547 DI 10.1097/00007890-199902270-00010 PG 4 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 172XL UT WOS:000078950900010 PM 10071025 ER PT J AU Ventura, ON Cachau, RE Kieninger, M AF Ventura, ON Cachau, RE Kieninger, M TI Density functional and coupled-cluster calculations of isodesmic reactions involving fluorine oxides SO CHEMICAL PHYSICS LETTERS LA English DT Article ID NITROSYL HYPOFLUORITE; THEORETICAL METHODS; PEROXIDE FOOF; THERMOCHEMISTRY; ABINITIO; FONO; PERTURBATION; EXCHANGE; ENERGY; FIELD AB Some isodesmic reactions, involving the fluorine oxide radical FO, have been studied employing density functional theory (DFT) and coupled-cluster (CC) calculations with an extended, uncontracted basis set. It is shown that CCSD(T) calculations can give more accurate enthalpies of reaction than DFT in some of the non-isodesmic reactions. DFT, however, gives more accurate results than CCSD(T) for the isodesmic reactions considered. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Univ Republ, Fac Quim, MTC Lab, Montevideo 11800, Uruguay. NCI, Frederick Biomed Supercomp Ctr, Frederick, MD 21702 USA. RP Ventura, ON (reprint author), Univ Republ, Fac Quim, MTC Lab, CC 1157, Montevideo 11800, Uruguay. NR 30 TC 17 Z9 17 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-2614 J9 CHEM PHYS LETT JI Chem. Phys. Lett. PD FEB 26 PY 1999 VL 301 IS 3-4 BP 331 EP 335 DI 10.1016/S0009-2614(99)00032-9 PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 170AE UT WOS:000078782300019 ER PT J AU Protasevich, II Schulga, AA Vasilieva, LI Polyakov, KM Lobachov, VM Hartley, RW Kirpichnikov, MP Makarov, AA AF Protasevich, II Schulga, AA Vasilieva, LI Polyakov, KM Lobachov, VM Hartley, RW Kirpichnikov, MP Makarov, AA TI Key role of barstar Cys-40 residue in the mechanism of heat denaturation of bacterial ribonuclease complexes with barstar SO FEBS LETTERS LA English DT Article DE barnase; binase; barstar mutant; protein-protein complex; thermal denaturation ID THERMAL-STABILITY; BARNASE; INHIBITOR; RECOGNITION; RESOLUTION; RNASE AB The mechanism by which barnase and binase are stabilized in their complexes with barstar and the role of the Cys-40 residue of barstar in that stabilization have been investigated by scanning microcalorimetry. Melting of ribonuclease complexes with barstar and its Cys-82-Ala mutant is described by two 2-state transitions. The lower-temperature one corresponds to barstar denaturation and the higher-temperature transition to ribonuclease melting. The barstar mutation Cys-40-Ala, which is within the principal barnase-binding region of barstar, simplifies the melting to a single 2-state transition. The presence of residue Cys-40 in barstar results in additional stabilization of ribonuclease in the complex. (C) 1999 Federation of European Biochemical Societies. C1 Russian Acad Sci, Engelhardt Inst Mol Biol, Moscow 117984, Russia. Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow 117871, Russia. Russian Acad Sci, Inst Crystallog, Moscow 117333, Russia. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Makarov, AA (reprint author), Russian Acad Sci, Engelhardt Inst Mol Biol, Moscow 117984, Russia. RI Makarov, Alexander/P-5279-2016 NR 21 TC 10 Z9 13 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD FEB 26 PY 1999 VL 445 IS 2-3 BP 384 EP 388 DI 10.1016/S0014-5793(99)00158-1 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 175YC UT WOS:000079122800034 PM 10094494 ER PT J AU Chen, X Chen, SM Powell, BS Court, DL Ji, XH AF Chen, X Chen, SM Powell, BS Court, DL Ji, XH TI Purification, characterization and crystallization of ERA, an essential GTPase from Escherichia coli SO FEBS LETTERS LA English DT Article DE ERA; GTPase; purification; crystallization; Escherichia coli ID CRYSTAL-STRUCTURE; BINDING PROTEIN; RESOLUTION; MECHANISM; MUTATIONS; GROWTH; MUTANT; ACID; GDP AB ERA is an essential GTPase widely conserved in bacteria, Homologues of ERA are also present in higher eukaryotic cells. ERA is involved in bacterial cell cycle control at a point preceding cell division. In order to aid the functional investigation of ERA and to facilitate structure-function studies, me have undertaken the X-ray crystallographic analysis of this protein. Here, we report the purification and crystallization procedures and results. The purified ERA exhibits nucleotide-binding activity and GTP-hydrolytic activity. ERA is one of the very few multi-domain GTPases crystallized to date. (C) 1999 Federation of European Biochemical Societies. C1 NCI, Biomol Struct Grp, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA. NCI, Mol Control & Genet Sect, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA. Fourth Mil Med Univ, Dept Biochem, Xian 710033, Peoples R China. RP Ji, XH (reprint author), NCI, Biomol Struct Grp, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, POB B, Ft Detrick, MD 21702 USA. RI Ji, Xinhua/C-9664-2012 OI Ji, Xinhua/0000-0001-6942-1514 NR 21 TC 6 Z9 9 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD FEB 26 PY 1999 VL 445 IS 2-3 BP 425 EP 430 DI 10.1016/S0014-5793(99)00178-7 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 175YC UT WOS:000079122800041 PM 10094501 ER PT J AU Chariot, A Princen, F Gielen, J Merville, MP Franzoso, G Brown, K Siebenlist, U Bours, V AF Chariot, A Princen, F Gielen, J Merville, MP Franzoso, G Brown, K Siebenlist, U Bours, V TI I kappa B-alpha enhances transactivation by the HOXB7 homeodomain-containing protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUMOR-NECROSIS-FACTOR; DNA-BINDING; HOMEOBOX GENE; EXPRESSION; ACTIVATION; DROSOPHILA; FAMILY; TRANSCRIPTION; VERTEBRATES; HOMODIMERS AB Combinatorial interactions between distinct transcription factors generate specificity in the controlled expression of target genes. In this report, we demonstrated that the HOXB7 homeodomain-containing protein, which plays a key role in development and differentiation, physically interacted in vitro with I kappa B-alpha, an inhibitor of NF-kappa B activity. This interaction was mediated by the I kappa B-alpha ankyrin repeats and C-terminal domain as well as by the HOXB7 N-terminal domain. In transient transfection experiments, I kappa B-alpha markedly increased HOXB7-dependent transcription from a reporter plasmid containing a homeodomain consensus-binding sequence. This report therefore showed a novel function for I kappa B-alpha, namely a positive regulation of transcriptional activation by homeodomain-containing proteins. C1 Univ Liege, Lab Med Chem & Med Oncol, B-4000 Sart, Belgium. NIAID, Natl Inst Hlth, Immunoregulat Lab, Bethesda, MD 20892 USA. RP Bours, V (reprint author), Univ Liege, Lab Med Chem & Med Oncol, CHU B35, B-4000 Sart, Belgium. NR 48 TC 27 Z9 28 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 FEB 26 PY 1999 VL 274 IS 9 BP 5318 EP 5325 DI 10.1074/jbc.274.9.5318 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 170KG UT WOS:000078804400010 PM 10026139 ER PT J AU Zimmermann, B Chiorini, JA Ma, YL Kotin, RM Herberg, FW AF Zimmermann, B Chiorini, JA Ma, YL Kotin, RM Herberg, FW TI PrKX is a novel catalytic subunit of the cAMP-dependent protein kinase regulated by the regulatory subunit type I SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ESCHERICHIA-COLI; MOLECULAR-CLONING; INHIBITOR PROTEIN; IDENTIFICATION; EXPRESSION; NUCLEUS; DOMAINS; GENE; RESONANCE; STABILITY AB The human X chromosome-encoded protein kinase X (PrKX) belongs to the family of cAMP-dependent protein kinases, The catalytically active recombinant enzyme expressed in COS cells phosphorylates the heptapeptide Kemptide (LRRASLG) with a specific activity of 1.5 mu mol/(min.mg). Using surface plasmon resonance, high affinity interactions were demonstrated with the regulatory subunit type I (RIalpha) of cAMP-dependent protein kinase (K-D = 10 nM) and the heat-stable protein kinase inhibitor (K-D = 15 nM), but not with the type II regulatory subunit (RIIalpha, K-D = 2.3 mu M) under physiological conditions. Kemptide and autophosphorylation activities of PrKX are strongly inhibited by the RIalpha subunit and by protein kinase inhibitor in vitro, but only weakly by the RIIalpha subunit. The inhibition by the RIalpha subunit is reversed by addition of nanomolar concentrations of cAMP (K-alpha = 40 nM), thus demonstrating that PrKX is a novel, type I cAMP-dependent protein kinase that is activated at lower cAMP concentrations than the holoenzyme with the C-alpha subunit of cAMP-dependent protein kinase. Microinjection data clearly indicate that the type I R subunit but not type II binds to PrKX in vivo, preventing the translocation of PrKX to the nucleus in the absence of cAMP. The RIIalpha subunit is an excellent substrate far PrKX and is phosphorylated in vitro in a cAMP-independent manner, me discuss how PrKX can modulate the cAMP-mediated signal transduction pathway by preferential binding to the RIalpha subunit and by phosphorylating the RIIalpha subunit in the absence of cAMP. C1 Ruhr Univ Bochum, Fak Med, Biochem Supramolek Syst Abt, Inst Physiol Chem 1, D-44801 Bochum, Germany. Univ Calif San Diego, Howard Hughes Med Inst, La Jolla, CA 92037 USA. Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92037 USA. NHLBI, Mol Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Ruhr Univ Bochum, Fak Med, Biochem Supramolek Syst Abt, Inst Physiol Chem 1, MA 2-40, D-44801 Bochum, Germany. EM friedrich.w.herberg@ruhr-uni-bochum.de RI kotin, robert/B-8954-2008; Herberg, Friedrich/B-5572-2015 OI Herberg, Friedrich/0000-0001-7117-7653 NR 48 TC 65 Z9 69 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 26 PY 1999 VL 274 IS 9 BP 5370 EP 5378 DI 10.1074/jbc.274.9.5370 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 170KG UT WOS:000078804400017 PM 10026146 ER PT J AU Hiraiwa, H Pan, CJ Lin, BC Moses, SW Chou, JY AF Hiraiwa, H Pan, CJ Lin, BC Moses, SW Chou, JY TI Inactivation of the glucose 6-phosphate transporter causes glycogen storage disease type 1b SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MICROSOMAL GLUCOSE-6-PHOSPHATASE SYSTEM; MUTATIONS; DEFECT; GENE; IB; 1A; ACID AB Glycogen storage disease type 1b (GSD-1b) is proposed to be caused by a deficiency in microsomal glucose 6-phosphate (G6P) transport, causing a loss of glucose-6-phosphatase activity and glucose homeostasis, However, for decades, this disorder has defied molecular characterization. In this study, we characterize the structural organization of the G6P transporter gene and identify mutations in the gene that segregate with the GSD-1b disorder. We report the functional characterization of the recombinant G6P transporter and demonstrate that mutations uncovered in GSD-1b patients disrupt G6P transport. Our results, for the first time, define a molecular basis for functional deficiency in GSD-1b and raise the possibility that the defective G6P transporter contributes to neutropenia and neutrophil/monocyte dysfunctions characteristic of GSD-1b patients. C1 NICHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. Ben Gurion Univ Negev, Div Pediat, IL-84101 Beer Sheva, Israel. RP Chou, JY (reprint author), NICHD, Heritable Disorders Branch, NIH, Rm 9S241,Bldg 10, Bethesda, MD 20892 USA. RI Lin, Baochuan/A-8390-2009 OI Lin, Baochuan/0000-0002-9484-0785 NR 27 TC 108 Z9 110 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 26 PY 1999 VL 274 IS 9 BP 5532 EP 5536 DI 10.1074/jbc.274.9.5532 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 170KG UT WOS:000078804400038 PM 10026167 ER PT J AU Suttles, J Milhorn, DM Miller, RW Poe, JC Wahl, LM Stout, RD AF Suttles, J Milhorn, DM Miller, RW Poe, JC Wahl, LM Stout, RD TI CD40 signaling of monocyte inflammatory cytokine synthesis through an ERK1/2-dependent pathway - A target of interleukin (IL)-4 and IL-10 anti-inflammatory action SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED PROTEIN-KINASE; NECROSIS-FACTOR-ALPHA; N-TERMINAL KINASE; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; CD40-CD40 LIGAND INTERACTIONS; COLLAGEN-INDUCED ARTHRITIS; CROSS-LINKING CD40; HYPER-IGM SYNDROME; T-CELL; B-CELLS AB Ligation of CD40 on monocytes through its interaction with CD40 ligand (CD154) present on activated T helper cells, results in activation of monocyte inflammatory cytokine synthesis and rescue of monocytes from apoptosis induced through serum deprivation, Both of these consequences of CD40 stimulation have been shown to be dependent on the induction of protein tyrosine kinase activity, CD40-mediated activation of protein tyrosine kinase activity and subsequent inflammatory cytokine production are abrogated by treatment of monocytes with the T helper type 2 cytokines interleukin 4 (IL-4) and interleukin 10 (IL-10), In the current study we demonstrate that stimulation of monocytes through CD40 resulted in the phosphorylation and activation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) mitogen-activated protein kinases, whereas phosphorylation of mitogen-activated protein kinases family members p38 and c-Jun N-terminal kinase was not observed in response to this stimuli over the time course examined, PD98059, an inhibitor of the upstream activator of ERK1/2, the MAP/ERK kinase MEK1/2, suppressed IL-1 beta and tumor necrosis factor-alpha production in a dose-dependent fashion, Pretreatment of monocytes with IL-4 and IL-10 inhibited CD40-mediated activation of ERK1/2 kinase activity when used individually, and are enhanced in effectiveness when used in combination. Together, the data demonstrate that CD40-mediated induction of IL-1 beta and tumor necrosis factor-a synthesis is dependent on a MEK/ERK pathway which is obstructed by signals generated through the action of IL-4 and IL-10. C1 E Tennessee State Univ, Quillen Dishner Coll Med, Dept Biochem & Mol Biol, Johnson City, TN 37614 USA. E Tennessee State Univ, Quillen Dishner Coll Med, Dept Microbiol, Johnson City, TN 37614 USA. NIDR, NIH, Immunopathol Sect, Bethesda, MD 20892 USA. RP Suttles, J (reprint author), E Tennessee State Univ, Quillen Dishner Coll Med, Dept Biochem & Mol Biol, Box 70581, Johnson City, TN 37614 USA. FU NIAID NIH HHS [AI34875] NR 80 TC 92 Z9 92 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 FEB 26 PY 1999 VL 274 IS 9 BP 5835 EP 5842 DI 10.1074/jbc.274.9.5835 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 170KG UT WOS:000078804400077 PM 10026206 ER PT J AU Fukuhara, S Murga, C Zohar, M Igishi, T Gutkind, JS AF Fukuhara, S Murga, C Zohar, M Igishi, T Gutkind, JS TI A novel PDZ domain containing guanine nucleotide exchange factor links heterotrimeric G proteins to Rho SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID VAV PROTOONCOGENE PRODUCT; GTP-BINDING PROTEIN; PLECKSTRIN HOMOLOGY DOMAIN; DBL ONCOGENE PRODUCT; NIH 3T3 CELLS; ALPHA-SUBUNIT; SIGNAL-TRANSDUCTION; TYROSINE PHOSPHORYLATION; CELLULAR-TRANSFORMATION; ACTIN CYTOSKELETON AB Small GTP-binding proteins of the Rho family play a critical role in signal transduction. However, there is still very limited information on how they are activated by cell surface receptors. Here, we used a consensus sequence for Dbl domains of Rho guanine nucleotide exchange factors (GEFs) to search DNA data bases, and identified a novel human GEF for Rho-related GTPases harboring structural features indicative of its possible regulatory mechanism(s). This protein contained a tandem DH/PH domain closely related to those of Rho-specific GEFs, a PDZ domain, a proline-rich domain, and an area of homology to Lsc, p115-RhoGEF, and a Drosophila RhoGEF that was termed Lsc-homology (LH) domain. This novel molecule, designated PDZ-RhoGEF, activated biological and biochemical pathways specific for Rho, and activation of these pathways required an intact DH and PH domain. However, the PDZ domain was dispensable for these functions, and mutants lacking the LH domain were more active, suggesting a negative regulatory role for the LII domain. A search for additional molecules exhibiting an LH domain revealed a limited homology with the catalytic region of a newly identified GTPase-activating protein for heterotrimeric G proteins, RGS14. This prompted us to investigate whether PDZ-RhoGEF could interact with representative members of each G protein family We found that PDZ-RhoGEF was able to form, in vivo, stable complexes with two members of the G alpha(12) family, G alpha(12) and G alpha(13) and that this interaction was mediated by the LR domain. Furthermore, we obtained evidence to suggest that PDZ-Rho-GEF mediates the activation of Rho by G alpha(12) and G alpha(13). Together, these findings suggest the existence of a novel mechanism whereby the large family of cell surface receptors that transmit signals through heterotrimeric G proteins activate Rho-dependent pathways: by stimulating the activity of members of the G alpha(12) family which, in turn, activate an exchange factor acting on Rho. C1 NIDCR, NIH, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. RP Gutkind, JS (reprint author), NIDCR, NIH, Oral & Pharyngeal Canc Branch, 30 Convent Dr,Bldg 30,Rm 212, Bethesda, MD 20892 USA. RI Gutkind, J. Silvio/A-1053-2009; Murga, Cristina/E-1965-2014 OI Murga, Cristina/0000-0002-8964-4077 NR 70 TC 294 Z9 298 U1 2 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 26 PY 1999 VL 274 IS 9 BP 5868 EP 5879 DI 10.1074/jbc.274.9.5868 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 170KG UT WOS:000078804400081 PM 10026210 ER PT J AU Sei, Y Gallagher, KL Basile, AS AF Sei, Y Gallagher, KL Basile, AS TI Skeletal muscle type ryanodine receptor is involved in calcium signaling in human B lymphocytes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL ANTIGEN RECEPTOR; SARCOPLASMIC-RETICULUM; RELEASE CHANNEL; CA-2+ RELEASE; CA2+ RELEASE; SURFACE-IMMUNOGLOBULIN; MALIGNANT HYPERTHERMIA; MOLECULAR-CLONING; BRAIN; ACTIVATION AB The regulation of intracellular free Ca2+ concentration ([Ca2+](i)) in B cells remains poorly understood and is presently explained almost solely by inositol 1,4,5-triphosphate (IP3)-mediated Ca2+ release, followed by activation of a store-operated channel mechanism. In fact, there are reports indicating that IP3 production does not always correlate with the magnitude of Ca2+ release. We demonstrate here that human B cells ex press a ryanodine receptor (RYR) that functions as a Ca2+ release channel during the B cell antigen receptor (BCR)-stimulated Ca2+ signaling process. Immunoblotting studies showed that both human primary CD19(+) B and DAHIKI cells express a 565-kDa immunoreactive protein that is indistinguishable in molecular size and immunoreactivity from the RYR. Selective reverse transcription-polymerase chain reaction, restriction fragment length polymorphism, and sequencing of cloned cDNA indicated that the major isoform of the RYR expressed in primary CD19(+) B and DAKIKI cells is identical to the skeletal muscle type (RYR1). Saturation analysis of [H-3]ryanodine binding yielded B-max = 150 fmol/mg of protein and K-d = 110 nM in DAKIKI cells. In fluo-3-loaded CD19(+) B and DAKIKI cells, 4-chloro-m-cresol, a potent activator of Ca2+ release mediated by the ryanodine-sensitive Ca2+ release channel, induced Ca2+ release in a dose-dependent and ryanodine-sensitive fashion. Furthermore, BCR-mediated Ca2+ release in CD19(+) B cells was significantly altered by 4-chloro-m-cresol and ryanodine. These results indicate that RYR1 functions as a Ca2+ release channel during BCR-stimulated Ca2+ signaling and suggest that complex Ca2+ signals that control the cellular activities of B cells may be generated by cooperation of the IP3 receptor and RYR1. C1 Uniformed Serv Univ Hlth Sci, Dept Anesthesiol, Bethesda, MD 20814 USA. NIDDK, NIH, Bioorgan Chem Lab, Bethesda, MD 20814 USA. RP Sei, Y (reprint author), Uniformed Serv Univ Hlth Sci, Dept Anesthesiol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM ysei@mx3.usuhs.mil NR 39 TC 80 Z9 82 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 26 PY 1999 VL 274 IS 9 BP 5995 EP 6002 DI 10.1074/jbc.274.9.5995 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 170KG UT WOS:000078804400097 PM 10026226 ER PT J AU Rao, GN Katki, KA Madamanchi, NR Wu, YX Birrer, MJ AF Rao, GN Katki, KA Madamanchi, NR Wu, YX Birrer, MJ TI JunB forms the majority of the AP-1 complex and is a target for redox regulation by receptor tyrosine kinase and G protein-coupled receptor agonists in smooth muscle cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA-BINDING ACTIVITY; C-FOS EXPRESSION; RAT MESANGIAL CELLS; HYDROGEN-PEROXIDE; REACTIVE-OXYGEN; ANGIOTENSIN-II; GROWTH-FACTOR; SIGNAL-TRANSDUCTION; OXIDATION-REDUCTION; ARACHIDONIC-ACID AB To understand the role of redox-sensitive mechanisms in vascular smooth muscle cell (VSMC) growth, we have studied the effect of N-acetylcysteine (NAC), a thiol antioxidant, and diphenyleneiodonium (DPI), a potent NADH/NADPH oxidase inhibitor, on serum-, platelet-derived growth factor BB-, and thrombin-induced ERK2, JNK1, and p38 mitogen-activated protein (MAP) kinase activation; c-Fos, c-Jun, and JunB expression; and DNA synthesis. Both NAC and DPI completely inhibited agonist-induced AP-1 activity and DNA synthesis in VSMC. On the contrary, these compounds had differential effects on agonist-induced ERK2, JNK1, and p38 MAP kinase activation and c-Fos, c-Jun, and JunB expression. NAC inhibited agonist-induced ERK2, JNK1, and p38 MAP kinase activation and c-Fos, c-Jun, and JunB expression except for platelet-derived growth factor BB-induced ERK2 activation. In contrast, DPI only inhibited agonist-induced p38 MAP kinase activation and c-Fos and JunB expression. Antibody supershift assays indicated the presence of c-Fos and JunB in the AP-1 complex formed in response to all three agonists. In addition, cotransfection of VSMC with expression plasmids for c-Fos and members of the Jun family along with the AP-l-dependent reporter gene revealed that AP-1 with c-Fos and JunB composition exhibited a higher transactivating activity than AP-I with other compositions tested. All three agonists significantly stimulated reactive oxygen species production, and this effect was inhibited by both NAC and DPI. Together, these results strongly suggest a role for redox-sensitive mechanisms in agonist-induced ERK2, JNK1, and p38 MAP kinase activation; c-Fos, c-Jun, and JunB expression; AP-1 activity; and DNA synthesis in VSMC. These results also suggest a role for NADH/NADPH oxidase activity in some subset of early signaling events such as p38 MAP kinase activation and c-Fos and JunB induction, which appear to be important in agonist-induced AP-I activity and DNA synthesis in VSMC. C1 Univ Texas, Med Branch, Div Cardiol, Galveston, TX 77555 USA. NCI, NIH, Div Canc Prevent & Control, Rockville, MD 20850 USA. RP Rao, GN (reprint author), Univ Texas, Med Branch, Old John Sealy Hosp 4 124B, 301 Univ Blvd,Route 0567, Galveston, TX 77555 USA. EM grao@utmb.edu OI Madamanchi, Nageswara/0000-0003-0590-0908 NR 68 TC 95 Z9 97 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 FEB 26 PY 1999 VL 274 IS 9 BP 6003 EP 6010 DI 10.1074/jbc.274.9.6003 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 170KG UT WOS:000078804400098 PM 10026227 ER PT J AU Taylor, KL Cheng, NQ Williams, RW Steven, AC Wickner, RB AF Taylor, KL Cheng, NQ Williams, RW Steven, AC Wickner, RB TI Prion domain initiation of amyloid formation in vitro from native Ure2p SO SCIENCE LA English DT Article ID YEAST SUP35 PROTEIN; SACCHAROMYCES-CEREVISIAE; IN-VITRO; PROPAGATION; DETERMINANT; TRANSLATION; TERMINATION; PSI(+); GENES; ERF1 AB The [URE3] non-Mendelian genetic element of Saccharomyces cerevisiae is an infectious protein (prion) form of Ure2p, a regulator of nitrogen catabolism. Here, synthetic Ure2p(1-65) were shown to polymerize to form filaments 40 to 45 angstroms in diameter with more than 60 percent beta sheet. Ure2p(1-65) specifically induced full-length native Ure2p to copolymerize under conditions where native Ure2p alone did not polymerize. Like Ure2p in extracts of [URE3] strains, these 180- to 220-angstrom-diameter filaments were protease resistant, The Ure2p(1-65)-Ure2p cofilaments could seed polymerization of native Ure2p to form thicker, Less regular filaments. All filaments stained with Congo Red to produce the green birefringence typical of amyloid. This self-propagating amyloid formation can explain the properties of [URE3]. C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Biochem & Mol Biol, Bethesda, MD 20814 USA. RP Wickner, RB (reprint author), NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. NR 34 TC 225 Z9 226 U1 0 U2 9 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 FEB 26 PY 1999 VL 283 IS 5406 BP 1339 EP 1343 DI 10.1126/science.283.5406.1339 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 171AM UT WOS:000078839900045 PM 10037606 ER PT J AU Bastien, N Trudel, M Simard, C AF Bastien, N Trudel, M Simard, C TI Complete protection of mice from respiratory syncytial virus infection following mucosal delivery of synthetic peptide vaccines SO VACCINE LA English DT Article DE RSV; synthetic peptide vaccine; intranasal inoculation; protective efficacy ID INTRANASAL IMMUNIZATION; ORAL IMMUNIZATION; STREPTOCOCCUS-MUTANS; ANTIBODY-RESPONSE; G-GLYCOPROTEIN; CHOLERA-TOXIN; PROTEIN; PNEUMONIA; INDUCTION; NEUTRALIZATION AB We have previously shown that intraperitoneal immunization of BALB/c mice with the 14 amino-acid long synthetic peptides G/174-187 and BG/174-187, representing the region 174-187 of the G-glycoprotein from human (H) and bovine (B) respiratory syncytial virus (RSV)I respectively, completely protects animals from infection with the corresponding virus. A current goal in vaccine development being the delivery of noninvasive protective antigens via mucosal surfaces, we have evaluated the: immunogenicity and protective efficacy of the two, peptides when administered to mice by the intranasal (i.n.) route in the presence or absence of the cholera toxin (CT) as a mucosal adjuvant. The two peptides given alone induced the production of RSV-specific circulating IgG, as revealed by ELISA titers of immune sera. When the peptides were administered intranasally with CT. the: higher IgG antibody titer which was induced was within the same order of magnitude as that obtained following i.n. immunization with live RSV or intraperitoneal injection with the peptides. thus demonstrating the stimulatory effect of the CT adjuvant. Moreover, although the peptides fail to induce a detectable level of secretory IgA, all animals immunized i.n. with peptide BG/174-187 (plus or minus CT) and all those immunized with peptide G/174-187 mixed with C-T were completely resistant to infection by the corresponding virus. To our knowledge,, this is the fil st study reporting that complete protection against a natural pathogen can be elicited by mucosally delivered synthetic peptides. This supports the usefulness of synthetic peptides in prophylactic vaccination. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 Univ Quebec, Inst Armand Frappier, Ctr Rech Virol, Laval, PQ H7V 1B7, Canada. RP Simard, C (reprint author), NIAID, Viral Dis Lab, NIH, Bldg 4,Room 137,4 Ctr Dr,MSC 0455, Bethesda, MD 20892 USA. EM claire_simard@iaf.uquebec.ca NR 28 TC 27 Z9 30 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD FEB 26 PY 1999 VL 17 IS 7-8 BP 832 EP 836 DI 10.1016/S0264-410X(98)00267-9 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 165MF UT WOS:000078524400024 PM 10067688 ER PT J AU Kalus, RM Kantor, JA Gritz, L Yafal, AG Mazzara, GP Schlom, J Hodge, JW AF Kalus, RM Kantor, JA Gritz, L Yafal, AG Mazzara, GP Schlom, J Hodge, JW TI The use of combination vaccinia vaccines and dual-gene vaccinia vaccines to enhance antigen-specific T-cell immunity via T-cell costimulation SO VACCINE LA English DT Article DE CEA; B7.1; vaccinia; combination vaccine; dual-gene vaccine; antitumor ID CARCINOEMBRYONIC ANTIGEN; ANTITUMOR RESPONSES; MOLECULE B7; POX VIRUS; INDUCTION; CANCER; IMMUNIZATION; GENERATION; IMMUNOTHERAPY; RECOMBINANTS AB Several recombinant vaccinia viruses are currently being evaluated to induce antigen-specific immunity to a variety of infectious disease agents and tumor associated antigens. T-cell costimulation is extremely important in enhancing T-cell responses, and recombinant vaccines have now been shown to be effective vectors to express a range of these molecules. Both combination vaccines (an admixture of a recombinant vaccinia virus expressing a specific target antigen and a recombinant vaccinia virus expressing a costimulatory molecule) and dual-gene vaccines expressing both transgenes on the same vector have been shown capable of effectively enhancing antigen-specific responses via T-cell costimulation. In this report, we compare for the first time the use of both types of approaches to enhance antigen-specific T-cell responses, and we demonstrate the importance of route of vaccine administration and vaccine dose in attaining optimal T-cell responses. These studies should have direct bearing on the design of vaccine clinical trials for infectious agents and/or tumor associated antigens, in which T-cell costimulatory molecules will be employed to enhance antigen-specific T-cell responses via the use of either combination or dual-gene vaccinia vaccines. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. Therion Biol Corp, Cambridge, MA 02142 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 NR 41 TC 36 Z9 37 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD FEB 26 PY 1999 VL 17 IS 7-8 BP 893 EP 903 DI 10.1016/S0264-410X(98)00275-8 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 165MF UT WOS:000078524400032 PM 10067696 ER PT J AU Fetsch, PA Marincola, FM Filie, A Hijazi, YM Kleiner, DE Abati, A AF Fetsch, PA Marincola, FM Filie, A Hijazi, YM Kleiner, DE Abati, A TI Melanoma-associated antigen recognized by T cells (MART-1) - The advent of a preferred immunocytochemical antibody for the diagnosis of metastatic malignant melanoma with fine-needle aspiration SO CANCER CYTOPATHOLOGY LA English DT Article; Proceedings Paper CT 87th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY FEB 28-MAR 06, 1998 CL BOSTON, MASSACHUSETTS SP US & Canadian Acad Pathol DE MART-1; HMB-45; immunocytochemistry; metastatic malignant melanoma; fine-needle aspiration ID TUMOR-INFILTRATING LYMPHOCYTES; MONOCLONAL-ANTIBODY; MELANOCYTIC TUMORS; SUGAR TUMOR; HMB-45; EXPRESSION; LESIONS; ANGIOMYOLIPOMA; IDENTIFICATION; PROTEIN AB BAGKGROUND. HMB-45, an antibody directed against a premelanosome glycoprotein, has thus far been considered the most specific antibody for the immunocytochemical substantiation of the diagnosis of malignant melanoma (MM). A recently described antigen, MART-1, is a transmembrane protein that is present in normal melanocytes and widely expressed in MM. Antibodies to MART-1 have recently become commercially available. Both HMB-45 and MART-1 form the basis of ongoing immunotherapy protocols at the National Institutes of Health/National Cancer Institute. METHODS, The authors evaluated 207 lesions from 160 patients with metastatic MM procured via fine-needle aspiration (FNA) for expression of MART-1 (clone M2-7C10) and HMB-45 prior to commencement of immunotherapy. FNAs were performed on subcutaneous soft tissue masses (190 lesions), lung (8 lesions), liver (5 lesions), pancreas (3 lesions), and brain (1 lesion). To test the specificity of the monoclonal antibody directed against MART-1, the authors evaluated its reactivity in normal tissues as well as in various nonpigmented neoplasms that are often included in the differential diagnosis of MM. RESULTS, Of all lesions tested, 13 (6%) were negative for both MART-1 and HMB-45. Of all patients tested, 20% had 1 or more lesions that were non-immunoreactive with HMB-45, whereas only 10% had 1 or more lesions that were nonimmunoreactive for MART-1. Eight percent of the lesions tested were negative for MART-1 only, whereas 16% of lesions tested were negative for HMB-45 only. In 35% of the lesions, MART-1 stained more cells than HMB-45. In 13%, MART-1 stained fewer cells than HMB-45, and in 52% both antibodies stained an equivalent number of cells. All samples of normal tissue were negative for staining with MART-1, as were the nonpigmented lesions tested. Melanocytes in normal skin samples stained positively for MART-1. CONCLUSIONS. The MART-1 antibody is a superior immunohistochemical marker for the diagnosis of MM. It has the potential to become the preferred antibody over HMB-45 for the diagnosis of metastatic RIM in FNA material, as MART-1 stains a higher percentage of lesions in a higher percentage of patients than does HMB-45. Cancer (Cancer Cytopathol) 1999;87:37-42. (C) 1999 American Cancer Society. C1 NCI, Cytopathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Abati, A (reprint author), NCI, Cytopathol Sect, Pathol Lab, NIH, Bldg 10,Room 2A19,10 Ctr Dr MSC 1500, Bethesda, MD 20892 USA. OI Kleiner, David/0000-0003-3442-4453 NR 32 TC 42 Z9 43 U1 0 U2 0 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD FEB 25 PY 1999 VL 87 IS 1 BP 37 EP 42 DI 10.1002/(SICI)1097-0142(19990225)87:1<37::AID-CNCR7>3.0.CO;2-7 PG 6 WC Oncology; Pathology SC Oncology; Pathology GA 171CT UT WOS:000078845400007 PM 10096358 ER PT J AU Burkhart, BA Alcorta, DA Chiao, C Isaacs, JS Barrett, JC AF Burkhart, BA Alcorta, DA Chiao, C Isaacs, JS Barrett, JC TI Two posttranscriptional pathways that regulate p21(Cip1/Waf1/Sdi1) are identified by HPV16-E6 interaction and correlate with life span and cellular senescence SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE p21(Cip1/Waf1/Sdi1); posttranscriptional regulation; human papilloma virus type 16 E6; cellular senescence; life span ID HUMAN-DIPLOID FIBROBLASTS; HUMAN PAPILLOMAVIRUS-16 E6; CYCLIN-DEPENDENT KINASES; BREAST EPITHELIAL-CELLS; WILD-TYPE P53; DNA-DAMAGE; EXPRESSION; IMMORTALIZATION; E7; INHIBITOR AB The p21((Cip1/Waf1/Sdi1)) protein is a cyclin-dependent kinase inhibitor that is induced in normal human fibroblasts (NHF) following DNA damage, following serum stimulation, and at cellular senescence. Expression of the human papilloma virus 16 E6 oncoprotein in NHF cells results in the loss of the p21 protein, independent of mRNA level under most conditions. The p21 protein levels in NHF-E6 cells remained low following DNA damage or serum stimulation even though mRNA levels increased. In contrast, the p21 protein was transiently induced in NHF-E6 cells at the onset of cellular senescence. Expression of the E6 oncoprotein in transformed cells had no effect on p21 protein levels. This demonstrates that two posttranscriptional pathways regulate expression of p21 protein in NHF cells under different conditions. Disruption of posttranscriptional regulation is correlated with extension of life span, altered cell fate, and transformation. C1 NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Curriculum Genet & Mol Biol, Chapel Hill, NC 27599 USA. NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. RP Barrett, JC (reprint author), NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. NR 35 TC 27 Z9 28 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD FEB 25 PY 1999 VL 247 IS 1 BP 168 EP 175 DI 10.1006/excr.1998.4345 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 171VD UT WOS:000078884000018 PM 10047459 ER PT J AU Smith, MR Newton, DL Mikulski, SM Rybak, SM AF Smith, MR Newton, DL Mikulski, SM Rybak, SM TI Cell cycle-related differences in susceptibility of NIH/3T3 cells to ribonucleases SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE ribonuclease; NIH/3T3; cell; cycle ID ACTIVATED PROTEIN-KINASE; P-30 PROTEIN; CYTOTOXIC RIBONUCLEASES; ANTITUMOR RIBONUCLEASE; ANNEXIN-V; IN-VITRO; HA-RAS; INHIBITION; CANCER; RAF-1 AB Microinjection of Onconase or RNase A into NIH/3T3 cells was used to study the intracellular actions of these two proteins. Onconase preferentially killed actively growing cells in both microinjection and cell culture experiments. Moreover, agents that increased the number of cells in S phase such as serum or microinjected signal transduction mediators (Ras, protein kinase C, and mitogen-activated protein kinase) enhanced Onconase cytotoxicity. Conversely, agents that decreased these proliferative pathways (dibutyryl cAMP and protein kinase A) correspondingly diminished Onconase cytotoxicity in microinjection experiments, These results were also mimicked in cell culture experiments since log-phase v-ras-transformed NIH/3T3 cells were more sensitive to Onconase (IC50 of 7 mu g/ml) than parental NIH/3T3 fibroblasts (IC50 of 40 mu g/ml). Based on those data we postulated that Onconase-mediated cell death in NIH/3T3 cells was related to events occurring at two or more points in the cell cycle preferentially associated with late G(1)/S and S phases. In contrast, quiescent NIH/3T3 cells were more sensitive to microinjected RNase A than log phase cells and positive mediators of proliferative signal transduction did not enhance RNase A-mediated cytotoxicity. Taken together, these results demonstrate that these two RNases use different pathways and/or mechanisms to elicit cytotoxic responses in NIH/3T3 cells. Predictions formulated from these studies can be tested for relevance to RNase actions in different target tumor cells. (C) 1999 Academic Press. C1 NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. Alfacell Corp, Bloomfield, NJ 07003 USA. NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Lab Biochem Physiol, Frederick, MD 21702 USA. RP Rybak, SM (reprint author), NCI, Frederick Canc Res & Dev Ctr, Div Canc Treatment & Diagnosis, Dev Therapeut Program,Lab Drug Discovery Res & De, Frederick, MD 21702 USA. EM rybak@ncifcrf.gov FU NCI NIH HHS [N01-CO-56000] NR 43 TC 38 Z9 42 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD FEB 25 PY 1999 VL 247 IS 1 BP 220 EP 232 DI 10.1006/excr.1998.4317 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 171VD UT WOS:000078884000023 PM 10047464 ER PT J AU Zhang, YX Huang, Y Rishi, AK Sheikh, MS Shroot, B Reichert, U Dawson, M Poirier, G Fontana, JA AF Zhang, YX Huang, Y Rishi, AK Sheikh, MS Shroot, B Reichert, U Dawson, M Poirier, G Fontana, JA TI Activation of the p38 and JNK/SAPK mitogen-activated protein kinase pathways during apoptosis is mediated by a novel retinoid SO EXPERIMENTAL CELL RESEARCH LA English DT Article ID BREAST-CANCER CELLS; SIGNAL-TRANSDUCTION PATHWAYS; RECEPTOR RAR-ALPHA; ACID RECEPTOR; NUCLEAR RECEPTORS; C-JUN; RESPONSE ELEMENT; MAMMALIAN-CELLS; THYROID-HORMONE; GENE-EXPRESSION AB 6-[3-(1-Adamantyl)]-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) is a novel retinoid which induces apoptosis in the retinoic acid-resistant HL-60R human leukemia cell line. CD437-mediated poly(ADP-ribose) polymerase (PARP) cleavage and apoptosis of HL-GOR cells does not require gene transcription or protein synthesis since it occurs in the presence or absence of either actinomycin D or cycloheximide. Marked activation of both the p38 and the JNK/SAPK serine and threonine kinases occurs at 1 h of exposure to CD437 with subsequent PARP cleavage at 2 h and apoptosis noted at 4 to 6 h, CD437 concentrations as little as 10 nM result in p38 activation and apoptosis of HL-GOR cells. However, inhibition of p38 activation utilizing the specific inhibitor SB203580 does not block CD437-mediated PARP cleavage or apoptosis. In addition, p38 activation is dependent upon the activation of the caspase system since p38 activation is blocked by the pan ICE inhibitor Z-VAD fmk, which also inhibits CD437-mediated apoptosis and PARP cleavage in these cells. CD437-mediated activation of JNK/SAPK is not inhibited by Z-VAD fmk, suggesting that it lies upstream of CD437 activation of caspase activity and subsequent apoptosis. The role of JNK/SAPK activation in CD437-mediated apoptosis remains to be defined. (C) 1999 Academic Press. C1 Wayne State Univ, Dept Med, Detroit, MI 48201 USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI 48201 USA. John D Dingell VA Med Ctr, Detroit, MI 48201 USA. NIA, Lab Biol Chem Gene Express, Baltimore, MD 21224 USA. NIA, Aging Sect, Baltimore, MD 21224 USA. NIH, Mol Pharmacol Lab, Bethesda, MD 20892 USA. Ctr Int Rech Dermatol Galderma, F-06565 Valbonne, France. SRI Int, Menlo Pk, CA 94025 USA. CHU Laval, Dept Mol Endocrinol, Poly ADP Ribose Metab Grp, St Foy, PQ, Canada. Univ Laval, St Foy, PQ G1K 7P4, Canada. RP Fontana, JA (reprint author), John D Dingell Med Ctr, 4646 John R St, Detroit, MI 48201 USA. OI Fontana, Joseph/0000-0003-3829-3358 FU NCI NIH HHS [CA63335, P01CA51993] NR 51 TC 52 Z9 53 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD FEB 25 PY 1999 VL 247 IS 1 BP 233 EP 240 DI 10.1006/excr.1998.4350 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 171VD UT WOS:000078884000024 PM 10047465 ER PT J AU Li, AH Moro, S Forsyth, N Melman, N Ji, XD Jacobson, KA AF Li, AH Moro, S Forsyth, N Melman, N Ji, XD Jacobson, KA TI Synthesis, CoMFA analysis, and receptor docking of 3,5-diacyl-2,4-dialkylpyridine derivatives as selective A(3) adenosine receptor antagonists SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MOLECULAR-CLONING; RAT-BRAIN; STIMULATION; PARAMETERS; ALCOHOLS; PROTEINS; AFFINITY; SYSTEM; FIELD; QSAR AB 3,5-Diacyl-2,4-dialkyl-6-phenylpyridine derivatives have been found to be selective antagonists at both human and rat A(3) adenosine receptors (Li et al. J. Med. Chem. 1998, 41, 3186-3201), In the present study, ring-constrained, fluoro, hydroxy, and other derivatives in this series have been synthesized and tested for affinity at adenosine receptors in radioligand binding assays. K-i values at recombinant human and rat A(3) adenosine receptors were determined using [I-125]AB-MECA (N-6-(4-amino-3-iodobenzyl)-5 '-N-methylcarbamoyladenosine). Selectivity for A(3) adenosine receptors was determined vs radioligand binding at rat brain A(1) and A(2A) receptors, and structure-activity relationships at various positions of the pyridine ring (the 3- and 5-acyl substituents and the 2- and 4-alkyl substituents) were probed. At the 5-position inclusion of a beta-fluoroethyl (7) or a gamma-fluoropropyl ester (26) was favorable for human A(3) receptor affinity, resulting in K-i values of 4.2 and 9.7 nM, respectively, while the pentafluoropropyl analogue was clearly less potent at human A(3) receptors. At the 2-, 3-, and 4-positions, fluoro or hydroxy substitution failed to enhance potency and selectivity at human A(3) receptors. Several analogues were nearly equipotent at rat and human A(3) receptors. To further define the pharmacophore conformationally, a lactam, a lactone, and thiolactones were tested in adenosine receptor binding. The most potent analogue in this group was compound 34, in which a thiolactone was formed between 3- and 4-positions and which had a K-i value of 248 nM at human A(3) receptors. Using affinity data and a general pharmacophore model for A(3) adenosine receptor antagonists recently proposed, we applied comparative molecular field analysis (CoMFA) to obtain a three-dimensional quantitative structure-activity relationship for pyridine derivatives, having good predictability (r(pred)(2) = 0.873) for compounds in the test set. A rhodopsin-based model of the human A(3) receptor was built, and the pyridine reference ligand 2,3,4,5-tetraethyl-6-phenylpyridine-3-thiocarboxylate-5-carboxylate (MRS 1476) was docked in the putative ligand binding site. Interactions between receptor transmembrane domains and the steric and the electrostatic contour plots obtained from the CoMFA analysis were analyzed. C1 NIDDK, Mol Recognit Sect, LBC, NIH, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, LBC, NIH, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Moro, Stefano/A-2979-2012; Jacobson, Kenneth/A-1530-2009 OI Moro, Stefano/0000-0002-7514-3802; Jacobson, Kenneth/0000-0001-8104-1493 NR 49 TC 162 Z9 163 U1 5 U2 8 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 FEB 25 PY 1999 VL 42 IS 4 BP 706 EP 721 DI 10.1021/jm980550w PG 16 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 170UW UT WOS:000078826300019 PM 10052977 ER PT J AU Dries, DL Exner, DV Gersh, BJ Cooper, HA Carson, PE Domanski, MJ AF Dries, DL Exner, DV Gersh, BJ Cooper, HA Carson, PE Domanski, MJ TI Racial differences in the outcome of left ventricular dysfunction SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HEART-FAILURE; CARVEDILOL AB Background Population-based studies have found that black patients with congestive heart failure have a higher mortality rate than white patients with the same condition. This finding has been attributed to differences in the severity, causes, and management of heart failure, the prevalence of coexisting conditions, and socioeconomic factors. Although these factors probably account for some of the higher mortality due to congestive heart failure among blacks, we hypothesized that racial differences in the natural history of left ventricular dysfunction might also have a role. Methods Using data from the Studies of Left Ventricular Dysfunction (SOLVD) prevention and treatment trials, in which all patients received standardized therapy and follow-up, we conducted a retrospective analysis of the outcomes of asymptomatic and symptomatic left ventricular systolic dysfunction among black and white participants. The mean (+/-SD) follow-up was 34.2+/-14.0 months in the prevention trial and 32.3+/-14.8 months in the treatment trial among the black and white participants. Results The overall mortality rates in the prevention trial were 8.1 per 100 person-years for blacks and 5.1 per 100 person years for whites. In the treatment trial, the rates were 16.7 per 100 person-years and 13.4 per 100 person-years, respectively. After adjustment for age, coexisting conditions, severity and causes of heart failure, and use of medications, blacks had a higher risk of death from all causes in both the SOLVD prevention trial (relative risk, 1.36; 95 percent confidence interval, 1.06 to 1.74; P=0.02) and the treatment trial (relative risk, 1.25; 95 percent confidence interval, 1.04 to 1.50; P=0.02). In both trials blacks were also at higher risk for death due to pump failure and for the combined end point of death from any cause or hospitalization for heart failure, our two predefined indicators of the progression of left ventricular systolic dysfunction. Conclusions Blacks with mild-to-moderate left ventricular systolic dysfunction appear to be at higher risk for progression of heart failure and death from any cause than similarly treated whites. These results suggest that there may be racial differences in the outcome of asymptomatic and symptomatic left ventricular systolic dysfunction. (N Engl J Med 1999;340:609-16.) (C)1999, Massachusetts Medical Society. C1 NHLBI, Clin Trials Sci Res Grp, Div Epidemiol & Clin Applicat, Rockledge Ctr 2, Bethesda, MD 20892 USA. Georgetown Univ Hosp, Div Cardiol, Washington, DC 20007 USA. Dept Vet Affairs, Washington, DC USA. RP Dries, DL (reprint author), NHLBI, Clin Trials Sci Res Grp, Div Epidemiol & Clin Applicat, Rockledge Ctr 2, 6701 Rockledge Dr,Rm 8149, Bethesda, MD 20892 USA. EM ddries@aol.com FU NHLBI NIH HHS [TA-HL-1002] NR 20 TC 214 Z9 217 U1 1 U2 1 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 FEB 25 PY 1999 VL 340 IS 8 BP 609 EP 616 DI 10.1056/NEJM199902253400804 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 169NP UT WOS:000078755700004 PM 10029645 ER PT J AU Klebanoff, MA AF Klebanoff, MA TI The interval between pregnancies and the outcome of subsequent births SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID ABORTION C1 NICHHD, Bethesda, MD 20892 USA. RP Klebanoff, MA (reprint author), NICHHD, Bethesda, MD 20892 USA. NR 11 TC 35 Z9 36 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 FEB 25 PY 1999 VL 340 IS 8 BP 643 EP 644 DI 10.1056/NEJM199902253400809 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 169NP UT WOS:000078755700009 PM 10029650 ER PT J AU Rutberg, SE Adams, TL Olive, M Alexander, N Vinson, C Yuspa, SH AF Rutberg, SE Adams, TL Olive, M Alexander, N Vinson, C Yuspa, SH TI CRE DNA binding proteins bind to the AP-1 target sequence and suppress AP-1 transcriptional activity in mouse keratinocytes SO ONCOGENE LA English DT Article DE keratinocyte; differentiation; AP-1; transcription ID DIFFERENTIATION-SPECIFIC EXPRESSION; HUMAN INVOLUCRIN GENE; C-JUN; EPIDERMAL DIFFERENTIATION; REPRESSES TRANSCRIPTION; SKIN CARCINOGENESIS; PROXIMAL PROMOTER; PROFILAGGRIN GENE; RESPONSE ELEMENT; CARCINOMA-CELLS AB Previously, we have shown that nuclear extracts from cultured mouse keratinocytes induced to differentiate by increasing the levels of extra-cellular calcium contain Fra-1, Fra-2, Jun B, Jun D and c-Jun proteins that bind to the AP-1 DNA binding sequence. Despite this DNA binding activity, AP-1 reporter activity was suppressed in these cells. Here, we have detected the CREB family proteins CREB and CREM alpha as additional participants in the AP-1 DNA binding complex in differentiating keratinocytes, AP-1 and CRE DNA binding activity correlated with the induction of CREB, CREM alpha and ATF-1 and CREB phosphorylation at ser(133) (ser(133) phospho-CREB) in the transition from basal to differentiating keratinocytes, but the activity of a CRE reporter remained unchanged. In contrast, the CRE reporter was activated in the presence of the dominant-negative (DN) CREB mutants, KCREB and A-CREB, proteins that dimerize with CREB family members and block their ability to bind to DNA. The increase in CRE reporter activity in the presence of these mutants suggests that CRE-mediated transcriptional activity is suppressed in keratinocytes through protein-protein interactions involving a factor that dimerizes with the CREB leucine zipper. In experiments where the A-CREB mutant was co-transfected with an AP-1 reporter construct, transcriptional activity was also increased indicating that a CREB family member binds AP-1 sites and represses AP-1 transcriptional activity as well. Exogenous expression of the transcriptional repressor CREM alpha down-regulated both CRE and AP-1 reporters in keratinocytes suggesting that this factor may contribute to the suppression of AP-1 transcriptional activity observed in differentiating keratinocytes. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. NCI, Biochem Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Yuspa, SH (reprint author), Bldg 37,Room 3B25,37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. NR 56 TC 38 Z9 38 U1 0 U2 1 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 25 PY 1999 VL 18 IS 8 BP 1569 EP 1579 DI 10.1038/sj.onc.1202463 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 169VX UT WOS:000078770700007 PM 10102627 ER PT J AU Riley, GF Potosky, AL Klabunde, CN Warren, JL Ballard-Barbash, R AF Riley, GF Potosky, AL Klabunde, CN Warren, JL Ballard-Barbash, R TI Stage at diagnosis and treatment patterns among older women with breast cancer - An HMO and fee-for-service comparison SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HEALTH MAINTENANCE ORGANIZATION; ACUTE MYOCARDIAL-INFARCTION; MEDICAL OUTCOMES; RESOURCE UTILIZATION; MANAGED CARE; MASTECTOMY; SYSTEMS; PREPAID; RADIOTHERAPY; RADIATION AB Context Few studies have compared patterns of care in health maintenance organization (HMO) and fee-for-service (FFS) settings. Objective To examine breast cancer stage at diagnosis and, for those at an early stage, treatment patterns for elderly women in HMO and FFS settings. Design Cancer registry data from the Surveillance, Epidemiology, and End Results (SEER) program linked to Medicare enrollment records. Settings and Participants Women aged 65 years or older residing in 11 geographic areas who were newly diagnosed as having breast cancer between 1988 and 1993. Main Outcome Measures Standardized percentage of cases diagnosed at late stages for HMO vs FFS; standardized percentage of early-stage cases undergoing initial treatment with breast-conserving surgery (BCS); and, among BCS cases, standardized percentage receiving adjuvant radiation therapy. Standardization was achieved through logistic regression, controlling for patient demographics, cancer history, county of residence, year of diagnosis, and educational attainment at the census tract level. Analyses of treatment patterns were controlled for stage at diagnosis and tumor size. Results The HMO enrollees were less likely to have breast cancer diagnosed at late stages than FFS patients (HMO, 7.6%; FFS, 10.8%; difference, -3.2% [95% confidence interval (CI), -4.2% to -2.2%]). Among early-stage cases, the percentages undergoing BCS were similar in HMO and FFS settings overall (HMO, 38.4%; FFS, 36.8%; difference, 1.6% [95% CI, 0.0%-3.2%]); percentages, varied markedly at the individual plan level. Among women undergoing BCS, HMO enrollees were significantly more likely to receive radiation therapy but, again, results varied by plan (HMO, 69.0%; FFS, 63.7%; difference, 5.3% [95% CI, 2.9%-7.7%]). In general, use of BCS and radiation therapy was substantially higher than that found in an earlier study examining cases diagnosed between 1985 and 1989. Conclusions Treatment of early-stage breast cancer in HMOs often differs from local FFS patterns, but not in a consistent way. During the period of our study, elderly HMO enrollees did not appear to have systematic access problems with adjuvant radiation therapy following BCS compared with women in an FFS setting. C1 US Hlth Care Financing Adm, Baltimore, MD 21244 USA. NCI, Bethesda, MD 20892 USA. RP Riley, GF (reprint author), US Hlth Care Financing Adm, 7500 Secur Blvd,Room C3-20-17, Baltimore, MD 21244 USA. EM griley@hcfa.gov NR 42 TC 152 Z9 153 U1 2 U2 6 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 FEB 24 PY 1999 VL 281 IS 8 BP 720 EP 726 DI 10.1001/jama.281.8.720 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 168BD UT WOS:000078669900031 PM 10052442 ER PT J AU Arni, RK Watanabe, L Ward, RJ Kreitman, RJ Kumar, K Walz, FG AF Arni, RK Watanabe, L Ward, RJ Kreitman, RJ Kumar, K Walz, FG TI Three-dimensional structure of ribonuclease T-1 complexed with an isosteric phosphonate substrate analogue of GpU: Alternate substrate binding modes and catalysis SO BIOCHEMISTRY LA English DT Article ID SITE-DIRECTED MUTAGENESIS; CRYSTAL-STRUCTURE; RNASE T1; 3-DIMENSIONAL STRUCTURE; SUBSITE INTERACTIONS; ENZYMATIC-REACTION; 1.9-A RESOLUTION; ACTIVE-SITE; MECHANISM; HISTIDINE-40 AB The X-ray crystal structure of a complex between ribonuclease T-1 and guanylyl(3'-6')-6'-deoxyhomouridine (GpcU) has been determined at 2.0 Angstrom resolution. This Ligand is an isosteric analogue of the minimal RNA substrate, guanylyl(3'-5')uridine (GpU), where a methylene is substituted for the uridine 5'-oxygen atom. Two protein molecules are part of the asymmetric unit and both have a GpcU bound at the active site in the same manner. The protein-protein interface reveals an extended aromatic stack involving both guanines and three enzyme phenolic groups. A third GpcU has its guanine moiety stacked on His92 at the active site on enzyme molecule A and interacts with GpcU on molecule B in a neighboring unit via hydrogen bonding between uridine ribose 2'- and 3'-OH groups. None of the uridine moieties of the three GpcU molecules in the asymmetric unit interacts directly with the protein. GpcU-active-site interactions involve extensive hydrogen bonding of the guanine moiety at the primary recognition site and of the guanosine 2'-hydroxyl group with His40 and Glu58. On the other hand, the phosphonate group is weakly bound only by a single hydrogen bond with Tyr38, unlike ligand phosphate groups of other substrate analogues and 3'-GMP, which hydrogen-bonded with three additional active-site residues. Hydrogen bonding of the guanylyl 2'-OH group and the phosphonate moiety is essentially the same as that recently observed for a novel structure of a RNase T-1-3'-GMP complex obtained immediately after in situ hydrolysis of exo-(S-p)-guanosine 2',3'-cyclophosphorothioate [Zegers et al. (1998) Nature Struct. Biol. 5, 280-283]. It is likely that GpcU at the active site represents a nonproductive binding mode for GpU [:Steyaert, J., and Engleborghs (1995) fur. J. Biochem. 233, 140-144]. The results suggest that the active site of ribonuclease T-1 is adapted for optimal tight binding of both the guanylyl 2'-OH and phosphate groups (of GpU) only in the transition state for catalytic transesterification, which is stabilized by adjacent binding of the leaving nucleoside (U) group. C1 UNESP, IBILCE, Dept Phys, BR-15054000 SJ Rio Preto, SP, Brazil. USP, FMRP, Dept Biochem, BR-14049900 Ribeirao Preto, Brazil. NCI, NIH, Div Basic Sci, Mol Biol Lab, Bethesda, MD 20892 USA. Kent State Univ, Dept Chem, Kent, OH 44242 USA. RP Walz, FG (reprint author), UNESP, IBILCE, Dept Phys, CEP 15054000,CP 136, BR-15054000 SJ Rio Preto, SP, Brazil. EM FWALZ@KENT.EDU RI Arni, Raghuvir/B-2222-2013; Ward, Richard/C-2460-2012 OI Ward, Richard/0000-0003-1136-5737 NR 49 TC 16 Z9 17 U1 1 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 FEB 23 PY 1999 VL 38 IS 8 BP 2452 EP 2461 DI 10.1021/bi982612q PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 173FW UT WOS:000078971300025 PM 10029539 ER PT J AU Pauls, JD Brems, J Pockros, PJ Saven, A Wagner, RL Weber, R Metcalfe, D Christiansen, SC AF Pauls, JD Brems, J Pockros, PJ Saven, A Wagner, RL Weber, R Metcalfe, D Christiansen, SC TI Mastocytosis - Diverse presentations and outcomes SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID C-KIT MUTATION; SYSTEMIC MASTOCYTOSIS; CUTANEOUS MASTOCYTOSIS; MAST-CELLS; MANAGEMENT; PATIENT AB Within the general category of mastocytosis lies an array of clinical presentations with differing prognostic implications. We report 3 cases of systemic mastocytosis distinguished by novel aspects of the disease. Case 1 documents the first successful orthotopic liver transplantation in a patient with mastocytosis; case 2 depicts a potential hereditary component of mastocytosis; and case 3 documents the progression of mastocytosis with hematologic abnormality to mast cell leukemia. Future investigations, such as the early definition of c-kit receptor mutations, may provide additional insight as to the molecular basis for this heterogeneous disease and guidance for prognostic implications and targeted therapies. C1 Scripps Clin & Res Fdn, Div Allergy Asthma & Immunol, La Jolla, CA 92037 USA. Scripps Clin & Res Fdn, Div Organ Transplantat, La Jolla, CA 92037 USA. Scripps Clin & Res Fdn, Div Gastroenterol, La Jolla, CA 92037 USA. Scripps Clin & Res Fdn, Div Hematol Oncol, La Jolla, CA 92037 USA. Scripps Clin & Res Fdn, Div Anesthesiol, La Jolla, CA 92037 USA. NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Christiansen, SC (reprint author), Scripps Clin & Res Fdn, Div Allergy Asthma & Immunol, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA. NR 20 TC 20 Z9 20 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD FEB 22 PY 1999 VL 159 IS 4 BP 401 EP 405 DI 10.1001/archinte.159.4.401 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 168QU UT WOS:000078704400011 PM 10030315 ER PT J AU Hermann, P Armant, M Brown, E Rubio, M Ishihara, H Ulrich, D Caspary, RG Lindberg, FP Armitage, R Maliszewski, C Delespesse, G Sarfati, M AF Hermann, P Armant, M Brown, E Rubio, M Ishihara, H Ulrich, D Caspary, RG Lindberg, FP Armitage, R Maliszewski, C Delespesse, G Sarfati, M TI The vitronectin receptor and its associated CD47 molecule mediates proinflammatory cytokine synthesis in human monocytes by interaction with soluble CD23 SO JOURNAL OF CELL BIOLOGY LA English DT Article DE CD47; CD23; vitronectin receptor; TNF-alpha; IFN-gamma ID INTEGRIN-ASSOCIATED PROTEIN; RHEUMATOID-ARTHRITIS; ADHESION MOLECULES; LIGAND; CELLS; THROMBOSPONDIN; PHAGOCYTOSIS; ALPHA(V)BETA(3); LOCALIZATION; NEUTROPHILS AB The vitronectin receptor, alpha(v)beta(3) integrin, plays an important role in tumor cell invasion, angiogenesis, and phagocytosis of apoptotic cells. CD47, a member of the multispan transmembrane receptor family, physically and functionally associates with vitronectin receptor (VnR). Although vitronectin (Vn) is not a ligand of CD47, anti-CD47 and beta(3) mAbs suppress Vn, but not fibronectin (Fn) binding and function. Here, we show that anti-CD47, anti-beta(3) mAb and Vn, but not Fn, inhibit sCD23-mediated proinflammatory function (TNF-alpha, IL-12, and IFN-gamma release). Surprisingly, anti-CD47 and beta(3) mAbs do not block sCD23 binding to alpha(v)(+)beta(3)(+) T cell lines, whereas Vn and an alpha(v) mAb (clone AMF7) do inhibit sCD23 binding, suggesting the VnR complex may be a functional receptor for sCD23. sCD23 directly binds alpha(v)(+)beta(3)(+)/CD47(-) cell lines, but coexpression of CD47 increases binding. Moreover, sCD23 binds purified alpha(v) protein and a single human alpha(v) chain CHO transfectant. We conclude that the VnR and its associated CD47 molecule may function as a novel receptor for sCD23 to mediate its proinflammatory activity and, as such, may be involved in the inflammatory process of the immune response. C1 Univ Montreal, Ctr Hosp, Ctr Rech Louis Charles Simard, Lab Allergie M4211K, Montreal, PQ H2L 4M1, Canada. NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. Immunex Res & Dev Corp, Seattle, WA 98101 USA. Washington Univ, Div Infect Dis, St Louis, MO 63110 USA. RP Sarfati, M (reprint author), Univ Montreal, Ctr Hosp, Ctr Rech Louis Charles Simard, Lab Allergie M4211K, Pavillon Notre Dame,1560 Sherbrooke St E, Montreal, PQ H2L 4M1, Canada. NR 37 TC 57 Z9 59 U1 0 U2 4 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 FEB 22 PY 1999 VL 144 IS 4 BP 767 EP 775 DI 10.1083/jcb.144.4.767 PG 9 WC Cell Biology SC Cell Biology GA 242GR UT WOS:000082932600015 PM 10037797 ER PT J AU Riess, J Bicout, D Duguet, T AF Riess, J Bicout, D Duguet, T TI Phonon assisted formation of quantum Hall plateaus SO PHYSICS LETTERS A LA English DT Article DE integer quantum Hall effect; plateau width; electron-phonon interaction; compensating current ID FINE-STRUCTURE CONSTANT; SCATTERING; SYSTEMS; TRANSPORT AB We present model calculations which elucidate the role of electron-phonon interaction in the formation of quantized Hall plateaus. In particular, we analyse the so-called compensating current, which plays the crucial part in the Hall plateau formation. Typically this current, is caused by electron scattering through a disorder potential, however, a small fraction can also arise from scattering with phonons, We demonstrate that in special situations even the entire compensating current, i.e., the entire Hall plateau is generated by scattering with phonons. Phonon induced Hall plateaus coexist with dissipation, This shows, that the absence of dissipation is, in principle, not indispensable for the appearance of the quantum Hall effect. (C) 1999 Elsevier Science B.V. C1 Univ Grenoble 1, CNRS, Ctr Rech Tres Basses Temp, F-38042 Grenoble 9, France. NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Riess, J (reprint author), Univ Grenoble 1, CNRS, Ctr Rech Tres Basses Temp, BP 166, F-38042 Grenoble 9, France. NR 14 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0375-9601 J9 PHYS LETT A JI Phys. Lett. A PD FEB 22 PY 1999 VL 252 IS 3-4 BP 205 EP 212 DI 10.1016/S0375-9601(98)00925-6 PG 8 WC Physics, Multidisciplinary SC Physics GA 170UK UT WOS:000078825100014 ER PT J AU Resnick, HE Harris, TB AF Resnick, HE Harris, TB TI New diagnostic criteria for diabetes mellitus - New criteria result in fewer cases in older adults SO BRITISH MEDICAL JOURNAL LA English DT Letter C1 NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. RP Resnick, HE (reprint author), NIA, Epidemiol Demog & Biometry Program, Gateway Bldg,Room 3C-309, Bethesda, MD 20892 USA. NR 3 TC 3 Z9 3 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-8138 J9 BRIT MED J JI Br. Med. J. PD FEB 20 PY 1999 VL 318 IS 7182 BP 531 EP 531 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 170QT UT WOS:000078818100037 PM 10024269 ER PT J AU Cutler, J AF Cutler, J TI Which drug for treatment of hypertension? SO LANCET LA English DT Editorial Material ID RATIONALE C1 NHLBI, Clin Applicat & Prevent Program, Bethesda, MD 20892 USA. RP Cutler, J (reprint author), NHLBI, Clin Applicat & Prevent Program, Bldg 10, Bethesda, MD 20892 USA. NR 7 TC 17 Z9 17 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD FEB 20 PY 1999 VL 353 IS 9153 BP 604 EP 605 DI 10.1016/S0140-6736(98)00361-4 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 170QU UT WOS:000078818200002 PM 10030320 ER PT J AU Hoon, MA Adler, E Lindemeier, J Battey, JF Ryba, NJP Zuker, CS AF Hoon, MA Adler, E Lindemeier, J Battey, JF Ryba, NJP Zuker, CS TI Putative mammalian taste receptors: A class of taste-specific GPCRs with distinct topographic selectivity SO CELL LA English DT Article ID PHEROMONE RECEPTORS; SWEET TASTE; CHORDA-TYMPANI; NECTURUS-MACULOSUS; MULTIGENE FAMILY; NERVE-FIBERS; RAT TONGUE; C-ELEGANS; TRANSDUCTION; CELLS AB Taste represents a major form of sensory input in the animal kingdom. In mammals, taste perception begins with the recognition of tastant molecules by unknown membrane receptors localized on the apical surface of receptor cells of the tongue and palate epithelium. We report the cloning and characterization of two novel seven-transmembrane domain proteins expressed in topographically distinct subpopulations of taste receptor cells and taste buds. These proteins are specifically localized to the taste pore and are members of a new group of G protein-coupled receptors distantly related to putative mammalian pheromone receptors. We propose that these genes encode taste receptors. C1 Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. Univ Calif San Diego, Howard Hughes Med Inst, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Biol, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. RP Zuker, CS (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. NR 57 TC 428 Z9 446 U1 4 U2 45 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD FEB 19 PY 1999 VL 96 IS 4 BP 541 EP 551 DI 10.1016/S0092-8674(00)80658-3 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 168XN UT WOS:000078718600005 PM 10052456 ER PT J AU Gaemers, S Elsevier, CJ Bax, A AF Gaemers, S Elsevier, CJ Bax, A TI NMR of biomolecules in low viscosity, liquid CO2 SO CHEMICAL PHYSICS LETTERS LA English DT Article ID CARBON-DIOXIDE MICROEMULSIONS; NUCLEAR MAGNETIC-RESONANCE; HIGH-RESOLUTION; SPECTROSCOPY; PROTEINS; ASSIGNMENT; RELAXATION; DYNAMICS; WATER AB We demonstrate that hetero- and homonuclear NMR spectra of cyclosporin A and pancreatic trypsin inhibitor (BPTI) can be recorded at room temperature in liquid CO2, a medium of very low viscosity, which has been reported to have no adverse effect on molecular structure or activity of several proteins. Rotational diffusion of cyclosporin A in a CO2/methanol mixture is approximately three-fold faster than in chloroform. Translational diffusion for BPTI, dissolved in liquid CO2 by co-adding detergent and trifluoroethanol, is measured to be faster than in water, but rotational diffusion is not. Development of improved detergents is anticipated to make feasible the encapsulation of most biological macromolecules in water-containing reverse micelles, which can be suspended in a wide array of apolar, supercritical or near-critical solvents. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Univ Amsterdam, Inst Mol Chem, NL-1018 WV Amsterdam, Netherlands. RP Bax, A (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5,Room 126, Bethesda, MD 20892 USA. NR 22 TC 21 Z9 21 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-2614 J9 CHEM PHYS LETT JI Chem. Phys. Lett. PD FEB 19 PY 1999 VL 301 IS 1-2 BP 138 EP 144 DI 10.1016/S0009-2614(99)00012-3 PG 7 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 167XU UT WOS:000078660800020 ER PT J AU Von Lubitz, DKJE Lin, RCS Boyd, M Bischofberger, N Jacobson, KA AF Von Lubitz, DKJE Lin, RCS Boyd, M Bischofberger, N Jacobson, KA TI Chronic administration of adenosine A(3) receptor agonist and cerebral ischemia: neuronal and glial effects SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE ischemia; adenosine A(3) receptor; GFAP (glial fibrillary acidic protein); MAP-2 (microtubule associated protein); nitric oxide (NO); synthase; (gerbil) ID NITRIC-OXIDE SYNTHASE; NADPH-DIAPHORASE ACTIVITY; RAT-BRAIN; REACTIVE ASTROCYTES; CELLS; STIMULATION; ACTIVATION; INDUCTION; FOREBRAIN; UNIQUE AB We have previously shown that chronic administration of the selective A, receptor agonist N-6-(3-iodobenzyl)-5'-N-methylcarboxoamidoadenosine (IB-MECA) leads to a significant improvement of postocclusive cerebral blood flow, and protects against neuronal damage and mortality induced by severe forebrain ischemia in gerbils. Using immunocytochemical methods we now show that chronic with IB-MECA results in a significant preservation of ischemia-sensitive microtubule associated protein 2 (MAP-2), enhancement of the expression of glial fibrillary acidic protein (GFAP), and a very intense depression of nitric oxide synthase in the brain of postischemic gerbils. These changes demonstrate that the cerebroprotective actions of chronically administered IB-MECA involve both neurons and glial cells, and indicate the possibility of distinct mechanisms that are affected in the course of chronic administration of the drug. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIDDK, Mol Recognit Sect, NIH, Bethesda, MD USA. Allegheny Univ Hlth Sci, Dept Anat & Neurobiol, Philadelphia, PA 19102 USA. Gilead Sci Inc, Foster City, CA 94404 USA. RP Von Lubitz, DKJE (reprint author), Univ Michigan, Med Ctr, Dept Emergency Med, Emergency Med Res Labs, TC-B1354-0303,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM dvlubitz@umich.edu RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031117-20, Z99 DK999999] NR 43 TC 38 Z9 38 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD FEB 19 PY 1999 VL 367 IS 2-3 BP 157 EP 163 DI 10.1016/S0014-2999(98)00977-7 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 170DD UT WOS:000078789900003 PM 10078988 ER PT J AU Yamamoto, K Takeshima, H Hamada, K Nakao, M Kino, T Nishi, T Kochi, M Kuratsu, J Yoshimura, T Ushio, Y AF Yamamoto, K Takeshima, H Hamada, K Nakao, M Kino, T Nishi, T Kochi, M Kuratsu, J Yoshimura, T Ushio, Y TI Cloning and functional characterization of the 5 '-flanking region of the human monocyte chemoattractant protein-1 receptor (CCR2) gene - Essential role of 5 '-untranslated region in tissue-specific expression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID 5' UNTRANSLATED REGION; MESSENGER-RNA; DIFFERENTIAL EXPRESSION; TRANSCRIPTION FACTORS; GLIOMA; HIV-1; ORGANIZATION; INFILTRATION; SEQUENCE; CELLS AB The human monocyte chemoattractant protein-1 receptor designated hCCR2 is an essential co-receptor in cell entry by the human immunodeficiency virus as well as a receptor for monocyte chemoattractant protein-1, a member of the family of C-C chemokines that mediate monocyte chemotaxis, To elucidate the molecular mechanisms underlying the transcriptional regulation of hCCR2, we cloned and sequenced the hCCR2 gene; it was approximately 8 kilobase pairs in length and consisted of three exons divided by two introns, In the 5'-flanking region, there were the typical mammalian promoter consensus elements, a CAAT box and a TATA box, resulting in a single transcription initiation site. In addition, we found clustered tissue-specific cis-regulatory elements such as GATA consensus sequences, Oct-1 binding sequences, and CAAT/enhancer-binding protein binding sequences, Luciferase assays with various promoter deletions and gel mobility shift assays indicated that three cis-regulatory elements located within the region from -89 to +118 are required for basal activity in THP-1 cells. One element is an octamer sequence 36-base pair upstream from the TATA box; it binds mainly to Oct-1 and is capable of increasing transcriptional activity. The other two elements, which are tandem recognition sites of the CAAT/enhancer-binding protein family, are located in the 5'-untranslated region and account for the transcriptional activation as well as the tissue specificity of hCCR2. C1 Kumamoto Univ, Sch Med, Dept Neurosurg, Kumamoto 8608556, Japan. Kumamoto Univ, Sch Med, Dept Tumor Genet & Biol, Kumamoto 8608556, Japan. Kagoshima Univ, Sch Med, Dept Neurosurg, Kagoshima 8908520, Japan. NCI, Immunopathol Sect, Immunol Lab, NIH, Frederick, MD 21702 USA. RP Takeshima, H (reprint author), Kumamoto Univ, Sch Med, Dept Neurosurg, 1-1-1 Honjo, Kumamoto 8608556, Japan. EM m2040@kaiju.medic.kumamoto-u.ac.jp NR 33 TC 37 Z9 37 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 FEB 19 PY 1999 VL 274 IS 8 BP 4646 EP 4654 DI 10.1074/jbc.274.8.4646 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 168NB UT WOS:000078698200026 PM 9988701 ER PT J AU Lee, SR Kim, JR Kwon, KS Yoon, HW Levine, RL Ginsburg, A Rhee, SG AF Lee, SR Kim, JR Kwon, KS Yoon, HW Levine, RL Ginsburg, A Rhee, SG TI Molecular cloning and characterization of a mitochondrial selenocysteine-containing thioredoxin reductase from rat liver SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LUNG ADENOCARCINOMA CELLS; GLUTATHIONE-REDUCTASE; DISULFIDE OXIDOREDUCTASES; LIPOAMIDE DEHYDROGENASE; NUCLEOTIDE-SEQUENCE; ESCHERICHIA-COLI; REDOX REGULATION; SELENOPROTEIN-W; SECIS ELEMENTS; C-ELEGANS AB A thioredoxin reductase (TrxR), named here TrxR2, that did not react with antibodies to the previously identified TrxR (now named TrxR1) was purified from rat liver. Like TrxR1, TrxR2 was a dimeric enzyme containing selenocysteine (Secys) as the COOH-terminal penultimate residue. A cDNA encoding TrxRa was cloned from rat liver; the open reading frame predicts a polypeptide of 526 amino acids with a COOH-terminal Gly-Cys-Secys-Gly motif provided that an in-frame TGA codon encodes Secys. The 3'-untranslated region of the cDNA contains a canonical Secys insertion sequence element, The deduced amino acid sequence of TrxR1 shows 54% identity to that of TrxR1 and contained 36 additional residues upstream of the experimentally determined NH2-terminal sequence. The sequence of this 36-residue region is typical of that of a mitochondrial leader peptide. Immunoblot analysis confirmed that TrxR2 is localized almost exclusively in mitochondria, whereas TrxR1 is a cytosolic protein. Unlike TrxR1, which was expressed at a level of 0.6 to 1.6 mu g/mill/gram of total soluble protein in all rat tissues examined, TrxRa was relatively abundant (0.3 to 0.6 mu g/mg) only in liver, kidney, adrenal gland, and heart. The specific localization of TrxR2 in mitochondria, together with the previous identification of mitochondria-specific thioredoxin and thioredoxin-dependent peroxidase, suggest that these three proteins provide a primary line of defense against H2O2 produced by the mitochondrial respiratory chain. C1 NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Rhee, SG (reprint author), NHLBI, Lab Cell Signaling, NIH, Bldg 3,Rm 122, Bethesda, MD 20892 USA. EM sgrhee@nih.gov RI Levine, Rodney/D-9885-2011 NR 63 TC 207 Z9 214 U1 1 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 FEB 19 PY 1999 VL 274 IS 8 BP 4722 EP 4734 DI 10.1074/jbc.274.8.4722 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 168NB UT WOS:000078698200034 PM 9988709 ER PT J AU Della Rocca, GJ Mukhin, YV Garnovskaya, MN Daaka, Y Clark, GJ Luttrell, LM Lefkowitz, RJ Raymond, JR AF Della Rocca, GJ Mukhin, YV Garnovskaya, MN Daaka, Y Clark, GJ Luttrell, LM Lefkowitz, RJ Raymond, JR TI Serotonin 5-HT1A receptor-mediated Erk activation requires calcium/calmodulin-dependent receptor endocytosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; CALMODULIN-BINDING DOMAIN; TYROSINE-KINASE; COATED VESICLES; PHOSPHORYLATION; CELLS; DESENSITIZATION; LOCALIZATION; PP60C-SRC; IDENTIFICATION AB Many receptors that couple to heterotrimeric guanine nucleotide-binding (G) proteins mediate rapid activation of the mitogen-activated protein kinases, Erk1 and Erk2. The G(i)-coupled serotonin (5-hydroxytryptamine (5-HT)) 5-HT1A receptor, heterologously expressed in Chinese hamster ovary or human embryonic kidney 293 cells, mediated rapid activation of Erk1/2 via a mechanism dependent upon both Ras activation and clathrin-mediated endocytosis. This activation was attenuated by chelation of intracellular Ca2+ and Ca2+/calmodulin (CAM) inhibitors or the CAM sequestrant protein calspermin, The CAM-dependent step in the Erk1/2 activation cascade is downstream of Ras activation, because inhibitors of CAM antagonize Erk1/2 activation induced by constitutively activated mutants of Ras and c-Src but not by constitutively activated mutants of Raf and MEK (mitogen and extracellular signal-regulated kinase). Inhibitors of the classical CAM effecters myosin light chain kinase, CAM-dependent protein kinases II and IV, PP2B, and CAM-sensitive phosphodiesterase had no effect upon 5-HT1A receptor-mediated Erk1/2 activation. Because clathrin-mediated endocytosis was required for 5-HT1A receptor-mediated Erk1/2 activation, we pos tulated a role for CAM in receptor endocytosis. Inhibition of receptor endocytosis by use of sequestration-defective mutants of beta-arrestin, and dynamin attenuated 5-HT1A receptor-stimulated Erk1/2 activation. Inhibition of CAM prevented agonist dependent endocytosis of epitope-tagged 5-HT1A receptors. We conclude that CAM-dependent activation of Erk1/2 through the 5-HT1A receptor reflects its role in endocytosis of the receptor, which is a required step in the activation of MEK and subsequently Erk1/2. C1 Med Univ S Carolina, Dept Med Nephrol, Charleston, SC 29425 USA. Duke Univ, Med Ctr, Howard Hughes Med Inst, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. NCI, NIH, Rockville, MD 20857 USA. Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29425 USA. RP Med Univ S Carolina, Dept Med Nephrol, 829 Clin Sci Bldg,171 Ashley Ave, Charleston, SC 29425 USA. EM raymondj@musc.edu RI Perez , Claudio Alejandro/F-8310-2010 OI Perez , Claudio Alejandro/0000-0001-9688-184X FU NHLBI NIH HHS [HL16037]; NIDDK NIH HHS [DK52448, DK02352] NR 44 TC 112 Z9 113 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 19 PY 1999 VL 274 IS 8 BP 4749 EP 4753 DI 10.1074/jbc.274.8.4749 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 168NB UT WOS:000078698200037 PM 9988712 ER PT J AU Fox, BA Yee, VC Pedersen, LC Le Trong, I Bishop', PD Stenkamp, RE Teller, DC AF Fox, BA Yee, VC Pedersen, LC Le Trong, I Bishop', PD Stenkamp, RE Teller, DC TI Identification of the calcium binding site and a novel ytterbium site in blood coagulation factor XIII by X-ray crystallography SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PLATELET FACTOR-XIII; PROTEIN STRUCTURES; CROSS-LINKING; CRYSTAL-STRUCTURE; HUMAN-PLACENTA; TRANSGLUTAMINASE; FIBRIN; THROMBIN; DEFICIENCY; ACTIVATION AB The presence or absence of calcium determines the activation, activity, oligomerization, and stability of blood coagulation factor XIII. To explore these observed effects, we have determined the x-ray crystal structure of recombinant factor XIII A(2) in the presence of calcium, strontium, and ytterbium. The main calcium binding site within each monomer involves the main chain oxygen atom of Ala-457, and also the side chains from residues Asn-436, Asp-438, Glu-485, and Glu-490. Calcium and strontium bind in the same location, while ytterbium binds several angstroms removed. A novel ytterbium binding site is also found at the dimer two-fold axis, near residues Asp-270 and Glu-272, and this site may be related to the reported inhibition by lanthanide metals (Achyuthan, K. E., Mary, A., and Greenberg, C. S. (1989) Biochem. J. 257, 331-338). The overall structure of ion-bound factor XIII is very similar to the previously determined crystal structures of factor XIII zymogen, likely due to the constraints of this monoclinic crystal form. We have merged the three independent sets of water molecules in the structures to determine which water molecules are conserved and possibly structurally significant. C1 Univ Washington, Dept Biochem, Seattle, WA 98195 USA. Cleveland Clin Fdn, Lerner Res Inst, Dept Mol Cardiol, Cleveland, OH 44195 USA. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA. Zymogenet Inc, Seattle, WA 98105 USA. RP Teller, DC (reprint author), Univ Washington, Dept Biochem, Box 357350, Seattle, WA 98195 USA. EM teller@u.washington.edu FU NHLBI NIH HHS [HL50355]; NIGMS NIH HHS [GM08268] NR 49 TC 66 Z9 68 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 FEB 19 PY 1999 VL 274 IS 8 BP 4917 EP 4923 DI 10.1074/jbc.274.8.4917 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 168NB UT WOS:000078698200059 PM 9988734 ER PT J AU Warner, DR Romanowski, R Yu, SH Weinstein, LS AF Warner, DR Romanowski, R Yu, SH Weinstein, LS TI Mutagenesis of the conserved residue Glu(259) of G(s)alpha demonstrates the importance of interactions between switches 2 and 3 for activation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN ALPHA-SUBUNITS; GS-ALPHA; ADENYLATE-CYCLASE; CRYSTAL-STRUCTURE; HEREDITARY OSTEODYSTROPHY; ESCHERICHIA-COLI; GTP HYDROLYSIS; G(S-ALPHA); RECEPTOR; MUTATION AB We previously reported that substitution of Arg(258) within the switch 3 region of G(s)alpha impaired activation and increased basal GDP release due to loss of an interaction between the helical and GTPase domains (Warner, D. R., Weng, G., Yu, S., Matalon, R., and Weinstein, L. S. (1998) J Biol. Chem. 273, 23976-23983). The adjacent residue (Glu(259)) is strictly conserved in G protein alpha-subunits and is predicted to be important in activation. To determine the importance of Glu(259), this residue was mutated to Ala (G(s)alpha-E259A), Gln (G(s)alpha-E259Q), Asp (G(s)alpha-E259D), or Val (G(s)alpha-E259V), and the properties of in vitro translation products were examined. The G(s)alpha-E259V was studied because this mutation was identified in a patient with Albright hereditary osteodystrophy. 549 eye reconstitution assays demonstrated that G(s)alpha-E259D stimulated adenylyl cyclase normally in the presence of GTP gamma S but was less efficient with isoproterenol or AlF4-. The other mutants had more severely impaired effector activation, particularly in response to AlF4-. In trypsin protection assays, GTP gamma S was a more effective activator than AlF4- for all mutants, with G(s)alpha-E259D being the least severely impaired. For G(s)alpha-E259D, the AlF4--induced activation defect was more pronounced at low Mg2+ concentrations. G(s)alpha-E259D and G(s)alpha-E259A purified from Escherichia coli had normal rates of GDP release (as assessed by the rate GrT gamma S binding). However, for both mutants, the ability of AlF4- to decrease the rate of GTP gamma S binding was impaired, suggesting that they bound AlF4- more poorly. GrTP gamma S bound to purified G(s)alpha-E259D irreversibly in the presence of 1 mM free Mg2+, but dissociated readily at micromolar concentrations. Sucrose density gradient analysis of in, vitro translates demonstrated that all mutants except G(s)alpha-E259V bind to beta gamma at 0 degrees C and were stable at higher temperatures. In the active conformation Glu(259) interacts with conserved residues in the switch 2 region that are important in maintaining both the active state and AlF4- in the guanine nucleotide binding pocket. Although both G(s)alpha Arg(258) and Glu(259) are critical for activation, the mechanisms by which these residues affect G(s)alpha. protein activation are distinct. C1 NINDS, Membrane Biochem Sect, Mol & Cellular Neurobiol Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Warner, DR (reprint author), NINDS, Membrane Biochem Sect, Mol & Cellular Neurobiol Lab, NIH, Bldg 49,Rm 2A28, Bethesda, MD 20892 USA. EM dwarner@helix.nih.gov RI Weinstein, Lee/I-5575-2015 NR 39 TC 11 Z9 11 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 19 PY 1999 VL 274 IS 8 BP 4977 EP 4984 DI 10.1074/jbc.274.8.4977 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 168NB UT WOS:000078698200067 PM 9988742 ER PT J AU van Leeuwen, JEM Paik, PK Samelson, LE AF van Leeuwen, JEM Paik, PK Samelson, LE TI Activation of nuclear factor of activated T cells-(NFAT) and activating protein 1 (AP-1) by oncogenic 70Z Cbl requires an intact phosphotyrosine binding domain but not Crk(L) or p85 phosphatidylinositol S-kinase association SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TYROSINE-PHOSPHORYLATED CBL; OF-FUNCTION MUTATION; PROTOONCOGENE C-CBL; EGF RECEPTOR; V-CBL; BCR-ABL; CELLS; CRKL; C3G; TRANSFORMATION AB The Cbl proto-oncogene product is a complex adapter protein that functions as a negative regulator of protein tyrosine kinases. It is rapidly tyrosine-phosphorylated and associates with Crk(L) and p85 phosphatidylinositol 3-kinase (PI3K) upon engagement of numerous receptors linked to tyrosine kinases. Elucidation of the mechanism(s) underlying Cbl deregulation is therefore of considerable interest. The 70Z Cbl oncoprotein shows increased baseline tyrosine phosphorylation in fibroblasts and enhances nuclear factor of activated T cells (NFAT) activity in Jurkat T cells. Its transforming ability has been proposed to relate to its increased phosphotyrosine content. We demonstrate that 70Z Cbl shows increased basal and activation-induced tyrosine phosphorylation and association with Crk(L) and p85 PI3K in Jurkat T cells. 70Z Cbl, however, retains the ability to enhance NFAT and activating protein 1 (AP1) activity in the absence of Crk(L)/p85 PI3K association. In contrast, the G306E mutation, which inactivates the phosphotyrosine binding domain of CM, blocks NFAT/AP1 activation by 70Z Cbl. We conclude that 70Z Cbl-induced NFAT/AP1 activation requires the phosphotyrosine binding domain but not Crk(L)/p85 PI3K association. We hypothesize that 70Z Cbl acts as a dominant negative by blocking the negative regulatory function of the Cbl phosphotyrosine binding domain on protein-tyrosine kinases. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP van Leeuwen, JEM (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM vanleeuj@box-v.nih.gov RI van Leeuwen, Jeroen/G-3555-2010 NR 41 TC 26 Z9 26 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 FEB 19 PY 1999 VL 274 IS 8 BP 5153 EP 5162 DI 10.1074/jbc.274.8.5153 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 168NB UT WOS:000078698200090 PM 9988765 ER PT J AU Shworak, NW Liu, JA Petros, LM Zhang, LJ Kobayashi, M Copeland, NG Jenkins, NA Rosenberg, RD AF Shworak, NW Liu, JA Petros, LM Zhang, LJ Kobayashi, M Copeland, NG Jenkins, NA Rosenberg, RD TI Multiple isoforms of heparan sulfate D-glucosaminyl 3-O-sulfotransferase - Isolation, characterization, and expression of human cDNAs and identification of distinct genomic loci SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID N-DEACETYLASE/N-SULFOTRANSFERASE; INTEGRATED MOLECULAR ANALYSIS; GENE CONVERSION; MESSENGER-RNA; CELL-LINE; CLONING; MOUSE; SEQUENCE; PROTEIN; BINDING AB 3-O-Sulfated glucosaminyl residues are rare constituents of heparan sulfate and are essential for the activity of anticoagulant heparan sulfate. Cellular production of the critical active structure is controlled by the rate-limiting enzyme, heparan sulfate D-glucosaminyl 3-O-sulfotransferase-1 (3-OST-1) (EC 2.8.2.23). We have probed the expressed sequence tag data base with the carboxyl-terminal sulfotransferase domain of 3-OST-1 to reveal three novel, incomplete human cDNAs. These were utilized in library screens to isolate full-length cDNAs. Clones corresponding to predominant transcripts were obtained for the 367-, 406-, and 390-amino acid enzymes 3-OST-2, 3-OST-3(A), and 3-OST-3(B), respectively. These type II integral membrane proteins are comprised of a divergent amino-terminal region and a very homologous carboxyl-terminal sulfotransferase domain of similar to 260 residues. Also recovered were partial length clones for 3-OST-4. Expression of the full-length enzymes confirms the 3-O-sulfation of specific glucosaminyl residues within heparan sulfate (Liu, J., Shworak, N. W., Sinay, P., Schwartz, J. J. Zhang, L., Fritze, L. M. S., and Rosenberg, R. D. (1999) J. Biol. Chem. 274, 5185-5192). Southern analyses suggest the human 3OST1, 3OST2, and 3OST4 genes, and the corresponding mouse isologs, are single copy. However, 3OST3A and 3OST3B genes are each duplicated in humans and show at least one copy each in mice. Intriguingly, the entire sulfotransferase domain sequence of the 3-OST-3(B) cDNA (774 base pairs) was 99.2% identical to the same region of 3-OST-3(A). Together, these data argue that the structure of this functionally important region is actively maintained by gene conversion between 3OST3A and 3OST3B loci. Interspecific mouse back-cross analysis identified the loci for mouse 3Ost genes and syntenic assignments of corresponding human isologs were confirmed by the identification of mapped sequence-tagged site markers, Northern blot analyses indicate brain exclusive and brain predominant expression of 3-OST-4 and 3-OST-2 transcripts, respectively; whereas, 3-OST-3(A) and 3-OST-3(B) isoforms show widespread expression of multiple transcripts. The reiteration and conservation of the 3-OST sulfotransferase domain suggest that this structure is a self-contained functional unit. Moreover, the extensive number of 3OST genes with diverse expression patterns of multiple transcripts suggests that the novel 3-OST enzymes, like 3-OST-1, regulate important biologic properties of heparan sulfate proteoglycans. C1 MIT, Dept Biol, Cambridge, MA 02139 USA. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med, Boston, MA 02215 USA. NCI, Mammalian Genet Lab, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Shworak, NW (reprint author), Beth Israel Deaconess Med Ctr, Angiogenesis Res Ctr, SL-418,330 Brookline Ave, Boston, MA 02215 USA. EM nshworak@caregroup.harvard.edu FU NHLBI NIH HHS [5-PO1-HL-41484] NR 64 TC 156 Z9 165 U1 1 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 19 PY 1999 VL 274 IS 8 BP 5170 EP 5184 DI 10.1074/jbc.274.8.5170 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 168NB UT WOS:000078698200092 PM 9988767 ER PT J AU Rajeswaran, WG Labroo, RB Cohen, LA King, MM AF Rajeswaran, WG Labroo, RB Cohen, LA King, MM TI Synthesis of 5-[(indol-2-on-3-yl)methyl]-2,2-dimethyl-1,3-dioxane-4,6-diones and spirocyclopropyloxindole derivatives. Potential aldose reductase inhibitors SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID DIABETIC COMPLICATIONS; ACIDS C1 NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. George Washington Univ, Dept Chem, Washington, DC 20052 USA. RP Rajeswaran, WG (reprint author), Tulane Univ, Med Ctr, Dept Med, Peptide Res Labs SL12, 1430 Tulane Ave, New Orleans, LA 70112 USA. NR 16 TC 77 Z9 79 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD FEB 19 PY 1999 VL 64 IS 4 BP 1369 EP 1371 DI 10.1021/jo981673r PG 3 WC Chemistry, Organic SC Chemistry GA 170UV UT WOS:000078826200052 ER PT J AU Zhang, SR Varma, A Williamson, PR AF Zhang, SR Varma, A Williamson, PR TI The yeast Cryptococcus neoformans uses 'mammalian' enhancer sites in the regulation of the virulence gene, CNLAC1 SO GENE LA English DT Article DE virulence; regulation; transcription; cryptococcosis; laccase; AIDS ID SACCHAROMYCES-CEREVISIAE; STIMULATE TRANSCRIPTION; ACTIVATION DOMAINS; PROMOTER; LACCASE; SP1; DNA; PHENOLOXIDASE; EXPRESSION; MUTANTS AB Transcriptional regulation in mammalian and plant cells is distinguished from fungi by the presence of blocks of multiple interacting DNA binding sites distributed over a relatively large upstream region of genes and the ability to use glutamine-rich enhancers such as Spl. We offer evidence that the haploid yeast Cryptococcus neoformans contains a virulence gene, CNLAC1, having regulatory properties more similar to mammalian systems than to that of yeast. We used a novel promoter plasmid, pVEW, and electromobility shift assay techniques adapted for the fungus for the first systematic structural and functional study of a 5'-enhancer region of a basidiomycete fungus using the upstream region of CNLAC1. Two groups of interactive enhancer regions, located over a range of 1.5 kb from the mRNA start site are involved in CNLAC1 regulation (region 2: -1721 to -1615 and region 7) in addition to a TATA promoter at position -539. Region 2 contains a consensus Spl site and region 7 contains a consensus E2F site, each of which shows significant binding to nuclear proteins under derepressed conditions; cooperative binding was also suggested between DNA-binding protein of these sites and those binding nearby CCAAT sequences in each region. Two regions of repression were also evident under derepressed conditions (region 5: -1351 to -1207 and region 8: -991 to -971). Identification of functional Spl binding sites and the presence of multiple interactive enhancer sites over a fairly large upstream range suggests that cryptococcal transcriptional regulation contains features often associated with higher eukaryotic regulation. C. neoformans thus may provide a unique system for the study of certain aspects of higher eukaryotic transcription, using yeast genetic approaches. In addition, properties of basidiomycete yeast such as Cryptococcus exemplified in the present study suggest an evolutionary progression in gene regulation within fungi toward properties exhibited in the kingdoms Animalia and Plantae. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Univ Illinois, Med Ctr, Infect Dis Sect, Chicago, IL 60612 USA. NIAID, Mol Microbiol Sect, Clin Invest Lab, Bethesda, MD 20892 USA. RP Williamson, PR (reprint author), Univ Illinois, Med Ctr, Infect Dis Sect, Chicago, IL 60612 USA. FU NIAID NIH HHS [AI38258] NR 38 TC 27 Z9 29 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD FEB 18 PY 1999 VL 227 IS 2 BP 231 EP 240 DI 10.1016/S0378-1119(98)00590-3 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 171ZF UT WOS:000078894300013 PM 10023069 ER PT J AU Reid, SNM Akhmedov, NB Piriev, NI Kozak, CA Danciger, M Farber, DB AF Reid, SNM Akhmedov, NB Piriev, NI Kozak, CA Danciger, M Farber, DB TI The mouse X-linked juvenile retinoschisis cDNA: expression in photoreceptors SO GENE LA English DT Article DE retinal degeneration; gene expression; genetic disease; intercellular adhesion molecules; Muller cell ID DICTYOSTELIUM-DISCOIDEUM; FACTOR-VIII; RD MOUSE; RECEPTOR; CLONING; GENE; IDENTIFICATION; CANDIDATE; DOMAIN; ADHESION AB Retinal photoreceptor cells are particularly vulnerable to degenerations that can eventually lead to blindness. Our purpose is to identify and characterize genes expressed specifically in photoreceptors in order to increase our understanding of the biochemistry and function of these cells, and then to use these genes as candidates for the sites of mutations responsible for degenerative retinal diseases. We have characterized a cDNA, a fragment of which (SR3.1) was originally isolated by subtractive hybridization of adult, photoreceptorless rd mouse retinal cDNAs from the cDNAs of normal mouse retina. The full-length sequence of this cDNA was determined from clones obtained by screening mouse retinal and eye cDNA libraries and by using the 5'- and 3'-RACE methods. Both Northern blot analysis and in situ hybridization showed that the corresponding mRNA is expressed in rod and cone photoreceptors. The gene encoding this cDNA was mapped to the X chromosome using an interspecific cross. Based on the nucleotide and amino acid sequences, as well as chromosome mapping, we determined that this gene is the mouse ortholog (Xlrs1) of the human X-linked juvenile retinoschisis gene (XLRS1). Analysis of the predicted amino acid sequence indicates that the Xlrs1 mRNA may encode a secretable, adhesion protein. Therefore, our data suggest that X-linked juvenile retinoschisis originates from abnormalities in a photoreceptor-derived adhesion protein. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Univ Calif Los Angeles, Sch Med, Jules Stein Eye Inst, Los Angeles, CA 90095 USA. NIAID, Bethesda, MD 20892 USA. Loyola Marymount Univ, Los Angeles, CA 90045 USA. Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. RP Reid, SNM (reprint author), Univ Calif Los Angeles, Sch Med, Jules Stein Eye Inst, Los Angeles, CA 90095 USA. EM reiddrs@aol.com FU NEI NIH HHS [EY08285] NR 30 TC 53 Z9 55 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD FEB 18 PY 1999 VL 227 IS 2 BP 257 EP 266 DI 10.1016/S0378-1119(98)00578-2 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 171ZF UT WOS:000078894300016 PM 10023077 ER PT J AU Kubota, S Copeland, TD Pomerantz, RJ AF Kubota, S Copeland, TD Pomerantz, RJ TI Nuclear and nucleolar targeting of human ribosomal protein S25: Common features shared with HIV-1 regulatory proteins SO ONCOGENE LA English DT Article DE ribosome; protein; nuclear targeting; rev; HIV-1 ID IMMUNODEFICIENCY-VIRUS TYPE-1; REV TRANS-ACTIVATOR; GENE-EXPRESSION; MESSENGER-RNA; POSTTRANSCRIPTIONAL REGULATION; FUNCTIONAL-ANALYSIS; VISNA VIRUS; I REX; LOCALIZATION; SEQUENCE AB The nuclear and nucleolar targeting properties of human ribosomal protein S25 (RPS25) were analysed by the expression of epitope-tagged RPS25 cDNAs in Cos-l cells. The tagged RPS25 was localized to the cell nucleus, with a strong predominance in the nucleolus. At the amino terminus of RPS25, two stretches of highly basic residues juxtapose. This configuration shares common features with the nucleolar targeting signals (NOS) of lentiviral RNA-binding transactivators, including human immunodeficiency viruses' (HIV) Rev proteins. Deletion and site-directed mutational analyses demonstrated that the first NOS-like stretch is dispensable for both nuclear and nucleolar localization of RPS25, and that the nuclear targeting signal is located within the second NOS-like stretch. It has also been suggested that a set of continuous basic residues and the total number of basic residues should be required for nucleolar targeting. Signal-mediated nuclear/nucleolar targeting was further characterized by the construction and expression of a variety of chimeric constructs, utilizing three different backbones with RPS25 cDNA fragments. Immunofluorescence analyses demonstrated a 17 residue peptide of RPS25 as a potential nuclear/nucleolar targeting signal. The identified peptide signal may belong to a putative subclass of NOS, characterized by compact structure, together with lentiviral RNA binding transactivators. C1 Thomas Jefferson Univ, Jefferson Med Coll, Dept Med,Dorrance H Hamilton Labs, Div Infect Dis,Ctr Human Virol, Philadelphia, PA 19107 USA. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Ft Detrick, MD 21702 USA. RP Pomerantz, RJ (reprint author), Thomas Jefferson Univ, Jefferson Med Coll, Dept Med,Dorrance H Hamilton Labs, Div Infect Dis,Ctr Human Virol, Philadelphia, PA 19107 USA. FU NIAID NIH HHS [AI36552] NR 51 TC 32 Z9 33 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 18 PY 1999 VL 18 IS 7 BP 1503 EP 1514 DI 10.1038/sj.onc.1202429 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 167UK UT WOS:000078651600012 PM 10050887 ER PT J AU Koenig, BW Hu, JS Ottiger, M Bose, S Hendler, RW Bax, A AF Koenig, BW Hu, JS Ottiger, M Bose, S Hendler, RW Bax, A TI NMR measurement of dipolar couplings in proteins aligned by transient binding to purple membrane fragments SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID X-RAY-DIFFRACTION C1 NIDDKD, Phys Chem Lab, Cell Biol Lab, Natl Heat Lung & Blood Inst,NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDKD, Phys Chem Lab, Cell Biol Lab, Natl Heat Lung & Blood Inst,NIH, Bethesda, MD 20892 USA. RI Koenig, Bernd/B-4315-2008 OI Koenig, Bernd/0000-0002-5300-6276 NR 18 TC 98 Z9 99 U1 0 U2 2 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 FEB 17 PY 1999 VL 121 IS 6 BP 1385 EP 1386 DI 10.1021/ja9837856 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 168CY UT WOS:000078674500034 ER PT J AU Dorgan, JF Longcope, C Stanczyk, FZ Stephenson, HE Hoover, RN AF Dorgan, JF Longcope, C Stanczyk, FZ Stephenson, HE Hoover, RN TI Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID SULFATE C1 NCI, Div Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Univ Massachusetts, Sch Med, Dept Obstet & Gynecol, Worcester, MA USA. Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. Univ So Calif, Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90033 USA. Univ Missouri, Hlth Sci Ctr, Dept Surg, Columbia, MO USA. RP Dorgan, JF (reprint author), NCI, Div Epidemiol & Genet, NIH, Execut Plaza S,Rm 7082, Bethesda, MD 20892 USA. NR 5 TC 14 Z9 14 U1 0 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 FEB 17 PY 1999 VL 91 IS 4 BP 380 EP 381 DI 10.1093/jnci/91.4.380 PG 2 WC Oncology SC Oncology GA 168DG UT WOS:000078675400019 PM 10050873 ER PT J AU Cong, LN Chen, H Li, YH Lin, CH Sap, J Quon, MJ AF Cong, LN Chen, H Li, YH Lin, CH Sap, J Quon, MJ TI Overexpression of protein tyrosine phosphatase-alpha (PTP-alpha) but not PTP-kappa inhibits translocation of GLUT4 in rat adipose cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID INSULIN-STIMULATED TRANSLOCATION; INTACT-CELLS; KINETIC-ANALYSIS; RPTP-ALPHA; RECEPTOR; EXPRESSION; ASSOCIATION; FAMILY; ADAPTER; CLONING AB Protein tyrosine phosphatases (PTPases) are likely to play important roles in insulin action. We recently demonstrated that the nontransmembrane PTPase PTP1B can act as a negative modulator of insulin-stimulated translocation of GLUT4. We now examine the role of PTP-alpha and PTP-kappa (two transmembrane PTPases) in this metabolic action of insulin. Rat adipose cells were transfected with either PTP-alpha or PTP-kappa and effects of these PTPases on the translocation of a cotransfected epitope-tagged GLUT4 were studied. Cells overexpressing wild-type PTP-alpha had significantly lower levels of cell surface GLUT4 in response to insulin and a threefold decrease in insulin sensitivity when compared with control cells expressing only tagged GLUT4. Co-overexpression of PTP-alpha and PTP1B did not have additive effects, suggesting that these PTPases share common substrate. Cells overexpressing either wild-type PTP-kappa or catalytically inactive mutants of PTP-alpha had dose-response curves similar to those of control cells. Since overexpression of PTP-alpha, but not PTP-kappa, had effects on translocation of GLUT4, our data suggest that PTP alpha may be a specific negative modulator of insulin-stimulated glucose transport. (C) 1999 Academic Press. C1 NHLBI, Hypertens Endocrine Branch, NIH, Bethesda, MD 20892 USA. NYU, Dept Pharmacol, Med Ctr, New York, NY 10016 USA. RP Quon, MJ (reprint author), NHLBI, Hypertens Endocrine Branch, NIH, Bldg 10,Room 8C-103,10 Ctr Dr MSC 1754, Bethesda, MD 20892 USA. RI Quon, Michael/B-1970-2008; OI Quon, Michael/0000-0002-9601-9915 NR 40 TC 27 Z9 30 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 FEB 16 PY 1999 VL 255 IS 2 BP 200 EP 207 DI 10.1006/bbrc.1999.0183 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 170UT UT WOS:000078826000003 PM 10049686 ER PT J AU Doanes, AM Hegland, DD Sethi, R Kovesdi, I Bruder, JT Finkel, T AF Doanes, AM Hegland, DD Sethi, R Kovesdi, I Bruder, JT Finkel, T TI VEGF stimulates MAPK through a pathway that is unique for receptor tyrosine kinases SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; ACTIVATED PROTEIN-KINASE; CELLS; RAF AB We demonstrate that stimulation of primary cultures of endothelial cells with vascular endothelial cell growth factor (VEGF) results in a rapid increase in labeled guanine nucleotide bound to p21ras. Surprisingly, although VEGF stimulates ras activity, adenoviral-mediated gene transfer of a dominant negative form of ras (N17ras) had no effect on VEGF-stimulated mitogen-activated protein kinase (MAPK) activity. In contrast, treatment of endothelial cells with two structurally unrelated inhibitors of protein kinase C (PKC) abrogated VEGF-stimulated MAPK activity. In addition, inhibition of ras-Raf interactions by expression of a truncated form of Raf containing only the ras binding domain blocked VEGF-stimulated MAPK activation. These results suggest that VEGF stimulation of MAPK in endothelial cells differs from the pathway used by other members of the receptor tyrosine kinase family. In contrast, analogous to certain G-coupled receptors, VEGF appears to activate MAPK through a PKC-dependent pathway that requires a stable ras-Raf interaction but is not inhibited by N17ras expression. (C) 1999 Academic Press. C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. Gen Vec Inc, Rockville, MD USA. RP Finkel, T (reprint author), NHLBI, Cardiol Branch, NIH, Bldg 10,7B-15,10 Ctr Dr, Bethesda, MD 20892 USA. NR 23 TC 73 Z9 74 U1 1 U2 6 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 FEB 16 PY 1999 VL 255 IS 2 BP 545 EP 548 DI 10.1006/bbrc.1999.0227 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 170UT UT WOS:000078826000062 PM 10049745 ER PT J AU Chen, XG Hamon, M Deng, ZM Centola, M Sood, R Taylor, K Kastner, DL Fischel-Ghodsian, N AF Chen, XG Hamon, M Deng, ZM Centola, M Sood, R Taylor, K Kastner, DL Fischel-Ghodsian, N TI Identification and characterization of a zinc finger gene (ZNF213) from 16p13.3 SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION LA English DT Article DE direct cDNA selection; Familial Mediterranean fever; zinc finger protein; gene structure and expression ID CANDIDATE REGION; BINDING DOMAINS; C-FOS; PROTEIN; TRANSCRIPTION; EXPRESSION; REPRESSION; SEQUENCES; SPERMATOGENESIS; DIFFERENTIATION AB During our search for the familial Mediterranean fever (FMF) gene, we identified by cDNA selection a 1.2 kb cDNA fragment representing a novel human gene that is expressed in a wide variety of tissues. This gene spans approx. 8.0 kb genomic DNA and has seven exons. Its 3' untranslated region contains a long tandem repeat that gives rise to a polymorphism with two alleles of approx. 1.1 kb and 1.0 kb, with the 1.1 kb allele in strong linkage disequilibrium with FMF in patients of different ethnic backgrounds. However, both genetic and mutational analyses have excluded this gene as the one responsible for FMF. The predicted 424 amino acid protein, designated ZNF213, contains three C2H2 zinc fingers, a Kruppel associated A box and a leucine rich motif (LeR domain/SCAN box), strongly suggestive of a transcription factor. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Cedars Sinai Med Ctr, Ctr Med Genet Birth Defects, Steven Spielberg Pediat Res Ctr, Ahmanson Dept Pediat, Los Angeles, CA 90048 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90048 USA. NIAMSD, Arthrit & Rheumatism Branch, Bethesda, MD 20892 USA. RP Fischel-Ghodsian, N (reprint author), Cedars Sinai Med Ctr, Ctr Med Genet Birth Defects, Steven Spielberg Pediat Res Ctr, Ahmanson Dept Pediat, 8700 Beverly Blvd, Los Angeles, CA 90048 USA. EM nfischel@xchg.peds.csmc.edu RI Hamon, Melanie/B-3501-2013 NR 41 TC 8 Z9 10 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4781 J9 BBA-GENE STRUCT EXPR JI Biochim. Biophys. Acta-Gene Struct. Expression PD FEB 16 PY 1999 VL 1444 IS 2 BP 218 EP 230 DI 10.1016/S0167-4781(98)00273-5 PG 13 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 173NJ UT WOS:000078986400006 PM 10023065 ER PT J AU Kristie, TM Vogel, JL Sears, AE AF Kristie, TM Vogel, JL Sears, AE TI Nuclear localization of the C1 factor (host cell factor) in sensory neurons correlates with reactivation of herpes simplex virus from latency SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TRANSCRIPTION FACTORS; TRIGEMINAL GANGLIA; GENE-EXPRESSION; PROTEIN HCF; FACTOR VP16; INDUCTION; TYPE-1; DNA; POLYPEPTIDES; INFECTION AB After a primary infection, herpes simplex virus is maintained in a latent state in neurons of sensory ganglia until complex stimuli reactivate viral lytic replication. Although the mechanisms governing reactivation from the latent state remain unknown, the regulated expression of the viral immediate early genes represents a critical point in this process. These genes are controlled by transcription enhancer complexes whose assembly requires and is coordinated by the cellular C1 factor (host cell factor). In contrast to other tissues, the C1 factor is not detected in the nuclei of sensory neurons. Experimental conditions that induce the reactivation of herpes simplex virus in mouse model systems result in rapid nuclear localization of the protein, indicating that the C1 factor is sequestered in these cells until reactivation signals induce a redistribution of the protein. The regulated localization suggests that C1 is a critical switch determinant of the viral lytic-latent cycle. C1 NIH, Viral Dis Lab, Bethesda, MD 20892 USA. Emory Univ, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. RP Kristie, TM (reprint author), NIH, Viral Dis Lab, Bldg 4-133,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Thomas_Kristie@nih.gov FU PHS HHS [A124009] NR 32 TC 73 Z9 78 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 FEB 16 PY 1999 VL 96 IS 4 BP 1229 EP 1233 DI 10.1073/pnas.96.4.1229 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 168ND UT WOS:000078698400014 PM 9990006 ER PT J AU Misquitta, L Paterson, BM AF Misquitta, L Paterson, BM TI Targeted disruption of gene function in Drosophila by RNA interference (RNA-i): A role for nautilus in embryonic somatic muscle formation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE myogenesis; founder cells ID SEX DETERMINATION GENE; MYOD FAMILY; CELLS; MYOGENESIS; NEURONS; EMBRYOGENESIS; DAUGHTERLESS; ABLATION; HOMOLOG; PROTEIN AB The expression of the MyoD gene homolog, nautilus (nau), in the Drosophila embryo defines a subset of mesodermal cells known as the muscle "pioneer" or "founder" cells. These cells are thought to establish the future muscle pattern in each hemisegment. Pounders appear to recruit fusion-competent mesodermal cells to establish a particular muscle fiber type. In support of this concept every somatic muscle in the embryo is associated with one or more nautilus-positive cells. However, because of the lack of known (isolated) nautilus mutations, no direct test of the founder cell hypothesis has been possible. We now have utilized toxin ablation and genetic interference by double-stranded RNA (RNA interference or RNA-i) to determine both the role of the nautilus-expressing cells and the nautilus gene, respectively, in embryonic muscle formation. In the absence of nautilus-expressing cells muscle formation is severely disrupted or absent. A similar phenotype is observed with the elimination of the nautilus gene product by genetic interference upon injection of nautilus double-stranded RNA. These results define a crucial role for nautilus in embryonic muscle formation. The application of RNA interference to a variety of known Drosophila mutations as controls gave phenotypes essentially indistinguishable from the original mutation. RNA-i provides a powerful approach for the targeted disruption of a given genetic function in Drosophila. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Paterson, BM (reprint author), NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NR 25 TC 254 Z9 278 U1 2 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 16 PY 1999 VL 96 IS 4 BP 1451 EP 1456 DI 10.1073/pnas.96.4.1451 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 168ND UT WOS:000078698400052 PM 9990044 ER PT J AU Edskes, HK Gray, VT Wickner, RB AF Edskes, HK Gray, VT Wickner, RB TI The [URE3] prion is an aggregated form of Ure2p that can be cured by overexpression of Ure2p fragments SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID YEAST SACCHAROMYCES-CEREVISIAE; SCRAPIE PRION; SHUTTLE VECTORS; SUP35 GENE; PROTEIN; PROPAGATION; PSI(+); PRP; IDENTIFICATION; DETERMINANT AB The [URE3] nonchromosomal genetic element is a prion of Ure2p, a regulator of nitrogen catabolism in Saccharomyces cerevisiae. Ure2p(1-65) is the prion domain of Ure2p, sufficient to propagate [URE3] in vivo. We show that full length Ure2p-green fluorescent protein (GFP) or a Ure2p(1-65)-GFP fusion protein is aggregated in cells carrying [URE3] but is evenly distributed in cells lacking the [URE3] prion. This indicates that [URE3] involves a self-propagating aggregation of Ure2p. Overexpression of Ure2p(1-65) induces the de novo appearance of [URE3] by 1,000-fold in a strain initially [ure-o], but cures [URE3] from a strain initially carrying the [URE3] prion. Overexpression of several other fragments of Ure2p or Ure2-GFP fusion proteins also efficiently cures the prion. We suggest that incorporation of fragments or fusion proteins into a putative [URE3] "crystal" of Ure2p poisons its propagation. C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP NIDDKD, Lab Biochem & Genet, NIH, Bldg 8,Room 225,8 Ctr Dr,MSC 0830, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov NR 42 TC 149 Z9 150 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 FEB 16 PY 1999 VL 96 IS 4 BP 1498 EP 1503 DI 10.1073/pnas.96.4.1498 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 168ND UT WOS:000078698400060 PM 9990052 ER PT J AU Podsypanina, K Ellenson, LH Nemes, A Gu, JG Tamura, M Yamada, KM Cordon-Cardo, C Catoretti, G Fisher, PE Parsons, R AF Podsypanina, K Ellenson, LH Nemes, A Gu, JG Tamura, M Yamada, KM Cordon-Cardo, C Catoretti, G Fisher, PE Parsons, R TI Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GERMINAL-CENTER FORMATION; TUMOR-SUPPRESSOR GENE; GERMLINE MUTATIONS; PROSTATE-CANCER; COWDENS-DISEASE; PTEN GENE; CELL; FREQUENT; BREAST; HYPERPLASIA AB Pten/Mmac1 +/- heterozygous mice exhibited neoplasms in multiple organs including the endometrium, liver, prostate, gastrointestinal tract, thyroid, and thymus. Loss of the wild-type allele was detected in neoplasms of the thymus and liver. Surprisingly, tumors of the gastrointestinal epithelium developed in association with gut lymphoid tissue. Tumors of the endometrium, thyroid, prostate, and liver were not associated with lymphoid tissue and appeared to be highly mitotic. In addition, these mice have nonneoplastic hyperplasia of lymph nodes that was caused by an inherited defect in apoptosis detected in B cells and macrophages. Examination of peripheral lymphoid tissue including lymphoid aggregates associated with polyps revealed that the normal organization of B and T cells was disrupted in heterozygous animals. Taken together, these data suggest that PTEN is a regulator of apoptosis and proliferation that behaves as a "landscaper" tumor suppressor in the gut and a "gatekeeper" tumor suppressor in other organs. C1 Columbia Univ Coll Phys & Surg, Dept Pathol, New York, NY 10032 USA. Columbia Univ Coll Phys & Surg, Dept Med, New York, NY 10032 USA. Columbia Univ Coll Phys & Surg, Howard Hughes Med Inst, New York, NY 10032 USA. Columbia Univ Coll Phys & Surg, Ctr Neurobiol & Behav, New York, NY 10032 USA. Cornell Univ, Sch Med, Dept Pathol, New York, NY 10021 USA. NIDR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. RP Parsons, R (reprint author), Columbia Univ Coll Phys & Surg, Dept Pathol, 630 W 168th St, New York, NY 10032 USA. OI Yamada, Kenneth/0000-0003-1512-6805; Cattoretti, Giorgio/0000-0003-3799-3221 NR 40 TC 661 Z9 681 U1 2 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 16 PY 1999 VL 96 IS 4 BP 1563 EP 1568 DI 10.1073/pnas.96.4.1563 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 168ND UT WOS:000078698400072 PM 9990064 ER PT J AU Longley, BJ Metcalfe, DD Tharp, M Wang, XM Tyrrell, L Lu, SZ Heitjan, D Ma, YS AF Longley, BJ Metcalfe, DD Tharp, M Wang, XM Tyrrell, L Lu, SZ Heitjan, D Ma, YS TI Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RECEPTOR TYROSINE KINASE; CELL GROWTH-FACTOR; LIGAND-INDEPENDENT ACTIVATION; PROTO-ONCOGENE; MELANOMA-CELLS; CONSTITUTIVE ACTIVATION; HUMAN PIEBALDISM; POINT MUTATION; W-LOCUS; PROTOONCOGENE AB Human mastocytosis is characterized by increased mast cells. It usually occurs as a sporadic disease that is often transient and limited in children and persistent or progressive in adults. The c-KIT protooncogene encodes KIT, a tyrosine kinase that is the receptor for mast cell growth factor. Because mutated KIT can transform cells, we examined c-KIT in skin lesions of 22 patients with sporadic mastocytosis and 3 patients with familial mastocytosis, All patients with adult sporadic mastocytosis had somatic c-KIT mutations in codon 816 causing substitution of valine for aspartate and spontaneous activation of mast cell growth factor receptor (P = 0.0001). A subset of four pediatric onset cases with clinically unusual disease also had codon 816 activating mutations substituting valine, tyrosine, or phenylalanine for aspartate, Typical pediatric patients lacked 816 mutations, but limited sequencing showed three of six had a novel dominant inactivating mutation substituting lysine for glutamic acid in position 839, the site of a potential salt bridge that is highly conserved in receptor tyrosine kinases. No c-KIT mutations were found in the entire coding region of three patients with familial mastocytosis, We conclude that c-KIT somatic mutations substituting valine in position 816 of KIT are characteristic of sporadic adult mastocytosis and may cause this disease. Similar mutations causing activation of the mast cell growth factor receptor are found in children apparently at risk for extensive or persistent disease. In contrast, typical pediatric mastocytosis patients lack these mutations and may express inactivating c-KIT mutations. Familial mastocytosis, however, may occur in the absence of c-KIT coding mutations. C1 Columbia Univ Coll Phys & Surg, Sect Dermatopathol, Dept Dermatol, New York, NY 10032 USA. Columbia Univ Coll Phys & Surg, Sect Dermatopathol, Dept Pathol, New York, NY 10032 USA. Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06510 USA. Yale Univ, Sch Med, Yale Skin Dis Res Ctr, New Haven, CT 06510 USA. NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. Rush Presbyterian St Lukes Med Ctr, Dept Dermatol, Chicago, IL 60612 USA. Columbia Univ, Herbert Irving Comprehens Ctr, Div Biostat, New York, NY 10032 USA. RP Longley, BJ (reprint author), Columbia Univ Coll Phys & Surg, Sect Dermatopathol, Dept Dermatol, 630 W 168th St, New York, NY 10032 USA. RI Heitjan, Daniel/D-1116-2009 FU NIAMS NIH HHS [R01 AR 43356-01A2, R01 AR043356] NR 36 TC 416 Z9 424 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 16 PY 1999 VL 96 IS 4 BP 1609 EP 1614 DI 10.1073/pnas.96.4.1609 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 168ND UT WOS:000078698400080 PM 9990072 ER PT J AU Patel, SC Suresh, S Kumar, U Hu, CY Cooney, A Blanchette-Mackie, EJ Neufeld, EB Patel, RC Brady, RO Patel, YC Pentchev, PG Ong, WY AF Patel, SC Suresh, S Kumar, U Hu, CY Cooney, A Blanchette-Mackie, EJ Neufeld, EB Patel, RC Brady, RO Patel, YC Pentchev, PG Ong, WY TI Localization of Niemann-Pick C1 protein in astrocytes: Implications for neuronal degeneration in Niemann-Pick type C disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; 3-HYDROXY-3-METHYLGLUTARYL-COENZYME-A REDUCTASE; CHOLESTEROL HOMEOSTASIS; STORAGE DISORDER; APOLIPOPROTEIN-D; NERVOUS-SYSTEM; BRAIN; IDENTIFICATION; DEGRADATION; RECEPTOR AB Niemann-Pick type C disease (NP-C) is an inherited neurovisceral lipid storage disorder characterized by progressive neurodegeneration, Most cases of NP C result from inactivating mutations of NPC1, a recently identified member of a family of genes encoding membrane-bound proteins containing putative sterol sensing domains. By using a specific antipeptide antibody to human NPC1, we have here investigated the cellular and subcellular localization and regulation of NPC1, By light and electron microscopic immunocytochemistry of monkey brain, NPC1 was expressed predominantly in perisynaptic astrocytic glial processes. At a subcellular level, NPC1 localized to vesicles with the morphological characteristics of lysosomes and to sites near the plasma membrane. Analysis of the temporal and spatial pattern of neurodegeneration in the NP-C mouse, a spontaneous mutant model of human NP-C, by amino-cupric-silver staining, showed that the terminal fields of axons and dendrites are the earliest sites of degeneration that occur well before the appearance of a neurological phenotype. Western blots of cultured human fibroblasts and monkey brain homogenates revealed NPC1 as a 165-kDa protein. NPC1 levels in cultured fibroblasts were unchanged by incubation with low density lipoproteins or oxysterols but were increased 2- to 3-foId by the drugs progesterone and U-18666A, which block cholesterol transport out of lysosomes, and by the lysosomotropic agent NH4Cl. These studies show that NPC1 in brain is predominantly a glial protein present in astrocytic processes closely associated with nerve terminals, the earliest site of degeneration in NP-C, Given the vesicular localization of NPC1 and its proposed role in mediating retroendocytic trafficking of cholesterol and other lysosomal cargo, these results suggest that disruption of NPC1-mediated vesicular trafficking in astrocytes may be linked to neuronal degeneration in NP-C. C1 NINCDS, Dev & Metab Neurol Branch, Sect Cellular & Mol Pathophysiol, NIH, Bethesda, MD 20892 USA. NINCDS, Sect Lipid Cell Biol, NIH, Bethesda, MD 20892 USA. McGill Univ, Fraser Labs, Montreal, PQ H3A 1A1, Canada. Clarkson Univ, Dept Chem, Potsdam, NY 13676 USA. Natl Univ Singapore, Dept Anat, Singapore 119260, Singapore. RP Patel, SC (reprint author), Vet Adm Connecticut Healthcare Syst, Neurobiol Res Lab, 555 Willard Ave, Newington, CT 06111 USA. EM patel.shutish_c@west-haven.va.gov FU NINDS NIH HHS [NS32160, NS34339] NR 37 TC 131 Z9 134 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 16 PY 1999 VL 96 IS 4 BP 1657 EP 1662 DI 10.1073/pnas.96.4.1657 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 168ND UT WOS:000078698400088 PM 9990080 ER PT J AU Gomeza, J Shannon, H Kostenis, E Felder, C Zhang, L Brodkin, J Grinberg, A Sheng, H Wess, J AF Gomeza, J Shannon, H Kostenis, E Felder, C Zhang, L Brodkin, J Grinberg, A Sheng, H Wess, J TI Pronounced pharmacologic deficits in M2 muscarinic acetylcholine receptor knockout mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SUBTYPE-SPECIFIC ANTIBODIES; CHOLINERGIC RECEPTORS; BRAIN; RAT; ANTINOCICEPTION; LOCALIZATION; STRIATUM; PROTEINS; AGONISTS; ANTISERA AB Members of the muscarinic acetylcholine receptor family (M1-M5) are known to be involved in a great number of important central and peripheral physiological and pathophysiological processes. Because of the overlapping expression patterns of the M1-M5 muscarinic receptor subtypes and the lack of ligands endowed with sufficient subtype selectivity, the precise physiological functions of the individual receptor subtypes remain to be elucidated. To explore the physiological roles of the M2 muscarinic receptor, we have generated mice lacking functional M2 receptors bg using targeted mutagenesis in mouse embryonic stem cells. The resulting mutant mice were analyzed in several behavioral and pharmacologic tests. These studies showed that the M2 muscarinic receptor subtype, besides its well documented involvement in the regulation of heart rate, plays a key role in mediating muscarinic receptor-dependent movement and temperature control as well as antinoeiceptive responses, three of the most prominent central muscarinic effects, These results offer a rational basis for the development of novel muscarinic drugs. C1 NIDDKD, Bioorgan Chem Lab, Bethesda, MD 20892 USA. Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. NICHHD, Lab Mammalian Genes & Dev, Bethesda, MD 20892 USA. RP Wess, J (reprint author), NIDDKD, Bioorgan Chem Lab, Bldg 8A,Room B1A-05, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov NR 38 TC 255 Z9 267 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 16 PY 1999 VL 96 IS 4 BP 1692 EP 1697 DI 10.1073/pnas.96.4.1692 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 168ND UT WOS:000078698400094 PM 9990086 ER PT J CA Natl Ctr Sleep Disorders Res Working Grp TI Recognizing problem sleepiness in your patients SO AMERICAN FAMILY PHYSICIAN LA English DT Article ID CONGESTIVE-HEART-FAILURE; PERIODIC LIMB MOVEMENTS; DAYTIME SLEEPINESS; INDIVIDUAL-DIFFERENCES; DISTURBANCES; PERFORMANCE; APNEA; MANAGEMENT; COMMUNITY; INSOMNIA AB Normal sleep is required for optimal functioning. Normal wakefulness should be effortless and free of unintended sleep episodes. Problem sleepiness is common and occurs when the quantity of sleep is inadequate because of primary steep disorders, other medical conditions or lifestyle factors. Medications and substances that disturb sleep, such as caffeine and nicotine, or those that have sedating side effects, may also cause problem sleepiness. This condition can lead to impairment in attention, performance problems at work and school, and potentially dangerous situations when the patient is driving or undertaking other safety-sensitive tasks. However, problem sleepiness is generally correctable when it is recognized. Asking a patient and his or her bed partner about the likelihood of drowsiness or of falling asleep during specific activities, as well as question; that uncover factors contributing to the sleepiness, helps the physician to recognize the disorder. Accurate diagnosis of specific sleep disorders may require evaluation by a specialist. The primary care physician is in an ideal position to identify signs and symptoms of problem sleepiness and initiate appropriate care of the patient, including educating the patient about the dangers of functioning while impaired by sleepiness. C1 Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Unit Expt Psychiat, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Div Sleep & Chronobiol, Philadelphia, PA 19104 USA. Walla Walla Clin, Walla Walla, WA USA. Mayo Clin Jacksonville, Dept Psychiat & Psychol, Jacksonville, FL 32224 USA. Mayo Clin Jacksonville, Sleep Disorders Ctr, Jacksonville, FL 32224 USA. Miriam Hosp, Sleep Physiol Lab, Providence, RI 02906 USA. Brown Univ, Sch Med, Providence, RI 02912 USA. Childrens Mem Hosp, Sleep Med Ctr, Div Pulm & Crit Care Med, Chicago, IL 60614 USA. Eastern Virginia Med Sch, Norfolk, VA 23501 USA. Sentara Norfolk Gen Hosp, Norfolk, VA USA. NHLBI, Natl Ctr Sleep Disorders Res, NIH, Bethesda, MD 20892 USA. NR 61 TC 0 Z9 0 U1 0 U2 0 PU AMER ACAD FAMILY PHYSICIANS PI KANSAS CITY PA 8880 WARD PARKWAY, KANSAS CITY, MO 64114-2797 USA SN 0002-838X EI 1532-0650 J9 AM FAM PHYSICIAN JI Am. Fam. Physician PD FEB 15 PY 1999 VL 59 IS 4 BP 937 EP 944 PG 8 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 170MQ UT WOS:000078809800020 ER PT J AU Shawl, FA Domanski, MJ Kaul, U Dougherty, KG Hoff, S Rigali, GE Cornell, SL Shahab, ST AF Shawl, FA Domanski, MJ Kaul, U Dougherty, KG Hoff, S Rigali, GE Cornell, SL Shahab, ST TI Procedural results and early clinical outcome of percutaneous transluminal myocardial revascularization SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID TRANSMYOCARDIAL LASER REVASCULARIZATION; CHANNELS AB A substantial number of patients present with medically refractory angina who are not candidates for angio plasty or bypass surgery. The creation of channels between the myocardium and the ventricular blood pool has been performed after thoracatomy with excellent relief of symptoms but has been associated with high perioperative mortality. We investigated the safety of a nonoperative, percutaneous technique for channel creation. Twenty-seven patients with angina and coronary anatomy not amenable to revascularization with coronary angioplasty or bypass surgery underwent percutaneous transluminal myocardial revascularization (PTMR), Energy from a Holmium:yttrium-aluminum-garnet (YAG) laser was directed through a fiber enclosed in a catheter to the ventricular myocardium creating channels between the blood pool and the myocardium, On average, 17 +/- 4 channels were formed per patient, There were no procedure-related deaths, episodes of tamponade, or other complications except for an increase in creatine phosphokinase in 1 patient. Immediately after the procedure, there was no worsening of regional wall motion function in any patient, but rather improvement in some. All patients were discharged alive after a hospital stay of 1.8 +/- 1.5 days. Mean Canadian Cardiovascular Society functional class declined from 3.6 +/- 0.5 before the procedure to 0.65 +/- 0.8 at 30 days after the procedure (p <0.01). For 12 patients eligible for 6-month follow-vp, mean functional class was 0.94 +/- 0.97. At 6-month stress testing, 9 of these 12 had no electrocardiographic evidence of ischemia. Thus, PTMR can be performed safely in the cardiac catheterization laboratory with a complication rate lower than that reported in surgical series and with excellent near-term symptomatic relief. The long-term effect of PTMR on mortality and relief of angina as well as its safety and effectiveness compared with the surgical approach remains to be defined. (C) 1999 by Excerpta Medica, Inc. C1 Washington Adventist Hosp, Dept Intervent Cardiol, Takoma Pk, MD 20912 USA. NHLBI, Bethesda, MD 20892 USA. RP Shawl, FA (reprint author), Washington Adventist Hosp, Dept Intervent Cardiol, 7600 Carroll Ave, Takoma Pk, MD 20912 USA. NR 17 TC 24 Z9 24 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 245 WEST 17TH STREET, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD FEB 15 PY 1999 VL 83 IS 4 BP 498 EP 501 DI 10.1016/S0002-9149(98)00902-3 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 166JV UT WOS:000078573200005 PM 10073850 ER PT J AU Egan, DA Garg, R Wilt, TJ Pettinger, MB Davis, KB Crouse, J Herd, JA Hunninghake, DB Sheps, DS Kostis, JB Probstfield, J Waclawiw, MA Applegate, W Elam, MB AF Egan, DA Garg, R Wilt, TJ Pettinger, MB Davis, KB Crouse, J Herd, JA Hunninghake, DB Sheps, DS Kostis, JB Probstfield, J Waclawiw, MA Applegate, W Elam, MB TI Rationale and design of the arterial disease multiple intervention trial (ADMIT) pilot study SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID PERIPHERAL VASCULAR-DISEASE; RANDOMIZED TRIAL; CARDIOVASCULAR-DISEASE; VITAMIN-C; ASPIRIN; LIPOPROTEIN; RISK; MEN; ANTIOXIDANTS; PREVENTION AB The primary objectives of the pilot study were to: (1) evaluate the feasibility of recruiting patients with peripheral arterial disease (PAD); (2) measure the efficacy and safety of high-density lipoprotein (HDL)-raising treatment, low-density lipoprotein (LDL)-lowering therapy, antioxidant therapy, antithrombotic therapy, and their combinations; and (3) assess adherence to a complex multiple drug regimen. Secondary objectives included measurement of the effect of the interventions on prespecified biochemical markers, maintenance of therapy masking (in particular with niacin), and measurement of the intervention's impact on functional status and on quality of life. To date, no secondary prevention trial has been conducted specifically among patients with PAD. Intermittent claudication affects about 0.5% to 1.0% of persons aged >35 years. There is a striking increase in incidence of PAD with age, particularly among those aged >50 years in bath sexes, although men are twice as likely as women to develop PAD. The Arterial Disease Multiple Intervention Trial was a double-blind randomized pilot trial of 458 participants with documented PAD. A 2 x 2 x 2 factorial design was used to evaluate the effect of 3 interventions. The pilot incorporated several major novel design features: first, the use of a simple noninvasive method (measurement of ankle brachial index) to identify a population with either symptomatic or asymptomatic PAD; and second, a lipid modifying strategy to increase HDL with nicotinic acid in the intervention group while lowering LDL levels equally with an hydroxymethylglutaryl-coenzyme A reductase inhibitor as needed in the intervention and control group. Two other arms, the antioxidant arm (consisting of beta-carotene and vitamins E and C) and the antithrombotic arm (using warfarin) were also added. Adherence to therapy was measured by pill count, and success in treatment was measured by the proportion of values in target range for HDL, LDL, and the international normalized ratio. (C) 1999 by Excerpta Medica, Inc. C1 NHLBI, Div Epidemiol & Clin Applicat, Clin Trials Sci Res Grp, Bethesda, MD 20892 USA. Eli Lilly & Co, Indianapolis, IN 46285 USA. Minneapolis VAMC, Minneapolis, MN USA. Stat & Epidemiol Res Corp, Seattle, WA USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. Baylor Univ, Houston, TX 77030 USA. Univ Minnesota, Minneapolis, MN 55455 USA. Univ N Carolina, Chapel Hill, NC 27515 USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, New Brunswick, NJ USA. Univ Washington, Seattle, WA 98195 USA. Univ Tennessee, Memphis, TN USA. RP Egan, DA (reprint author), NHLBI, Div Epidemiol & Clin Applicat, Clin Trials Sci Res Grp, Rockledge Bldg 2,6701 Rockledge Dr,Room 8142, Bethesda, MD 20892 USA. NR 28 TC 16 Z9 17 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 245 WEST 17TH STREET, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD FEB 15 PY 1999 VL 83 IS 4 BP 569 EP 575 DI 10.1016/S0002-9149(98)00915-1 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 166JV UT WOS:000078573200018 PM 10073863 ER PT J AU Fabsitz, RR Sidawy, AN Go, O Lee, ET Welty, TK Devereux, RB Howard, BV AF Fabsitz, RR Sidawy, AN Go, O Lee, ET Welty, TK Devereux, RB Howard, BV TI Prevalence of peripheral arterial disease and associated risk factors in American Indians - The Strong Heart Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE albuminuria; arterial occlusive diseases; atherosclerosis; blood pressure; diabetes mellitus; fibrinogen; Indians; North American; smoking ID ANKLE-BRACHIAL INDEX; INTERMITTENT CLAUDICATION; EDINBURGH ARTERY; VASCULAR-DISEASE; CARDIOVASCULAR-DISEASE; DEFINED POPULATION; BLOOD-PRESSURE; ATHEROSCLEROSIS; MORTALITY; WOMEN AB Studies of peripheral arterial disease (PAD) in minority populations provide researchers with an opportunity to evaluate PAD risk factors and disease severity under different types of conditions. Examination 1 of the Strong Heart Study (1989-1992) provided data on the prevalence of PAD and its risk factors in a sample of American Indians. Participants (N = 4,549) represented 13 tribes located in three geographically diverse centers in the Dakotas, Oklahoma, and Arizona. Participants in this epidemiologic study were aged 45-74 years; 60% were women. Using the single criterion of an ankle brachial index less than 0.9 to define PAD, the prevalence of PAD was approximately 5.3% across centers, with women having slightly higher rates than men. Factors significantly associated with PAD in univariate analyses for both men and women included age, systolic blood pressure, hemoglobin Ale level, albuminuria, fibrinogen level, fasting glucose level, prevalence of diabetes mellitus, and duration of diabetes. Multiple logistic regression analyses were used to predict PAD for women and men combined. Age, systolic blood pressure, current cigarette smoking, pack-years of smoking, albuminuria (micro and macro-), low density lipoprotein cholesterol level, and fibrinogen level were significantly positively associated with PAD, Current alcohol consumption was significantly negatively associated with PAD. In American Indians, the association of albuminuria with PAD may equal or exceed the association of cigarette smoking with PAD. C1 NHLBI, Bethesda, MD 20892 USA. Vet Affairs Med Ctr, Washington, DC 20422 USA. Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. Aberdeen Area Tribal Chairmens Hlth Board, Aberdeen, Scotland. Cornell Univ, Med Ctr, Dept Med, Div Cardiol, New York, NY 10021 USA. Medlant Res Inst, Washington, DC USA. RP Fabsitz, RR (reprint author), 2 Rockledge Ctr, MSC 7934,6701 Rockledge Dr, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [HL41642, HL41652, HL41654] NR 44 TC 77 Z9 82 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 FEB 15 PY 1999 VL 149 IS 4 BP 330 EP 338 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 165ZL UT WOS:000078551700007 PM 10025475 ER PT J AU Nagata, K Ogino, M Shimada, M Miyata, M Gonzalez, FJ Yamazoe, Y AF Nagata, K Ogino, M Shimada, M Miyata, M Gonzalez, FJ Yamazoe, Y TI Structure and expression of the rat CYP3A1 gene: Isolation of the gene (P450/6 beta B) and characterization of the recombinant protein SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE CYP3A1 gene; structure; expression ID TESTOSTERONE 6-BETA-HYDROXYLASE; LIVER MICROSOMES; MESSENGER-RNAS; CDNA; CYTOCHROME-P-450; P450; FORM; DNA; CYTOCHROMES-P-450; RECONSTITUTION AB A P450 gene (P450/6 beta B) of the CYP3A subfamily was isolated from a rat genomic library. Nucleotide sequencing of the exons revealed a high similarity with P450PCN1 cDNA (Gonzalez ef al. (1985), J. Biol. Chem. 260, 7345-7441), but differed in 41 nucleotides, resulting in 11 changes and 2 deletions of amino acid residues. The P450/6 beta B spanned about 30 kbp and consisted of 13 exons, and was in exon number and size identical with CYP3A2 gene except in the 6th exon, which was shorter than that of CYP3A2, 6 beta-B mRNA, which may be transcribed from P450/6 beta B, was detected on Northern blotting and by reverse transcription-polymerase chain reaction (RT-PCR). Profiles of the developmental change and induction by a treatment with several chemicals were very similar to those of P450PCN1 mRNA reported previously, P450PCN1 mRNA and gene, however, were not detected by PCR in rats. To determine whether P450/6 beta B encodes an active protein, a cDNA was isolated and expressed, Expression of 6 beta-B cDNA in COS-1 cells was carried out and revealed that the recombinant protein comigrated with purified P450(6 beta-4) previously identified as CYP3A1. The recombinant 6 beta-B protein showed similar turnover rate and regioselectivity for testosterone with purified P450(6 beta-4) by the simultaneous addition of NADPH-cytochrome P450 reductase and cytochrome b(5). These data suggest that P450/6 beta B encodes an active P450 form corresponding to CYP3A1 and P450PCN1 reported previously does not exist in rats, (C) 1999 Academic Press. C1 Tohoku Univ, Fac Pharmaceut Sci, Div Drug Metab & Mol Toxicol, Aoba Ku, Sendai, Miyagi 9808578, Japan. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Nagata, K (reprint author), Tohoku Univ, Fac Pharmaceut Sci, Div Drug Metab & Mol Toxicol, Aoba Ku, Sendai, Miyagi 9808578, Japan. NR 25 TC 21 Z9 22 U1 2 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD FEB 15 PY 1999 VL 362 IS 2 BP 242 EP 253 DI 10.1006/abbi.1998.1030 PG 12 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 168DE UT WOS:000078675200008 PM 9989933 ER PT J AU Li, QD Tsang, B Bostick-Bruton, F Reed, E AF Li, QD Tsang, B Bostick-Bruton, F Reed, E TI Modulation of excision repair cross complementation group 1 (ERCC-1) mRNA expression by pharmacological agents in human ovarian carcinoma cells SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE cisplatin; ovarian cancer; ERCC-1; phorbol ester; cyclosporine; herbimycin A ID PIGMENTOSUM GROUP-F; CISPLATIN RESISTANCE; CYCLOSPORINE-A; DNA-REPAIR; C-JUN; GENE-EXPRESSION; CANCER-CELLS; ACTIVATION; LINES; PHOSPHORYLATION AB Excision repair cross complementation group 1 (ERCC-1) is a DNA repair gene that is essential for life, and it appears to be a marker gene for nucleotide excision repair activity. Overexpression of ERCC-1 during cisplatin based chemotherapy is associated with clinical and cellular drug resistance. We therefore began to assess the influence of various pharmacological agents on the induction of ERCC-1 mRNA in A2780/CP70 human ovarian carcinoma cells. Cisplatin exposure in culture resulted in a 4- to 6-fold induction for the steady-state level of ERCC-1 mRNA in A2780/CP70 cells. ERCC-1 mRNA induction was concentration and time dependent. Cyclosporin A and herbimycin A, which suppress c-fos and c-jun gene expressions, respectively, blocked the cisplatin-induced increase in ERCC-I mRNA. This effect of cyclosporin A or herbimycin A on the down-regulation of ERCC-I correlates with enhanced cytotoxicity of cisplatin in this system. The products of c-Jos and c-jun are components of the transcription factor AP-1 (activator protein 1). 12-O- Tetradecanoylphorbal 13 acetate (TPA), a known AP-1 agonist, induced ERCC-1 mRNA to the same extent as cisplatin, but did not synergize with cisplatin in this regard. The TPA effect was biphasic, with an initial increase during the first 1-6 hr, followed by decreasing mRNA levels at 24-72 hr. These data suggest that the effects of these pharmacological agents on ERCC-I gene expression may be mediated through the modulation of AP-1 activities. (C) 1999 Elsevier Science Inc. C1 NCI, Ovarian Canc Sect, Med Branch, NIH, Bethesda, MD 20892 USA. RP Reed, E (reprint author), NCI, Ovarian Canc Sect, Med Branch, NIH, Bldg 10,Room 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 45 TC 36 Z9 37 U1 0 U2 2 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 FEB 15 PY 1999 VL 57 IS 4 BP 347 EP 353 DI 10.1016/S0006-2952(98)00291-3 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 159XX UT WOS:000078201600003 PM 9933022 ER PT J AU Weinberger, DR AF Weinberger, DR TI Cell biology of the hippocampal formation in schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Review DE schizophrenia; hippocampus; gene expression; proteins ID MESSENGER-RNA LEVELS; ENTORHINAL CORTEX; ALZHEIMERS-DISEASE; MONOZYGOTIC TWINS; TEMPORAL-LOBE; BRAIN-DAMAGE; NEURONS; STRESS; POSTMORTEM; SIZE AB The hippocampal formation (HF) has been a centerpiece of neuropathologic investigations of schizophrenia. Numerous MRI studies have demonstrated a slight bilateral reduction in HF volume. Reports of reduced N-acetyl aspartate measured with in vivo proton spectroscopy suggest that neuronal pathology exists. However, morphometric data from postmortem studies have not revealed a clear change in HF size, and recent studies of neuronal number and of cytoarchitecture have been largely negative. Evidence of glial proliferation is consistently absent. The most reproducible positive anatomic finding in post-mortem HF has been reduced size of neuronal cell bodies. Studies of gene transcription have provided replicable evidence of decreased expression of mRNAs for synaptophysin, GAP-43, cholecystokinin, and non-NMDA glutamate receptor subunits (GLU R I and 2), particularly in CA 3-4. These data about the cellular and molecular biology of the HF in schizophrenia are different from that found in a number of conditions associated with hippocampal damage, including excitotoxicity, epilepsy, alcoholism, Alzheimer's disease, steroid neurotoxicity, and normal aging. Notwithstanding the real possibility that the data are epiphenomena of chronic illness, the findings may implicate a unique cellular defect in schizophrenia-a generic variation affecting the plasticity of HF circuitry and connectivity. Directions for further research are proposed. (C) 1999 Society of Biological Psychiatry. C1 NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Weinberger, DR (reprint author), NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bldg 10-4S237A,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 49 TC 242 Z9 248 U1 0 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 15 PY 1999 VL 45 IS 4 BP 395 EP 402 DI 10.1016/S0006-3223(98)00331-X PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 170LZ UT WOS:000078808300003 PM 10071707 ER PT J AU Yin, ZN Giacomello, E Gabriele, E Zardi, L Aota, S Yamada, KM Skerlavaji, B Doliana, R Colombatti, A Perris, R AF Yin, ZN Giacomello, E Gabriele, E Zardi, L Aota, S Yamada, KM Skerlavaji, B Doliana, R Colombatti, A Perris, R TI Cooperative activity of alpha 4 beta 1 and alpha 4 beta 7 integrins in mediating human B-cell lymphoma adhesion and chemotaxis on fibronectin through recognition of multiple synergizing binding sites within the central cell-binding domain SO BLOOD LA English DT Article ID III CONNECTING SEGMENT; PLASMA FIBRONECTIN; HEP-II; SEQUENCE; IDENTIFICATION; MOLECULE-1; ATTACHMENT; REGIONS; CS-1; LYMPHOCYTES AB We have quantitated the relative contributions of the constitutively active alpha 4 beta 1 and alpha 4 beta 7 integrins and the domains embodying their cognate binding sites in mediating human B-cell lymphoma adhesion and chemotaxis on fibronectin. By cooperating, the central cell-binding and IIICS carboxyterminal domains were entirely responsible for the adhesion activity displayed by fibronectin, and their relative contribution to this process was estimated to be 30% versus 70%. Assessment of the leukocyte-substrate binding strength (ie, dynes/cell) indicated a 10-fold higher avidity of the cell-IIICS domain interaction. The two integrins interchangeably recognized both domains, but differed quantitatively in their participation in the adhesive event, as well as in domain preference. The use of 3Fn (according to the nomenclature proposed by Bork and Koonin [Curr Opin Struct Biol 6:366, 1996] for the type III fibronectin modules) module-specific antibodies and recombinant polypeptides showed that alpha 4 integrins recognized both the RGD sequence (3Fn10) and an apparently novel synergistic site located within the 3Fn8 module; even in this case, the integrins displayed a distinct binding site preference. Interleukin-1 beta (IL-1 beta)/IL-2-induced chemotaxis also involved cooperative function of the central cell-binding and IIICS domains, but the mechanisms regulating this phenomenon differed markedly from those controlling cell adhesion. First, the relative contribution of the individual domains was comparable, but neither of the individual domains promoted migration to the extent observed on intact fibronectin. Secondly, alpha 4 beta 1and alpha 4 beta 7 integrins were both involved in the domain-binding necessary for initiation of migration, but the relative contribution of each receptor in the chemotactic process was less disparate than for initial cell adhesion. Thirdly, the mode by which chemotactic B-lymphoma movement was supported by the central cell-binding domain differed from that sustaining cell adhesion in that it involved independent recognition of either the 3Fn8 or the 3Fn9 module, which acted in synergy with the 3Fn10 module. Our data provide novel evidence concerning the relative importance of the constitutively active alpha 4 beta 1 and alpha 4 beta 7 integrins for the interaction of B-cell lymphoma cells with fibronectin, and they emphasize a multiple and diverse recognition of sites responsible for either anchorage or locomotion of tumor leukocytes on this matrix molecule. (C) 1999 by The American Society of Hematology. C1 Ist Nazl Ctr Europeo, Div Expt Oncol 2, Ctr Riferimento Oncol Aviano, I-33081 Aviano, PN, Italy. Univ Parma, Dept Evolutionary & Funct Biol, I-43100 Parma, Italy. Ctr Biotecnol Avanzate, Ist Nazl Ric Canc, Genoa, Italy. NIDR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. Univ Udine, Dipartimento Sci & Tecnol Biomed, I-33100 Udine, Italy. RP Perris, R (reprint author), Ist Nazl Ctr Europeo, Div Expt Oncol 2, Ctr Riferimento Oncol Aviano, I-33081 Aviano, PN, Italy. OI Giacomello, Emiliana/0000-0003-3329-6269; colombatti, alfonso/0000-0002-3676-2379 NR 33 TC 19 Z9 19 U1 0 U2 4 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 FEB 15 PY 1999 VL 93 IS 4 BP 1221 EP 1230 PG 10 WC Hematology SC Hematology GA 166CT UT WOS:000078559200011 PM 9949164 ER PT J AU Shi, CS Tuscano, JM Witte, ON Kehrl, JH AF Shi, CS Tuscano, JM Witte, ON Kehrl, JH TI GCKR links the Bcr-Abl oncogene and Ras to the stress-activated protein kinase pathway SO BLOOD LA English DT Article ID GERMINAL CENTER KINASE; N-TERMINAL KINASE; PHILADELPHIA-CHROMOSOME; TRANSFORMATION; JUN; JNK; LEUKEMIA; DOMAIN; IDENTIFICATION; CASCADE AB The Bcr-Abl oncogene, found in Philadelphia chromosome-positive myelogenous leukemia (CML), activates Ras and triggers the stress-activated protein kinase (SAPK or Jun NH2-terminal kinase [JNK]) pathway. Interruption of Res or SAPK activation dramatically reduces Bcr-Abl-mediated transformation. Here, we report that Bcr-Abl through a Ras-dependent pathway signals the serine/threonine protein kinase GCKR (Germinal Center Kinase Related) leading to SAPK activation. Either an oncogenic form of Ras or Bcr-Abl enhances GCKR catalytic activity and its activation of SAPK, whereas inhibition of GCKR impairs Bcr-Abl-induced SAPK activation. Bcr-Abl mutants that are Impaired for GCKR activation ape also unable to activate SAPK, Consistent with GCKR being a functional target in CML, GCKR is constitutively active in CML cell lines and found in association with Bcr-Abl. Our results indicate that GCKR is a downstream target of Bcr-Abl and strongly implicate GCKR as a mediator of Bcr-Abl in its transformation of cells. C1 NIAID, Immunoregulat Lab, NIH, B Cell Mol Immunol Sect, Bethesda, MD 20892 USA. Univ Calif Davis, Ctr Canc, Dept Oncol, Sacramento, CA 95817 USA. Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA USA. RP Kehrl, JH (reprint author), NIAID, Immunoregulat Lab, NIH, B Cell Mol Immunol Sect, Bldg 10,Room 11B08,10 Ctr DR MSC 1876, Bethesda, MD 20892 USA. EM jkehrl@atlas.niaid.nih.gov OI Kehrl, John/0000-0002-6526-159X NR 33 TC 21 Z9 23 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 FEB 15 PY 1999 VL 93 IS 4 BP 1338 EP 1345 PG 8 WC Hematology SC Hematology GA 166CT UT WOS:000078559200024 PM 9949177 ER PT J AU Moriuchi, M Moriuchi, H Fauci, AS AF Moriuchi, M Moriuchi, H Fauci, AS TI GATA-1 transcription factor transactivates the promoter for CCR5, a coreceptor for human immunodeficiency virus type 1 entry SO BLOOD LA English DT Letter C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Moriuchi, M (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 8 TC 14 Z9 14 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 FEB 15 PY 1999 VL 93 IS 4 BP 1433 EP 1435 PG 3 WC Hematology SC Hematology GA 166CT UT WOS:000078559200039 PM 10075456 ER PT J AU Bubendorf, L Kononen, J Koivisto, P Schraml, P Moch, H Gasser, TC Willi, N Mihatsch, MJ Sauter, G Kallioniemi, OP AF Bubendorf, L Kononen, J Koivisto, P Schraml, P Moch, H Gasser, TC Willi, N Mihatsch, MJ Sauter, G Kallioniemi, OP TI Survey of gene amplifications during prostate cancer progression by high throughput fluorescence in situ hybridization on tissue microarrays SO CANCER RESEARCH LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; ANDROGEN RECEPTOR GENE; CARCINOMA; METASTASIS AB Prostate cancer development and progression is driven by the accumulation of genetic changes, the nature of which remains incompletely understood. To facilitate high-throughput analysis of molecular events taking place in primary, recurrent, and metastatic prostate cancer, we constructed a tissue microarray containing small 0.6-mm cylindrical samples acquired from 371 formalin-fixed blocks, including benign prostatic hyperplasia (n = 32) and primary tumors (n = 223), as well as both locally recurrent tumors (n = 54) and metastases (n = 62) from patients with hormone-refractory disease. Fluorescence in situ hybridization (FISH) was applied to the analysis of consecutive tissue microarray sections with probes for five different genes. High-level (greater than or equal to 3X) amplifications were very rare (<2%) in primary prostate cancers. However, in metastases from patients with hormone-refractory disease, amplification of the androgen receptor gene was seen in 22%, MYC in 11%, and Cyclin-D1 in 5% of the cases, In specimens from locally recurrent tumors, the corresponding percentages were 23, 4, and 8%. ERBB2 and NMYC amplifications were never detected at any stage of prostate cancer progression. In conclusion, FISH to tissue microarray sections enables high-throughput analysis of genetic alterations contributing to cant er development and progression, Our results implicate a role for amplification of androgen receptor in hormonal therapy failure and that of MYC in the metastatic progression of human prostate cancer. C1 Natl Human Genome Res Inst, Canc Genet Lab, NIH, Bethesda, MD 20892 USA. Tampere Univ Hosp, Canc Genet Lab, Tampere 33521, Finland. Univ Basel, Inst Pathol, CH-4003 Basel, Switzerland. Univ Basel, Urol Clin, CH-4003 Basel, Switzerland. RP Kallioniemi, OP (reprint author), Natl Human Genome Res Inst, Canc Genet Branch, NIH, 49 Convent Dr,MSC 4470,Room 4A24, Bethesda, MD 20892 USA. RI Kallioniemi, Olli/H-5111-2011; Bubendorfl, Lukas/H-5880-2011; Kallioniemi, Olli/H-4738-2012 OI Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332 NR 19 TC 447 Z9 481 U1 3 U2 13 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 FEB 15 PY 1999 VL 59 IS 4 BP 803 EP 806 PG 4 WC Oncology SC Oncology GA 167DQ UT WOS:000078617700008 PM 10029066 ER PT J AU Lin, HC Huber, R Schlessinger, D Morin, PJ AF Lin, HC Huber, R Schlessinger, D Morin, PJ TI Frequent silencing of the GPC3 gene in ovarian cancer cell lines SO CANCER RESEARCH LA English DT Article ID ALLELOTYPE; EXPRESSION; CARCINOMA; MUTATIONS; GROWTH AB GPC3 encodes a glypican integral membrane protein and Is mutated in the Simpson-Golabi-Behmel syndrome. Simpson-Golabi-Behmel syndrome, an X-linked condition, is characterized by pre- and postnatal overgrowth as well as by various other abnormalities, including increased risk of embryonal tumors. The GPC3 gene is located at Xq26, a region frequently deleted in advanced ovarian cancers. To determine whether GPC3 is a tumor suppressor in ovarian neoplasia, we studied its expression and mutational status in 13 ovarian cancer cell lines. No mutations were found in GPC3, but its expression was lost in four (31%) of the cell lines analyzed. In all of the cases where GPC3 expression was lost, the GPC3 promoter was hypermethylated, as demonstrated by Southern analysis, Expression of GPC3 was restored by treatment of the cells with the demethylating agent 5-aza-2'-deoxycytidine. A colony-forming assay confirmed that ectopic GPC3 expression inhibited the growth of ovarian cancer cell lines. Our results show that GPC3, a gene involved in the control of organ growth, is frequently inactivated in a subset of ovarian cancers and suggest that it may function as a tumor suppressor in the ovary. C1 NIA, Biol Chem Lab, Ctr Gerontol Res, NIH, Baltimore, MD 21224 USA. NIA, Genet Lab, Ctr Gerontol Res, NIH, Baltimore, MD 21224 USA. Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. RP Morin, PJ (reprint author), NIA, Biol Chem Lab, Ctr Gerontol Res, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 22 TC 133 Z9 141 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 FEB 15 PY 1999 VL 59 IS 4 BP 807 EP 810 PG 4 WC Oncology SC Oncology GA 167DQ UT WOS:000078617700009 PM 10029067 ER PT J AU Bocher, T Barusevicius, A Snowden, T Rasio, D Guerrette, S Robbins, D Schmidt, C Burczak, J Croce, CM Copeland, T Kovatich, AJ Fishel, R AF Bocher, T Barusevicius, A Snowden, T Rasio, D Guerrette, S Robbins, D Schmidt, C Burczak, J Croce, CM Copeland, T Kovatich, AJ Fishel, R TI hMSH5: A human MutS homologue that forms a novel heterodimer with hMSH4 and is expressed during spermatogenesis SO CANCER RESEARCH LA English DT Article ID NONPOLYPOSIS COLON-CANCER; DNA MISMATCH REPAIR; HUMAN MSH2 PROTEIN; SACCHAROMYCES-CEREVISIAE; COLORECTAL-CANCER; HUMAN GENOME; MUTATION; GENE; BINDING; CLONING AB MutS homologues have been identified in nearly all organisms examined to date. They play essential roles in maintaining mitotic genetic fidelity and meiotic segregation fidelity, MutS homologues appear to function as a molecular switch that signals genomic manipulation events. Here we describe the identification of the human homologue of the Saccharomyces cerevisiae MSH5, which is known to participate in meiotic segregation fidelity and crossing-over. The human MSH5 (hMSH5) was localized to chromosome 6p22-21 and appears to play a role in meiosis because expression is induced during spermatogenesis between the late primary spermatocytes and the elongated spermatid phase, hMSH5 interacts specifically with hMSH4, confirming the generality of functional heterodimeric interactions in the eukaryotic MutS homologue, which also includes hMSH2-hMSH3 and hMSH2-hMSH6. C1 Thomas Jefferson Univ, Jefferson Med Coll, Kimmel Canc Inst, Dept Microbiol & Immunol, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Jefferson Med Coll, Kimmel Canc Inst, Dept Pathol & Cell Biol, Philadelphia, PA 19107 USA. SmithKline Beecham Pharmaceut, King Of Prussia, PA 19406 USA. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. RP Fishel, R (reprint author), Thomas Jefferson Univ, Jefferson Med Coll, Kimmel Canc Inst, Dept Microbiol & Immunol, 233 S 10th St, Philadelphia, PA 19107 USA. EM rfishel@hendrix.jci.tju.edu OI Schmidt, Carl/0000-0002-8386-4781 NR 25 TC 2 Z9 2 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 1999 VL 59 IS 4 BP 816 EP 822 PG 7 WC Oncology SC Oncology GA 167DQ UT WOS:000078617700011 ER PT J AU Horikawa, I Cable, PL Afshari, C Barrett, JJ AF Horikawa, I Cable, PL Afshari, C Barrett, JJ TI Cloning and characterization of the promoter region of human telomerase reverse transcriptase gene SO CANCER RESEARCH LA English DT Article ID MAMMALIAN TELOMERASE; RNA COMPONENT; PROTEIN; DNA; SENESCENCE; VIRUS; ACTIVATION; CANCER; CELLS; MAZ AB Activation of telomerase is one of the rate-limiting steps in human cell immortalization and carcinogenesis. Human telomerase is composed of at least two protein subunits and an RNA component. Regulation of expression of the catalytic subunit, human telomerase reverse transcriptase (hTERT), is suggested as the major determinant of the enzymatic activity. We report here the cloning and characterization of the 5'-regulatory region of the hTERT gene, The highly GC-rich content of the 5' end of the hTERT cDNA spans to the 5'-flanking region and intron 1, making a CpG island. A 1.7-kb DNA fragment encompassing the hTERT gene promoter was placed upstream of the luciferase reporter gene and transiently transfected into human cell lines of fibroblastic and epithelial origins that differed in their expression of the endogenous hTERT gene. Endogenous hTERT-expressing cells, but not nonexpressing cells, showed high levels of luciferase activity, suggesting that the regulation of hTERT gene expression occurs mainly at the transcriptional level. Additional luciferase assays using a series of constructs containing unidirectionally deleted fragments revealed that a 59-bp region (-208 to -150) is required for the maximal promoter activity. The region contains a potential Myc oncoprotein binding site (E-box), and cotransfection of a c-myc expression plasmid markedly enhanced the promoter activity, suggesting a role of the Myc protein in telomerase activation, Identification of the regulatory regions of the hTERT promoter sequence will be essential in understanding the molecular mechanisms of positive and negative regulation of telomerase. C1 NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Barrett, JJ (reprint author), NIEHS, Mol Carcinogenesis Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM barrett@niehs.nih.gov NR 32 TC 313 Z9 357 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 FEB 15 PY 1999 VL 59 IS 4 BP 826 EP 830 PG 5 WC Oncology SC Oncology GA 167DQ UT WOS:000078617700013 PM 10029071 ER PT J AU Zhou, XL Wang, XW Xu, LX Hagiwara, K Nagashima, M Wolkowicz, R Zurer, I Rotter, V Harris, CC AF Zhou, XL Wang, XW Xu, LX Hagiwara, K Nagashima, M Wolkowicz, R Zurer, I Rotter, V Harris, CC TI COOH-terminal domain of p53 modulates p53-mediated transcriptional transactivation, cell growth, and apoptosis SO CANCER RESEARCH LA English DT Article ID TUMOR-SUPPRESSOR P53; WILD-TYPE P53; CYCLIN-DEPENDENT KINASES; DNA-BINDING ACTIVITY; SPLICED FORM; MUTANT P53; IN-VITRO; BAX GENE; PROTEIN; ACTIVATION AB The tumor suppressor protein p53 contributes to the control of cell cycle checkpoints and stress-induced apoptosis and is frequently mutated in many different types of human cancers. The COOH terminus of p53 modulates the transcriptional and apoptotic activities of the protein. Although COOH-terminal mutants of p53 are uncommon, we proposed that these p53 mutants nevertheless contributed to the selective clonal expansion of the cancer cells. Therefore, we analyzed the tumor-derived p53 COOH-terminal domain (CTD) mutants (352D/H, 356G/W, 342-stop, 360-del, and 387-del) functionally. The results have revealed that all mutants have impaired apoptotic activity when compared with wild-type p53. However, some of these mutants still transcriptionally transactivate p21(Waf1/Cip1) and inhibit cell growth. Interestingly, of the tumor-derived CTD mutants, oligomerization-defective mutant 342-stop was the only one that did not exhibit sequence-specific DNA binding or failed to transactivate p21(Waf1/Cip1), Bax, and IGF-BP3 transcriptionally. The failure to inhibit cell growth by this tumor-derived CTD mutant supports the hypothesis that p53 sequence-specific transcriptional transactivity to p21(Waf1/Cip1) is correlated with induction of cell cycle arrest and that the p53 transcriptional transactivity requires oligomerization of the p53 protein. These and other data indicate that the CTD of p53 is an important component of p53-mediated apoptosis and cell growth arrest and that inactivation of the apoptotic function, but not the inhibition of growth, is an important step during human tumorigenesis. C1 NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM Curtis_Harris@nih.gov RI Wang, Xin/B-6162-2009 NR 66 TC 38 Z9 39 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 1999 VL 59 IS 4 BP 843 EP 848 PG 6 WC Oncology SC Oncology GA 167DQ UT WOS:000078617700015 PM 10029073 ER PT J AU Zhang, JM Wei, Q Zhao, XH Paterson, BM AF Zhang, JM Wei, Q Zhao, XH Paterson, BM TI Coupling of the cell cycle and myogenesis through the cyclin D1-dependent interaction of MyoD with cdk4 SO EMBO JOURNAL LA English DT Article DE cdk4; cell cycle; cyclin D1; myogenesis ID RETINOBLASTOMA GENE-PRODUCT; DEPENDENT KINASE-4 CDK4; SKELETAL MYOGENESIS; MUSCLE-CELLS; DIFFERENTIATION; PHOSPHORYLATION; INHIBITION; EXPRESSION; BINDING; TRANSCRIPTION AB Proliferating myoblasts express the muscle determination factor, MyoD, throughout the cell cycle in the absence of differentiation. Here we show that a mitogen-sensitive mechanism, involving the direct interaction between MyoD and cdk4, restricts myoblast differentiation to cells that have entered into the G(0) phase of the cell cycle under mitogen withdrawal, Interaction between MyoD and cdk4 disrupts MyoD DNA-binding, muscle-specific gene activation and myogenic conversion of 10T1/2 cells independently of cyclin D1 and the CAK activation of cdk4, Forced induction of cyclin D1 in myotubes results in the cytoplasmic to nuclear translocation of cdk4. The specific MyoD-cdk4 interaction in dividing myoblasts, coupled with the cyclin D1-dependent nuclear targeting of cdk4, suggests a mitogen-sensitive mechanism whereby cyclin D1 can regulate MyoD function and the onset of myogenesis by controlling the cellular location of cdk4 rather than the phosphorylation status of MyoD. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Paterson, BM (reprint author), NCI, Biochem Lab, NIH, Bldg 37,Room 4A21,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 33 TC 96 Z9 97 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD FEB 15 PY 1999 VL 18 IS 4 BP 926 EP 933 DI 10.1093/emboj/18.4.926 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 173ZG UT WOS:000079009200014 PM 10022835 ER PT J AU Mao, NC Steingrimsson, E DuHadaway, J Wasserman, W Ruiz, JC Copeland, NG Jenkins, NA Prendergast, GC AF Mao, NC Steingrimsson, E DuHadaway, J Wasserman, W Ruiz, JC Copeland, NG Jenkins, NA Prendergast, GC TI The murine Bin1 gene functions early in myogenesis and defines a new region of synteny between mouse chromosome 18 and human chromosome 2 SO GENOMICS LA English DT Article ID NF-KAPPA-B; SKELETAL-MUSCLE; TRANSCRIPTION FACTORS; MEDIATED ENDOCYTOSIS; AMPHIPHYSIN ISOFORM; TUMOR-SUPPRESSOR; CDNA CLONING; SH3 DOMAIN; EXPRESSION; PROTEIN AB We cloned and functionally characterized the murine Bin1 gene as a first step to investigate its physiological roles in differentiation, apoptosis, and tumorigenesis. The exon-intron organization of the greater than or equal to 55-kb gene is similar to that of the human gene. Consistent with a role for Bin1 in apoptosis, the promoter included a functional consensus motif for activation by NF-kappa B, an important regulator of cell death. A muscle regulatory module defined in the human promoter that includes a consensus recognition site for myoD family proteins was not conserved in the mouse promoter. However, Bin1 is upregulated in embryonic development by E10.5 in myotomes, the progenitors of skeletal muscle, supporting a role in myogenesis and suggesting that the mouse and human genes may be controlled somewhat differently during development. In C2C12 myoblasts antisense Bin1 prevents induction of the cell cycle kinase inhibitor p21WAF1, suggesting that it acts at an early time during the muscle differentiation program. Interspecific mouse backcross mapping located the Bin1 locus between Mep1b and Ape on chromosome 18. Since the human gene was mapped previously to chromosome 2q14, the location of Bin1 defines a previously unrecognized region of synteny between human chromosome 2 and mouse chromosome 18. (C) 1999 Academic Press. C1 Wistar Inst, Philadelphia, PA 19104 USA. NCI, Mammalian Genet Lab, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Smith Kline Beecham Res Labs, King Of Prussia, PA 19190 USA. RP Prendergast, GC (reprint author), Wistar Inst, 3601 Spruce St, Philadelphia, PA 19104 USA. RI Wasserman, Wyeth/I-4866-2015 NR 38 TC 24 Z9 24 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD FEB 15 PY 1999 VL 56 IS 1 BP 51 EP 58 DI 10.1006/geno.1998.5709 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 171ET UT WOS:000078850100006 PM 10036185 ER PT J AU Gao, JL Lee, EJ Murphy, PM AF Gao, JL Lee, EJ Murphy, PM TI Impaired antibacterial host defense in mice lacking the N-formylpeptide receptor SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE chemotaxis; Listeria; inflammation; chemoattractant; neutrophil ID FORMYL PEPTIDE RECEPTOR; CHEMOKINE RECEPTOR-2; CHEMOTACTIC RECEPTOR; LEUKOCYTE ADHESION; ESCHERICHIA-COLI; NEUTROPHIL; CDNA; GENE; IDENTIFICATION; INFLAMMATION AB N-formylpeptides derive from bacterial and mitochondrial proteins, and bind to specific receptors on mammalian phagocytes. Since binding induces chemotaxis and activation of phagocytes in vitro, it has been postulated that N-formylpeptide receptor signaling in vivo may be important in antimicrobial host defense, although direct proof has been lacking. Here we test this hypothesis in mice lacking the high affinity N-formylpeptide receptor (FPR), created by targeted gene disruption. FPR-/- mice developed normally, but had increased susceptibility to challenge with Listeria monocytogenes, as measured by increased mortality compared with wild-type littermates. FPR-/- mice also had increased bacterial load in spleen and liver 2 d after infection, which is before development of a specific cellular immune response, suggesting a defect in innate immunity. Consistent with this, neutrophil chemotaxis in vitro and neutrophil mobilization into peripheral blood in vivo in response to the prototype N-formylpeptide fMLF (formyl-methionyl-leucyl-phenylalanine) were both absent in FPR-/- mice. These results indicate that FPR functions in antibacterial host defense in vivo. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Gao, JL (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Rm 11N113, Bethesda, MD 20892 USA. NR 36 TC 192 Z9 192 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 FEB 15 PY 1999 VL 189 IS 4 BP 657 EP 662 DI 10.1084/jem.189.4.657 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 168NA UT WOS:000078698100007 PM 9989980 ER PT J AU D'Oro, U Ashwell, JD AF D'Oro, U Ashwell, JD TI Cutting edge: The CD45 tyrosine phosphatase is an inhibitor of Lck activity in thymocytes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL RECEPTOR; LEUKOCYTE-COMMON ANTIGEN; KINASE-ACTIVITY; PROTEIN-KINASE; PHOSPHOTYROSINE PHOSPHATASE; SIGNAL-TRANSDUCTION; PHOSPHORYLATION; ACTIVATION; PP56LCK; TRANSMEMBRANE AB A widely accepted model for regulation of the Lck tyrosine kinase is that it is activated by CD45-mediated dephosphorylation of its COOH-terminal negative regulatory tyrosine (Tyr(505)). Previous work from our laboratory, however, found that despite hyperphosphorylation of Tyr(505), the activity of Lck from CD45(-) T cell lines was actually increased due to hyperphosphorylation of the positive regulatory tyrosine, residue 394. To avoid potential complications introduced by transformed cells, in this study we have characterized the effect of CD45 on Lck activity in normal cells. Lck in thymocytes from CD45(-/-) mice was hyperphosphorylated on tyrosine residues. Importantly, and in disagreement with the model that CD45 only activates Lck in vivo, the kinase activity of Lck from cells lacking CD45 was substantially increased. These results support a model in which CD45 dephosphorylates both Tyr(505) and Tyr(394), the net effect in normal thymocytes being a decrease in enzymatic activity. C1 NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. RP Ashwell, JD (reprint author), NCI, Lab Immune Cell Biol, NIH, 9000 Rockville Pike,Bldg 10,Room 1B40, Bethesda, MD 20892 USA. NR 33 TC 103 Z9 105 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 1999 VL 162 IS 4 BP 1879 EP 1883 PG 5 WC Immunology SC Immunology GA 165FV UT WOS:000078510800001 PM 9973453 ER PT J AU Baroja, ML Cieslinski, LB Torphy, TJ Wange, RL Madrenas, J AF Baroja, ML Cieslinski, LB Torphy, TJ Wange, RL Madrenas, J TI Specific CD3 epsilon association of a phosphodiesterase 4B isoform determines its selective tyrosine phosphorylation after CD3 ligation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; CAMP-SPECIFIC PHOSPHODIESTERASE; AMP-SPECIFIC PHOSPHODIESTERASE; CYTOKINE GENE-EXPRESSION; ACTIVATED PROTEIN-KINASE; BLOOD MONONUCLEAR-CELLS; HUMAN T-CELLS; DIFFERENTIAL EXPRESSION; SURFACE MOLECULES; HUMAN-LYMPHOCYTES AB cAMP-specific phosphodiesterases (PDE) comprise an extensive family of enzymes that control intracellular levels of cAMP and thus regulate T cell responses. It is not known how the function of these enzymes is altered by TCR engagement, We have examined this issue by studying one of the PDE isozymes (PDE4B), PDE4B RNA and protein were detected in resting PBLs, and the levels of PDE4B protein increased with cell cycling. In peripheral blood T cells, two previously reported PDE4B isoforms could be detected: one was 75-80 kDa (PDE4B1) and the other was 65-67 kDa (PDE4B2), These two isoforms differed in their N-terminal sequence, with the presence of four potential myristylation sites in the PDE4B2 that are absent in PDE4B1. Consequently, only PDE4B2 was found in association with the CD3 epsilon chain of the TCR, In addition, although both isoforms were phosphorylated in tyrosines in pervanadate-stimulated T cells, only the TCR-associated PDE4B2 was tyrosine-phosphorylated following CD3 ligation, The kinetics of phosphorylation of TCR-associated PDE4B2 correlated with changes in cAMP levels, suggesting that tyrosine phosphorylation of the TCR-associated PDE4B isoform upon engagement of this receptor may be an important regulatory step in PDE4B function. Our results reveal that selectivity of PDE4B activation can be achieved by differential receptor association and phosphorylation of the alternatively spliced forms of this PDE. C1 John P Robarts Res Inst, Transplantat & Immunobiol Grp, London, ON N6A 5K8, Canada. Univ Western Ontario, Dept Microbiol & Immunol, London, ON, Canada. Univ Western Ontario, Dept Med, London, ON, Canada. SmithKline Beecham Pharmaceut, Div Pharmacol Sci, King Of Prussia, PA 19406 USA. NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Madrenas, J (reprint author), John P Robarts Res Inst, Transplantat & Immunobiol Grp, POB 5015,Room 2-05,100 Perth Dr, London, ON N6A 5K8, Canada. EM madrenas@rri.on.ca NR 54 TC 29 Z9 30 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 1999 VL 162 IS 4 BP 2016 EP 2023 PG 8 WC Immunology SC Immunology GA 165FV UT WOS:000078510800021 PM 9973473 ER PT J AU George, TC Mason, LH Ortaldo, JR Kumar, V Bennett, M AF George, TC Mason, LH Ortaldo, JR Kumar, V Bennett, M TI Positive recognition of MHC class T molecules by the Ly49D receptor of murine NK cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; BONE-MARROW ALLOGRAFTS; CLASS-I MHC; HYBRID RESISTANCE; GRAFT-REJECTION; MICE; COMPLEX; LY-49; GENE; EXPRESSION AB Members of the murine Ly49 family of receptors have been shown to inhibit and activate NK cell function, Subsets of Ly49-expressing NK cells mediate the rejection of bone marrow cell allografts and the lysis of allogeneic lymphoblasts. In this report we have studied Ly49-mediated positive and negative signaling in an in vitro cytotoxicity assay using sorted NK cell subsets as effecters and a panel of Cr-51-labeled Con A lymphoblasts as targets in the presence or the absence of Abs to Ly49 and/or class I molecules, Our results demonstrate that the activating receptor Ly49D delivers stimulatory signals for target cell lysis upon interacting with H2-D-d, D-r, and D-sp2, but not H2(b) or H2(k) class I Ags, On the other hand, the inhibitory receptor Ly49G2 delivers negative signals for target cell lysis upon interacting with D-d, D-r, and H2(k), but not H2(b) or D-sp2, class I Ags, Furthermore, Ly49-mediated negative signaling dominates Ly49D-mediated positive signaling. Thus, lysis of class I MHC-bearing targets by NK cells is not merely the consequence of the absence of an Ly49-mediated negative signal, but also requires positive recognition of class I molecules by certain Ly49 receptors, Activation of NK cells by nonself Class I molecules was not predicted by the missing self hypothesis. C1 Univ Texas, SW Med Ctr, Dept Pathol, Dallas, TX 75235 USA. NCI, Frederick Canc Res & Dev Ctr, Expt Immunol Lab, Div Basic Sci, Frederick, MD 21702 USA. RP Bennett, M (reprint author), Univ Texas, SW Med Ctr, Dept Pathol, 6000 Harry Hines Blvd, Dallas, TX 75235 USA. FU NCI NIH HHS [CA36921]; NIAID NIH HHS [AI25401, AI38938] NR 49 TC 105 Z9 106 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 1999 VL 162 IS 4 BP 2035 EP 2043 PG 9 WC Immunology SC Immunology GA 165FV UT WOS:000078510800023 PM 9973475 ER PT J AU Itoh, Y Hemmer, B Martin, R Germain, RN AF Itoh, Y Hemmer, B Martin, R Germain, RN TI Serial TCR engagement and down-modulation by peptide : MHC molecule ligands: Relationship to the quality of individual TCR signaling events SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL-RECEPTOR; MONOCLONAL-ANTIBODY; AGONIST PROPERTIES; LYMPHOCYTES-T; TARGET-CELL; ACTIVATION; COMPLEXES; AFFINITY; SURFACE; CD8 AB In the present study, we examined the relationships among quantitative aspects of TCR engagement as measured by receptor down-modulation, functional responses, and biochemical signaling events using both mouse and human T cell clones, For T cells from both species, ligands that are more potent in inducing functional responses promote TCR down-modulation more efficiently than weaker ligands, At low ligand density, the number of down-modulated TCR exceeds the number of available ligands by as much as 80-100:1 in the optimal human case, confirming the previous description of serial ligand engagement of TCR (Valitutti, et al, 1995, Nature 375:148-151), A previously unappreciated relationship involving TCR down-modulation, the pattern of proximal TCR signaling., and the extent of serial engagement was revealed by analyzing different ligands for the same TCR, Functionally, more potent ligands induce a higher proportion of fully tyrosine phosphorylated zeta-chains and a greater amount of phosphorylated ZAP-70 than less potent ligands, and the number of TCR down-modulated per available ligand is higher with ligands showing this full agonist-like pattern. The large number of receptors showing partial zeta phosphorylation following exposure to weak ligands indicates that the true extent of TCR engagement and signaling, and thus the amount of sequential engagement, is underestimated by measurement of TCR down-modulation alone, which depends on full receptor activation. These data provide new insight into T cell activation by revealing a clear relationship among intrinsic ligand quality, signal amplification by serial engagement, functional T cell responses, and observable TCR clearance from the cell surface. C1 NIAID, Lymphocyte Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. NINDS, Cellular Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Germain, RN (reprint author), NIAID, Lymphocyte Biol Sect, Immunol Lab, NIH, Bldg 10,Room 11N311,10 Ctr Dr,MSC-1892, Bethesda, MD 20892 USA. EM Ronald_Germain@nih.gov NR 49 TC 99 Z9 99 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 FEB 15 PY 1999 VL 162 IS 4 BP 2073 EP 2080 PG 8 WC Immunology SC Immunology GA 165FV UT WOS:000078510800028 PM 9973480 ER PT J AU Gadina, M Sudarshan, C O'Shea, JJ AF Gadina, M Sudarshan, C O'Shea, JJ TI IL-2, but not IL-4 and other cytokines, induces phosphorylation of a 98-kDa protein associated with SHP-2, phosphatidylinositol 3 '-kinase, and Grb2 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RECEPTOR-BETA-CHAIN; T-CELL PROLIFERATION; TYROSINE-PHOSPHATASE; SIGNAL-TRANSDUCTION; PHOSPHOTYROSINE PHOSPHATASE; HEMATOPOIETIC-CELLS; KINASE ACTIVATION; JANUS KINASE; INTERLEUKIN-2; BINDING AB Binding of IL-2 to its receptor activates several biochemical pathways, including JAR-STAT, Ras-mitogen-activated protein kinase, and phosphatidylinositol 3'-kinase (PI 3'-kinase) pathways. Recently, it has been shown that the SH2-containing phosphatase, SHP-2, becomes phosphorylated in response to IL-2 stimulation, associates with PI3'-kinase and Grb2, and can exert a positive regulatory role in IL-2 signaling. We now report the identification of a prominent 98-kDa protein (p98) found to be phosphorylated in response to IL-2 stimulation and coprecipitated with SHP-2, the p85 subunit of PI 3'-kinase and Grb2. Interestingly, whereas IL-4 is known to activate PI3'-kinase, we did not observe any p98 phosphorylation in response to IL-4 stimulation. p98 can form a multipartite complex with all these proteins as immunodepleting with anti-p85 antiserum substantially reduced the amount of p98 immunoprecipitated by SHP-2 and Grb2; the converse was also true. Furthermore, phosphorylation of p98 did not occur in cells lacking JAK3, suggesting that it may be a JAK substrate, Finally, deglycosylation of p98 did not alter its migration, suggesting p98 is not a member of the recently described SHP substrate/signal-regulatory proteins family of transmembrane glycoproteins. Thus p98 is a prominent IL-2-dependent substrate that associates with multiple proteins involved in IL-2 signaling and may play an important role in coupling the different signal transduction pathways activated by IL-2. C1 NIAMSD, Lymphocyte Cell Biol Sect, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. RP O'Shea, JJ (reprint author), Bldg 10,Room 9N228,10 Ctr Dr,MSC 1820, Bethesda, MD 20892 USA. NR 42 TC 16 Z9 16 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 FEB 15 PY 1999 VL 162 IS 4 BP 2081 EP 2086 PG 6 WC Immunology SC Immunology GA 165FV UT WOS:000078510800029 PM 9973481 ER PT J AU McFarland, HI Lobito, AA Johnson, MM Nyswaner, JT Frank, JA Palardy, GR Tresser, N Genain, CP Mueller, JP Matis, LA Lenardo, MJ AF McFarland, HI Lobito, AA Johnson, MM Nyswaner, JT Frank, JA Palardy, GR Tresser, N Genain, CP Mueller, JP Matis, LA Lenardo, MJ TI Determinant spreading associated with demyelination in a nonhuman primate model of multiple sclerosis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; MYELIN OLIGODENDROCYTE GLYCOPROTEIN; BASIC-PROTEIN; PROTEOLIPID PROTEIN; MONOCLONAL-ANTIBODY; ADOPTIVE TRANSFER; DENDRITIC CELLS; LYMPHOCYTES-T; DISEASE AB Definition of the immune process that causes demyelination in multiple sclerosis is essential to determine the feasibility of Ag-directed immunotherapy. Using the nonhuman primate, Callithrix jacchus jacchus (common marmoset), we show that immunization with myelin basic protein and proteolipid protein determinants results in clinical disease with significant demyelination. Demyelination was associated with spreading to myelin oligodendrocyte glycoprotein (MOG) determinants that generated anti-MOG serum Abs and Ig deposition in central nervous system white matter lesions. These data associate intermolecular "determinant spreading" with clinical autoimmune disease in primates and raise important-issues for the pathogenesis and treatment of multiple sclerosis. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. NINDS, Lab Diagnost Radiol Res, NIH, Bethesda, MD 20892 USA. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. Alex Pharmaceut, New Haven, CT 06511 USA. RP Lenardo, MJ (reprint author), NIAID, Immunol Lab, NIH, Bldg 10,Room 11N311,10 Ctr Dr, Bethesda, MD 20892 USA. EM mlenardo@pop.niaid.nih.gov RI McFarland, Hugh/K-1503-2016 OI McFarland, Hugh/0000-0002-3322-038X NR 50 TC 54 Z9 55 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 FEB 15 PY 1999 VL 162 IS 4 BP 2384 EP 2390 PG 7 WC Immunology SC Immunology GA 165FV UT WOS:000078510800067 PM 9973519 ER PT J AU Jia, M Li, MX Dunlap, V Nelson, PG AF Jia, M Li, MX Dunlap, V Nelson, PG TI The thrombin receptor mediates functional activity-dependent neuromuscular synapse reduction via protein kinase C activation in vitro SO JOURNAL OF NEUROBIOLOGY LA English DT Article DE thrombin receptor; activity-dependent; neuromuscular; protein kinase; synapse reduction ID NEURITE OUTGROWTH; TYROSINE PHOSPHORYLATION; ELECTRICAL-ACTIVITY; CALCIUM CURRENTS; NEURAL INFLUENCE; RAT MOTONEURONS; SKELETAL-MUSCLE; MOUSE MUSCLE; CELL-DEATH; IN-VITRO AB Activity-dependent selective reduction of synaptic efficacy is expressed in an in vitro system involving mouse spinal cord and muscle cells, Thrombin or electrical stimulation of the innervating axons induces a decrease in neuromuscular synapse strength, and a specific thrombin inhibitor, hirudin, blocks the electrically evoked down-regulation of synapse effectiveness. We further demonstrate that a thrombin receptor-activating peptide (TRAP), SFLLRNPNDKYEPF, produces a decrement of synapse strength. Both TRAP and electrically evoked synapse decrement are prevented by the specific protein kinase C blocker calphostin C, and the TRAP-evoked synapse decrement is unaffected by a specific protein kinase A blocker, H-89, Thus, we propose that muscle activity, thrombin release, and thrombin receptor and PKC activation are initial steps in the process of the activity-dependent synapse reduction expressed in our system. (C) 1999 John Wiley * Sons, Inc.*. C1 NICHHD, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Nelson, PG (reprint author), NICHHD, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. NR 49 TC 26 Z9 26 U1 0 U2 0 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0022-3034 J9 J NEUROBIOL JI J. Neurobiol. PD FEB 15 PY 1999 VL 38 IS 3 BP 369 EP 381 DI 10.1002/(SICI)1097-4695(19990215)38:3<369::AID-NEU6>3.0.CO;2-Q PG 13 WC Neurosciences SC Neurosciences & Neurology GA 162LZ UT WOS:000078349500006 PM 10022579 ER PT J AU Fay, MP AF Fay, MP TI Comparing several score tests for interval censored data SO STATISTICS IN MEDICINE LA English DT Article ID PROPORTIONAL HAZARDS MODEL; LINEAR RANK-TESTS; FAILURE TIME DATA; REGRESSION AB I create a general model to perform score tests on interval censored data. Special cases of this model are the score tests of Finkelstein, Sun and Fay. Although Sun's was derived as a test for discrete data and Finkelstein's and Fay's tests were derived under a grouped continuous model, by writing all tests under one general model we see that as long as the regularity conditions hold, any of these three classes of tests may be applied to either grouped continuous or discrete data. I show the equivalence between the weighted logrank form of the general test and the form with a term for each individual, the form often used with permutation tests. From the weighted logrank form of the tests, we see that Sun's and Finkelstein's test are similar, giving constant (or approximately constant) weights to differences in survival distributions over time. In contrast, the proportional odds model (Fay's model with logistic error) gives more weight to early differences. Copyright (C) 1999 John Wiley & Sons, Ltd. C1 NCI, Bethesda, MD 20892 USA. RP Fay, MP (reprint author), NCI, Execut Plaza N,Suite 344,6130 Execut Blvd,MSC 735, Bethesda, MD 20892 USA. EM M7f@helix.nih.gov RI Fay, Michael/A-2974-2008; OI Fay, Michael P./0000-0002-8643-9625 NR 16 TC 20 Z9 20 U1 0 U2 2 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD FEB 15 PY 1999 VL 18 IS 3 BP 273 EP 285 DI 10.1002/(SICI)1097-0258(19990215)18:3<273::AID-SIM19>3.0.CO;2-7 PG 13 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 164AF UT WOS:000078439200005 PM 10070674 ER PT J AU Sugiura, W Broder, CC Moss, B Earl, PL AF Sugiura, W Broder, CC Moss, B Earl, PL TI Characterization of conformation-dependent anti-gp120 murine monoclonal antibodies produced by immunization with monomeric and oligomeric human immunodeficiency virus type 1 envelope proteins SO VIROLOGY LA English DT Article ID GP120 SURFACE GLYCOPROTEIN; RECEPTOR-BINDING; EPITOPE EXPOSURE; VARIABLE LOOP; CD4 BINDING; NEUTRALIZATION; REGION; HIV-1; INFECTIVITY; MOLECULES AB Twenty-five conformation-dependent monoclonal antibodies (MAbs) produced by immunization of mice with oligomeric forms of the human immunodeficiency virus type 1 (HIV-1) envelope (env) glycoprotein were used to map exposed, immunogenic regions on oligomeric env. Based on MAb cross-competition, reactivity with diverse env proteins, and reactivity with a panel of gp120 mutants, seven distinct epitope clusters were identified. These include the classic CD4 binding site, V1/V2, and V3. in addition, several novel epitope clusters, including one mapping to the N- and C-termini of gp120, were identified. The locations of the seven epitope clusters on the gp120 core structure are proposed. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM pearl@niaid.nih.gov NR 38 TC 17 Z9 17 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 FEB 15 PY 1999 VL 254 IS 2 BP 257 EP 267 DI 10.1006/viro.1998.9549 PG 11 WC Virology SC Virology GA 168HL UT WOS:000078686100007 PM 9986792 ER PT J AU Funkhouser, AW Schultz, DE Lemon, SM Purcell, RH Emerson, SU AF Funkhouser, AW Schultz, DE Lemon, SM Purcell, RH Emerson, SU TI Hepatitis A virus translation is rate-limiting for virus replication in MRC-5 cells SO VIROLOGY LA English DT Article ID 5' NONTRANSLATED REGION; COMPLETE NUCLEOTIDE-SEQUENCE; CAP-INDEPENDENT TRANSLATION; MONKEY KIDNEY-CELLS; WILD-TYPE VIRUS; A VIRUS; 5'-NONTRANSLATED RNA; CULTURE ADAPTATION; POLIOVIRUS RNA; STRAIN GBM AB Translation of hepatitis A virus (HAV) RNA is controlled by an internal ribosome entry site (IRES) located within the 5' untranslated region (UTR). In some cell types, the characteristically slow growth of HAV may be due to inefficient viral translation. We investigated whether this is true in MRC-5 cells, which are used for vaccine production. We measured the impact of two clusters of mutations in the 5' UTR on virus translation and replication: the AG group was selected during passage in African green monkey kidney cells, and the MR group was selected during subsequent passage in MRC-5 cells. The efficiency of cap-independent translation was assessed by inserting cDNA encoding an HAV IRES upstream of the chloramphenicol acetyl transferase gene and transcription was driven in vivo by a hybrid T7/vaccinia virus system. A luciferase gene was inserted upstream of the IRES to serve as an internal control. Each HAV UTR was also inserted into an infectious cDNA clone; the average rate of viral RNA accumulation was determined for each mutant virus. In MRC-5 cells, the rate of virus replication was highly correlated with the efficiency of cap-independent translation (P = 0.006). The MR but not the AG mutations significantly increased both translation and viral RNA accumulation. Reversion of just one MR mutation (687 G to A) eliminated all of the replication-stimulating and translation-enhancing effects of the MR mutations. In the control BS-C-1 cells, there was no discernible correlation between the rate of virus replication and the efficiency of cap-independent translation (P = 0.136): the AG and MR groups combined had a small impact on translation, but no detectable impact on virus replication. We conclude that in MRC-5 cells viral translation is rate-limiting for HAV replication, (C) 1999 Academic Press. C1 NIAID, Infect Dis Lab, Hepatitis Viruses Sect, Bethesda, MD 20892 USA. Univ Texas, Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. RP Funkhouser, AW (reprint author), Univ Chicago, Dept Pediat, Infect Dis Sect, 5841 S Maryland Ave,Room C638B, Chicago, IL 60637 USA. NR 32 TC 23 Z9 23 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 FEB 15 PY 1999 VL 254 IS 2 BP 268 EP 278 DI 10.1006/viro.1998.9548 PG 11 WC Virology SC Virology GA 168HL UT WOS:000078686100008 PM 9986793 ER PT J AU Lamensdorf, I Meiri, N Harvey-White, J Jacobowitz, DM Kopin, IJ AF Lamensdorf, I Meiri, N Harvey-White, J Jacobowitz, DM Kopin, IJ TI Kir6.2 oligoantisense administered into the globus pallidus reduces apomorphine-induced turning in 6-OHDA hemiparkinsonian rats SO BRAIN RESEARCH LA English DT Article DE antisense; potassium ATP channel; 6-hydroxydopamine; Kir6.2; globus pallidus; apomorphine ID SENSITIVE POTASSIUM CHANNELS; SUBSTANTIA-NIGRA; K+ CHANNELS; NEURONS; DOPAMINE; ACTIVATION; EXPRESSION; RECEPTORS; CLONING; GABA AB ATP-sensitive inwardly rectifying potassium channels (KATPs) couple cell metabolism with its membrane potential. The best characterized KATP is the pancreatic KATP which is an heteromultimer of Kir6.2 and SUR1 protein subunits. KATPs are found in a variety of excitable cells, including neurons of the central nervous system. Basal ganglia (BG), especially in the substantia nigra (SN) reticulata and the globus pallidus (GP), have a high density of KATPs. Pharmacological modulation of the KATPs within the BG alters GABAergic activity and produces behavioural changes. However, the relatively high concentrations of drugs used might not have been entirely selective for the KATPs and may have acted at presynaptic nerve terminals as well as on the post-synaptic neurons. As an alternative means of examining the role of KATPs in regulating motor behavior, we used oligoantisense technology to diminish selectively Kir6.2 formation in the GP neurons. We then examined the effect of reduction in Kir6.2 expression on apomorphine-induced turning behavior in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the SN. Two weeks after injection of 6-OHDA, contralateral circling in response to apomorphine (0.25 mg/kg sc) was recorded. Kir6.2 antisense oligodeoxyribonucleotide (ODN) was then administered daily for 6 days into the GP ipsilateral to the 6-OHDA injection. Responses to apomorphine were then tested again and the animals killed to determine the effect of the antisense ODN on Kir6.2 mRNA. Administration of Kir6.2 antisense ODN significantly attenuated apomorphine-induced contralateral turning and specifically reduced Kir6.2 mRNA in the injected GP. These results are consistent with pharmacological experiments which suggest that KATP channels in the GP are involved in motor responses to apomorphine in 6-OHDA lesioned rats, localizing the effects to the GP neurons, probably through modulation of the GABAergic system. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NINDS, Clin Neurosci Branch, NIH, Bethesda, MD 20892 USA. NIH, Lab Adapt Syst, Bethesda, MD 20892 USA. NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. RP Lamensdorf, I (reprint author), NINDS, Clin Neurosci Branch, NIH, Bldg 10,Room 4D-20, Bethesda, MD 20892 USA. EM il25v@nih.gov NR 43 TC 13 Z9 14 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD FEB 13 PY 1999 VL 818 IS 2 BP 275 EP 284 DI 10.1016/S0006-8993(98)01290-6 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 166DD UT WOS:000078560200011 PM 10082813 ER PT J AU Hitchcock, P Fransen, L AF Hitchcock, P Fransen, L TI Preventing HIV infection: lessons from Mwanza and Rakai SO LANCET LA English DT Editorial Material ID TRANSMISSION C1 NIAID, Sexually Transmitted Dis Branch, Bethesda, MD 20892 USA. Commiss European Communities, Human Dev Unit DG VIII A2, B-1049 Brussels, Belgium. RP Hitchcock, P (reprint author), NIAID, Sexually Transmitted Dis Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 8 TC 55 Z9 55 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD FEB 13 PY 1999 VL 353 IS 9152 BP 513 EP 515 DI 10.1016/S0140-6736(99)00031-8 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 168BG UT WOS:000078670200003 PM 10028974 ER PT J AU Wawer, MJ Sewankambo, NK Serwadda, D Quinn, TC Paxton, LA Kiwanuka, N Wabwire-Mangen, F Li, CJ Lutalo, T Nalugoda, F Gaydos, CA Moulton, LH Meehan, MO Ahmed, S Gray, RH AF Wawer, MJ Sewankambo, NK Serwadda, D Quinn, TC Paxton, LA Kiwanuka, N Wabwire-Mangen, F Li, CJ Lutalo, T Nalugoda, F Gaydos, CA Moulton, LH Meehan, MO Ahmed, S Gray, RH CA Rakai Project Study Grp TI Control of sexually transmitted diseases for AIDS prevention in Uganda: a randomised community trial SO LANCET LA English DT Article ID BACTERIAL VAGINOSIS; RURAL TANZANIA; CHLAMYDIA-TRACHOMATIS; HIV-1 INFECTION; RISK-FACTORS; TRANSMISSION; IMPACT; WOMEN AB Background The study tested the hypothesis that community-level control of sexually transmitted disease (STD) would result in lower incidence of HIV-1 infection in comparison with control communities. Methods This randomised, controlled, single-masked, community-based trial of intensive STD control, via home-based mass antibiotic treatment, took place in Rakai District, Uganda. Ten community clusters were randomly assigned to intervention or control groups. All consenting residents aged 15-59 years were enrolled; visited in the home every 10 months; interviewed; asked to provide biological samples for assessment of HIV-1 infection and STDs; and were provided with mass treatment (azithromycin, ciprofloxacin, metronidazole in the intervention group, vitamins/anthelmintic drug in the control). intention-to-treat analyses used multivariate, paired, cluster-adjusted rate ratios. Findings The baseline prevalence of HIV-1 infection was 15.9%. 6602 HIV-1-negative individuals were enrolled in the intervention group and 6124 in the control group. 75.0% of intervention-group and 72.6% of control-group participants provided at least one follow-up sample for HIV-1 testing. At enrolment, the two treatment groups were similar in STD prevalence rates. At 20-month follow-up, the prevalences of syphilis (352/6238 [5.6%) vs 359/5284 [6.8%]; rate ratio 0.80 [95% CI 0.71-0.89]) and trichomoniasis (182/1968 [9.3%] vs 261/1815 [14.4%]; rate ratio 0.59 [0.38-0.91]) were significantly lower in the intervention group than in the control group. The incidence of HIV-1 infection was 1.5 per 100 person-years in both groups (rate ratio 0.97 [0.81-1.16]). In pregnant women, the follow-up prevalences of trichomoniasis, bacterial vaginosis, gonorrhoea, and chlamydia infection were significantly lower in the intervention group than in the control group. No effect of the intervention on incidence of HIV-1 infection was observed in pregnant women or in stratified analyses. Interpretation We observed no effect of the STD intervention on the incidence of HIV-1 infection. In the Rakai population, a substantial proportion of HIV-1 acquisition appears to occur independently of treatable STD cofactors. C1 Columbia Univ, Sch Publ Hlth, Ctr Populat & Family Hlth, New York, NY 10032 USA. Makerere Univ, Dept Med, Kampala, Uganda. Makerere Univ, Clin Epidemiol Unit, Kampala, Uganda. Makerere Univ, Inst Publ Hlth, Dept Populat & Family Hlth Sci, Kampala, Uganda. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Baltimore, MD 21205 USA. Johns Hopkins Univ, Dept Int Hlth, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Uganda Virus Res Inst, Rakai Project, Entebbe, Uganda. NIAID, Bethesda, MD 20892 USA. RP Wawer, MJ (reprint author), Columbia Univ, Sch Publ Hlth, Ctr Populat & Family Hlth, Floor B-2,60 Haven Ave, New York, NY 10032 USA. RI Gaydos, Charlotte/E-9937-2010; Quinn, Thomas/A-2494-2010; OI Sewankambo, Nelson/0000-0001-9362-053X; Moulton, Lawrence/0000-0001-7041-7387 FU NIAID NIH HHS [R01 AI34826, R01 AI34826S]; NICHD NIH HHS [5P30HD06826] NR 37 TC 503 Z9 509 U1 1 U2 17 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD FEB 13 PY 1999 VL 353 IS 9152 BP 525 EP 535 DI 10.1016/S0140-6736(98)06439-3 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 168BG UT WOS:000078670200009 PM 10028980 ER PT J AU McCann, UD Szabo, Z Scheffel, U Dannals, RF Ricaurte, GA AF McCann, UD Szabo, Z Scheffel, U Dannals, RF Ricaurte, GA TI Positron emission tomography findings in heavy users of MDMA - Reply SO LANCET LA English DT Letter ID DRUG C1 NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Dept Neurol, Baltimore, MD 21224 USA. Johns Hopkins Med Inst, Dept Nucl Med, Baltimore, MD 21224 USA. RP Ricaurte, GA (reprint author), NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. NR 3 TC 1 Z9 1 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD FEB 13 PY 1999 VL 353 IS 9152 BP 592 EP 593 DI 10.1016/S0140-6736(05)75652-X PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 168BG UT WOS:000078670200056 ER PT J AU Kriegler, S Sudweeks, S Yakel, JL AF Kriegler, S Sudweeks, S Yakel, JL TI The nicotinic alpha 4 receptor subunit contributes to the lining of the ion channel pore when expressed with the 5-HT3 receptor subunit SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CYSTEINE-SUBSTITUTION; M2 SEGMENT; RESIDUES; IDENTIFICATION; MUTANTS AB To understand the wide variation of calcium permeability seen in native and recombinant 5-HT3, receptor (5-HT3R) channels, we reported previously the novel hypothesis that the serotonin 5-HT3R subunit can co-assemble with the alpha 4 subunit of the nicotinic acetylcholine receptor (van Hooft, J. A., Spier, A. D., Yakel, J. L., Lummis, S. C. R. & Vijverberg, H. P. M. (1998) Proc. Natl. Acad, Sci. U. S. A. 95, 11456-11461), To test the hypothesis that the alpha 4 subunit contributes to the lining of the pore of the resulting 5-HT3R channel, a mutant nicotinic alpha 4 subunit with a reactive cysteine residue engineered into the putative pore region was constructed by substituting the leucine at position 285 (alpha 4-L285C), The sulfhydryl-modifying reagent [2-(trimethylammonium) ethyl]methanethiosulfonate (MTSET) reduced the acetylcholine-induced current in oocytes expressing this mutant nicotinic (alpha 4-L285C subunit along with the nicotinic beta 2 subunit by similar to 60%. When the alpha 4-L285C subunit was co-expressed with the 5-HT3R subunit, both MTSET and silver nitrate (AgNO3), another cysteine-modifying reagent, significantly reduced the serotonin-induced current, No reduction was seen when the 5-HT3R was expressed alone or with the wild-type alpha 4 subunit, These data provide direct molecular evidence that the nicotinic alpha 4 subunit co-assembles with the 5-HT3R subunit and forms an integral part of the ion channel pore. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Yakel, JL (reprint author), NIEHS, Lab Signal Transduct, NIH, F2-08,POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 17 TC 20 Z9 21 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 FEB 12 PY 1999 VL 274 IS 7 BP 3934 EP 3936 DI 10.1074/jbc.274.7.3934 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 166KQ UT WOS:000078575500005 PM 9933581 ER PT J AU Rodighiero, C Aman, AT Kenny, MJ Moss, J Lencer, WI Hirst, TR AF Rodighiero, C Aman, AT Kenny, MJ Moss, J Lencer, WI Hirst, TR TI Structural basis for the differential toxicity of cholera toxin and Escherichia coli heat-labile enterotoxin - Construction of hybrid toxins identifies the A2-domain as the determinant of differential toxicity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INTESTINAL EPITHELIAL-CELLS; VIBRIO-CHOLERAE; ENDOPLASMIC-RETICULUM; B-SUBUNIT; RIBOSYLATION FACTORS; RECEPTOR; PROTEIN; SEQUENCE; BINDING; ACTIVATION AB Cholera toxin (Ctx) and E. coli heat-labile enterotoxin (Etx) are structurally and functionally similar AB, toxins with over 80% sequence identity. When their action in polarized human epithelial (T84) cells was monitored by measuring toxin-induced Cl- ion secretion, Ctx was found to be the more potent of the two toxins. Here, we examine the structural basis for this difference in toxicity by engineering a set of mutant and hybrid toxins and testing their activity in T84 cells, This revealed that the differential toxicity of Ctx and Etx was (i) not due to differences in the A-subunit's C-terminal KDEL targeting motif (which is RDEL in Etx), as a RDEL to RDEL substitution had no effect on cholera toxin activity; (ii) not attributable to the enzymatically active AI-fragment, as hybrid toxins in which the Al-fragment in Ctx was substituted for that of Etx (and vice versa) did not alter relative toxicity; and (iii) not due to the B-subunit, as the replacement of the B-subunit in Ctx for that of Etx caused no alteration in toxicity, thus excluding the possibility that the broader receptor specificity of EtxB is responsible for reduced activity. Remarkably, the difference in toxicity could be mapped to a 10-amino acid segment of the A2-fragment that penetrates the central pore of the B-subunit pentamer, A comparison of the in vitro stability of two hybrid toxins, differing only in this 10-amino acid segment, revealed that the Ctx A2-segment conferred a greater stability to the interaction between the A- and B-subunits than the corresponding: segment from Etx A2. This suggests that the reason for the relative potency of Ctx compared with Etx stems from the increased ability of the A2-fragment of Ctx to maintain holotoxin stability during uptake and transport into intestinal epithelia. C1 Univ Bristol, Sch Med Sci, Dept Pathol & Microbiol, Bristol BS8 1TD, Avon, England. NHLBI, NIH, Bethesda, MD 20892 USA. Childrens Hosp, Combined Program Pediat Gastroenterol & Nutr, Boston, MA 02115 USA. RP Hirst, TR (reprint author), Univ Bristol, Sch Med Sci, Dept Pathol & Microbiol, Univ Walk, Bristol BS8 1TD, Avon, England. EM t.r.hirst@bristol.ac.uk NR 47 TC 40 Z9 45 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 12 PY 1999 VL 274 IS 7 BP 3962 EP 3969 DI 10.1074/jbc.274.7.3962 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 166KQ UT WOS:000078575500010 PM 9933586 ER PT J AU Chiorini, JA Miyamoto, S Harkin, SJ Safer, B AF Chiorini, JA Miyamoto, S Harkin, SJ Safer, B TI Genomic cloning and characterization of the human eukaryotic initiation factor-2 beta promoter SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BETA-SUBUNIT; GENE; FACTOR-EIF-2; EXPRESSION AB The translation initiation factor eIF2 consists of three subunits that are present in equal molar amounts. The genomic DNA containing the gene for eIF2 beta and its promoter were cloned and sequenced to characterize further the mechanism of their regulated synthesis. Whereas Southern blot analysis indicated that a number of copies of the gene may exist, only one full-length intron-containing copy was identified. Similar to the eIF2 alpha promoter, the eIF2 beta promoter is TATA-less, CAAT-less, and CC-rich and contains an alpha-Pal binding motif, Mutation of the alpha-Pal binding sequence resulted in an 8-fold decrease in activity when assayed by the luciferase reporter gene constructs. The data suggest a common mechanism of transcriptional control for the two cloned subunits of eIF2. C1 NHLBI, DIR, Mol Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Safer, B (reprint author), NHLBI, DIR, Mol Hematol Branch, NIH, Bldg 10,Rm 7D18,MSC 1654, Bethesda, MD 20892 USA. NR 14 TC 5 Z9 5 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 FEB 12 PY 1999 VL 274 IS 7 BP 4195 EP 4201 DI 10.1074/jbc.274.7.4195 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 166KQ UT WOS:000078575500040 PM 9933616 ER PT J AU Posey, SC Bierer, BE AF Posey, SC Bierer, BE TI Actin stabilization by jasplakinolide enhances apoptosis induced by cytokine deprivation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; INTERLEUKIN 1-BETA-CONVERTING ENZYME; CELL ANTIGEN-RECEPTOR; T-LYMPHOCYTES; F-ACTIN; CARCINOMA-CELLS; ZETA-CHAIN; IN-VITRO; DNASE-I; ACTIVATION AB Participation of the actin cytoskeleton in the transduction of proliferative signals has been established through the use of compounds that disrupt the cytoskeleton, To address the possibility that actin also participates in the transduction of an apoptotic signal, we have studied the response of the murine interleukin 2 (IL-2)-dependent T cell line CTLL-20 to treatment with the actin-binding compound jasplakinolide upon IL-2 deprivation, Like phalloidin, jasplakinolide stabilizes F-actin and promotes actin polymerization, Treatment of CTLL-20 cells with jasplakinolide, in the presence or absence of recombinant human IL-2, altered actin morphology as assessed by confocal fluorescence microscopy. Jasplakinolide was not toxic to CTLL-20 cells, nor was apoptosis induced in the presence of exogenous recombinant human IL-2, However, actin stabilization at the time of IL-2 deprivation enhanced apoptosis by changing the time at which CTLL-20 cells committed to the apoptotic pathway. This effect of jasplakinolide correlated with its ability to stabilize polymerized actin, as treatment with a synthetic analog of jasplakinolide with a greatly reduced ability to bind actin, jasplakinolide B, did not enhance apoptosis. The enhancement occurred upstream of the induction of caspase-3-like activity and could be inhibited by the overexpression of the anti-apoptotic protein Bcl-x(L), These data suggest that the actin cytoskeleton plays an active role in modulating lymphocyte apoptosis induced by cytokine deprivation. C1 NHLBI, NIH, Bethesda, MD 20892 USA. Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Div Med Sci, Comm Immunol, Boston, MA 02115 USA. RP Bierer, BE (reprint author), NHLBI, NIH, Bldg 10,Rm 5D49,10 Ctr Dr, Bethesda, MD 20892 USA. FU NCI NIH HHS [T32 CA09141]; NIGMS NIH HHS [T32 GM007753, T32 GM07753-19] NR 52 TC 86 Z9 89 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 FEB 12 PY 1999 VL 274 IS 7 BP 4259 EP 4265 DI 10.1074/jbc.274.7.4259 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 166KQ UT WOS:000078575500050 PM 9933626 ER PT J AU Laird, AD Morrison, DK Shalloway, D AF Laird, AD Morrison, DK Shalloway, D TI Characterization of Raf-1 activation in mitosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; CELL-CYCLE; PLASMA-MEMBRANE; TYROSINE PHOSPHORYLATION; DEPENDENT ACTIVATION; INDEPENDENT MANNER; RAS BINDING; REQUIREMENT; PATHWAY; DOMAIN AB We have used site-directed mutagenesis to explore the mechanisms underlying Raf-1 activation in mitosis, and we have excluded most previously characterized activating interactions. Our results indicate that the primary locus of activation lies in the carboxyl-half of the molecule, although the extent of activation can be influenced by the amino-proximal region, particularly by the Raf-1 zinc finger, We also found that Raf-1 is hyperphosphorylated in mitosis at multiple sites within residues 283-302 and that these hyperphosphorylations are not required for activation, In addition, neither Mek1 nor Mek2 are stably activated in coordination with Raf-1 in nocodazole-arrested cells. Overall, the data suggest that the mechanism(s) responsible for activating Raf-1 during mitosis, and the subsequent downstream effects, are distinct from those involved in growth factor stimulation. C1 Cornell Univ, Biochem Mol & Cell Biol Sect, Ithaca, NY 14853 USA. NCI, Frederick Canc Res & Dev Ctr, ABL, Mol Basis Carcinogenesis Lab,Basic Res Program, Frederick, MD 21702 USA. RP Shalloway, D (reprint author), Cornell Univ, Biochem Mol & Cell Biol Sect, Ithaca, NY 14853 USA. EM dis2@cornell.edu FU NCI NIH HHS [CA 68743, CA32317] NR 82 TC 37 Z9 38 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 FEB 12 PY 1999 VL 274 IS 7 BP 4430 EP 4439 DI 10.1074/jbc.274.7.4430 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 166KQ UT WOS:000078575500071 PM 9933647 ER PT J AU Nash, HA AF Nash, HA TI General anesthesia SO CURRENT BIOLOGY LA English DT Article ID SITES C1 NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Nash, HA (reprint author), NIMH, Mol Biol Lab, Bldg 36, Bethesda, MD 20892 USA. NR 7 TC 5 Z9 5 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD FEB 11 PY 1999 VL 9 IS 3 BP R83 EP R85 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 167AU UT WOS:000078611100006 PM 10021392 ER PT J AU Strumberg, D Pommier, Y Paull, K Jayaraman, M Nagafuji, P Cushman, M AF Strumberg, D Pommier, Y Paull, K Jayaraman, M Nagafuji, P Cushman, M TI Synthesis of cytotoxic indenoisoquinoline topoisomerase I poisons SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ALKALOID FAGARONINE; STRUCTURAL ANALOGS; CYTOSTATIC DRUGS; BACTERIAL SYSTEM; MUTAGENICITY; SAINTOPIN; INHIBITOR; CHLORIDE; AGENT AB A number of indenoisoquinolines were prepared and evaluated for cytotoxicity in human cancer cell cultures and for activity vs topoisomerase 1 (top1). The two most cytotoxic indenoisoquinolines proved to be cis-6-ethyl-5,6,12,13-tetrahydro-2,3-dimethoxy-8,9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (21) and cis-6-allyl-5,6,12,13-tetrahydro-2,3-dimethoxy-6,9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (22), both of which displayed submicromolar mean graph midpoints when tested in 55 human cancer cell cultures. Two of the most potent top1 inhibitors were 6-(3-carboxy-1-propyl)-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (26) and 6-ethyl-2,3-dimethoxy-8,9-(methylenedioxy)-11H-indeno[1,2-c]isoquinolinium chloride (27), both of which also inhibited top2, unwound DNA, and are assumed to be DNA intercalators. However, two additional potent top1 inhibitors, 6-allyl-5,6-dihydro-2,3-dimethoxy-8,9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (13c) and 5,6-dihydro-6-(4-hydroxybut-1-yl)-2,3-dimethoxy-8,9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (19a), did not unwind DNA and did not affect top2, Some of the DNA cleavage sites detected in the presence of the indenoisoquinolines were different from those seen with the camptothecins. The cleavage sites induced by the indenoisoquinolines were reversed by salt treatment, which is consistent with the reversible trapping of top1 cleavable complexes by the indenoisoquinolines. In general, the potencies of the indenoisoquinolines as top1 inhibitors did not correlate with their potencies as cytotoxic agents, as some of the most cytotoxic agents had little if any effect on top1. On the other hand, the most potent of the indenoisoquinolines vs top1 were not the most-cytotoxic. In several cases, moderate activity was observed for both cytotoxicity and activity vs top1. C1 Purdue Univ, Sch Pharm, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47906 USA. NCI, Informat Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Lab, Div Basic Sci, Bethesda, MD 20892 USA. RP Cushman, M (reprint author), Purdue Univ, Sch Pharm, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47906 USA. FU NCI NIH HHS [N01-CM-67260] NR 24 TC 98 Z9 100 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD FEB 11 PY 1999 VL 42 IS 3 BP 446 EP 457 DI 10.1021/jm9803323 PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 166XF UT WOS:000078602600015 PM 9986716 ER PT J AU Williamson, DF Yanovski, SZ AF Williamson, DF Yanovski, SZ TI Appetite-suppressant drugs and valvular heart disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Ctr Dis Control & Prevent, Atlanta, GA 30341 USA. NIH, Bethesda, MD 20892 USA. RP Williamson, DF (reprint author), Ctr Dis Control & Prevent, Atlanta, GA 30341 USA. NR 4 TC 2 Z9 2 U1 0 U2 1 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 FEB 11 PY 1999 VL 340 IS 6 BP 476 EP 476 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 166HW UT WOS:000078571000013 PM 9988618 ER PT J AU Saxena, A Shriml, LM Dean, M Ali, IU AF Saxena, A Shriml, LM Dean, M Ali, IU TI Comparative molecular genetic profiles of anaplastic astrocytomas glioblastomas multiforme and their subsequent recurrences SO ONCOGENE LA English DT Article DE malignant gliomas; recurrence; genetic profiles ID TUMOR-SUPPRESSOR GENE; MALIGNANT BRAIN-TUMORS; GROWTH-FACTOR RECEPTOR; TISSUE INHIBITOR; GELATINASE-A; P53; GLIOMAS; PROGRESSION; EXPRESSION; MUTATION AB Malignant glial tumors (anaplastic astrocytomas and glioblastomas multiforme) arise mostly either from the progression of low grade precursor lesions or rapidly in a de novo fashion and contain distinct genetic alterations. There is, however, a third subset of malignant gliomas in which genetic lesions remain to be identified, Following surgical resection, all gliomas appear to have an inherent tendency to recur, Comparative molecular analysis of ten primary malignant gliomas (three anaplastic astrocytomas and seven glioblastomas multiforme) with their recurrences identified two distinct subgroups of recurrent tumors. In one group, primary tumors harbored genetic aberrations frequently associated with linear progression or ne novo formation pathways of glial tumorigenesis and maintained their genetic profiles upon recurrence. In the other subset with no detectable known genetic mutations at first presentation, the recurrent tumors sustained specific abnormalities associated with pathways of linear progression or ne novo formation. These included loss of genes on chromosomes 17 and 10, mutations in the p53 gene, homozygous deletion of the DMBTA1 and p16 and/or p15 genes and amplification and/or overexpression of CDK4 and alpha form of the PDGF receptor. Recurrent tumors from both groups also displayed an abnormal expression profile of the metalloproteinase, gel A, and its inhibitor, TIMP-2, consistent with their highly invasive behavior, Delineation of the molecular differences between malignant glioblastomas and their subsequent recurrences may have important implications for the development of rational clinical approaches for this neoplasm that remains refractory to existing therapeutic modalities. C1 NCI, Chemoprevent Branch, NIH, Bethesda, MD 20892 USA. NINCDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NCI, Lab Genom Divers, NIH, Frederick, MD 21702 USA. RP Ali, IU (reprint author), NCI, Chemoprevent Branch, NIH, Bethesda, MD 20892 USA. RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 NR 35 TC 31 Z9 31 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 11 PY 1999 VL 18 IS 6 BP 1385 EP 1390 DI 10.1038/sj.onc.1202440 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 165FW UT WOS:000078510900015 PM 10022821 ER PT J AU Ramachandran, S AF Ramachandran, S TI A new curriculum SO CURRENT SCIENCE LA English DT Letter C1 NIAID, Bethesda, MD 20892 USA. RP Ramachandran, S (reprint author), NIAID, 9000 Rockville Pike,Bldg 4,Room 126, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU CURRENT SCIENCE ASSN PI BANGALORE PA C V RAMAN AVENUE, PO BOX 8005, BANGALORE 560 080, INDIA SN 0011-3891 J9 CURR SCI INDIA JI Curr. Sci. PD FEB 10 PY 1999 VL 76 IS 3 BP 263 EP 263 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 168YC UT WOS:000078719900002 ER PT J AU Toda, M Rabkin, SD Kojima, H Martuza, RL AF Toda, M Rabkin, SD Kojima, H Martuza, RL TI Herpes simplex virus as an in situ cancer vaccine for the induction of specific anti-tumor immunity SO HUMAN GENE THERAPY LA English DT Article ID HUMAN BRAIN-TUMORS; IMMUNOCOMPETENT RATS; MALIGNANT GLIOMAS; T-LYMPHOCYTES; GENE-TRANSFER; MUTANT; CELLS; THERAPY; COMPLEX; REPLICATION AB The success of cancer gene therapy is likely to require the targeting of multiple antitumor mechanisms. One strategy involves the use of attenuated, replication-competent virus vectors, such as herpes simplex virus type 1 (HSV-1) mutant G207, which is able to replicate in human tumor cells with resultant cell death and tumor growth inhibition, yet is nonpathogenic in normal tissue. In this study, we demonstrate that infection of established tumors with G207 also induces a highly specific systemic anti-tumor immune response. In a syngeneic, bilateral established subcutaneous tumor model, with mouse CT26 colorectal carcinoma cells in BALB/c mice or M3 melanoma cells in DBA/2 mice, unilateral intratumoral inoculation with G207 caused a significant reduction in the growth of both the inoculated and contralateral noninoculated tumors. This elicited anti-tumor response is dependent on viral infection of the tumor, as intradermal inoculation of G207 in BALB/c mice had no effect on CT26 tumor growth. Treatment of subcutaneous CT26 tumors by intratumoral inoculation of G207 induced a tumor-specific T cell response. CD8(+) cytotoxic T lymphocyte (CTL) activity was generated that recognized a dominant "tumor-specific" major histocompatibility complex (MHC) class I-restricted epitope (AH1) from CT26 cells. In immune-competent animals, G207 is acting as an in situ tumor vaccine. Therefore, intratumoral G207 inoculation is able to inhibit tumor growth both by local cytotoxic viral replication in tumor cells and induction of a systemic anti-tumor immune response. C1 Georgetown Univ, Med Ctr, Dept Neurosurg, Washington, DC 20007 USA. Keio Univ, Sch Med, Dept Physiol, Tokyo 160, Japan. Keio Univ, Sch Med, Dept Neurosurg, Tokyo 160, Japan. Georgetown Univ, Med Ctr, Dept Microbiol & Immunol, Washington, DC 20007 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Georgetown Brain Tumor Ctr, Washington, DC 20007 USA. RP Martuza, RL (reprint author), Georgetown Univ, Med Ctr, Dept Neurosurg, 3800 Reservoir Rd NW, Washington, DC 20007 USA. RI rabkin, samuel/C-2443-2012; Toda, Masahiro/L-2268-2013 OI rabkin, samuel/0000-0003-2344-2795; FU NCI NIH HHS [CA60176]; NINDS NIH HHS [NS32677] NR 38 TC 188 Z9 189 U1 2 U2 10 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 FEB 10 PY 1999 VL 10 IS 3 BP 385 EP 393 DI 10.1089/10430349950018832 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 167DG UT WOS:000078616900006 PM 10048391 ER PT J AU Burstein, GR Zenilman, JM Quinn, TC AF Burstein, GR Zenilman, JM Quinn, TC TI Screening adolescent females for Chlamydia infection - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID TRACHOMATIS C1 Johns Hopkins Univ, Baltimore, MD 21218 USA. NIH, Bethesda, MD 20892 USA. RP Burstein, GR (reprint author), Johns Hopkins Univ, Baltimore, MD 21218 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 FEB 10 PY 1999 VL 281 IS 6 BP 515 EP 515 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 164FQ UT WOS:000078452900027 ER PT J AU Rantanen, T Guralnik, JM Foley, D Masaki, K Leveille, S Curb, JD White, L AF Rantanen, T Guralnik, JM Foley, D Masaki, K Leveille, S Curb, JD White, L TI Midlife hand grip strength as a predictor of old age disability SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PHYSICAL-ACTIVITY; LATE-LIFE; WOMEN; MEN; PEOPLE; HEALTH AB Context Poor muscle strength, functional limitations, and disability often coexist, but whether muscle strength during midlife predicts old age functional ability is not known. Objective To determine whether hand grip strength measured during midlife predicts old age functional limitations and disability in initially healthy men, Design and Setting A 25-year prospective cohort study, the Honolulu Heart Program, which began in 1965 among Japanese-American men living on Oahu, Hawaii. Participants A total of 6089 45- to 68-year-old men who were healthy at baseline and whose maximal hand grip strength was measured from 1965 through 1970, Altogether, 2259 men died over the follow-up period and 3218 survivors participated in the disability assessment in 1991 through 1993, Main Outcome Measures Functional limitations including slow customary walking speed (less than or equal to 0.4 m/s) and inability to rise from a seated position without using the arms, and multiple self-reported upper extremity, mobility, and self-care disability outcomes, Results After adjustment for multiple potential confounders, risk of functional limitations and disability 25 years later increased as baseline hand grip strength. divided into tertiles, declined. The odds ratio (OR) of walking speed of 0.4 m/s or slower was 2.87 (95% confidence interval [CI], 1.76-4.67) in those in the lowest third and 1.79 (95% CI, 1.14-2.81) in the middle third of grip strength vs those in the highest third, The risk of self-care disability was more than 2 times greater in the lowest vs the highest grip strength tertile. Adding chronic conditions identified at follow-up to the models predicting disability reduced the ORs related to grip strength only minimally, Conclusions Among healthy 45- to 68-year-old men, hand grip strength was highly predictive of functional limitations and disability 25 years later. Good muscle strength in midlife may protect people from old age disability by providing a greater safety margin above the threshold of disability. C1 NIA, Epidemiol Demog Biometry Program, NIH, Bethesda, MD 20892 USA. Kuakini Med Ctr, Asia Aging Study, Honolulu, HI USA. Honolulu Heart Program, Honolulu, HI USA. Univ Hawaii, Sch Med, Honolulu, HI 96822 USA. RP Rantanen, T (reprint author), Univ Jyvaskyla, Dept Hlth Sci, POB 35, SF-40351 Jyvaskyla, Finland. EM Taina@maila.jyu.fi RI Rantanen, Taina/O-6579-2016 OI Rantanen, Taina/0000-0002-1604-1945 NR 23 TC 591 Z9 604 U1 5 U2 32 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 FEB 10 PY 1999 VL 281 IS 6 BP 558 EP 560 DI 10.1001/jama.281.6.558 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 164FQ UT WOS:000078452900035 PM 10022113 ER PT J AU LaRochelle, WJ Sakaguchi, K Atabey, N Cheon, HG Takagi, Y Kinaia, T Day, RM Miki, T Burgess, WH Bottaro, DP AF LaRochelle, WJ Sakaguchi, K Atabey, N Cheon, HG Takagi, Y Kinaia, T Day, RM Miki, T Burgess, WH Bottaro, DP TI Heparan sulfate proteoglycan modulates keratinocyte growth factor signaling through interaction with both ligand and receptor SO BIOCHEMISTRY LA English DT Article ID PLASMINOGEN-ACTIVATOR PRODUCTION; INFLAMMATORY BOWEL-DISEASE; AFFINITY BINDING-SITES; FIBROBLAST GROWTH; CELL-GROWTH; EXPRESSION; IDENTIFICATION; STIMULATION; MITOGENESIS; ATTACHMENT AB Keratinocyte growth factor (KGF) is an unusual fibroblast growth factor (FGF) family member in that its activity is largely restricted to epithelial cells, and added heparin/heparan sulfate inhibits its activity in most cell types. The effects of heparan sulfate proteoglycan (HSPG) on binding and signaling by acidic FGF (aFGF) and KGF via the KGFR were studied using surface-bound and soluble receptor isoforms expressed in wild type and mutant Chinese hamster ovary (CHO) cells lacking HSPG. Low concentrations of added heparin (1 mu g/mL) enhanced the affinity of ligand binding to surface-bound KGFR in CHO mutants, as well as ligand-stimulated MAP kinase activation and c-fos induction, but had little effect on binding or signaling in wild type CHO cells. Higher heparin concentrations inhibited KGF, but not aFGF, binding and signaling. In addition to the known interaction between HSPG and KGF, we found that the KGFR also bound heparin. The biphasic effect of heparin on KGF, but not aFGF, binding and signaling suggests that occupancy of the HSPG binding site on the KGFR may specifically inhibit KGF signaling. In contrast to events on the cell surface, added heparin was not required for high-affinity soluble KGF-KGFR interaction. These results suggest that high-affinity ligand binding is an intrinsic property of the receptor, and that the difference between the HSPG-dependent ligand binding to receptor on cell surfaces and the HSPG-independent binding to soluble receptor may be due to other molecule(s) present on cell surfaces. C1 NCI, Cellular & Mol Biol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NIDR, Glycobiol Program, NIH, Bethesda, MD 20892 USA. NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. Amer Red Cross, Holland Lab, Dept Mol Biol, Rockville, MD 20895 USA. RP Bottaro, DP (reprint author), NCI, Cellular & Mol Biol Lab, Div Basic Sci, NIH, Bldg 37,Room 1E24,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM dbottaro@helix.nih.gov RI Bottaro, Donald/F-8550-2010 OI Bottaro, Donald/0000-0002-5057-5334 NR 47 TC 39 Z9 40 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 9 PY 1999 VL 38 IS 6 BP 1765 EP 1771 DI 10.1021/bi982092z PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 170ZK UT WOS:000078837200013 PM 10026256 ER PT J AU Lacroix, L Lacoste, J Reddoch, JF Mergny, JL Levy, DD Seidman, MM Matteucci, MD Glazer, PM AF Lacroix, L Lacoste, J Reddoch, JF Mergny, JL Levy, DD Seidman, MM Matteucci, MD Glazer, PM TI Triplex formation by oligonucleotides containing 5-(1-propynyl)-2 '-deoxyuridine: Decreased magnesium dependence and improved intracellular gene targeting SO BIOCHEMISTRY LA English DT Article ID HELIX-FORMING OLIGONUCLEOTIDE; MESSENGER-RNA LEVELS; MAMMALIAN-CELLS; COOPERATIVE BINDING; SHUTTLE VECTOR; STRANDED DNA; OLIGODEOXYNUCLEOTIDES; ANTISENSE; MUTAGENESIS; INHIBITION AB Oligonucleotides capable of sequence-specific triple helix formation have been proposed as DNA binding ligands useful for modulation of gene expression and for directed genome modification. However, the effectiveness of such tripler-forming oligonucleotides (TFOs) depends on their ability to bind to their target sites within cells, and this can be limited under physiologic conditions. In particular, tripler formation in the pyrimidine motif is favored by unphysiologically low pH and high magnesium concentrations. To address these limitations, a series of pyrimidine TFOs were tested for third-strand binding under a variety of conditions. Those containing 5-(1-propynyl)-2'-deoxyuridine (pdU) and 5-methyl-2'-deoxycytidine (5meC) showed superior binding characteristics at neutral pH and at low magnesium concentrations, as determined by gel mobility shift assays and thermal dissociation profiles. Over a range of Mg2+ concentrations, pdU-modified TFOs formed more stable triplexes than did TFOs containing 2'-deoxythymidine. At 1 mM Mg2+, a Delta Tm of 30 degrees C was observed for pdU- versus T-containing 15-mers (of generic sequence 5' TTTTCTTTTTTCTTTTCT 3') binding to the cognate A:T bp rich site, indicating that pdU-containing TFOs are capable of substantial binding even at physiologically low Mg2+ concentrations. In addition, the pdU-containing TFOs were superior in gene targeting experiments in mammalian cells, yielding 4-fold higher mutation frequencies in a shuttle vector-based mutagenesis assay designed to detect mutations induced by third-strand-directed psoralen adducts. These results suggest the utility of the pdU substitution in the pyrimidine motif for tripler-based gene targeting experiments. C1 Yale Univ, Boyer Ctr 354, Dept Therapeut Radiol, New Haven, CT 06536 USA. Yale Univ, Boyer Ctr 354, Dept Genet, New Haven, CT 06536 USA. Museum Natl Hist Nat, Biophys Lab, CNRS,UA481, INSERM,U201, F-75005 Paris, France. US FDA, Washington, DC 20204 USA. NIA, NIH, Baltimore, MD 21224 USA. Gilead Sci Inc, Foster City, CA 94404 USA. RP Glazer, PM (reprint author), Yale Univ, Boyer Ctr 354, Dept Therapeut Radiol, 295 Congress Ave, New Haven, CT 06536 USA. RI Lacroix, Laurent/C-7024-2009; Mergny, Jean-Louis/E-2860-2013 OI Lacroix, Laurent/0000-0002-6382-9057; Mergny, Jean-Louis/0000-0003-3043-8401 FU NCI NIH HHS [CA64186] NR 41 TC 53 Z9 54 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 9 PY 1999 VL 38 IS 6 BP 1893 EP 1901 DI 10.1021/bi982290q PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 170ZK UT WOS:000078837200027 PM 10026270 ER PT J AU Houser, SR Lakatta, EG AF Houser, SR Lakatta, EG TI Function of the cardiac myocyte in the conundrum of end-stage, dilated human heart failure SO CIRCULATION LA English DT Editorial Material DE editorials; myocardium; sarcoplasmic reticulum; heart failure ID FORCE-FREQUENCY RELATION; VENTRICULAR MYOCYTES; CARDIOMYOPATHY; CALCIUM; MICE; HYPERTROPHY; MECHANISMS; RECEPTOR; PROTEINS C1 NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. Temple Univ, Sch Med, Dept Physiol, Philadelphia, PA 19122 USA. RP Lakatta, EG (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 29 TC 24 Z9 25 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 9 PY 1999 VL 99 IS 5 BP 600 EP 604 PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 164PP UT WOS:000078473000002 PM 9950654 ER PT J AU Detre, KM Guo, P Holubkov, R Califf, RM Sopko, G Bach, R Brooks, MM Bourassa, MG Shemin, RJ Rosen, AD Krone, RJ Frye, RL Feit, F AF Detre, KM Guo, P Holubkov, R Califf, RM Sopko, G Bach, R Brooks, MM Bourassa, MG Shemin, RJ Rosen, AD Krone, RJ Frye, RL Feit, F TI Coronary revascularization in diabetic patients - A comparison of the randomized and observational components of the Bypass Angioplasty Revascularization Investigation (BARI) SO CIRCULATION LA English DT Article DE diabetes mellitus; coronary disease; angioplasty; bypass; surgery C1 Univ Pittsburgh, Pittsburgh, PA 15261 USA. Duke Univ, Med Ctr, Durham, NC USA. NHLBI, Bethesda, MD 20892 USA. St Louis Univ, Ctr Sci, St Louis, MO 63103 USA. Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. Boston Univ, Med Ctr, Boston, MA USA. Jewish Hosp St Louis, St Louis, MO 63110 USA. Mayo Clin, Rochester, NY USA. NYU Med Ctr, Bellevue Hosp, New York, NY 10016 USA. RP Detre, KM (reprint author), Univ Pittsburgh, 127 Parran Hall,130 Desoto St, Pittsburgh, PA 15261 USA. EM detre@edc.gsph.pitt.edu OI Brooks, Maria/0000-0002-2030-7873; Bourassa, Martial G./0000-0002-4439-8650 NR 10 TC 179 Z9 189 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 FEB 9 PY 1999 VL 99 IS 5 BP 633 EP 640 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 164PP UT WOS:000078473000008 PM 9950660 ER PT J AU Af Geijersstam, V Eklund, C Wang, ZH Sapp, M Schiller, JT Dillner, J Dillner, L AF Af Geijersstam, V Eklund, C Wang, ZH Sapp, M Schiller, JT Dillner, J Dillner, L TI A survey of seroprevalence of human papillomavirus types 16, 18 and 33 among children SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID VIRUS-LIKE PARTICLES; CERVICAL INTRAEPITHELIAL NEOPLASIA; SERUM ANTIBODIES; HPV DNA; CHLAMYDIA-TRACHOMATIS; SEXUAL-BEHAVIOR; WOMEN; CAPSIDS; INFECTION; EPITOPES AB The importance and natural history of HPV infections in childhood is incompletely understood. We performed a survey for presence of serum antibodies to HPV capsids among 1031 children aged 0 to 13 years, resident in Stockholm, Sweden. The HPV seroprevalence among these children was 3.0% for HPV16, 0.6% for HPV18 and 2.7% for HPV33. By comparison, among simultaneously analyzed positive control panels comprising women with CIN or healthy women with type-specific cervical HPV DNA, seroprevalence of HPV 16, 18 and 33 was 69%, 58% and 63% respectively. The results suggest that HPV infection in childhood is not common. (C) 1999 Wiley-Liss, Inc. C1 Karolinska Inst, Ctr Microbiol & Tumor Biol, S-17177 Stockholm, Sweden. Univ Mainz, Dept Med Microbiol, D-6500 Mainz, Germany. NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. Natl Publ Hlth Inst, Dept Infect Dis Epidemiol, Helsinki, Finland. Karolinska Hosp, Dept Clin Virol, S-10401 Stockholm, Sweden. RP Dillner, J (reprint author), Karolinska Inst, Ctr Microbiol & Tumor Biol, Box 280, S-17177 Stockholm, Sweden. NR 34 TC 40 Z9 44 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 9 PY 1999 VL 80 IS 4 BP 489 EP 493 DI 10.1002/(SICI)1097-0215(19990209)80:4<489::AID-IJC1>3.0.CO;2-9 PG 5 WC Oncology SC Oncology GA 159AH UT WOS:000078149300001 PM 9935145 ER PT J AU DeFatta, RJ Turbat-Herrera, EA Li, BDL Anderson, W De Benedetti, A AF DeFatta, RJ Turbat-Herrera, EA Li, BDL Anderson, W De Benedetti, A TI Elevated expression of eIF4E in confined early breast cancer lesions: Possible role of hypoxia SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID INITIATION-FACTOR 4E; VASCULAR-PERMEABILITY FACTOR; ENDOTHELIAL GROWTH-FACTOR; TRANSLATION INITIATION; C-MYC; CARCINOMA; OVEREXPRESSION; ACTIVATION; FGF-2; GENE AB The translation-initiation factor eIF4E is rate-limiting for protein synthesis, and its over-expression results in oncogenic transformation of mammalian cells. eIF4E facilitates the synthesis of several powerful tumor angiogenic factors (FGF-2 and VEGF) by selectively enhancing their translation, In breast carcinomas, eIF4E is commonly over-expressed, but the pathology where this elevation is initially manifested is presently unknown. To probe whether the elevation of eIF4E marks an early stage of cancer development, we focused our research on early cancerous lesions, We have analyzed 70 invasive ductal carcinomas (IDCs), 78 ductal carcinomas in situ (DCIS), 51 benign lesions and 4 model cell lines for elevated expression of eIF4E by several different methods: Northern/Western blots, immuno-histochemistry and in situ RT-PCR, eIF4E expression was markedly increased in IDC and in islets of viable cells in the center of poorly vascularized DCIS, which are not easily identifiable by standard histological stains. We also show that expression of eIF4E is increased by hypoxia and, presumably, in hypoxic areas of these lesions, We propose that clonal expansion of cancer cells, permanently over-expressing eIF4E, gives them a critical advantage to survive hypoxia and marks the transition toward the vascular phase of cancer progression, Hence, eIF4E may be useful in stratifying DCIS lesions according to their malignant stage, (C) 1999 Wiley-Liss, Inc. C1 Louisiana State Univ, Med Ctr, Dept Biochem & Mol Biol, Shreveport, LA 71130 USA. Louisiana State Univ, Med Ctr, Dept Pathol, Shreveport, LA 71130 USA. Louisiana State Univ, Med Ctr, Dept Surg, Shreveport, LA 71130 USA. NCI, Frederick, MD 21701 USA. RP De Benedetti, A (reprint author), Louisiana State Univ, Med Ctr, Dept Biochem & Mol Biol, 1501 Kings Highway, Shreveport, LA 71130 USA. FU NCI NIH HHS [CA69148-01A1] NR 23 TC 41 Z9 45 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 FEB 9 PY 1999 VL 80 IS 4 BP 516 EP 522 DI 10.1002/(SICI)1097-0215(19990209)80:4<516::AID-IJC6>3.0.CO;2-7 PG 7 WC Oncology SC Oncology GA 159AH UT WOS:000078149300006 PM 9935150 ER PT J AU Hassan, R Wu, CC Brechbiel, MW Margulies, I Kreitman, RJ Pastan, I AF Hassan, R Wu, CC Brechbiel, MW Margulies, I Kreitman, RJ Pastan, I TI (111)Indium-labeled monoclonal antibody K1: Biodistribution study in nude mice bearing a human carcinoma xenograft expressing mesothelin SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID MALIGNANT MESOTHELIOMA; OVARIAN CANCERS; RADIOIMMUNOSCINTIGRAPHY; IMMUNOSCINTIGRAPHY; ANTIGEN; DIAGNOSIS; LYMPHOMA; OC-125 AB The monoclonal antibody (MAb) KI is a murine IgG(I) that recognizes mesothelin, a differentiation antigen present on mesothelium which is highly expressed on cancers derived from mesothelium, including most ovarian cancers and epithelioid mesotheliomas. MAb KI was conjugated to 2-(p-isothiocyanatobenzyl)-cyclohexyl- diethylenetriaminepentaacetic acid and labeled with (111)ln. The biodistribution of (111)ln-KI was studied in athymic nude mice bearing 2 s.c. tumors, one expressing a stably transfected plasmid encoding mesothelin and one composed of the parental untransfected A431 epidermoid carcinoma cells which do not express mesothelin. Tumor-bearing mice were given an i.v. injection of (111)ln-KI and killed at different time points to determine the uptake of radiolabeled antibody. Significantly higher uptake was seen in antigen-positive tumors at all time points, with peak values at 72 hr (52.9% vs. 8% of the injected dose/g tissue for antigen-positive and antigen-negative tumors, respectively). Uptake in antigen-positive tumors was higher than the blood level at all time points, and the tumors contained a high level of the radiolabeled MAb even at 7 days (28.6% of the injected dose/g tumor). Published 1999 Wiley-Liss, Inc. C1 NCI, Mol Biol Lab, Div Canc Biol, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. NCI, RadioImmune & Inorgan Chem Sect, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Div Canc Biol, NIH, 37-4E16,37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. NR 23 TC 27 Z9 27 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 9 PY 1999 VL 80 IS 4 BP 559 EP 563 DI 10.1002/(SICI)1097-0215(19990209)80:4<559::AID-IJC13>3.0.CO;2-Y PG 5 WC Oncology SC Oncology GA 159AH UT WOS:000078149300013 PM 9935157 ER PT J AU De Luca, A Casamassimi, A Selvam, MP Losito, S Ciardiello, F Agrawal, S Salomon, DS Normanno, N AF De Luca, A Casamassimi, A Selvam, MP Losito, S Ciardiello, F Agrawal, S Salomon, DS Normanno, N TI EGF-related peptides are involved in the proliferation and survival of MDA-MB-468 human breast carcinoma cells SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID EPIDERMAL GROWTH-FACTOR; MAMMARY EPITHELIAL-CELLS; ANTISENSE OLIGONUCLEOTIDES; CANCER CELLS; APOPTOSIS; AMPHIREGULIN; EXPRESSION; CRIPTO; ALPHA; DEATH AB A majority of human breast carcinomas co-express the epidermal growth factor (EGF)-like peptides CRIPTO (CR), amphiregulin (AR) and transforming growth factor alpha (TGF-alpha). MDA-MB-468 breast carcinoma cells express CR, AR and TGF alpha, while SK-BR-3 cells express CR and TGF-alpha. Anti-sense phosphorothioate oligodeoxynucleotides (AS S-oligos) directed against either CR or TGF-alpha inhibit the proliferation of both cell lines. A 40-50% growth inhibition was observed at a 2-mu M concentration of each AS S-oligo. Treatment with the AR AS S-oligo also resulted in a significant inhibition of MDA-MB-468 anchorage dependent growth (ADG), No significant growth inhibition was observed when MDA-MB-468 or SK-BR-3 cells were treated with a mis-sense S-oligo, The AS S-oligos inhibited the expression of AR, CR or TGF-alpha proteins and mRNAs, as assessed by immuno-cytochemistry and semi-quantitative RT-PCR. An additive growth-inhibitory effect was observed when MDA-MB-468 cells were treated with a combination of EGF-related AS S-oligos, Indeed, treatment of MDA-MB-468 cells with a combination of AR, CR and TGF-alpha AS S-oligos resulted in about 70% growth inhibition at a concentration of 0.7 mu M each. Finally, treatment of MDA-MB-468 cells with a combination either of the 3 AS S-oligos or of an EGF receptor-blocking antibody (MAb 225) and either CR, AR or TGF alpha AS S-oligos resulted in a significant increase in DNA fragmentation. Our data suggest that the EGF-related peptides are involved in the proliferation and survival of breast carcinoma cells. (C) 1999 Wiley-Liss, Inc. C1 ITN, Fdn Pascale, I-80131 Naples, Italy. DBA, CBER, Food & Drug Adm, Rockville, MD USA. Univ Naples Federico II, Fac Med & Chirurg, Dipartimento Endocrinol & Oncol Mol & Clin, Cattedra Oncol Med, Naples, Italy. Hybridon Inc, Cambridge, MA USA. NCI, LTIB, Tumor Growth Factor Sect, NIH, Bethesda, MD 20892 USA. RP Normanno, N (reprint author), ITN, Fdn Pascale, I-80131 Naples, Italy. RI De Luca, Antonella/J-8737-2016; OI De Luca, Antonella/0000-0001-5762-447X; Ciardiello, Fortunato/0000-0002-3369-4841; Normanno, Nicola/0000-0002-7158-2605 NR 20 TC 36 Z9 37 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 FEB 9 PY 1999 VL 80 IS 4 BP 589 EP 594 DI 10.1002/(SICI)1097-0215(19990209)80:4<589::AID-IJC17>3.0.CO;2-D PG 6 WC Oncology SC Oncology GA 159AH UT WOS:000078149300017 PM 9935161 ER PT J AU Svetkey, LP Simons-Morton, D Vollmer, WM Appel, LJ Conlin, PR Ryan, DH Ard, J Kennedy, BM AF Svetkey, LP Simons-Morton, D Vollmer, WM Appel, LJ Conlin, PR Ryan, DH Ard, J Kennedy, BM CA DASH Res Grp TI Effects of dietary patterns on blood pressure - Subgroup analysis of the Dietary Approaches to Stop Hypertension (DASH) randomized clinical trial SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT Scientific Session of the American-Federation-of-Medical-Research - Biomedicine 97 CY APR 27, 1997 CL WASHINGTON, D.C. SP Amer Federat Med Res ID POTASSIUM AB Objective: To determine the effects of dietary patterns on blood pressure in subgroups. Methods: Dietary Approaches to Stop Hypertension (DASH) was a randomized controlled feeding study conducted at 4 academic medical centers. Participants were 459 adults with untreated systolic blood pressure less than 160 mm Hg and diastolic blood pressure 80 to 95 mm Hg. For 3 weeks, participants were fed a "control" diet. They were then randomized to 8 weeks of (1) control diet; (2) a diet rich in fruits and vegetables; or (3) a combination diet rich in fruits, vegetables, and low-fat dairy foods, and reduced in saturated fat, total fat, and cholesterol (the DASH combination diet). Weight and salt intake were held constant. Change in diastolic blood pressure was the primary outcome variable, and systolic blood pressure a secondary outcome. Subgroups analyzed included race, sex, age, body mass index, years of education, income, physical activity, alcohol intake, and hypertension status. Results: The combination diet significantly lowered systolic blood pressure in all subgroups (P<.008), and significantly lowered diastolic blood pressure (P<.01) in all but 2 subgroups. The fruits-and-vegetables diet also reduced blood pressure in the same subgroups, but to a lesser extent. The combination diet lowered systolic blood pressure significantly more in African Americans (6.8 mm Hg) than in whites (3.0 mm Hg), and in hypertensive subjects (11.4 mm Hg) than in nonhypertensive subjects (3.4 mm Hg) (P<.05 for both interactions). Conclusions: The DASH combination diet, without sodium reduction or weight loss, significantly lowered blood pressure in virtually all subgroups examined, and was particularly effective in African Americans and those with hypertension. The DASH combination diet may be an effective strategy for preventing and treating hypertension in a broad cross section of the population, including segments of the population at highest risk for blood pressure-related cardiovascular disease. C1 Duke Univ, Med Ctr, Dept Med, Hypertens Ctr, Durham, NC 27705 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Ctr Hlth Res, Portland, OR USA. Johns Hopkins Univ, Baltimore, MD USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Pennington Biomed Res Ctr, Baton Rouge, LA USA. RP Svetkey, LP (reprint author), Duke Univ, Med Ctr, Dept Med, Hypertens Ctr, 3020 Pickett Rd,Suite 401, Durham, NC 27705 USA. FU NHLBI NIH HHS [HL50968, HL50972, HL50981] NR 26 TC 238 Z9 247 U1 1 U2 24 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD FEB 8 PY 1999 VL 159 IS 3 BP 285 EP 293 DI 10.1001/archinte.159.3.285 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 163ZR UT WOS:000078437600009 PM 9989541 ER PT J AU Burke, TR Luo, J Yao, ZJ Gao, Y Zhao, H Milne, GWA Guo, RB Voigt, JH King, CR Yang, DJ AF Burke, TR Luo, J Yao, ZJ Gao, Y Zhao, H Milne, GWA Guo, RB Voigt, JH King, CR Yang, DJ TI Monocarboxylic-based phosphotyrosyl mimetics in the design of Grb2 SH2 domain inhibitors SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID HIGH-AFFINITY; CRYSTAL-STRUCTURES; LIGAND-BINDING; PEPTIDE; P56(LCK); SITE AB Three monocarboxylic-containing analogues, O-carboxymethyltyrosine (cmT, 5), 4-(carboxymethyl)phenylalanine (cmF, 6), and 4-(carboxydifluoromethyl)phenylalanine (F(2)cmF, 7) were utilized as phosphotyrosyl (pTyr) replacements in a high affinity a-bend mimicking platform, where they exhibited IC50 values of 2.5 mu M, 65 mu M and 28 mu M, respectively, in a Grb2 SH2 domain Biacore binding assay. When a terminal Na-oxalyl axillary was utilized to enhance ligand interactions with a critical SH2 domain Arg67 residue (alpha A-helix), binding potencies increased from 4- to 10-fold, resulting in submicromolar affinity for cmF (IC50 = 0.6 mu M) and low micromolar affinity for F(2)cmF (IC50 = 2 mu M) Cell lysate binding studies also showed inhibition of cognate Grb2 binding to the p185(erbB-2) phosphoprotein in the same rank order of potency as observed in the Biacore assay. These results indicate the potential value of cmF and F(2)cmF residues as pTyr mimetics for the study of Grb2 SH2 domains and suggest new strategies for improvements in inhibitor design. (C) 1999 Published by Elsevier Science Ltd. C1 NCI, Med Chem Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Washington, DC 20007 USA. RP Burke, TR (reprint author), NCI, Med Chem Lab, Div Basic Sci, NIH, Bldg 37,Room 5C06, Bethesda, MD 20892 USA. RI Burke, Terrence/N-2601-2014; Yao, Zhu-Jun/E-7635-2015 NR 26 TC 38 Z9 40 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD FEB 8 PY 1999 VL 9 IS 3 BP 347 EP 352 DI 10.1016/S0960-894X(98)00740-9 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 168TB UT WOS:000078707800010 PM 10091682 ER PT J AU Coop, A Jacobson, AE AF Coop, A Jacobson, AE TI The LMC delta opioid recognition pharmacophore: Comparison of SNC80 and oxymorphindole SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID MESSAGE-ADDRESS CONCEPT; RECEPTOR-BINDING; AGONISTS; ANTAGONISTS; RESIDUE AB A recognition pharmacophore for the delta opioid receptor was developed de novo. Through the use of the pharmacophore and a novel four-point recognition model, major differences were observed between oxymorphindole and SNC80. This work suggests that these two classes of delta selective opioids do not bind to the delta opioid receptor in the same orientation. (C) 1999 Published by Elsevier Science Ltd. C1 NIDDKD, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RP Coop, A (reprint author), NIDDKD, Med Chem Lab, NIH, Bldg 8,Room B1-23, Bethesda, MD 20892 USA. NR 11 TC 16 Z9 16 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD FEB 8 PY 1999 VL 9 IS 3 BP 357 EP 362 DI 10.1016/S0960-894X(98)00745-8 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 168TB UT WOS:000078707800012 PM 10091684 ER PT J AU Zhang, J Kovac, P AF Zhang, J Kovac, P TI A highly efficient preparation of neoglycoconjugate vaccines using subcarriers that bear clustered carbohydrate antigens SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID IMMUNOGENICITY; PROTEIN; GLYCOSIDES AB A limited amount of spacer-equipped carbohydrate haptens was linked by reductive amination to a subcarrier, an oligopeptide containing 16 amino groups, to give a hapten-carrying subcarrier (HCS). It was then linked, via the remaining free amino groups, to chicken serum albumin (CSA) to give a cross-linked neoglycoconjugate bearing the haptens in the form of clusters. Alternatively, the same type of a glycoconjugate, but with higher conjugation efficiency, was obtained when HCS was treated successively with squaric acid diethyl ester and CSA. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 NIDDK, NIH, Bethesda, MD 20892 USA. RP Kovac, P (reprint author), NIDDK, NIH, 8 Ctr Dr, Bethesda, MD 20892 USA. NR 22 TC 10 Z9 10 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD FEB 8 PY 1999 VL 9 IS 3 BP 487 EP 490 DI 10.1016/S0960-894X(99)00018-9 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 168TB UT WOS:000078707800035 PM 10091707 ER PT J AU Antzutkin, ON Tycko, R AF Antzutkin, ON Tycko, R TI High-order multiple quantum excitation in C-13 nuclear magnetic resonance spectroscopy of organic solids SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID ANGLE-SPINNING NMR; ROTATING SOLIDS; STATE NMR; TORSIONAL ANGLE; DYNAMICS; FILMS; POLARIZATION; TRANSITIONS; ADAMANTANE; SILICON AB Excitation and detection of high-order multiple quantum (MQ) coherences among C-13 nuclear spins in singly-C-13-labeled organic solids is demonstrated experimentally. MQ signals involving at least ten quanta of spin angular momentum are observed in nuclear magnetic resonance (NMR) measurements on polycrystalline L-methionine-methyl-C-13 and L-alanine-1-C-13, using a time-reversible multiple pulse excitation sequence modified specifically for experiments on systems with weak homonuclear dipole-dipole couplings and strong inhomogeneous interactions such as anisotropic chemical shifts. The feasibility of high-order MQ excitation and detection in C-13-labeled organic solids promises to expand significantly the range of applications of MQ NMR as a structural tool, to include such systems as C-13- labeled synthetic polymers and biopolymers. (C) 1999 American Institute of Physics. [S0021-9606(99)01906-6]. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. NR 45 TC 49 Z9 49 U1 1 U2 5 PU AMER INST PHYSICS PI WOODBURY PA CIRCULATION FULFILLMENT DIV, 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2999 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD FEB 8 PY 1999 VL 110 IS 6 BP 2749 EP 2752 DI 10.1063/1.477876 PG 4 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 163AJ UT WOS:000078379800002 ER PT J AU Schuback, DE Mulligan, EL Sims, KB Tivol, EA Greenberg, BD Chang, SF Yang, SL Mau, YC Shen, CY Ho, MS Yang, NH Butler, MG Fink, S Schwartz, CE Berlin, F Breakefield, XO Murphy, DL Hsu, YPP AF Schuback, DE Mulligan, EL Sims, KB Tivol, EA Greenberg, BD Chang, SF Yang, SL Mau, YC Shen, CY Ho, MS Yang, NH Butler, MG Fink, S Schwartz, CE Berlin, F Breakefield, XO Murphy, DL Hsu, YPP TI Screen for MAOA mutations in target human groups SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE biogenic amines; monoamine oxidase; mental retardation; X-linked disorders; genetics ID MONOAMINE OXIDASE-A; FRAGILE-X SYNDROME; PRESSOR SENSITIVITY CHANGES; MENTALLY-RETARDED MALES; GENE; PLASMA; BEHAVIOR; EMPHASIS; PLATELET; DISEASE AB Brunner et al. [1993: Am J Hum Genet 52: 1032-1039; 1993: Science 262:578-580] described males with an MAO-A deficiency state resulting from a premature stop codon in the coding region of the MAOA gene. This deficiency state was associated with abnormal levels of amines and amine metabolites in urine and plasma of affected males, as well as low normal intelligence and apparent difficulty in impulse control, including inappropriate sexual behavior. In the present study, disruption of the MAOA gene was evaluated in males with mental retardation with and without a history of sexually deviant behavior, as well as normal controls, healthy males, and patients with other diseases (Parkinson disease, Lesch-Nyhan syndrome). When available, plasma samples were evaluated first for levels of 3-methoxy, 4-hydroxyphenolglycol (MHPG), a metabolite of norepinephrine which serves as the most sensitive index of MAO-A activity in humans. Blood DNA from individuals with abnormally low MHPG, and from other individuals for whom metabolite levels were not available, were screened for nucleotide variations in the coding region of the MAOA gene by single-strand conformational polymorphism (SSCP) analysis across all 15 exons and splice junctions, and by sequencing, when indicated by either altered metabolites or SSCP shifts. No evidence for mutations disrupting the MAOA gene was found in 398 samples from the target populations, including institutionalized mentally retarded males (N = 352) and males participating in a sexual disorders clinic (N = 46), as well as control groups (N = 75). These studies indicate that MAOA deficiency states are not common in humans. Am. J. Med. Genet. (Neuropsychiatr. G;enet.) 88:25-28, 1999. (C) 1999 Wiley-Liss, Inc. C1 Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. Tainan Educ Nursing Inst, Tainan, Taiwan. Vanderbilt Univ, Sch Med, Dept Pediat, Div Genet, Nashville, TN 37212 USA. JC Self Res Inst, Greenwood, SC USA. Greenwood Genet Ctr, Greenwood, SC 29646 USA. Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. Natl Tsing Hua Univ, Dept Life Sci, Hsinchu, Taiwan. RP Breakefield, XO (reprint author), Massachusetts Gen Hosp E, Mol Neurogenet Unit, 13th St,Bldg 149, Charlestown, MA 02129 USA. RI Shen, CY/F-6271-2010 FU NICHD NIH HHS [P01 HD030329]; NIMH NIH HHS [MH52416]; NINDS NIH HHS [NS21921] NR 26 TC 20 Z9 20 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 FEB 5 PY 1999 VL 88 IS 1 BP 25 EP 28 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 163GX UT WOS:000078397400004 PM 10050962 ER PT J AU Greenberg, BD Tolliver, TJ Huang, SJ Li, Q Bengel, D Murphy, DL AF Greenberg, BD Tolliver, TJ Huang, SJ Li, Q Bengel, D Murphy, DL TI Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE serotonin transporter promoter; genetic variants; platelet serotonin uptake ID BINDING AB The human serotonin transporter (5-HTT), encoded by a single gene on chromosome 17q11.2, is expressed in brain and blood cells. 5-HTT is implicated in mood and anxiety regulation, and is where antidepressant and antianxiety drugs initially act in the brain, A 5-HTT-linked promoter region (5-HTTLPR) insertion/deletion polymorphism with long (l) and short (s) forms affects transporter expression and function. The s variant reduced 5-HTT gene transcription in a reporter gene construct and human lymphoblasts, resulting in reduced transporter levels and 5-HT uptake, acting as a dominant allele, In this study, we investigated the expression and function of 5-HTT in platelets from healthy male volunteers. The l variant was associated with more rapid initial platelet 5-HT uptake (V-max), the index of platelet 5-HTT function most clearly heritable, while the s allele was dominant. The 5-HTTLPR genotype had no effect on platelet [H-3]paroxetine binding (B-max), affinity for [H-3]5-HT or [H-3]paroxetine, or 5-HT content. The 5-HT uptake findings support a functional difference in the two 5-HTTLPR variants, reinforcing their attractiveness as candidate genes in neuropsychiatric research, Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:83-87, 1999. Published 1999 Wiley-Liss, Inc. C1 NIMH, Adult OCD Res Unit, Clin Sci Lab, Bethesda, MD 20892 USA. RP Greenberg, BD (reprint author), NIMH, Adult OCD Res Unit, Clin Sci Lab, Bldg 10,Room 3D-41, Bethesda, MD 20892 USA. EM bdg@helix.nih.gov NR 17 TC 402 Z9 414 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 FEB 5 PY 1999 VL 88 IS 1 BP 83 EP 87 DI 10.1002/(SICI)1096-8628(19990205)88:1<83::AID-AJMG15>3.0.CO;2-0 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 163GX UT WOS:000078397400015 PM 10050973 ER PT J AU Mu, Y Kamada, H Kaneda, Y Yamamoto, Y Kodaira, H Tsunoda, S Tsutsumi, Y Maeda, M Kawasaki, K Nomizu, M Yamada, Y Mayumi, T AF Mu, Y Kamada, H Kaneda, Y Yamamoto, Y Kodaira, H Tsunoda, S Tsutsumi, Y Maeda, M Kawasaki, K Nomizu, M Yamada, Y Mayumi, T TI Bioconjugation of laminin peptide YIGSR with poly(styrene co-maleic acid) increases its antimetastatic effect on lung metastasis of B16-BL6 melanoma cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE peptide modification; YIGSR; poly(styrene-co-maleic anhydrid); plasma half-life; albumin; binding affinity ID NECROSIS-FACTOR-ALPHA; POLYETHYLENE-GLYCOL; ANTITUMOR POTENCY; MOLECULAR DESIGN; AMINO-ACIDS; TUMOR; DERIVATIVES AB A comb-shaped polymeric modifier, SMA [poly(styrene comaleic anhydride)], which binds to plasma albumin in blood was used to modify the synthetic cell-adhesive laminin peptide YIGSR, and its inhibitory effect on experimental lung metastasis of B16-BL6 melanoma cells was examined. YIGSR was chemically conjugated with SMA via formation of an amide bond between the N-terminal amino group of YIGSR and the carboxyl anhydride of SMA. The antimetastatic effect of SMA-conjugated YIGSR was approximately 50-fold greater than that of native YIGSR. When injected intravenously, SMA-YIGSR showed a 10-fold longer plasma half-life than native YIGSR in vivo. In addition, SMA-YIGSR had the same binding affinity to plasma albumin as SMA, while native YIGSR did not bind to albumin. These findings suggested that the enhanced antimetastatic effect of SMA-YIGSR may be due to its prolonged plasma half-life by binding to plasma albumin, and that bioconjugation of in vivo unstable peptides with SMA may facilitate their therapeutic use, (C) 1999 Academic Press. C1 Osaka Univ, Grad Sch Pharmaceut Sci, Dept Biopharmaceut, Suita, Osaka 5650871, Japan. Kobe Gakuin Univ, Fac Pharmaceut Sci, Nishi Ku, Kobe, Hyogo 6512180, Japan. Natl Inst Dent & Craniofacial Res, Mol Biol Sect, NIH, Bethesda, MD 20892 USA. RP Mayumi, T (reprint author), Osaka Univ, Grad Sch Pharmaceut Sci, Dept Biopharmaceut, 1-6 Yamadaoka, Suita, Osaka 5650871, Japan. EM mayumi@phs.osaka-u.ac.jp OI Tsunoda, Shin-ichi/0000-0003-3299-2182 NR 24 TC 27 Z9 30 U1 1 U2 8 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 FEB 5 PY 1999 VL 255 IS 1 BP 75 EP 79 DI 10.1006/bbrc.1999.9930 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 166WA UT WOS:000078599700014 PM 10082658 ER PT J AU Chakravarti, D Ogryzko, V Kao, HY Nash, A Chen, HW Nakatani, Y Evans, RM AF Chakravarti, D Ogryzko, V Kao, HY Nash, A Chen, HW Nakatani, Y Evans, RM TI A viral mechanism for inhibition of p300 and PCAF acetyltransferase activity SO CELL LA English DT Article ID STEROID-RECEPTOR COACTIVATOR-1; HISTONE ACETYLTRANSFERASE; TRANSCRIPTIONAL ADAPTER; RNA-POLYMERASE; CELL-CYCLE; ACTIVATION; ACETYLATION; BINDING; CBP; PROTEINS AB Nucleosomal histone modification is believed to be a critical step in the activation of RNA polymerase II-dependent transcription. p300/CBP and PCAF histone acetyltransferases (HATs) are coactivators for several transcription factors, including nuclear hormone receptors, p53, and Stat1 alpha, and participate in transcription by forming an activation complex and by promoting histone acetylation. The adenoviral E1A oncoprotein represses transcriptional signaling by binding to p300/CBP and displacing PCAF and p/CIP proteins from the complex. Here, we show that E1A directly represses the HAT activity of both p300/CBP and PCAF in vitro and p300-dependent transcription in vivo. Additionally, E1A inhibits nucleosomal histone modifications by the PCAF complex and blocks p53 acetylation. These results demonstrate the modulation of HAT activity as a novel mechanism of transcriptional regulation. C1 Salk Inst Biol Studies, Gene Express Lab, La Jolla, CA 92037 USA. Univ Penn, Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA. NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA. RP Chakravarti, D (reprint author), Salk Inst Biol Studies, Gene Express Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. RI Ogryzko, Vasily/M-6665-2015 OI Ogryzko, Vasily/0000-0002-8548-1389 NR 44 TC 280 Z9 285 U1 2 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD FEB 5 PY 1999 VL 96 IS 3 BP 393 EP 403 DI 10.1016/S0092-8674(00)80552-8 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 165HE UT WOS:000078514600012 PM 10025405 ER PT J AU Hamamori, Y Sartorelli, V Ogryzko, V Puri, PL Wu, HY Wang, JYJ Nakatani, Y Kedes, L AF Hamamori, Y Sartorelli, V Ogryzko, V Puri, PL Wu, HY Wang, JYJ Nakatani, Y Kedes, L TI Regulation of histone acetyltransferases p300 and PCAF by the bHLH protein twist and adenoviral oncoprotein E1A SO CELL LA English DT Article ID LOOP-HELIX PROTEIN; TRANSCRIPTION FACTORS; MUSCLE DIFFERENTIATION; GENE-TRANSCRIPTION; DEVELOPING SOMITES; GROWTH-FACTOR; CELL-CYCLE; MYOD; COACTIVATOR; ACETYLATION AB Histone acetyltransferases (HAT) play a critical role in transcriptional control by relieving repressive effects of chromatin, and yet how HATs themselves are regulated remains largely unknown. Here, it is shown that Twist directly binds two independent HAT domains of acetyltransferases, p300 and p300/CBP-associated factor (PCAF), and directly regulates their HAT activities. The N terminus of Twist is a primary domain interacting with both acetyltransferases, and the same domain is required for inhibition of p300-dependent transcription by Twist. Adenovirus E1A protein mimics the effects of Twist by inhibiting the HAT activities of p300 and PCAF. These findings establish a cogent argument for considering the HAT domains as a direct target for acetyltransferase regulation by both a cellular transcription factor and a viral oncoprotein. C1 Univ So Calif, Sch Med, Dept Biochem & Mol Biol, Inst Med Genet, Los Angeles, CA 90033 USA. NICHHD, Lab Mol Growth Regulat, Bethesda, MD 20892 USA. Univ Calif San Diego, Ctr Mol Genet, Dept Biol, La Jolla, CA 92093 USA. Univ Rome La Sapienza, Policlin Umberto I, Inst Clin Med 1, Fdn Andrea Cesalpino,Lab Gene Express, I-00161 Rome, Italy. RP Hamamori, Y (reprint author), Univ So Calif, Sch Med, Dept Biochem & Mol Biol, Inst Med Genet, Los Angeles, CA 90033 USA. RI Ogryzko, Vasily/M-6665-2015 OI Ogryzko, Vasily/0000-0002-8548-1389 FU NCI NIH HHS [CA58320, R01 CA058320]; Telethon [1072] NR 55 TC 292 Z9 298 U1 1 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD FEB 5 PY 1999 VL 96 IS 3 BP 405 EP 413 DI 10.1016/S0092-8674(00)80553-X PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 165HE UT WOS:000078514600013 PM 10025406 ER PT J AU Hayashi, T Tsao, LI Cadet, JL Su, TP AF Hayashi, T Tsao, LI Cadet, JL Su, TP TI [D-Ala(2), D-Leu(5)]enkephalin blocks the methamphetamine-induced c-fos mRNA increase in mouse striatum SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE DADLE ([D-Ala(2), D-Leu(5)]enkephalin); c-fos mRNA; methamphetamine; opioid ID INDUCED NEUROTOXICITY; MICE AB The administration of methamphetamine caused an increase of c-fos mRNA in the striatum of the mouse. A systemic injection of the delta-opioid receptor agonist, [D-Ala(2), D-Leu(5)]enkephalin (DADLE), attenuated the c-Sos mRNA increase induced by methamphetamine. These results suggest that endogenous S-opioid peptides might counteract certain genomic influences exerted by psychostimulants such as methamphetamine. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIDA, Mol Neuropsychiat Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Su, TP (reprint author), NIDA, Mol Neuropsychiat Sect, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Hayashi, Teruo/A-9690-2008 NR 8 TC 9 Z9 9 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD FEB 5 PY 1999 VL 366 IS 2-3 BP R7 EP R8 DI 10.1016/S0014-2999(98)00947-9 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 166EV UT WOS:000078564000027 PM 10082218 ER PT J AU Sora, I Li, XF Funada, M Kinsey, S Uhl, GR AF Sora, I Li, XF Funada, M Kinsey, S Uhl, GR TI Visceral chemical nociception in mice lacking mu-opioid receptors: effects of morphine, SNC80 and U-50,488 SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE visceral pain; writhing test; mu-opioid receptor knockout mouse ID INDUCED ANALGESIA; STIMULI AB Writhing responses to intraperitoneal acetic acid administration and their modulation by mu-, kappa- and delta-opioid receptor agonists were compared in wild-type and mu-opioid receptor knockout mice. Unpretreated homozygous knockout mice displayed less writhing than wild-type mice. U-50,488 [trans-3,4-dichloro-N-methyl-N-[2-(1-pyrolidinyl)cyclohexyl]-benzeneacetamide]) reduced writhing responses in wild-type and knockouts. Morphine and SNC80 [(+)-4-[9-alpha-R)-alpha-(2S,5RO-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N, N-diethylbenzamide] were effective in wild-type mice but ineffective in knockouts. CL-opioid receptors appear to play important roles in responses to this visceral nociceptive stimulus and its modulation by mu- and delta-opioid receptor agonists. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIDA, Mol Neurobiol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Uhl, GR (reprint author), NIDA, Mol Neurobiol Branch, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 8 TC 45 Z9 46 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD FEB 5 PY 1999 VL 366 IS 2-3 BP R3 EP R5 DI 10.1016/S0014-2999(98)00933-9 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 166EV UT WOS:000078564000026 PM 10082217 ER PT J AU Foti, M Omichinski, JG Stahl, S Maloney, D West, J Schweitzer, BI AF Foti, M Omichinski, JG Stahl, S Maloney, D West, J Schweitzer, BI TI Effects of nucleoside analog incorporation on DNA binding to the DNA binding domain of the GATA-1 erythroid transcription factor SO FEBS LETTERS LA English DT Article DE ganciclovir; cytosine arabinoside; GATA-1; binding; nuclear magnetic resonance ID THYMIDINE KINASE GENE; RESTRAINED MOLECULAR-DYNAMICS; RELAXATION MATRIX REFINEMENT; BRAIN-TUMORS; IN-VIVO; 9-(1,3-DIHYDROXY-2-PROPOXYMETHYL)GUANINE TRIPHOSPHATE; 1-BETA-D-ARABINOFURANOSYLCYTOSINE 5'-TRIPHOSPHATE; TRANSPLANT RECIPIENTS; COLONY FORMATION; NUCLEIC-ACIDS AB We investigate here the effects of the incorporation of the nucleoside analogs araC (1-beta-D-arabinofuranosylcytosine) and ganciclovir (9-[(1,3-dihydroxy-2-propoxy)methyl] guanine) into the DNA binding recognition sequence for the GATA-1 erythroid transcription factor. A 10-fold decrease in binding affinity was observed for the ganciclovir-substituted DNA complex in comparison to an unmodified DNA of the same sequence composition. AraC substitution did not result in any changes in binding affinity, H-1-N-15 HSQC and NOESY NMR experiments revealed a number of chemical shift changes in both DNA and protein in the ganciclovir-modified DNA-protein complex when compared to the unmodified DNA-protein complex, These changes in chemical shift and binding affinity suggest a change in the binding mode of the complex when ganciclovir is incorporated into the GATA DNA binding site. (C) 1999 Federation of European Biochemical Societies. C1 Florida Hosp Med Ctr, Walt Disney Mem Canc Inst, Orlando, FL 32826 USA. Univ Cent Florida, Dept Chem, Orlando, FL 32816 USA. Univ S Florida, Dept Chem, Tampa, FL 33620 USA. NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Schweitzer, BI (reprint author), Mol Staging Inc, 4 Pearl Court, Allendale, NJ 07401 USA. NR 42 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD FEB 5 PY 1999 VL 444 IS 1 BP 47 EP 53 DI 10.1016/S0014-5793(99)00026-5 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 167CZ UT WOS:000078616200010 PM 10037146 ER PT J AU Matsunaga, J Sinha, D Pannell, L Santis, C Solano, F Wistow, GJ Hearing, VJ AF Matsunaga, J Sinha, D Pannell, L Santis, C Solano, F Wistow, GJ Hearing, VJ TI Enzyme activity of macrophage migration inhibitory factor toward oxidized catecholamines SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DOPAMINE INDUCES APOPTOSIS; FACTOR MIF; PARKINSONS-DISEASE; CRYSTAL-STRUCTURE; DOPACHROME TAUTOMERASE; MOLECULAR-CLONING; SUBSTANTIA-NIGRA; BOVINE BRAIN; CELL-DEATH; NEUROMELANIN AB Macrophage migration inhibitory factor (MIF) is a relatively small, 12.5-kDa protein that is structurally related to some isomerases and for which multiple immune and catalytic roles have been proposed. MIF is widely expressed in tissues with particularly high levels in neural tissues. Here we show that MIF is able to catalyze the conversion of 3,4-dihydroxyphenylaminechrome and norepinephrinechrome, toxic quinone products of the neurotransmitter catecholamines 3,4-dihydroxyphenylamine and norepinephrine, to indoledihydroxy derivatives that may serve as precursors to neuromelanin. This raises the possibility that MIF participates in a detoxification pathway for catecholamine products and could therefore have a protective role in neural tissues, which as in Parkinson's disease, may be subject to catecholamine-related cell death. C1 NCI, Pigment Cell Biol Sect, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NEI, Sect Mol Struct & Funct, NIH, Bethesda, MD 20892 USA. Univ Murcia, Dept Biochem, E-30100 Murcia, Spain. RP Hearing, VJ (reprint author), NCI, Pigment Cell Biol Sect, Cell Biol Lab, NIH, Bldg 37,Rm 1B25, Bethesda, MD 20892 USA. EM hearingv@nih.gov RI Solano, Francisco/G-5001-2013 OI Solano, Francisco/0000-0001-9612-761X NR 53 TC 62 Z9 65 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 FEB 5 PY 1999 VL 274 IS 6 BP 3268 EP 3271 DI 10.1074/jbc.274.6.3268 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 163VZ UT WOS:000078428200005 PM 9920865 ER PT J AU Chen, YR Gunther, MR Mason, RP AF Chen, YR Gunther, MR Mason, RP TI An electron spin resonance spin-trapping investigation of the free radicals formed by the reaction of mitochondrial cytochrome c oxidase with H2O2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ASCORBATE-INDUCED PEROXIDATION; RAT-LIVER MITOCHONDRIA; BOVINE SERUM-ALBUMIN; HYDROGEN-PEROXIDE; RESPIRATORY-CHAIN; ESCHERICHIA-COLI; NITRIC-OXIDE; FATTY-ACIDS; OXYGEN; PROTEIN AB The reaction of purified bovine mitochondrial cytochrome c oxidase (CcO) and hydrogen peroxide was studied using the ESR spin-trapping technique. A protein-centered radical adduct was trapped by 5,5-dimethyl-1-pyrroline N-oxide and was assigned to a thiyl radical adduct based on its hyperfine coupling constants of a(N) = 14.7 G and a(beta)(H) = 15.7 G. The ESR spectra obtained using the nitroso spin traps 3,5-dibromo-4-nitrosobenzenesulfonic acid (DBNBS) and 2-methyl-2-nitrosopropane (MNP) indicated that both DBNBS/.CcO and MNP/.CcO radical adducts are immobilized nitroxides formed by the trapping of protein-derived radicals. Alkylation of the free thiols on the enzyme with N-ethylmaleimide (NEM) prevented 5,5 dimethyl-1-pyrroline N-oxide adduct formation and changed the spectra of the MNP and DBNBS radical adducts, Nonspecific protease treatment of MNP-d(9)/(NEM)-N-.-CcO converted its spectrum from that of an immobilized nitroxide to an isotropic three-line spectrum characteristic of rapid molecular motion, Super-hyperfine couplings were detected in this spectrum and assigned to the MNP/.tyrosyl adduct(s), The inhibition of either CcO or NEM-CcO with potassium cyanide prevented detectable MNP adduct formation, indicating heme involvement in the reaction. The results indicate that one or more cysteine residues are the preferred reductant of the presumed ferryl porphyrin cation radical residue intermediate. When the cysteine residues are blocked with NEM, one or more tyrosine residues become the preferred reductant, forming the tyrosyl radical. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Chen, YR (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM chen6@niehs.nih.gov NR 53 TC 67 Z9 67 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 5 PY 1999 VL 274 IS 6 BP 3308 EP 3314 DI 10.1074/jbc.274.6.3308 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 163VZ UT WOS:000078428200011 PM 9920871 ER PT J AU Osheroff, WP Jung, HK Beard, WA Wilson, SH Kunkel, TA AF Osheroff, WP Jung, HK Beard, WA Wilson, SH Kunkel, TA TI The fidelity of DNA polymerase beta during distributive and processive DNA synthesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BASE-EXCISION-REPAIR; HIV-1 REVERSE-TRANSCRIPTASE; TEMPLATE-PRIMER; TRANSIENT MISALIGNMENT; MUTATIONAL SPECIFICITY; CRYSTAL-STRUCTURES; ESCHERICHIA-COLI; MAMMALIAN-CELLS; CROSS-LINKING; DNTP BINDING AB During base excision repair, DNA polymerase beta fills 1-6-nucleotide gaps processively, reflecting a contribution of both its 8- and 31-kDa domains to DNA binding. Here we report the fidelity of pol beta during synthesis to fill gaps of 1, 5, 6, or >300 nucleotides. Error rates during distributive synthesis by recombinant rat and human polymerase (pol) beta with a 390-base gap are similar to each other and to previous values with pol beta purified from tissues. The base substitution fidelity of human pol beta when processively filling a 5-nucleotide gap is similar to that with a 361-nucleotide gap, but "closely-spaced" substitutions are produced at a rate at least 60-fold higher than for distributive synthesis, Base substitution fidelity when filling a 1-nucleotide gap is higher than when filling a 5-nucleotide gap, suggesting a contribution of the 8-kDa domain to the dNTP binding pocket and/or a difference in base stacking or DNA structure imposed by pol beta. Nonetheless, 1-nucleotide gap filling is inaccurate, even generating complex substitution-addition errors. Finally, the single-base deletion error rate during processive synthesis to fill a 6-nucleotide gap is indistinguishable from that of distributive synthesis to fill a 390-nucleotide gap. Thus the mechanism of processivity by pol beta does not allow the enzyme to suppress template misalignments. C1 NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. Natl Inst Safety Res, Div Mutagenesis, Seoul, South Korea. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov NR 63 TC 117 Z9 119 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 FEB 5 PY 1999 VL 274 IS 6 BP 3642 EP 3650 DI 10.1074/jbc.274.6.3642 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 163VZ UT WOS:000078428200053 PM 9920913 ER PT J AU Pham, PT Olson, MW McHenry, CS Schaaper, RM AF Pham, PT Olson, MW McHenry, CS Schaaper, RM TI Mismatch extension by Escherichia coli DNA polymerase III holoenzyme SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NUCLEOTIDE MISINCORPORATION; FIDELITY; REPLICATION; BACTERIOPHAGE-T4; EXONUCLEASE; FREQUENCIES; MUTATIONS; COMPLEX; ERRORS; GENE AB The in vitro fidelity of Escherichia coli DNA polymerase III holoenzyme (HE) is characterized by an unusual propensity for generating (-1)-frameshift mutations, Here we have examined the capability of HE isolated from both a wild-type and a proofreading-impaired mutD5 strain to polymerize from M13mp2 DNA primer-templates containing a terminal T(template).C mismatch, These substrates contained either an A or a G as the next (5') template base. The assay allows distinction between: (i) direct extension of the terminal C (producing a base substitution), (ii) exonucleolytic removal of the C, or (iii), for the G-containing template, extension after misalignment of the C on the next template G (producing a (-1)-frameshift), On the A-containing substrate, both HEs did not extend the terminal C (<1%); instead, they exonucleolytically removed it (>99%), In contrast, on the G-containing substrate, the MutD5 HE yielded 61% (-1)-frameshifts and 6% base substitutions, The wild-type HE mostly excised the mispaired C from this substrate before extension (98%), but among the 2% mutants, (-1)-frameshifts exceeded base substitutions by 20 to 1, The preference of polymerase III HE for misalignment extension over direct mismatch extension provides a basis for explaining the in vitro (-1)-frameshift specificity of polymerase III HE. C1 NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Colorado, Hlth Sci Ctr, Dept Biochem & Mol Genet, Denver, CO 80262 USA. RP Schaaper, RM (reprint author), NIEHS, Mol Genet Lab, NIH, E3-01,POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM schaaper@niehs.nih.gov NR 24 TC 23 Z9 23 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 5 PY 1999 VL 274 IS 6 BP 3705 EP 3710 DI 10.1074/jbc.274.6.3705 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 163VZ UT WOS:000078428200062 PM 9920922 ER PT J AU Medvedev, A Saunders, NA Matsuura, H Chistokhina, A Jetten, AM AF Medvedev, A Saunders, NA Matsuura, H Chistokhina, A Jetten, AM TI Regulation of the transglutaminase I gene - Identification of DNA elements involved in its transcriptional control in tracheobronchial epithelial cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CROSS-LINKED ENVELOPE; INVITRO SQUAMOUS DIFFERENTIATION; MOUSE EPIDERMAL-KERATINOCYTES; RETINOIC ACID; TERMINAL DIFFERENTIATION; TISSUE TRANSGLUTAMINASE; PROXIMAL PROMOTER; BINDING PROTEINS; RESPONSE ELEMENT; LINKING ENZYMES AB The transglutaminase I (TGase I) gene encodes an enzyme that catalyzes the cross-linking of structural proteins involved in the formation of the cornified envelope during squamous cell differentiation. To identify DNA elements important for the transcriptional control of the TGase I gene, we analyzed the ability of a 2.9-kilobase pair (kb) upstream regulatory region to control the expression of a reporter gene in vivo and in vitro. Transgenic mice bearing the pTG(-2.9kb)CAT construct exhibited the same pattern of tissue-specific expression of CAT as reported for TGase I. Deletion analysis in transiently transfected rabbit tracheal epithelial cells indicated that two sequences from bp -490 to -470 and from -54 to -37 are involved in the activation of TGase I transcription. Point mutation analysis and mobility shift assays showed that the sequence located between -54 and -37 is a functional Spl-like transcription element. Sp1 and Sp3, but not Sp2, are part of nuclear protein complexes from differentiated RbTE cells binding to this site. The element TGATGTCA between bp -490 and -470 is contained in a larger 22-bp palindrome and resembles the consensus cAMP response element-binding protein (CREB)/AP-1 element recognized by dimeric complexes of members of the CREB, ATF, Fos, and Jun families, Mutations in this sequence greatly reduced promoter activity. Supershift analysis identified CREB1; JunB, c-Fos, Fra-1, and c-Jun in protein complexes isolated from differentiated rabbit tracheal epithelial cells binding to this site. Our study shows that the Sp1- and CREB/AP-1-like sites act in concert to stimulate transcription of the TGase I gene. The 2.9-kb promoter region could guide expression of specific genes in the granular layer of the epidermis and could be useful in gene therapy. C1 NIEHS, Cell Biol Sect, Pulm Pathobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Jetten, AM (reprint author), NIEHS, Cell Biol Sect, Pulm Pathobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. EM jetten@niehs.nih.gov RI saunders, nicholas/E-1544-2014; McTaggart, Jill/G-4696-2010; OI saunders, nicholas/0000-0002-2478-3420; McTaggart, Jill/0000-0002-9000-8529; Jetten, Anton/0000-0003-0954-4445 NR 73 TC 36 Z9 36 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 FEB 5 PY 1999 VL 274 IS 6 BP 3887 EP 3896 DI 10.1074/jbc.274.6.3887 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 163VZ UT WOS:000078428200084 PM 9920944 ER PT J AU Radko, SP Chrambach, A AF Radko, SP Chrambach, A TI Capillary electrophoresis of subcellular-sized particles SO JOURNAL OF CHROMATOGRAPHY B LA English DT Article DE polystyrene-size standards; inorganic particles; organic particles; lipoprotein particles; liposomes; microsomes; viruses ID FIELD-FLOW FRACTIONATION; ZONE ELECTROPHORESIS; COLLOIDAL PARTICLES; HYDRODYNAMIC CHROMATOGRAPHY; POLYMER-SOLUTIONS; LATEX-PARTICLES; SEPARATION; APPARATUS; MICROELECTROPHORESIS; POLYACRYLAMIDE AB Utilization of capillary electrophoresis (CE) for characterization and analytical separation of submicron- and micron-sized organic and inorganic particles as well as biological vesicles is reviewed. CE has been applied to charged polystyrene size standards, inorganic and organic colloidal particles, lipoprotein particles, liposomes, microsomes and viruses. These particle separations generally occur in a size-dependent manner and provide values of electrophoretic mobility which are in good agreement with those obtained by other electrophoretic techniques. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NICHHD, Lab Cellular & Mol Biophys, Macromol Anal Sect, NIH, Bethesda, MD 20892 USA. RP Chrambach, A (reprint author), NICHHD, Lab Cellular & Mol Biophys, Macromol Anal Sect, NIH, Bldg 10,Room 9D50, Bethesda, MD 20892 USA. NR 51 TC 59 Z9 60 U1 1 U2 5 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 FEB 5 PY 1999 VL 722 IS 1-2 BP 1 EP 10 DI 10.1016/S0378-4347(98)00307-7 PG 10 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 165ZE UT WOS:000078551100001 PM 10068130 ER PT J AU Sheikhnejad, G Brank, A Christman, JK Goddard, A Alvarez, E Ford, H Marquez, VE Marasco, CJ Sufrin, JR O'Gara, M Cheng, XD AF Sheikhnejad, G Brank, A Christman, JK Goddard, A Alvarez, E Ford, H Marquez, VE Marasco, CJ Sufrin, JR O'Gara, M Cheng, XD TI Mechanism of inhibition of DNA (cytosine C5)-methyltransferases by oligodeoxyribonucleotides containing 5,6-dihydro-5-azacytosine SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE DNA methylation; ODN inhibitors of DNA C5-methyltransferase; synthesis of the cyanoethyl phosphoramidite of; 5,6-dihydro-5-aza-2 '-deoxycytidine; transition state analogs; X-ray crystallography ID HHAI METHYLTRANSFERASE; CYTOSINE METHYLTRANSFERASE; METHYL-DEFICIENT; TARGET BASE; 5-AZACYTIDINE; 5-AZA-2'-DEOXYCYTIDINE; BINDING; CELLS; DIFFERENTIATION; RECOGNITION AB A key step in the predicted mechanism of enzymatic transfer of methyl groups from 5-adenosyl-L-methionine (AdoMet) to cytosine residues in DNA is the transient formation of a dihydrocytosine intermediate covalently linked to cysteine in the active site of a DNA (cytosine C5)-methyltransferase (DNA C5-MTase). Crystallographic analysis of complexes formed by HhaI methyltransferase (M.HhaI), AdoMet and a target oligodeoxyribonucleotide containing 5-fluorocytosine confirmed the existence of this dihydrocytosine intermediate. Based on the premise that 5,6-dihydro-5-azacytosine (DZCyt), a cytosine analog with an sp3-hybridized carbon (CH2) at position 6 and an NH group at position 5, could mimic the non-aromatic character of the cytosine ring in this transition state, we synthesized a series of synthetic substrates for DNA C5-MTase containing DZCyt. Substitution of DZCyt for target cytosines in C-G dinucleotides of single-stranded or double-stranded oligodeoxyribonucleotide substrates led to complete inhibition of methylation by murine DNA C5-MTase. Substitution of DZCyt for the target cytosine in G-C-G-C sites in double-stranded oligodeoxyribonucleotides had a similar effect on methylation by M.HhaI. Oligodeoxyribonudeotides containing DZCyt formed a tight but reversible complex with M.HhaI, and were consistently more potent as inhibitors of DNA methylation than oligodeoxyribonucleotides identical in sequence containing 5-fluorocytosine. Crystallographic analysis of a ternary complex involving M.HhaI, 5-adenosyl-L-homocysteine and a double-stranded 13-mer oligodeoxyribonucleotide containing DZCyt at the target position showed that the analog is flipped out of the DNA helix in the same manner as cytosine, 5-methylcytosine, and 5-fluorocytosine. However, no formation of a covalent bond was detected between the sulfur atom of the catalytic site nucleophile, cysteine 81, and the pyrimidine C6 carbon. These results indicate that DZCyt can occupy the active site of M.HhaI as a transition state mimic and, because of the high degree of affinity of its interaction with the enzyme, it can act as a potent inhibitor of methylation. (C) 1999 Academic Press. C1 Univ Nebraska, Med Ctr, Dept Biochem & Mol Biol, Omaha, NE 68198 USA. Univ Nebraska, Med Ctr, Eppley Canc Ctr, Omaha, NE 68198 USA. NCI, Med Chem Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Roswell Pk Canc Inst, Grace Canc Drug Ctr, Buffalo, NY 14263 USA. Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. Emory Univ, Sch Med, Dept Biochem, Atlanta, GA 30322 USA. RP Christman, JK (reprint author), Univ Nebraska, Med Ctr, Dept Biochem & Mol Biol, 600 S 42nd St, Omaha, NE 68198 USA. FU NIGMS NIH HHS [GM 17052, GM 49245] NR 45 TC 55 Z9 57 U1 1 U2 14 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 FEB 5 PY 1999 VL 285 IS 5 BP 2021 EP 2034 DI 10.1006/jmbi.1998.2426 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 164DQ UT WOS:000078447500010 PM 9925782 ER PT J AU McDonald, JP Peat, TS Levine, AS Woodgate, R AF McDonald, JP Peat, TS Levine, AS Woodgate, R TI Intermolecular cleavage by UmuD-like enzymes: Identification of residues required for cleavage and substrate specificity SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE enzymatic reactions; Escherichia coli UmuD; protein-protein interactions; Salmonella typhimurium UmuD; SOS mutagenesis ID RECA-MEDIATED CLEAVAGE; SOS MUTATOR ACTIVITY; ESCHERICHIA-COLI; LEXA CLEAVAGE; MUCA PROTEIN; MUTAGENESIS; ACTIVATION; REPRESSORS; DAMAGE AB The UmuD-like proteins are best characterized for their role in damage-induced SOS mutagenesis. An essential step in this process is the enzymatic self-processing of the UmuD-like proteins. This reaction is thought to occur either via an intramolecular or intermolecular self-cleavage mechanism. Here, we demonstrate that it can also occur via an heterologous intermolecular cleavage reaction. The Escherichia coli UmuD enzyme demonstrated the broadest substrate specificity, cleaving both E. coli and Salmonella typhimurium UmuD substrates in vivo. In comparison, the wild-type S. typhimurium UmuD (UmuD(St)) and MucA enzymes catalyzed intermolecular self-cleavage, but did not facilitate heterologous cleavage. Heterologous cleavage by the UmuD(St) enzyme was, however, observed with chimeric UmuD substrates that possess residues 30-55 of UmuD(St). We have further localized the residue predominantly responsible for UmuD(St)-catalyzed heterologous cleavage to Ser50 in the substrate molecule. We hypothesize that changes at this residue affect the positioning of the cleavage site of a substrate molecule within the catalytic cleft of the UmuD(St) enzyme by affecting the formation of a so-called UmuD "filament-dimer". This hypothesis is further supported by the observation that mutations known to disrupt an E. coli UmuD' filament dimer also block intermolecular UmuD(Ec) cleavage. (C) 1999 Academic Press. C1 NICHHD, Sect DNA Replicat Repair & Mutagenesis, NIH, Bethesda, MD 20892 USA. Univ Calif Los Alamos Natl Lab, Los Alamos, NM 87545 USA. RP Woodgate, R (reprint author), NICHHD, Sect DNA Replicat Repair & Mutagenesis, NIH, Bethesda, MD 20892 USA. EM woodgate@helix.nih.gov RI Peat, Thomas/F-9817-2010 OI Peat, Thomas/0000-0002-6488-0831 NR 33 TC 18 Z9 18 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 FEB 5 PY 1999 VL 285 IS 5 BP 2199 EP 2209 DI 10.1006/jmbi.1998.2433 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 164DQ UT WOS:000078447500022 PM 9925794 ER PT J AU Cardenas, AM Rodriguez, MP Cortes, MP Alvarez, RM Wei, WZ Rapoport, SI Shimahara, T Caviedes, R Caviedes, P AF Cardenas, AM Rodriguez, MP Cortes, MP Alvarez, RM Wei, WZ Rapoport, SI Shimahara, T Caviedes, R Caviedes, P TI Calcium signals in cell lines derived from the cerebral cortex of normal and trisomy 16 mice SO NEUROREPORT LA English DT Article DE calcium; cell line; Down syndrome; neurotransmitters; trisomy 16 ID ROOT GANGLION NEURONS; DOWN-SYNDROME; ALZHEIMERS-DISEASE; FETAL MOUSE; MODEL; CHROMOSOME-21; ABNORMALITIES; GENERATION; INDICATORS; DISORDERS AB WE established two immortalized cell lines from cerebral cortex of normal (CNh) and trisomy 16 (CTb) mouse fetuses, an animal model of human trisomy 21. Those cells loaded with the fluorescent Ca2+ dyes, Indo-1 and Fluo-3, exhibited increments of intracellular Ca2+ ([Ca2+](i)) in response to external glutamate, NMDA, AMPA and kainate. CTb cells exhibited higher basal Ca2+ concentrations and had higher amplitude and slower time-dependent kinetics in the decay than CNh cells, suggesting an impaired Ca2+ buffering capacity in the trisomy 16-derived cell line. Nicotine also induced increments of [Ca2+](i). The CTb cell line could represent a model for studying cellular alterations related to Down syndrome. (C) 1999 Lippincott Williams & Wilkins. C1 Univ Chile, Fac Med, ICBM, Physiol & Biophys Program, Santiago 7, Chile. Univ Valparaiso, Sch Med, Pharmacol Lab, Valparaiso, Chile. Ctr Estudios Cient, Valdivia 9, Chile. NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. CNRS, Neurobiol Cellulaire & Mol Lab, F-91198 Gif Sur Yvette, France. RP Caviedes, P (reprint author), Univ Chile, Fac Med, ICBM, Physiol & Biophys Program, Casilla 70005,Correo 7, Santiago 7, Chile. NR 26 TC 30 Z9 30 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD FEB 5 PY 1999 VL 10 IS 2 BP 363 EP 369 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 180NX UT WOS:000079393000029 PM 10203336 ER PT J AU Li, BS Su, QN Kiyama, H Miki, N Robinow, DR Zhang, L AF Li, BS Su, QN Kiyama, H Miki, N Robinow, DR Zhang, L TI Expression of gicerin, a novel cell adhesion molecule, is unregulated in the astrocytes after hypoglossal nerve injury in rats SO NEUROSCIENCE LETTERS LA English DT Article DE hypoglossal nerve; nerve regeneration; reactive astrocytes; adhesion molecule; gicerin ID NEURITE OUTGROWTH FACTOR; UP-REGULATION; REGENERATION; INVOLVEMENT; GLIA AB Gicerin is an integral membrane glycoprotein which mediates cell-cell and cell-extracellular matrix (ECM) interactions in the nervous system, We studied gicerin expression in the hypoglossal nucleus post transection using in situ hybridization and immunocytochemistry. We found that hypoglossal nerve injury resulted in a significant increase in gicerin expression. Its expression levels reached peak values in reactive astrocytes surrounding axotomized motoneurons of the ipsilateral hypoglossal nucleus 14 days after hypoglossal nerve injury. The results indicate that gicerin is up-regulated during nerve regeneration, suggesting that gicerin expressed in the reactive astrocytes might be involved in the processes of nerve regeneration. (C) 1999 Published by Elsevier Science Ireland Ltd. All rights reserved. C1 NIMH, Behav Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Osaka Univ, Sch Med, Dept Pharmacol 1, Suita, Osaka 565, Japan. Asahikawa Med Coll, Dept Anat, Asahikawa, Hokkaido 078, Japan. RP Zhang, L (reprint author), NIMH, Behav Endocrinol Branch, NIH, Bldg 36,2C02, Bethesda, MD 20892 USA. RI Kiyama, Hiroshi/M-8867-2014 OI Kiyama, Hiroshi/0000-0001-5963-046X NR 21 TC 3 Z9 3 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 FEB 5 PY 1999 VL 260 IS 3 BP 149 EP 152 DI 10.1016/S0304-3940(98)00979-3 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 168EB UT WOS:000078677400001 PM 10076889 ER PT J AU George, KM Chatterjee, D Gunawardana, G Welty, D Hayman, J Lee, R Small, PLC AF George, KM Chatterjee, D Gunawardana, G Welty, D Hayman, J Lee, R Small, PLC TI Mycolactone: A polyketide toxin from Mycobacterium ulcerans required for virulence SO SCIENCE LA English DT Article AB Mycobacterium ulcerans is the causative agent of Buruli ulcer, a severe human skin disease that occurs primarily in Africa and Australia, Infection with M. ulcerans results in persistent severe necrosis without an acute inflammatory response. The presence of histopathological changes distant from the site of infection suggested that pathogenesis might be toxin mediated. A polyketide-derived macrolide designated mycolactone was isolated that causes cytopathicity and cell cycle arrest in cultured L929 murine fibroblasts. Intradermal inoculation of purified toxin into guinea pigs produced a lesion similar to that of Buruli ulcer in humans. This toxin may represent one of a family of virulence factors associated with pathology in mycobacterial diseases such as leprosy and tuberculosis. C1 NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Colorado State Univ, Dept Microbiol, Ft Collins, CO 80523 USA. Abbott Labs, Abbott Pk, IL 60064 USA. Box Hill Hosp, Box Hill, Vic 3128, Australia. NIAID, NIH, Rockville, MD 20852 USA. RP Small, PLC (reprint author), NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RI Lee, Richard/J-4997-2013 OI Lee, Richard/0000-0002-2397-0443 NR 16 TC 347 Z9 355 U1 0 U2 17 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD FEB 5 PY 1999 VL 283 IS 5403 BP 854 EP 857 DI 10.1126/science.283.5403.854 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 165AT UT WOS:000078496800048 PM 9933171 ER PT J AU Bringmann, G Wenzel, M Kelly, TR Boyd, MR Gulakowski, RJ Kaminsky, R AF Bringmann, G Wenzel, M Kelly, TR Boyd, MR Gulakowski, RJ Kaminsky, R TI Acetogenic isoquinoline alkaloids. Part 123. Octadehydromichellamine, a structural analog of the anti-HIV michellamines without centrochirality SO TETRAHEDRON LA English DT Article ID ACETOGENIC ISOQUINOLINE ALKALOIDS; NAPHTHYLISOQUINOLINE ALKALOIDS; BIOLOGICAL-ACTIVITY; KORUPENSAMINE AB The synthesis of octadehydromichellamine (4), as the fully dehydrogenated structural analog of the naturally occurring michellamines (1), is described. This derivative is the first michellamine-type quateraryl without centrochirality and thus constitutes a distinctly simplified structural michellamine analog. Key step of the total synthesis is the twofold coupling of a bis-O-triflate activated central binaphthalene building block 9 with 2 eq. of the isoquinoline boronic acid 8, to give the quateraryl 11, whose deprotection delivers the target molecule 4, in an apparently stereochemically pure form. Octadehydromichellamine (4) shows a good order of anti-HIV activity and, compared with natural michellamines, enhanced antimalarial activity against Plasmodium falciparum. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 Univ Wurzburg, Inst Organ Chem, D-97074 Wurzburg, Germany. Boston Coll, Dept Chem, Eugene F Merkert Chem Ctr, Chestnut Hill, MA 02467 USA. NCI, Lab Drug Discovery Res & Dev, Frederick, MD 21702 USA. Swiss Trop Inst, CH-4002 Basel, Switzerland. RP Bringmann, G (reprint author), Univ Wurzburg, Inst Organ Chem, Hubland, D-97074 Wurzburg, Germany. NR 25 TC 18 Z9 19 U1 1 U2 3 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 FEB 5 PY 1999 VL 55 IS 6 BP 1731 EP 1740 DI 10.1016/S0040-4020(98)01195-8 PG 10 WC Chemistry, Organic SC Chemistry GA 162FK UT WOS:000078334900014 ER PT J AU Gao, F Bailes, E Robertson, DL Chen, YL Rodenburg, CM Michael, SF Cummins, LB Arthur, LO Peeters, M Shaw, GM Sharp, PM Hahn, BH AF Gao, F Bailes, E Robertson, DL Chen, YL Rodenburg, CM Michael, SF Cummins, LB Arthur, LO Peeters, M Shaw, GM Sharp, PM Hahn, BH TI Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes SO NATURE LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; WILD-CAPTURED CHIMPANZEE; TANTALUS MONKEYS; LENTIVIRUS; SEQUENCE; ORGANIZATION; GENOME; TYPE-2; AFRICA; GABON AB The human AIDS viruses human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) represent cross-species (zoonotic) infections(1-4). Although the primate reservoir of HIV-2 has been clearly identified as the sooty mangabey (Cercocebus atys)(2,4-7), the origin of HIV-1 remains uncertain. Viruses related to HIV-1 have been isolated from the common chimpanzee (Pan troglodytes)(8,9), but only three such SIVcpz infections have been documented(1,10,11), one of which involved a virus so divergent(11) that it might represent a different primate lentiviral lineage. In a search for the HIV-1 reservoir, rye have now sequenced the genome of a new SIVcpz strain (SIVcpzUS) and have determined, by mitochondrial DNA analysis, the subspecies identity of all known SIVcpz-infected chimpanzees. We find that two chimpanzee subspecies in Africa, the central P. t. troglodytes and the eastern P. t. schweinfurthii, harbour SIVcpz and that their respective viruses form two highly divergent (but subspecies-specific) phylogenetic lineages. All HIV-1 strains known to infect man, including HIV-1 groups M, N and O, are closely related to just one of these SIVcpz lineages, that found in P. t. troglodytes. Moreover, we find that HIV-1 group N is a mosaic of SIVcpzUS- and HTV-1-related sequences, indicating an ancestral recombination event in a chimpanzee host. These results, together with the observation that the natural range of P. t. troglodytes coincides uniquely with areas of HIV-1 group M, N and O endemicity, indicate that P. t. troglodytes is the primary reservoir for HIV-I and has been the source of at least three independent introductions of SIVcpz into the human population. C1 Univ Alabama, Dept Med & Microbiol, Birmingham, AL 35294 USA. Univ Nottingham, Queens Med Ctr, Inst Genet, Nottingham NG7 2UH, England. CNRS, Lab Struct & Genet Informat, F-13402 Marseille, France. SW Fdn Biomed Res, San Antonio, TX 78245 USA. NCI, AIDS Vaccine Program, Frederick Canc Res & Dev Ctr, SAIC Frederick, Ft Detrick, MD 21702 USA. ORSTOM, Retrovirus Lab, F-34032 Rennes, France. Univ Alabama, Howard Hughes Med Inst, Birmingham, AL 35294 USA. RP Hahn, BH (reprint author), Univ Alabama, Dept Med & Microbiol, 701 S 19th St,LHRB 613, Birmingham, AL 35294 USA. EM bhahn@uab.edu RI Sharp, Paul/F-5783-2010 OI Sharp, Paul/0000-0001-9771-543X NR 28 TC 836 Z9 861 U1 15 U2 147 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 4 PY 1999 VL 397 IS 6718 BP 436 EP 441 DI 10.1038/17130 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 164KA UT WOS:000078461700049 PM 9989410 ER PT J AU Travis, LB Holowaty, EJ Bergfeldt, K Lynch, CF Kohler, BA Wiklund, T Curtis, RE Hall, P Andersson, M Pukkala, E Sturgeon, J Stovall, M AF Travis, LB Holowaty, EJ Bergfeldt, K Lynch, CF Kohler, BA Wiklund, T Curtis, RE Hall, P Andersson, M Pukkala, E Sturgeon, J Stovall, M TI Risk of leukemia after platinum-based chemotherapy for ovarian cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID 2ND MALIGNANT NEOPLASMS; LONG-TERM SURVIVORS; CISPLATIN; RADIOTHERAPY; MELPHALAN; DNA AB Background Platinum-based chemotherapy is the cornerstone of modern treatment for ovarian, testicular, and other cancers, but few investigations have quantified the late sequelae of such treatment. Methods We conducted a case-control study of secondary leukemia in a population-based cohort of 28,971 women in North America and Europe who had received a diagnosis of invasive ovarian cancer between 1980 and 1993. Leukemia developed after the administration of platinum-based therapy in 96 women. These women were matched to 272 control patients. The type, cumulative dose, and duration of chemotherapy and the dose of radiation delivered to active bone marrow were compared in the two groups. Results Among the women who received platinum-based combination chemotherapy for ovarian cancer, the relative risk of leukemia was 4.0 (95 percent confidence interval, 1.4 to 11.4). The relative risks for treatment with carboplatin and for treatment with cisplatin were 6.5 (95 percent confidence interval, 1.2 to 36.6) and 3.3 (95 percent confidence interval, 1.1 to 9.4), respectively. We found evidence of a dose-response relation, with relative risks reaching 7.6 at doses of 1000 mg or more of platinum (P for trend <0.001). Radiotherapy without chemotherapy (median dose, 18.4 Gy) did not increase the risk of leukemia. Conclusions Platinum-based treatment of ovarian cancer increases the risk of secondary leukemia. Nevertheless, the substantial benefit that platinum-based treatment offers patients with advanced disease outweighs the relatively small excess risk of leukemia. (N Engl J Med 1999;340:351-7.) (C) 1999, Massachusetts Medical Society. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Canc Care Ontario, Toronto, ON, Canada. Karolinska Univ Hosp, Stockholm, Sweden. Univ Iowa, Iowa City, IA USA. Dept Hlth & Senior Serv, Trenton, NJ USA. Univ Helsinki, Cent Hosp, Helsinki, Finland. Danish Canc Soc, Copenhagen, Denmark. Finnish Canc Registry, FIN-00170 Helsinki, Finland. Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Travis, LB (reprint author), NCI, Div Canc Epidemiol & Genet, Execut Plaza N,Suite 408, Bethesda, MD 20892 USA. RI Bergfeldt, Kjell/C-3581-2012 NR 33 TC 175 Z9 179 U1 1 U2 3 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 FEB 4 PY 1999 VL 340 IS 5 BP 351 EP 357 DI 10.1056/NEJM199902043400504 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 163WC UT WOS:000078428500004 PM 9929525 ER PT J AU Mills, JL AF Mills, JL TI Cocaine, smoking, and spontaneous abortion SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 NICHHD, Bethesda, MD 20892 USA. RP Mills, JL (reprint author), NICHHD, Bethesda, MD 20892 USA. NR 6 TC 2 Z9 2 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 FEB 4 PY 1999 VL 340 IS 5 BP 380 EP 381 DI 10.1056/NEJM199902043400509 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 163WC UT WOS:000078428500009 PM 9929530 ER PT J AU Elly, C Witte, S Zhang, ZH Rosnet, O Lipkowitz, S Altman, A Liu, YC AF Elly, C Witte, S Zhang, ZH Rosnet, O Lipkowitz, S Altman, A Liu, YC TI Tyrosine phosphorylation and complex formation of Cbl-b upon T cell receptor stimulation SO ONCOGENE LA English DT Article DE protein tyrosine kinase; Cbl; proto-oncogene; Crk-L ID EXCHANGE PROTEIN C3G; C-CBL; ANTIGEN RECEPTOR; V-CBL; ASSOCIATION; ACTIVATION; ZAP-70; PROTOONCOGENE; KINASE; 14-3-3-PROTEINS AB Cbl-b, a mammalian homolog of Cbl, consists of an N-terminal region (Cbl-b-N) highly homologous to oncogenic v-Cbl, a Ring finger, and a C-terminal region containing multiple proline-rich stretches and potential tyrosine phosphorylation sites. In the present study, we demonstrate that upon engagement of the T cell receptor (TCR), endogenous Cbl-b becomes rapidly tyrosine-phosphorylated, In heterogeneous COS-1 cells, Cbl-b was phosphorylated on tyrosine residues by both Syk(Syk/Zap-70) and Src- (Fyn/Lck) family kinases, with Syk kinase inducing the most prominent effect. Syk associates and phosphorylates Cbl-b in Jurkat T cells, A Tyr-316 Chi-binding site in Syk was required for the association with and for the maximal tyrosine phosphorylation of Cbl-b, Mutation at a loss-of-function site (Gly-298) in Cbl-b-N disrupts its interaction with Syk, Cbl-b constitutively binds Grb2 and becomes associated with Crk-L upon TCR stimulation. The Grb2- and the Crk-L-binding regions were mapped to the C-terminus of Cbl-b, The Crk-L-binding sites were further determined to be (YDVP)-D-655 and (YKIP)-K-709, With th, latter being the primary binding site. Taken together, these results implicate that Cbl-b is involved in TCR-mediated intracellular signaling pathways. C1 La Jolla Inst Allergy & Immunol, Div Cell Biol, San Diego, CA 92121 USA. INSERM U119, Mol Oncol Lab, F-13009 Marseille, France. NCI, Navy Med Oncol Branch, Gaithersburg, MD 20899 USA. RP Liu, YC (reprint author), La Jolla Inst Allergy & Immunol, Div Cell Biol, 10355 Sci Ctr Dr, San Diego, CA 92121 USA. RI Rosnet, Olivier/G-3536-2013 NR 33 TC 43 Z9 48 U1 1 U2 5 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 4 PY 1999 VL 18 IS 5 BP 1147 EP 1156 DI 10.1038/sj.onc.1202411 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 165FU UT WOS:000078510700003 PM 10022120 ER PT J AU Cook, J Krishnan, S Ananth, S Sells, SF Shi, Y Walther, MM Linehan, WM Sukhatme, VP Weinstein, MH Rangnekar, VM AF Cook, J Krishnan, S Ananth, S Sells, SF Shi, Y Walther, MM Linehan, WM Sukhatme, VP Weinstein, MH Rangnekar, VM TI Decreased expression of the pro-apoptotic protein Par-4 in renal cell carcinoma SO ONCOGENE LA English DT Article DE Par-4; renal cell carcinoma; apoptosis ID TUMOR-SUPPRESSOR GENE; VONHIPPEL-LINDAU DISEASE; KINASE-C; MUTATIONS; CANCER; IDENTIFICATION; PHENOTYPE; ISOFORMS; TISSUES; PRODUCT AB Par-4 is a widely expressed leucine zipper protein that confers sensitization to apoptosis induced by exogenous insults. Because the expression of genes that promote apoptosis may be down-regulated during tumorigenesis, we sought to examine the expression of Par-4 in human tumors, We present here evidence that Par-4 protein levels were severely decreased in human renal cell carcinoma specimens relative to normal tubular cells, Replenishment of Par-4 protein levels in renal cell carcinoma cell lines conferred sensitivity to apoptosis, Because apoptosis may serve as a defense mechanism against malignant transformation or progression, decreased expression of Par-4 may contribute to the pathophysiology of renal cell carcinoma. C1 Univ Kentucky, Dept Surg, Div Urol, Lexington, KY 40536 USA. Univ Kentucky, Dept Pathol, Lexington, KY 40536 USA. Univ Kentucky, Dept Microbiol & Immunol, Lexington, KY 40536 USA. Univ Kentucky, Markey Canc Ctr, Lexington, KY 40536 USA. Beth Israel Deaconess Med Ctr, Div Renal, Boston, MA USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA USA. NCI, Urol Oncol Sect, NIH, Bethesda, MD 20892 USA. RP Rangnekar, VM (reprint author), Univ Kentucky, Dept Surg, Div Urol, Combs Res Bldg,Room 303,800 Rose St, Lexington, KY 40536 USA. FU NCI NIH HHS [CA60872, CA68258]; NIDDK NIH HHS [DK44921] NR 20 TC 71 Z9 72 U1 0 U2 2 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 4 PY 1999 VL 18 IS 5 BP 1205 EP 1208 DI 10.1038/sj.onc.1202416 PG 4 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 165FU UT WOS:000078510700009 PM 10022126 ER PT J AU Palefsky, JM Minkoff, H Kalish, LA Levine, A Sacks, HS Garcia, P Young, M Melnick, S Miotti, P Burk, R AF Palefsky, JM Minkoff, H Kalish, LA Levine, A Sacks, HS Garcia, P Young, M Melnick, S Miotti, P Burk, R TI Cervicovaginal human papillomavirus infection in human immunodeficiency virus-1 (HIV)-positive and high-risk HIV-negative women SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID CERVICAL INTRAEPITHELIAL NEOPLASIA; CYTOLOGICALLY NORMAL WOMEN; SEROPOSITIVE WOMEN; YOUNG-WOMEN; PREVALENCE; ABNORMALITIES; DETERMINANTS; CANCER; EPIDEMIOLOGY; DYSPLASIA AB Background: Human papillomavirus (HPV) infection is associated with precancerous cervical squamous intraepithelial lesions commonly seen among women infected with human immunodeficiency virus-1 (HIV), We characterized HPV infection in a large cohort of HIV-positive and HIV-negative women participating in the Women's Interagency HIV Study to determine the prevalence of and risk factors for cervicovaginal HPV infection in HIV-positive women, Methods: HIV-positive (n = 1778) and HIV-negative (n = 500) women were tested at enrollment for the presence of HPV DNA in a cervicovaginal lavage specimen. Blood samples were tested for HIV antibody status, level of CD4-positive T cells, and HIV RNA load (copies/mL), An interview detailing risk factors was conducted. Univariate and multivariate analyses were performed. Results: Compared with HIV-negative women, HIV-positive women with a CD4(+) cell count of less than 200/mm(3) were at the highest risk of HPV infection, regardless of HIV RNA load (odds ratio [OR] = 10.13; 95% confidence interval [CI] = 7.32-14.04), followed by women with a CD4+ count greater than 200/mm3 and an HIV RNA load greater than 20 000 copies/mL (OR = 5.78; 95% CI = 4.17-8.08) and women with a CD4(+) count greater than 200/mm3 and an HIV RNA load less than 20 000 copies/mL (OR = 3.12; 95% CI = 2.36-4.12), after adjustment for other factors. Other risk factors among HIV-positive women included racial/ethnic background (African-American versus Caucasian, OR = 1.64; 95% CI = 1.19-2.28), current smoking (yes versus no; OR = 1.55; 95% CI = 1.20-1.99), and younger age (age <30 years versus greater than or equal to 40 years; OR = 1.75; 95% CI = 1.23-2.49). Conclusions: Although the strongest risk factors of HPV infection among HIV-positive women were indicators of more advanced HIV-related disease, other factors commonly found in studies of HIV-negative women, including racial/ethnic background, current smoking, and age, were important in HIV-positive women as well. C1 Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. SUNY, New York, NY USA. New England Res Inst, Watertown, MA 02172 USA. Univ So Calif, Los Angeles, CA USA. Mt Sinai Med Ctr, New York, NY 10029 USA. Northwestern Univ, Chicago, IL 60611 USA. Georgetown Univ, Washington, DC USA. NCI, Bethesda, MD 20892 USA. NIAID, Bethesda, MD 20892 USA. Albert Einstein Coll Med, New York, NY USA. RP Palefsky, JM (reprint author), Univ Calif San Francisco, Dept Lab Med, Rm C634,Box 0100, San Francisco, CA 94143 USA. EM joelp@labmed.ucsf.edu NR 56 TC 308 Z9 320 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD FEB 3 PY 1999 VL 91 IS 3 BP 226 EP 236 DI 10.1093/jnci/91.3.226 PG 11 WC Oncology SC Oncology GA 163VQ UT WOS:000078427400009 PM 10037100 ER PT J AU Hursting, SD Slaga, TJ Fischer, SM DiGiovanni, J Phang, JM AF Hursting, SD Slaga, TJ Fischer, SM DiGiovanni, J Phang, JM TI Mechanism-based cancer prevention approaches: Targets, examples, and the use of transgenic mice SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID APC(DELTA-716) KNOCKOUT MICE; TUMOR-SUPPRESSOR GENES; SPONTANEOUS TUMORIGENESIS; CHEMICAL CARCINOGENESIS; CALORIE RESTRICTION; P53-DEFICIENT MICE; DIALLYL SULFIDE; BENZOPYRENE-INDUCED NEOPLASIA; ARYLALKYL ISOTHIOCYANATES; ORGANOSULFUR COMPOUNDS AB Humans are exposed to a wide variety of carcinogenic insults, including endogenous and man-made chemicals, radiation, physical agents, and viruses. The ultimate goal of carcin genesis research is to elucidate the processes involved in the induction of human cancer so that interventions may be developed to prevent the disease, either in the general population or in susceptible subpopulations. Progress to date in the carcinogenesis field, particularly regarding the mechanisms of chemically induced cancer, has revealed several points along the carcinogenesis pathway that may be amenable to mechanism-based prevention strategies. The purpose of this review is to examine the basic mechanisms and stages of chemical carcinogenesis, with an emphasis on ways in which preventive interventions can modify those processes. Possible ways of interfering with tumor initiation events include the following: i) modifying carcinogen activation by inhibiting enzymes responsible for that activation or by direct scavenging of DNA-reactive electrophiles and free radicals; ii) enhancing carcinogen detoxification processes by altering the activity of the detoxifying enzymes; and iii) modulating certain DNA repair processes. Possible ways of blocking the processes involved in the promotion and progression stages of carcinogenesis include the following: i) scavenging of reactive oxygen species; ii) altering the expression of genes involved in cell signaling, particularly those regulating cell proliferation, apoptosis, and differentiation; and iii) decreasing inflammation. In addition, the utility for mechanism-based cancer prevention research of new animal models that are based on the overexpression or inactivation of specific cancer-related genes is examined. C1 Univ Texas, MD Anderson Cancer Ctr, Dept Epidemiol, Houston, TX 77030 USA. Univ Texas, MD Anderson Cancer Ctr, Dept Carcinogenesis, Div Sci Pk Res, Smithville, TX USA. AMC Canc Res Ctr, Ctr Canc Causat & Prevent, Denver, CO USA. NCI, Lab Nutr & Mol Regulat, Frederick Canc Res & Dev Ctr, Frederick, MD USA. RP Hursting, SD (reprint author), Univ Texas, MD Anderson Cancer Ctr, Dept Epidemiol, Box 189, Houston, TX 77030 USA. EM shursting@request.mdace.tmc.edu NR 113 TC 111 Z9 112 U1 0 U2 3 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 3 PY 1999 VL 91 IS 3 BP 215 EP 225 DI 10.1093/jnci/91.3.215 PG 11 WC Oncology SC Oncology GA 163VQ UT WOS:000078427400008 PM 10037099 ER PT J AU Koo, HM Gray-Goodrich, M Kohlhagen, G McWilliams, MJ Jeffers, M Vaigro-Wolff, A Alvord, WG Monks, A Paull, KD Pommier, Y Vande Woude, GF AF Koo, HM Gray-Goodrich, M Kohlhagen, G McWilliams, MJ Jeffers, M Vaigro-Wolff, A Alvord, WG Monks, A Paull, KD Pommier, Y Vande Woude, GF TI The ras oncogene-mediated sensitization of human cells to topoisomerase II inhibitor-induced apoptosis SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ANTICANCER DRUG SCREEN; ACUTE MYELOID-LEUKEMIA; DNA-DAMAGE; P53-INDEPENDENT APOPTOSIS; P-GLYCOPROTEIN; MULTIDRUG-RESISTANCE; KINASE ACTIVATION; EPITHELIAL-CELLS; CANCER; LINES AB Background: Among the inhibitors of the enzyme topoisomerase II (an important target for chemotherapeutic drugs) tested in the National Cancer Institute's In Vitro Antineoplastic Drug Screen, NSC 284682 (3'-hydroxydaunorubicin) and NSC 659687 [9-hydroxy-5,6-dimethyl-1-(N-{2(dimethylamino)ethyl}carbamoyl)-6H-pyrido-(4,3-b)carbazole] were the only compounds that were more cytotoxic to tumor cells harboring an activated ras oncogene than to tumor cells bearing wild-type ras alleles. Expression of the multidrug resistance proteins P-glycoprotein and MRP (multidrug resistance-associated protein) facilitates tumor cell resistance to topoisomerase II inhibitors. We investigated whether tumor cells with activated ras oncogenes showed enhanced sensitivity to other topoisomerase II inhibitors in the absence of the multidrug-resistant phenotype. Methods: We studied 20 topoisomerase II inhibitors and individual cell lines with or without activated ras oncogenes and with varying degrees of multidrug resistance. Results: In the absence of multidrug resistance, human tumor cell lines with activated ras oncogenes were uniformly more sensitive to most topoisomerase II inhibitors than were cell lines containing wild-type ras alleles, The compounds NSC 284682 and NSC 659687 were especially effective irrespective of the multidrug resistant phenotype. The ras oncogene-mediated sensitization to topoisomerase II inhibitors was far more prominent with the non-DNA-intercalating epipodophyllotoxins than with the DNA-intercalating inhibitors. This difference in sensitization appears to be related to a difference in apoptotic sensitivity, since the level of DNA damage generated by etoposide (an epipodophyllotoxin derivative) in immortalized human kidney epithelial cells expressing an activated ras oncogene was similar to that in the parental cells, but apoptosis was enhanced only in the former cells. Conclusions: Activated ras oncogenes appear to enhance the sensitivity of human tumor cells to topoisomerase II inhibitors by potentiating an apoptotic response. Epipodophyllotoxin-derived topoisomerase II inhibitors should be more effective than the DNA-intercalating inhibitors against tumor cells with activated ras oncogenes. C1 NCI, Div Basic Sci, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, Sci Applicat Int Corp, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, Data Management Serv Inc, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, Mol Pharmacol Lab, Div Canc Treatment, Bethesda, MD 20892 USA. NCI, Informat Technol Branch, Dev Therapeut Program, Div Canc Treatment, Bethesda, MD 20892 USA. RP Vande Woude, GF (reprint author), NCI, Div Basic Sci, Frederick Canc Res & Dev Ctr, POB B,Bldg 469, Frederick, MD 21702 USA. FU PHS HHS [N01C046000] NR 53 TC 37 Z9 37 U1 0 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 FEB 3 PY 1999 VL 91 IS 3 BP 236 EP 244 DI 10.1093/jnci/91.3.236 PG 9 WC Oncology SC Oncology GA 163VQ UT WOS:000078427400010 PM 10037101 ER PT J AU Lee, JS Wacholder, S Struewing, JP McAdams, M Pee, D Brody, LC Tucker, MA Hartge, P AF Lee, JS Wacholder, S Struewing, JP McAdams, M Pee, D Brody, LC Tucker, MA Hartge, P TI Survival after breast cancer in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID INDIVIDUALS; FREQUENCY; GRADE; WOMEN; RISK AB Background: Studies of survival following breast and ovarian cancers in BRCA1 and/or BRCA2 mutation carriers have yielded conflicting results. We undertook an analysis of a community-based study of Ashkenazi Jews to investigate the effect of three founder mutations in BRCA1 and BRCA2 on survival among patients with breast or ovarian cancer. Methods: We collected blood samples and questionnaire data from 5318 Ashkenazi Jewish volunteers. The blood samples were tested for 185delAG (two nucleotide deletion) and 5382insC (single nucleotide insertion) mutations in BRCA1 and the 6174delT (single nucleotide deletion) mutation in BRCA2. To estimate survival differences in the affected relatives according to their BRCA1 and/or BRCA2 mutation carrier status, we devised and applied a novel extension of the kin-cohort method. Results: Fifty mutation carriers reported that 58 of their first-degree relatives had been diagnosed with breast cancer and 10 with ovarian cancer; 907 noncarriers reported 979 first-degree relatives with breast cancer and 116 with ovarian cancer. Kaplan-Meier estimates of median survival after breast cancer were 16 years (95% confidence interval [CI] = 11-40) in the relatives of carriers and 18 years (95% CI = 15-22) in the relatives of noncarriers, a difference that was not statistically significant (two-sided P = .87). There was also no difference in survival times among the 126 first-degree relatives with ovarian cancer. We found no survival difference between patients with breast or ovarian cancer who were inferred carriers of BRCA1 and/or BRCA2 mutations and noncarriers. Conclusions: Carriers of BRCA1 and BRCA2 mutations appeared to have neither better nor worse survival prognosis. C1 NCI, Howard Hughes Med Inst, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Informat Management Serv Inc, Silver Spring, MD USA. Natl Human Genome Res Inst, Genet & Mol Biol Branch, Bethesda, MD USA. RP Hartge, P (reprint author), NIH, Execut Plaza N,Rm 443, Bethesda, MD 20852 USA. EM hartge@nih.gov RI Struewing, Jeffery/C-3221-2008; Tucker, Margaret/B-4297-2015; Struewing, Jeffery/I-7502-2013 OI Struewing, Jeffery/0000-0002-4848-3334 NR 22 TC 58 Z9 60 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 FEB 3 PY 1999 VL 91 IS 3 BP 259 EP 263 DI 10.1093/jnci/91.3.259 PG 5 WC Oncology SC Oncology GA 163VQ UT WOS:000078427400013 PM 10037104 ER PT J AU Schairer, C Gail, M Byrne, C Rosenberg, PS Sturgeon, SR Brinton, LA Hoover, RN AF Schairer, C Gail, M Byrne, C Rosenberg, PS Sturgeon, SR Brinton, LA Hoover, RN TI Estrogen replacement therapy and breast cancer survival in a large screening study SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID POSTMENOPAUSAL WOMEN; PROGNOSTIC FACTORS; FOLLOW-UP; COMPETING RISKS; MORTALITY; FAILURE; COHORT; USERS AB Background: Hormone replacement therapy has been associated in some studies with reductions in breast cancer mortality among women who develop this disease. It is unclear whether this association reflects the biologic activity of the hormones or the earlier detection of tumors among hormone users. We examined breast cancer mortality among women who were diagnosed with axillary lymph node-negative and node-positive breast cancer according to the currency of estrogen use at diagnosis. Methods: Vital status through June 1995 was determined for 2614 patients with postmenopausal breast cancer diagnosed during the period from 1973 to January 1981. We estimated adjusted hazard-rate ratios (adjusting for tumor size, age, race, Quetelet [body mass] index, and number of positive lymph nodes in women with nodepositive disease) and unadjusted cumulative probabilities of breast cancer death over time since diagnosis, Results: Among patients with nodenegative disease, rate ratios for breast cancer mortality associated with current use compared with nonuse at diagnosis were 0.5 (95% confidence interval [CI] = 0.3-0.8) until 144 months after diagnosis and 2.2 (95% CI = 0.9-5.2) thereafter. Mortality was not statistically significantly lower in past users. The cumulative probabilities of breast cancer mortality at the end of follow-up were 0.14, 0.14, and 0.09 in nonusers, past users, and current users, respectively. Among women with nodepositive disease, the rate ratios associated with current and past use were both 0.5 until 48 months after diagnosis (95% CI = 0.3-0.8 for current users; 95% CI = 0.3-0.9 for past users) and were 1.1 (95% CI = 0.7-1.7) and 1.8 (95% CI = 1.2-2.7), respectively, thereafter. The cumulative probabilities of breast cancer mortality were 0.32, 0.39, and 0.27 in nonusers, past users, and current users, respectively. Conclusions: Patients with breast cancer who were using replacement estrogens at the time of diagnosis experienced reductions in breast cancer mortality, which waned with the time since diagnosis. C1 NCI, Environm Epidemiol Branch, Bethesda, MD 20892 USA. NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Channing Lab, Boston, MA 02115 USA. RP Schairer, C (reprint author), NIH, EPN, Rm 443,6130 Execut Blvd,MSC 7374, Bethesda, MD 20892 USA. EM Schairec@epndce.nci.nih.gov RI Brinton, Louise/G-7486-2015; Byrne, Celia/K-2964-2015 OI Brinton, Louise/0000-0003-3853-8562; Byrne, Celia/0000-0001-8289-4252 NR 32 TC 96 Z9 97 U1 0 U2 2 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 FEB 3 PY 1999 VL 91 IS 3 BP 264 EP 270 DI 10.1093/jnci/91.3.264 PG 7 WC Oncology SC Oncology GA 163VQ UT WOS:000078427400014 PM 10037105 ER PT J AU Ferris, HA Tapia, JA Garcia, LJ Jensen, RT AF Ferris, HA Tapia, JA Garcia, LJ Jensen, RT TI CCKA receptor activation stimulates p130(Cas) tyrosine phosphorylation, translocation, and association with Crk in rat pancreatic acinar cells SO BIOCHEMISTRY LA English DT Article ID FOCAL ADHESION KINASE; SWISS 3T3 CELLS; GROWTH-FACTOR; PROTEIN-KINASE; LYSOPHOSPHATIDIC ACID; ACTIN CYTOSKELETON; V-CRK; SUBSTRATE P130(CAS); SIGNALING PATHWAYS; SMOOTH-MUSCLE AB p130(Cas) (Crk-associated substrate), because of its structure as an adapter protein, can interact when tyrosine-phosphorylated with a large number of cellular proteins and therefore be an important modulator of downstream signals. A number of growth factors, lipids, and a few G protein-coupled receptors can stimulate p130(Cas) tyrosine phosphorylation. Recent studies show that tyrosine phosohorylation of intracellular proteins by the hormone/neurotransmitter cholecystokinin (CCK) in rat pancreatic acinar cells may be an important signaling cascade. In this study, we show in rat dispersed pancreatic acini CCK-8 rapidly stimulates tyrosine phosphorylation of p130(Cas), reaching a maximum (6.6 +/- 1.4)-fold increase with a half-maximal effect at 0.3 nM. Activation of protein kinase C by TPA or increases in [Ca2+](i) by the calcium ionophore A23187 stimulated p130(Cas) phosphorylation. Blockade of CCK increases in [Ca2+](i) or PKC activity did not alter CCK-8-stimulated p130(Cas) phosphorylation; however, simultaneous blockage of both cascades caused a 50% inhibition. Partial inactivation by C. botulinum toxin of the small GTP-binding protein Rho caused a 41 +/- 12% decrease in the CCK-stimulated p130(Cas) phosphorylation. Disruption of the actin cytoskeleton with cytochalasin D, but not the microtubule network with colchicine, completely inhibited CCK-8-stimulated p130(Cas) phosphorylation. Total p130(Cas) under basal conditions was largely localized (70 +/- 2%) in the membrane fraction, and stimulation with CCK-8 induced total p130(Cas) translocation from the cytosolic fraction, CCK stimulation also caused a (5 +/- 1)-fold increase in p130(Cas) tyrosine phosphorylated in the plasmamembrane. Treatment with tyrphostin B44 inhibited CCK-8-stimulated p130(Cas) phosphorylation, but it had no effect on p130(Cas) translocation. CCK-8 caused rapid formation of a p130(Cas)-Crk complex. In conclusion, our results demonstrate CCKA receptor activation causes rapid tyrosine phosphorylation of p130(Cas) through PLC-dependent and -independent mechanisms that require the participation of the small GTP-binding protein Rho and the integrity of the actin cytoskeleton, but not the microtubule network. Moreover, CCKA receptor activation causes translocation of p130(Cas) to the membrane and an increase in membrane tyrosine-phosphorylated p130(Cas). The translocation to the membrane does not require antecedent tyrosine phosphorylation. CCKA activation promotes the rapid formation of a p130(Cas)-Crk complex. These results suggest that p130(Cas) is likely an important modulator of downstream signals activated by CCK-8, possibly involved in regulating numerous cellular effects, such as effects on cell growth or cell shape. C1 NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. Univ Extremadura, Dept Physiol, Caceres 10080, Spain. RP Jensen, RT (reprint author), NIDDK, Digest Dis Branch, NIH, DDB,Bldg 10,Room 9C-103,10 Ctr Dr,MSC 1804, Bethesda, MD 20892 USA. RI Garcia-Marin, Luis /L-4680-2014; Tapia, Jose/C-5181-2008 OI Garcia-Marin, Luis /0000-0002-1795-7381; Tapia, Jose/0000-0002-3614-6867 NR 80 TC 28 Z9 28 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 2 PY 1999 VL 38 IS 5 BP 1497 EP 1508 DI 10.1021/bi981903w PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 170ZF UT WOS:000078836700013 PM 9931015 ER PT J AU Watari, H Blanchette-Mackie, EJ Dwyer, NK Glick, JM Patel, S Neufeld, EB Brady, RO Pentchev, PG Strauss, JF AF Watari, H Blanchette-Mackie, EJ Dwyer, NK Glick, JM Patel, S Neufeld, EB Brady, RO Pentchev, PG Strauss, JF TI Niemann-pick C1 protein: Obligatory roles for N-terminal domains and lysosomal targeting in cholesterol mobilization SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LIPOPROTEIN-DERIVED CHOLESTEROL; MEMBRANE-PROTEINS; DISEASE; FIBROBLASTS; TRANSPORT; LDL; ESTERIFICATION; ACCUMULATION; TRAFFICKING; HOMEOSTASIS AB Niemann-Pick type C (NPC) disease is an inherited lipid storage disorder that affects the viscera and central nervous system. A characteristic feature of NPC cells is the lysosomal accumulation of low density lipoprotein-derived cholesterol. To elucidate important structural features of the recently identified NPC1 gene product defective in NPC disease, we examined the ability of wild-type NPC1 and NPC1 mutants to correct the excessive lysosomal storage of low density lipoprotein-derived cholesterol in a model cell line displaying the NPC cholesterol-trafficking defect (CT60 Chinese hamster ovary cells). CT60 cells transfected with human wild-type NPC1 contained immunoreactive proteins of 170 and 190 kDa localized to the lysosomal/endosomal compartment. Wild-type NPC1 protein corrected the NPC cholesterol-trafficking defect in the CT60 cells. Mutation of conserved cysteine residues in the NPC1 N terminus to serine residues resulted in proteins targeted to lysosomal membranes encircling cholesterol-laden cores, whereas deletion of the C-terminal 4-aa residues containing the LLNF lysosome-targeting motif resulted in the expression of protein localized to the endoplasmic reticulum. None of these mutant NPC1 proteins corrected the NPC cholesterol-trafficking defect in CT60 cells. We conclude that transport of the NPC1 protein to the cholesterol-laden lysosomal compartment is essential for expression of its biological activity and that domains in the N terminus of the NPC1 protein are critical for mobilization of cholesterol from lysosomes. C1 Univ Penn, Med Ctr, Dept Obstet & Gynecol, Ctr Res Reprod & Womens Hlth, Philadelphia, PA 19104 USA. Univ Penn, Med Ctr, Dept Cellular & Mol Engn, Philadelphia, PA 19104 USA. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Sect Lipid Cell Biol, NIH, Bethesda, MD 20892 USA. Vet Adm Connecticut Healthcare Syst, Neurol Res Lab, Newington, CT 06111 USA. RP Strauss, JF (reprint author), 778 Clin Res Bldg,415 Curie Blvd, Philadelphia, PA 19104 USA. EM jfs3@mail.med.upenn.edu FU NICHD NIH HHS [HD06274, P01 HD006274]; NINDS NIH HHS [NS34339] NR 29 TC 98 Z9 103 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 FEB 2 PY 1999 VL 96 IS 3 BP 805 EP 810 DI 10.1073/pnas.96.3.805 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 164VK UT WOS:000078484100004 PM 9927649 ER PT J AU Gladyshev, VN Stadtman, TC Hatfield, DL Jeang, KT AF Gladyshev, VN Stadtman, TC Hatfield, DL Jeang, KT TI Levels of major selenoproteins in T cells decrease during HIV infection and low molecular mass selenium compounds increase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE selenocysteine; thioredoxin reductase; glutathione peroxidase; 15-kDa protein ID NICOTINIC-ACID HYDROXYLASE; CLOSTRIDIUM-BARKERI; TAT PROTEIN; SELENOCYSTEINE; INDUCTION; APOPTOSIS; AIDS AB It has been observed previously that plasma selenium and glutathione levels are subnormal in HIV-infected individuals, and plasma glutathione peroxidase activity is decreased. Under these conditions the survival rate of AIDS patients is reduced significantly. In the present study, using Se-75-labeled human Jurkat T cells, we show that the levels of four Se-75-containing proteins are lower in HIV-infected cell populations than in uninfected cells. These major selenoproteins migrated as 57-, 26-, 21-, and 15-kDa species on SDS/PAGE gels. In our earlier studies, the 57-kDa protein was purified from T cells and identified as a subunit of thioredoxin reductase, The 26- and 21-kDa proteins were identified in immunoblot assays as the glutathione peroxidase (cGPX or GPX1) subunit and phospholipid hydroperoxide glutathione peroxidase (PHGPX or GPX4), respectively. We recently purified the 15-kDa protein and characterized it as a selenoprotein of unknown function. In contrast to selenoproteins, low molecular mass [Se-75]compounds accumulated during HIV infection and migrated as a diffuse band near the front of SDS/PAGE gels. C1 Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NCI, Sect Mol Biol Selenium, Basic Res Lab, NIH, Bethesda, MD 20892 USA. NIAID, Mol Microbiol Lab, Mol Virol Sect, NIH, Bethesda, MD 20892 USA. RP Gladyshev, VN (reprint author), Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. RI Jeang, Kuan-Teh/A-2424-2008; Gladyshev, Vadim/A-9894-2013 NR 27 TC 61 Z9 62 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 FEB 2 PY 1999 VL 96 IS 3 BP 835 EP 839 DI 10.1073/pnas.96.3.835 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 164VK UT WOS:000078484100009 PM 9927654 ER PT J AU Tailor, CS Nouri, A Lee, CG Kozak, C Kabat, D AF Tailor, CS Nouri, A Lee, CG Kozak, C Kabat, D TI Cloning and characterization of a cell surface receptor for xenotropic and polytropic murine leukemia viruses SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ECOTROPIC RETROVIRUS RECEPTOR; FOCUS-INDUCING VIRUSES; ENVELOPE GLYCOPROTEINS; EXPRESSION CLONING; MOUSE CELLS; SUBGROUP-B; INFECTION; SUSCEPTIBILITY; PROTEIN; GENES AB Xenotropic and polytropic murine leukemia viruses (X-MLVs and P-MLVs) cross-interfere to various extents in non-mouse species and in wild Asian mice, suggesting that they might use a common receptor for infection. Consistent with this hypothesis, the susceptibility of some wild mice to X-MLVs has been mapped to the P-MLV receptor locus at the distal end of mouse chromosome 1, In this study, we report the isolation and characterization of a cDNA for the human X-MLV cell surface receptor (X-receptor) by using a human T lymphocyte cDNA library in a retroviral vector, The predicted X-receptor contains 696 amino acids with multiple hydrophobic potential membrane-spanning sequences and with weak homologies to the yeast proteins SYG1, of unknown function, and PHO81, which has been implicated in a system that regulates transport of inorganic phosphate, Expression of the X-receptor in Chinese hamster ovary cells, which are substantially resistant to P-MLVs and to X-MLVs, made them susceptible to both of these virus groups. The mouse homologue of the X-receptor was mapped by hybridization to the distal end of chromosome 1 at the same position as the P-MLV receptor gene Rmc1. These results strongly support the hypothesis that a common gene encodes the receptors for X-MLVs and P-MLVs, with the human X-receptor preferentially mediating X-MLV infections and the homologous protein of inbred mice mediating only P-MLV infections. We propose that X-MLVs and P-MLVs comprise a single family of retroviruses that have coevolved in response to diversification in X-receptor genes of the host. C1 Oregon Hlth Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97201 USA. NIAID, Mol Biol Lab, Bethesda, MD 20892 USA. RP Tailor, CS (reprint author), Oregon Hlth Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97201 USA. FU NCI NIH HHS [CA25810, CA54149] NR 41 TC 136 Z9 140 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 FEB 2 PY 1999 VL 96 IS 3 BP 927 EP 932 DI 10.1073/pnas.96.3.927 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 164VK UT WOS:000078484100025 PM 9927670 ER PT J AU Stephan, DA Gillanders, E Vanderveen, D Freas-Lutz, D Wistow, G Baxevanis, AD Robbins, CM VanAuken, A Quesenberry, MI Bailey-Wilson, J Juo, SHH Trent, JM Smith, L Brownstein, MJ AF Stephan, DA Gillanders, E Vanderveen, D Freas-Lutz, D Wistow, G Baxevanis, AD Robbins, CM VanAuken, A Quesenberry, MI Bailey-Wilson, J Juo, SHH Trent, JM Smith, L Brownstein, MJ TI Progressive juvenile-onset punctate cataracts caused by mutation of the gamma D-crystallin gene SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID X-RAY-ANALYSIS; EYE LENS; ASSOCIATION; RESOLUTION AB Cataracts are a significant public health problem. Here, we describe the genetic alteration responsible far a progressive form of cataract, segregating as an autosomal dominant trait in a three-generation pedigree, Unlike most autosomal dominant cataracts, these are not clinically apparent at birth but are initially observed in the first year or two of life. The opacification evolves relatively slowly, generally necessitating removal of the lens in childhood or early adolescence. A genome-wide search in our kindred revealed linkage at 2q33-35 where the gamma-crystallin gene cluster resides. A single base alteration resulting in an Arg- 14 --> Cys (R14C) substitution in gamma D-crystallin was subsequently identified. Protein modeling suggests that the effect of this mutation is a subtle one, affecting the surface properties of the crystallin molecule rather than its tertiary structure, consistent with the fact that the patients' lenses are normal at birth. This is the first gene defect shown to be responsible for a noncongenital progressive cataract, and studying the defective protein should teach us more about the mechanisms underlying cataract formation. C1 NIMH, Genet Lab, NHGRI, NIH, Bethesda, MD 20892 USA. NIH, Canc Genet Branch, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. NEI, Sect Mol Struct & Funct, NIH, Bethesda, MD 20892 USA. NIH, Genome Technol Branch, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02115 USA. Childrens Hosp, Boston, MA 02115 USA. NIH, Sect Stat Genet, Ctr Inherited Dis Res, Natl Human Genome Res Inst, Baltimore, MD 21224 USA. RP Brownstein, MJ (reprint author), NIMH, Genet Lab, NHGRI, NIH, Bldg 36,Room 3D-06, Bethesda, MD 20892 USA. RI Juo, Suh-Hang/A-1765-2010; Juo, Suh-Hang/C-9545-2009 NR 18 TC 160 Z9 172 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 FEB 2 PY 1999 VL 96 IS 3 BP 1008 EP 1012 DI 10.1073/pnas.96.3.1008 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 164VK UT WOS:000078484100039 PM 9927684 ER PT J AU Vemuri, R Lankford, EB Poetter, K Hassanzadeh, S Takeda, K Yu, ZX Ferrans, VJ Epstein, ND AF Vemuri, R Lankford, EB Poetter, K Hassanzadeh, S Takeda, K Yu, ZX Ferrans, VJ Epstein, ND TI The stretch-activation response may be critical to the proper functioning of the mammalian heart SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SKELETAL-MUSCLE MYOSIN; SKINNED RABBIT PSOAS; LIGHT-CHAIN ISOFORMS; REGULATORY DOMAIN; FORCE GENERATION; SCALLOP MYOSIN; PHOSPHORYLATION; LENGTH; FIBERS; MUTATIONS AB The "stretch-activation" response is essential to the generation of the oscillatory power required for the beating of insect wings. It has been conjectured but not previously shown that a stretch-activation response contributes to the performance of a beating heart. Here, we generated transgenic mice that express a human mutant myosin essential light chain derived from a family with an inherited cardiac hypertrophy, These mice faithfully replicate the cardiac disease of the patients with this mutant allele, They provide the opportunity to study the stretch-activation response before the hearts are distorted by the hypertrophic process. Studies disclose a mismatch between the physiologic heart rate and resonant frequency of the cardiac papillary muscles expressing the mutant essential light chain. This discordance reduces oscillatory power at frequencies that correspond to physiologic heart-rates and is followed by subsequent hypertrophy. It appears, therefore, that the stretch-activation response, first described in insect flight muscle, may play a role in the mammalian heart, and its further study may suggest a new way to modulate human cardiac function. C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. Hosp Univ Penn, Cardiovasc Sect, Philadelphia, PA 19104 USA. NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. RP Epstein, ND (reprint author), NHLBI, Cardiol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM nepstein@helix.nih.gov FU NHLBI NIH HHS [K08HL03172] NR 35 TC 58 Z9 60 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 FEB 2 PY 1999 VL 96 IS 3 BP 1048 EP 1053 DI 10.1073/pnas.96.3.1048 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 164VK UT WOS:000078484100046 PM 9927691 ER PT J AU Friedman, CP Corn, M Frisse, M Hales, JW Hoffman, H Lehmann, H Rathe, R Salas, AA Moore, G Harris, J Henry, R Leach, D LaForce, FM Lurie, N Rosenfield, A Rubenstein, S Ruffin, A AF Friedman, CP Corn, M Frisse, M Hales, JW Hoffman, H Lehmann, H Rathe, R Salas, AA Moore, G Harris, J Henry, R Leach, D LaForce, FM Lurie, N Rosenfield, A Rubenstein, S Ruffin, A CA Informatics Panel Population Hlth Perspective Panel TI Contemporary issues in medicine - Medical informatics and population health: Report II of the Medical School Objectives Project SO ACADEMIC MEDICINE LA English DT Article AB The Association of American Medical Colleges established the Medical School Objectives Project (MSOP) to set forth program-level learning objectives that medical school deans and faculties can use as guides in reviewing their medical student education programs (initial phase), and to suggest strategies that they might employ in implementing agreed-upon changes in those programs (implementation phase). The publication of MSOP Report I in 1998 concluded the initial phase of the project by presenting 30 program-level learning objectives that represent a consensus within the medical education community on the knowledge, skills, and attitudes that students should possess before graduation from medical school. Report II, published here, is the work of two expert panels that focus on the two interrelated topics of medical informatics and population health for which Report I developed learning objectives. The Medical Informatics Panel identified five roles played by physicians-lifelong learner, clinician, educator-communicator, researcher, and manager-in which medical informatics plays a vital part, and defined one or more informatics learning objectives important for each role (e.g., the successful medical school graduate, in his or her role as a clinician, should be able to retrieve patient-specific information from a clinical information system). The panel then identified ways that schools might implement educational programs to address the various informatics learning objectives and to eventually embed informatics experiences throughout the curriculum rather than relying on an informatics course to achieve some or all of the objectives. The Population Health Perspective Panel developed a consensus definition of "population health perspective" (PHP); chose four types of populations to discuss (e.g., the geographic community); reviewed pressures for and against the implementation of a PHS in the curriculum (e.g., the cross-disciplinary nature of the topic is a barrier); named the fields that encompass training in a PHP (e.g., public health); listed several educational objectives, three principles to govern the design of educational activities, and a number of recommendations; and closed with a list of the knowledge, skills, and attitudes that should be instilled by a successful PHF curriculum. C1 Assoc Amer Med Coll, Washington, DC 20037 USA. Univ Pittsburgh, Sch Med, Ctr Biomed Informat, Pittsburgh, PA 15260 USA. Natl Lib Med, Extramural Programs, Bethesda, MD 20894 USA. Washington Univ, Sch Med, St Louis, MO 63130 USA. Duke Univ, Med Ctr, Div Med Informat, Durham, NC 27706 USA. Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. Johns Hopkins Univ, Baltimore, MD 21218 USA. Univ Florida, Coll Med, Gainesville, FL 32611 USA. RP Friedman, CP (reprint author), Assoc Amer Med Coll, 2450 N St NW, Washington, DC 20037 USA. NR 4 TC 76 Z9 77 U1 0 U2 4 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 FEB PY 1999 VL 74 IS 2 BP 130 EP 141 PG 12 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 168RF UT WOS:000078705800013 ER PT J AU Martin, C Richard, V Salem, M Hartley, R Mauguen, Y AF Martin, C Richard, V Salem, M Hartley, R Mauguen, Y TI Refinement and structural analysis of barnase at 1.5 angstrom resolution SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID MICROBIAL RIBONUCLEASES; DIRECTED MUTAGENESIS; CRYSTAL-STRUCTURES; HYDROPHOBIC CORES; PROTEIN STABILITY; COMPLEX; BARSTAR; SPECTROSCOPY; RECOGNITION; MUTATIONS AB The structure of Bacillus amyloliquefaciens ribonuclease (barnase), an extracellular 110-residue enzyme initially solved at 2.0 Angstrom resolution, has been refined at 1.5 Angstrom using synchrotron radiation and an imaging-plate scanner. Refinement with anisotropic atomic displacement parameters resulted in increased accuracy of the structure. The final model has a crystallographic R factor of 11.5% and an R-free of 17.4%. The three independent molecules in the asymmetric unit, referred to as A, B and C, allowed detailed analysis of this final model and meaningful comparison with structures of barnase complexed either with nucleotide inhibitors or with its natural intracellular inhibitor, barstar, The analysis of the overall solvent structure revealed a similar number of water molecules associated with each barnase molecule; among these were 16 equivalent buried solvent molecules, the locations of which are discussed in detail and classified on the basis of their structural role. The importance of the water molecules' contribution to the barnase-barstar interaction is also highlighted. The high accuracy of the present analysis revealed the presence of a Zn2+ ion mediating the contacts between pairs of symmetry-related A, B or C molecules: such an ion had previously only been identified for pairs of C molecules. C1 Ctr Etud Pharmaceut, CNRS, ERS 582, Phys Lab, F-92296 Chatenay Malabry, France. NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Martin, C (reprint author), Ctr Etud Pharmaceut, CNRS, ERS 582, Phys Lab, F-92296 Chatenay Malabry, France. EM yves.mauguen@cep.u-psud.fr NR 50 TC 26 Z9 28 U1 1 U2 3 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 FEB PY 1999 VL 55 BP 386 EP 398 DI 10.1107/S0907444998010865 PN 2 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 165UU UT WOS:000078540900003 PM 10089345 ER PT J AU Kajava, AV AF Kajava, AV TI Dimorphism of polyglycine I: structural models for crystal modifications SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID GLYCINE; PROTEIN; GENE; CONFORMATION; PROGRAM AB Re-examination of the known data on crystalline forms of polyglycine reveals that the crystal modification 'polyglycine I' has two different three-dimensional structures depending on the molecular weight. Structural models for both low molecular weight (LMW) and high molecular weight (HMW) polyglycine I crystals are described. In the LMW crystal model, the molecules have an unusual extended conformation generated by alternation of two mirror-symmetrical residual conformations along the chain. The molecules are parallel and each chain forms interpeptide hydrogen bonds with four adjacent chains, The structural model for the HMW crystal represents a composition of twinning crystallites. The crystallites themselves consist of antiparallel enantiomorphous chains united by hydrogen bonds to form rippled sheets. Calculations of the diffraction patterns and packing energy show that these polyglycine I structures have a higher level of conformity with the experimental data than previously suggested models. New insight into the structure of the polyglycine associates opens up the possibility of designing improved silk-like and nylon materials. C1 Swiss Inst Expt Canc Res, CH-1066 Epalinges, Switzerland. RP Kajava, AV (reprint author), NIH, Ctr Mol Modeling, CIT, Bldg 12A, Bethesda, MD 20892 USA. RI Kajava, Andrey/E-1107-2014 OI Kajava, Andrey/0000-0002-2342-6886 NR 26 TC 20 Z9 20 U1 0 U2 7 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 FEB PY 1999 VL 55 BP 436 EP 442 DI 10.1107/S0907444998012438 PN 2 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 165UU UT WOS:000078540900010 PM 10089352 ER PT J AU Taaffe, DR Cooper, CS Holloway, L Duret, C Marcus, R AF Taaffe, DR Cooper, CS Holloway, L Duret, C Marcus, R TI Lack of association of anabolic hormone status and muscle strength with regional and whole body bone mineral density in healthy men aged 60-79 years SO AGING-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE anabolic hormones; bone density; muscle strength ID HUMAN GROWTH-HORMONE; SEX STEROID-LEVELS; POSTMENOPAUSAL WOMEN; ELDERLY MEN; MAJOR DETERMINANT; PHYSICAL-ACTIVITY; SERUM-ALBUMIN; LUMBAR SPINE; OLDER MEN; MASS AB This study investigated the capacity of muscle strength and anabolic hormone status to predict regional and whole body bone mineral density (BMD) in older men. Fifty-two healthy men aged 60-79 years served as subjects. BMD of the lumbar spine, proximal femur, upper and lower limbs, and whole body was assessed by dual Xray absorptiometry. Dynamic muscle strength for several upper and lower body muscle groups was determined by the one-repetition maximum and isometric grip strength by dynamometry. Anabolic hormone status was assessed by the ratio of testosterone (T) to sex hormone binding globulin (SHBG), given as the free androgen index (FAI), and the ratio of insulin-like growth factor I (IGF-I) to IGF binding protein-3 (IGFBP-3). Age was associated with declines in dynamic strength and the log FAI. In stepwise regression analysis, only body mass was an independent predictor of whole body and upper limb BMD (R-2=0.14), and hip adductor strength predicted the Ward's triangle (R-2=0.13). For lumbar spine BMD, triceps extensor strength teas significantly correlated (r=0.36, p<0.01), while no strength or hormonal variable was associated with the femoral neck, trochanter, or lower limb. The lack of association between muscle strength and BMD was generally unaltered after controlling for hormone status and body mass. There was no difference in BMD when analyzed by tertiles of log FAI or IGF-I/IGFBP-3 or by tertiles of muscle strength. These results suggest that in healthy community-dwelling men in the seventh and eighth decade, muscle strength and hormonal status are not significant contributors to regional or whole body BMD. C1 NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. RP Taaffe, DR (reprint author), NIA, Epidemiol Demog & Biometry Program, Gateway Bldg,7201 Wisconsin Ave,Suite 3C-309, Bethesda, MD 20892 USA. RI Perez , Claudio Alejandro/F-8310-2010 OI Perez , Claudio Alejandro/0000-0001-9688-184X NR 57 TC 16 Z9 17 U1 1 U2 2 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 0394-9532 J9 AGING-CLIN EXP RES JI Aging-Clin. Exp. Res. PD FEB PY 1999 VL 11 IS 1 BP 4 EP 11 PG 8 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 182BF UT WOS:000079478100002 PM 10337436 ER PT J AU George, DT Rawlings, R Eckardt, MJ Phillips, MJ Shoaf, SE Linnoila, M AF George, DT Rawlings, R Eckardt, MJ Phillips, MJ Shoaf, SE Linnoila, M TI Buspirone treatment of alcoholism: Age of onset, and cerebrospinal fluid 5-hydroxyindolacetic acid and homovanillic acid concentrations, but not medication treatment, predict return to drinking SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE alcoholism; alcohol treatment; CSF HVA; CSF 5HIAA ID PLACEBO-CONTROLLED TRIAL; NUCLEUS-ACCUMBENS; ETHANOL INTAKE; NEUROENDOCRINE EVIDENCE; RECEPTOR SENSITIVITY; 5-HT1A RECEPTOR; DOPAMINE; SEROTONIN; BRAIN; RATS AB Disturbances in central nervous system serotonin (5-HT) have been implicated in the pathophysiology of alcoholism, To test the hypothesis that increasing 5-HT function could promote treatment compliance, we randomized patients who had completed a 5-week inpatient treatment program for alcoholism to receive either buspirone or placebo for 1 year. Ten of the 49 patients remained in the study for the entire year. The days to relapse did not differ significantly between patients receiving buspirone or placebo. Regardless of the medication, late-onset alcoholics had a longer time to relapse than early-onset alcoholics, Cerebrospinal fluid showed that patients with high concentrations of both the 5-HT metabolite, 5-hydroxyindoleacetic acid, and the dopamine metabolite, homovanillic acid, were more likely to relapse, compared with patients with low concentrations of cerebrospinal fluid 5-hydroxyindoleacetic acid and homovanillic acid. C1 NIAAA, Clin Studies Lab, Bethesda, MD 20892 USA. RP George, DT (reprint author), NIAAA, Clin Studies Lab, 10 Ctr Dr,MSC 1610,Bldg 10,Room 6S240, Bethesda, MD 20892 USA. NR 65 TC 34 Z9 34 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD FEB PY 1999 VL 23 IS 2 BP 272 EP 278 DI 10.1097/00000374-199902000-00012 PG 7 WC Substance Abuse SC Substance Abuse GA 168EN UT WOS:000078678700012 PM 10069556 ER PT J AU Pawlosky, RJ Salem, N AF Pawlosky, RJ Salem, N TI Alcohol consumption in rhesus monkeys depletes tissues of polyunsaturated fatty acids and alters essential fatty acid metabolism SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE ethanol; essential fatty acids; liver; arachidonic acid; docosahexaenoic acid; lipid metabolism; peroxidation ID LIPID-PEROXIDATION; RAT-LIVER; 4-HYDROXYNONENAL LEVELS; ETHANOL EXPOSURE; ARACHIDONIC-ACID; DISEASE; BABOON AB Rhesus monkeys that were maintained on an adequate diet but with low levels of essential fatty acids (1.4 en% linoleic, 18:2n-6, and 0.08 en%, linolenic acid, 18:3n-3) became depleted of 20:4n-6, and 22: 6n-3 in their livers, plasma lipoproteins, and erythrocytes during an 18-month period of alcohol exposure (2.6 g kg(-1) day(-1)). Monkeys that consumed alcohol also had higher plasma concentrations of 4-hydroxynonenal compared to controls. The metabolism of 18:2n-6 and 18:3n-3 were evaluated in both groups of animals using deuterium-labeled substrates over a 9-day period. Alcohol consumption did not appear to have an effect on the absorption of either H-2(5)-18:2n-6 or H-2(5)-18:3n-3 ethyl esters into the circulation after a single oral dose. However, there was a greater enrichment of deuterium in the biosynthesized fatty acids, 20:4n-6 and 22:6n-3, in the plasma of the monkeys exposed to alcohol compared to controls, These results suggest that chronic alcohol exposure may lead to a stimulation of the rate at which long-chain polyunsaturated fatty acids are biosynthesized to compensate for an increase in lipid peroxidation. C1 NIAAA, Lab Membrane Biochem & Biophys, Rockville, MD 20852 USA. RP Pawlosky, RJ (reprint author), 10300 Baltimore Ave,Bldg 161, Beltsville, MD 20705 USA. NR 29 TC 36 Z9 36 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD FEB PY 1999 VL 23 IS 2 BP 311 EP 317 DI 10.1097/00000374-199902000-00017 PG 7 WC Substance Abuse SC Substance Abuse GA 168EN UT WOS:000078678700017 PM 10069561 ER PT J AU Parascandola, J AF Parascandola, J TI The progress of experiment: Science and therapeutic reform in the United States, 1900-1990. SO AMERICAN HISTORICAL REVIEW LA English DT Book Review C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Parascandola, J (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. NR 1 TC 0 Z9 0 U1 1 U2 2 PU AMER HISTORICAL REVIEW PI WASHINGTON PA 400 A ST SE, WASHINGTON, DC 20003 USA SN 0002-8762 J9 AM HIST REV JI Am. Hist. Rev. PD FEB PY 1999 VL 104 IS 1 BP 206 EP 206 DI 10.2307/2650255 PG 1 WC History SC History GA 171MQ UT WOS:000078868100078 ER PT J AU Koh, KK Bui, MN Hathaway, L Csako, G Waclawiw, MA Panza, JA Cannon, RO AF Koh, KK Bui, MN Hathaway, L Csako, G Waclawiw, MA Panza, JA Cannon, RO TI Mechanism by which Quinarpril improves vascular function in coronary artery disease SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ENDOTHELIUM-DEPENDENT DILATION; RENIN-ANGIOTENSIN SYSTEM; NITRIC-OXIDE; RISK-FACTORS; ADHESION MOLECULES; ATHEROSCLEROSIS; ACETYLCHOLINE; DYSFUNCTION; EXPRESSION; ADULTS AB Angiotensin-converting enzyme (ACE) inhibition has been shown to improve endothelium-dependent vasodilator responsiveness, but the contribution and mechanism of enhanced nitric oxide (NO) bioactivity to this effect in patients with coronary artery disease are unknown. We investigated the effect of ACE inhibition on brachial artery dilator responsiveness to increased shear stress after forearm ischemia by ultrasonography asa bioassay for endothelial NO available to vascular smooth muscle in 9 men with coronary artery disease, Serum nitrogen oxides were measured after 3 days of nitrate-restricted diet as an index of endothelial NO release. Patients received quinapril 20 to 40 mg/day for 8 weeks. Relative to pretreatment measurements, quinapril increased flow-mediated dilation (from 2.4 +/- 0.4 to 10.8 +/- 2.2, p < 0.001), with significant improvement persisting 1 week after discontinuation of therapy (6.7 +/- 2.5%, p < 0.01). However, quinapril decreased serum nitrogen oxide levels by 19 +/- 17% compared with pretreatment values (from 58.2 +/- 19.0 to 46.0 +/- 13.3 mu mol/L, p < 0.01). Thus, ACE inhibitor therapy with quinapril selectively improves endothelium-dependent vasodilator responsiveness by increased NO bioactivity in relation to vascular smooth muscle in patients with coronary artery disease, an effect achieved at a lower rate of NO release from the endothelium. These findings suggest that ACE inhibitors may reduce angiotensin Ii-induced oxidant stress within the vessel wall and protect NO from oxidative inactivation. This effect may reduce endothelial NO synthesis required for vasomotor regulation. (C)1999 by Excerpta Medica, Inc. C1 NIH, Dept Clin Pathol, Ctr Clin, Bethesda, MD 20892 USA. NHLBI, Cardiol Branch, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. RP Cannon, RO (reprint author), NIH, Dept Clin Pathol, Ctr Clin, Bldg 10,Room 7B15,10 Ctr Dr,MSC-1650, Bethesda, MD 20892 USA. NR 28 TC 57 Z9 57 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 245 WEST 17TH STREET, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD FEB 1 PY 1999 VL 83 IS 3 BP 327 EP 331 DI 10.1016/S0002-9149(98)00862-5 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 161PT UT WOS:000078298300005 PM 10072217 ER PT J AU Koh, KK Horne, MK Csako, G Waclawiw, MA Cannon, RO AF Koh, KK Horne, MK Csako, G Waclawiw, MA Cannon, RO TI Relation of fibrinolytic potentiation by estrogen to coagulation pathway activation in postmenopausal women SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID HORMONE-REPLACEMENT THERAPY; HIGH PAI-1 ACTIVITY; VENOUS THROMBOEMBOLISM; MYOCARDIAL-INFARCTION; T-PA; RISK; INHIBITOR; ASSOCIATION; COMPLEX; DISEASE AB To determine whether enhanced fibrinolysis is a primary effect of estrogen or is secondary to activation of coagulation, we measured hemostatic factors before and after conjugated equine estrogen 0.625 mg/day for 1 month in 9 postmenopausal women. We found that potentiation of fibrinolysis is a primary effect of conjugated equine estrogens at this commonly used dosage in healthy postmenopausal women. C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Clin Pathol, Bethesda, MD 20892 USA. RP Cannon, RO (reprint author), NHLBI, Cardiol Branch, NIH, Bldg 10,Room 7B15,10 Ctr Dr MSC-1650, Bethesda, MD 20892 USA. NR 18 TC 32 Z9 33 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 FEB 1 PY 1999 VL 83 IS 3 BP 466 EP + DI 10.1016/S0002-9149(98)00891-1 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 161PT UT WOS:000078298300035 PM 10072247 ER PT J AU Mingrone, G Capristo, E Greco, AV Benedetti, G De Gaetano, A Tataranni, PA Gasbarrini, G AF Mingrone, G Capristo, E Greco, AV Benedetti, G De Gaetano, A Tataranni, PA Gasbarrini, G TI Elevated diet-induced thermogenesis and lipid oxidation rate in Crohn disease SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE body composition; Crohn disease; diet-induced thermogenesis; substrate oxidation rates; lipid oxidation; carbohydrate oxidation; indirect calorimetry; labeled-water-bolus injection technique; resting energy expenditure; basal metabolic rate; respiratory quotient; fat mass; fat-free mass ID TOTAL PARENTERAL-NUTRITION; RESTING METABOLIC-RATE; FATTY-ACID METABOLISM; ANOREXIA-NERVOSA; CONTROLLED TRIAL; ENERGY-EXPENDITURE; OBESITY; WEIGHT; STARVATION; TURNOVER AB Background: Although malnutrition is frequently observed in Crohn disease (CD), its cause is not clear. Regulation of energy metabolism and diet-induced thermogenesis (DIT) have not been adequately studied in CD, Objective: The aim was to study DIT and substrate oxidation in patients with inactive ileal CD. Design: After a test meal providing 50.2 kJ/kg body wt, DIT was assessed by indirect calorimetry performed over 360 min in 18 CD patients and 12 healthy volunteers matched for age, sex, weight, and height. Body composition was evaluated with the labeled-water-bolus injection technique. Results: Fat-free mass did not differ significantly between groups, but CD patients had markedly lower fat mass than control subjects (13.8 +/- 5.63 compared with 19.0 +/- 3.49 kg; P < 0.001). Nonprotein respiratory quotient was lower in CD patients than control subjects (0.80 +/- 0.04 compared with 0.86 +/- 0.03; P < 0.001), Average respiratory quotient between 75 and 150 min after the test meal was 0.85 +/- 0.03 in CD patients and 0.91 +/- 0.02 in control subjects (P < 0.001). Lipid oxidation rate was higher in CD patients than in control subjects (2.26 +/- 1.13 compared with 1.50 +/- 0.75 kJ/min; P < 0.05). DIT was higher in CD patients than in control subjects (9.89 +/- 1.93% compared with 5.67 +/- 0.91% of energy intake; P < 0.001). Conclusions: Patients with inactive ileal CD had significantly higher DIT and lipid oxidation rate than do healthy volunteers. These results may explain why CD patients have difficulty maintaining adequate nutritional status, and the findings also suggest that a diet relatively rich in fat may attain better energy balance. C1 Univ Cattolica Sacro Cuore, Ist Med Interna & Geriatr, Ctr Fisiopatol Shock, Cattedra Med Interna 2,CNR, I-00168 Rome, Italy. NIDDK, Clin Diabet & Nutr Ctr, Phoenix, AZ USA. RP Mingrone, G (reprint author), Univ Cattolica Sacro Cuore, Ist Med Interna & Geriatr, Ctr Fisiopatol Shock, Cattedra Med Interna 2,CNR, Largo A Gemelli 8, I-00168 Rome, Italy. EM mrccst@tin.it NR 42 TC 25 Z9 26 U1 1 U2 2 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 FEB PY 1999 VL 69 IS 2 BP 325 EP 330 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 159WH UT WOS:000078198000024 PM 9989699 ER PT J AU Montello, MJ Ames, T AF Montello, MJ Ames, T TI Therapeutic selection during an emergency response SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article DE disasters; dispensing; documentation; drugs; formularies; patients; pharmaceutical care; pharmacists; prescribing; prescriptions; rational therapy AB Therapeutic selection in a postdisaster setting is described. Therapeutic selection is the process of assessing a patient's pharmaceutical requirements and selecting the appropriate therapy. Although the primary criteria for drug selection during a disaster response are the same as in usual pharmacy practice, there Is a shift in emphasis created by communication and transportation limitations and by changes in the patient's general living environment. The cost of agents is no longer viewed in terms of dollars but in the context of limited inventories. A disaster may exacerbate health problems or make adverse chug effects more common and problematic. Drug administration and patient compliance will be hampered. Pre-established guidelines for appropriate patient care should be reviewed and approved by a group of representative hearth care providers. General policies for pharmaceutical care should include guidelines for a formulary, prescription refills, dispensing limitations, and prescriber approval. Therapeutic selection should involve obtaining a medical history, selecting a drug regimen, educating and counseling the patient, and documenting the process. Pharmacists should use familiar procedures that they are comfortable with to minimize stress and optimize outcomes. Procedures should be flexible to adjust to circumstances and individual patient needs. Therapeutic selection during a disaster response, although based on the same principles as traditional therapeutic selection, is more complex. Pharmacists will need to tailor their approach to the circumstances and to individual patient needs. C1 US Publ Hlth Serv, Disaster Med Assistance Team 1, Bethesda, MD USA. US Publ Hlth Serv, Disaster Med Assistance Team 1, Rockville, MD USA. RP Montello, MJ (reprint author), NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Execut Plaza N,Room 707, Bethesda, MD 20892 USA. NR 3 TC 3 Z9 3 U1 1 U2 1 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 FEB 1 PY 1999 VL 56 IS 3 BP 236 EP 240 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 167KR UT WOS:000078632300012 PM 10030508 ER PT J AU Lewis, RA Shroyer, NF Singh, N Allikmets, R Hutchinson, A Li, YX Lupski, JR Leppert, M Dean, M AF Lewis, RA Shroyer, NF Singh, N Allikmets, R Hutchinson, A Li, YX Lupski, JR Leppert, M Dean, M TI Genotype/phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID ROD OUTER SEGMENTS; FUNDUS-FLAVIMACULATUS; MACULAR DYSTROPHY; CHROMOSOME 1P; RIM PROTEIN; SUPERFAMILY; DATABASE; MUTATION; MEMBRANE; MAPS AB Mutation scanning and direct DNA sequencing of all 50 exons of ABCR were completed for 150 families segregating recessive Stargardt disease (STGD1). ABCR variations were identified in 173 (57%) disease chromosomes, the majority of which represent missense amino acid substitutions. These ABCR variants were not found in 220 unaffected control individuals (440 chromosomes) but do cosegregate with the disease in these families with STGD1, and many occur in conserved functional domains. Missense amino acid substitutions located in the amino terminal one-third of the protein appear to be associated with earlier onset of the disease and may represent misfolding alleles. The two most common mutant alleles, G1961E and A1038V, each identified in 16 of 173 disease chromosomes, composed 18.5% of mutations identified. G1961E has been associated previously, at a statistically significant level in the heterozygous state, with age-related macular degeneration (AMD). Clinical evaluation of these 150 families with STGD1 revealed a high frequency of AMD in first- and second-degree relatives. These findings support the hypothesis that compound heterozygous ABCR mutations are responsible for STGD1 and that some heterozygous ABCR mutations may enhance susceptibility to AMD. C1 Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. Baylor Coll Med, Dept Ophthalmol, Houston, TX 77030 USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. Univ Utah, Eccles Inst Human Genet, Dept Human Genet, Salt Lake City, UT USA. NCI, Sci Applicat Int Corp, Frederick Intramural Res Support Program, Frederick Canc Res & Dev Ctr, Frederick, MD USA. NCI, Lab Genome Divers, Frederick Canc Res & Dev Ctr, Frederick, MD USA. RP Lupski, JR (reprint author), Baylor Coll Med, Dept Pediat, 1 Baylor Plaza,609-E, Houston, TX 77030 USA. EM jlupski@bcm.tmc.edu RI Dean, Michael/G-8172-2012; OI Dean, Michael/0000-0003-2234-0631; Shroyer, Noah/0000-0002-5934-2852 FU NCI NIH HHS [N01-CO-56000] NR 41 TC 183 Z9 192 U1 0 U2 4 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 FEB PY 1999 VL 64 IS 2 BP 422 EP 434 DI 10.1086/302251 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 169HA UT WOS:000078740600012 PM 9973280 ER PT J AU Petralia, SA Vena, JE Freudenheim, JL Michalek, A Goldberg, MS Blair, A Brasure, J Graham, S AF Petralia, SA Vena, JE Freudenheim, JL Michalek, A Goldberg, MS Blair, A Brasure, J Graham, S TI Risk of premenopausal breast cancer and patterns of established breast cancer risk factors among teachers and nurses SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE teachers; nurses; breast cancer; case-control; occupation; women ID OCCUPATION; MORTALITY; WOMEN AB Background Contrasting results have been published regarding the risk of breast cancer among teachers and nurses. Confounding by reproductive factors may explain the increased risk observed among women in these occupations as information on those factors were not available in most studies. Methods We examined the risk of premenopausal breast cancer among teachers and nurses using occupational histories in a case-control study where information on established risk factors was available. Results Having ever held a teaching job was not related to breast cancer (OR = 0.74, 95% CI = 0.44-1.28) and women who worked for 10 years or less in this occupation had a non-significant deficit of risk (OR = 0.52, 95% CI = 0.27-1.02). No elevation in risk was found in association with having ever been, a nurse (OR = 0.85 95% CI = 0.45-1.61) or with duration of nursing. Although direct comparison of established risk factors among teachers and nurses and other women in the study showed some evidence of differential distribution, especially when comparing teachers to other women, adjustment for reproductive variables and other breast cancer risk factors did not change the results of this study. Conclusion These findings suggest that teachers and nurses are not at an increased risk of breast cancer: This study also suggests that established risk factors for premenopausal breast cancer may not explain the elevation of risk found in other studies of teachers and nurses. However; this conclusion is limited by the fact that in the present study teachers and nurses had lower than expected breast cancer risk with or without adjustment for established risk factors. Limitations of this study such as low response rates and limited statistical power should be considered in the interpretation of these findings. Am. J. Ind. Med. 35:137-141, 1999. Published 1999 Wiley-Liss, Inc.dagger C1 SUNY Buffalo, Sch Med & Biomed Sci, Dept Social & Prevent Med, Buffalo, NY 14260 USA. NCI, Bethesda, MD 20892 USA. Univ Quebec, Inst Armand Frappier, Montreal, PQ H3C 3P8, Canada. McGill Univ, Dept Epidemiol & Biostat, Montreal, PQ, Canada. McGill Univ, Dept Occupat Hlth, Montreal, PQ, Canada. RP Petralia, SA (reprint author), NCI, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, 6130 Execut Blvd,EPN 418, Rockville, MD 20892 USA. EM spi126@nih.gov NR 19 TC 17 Z9 17 U1 2 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD FEB PY 1999 VL 35 IS 2 BP 137 EP 141 DI 10.1002/(SICI)1097-0274(199902)35:2<137::AID-AJIM5>3.0.CO;2-A PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 154JN UT WOS:000077885900005 PM 9894537 ER PT J AU Leypoldt, JK Cheung, AK Carroll, CE Stannard, DC Pereira, BJG Agodoa, LY Port, FK AF Leypoldt, JK Cheung, AK Carroll, CE Stannard, DC Pereira, BJG Agodoa, LY Port, FK TI Effect of dialysis membranes and middle molecule removal on chronic hemodialysis patient survival SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE clearance; dialyzer; hemodialysis patient survival; middle molecules; vitamin B-12 ID RENAL-FAILURE; UNITED-STATES; MORTALITY; UREMIA; PREDICTORS; INHIBITOR; CLEARANCE; TRANSPORT; PLASMA; MODELS AB The type of dialysis membrane used for routine therapy has been recently shown to correlate with the survival of chronic hemodialysis patients, We examined whether this effect of dialysis membrane could be explained by differences in dialyzer removal of middle molecules using data from the 1991 Case Mix Adequacy Study of the United States Renal Data System, The sample analyzed included patients who had been treated by hemodialysis for 1 year or more, who were dialyzed with the 19 most commonly used dialyzers in 1991, and for whom delivered urea Kt/V could be calculated from predialysis and postdialysis blood urea nitrogen concentrations. Vitamin B-12 (1,355 daltons) was used as a marker for middle molecules, and the clearance of Vitamin Bla was estimated based on in vitro data. After adjustments for case mix, comorbidities, and urea KW, the relative risk of mortality for a 10% higher calculated total cleared Volume of Vitamin B-12 was 0.953 (P < 0.0001 v 1.000). Similar results were obtained when middle molecule removal was adjusted for body size. We conclude that both small and middle molecule removal indices appear to be independently associated with the risk of mortality in chronic hemodialysis patients, Differences in mortality when using different types of dialysis membrane may be explained by differences in middle molecule removal. This is a US government work. There are no restrictions on its use. C1 Univ Utah, Div Nephrol & Hypertens, Salt Lake City, UT 84112 USA. Univ Utah, Dept Bioengn, Salt Lake City, UT 84112 USA. Vet Affairs Med Ctr, Res Serv, Salt Lake City, UT USA. Vet Affairs Med Ctr, Med Serv, Salt Lake City, UT USA. Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. Univ Michigan, US Renal Data Syst Coordinating Ctr, Ann Arbor, MI 48109 USA. New England Med Ctr, Div Nephrol, Boston, MA 02111 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Leypoldt, JK (reprint author), Univ Utah, Div Nephrol & Hypertens, Dumke Bldg 535, Salt Lake City, UT 84112 USA. NR 39 TC 124 Z9 129 U1 0 U2 5 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD FEB PY 1999 VL 33 IS 2 BP 349 EP 355 DI 10.1016/S0272-6386(99)70311-2 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 163JW UT WOS:000078403100018 PM 10023649 ER PT J AU McAlindon, TE Wilson, PWF Aliabadi, P Weissman, B Felson, DT AF McAlindon, TE Wilson, PWF Aliabadi, P Weissman, B Felson, DT TI Level of physical activity and the risk of radiographic and symptomatic knee osteoarthritis in the elderly: The Framingham Study SO AMERICAN JOURNAL OF MEDICINE LA English DT Article ID ARTICULAR-CARTILAGE; JOINT; EXERCISE; ARTHRITIS; HEALTH; IMMOBILIZATION; PROGRESSION; DISEASE; FITNESS AB PURPOSE: Because osteoarthritis may be caused by "wear and tear," we examined the association between level of physical activity and risk of knee osteoarthritis in the elderly. SUBJECTS AND METHODS: Eligible subjects were participants in the Framingham Heart Study cohort who had radiographically normal knees at biennial exam 18 (1983-1985) and who also completed a physical activity questionnaire at exam 20 (1988-1989). Follow-up knee radiographs were obtained at biennial exam 22 (1992-1993). The study outcomes were the development of incident radiographic or symptomatic knee osteoarthritis between the baseline and follow-up exams. RESULTS: The number of hours per day of heavy physical activity was associated with the risk of incident radiographic knee osteoarthritis (odds ratio = 1.3 per hour, 95% confidence limits 1.1-1.6, P for trend = 0.006). Adjustment for age, sex, body mass index, weight loss, knee injury, health status, total calorie intake, and smoking strengthened this association (eg, odds ratio for greater than or equal to 4 hours heavy physical activity/day compared with no heavy physical activity = 7.0, 95% confidence limits 2.4-20, P for trend = 0.0002). Risk was greatest among individuals in the upper tertile of body mass index (odds ratio for greater than or equal to 3 hours/day of heavy physical activity = 13.0, 95% confidence limits 3.3-51). For incident symptomatic knee osteoarthritis, the results were similar, although the number of cases was small. No effects on these outcomes were observed from moderate and light physical activity, number of blocks walked, or number of flights of stairs climbed daily. CONCLUSIONS: Heavy physical activity is an important risk Factor for the development of knee osteoarthritis in the elderly, especially among obese individuals. Light and moderate activities do not appear to increase risk. Am J Med. 1999;106: 151-157. (C) 1999 by Excerpta Medica, Inc. C1 Boston Univ, Med Ctr, Arthrit Ctr, Boston, MA 02118 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. RP McAlindon, TE (reprint author), Boston Univ, Med Ctr, Arthrit Ctr, A203,715 Albany St, Boston, MA 02118 USA. FU NHLBI NIH HHS [N01-HC-38038]; NIA NIH HHS [AG09300]; NIAMS NIH HHS [AR20613] NR 42 TC 137 Z9 139 U1 0 U2 8 PU EXCERPTA MEDICA INC PI NEW YORK PA 245 WEST 17TH STREET, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD FEB PY 1999 VL 106 IS 2 BP 151 EP 157 DI 10.1016/S0002-9343(98)00413-6 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 172CD UT WOS:000078904000005 PM 10230743 ER PT J AU White, RH McBurnie, MA Manolio, T Furberg, CD Gardin, JM Kittner, SJ Bovill, E Knepper, L AF White, RH McBurnie, MA Manolio, T Furberg, CD Gardin, JM Kittner, SJ Bovill, E Knepper, L TI Oral anticoagulation in patients with atrial fibrillation: Adherence with guidelines in an elderly cohort SO AMERICAN JOURNAL OF MEDICINE LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; CARDIOVASCULAR HEALTH; STROKE PREVENTION; FACTOR-VII; FACTOR-II; FACTOR-X; WARFARIN; THERAPY; MANAGEMENT; HOSPITALS AB PURPOSE: To determine adherence with practice guidelines in a population-based cohort of elderly persons aged 70 years or older with atrial fibrillation. SUBJECTS AND METHODS: This was a cross-sectional analysis of a subgroup of participants in the Cardiovascular Health Study, a prospective observational study involving four communities in the United States. Subjects were participants with atrial fibrillation on electrocardiogram at one or more yearly examinations from 1993 to 1995. The outcome measure was self-reported use of warfarin in 1995. RESULTS: In 1995, 172 (4.1%) participants had atrial fibrillation together with information regarding warfarin use and no preexisting indication for its use, Warfarin was used by 63 (37%) of these participants. Of the 109 participants not reporting warfarin use, 92 (84%) had at least one of the clinical risk factors (aside from age) associated with stroke in patients with atrial fibrillation. Among participants not taking warfarin, 47% were taking aspirin. Several characteristics were independently associated with warfarin use, including age [odds ratio (OR) = 0.6 per 5-year increment, 95% CI 0.5-0.9], a modified mini-mental examination score <85 points [OR = 0.3, 95% confidence interval (CI) 0.1-0.9], and among patients without prior stroke, female sex (OR = 0.5, 95% CI 0.2-1.0). CONCLUSIONS: Despite widely publicized practice guidelines to treat patients who have atrial fibrillation with warfarin, most participants who had atrial fibrillation were at high risk for stroke but were not treated with warfarin. More studies are needed to determine wily elderly patients with atrial fibrillation are not being treated with warfarin. Am J Med. 1999;106: 165-171. (C) 1999 by Excerpta Medica, Inc. C1 Univ Calif Davis, Sacramento, CA 95817 USA. Cardiovasc Hlth Coordinating Ctr, Seattle, WA USA. NHLBI, Bethesda, MD 20892 USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. Univ Calif Irvine, Orange, CA 92668 USA. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. Univ Vermont, Sch Med, Colchester, VT USA. Univ Pittsburgh, Pittsburgh, PA USA. RP White, RH (reprint author), Div Gen Med, Room 3107,PCC 2221 Stockton Blvd, Sacramento, CA 95817 USA. FU NHLBI NIH HHS [N01-HC-85083] NR 39 TC 76 Z9 77 U1 0 U2 1 PU EXCERPTA MEDICA INC PI NEW YORK PA 245 WEST 17TH STREET, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD FEB PY 1999 VL 106 IS 2 BP 165 EP 171 DI 10.1016/S0002-9343(98)00389-1 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 172CD UT WOS:000078904000007 PM 10230745 ER PT J AU Doppman, JL AF Doppman, JL TI There is no simple answer to a rare complication of inferior petrosal sinus sampling SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Editorial Material ID CUSHINGS-SYNDROME C1 NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Doppman, JL (reprint author), Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, Bldg 10,Room 1C660, Bethesda, MD 20892 USA. NR 4 TC 11 Z9 11 U1 0 U2 1 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD FEB PY 1999 VL 20 IS 2 BP 191 EP 192 PG 2 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 173LQ UT WOS:000078982400005 PM 10094336 ER PT J AU Regis, J Semah, F Bryan, RN Levrier, O Rey, M Samson, Y Peragut, JC AF Regis, J Semah, F Bryan, RN Levrier, O Rey, M Samson, Y Peragut, JC TI Early and delayed MR and PET changes after selective temporomesial radiosurgery in mesial temporal lobe epilepsy SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article; Proceedings Paper CT 50th Annual Meeting of the American-Epilepsy-Society CY DEC 05-11, 1996 CL SAN FRANCISCO, CALIFORNIA SP Amer Epilepsy Soc ID POSITRON EMISSION TOMOGRAPHY; GLUCOSE-METABOLISM; RADIOBIOLOGY; MESIOBASAL; MODEL AB We report a patient with medically refractory mesial temporal lobe epilepsy treated by gamma knife radiosurgery. In lieu of a microsurgical procedure, an entorhinoamygdalohippocampectomy was performed with a gamma knife and low marginal doses (25 Gy). The clinical and imaging studies, including CT, MR imaging, F-18-fluorodeoxyglucose positron emission tomography (FDG-PET), and long-term follow-up MR examinations, are reported. The patient has been seizure-free since the day of treatment, with no clinical complications. MR studies accurately depicted the effect on the target structures and the transient secondary changes around them. FDG-PET scans showed decreased metabolism after gamma knife surgery throughout the anteromesial part of the epileptogenic temporal lobe. This metabolic decrease was reversible in the lateral temporal cortex. Our case suggests that gamma knife surgery is a promising tool for use as a minimally invasive approach to the treatment of epilepsy. C1 Hop Enfants La Timone, Dept Stereotact & Funt Neurosurg, Serv Neurochirurg Fonctionnelle & Stereotax, F-13008 Marseille, France. Hop Enfants La Timone, Dept Neuroradiol, F-13008 Marseille, France. Hop Enfants La Timone, Dept Neurophysiol, F-13008 Marseille, France. CEA, Serv Hosp Frederic Joliot, INSERM, U334, F-91406 Orsay, France. Hop La Pitie Salpetriere, Dept Neurol, Paris, France. NIH, Dept Radiol, Baltimore, MD USA. RP Regis, J (reprint author), Hop Enfants La Timone, Dept Stereotact & Funt Neurosurg, Serv Neurochirurg Fonctionnelle & Stereotax, Blvd Jean Moulin, F-13008 Marseille, France. RI semah, franck/O-4716-2014; Bryan, R. Nick/P-1661-2014; samson, yves/C-5647-2013 OI semah, franck/0000-0002-9190-1116; NR 22 TC 46 Z9 47 U1 2 U2 2 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD FEB PY 1999 VL 20 IS 2 BP 213 EP 216 PG 4 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 173LQ UT WOS:000078982400009 PM 10094340 ER PT J AU Schneider, DL Herrero, R Bratti, C Greenberg, MD Hildesheim, A Sherman, ME Morales, J Hutchinson, ML Sedlacek, TV Lorincz, A Mango, L Wacholder, S Alfaro, M Schiffman, M AF Schneider, DL Herrero, R Bratti, C Greenberg, MD Hildesheim, A Sherman, ME Morales, J Hutchinson, ML Sedlacek, TV Lorincz, A Mango, L Wacholder, S Alfaro, M Schiffman, M TI Cervicography screening for cervical cancer among 8460 women in a high-risk population SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE cervicography; cervical cancer; screening; visual; cervix ID HUMAN-PAPILLOMAVIRUS; CYTOLOGY AB OBJECTIVE: Cervicography was evaluated as a primary screening method for cervical cancer. STUDY DESIGN: Cervigrams of 8460 women were taken on enrollment into a population-based study of cervical neoplasia. Cervicography results were compared with a referent diagnosis determined by histologic analysis and 3 cytologic tests, and with the performance of conventional cytologic evaluation. RESULTS: Cervicography identified all 11 cancers, whereas cytologic testing missed 1. Cervicography yielded sensitivities for detecting high-grade squamous intraepithelial lesions or cancer of 49.3% overall (specificity, 95.0%), 54.6% in women younger than 50 years of age, and 26.9% in women 50 years of age and older. Cytologic testing yielded sensitivities for detecting high-grade squamous intraepithelial lesions or cancer of 77.2% overall (specificity, 94.2%), 75.5% in women younger than 50 years of age, and 84.6% in women 50 years of age and older. CONCLUSIONS: Cytologic testing performed better than cervicography for the detection of high-grade squamous intraepithelial lesions. Cervicography performed marginally better than cytologic testing for the detection of invasive cervical cancer. Cervicography is not recommended for postmenopausal women. C1 NCI, Environm Epidemiol Branch, Bethesda, MD 20892 USA. NCI, Biostat Branch, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. Int Agcy Res Canc, F-69372 Lyon, France. Minist Salud, San Jose, Costa Rica. Omnia Inc, Philadelphia, PA USA. Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. Caja Costarricense Seguro Social, Dept Ginecol, San Jose, Costa Rica. Women & Infants Hosp Rhode Isl, Providence, RI 02908 USA. Univ Penn, Grad Hosp, Dept Gynecol, Philadelphia, PA 19104 USA. Digene Corp, Silver Spring, MD USA. Neuromed Syst, Suffern, NY USA. Caja Costarricense Seguro Social, Dept Patol, San Jose, Costa Rica. RP Schneider, DL (reprint author), NCI, Environm Epidemiol Branch, Execut Plaza N Room 443,6130 Execut Blvd,MSC 7374, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CP-21081, N01-CP-31061] NR 25 TC 27 Z9 27 U1 0 U2 0 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD FEB PY 1999 VL 180 IS 2 BP 290 EP 298 DI 10.1016/S0002-9378(99)70202-4 PN 1 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 167UL UT WOS:000078651700006 PM 9988789 ER PT J AU Fong, DS Ferris, FL Davis, MD Chew, EY AF Fong, DS Ferris, FL Davis, MD Chew, EY CA Early Treatment Diabet Retinopathy Study Res Gr TI Causes of severe visual loss in the early treatment diabetic retinopathy study: ETDRS report no. 24 SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article AB PURPOSE: To describe the causes of and risk factors for persistent severe visual loss occurring in the Early Treatment Diabetic Retinopathy Study (ETDRS). METHODS: The ETDRS was a randomized clinical trial investigating photocoagulation and aspirin in 3,711 persons with mild to severe nonproliferative or early proliferative diabetic retinopathy. Severe visual loss, defined as best-corrected visual acuity of less than 5/200 on at least two consecutive 4-month follow-up visits, developed in 257 eyes (219 persons). Of these 257 eyes, 149 (127 persons) did not recover to 5/200 or better at any visit (persistent severe visual loss). Ocular characteristics of these eyes were compared with those of eyes with severe visual loss that improved to 5/200 or better at any subsequent visit. Characteristics of patients with severe visual loss that did and did not improve and those without severe visual loss were also compared. RESULTS: Severe visual loss that persisted developed in 149 eyes of 127 persons. In order of decreasing frequency, reasons recorded for persistent visual loss included vitreous or preretinal hemorrhage, macular edema or macular pig mentary changes related to macular edema, macular or retinal detachment, and neovascular glaucoma. Compared with all patients without persistent severe visual loss, patients with persistent severe visual loss had higher mean levels of hemoglobin A(1c) (10.4 % vs 9.7%; P = .001) and higher levels of cholesterol (244.1 vs 228.5 mg/dl; P = .0081) at baseline. Otherwise, patients with persistent severe visual loss were similar to patients with severe visual loss that improved and to those without severe visual loss. CONCLUSIONS: Persistent severe visual loss was an infrequent occurrence in the ETDRS. Its leading cause was vitreous or preretinal hemorrhage, followed by macular edema or macular pigmentary changes related to macular edema and retinal detachment. The low frequency of persistent severe visual loss in the ETDRS is most likely related to the nearly universal intervention with scatter photocoagulation (either before or soon after high risk proliferative diabetic retinopathy developed) and the intervention with vitreous surgery when clinically indicated, (Am J Ophthalmol 1999;127: 137-141. (C) 1999 by Elsevier Science Inc. All rights reserved.) C1 NEI, Clin Trials Branch, Div Biometry & Epidemiol, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Sch Med, Dept Ophthalmol, Los Angeles, CA 90024 USA. Univ Wisconsin, Fundus Photograph Reading Ctr, Madison, WI USA. RP Fong, DS (reprint author), Kaiser Permanente Med Ctr, Dept Ophthalmol, 1011 Baldwin Pk Ave, Baldwin Pk, CA 91706 USA. EM donald.s.fong@kp.org FU Intramural NIH HHS [Z99 EY999999] NR 11 TC 86 Z9 108 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 EI 1879-1891 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD FEB PY 1999 VL 127 IS 2 BP 137 EP 141 DI 10.1016/S0002-9394(98)00309-2 PG 5 WC Ophthalmology SC Ophthalmology GA 164LB UT WOS:000078464500003 PM 10030553 ER PT J AU Smith, JA Mueller, BU Nussenblatt, RB Whitcup, SM AF Smith, JA Mueller, BU Nussenblatt, RB Whitcup, SM TI Corneal endothelial deposits in children positive for human immunodeficiency virus receiving rifabutin prophylaxis for Mycobacterium avium complex bacteremia SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID ACUTE UVEITIS; INFECTION; AIDS; DISEASE AB PURPOSE: To assess the potential ocular effects of prophylactic administration of rifabutin in children with symptomatic human immunodeficiency virus (HIV) infection and CD4 counts less than 50 cells per mm(3). METHODS: Twenty-five children with HIV infection were enrolled in a phase I-II study of prophylactic administration of systemic rifabutin for prevention of disseminated Mycobacterium avium complex infection and monitored prospectively for the development of ocular complications secondary to HIV infection or drug toxicity. RESULTS: The dose of rifabutin ranged from 5.0 mg to 15.0 mg per kg, and the median ophthalmic follow-up was 24 months. During the study period, six of the children receiving rifabutin prophylaxis for M. avium complex developed unusual bilateral, initially peripheral, stellate, corneal endothelial deposits without associated uveitis. Review of serial corneal drawings and photographs showed an increase in the number of corneal deposits with continued administration of rifabutin. The duration of rifabutin treatment (P = .017) and follow up (P = .0011) was significantly longer in patients who developed these corneal endothelial changes. CONCLUSION: Corneal endothelial deposits should be considered a potential side effect of rifabutin therapy. To date, these findings have not been sight threatening. (Am J Ophthalmol 1999;127:164-169. (C) 1999 by Elsevier Science Inc. All rights reserved.) C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NEI, Clin Branch, NIH, Bethesda, MD 20892 USA. RP Smith, JA (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Rm 10N113, Bethesda, MD 20892 USA. NR 25 TC 18 Z9 22 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD FEB PY 1999 VL 127 IS 2 BP 164 EP 169 PG 6 WC Ophthalmology SC Ophthalmology GA 164LB UT WOS:000078464500008 PM 10030558 ER PT J AU Chan, CC Pack, S Pak, E Tsogos, M Zhuang, Z AF Chan, CC Pack, S Pak, E Tsogos, M Zhuang, Z TI Translocation of chromosomes 11 and 22 in choroidal metastatic Ewing sarcoma detected by fluorescent in situ hybridization SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID FUSION AB PURPOSE: To describe a patient with metastasis of Ewing sarcoma to the choroid and the molecular genetics of the tumor. METHODS: A 26-year old woman with metastatic Ewing sarcoma developed large choroidal masses in the left eye and died 2 months later, Autopsy of the eyes was performed. Dual-color fluorescent in situ hybridization was used to detect genetic alteration in the ocular tumor with EWS and FLI-1 probes, RESULTS: Histopathology confirmed choroidal metastatic Ewing sarcoma. Molecular analysis showed chromosomal translocation t(11;22)(q24;q12) or EWS/FLI-1 rearrangement in the malignant cells of the eye. CONCLUSIONS: Ewing sarcoma can rarely metastasize to the uvea, Molecular detection of the t(11;22)(q24;q12) translocation in Ewing sarcoma is valuable in the differential diagnosis of small round cell tumors. (Am J Ophthalmol 1999;127:226-228, (C) 1999 by Elsevier Science Inc. All rights reserved.). C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NCI, Pathol 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. RI Pack, Svetlana/C-2020-2014 NR 5 TC 5 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD FEB PY 1999 VL 127 IS 2 BP 226 EP 228 DI 10.1016/S0002-9394(98)00295-5 PG 3 WC Ophthalmology SC Ophthalmology GA 164LB UT WOS:000078464500027 PM 10030577 ER PT J AU Ghadimi, BM Schrock, E Walker, RL Wangsa, D Jauho, A Meltzer, PS Ried, T AF Ghadimi, BM Schrock, E Walker, RL Wangsa, D Jauho, A Meltzer, PS Ried, T TI Specific chromosomal aberrations and amplification of the AIB1 nuclear receptor coactivator gene in pancreatic carcinomas SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; ADENOCARCINOMA; LOSSES; CANCER; ABNORMALITIES; TUMORS; GAINS; IDENTIFICATION; REARRANGEMENTS; IMBALANCES AB To screen pancreatic carcinomas for chromosomal aberrations we have applied molecular cytogenetic techniques, including fluorescent in situ hybridization, comparative genomic hybridization, and spectral karyotyping to a series of nine established cell lines. Comparative genomic hybridization revealed recurring chromosomal gains on chromosome arms 3q, 5p, 7p, 8q, 12p, and 20q. Chromosome losses were mapped to chromosome arms 8p, 9p, 17p, 18q, 19p, and chromosome 21. The comparison with comparative genomic hybridization data from primary pancreatic tumors indicates that a specific pattern of chromosomal copy number changes is maintained in cell culture. Metaphase chromosomes from six cell lines were analyzed by spectral karyotyping, a technique that allows one to visualize all chromosomes simultaneously in different colors, Spectral karyotyping identified multiple chromosomal rearrangements, the majority of which were unbalanced. No recurring reciprocal translocation was detected. Cytogenetic aberrations were confirmed using fluorescent in situ hybridization with probes for the MDR gene and the tumor suppressor genes p16 and DCC, Copy number increases on chromosome 20q were validated with a probe specific for the nuclear receptor coactivator AIB1 that maps to chromosome 20q12, Amplification of this gene was identified in six of nine pancreatic cancer cell lines and correlated with increased expression. C1 Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. RP Ghadimi, BM (reprint author), Natl Human Genome Res Inst, NIH, Bldg 49,Room 4C24,49 Convent Dr, Bethesda, MD 20892 USA. NR 46 TC 148 Z9 153 U1 0 U2 0 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD FEB PY 1999 VL 154 IS 2 BP 525 EP 536 DI 10.1016/S0002-9440(10)65298-4 PG 12 WC Pathology SC Pathology GA 166KU UT WOS:000078575900022 PM 10027410 ER PT J AU Xie, CL Turley, SD Pentchev, PG Dietschy, JM AF Xie, CL Turley, SD Pentchev, PG Dietschy, JM TI Cholesterol balance and metabolism in mice with loss of function of Niemann-Pick C protein SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE neurodegeneration; cholesterol synthesis; lysosome; endoplasmic reticulum; low-density lipoprotein receptor ID DENSITY-LIPOPROTEIN RECEPTOR; APOLIPOPROTEIN-E; SCAVENGER RECEPTOR; CYNOMOLGUS MONKEY; MESSENGER-RNA; CLASS-B; DISEASE; LIVER; BRAIN; HOMEOSTASIS AB Type C Niemann-Pick disease is due to a mutation in Niemann-Pick C (NPC) protein, a putative determinant of intracellular cholesterol transport. This study quantifies cholesterol balance in vivo across all tissues in mice with this defect. Cholesterol balance in the heterozygous animal is normal, but in the homozygous mouse the whole animal cholesterol pool expands continuously from birth, reaching 5,442 mg/kg at 7 wk. The size of this pool in each organ is proportional to the rate at which each tissue clears low-density lipoprotein-cholesterol. Despite this expansion, however, cholesterol synthesis is increased so that whole animal synthesis equals 180 mg.day(-1).kg(-1). Forcing additional cholesterol into the liver through the clathrin-coated pit pathway increases the hepatic cholesterol pool in control mice, all of which is esterified, while there is a much greater increase in this pool in mutant mice, all of which is unesterified. These findings are consistent with the view that there is a block in sterol movement from the lysosome to the sites of regulation in NPC disease and have important implications for understanding the function of the NPC protein in intracellular cholesterol metabolism, in general, and in the brain, in particular. C1 Univ Texas, SW Med Ctr, Dept Internal Med, Dallas, TX 75235 USA. NIH, Dev & Metab Neurol Branch, Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20892 USA. RP Dietschy, JM (reprint author), Univ Texas, SW Med Ctr, Dept Internal Med, 5323 Harry Hines Blvd, Dallas, TX 75235 USA. FU NHLBI NIH HHS [R37 HL-09610] NR 42 TC 98 Z9 99 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD FEB PY 1999 VL 276 IS 2 BP E336 EP E344 PG 9 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 166TL UT WOS:000078593200015 PM 9950794 ER PT J AU Grisham, MB Jourd'Heuil, D Wink, DA AF Grisham, MB Jourd'Heuil, D Wink, DA TI Nitric oxide - I. Physiological chemistry of nitric oxide and its metabolites: implications in inflammation SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE arthritis; colitis; leukocytes; free radicals; superoxide; cancer ID SUPEROXIDE; PEROXYNITRITE; OXIDATION; OXYGEN AB The role of nitric oxide (NO) in inflammation represents one of the most studied yet controversial subjects in physiology. A number of reports have demonstrated that NO possesses potent anti-inflammatory properties, whereas an equally impressive number of studies suggest that NO may promote inflammation-induced cell and tissue dysfunction. The reasons for these apparent paradoxical observations are not entirely clear; however, we propose that understanding the physiological chemistry of NO and its metabolites will provide a blueprint by which one may distinguish the regulatory/anti-inflammatory properties of,NO from its deleterious/proinflammatory effects. The physiological chemistry of NO is complex and encompasses numerous potential reactions. In an attempt to simplify the understanding of this chemistry, the physiological aspects of NO chemistry may be categorized into direct and indirect effects. This type of classification allows for consideration of timing, location, and rate of production of NO and the relevant targets likely to be affected. Direct effects are those reactions in which NO interacts directly with a biological molecule or target and are thought to occur under normal physiological conditions when the rates of NO production are low. Generally, these types of reactions may serve regulatory and/or anti-inflammatory functions. Indirect effects, on the other hand, are those reactions mediated by NO-derived intermediates such as reactive nitrogen oxide species derived from the reaction of NO with oxygen or superoxide and are produced when fluxes of NO are enhanced. We postulate that these types of reactions may predominate during times of active inflammation. Consideration of the physiological chemistry of NO and its metabolites will hopefully allow one to identify which of the many NO-dependent reactions are important in modulating the inflammatory response and may help in the design of new therapeutic strategies for the treatment of inflammatory tissue injury. C1 Louisiana State Univ, Med Ctr, Dept Cellular & Mol Physiol, Shreveport, LA 71130 USA. NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. RP Grisham, MB (reprint author), Louisiana State Univ, Med Ctr, Dept Cellular & Mol Physiol, POB 33932, Shreveport, LA 71130 USA. FU NIDDK NIH HHS [DK-43785] NR 27 TC 254 Z9 268 U1 2 U2 15 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD FEB PY 1999 VL 276 IS 2 BP G315 EP G321 PG 7 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 166TM UT WOS:000078593300002 PM 9950804 ER PT J AU Stonestreet, BS Petersson, KH Sadowska, GB Pettigrew, KD Patlak, CS AF Stonestreet, BS Petersson, KH Sadowska, GB Pettigrew, KD Patlak, CS TI Antenatal steroids decrease blood-brain barrier permeability in the ovine fetus SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE alpha-aminoisobutyric acid; brain; corticosteroids; sheep ID ALPHA-AMINOISOBUTYRIC-ACID; INTRAVENTRICULAR HEMORRHAGE; PRETERM INFANTS; PREMATURE RAT; DEXAMETHASONE; TRANSPORT; DELIVERY; MEMBRANES; OCCLUDIN; INJURY AB Antenatal corticosteroid therapy reduces the incidence of intraventricular hemorrhage in premature infants. Enhanced microvascular integrity might provide protection against intraventricular hemorrhage. In the adult, there is evidence to suggest that the blood-brain barrier may be under hormonal control. We hypothesized that antenatal corticosteroids decrease blood-brain barrier permeability in the preterm ovine fetus. Chronically instrumented 120-day-gestation fetuses were studied 12 h after the last of four 6-mg dexamethasone (n = 5) or placebo (n = 6) injections had been given over 48 h to the ewes. Blood-brain barrier function was quantified with the blood-to-brain transfer constant (K-i) for a-aminoisobutyric acid (AIB). K-i was significantly lower across brain regions in the fetuses of ewes that received antenatal dexamethasone compared with placebo (ANOVA; interaction, F = 2.54, P < 0.004). In fetuses of dexamethasone- and placebo-treated ewes, K-i (mu l . g brain wt(-1) . min(-1), mean +/- SD) was, respectively, 2.43 +/- 0.27 vs. 3.41 +/- 0.74 in the cortex, 4.46 +/- 0.49 vs. 5.29 +/- 0.85 in the cerebellum, and 3.70 +/- 0.49 vs. 5.11 +/- 0.70 in the medulla. We conclude that antenatal treatment with corticosteroids reduces blood-brain permeability in the ovine fetus. C1 Brown Univ, Women & Infants Hosp Rhode Isl, Sch Med, Dept Pediat, Providence, RI 02905 USA. NIMH, Div Serv Intervent Res, Bethesda, MD 20892 USA. SUNY Stony Brook, Dept Surg, Stony Brook, NY 11794 USA. RP Stonestreet, BS (reprint author), Brown Univ, Women & Infants Hosp Rhode Isl, Sch Med, Dept Pediat, 101 Dudley St, Providence, RI 02905 USA. FU NICHD NIH HHS [R01-HD-34618] NR 40 TC 37 Z9 37 U1 0 U2 0 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 FEB PY 1999 VL 276 IS 2 BP R283 EP R289 PG 7 WC Physiology SC Physiology GA 164PW UT WOS:000078473600001 PM 9950903 ER PT J AU Frokiaer, J Marples, D Valtin, H Morris, JF Knepper, MA Nielsen, S AF Frokiaer, J Marples, D Valtin, H Morris, JF Knepper, MA Nielsen, S TI Low aquaporin-2 levels in polyuric DI +/+ severe mice with constitutively high cAMP-phosphodiesterase activity SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE collecting duct; nephrogenic diabetes insipidus; water balance; vasopressin ID NEPHROGENIC DIABETES-INSIPIDUS; WATER CHANNEL EXPRESSION; INTRAMEMBRANOUS PARTICLE CLUSTERS; INDUCED DOWN-REGULATION; RAT-KIDNEY MEDULLA; COLLECTING DUCT; VASOPRESSIN; PERMEABILITY; PHOSPHORYLATION; MEMBRANE AB In the renal collecting duct, vasopressin acutely activates cAMP production, resulting in trafficking of aquaporin-2 water channels (AQP2) to the apical plasma membrane, thereby increasing water permeability. This acute response is modulated by long-term changes in AQP2 expression. Recently, a cAMP-responsive element has been identified in the AQP2 gene, raising the possibility that changes in cAMP levels may control AQP2 expression. To investigate this possibility, we determined AQP2 protein levels in a strain of mice, DI +/+ severe (DI), which have genetically high levels of cAMP-phosphodiesterase activity, and hence low cellular cAMP levels, and severe polyuria. Semiquantitative immunoblotting of membrane fractions prepared from whole kidneys revealed that AQP2 levels in DI mice were only 26 +/- 7% (+/-SE) of those in control mice (n = 10, P < 0.01). In addition, semiquantitative Northern blotting revealed a significantly lower AQP2 mRNA expression in kidneys from DI mice compared with control mice (43 +/- 6% vs. 100 +/- 10%; n = 6 in each group, P < 0.05). AQP3 levels were also reduced. The mice were polyuric and urine osmolalities were accordingly substantially lower in the DI mice than in controls (496 +/- 53 vs. 1,696 +/- 105 mosmol/kgH(2)O, respectively). Moreover, there was a linear correlation between urine osmolalities and AQP2 levels (P < 0.05). Immunoelectron microscopy confirmed the markedly lower expression of AQP2 in collecting duct principal cells in kidneys of DI mice and, furthermore, demonstrated that AQP2 was almost completely absent from the apical plasma membrane. Thus expression of AQP2 and AQP2 trafficking were severely impaired in DI mice. These results are consistent with the view that in vivo regulation of AQP2 expression by vasopressin is mediated by cAMP. C1 Aarhus Univ, Inst Anat, Dept Cell Biol, DK-8000 Aarhus, Denmark. Aarhus Univ Hosp, Dept Clin Physiol, DK-8000 Aarhus, Denmark. Aarhus Univ, Inst Expt Clin Res, DK-8000 Aarhus, Denmark. Univ Leeds, Dept Physiol, Leeds LS2 9NQ, W Yorkshire, England. Univ Oxford, Dept Anat, Oxford OX1 3QX, England. Dartmouth Med Sch, Dept Physiol, Hanover, NH 03755 USA. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Nielsen, S (reprint author), Aarhus Univ, Inst Anat, Dept Cell Biol, DK-8000 Aarhus, Denmark. FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 38 TC 36 Z9 36 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD FEB PY 1999 VL 276 IS 2 BP F179 EP F190 PG 12 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 164RR UT WOS:000078477800001 PM 9950948 ER PT J AU Ellsworth, DL Sholinsky, P Jaquish, C Fabsitz, RR Manolio, TA AF Ellsworth, DL Sholinsky, P Jaquish, C Fabsitz, RR Manolio, TA TI Coronary heart disease - At the interface of molecular genetics and preventive medicine SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article DE cardiovascular diseases; coronary disease; polymorphism (genetics); pharmacogenetics; chemical and pharmacologic phenomena; risk factors ID CONVERTING ENZYME GENE; APOLIPOPROTEIN-E POLYMORPHISM; FAMILIAL HYPERTROPHIC CARDIOMYOPATHY; E GENOTYPE INFLUENCE; VASCULAR-DISEASE; RISK FACTOR; PLASMA HOMOCYSTEINE; ARTERY DISEASE; METHYLENETETRAHYDROFOLATE REDUCTASE; MYOCARDIAL-INFARCTION AB Background: Susceptibility to common chronic diseases such as coronary heart disease (CHD) appears to be influenced by "context-dependent effects," which include interactions among genes (genetic epistasis) and among genes and environmental factors (gene-environment interactions). Methods: A synthesis of current knowledge and research findings demonstrates the importance of integrating genetic research on cardiovascular disease with preventive medicine and public health initiatives. Results: A variety of candidate genes have been implicated in risk for CIID, but only limited examples of context-dependent effects have been described. Interactions between genetic and environmental factors appear to influence lipid metabolism, plasma homocysteine levels, and pharmacologic response to many commonly prescribed medications. Quantification of genetic effects associated with increased disease risk that are modifiable by interventions such, as diet, exercise, and smoking cessation is an important: interface between molecular genetics and preventive medicine. Conclusions: As a primary focus of preventive medicine expands to encompass early detection and treatment of asymptomatic individuals at risk for disease, the ability to quantify tie influence of context-dependent effects on disease risk will be critical for determining drug safety and effectiveness in diverse patient populations and for implementing effective prevention and treatment programs. C1 NHLBI, Epidemiol & Biometry Program, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. RP Ellsworth, DL (reprint author), NHLBI, Epidemiol & Biometry Program, Div Epidemiol & Clin Applicat, NIH, 6701 Rockledge Dr,MSC 7934,Room 8166, Bethesda, MD 20892 USA. NR 86 TC 28 Z9 28 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD FEB PY 1999 VL 16 IS 2 BP 122 EP 133 DI 10.1016/S0749-3797(98)00138-X PG 12 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 168RT UT WOS:000078707000008 PM 10343889 ER PT J AU Breier, AF Malhotra, AK Su, TP Pinals, DA Elman, I Adler, CM Lafargue, T Clifton, A Pickar, D AF Breier, AF Malhotra, AK Su, TP Pinals, DA Elman, I Adler, CM Lafargue, T Clifton, A Pickar, D TI Clozapine and risperidone in chronic schizophrenia: Effects on symptoms, parkinsonian side effects, and neuroendocrine response SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID ATYPICAL ANTIPSYCHOTIC-DRUGS; NEGATIVE SYMPTOMS; RECEPTOR OCCUPANCY; HALOPERIDOL; BINDING; PROFILE; D-2 AB Objective: Clozapine and risperidone were the first two "second-generation" antipsychotic drugs approved for schizophrenia. There is currently little information about their comparative efficacy from head-to-head clinical trials. The purpose of this study was to examine the comparative efficacy of clozapine and risperidone for positive and negative symptoms, depression, parkinsonian side effects, and indexes of neuroendocrine function in schizophrenic patients who met a priori criteria for partial response to traditional neuroleptic agents. Method: After a baseline fluphenazine treatment period, 29 patients participated in a 6-week, double-blind, parallel-group comparison of the effects of these agents. Results: Clozapine was superior to risperidone for positive symptoms and parkinsonian side effects, but there were no significant differences between the drugs on two measures of negative symptoms, Brief Psychiatric Rating Scale total scores, and depression scores. The clozapine patients, but not the risperidone patients, demonstrated significant reductions from the fluphenazine baseline in positive symptoms, total symptoms, and depression. In addition, clozapine produced fewer effects on plasma prolactin than risperidone or fluphenazine, The mean daily doses during week 6 of the trial were 403.6 mg of clozapine and 5.9 mg of risperidone. Conclusions: The findings from this study indicate that these drugs have both important differences and similarities in their comparative efficacy in chronically ill, partially responsive patients with schizophrenia. Further research on second-generation antipsychotic drugs in this patient population that addresses key methodological issues, such as optimal dose and treatment duration, are needed. C1 NIMH, Expt Therapeut Branch, Div Intramural Res Programs, Bethesda, MD USA. RP Breier, AF (reprint author), Eli Lilly & Co, Lilly Corp Ctr, Drop Code 0538, Indianapolis, IN 46285 USA. EM breier_alan@iily.com NR 31 TC 138 Z9 145 U1 1 U2 2 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 FEB PY 1999 VL 156 IS 2 BP 294 EP 298 PG 5 WC Psychiatry SC Psychiatry GA 163ZF UT WOS:000078436500018 PM 9989566 ER PT J AU Gjessing, HK Skjaerven, R Wilcox, AJ AF Gjessing, HK Skjaerven, R Wilcox, AJ TI Errors in gestational age: Evidence of bleeding early in pregnancy SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID BIRTH-WEIGHT; INFANTS; WALES AB Objectives. This study explored the extent of errors in gestational age as ascertained by last menstrual period. Methods. More than 1.5 million birth records (covering the years 1967-1994) from the population-based Medical Birth Registry of Norway were used to study variation in gestational age within strata of birthweight. Results. Within 100-g strata of birthweight, it was found that the observed gestational age distribution could be divided into 3 distinct underlying distributions separated by approximately 4 week. This pattern was present through all birthweight strata, from 200 g up to 4700 g. In addition, the apparent misclassification causing a gestational age 4 weeks too short was much more common among low-birthweight birth than among heavier births. Conclusions. The separation of the gestational age distributions by intervals of close to 4 weeks suggests that errors in gestational age measurements are caused by factors related to menstrual bleeding. Furthermore:, there is evidence for a strong relation between bleeding at the time of the next menstrual period after conception and low birthweight. This conclusion should be approached with caution because of the retrospective nature of the data. C1 Univ Bergen, Dept Med Stat, N-5021 Bergen, Norway. Univ Bergen, Med Birth Registry Norway, N-5021 Bergen, Norway. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Gjessing, HK (reprint author), Univ Bergen, Dept Med Stat, Armauer Hansens Bldg, N-5021 Bergen, Norway. RI Gjessing, Hakon/A-5871-2012; OI Wilcox, Allen/0000-0002-3376-1311 NR 18 TC 83 Z9 84 U1 0 U2 2 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 FEB PY 1999 VL 89 IS 2 BP 213 EP 218 DI 10.2105/AJPH.89.2.213 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 161NW UT WOS:000078296200013 PM 9949752 ER PT J AU Rimer, BK AF Rimer, BK TI Mammography screening - Rimer responds SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Letter C1 NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Rimer, BK (reprint author), NCI, Div Canc Control & Populat Sci, Execut Plaza N,Suite 242,6130 Execut Blvd, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 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 FEB PY 1999 VL 89 IS 2 BP 254 EP 255 DI 10.2105/AJPH.89.2.254-a PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 161NW UT WOS:000078296200022 ER PT J AU Grabczyk, E Usdin, K AF Grabczyk, E Usdin, K TI Generation of microgram quantities of trinucleotide repeat tracts of defined length, interspersion pattern, and orientation SO ANALYTICAL BIOCHEMISTRY LA English DT Article ID DNA-SEQUENCES; TRIPLET; INSTABILITY; EXPANSION; DISEASE C1 NIDDKD, Sect Genome Struct & Funct, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. RP Grabczyk, E (reprint author), NIDDKD, Sect Genome Struct & Funct, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. NR 9 TC 14 Z9 15 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD FEB 1 PY 1999 VL 267 IS 1 BP 241 EP 243 DI 10.1006/abio.1998.2962 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 162RG UT WOS:000078360100032 PM 9918680 ER PT J AU Gilron, I Quirion, R Coderre, TJ AF Gilron, I Quirion, R Coderre, TJ TI Pre- versus postinjury effects of intravenous GABAergic anesthetics on formalin-induced Fos immunoreactivity in the rat spinal cord SO ANESTHESIA AND ANALGESIA LA English DT Article; Proceedings Paper CT 27th Annual Meeting of the Society-of-Neuroscience CY OCT 25-30, 1997 CL NEW ORLEANS, LOUISIANA SP Soc Neurosci ID C-FOS; SUBCUTANEOUS FORMALIN; EXPRESSION; STIMULATION; RECEPTOR; PROTEIN; NEURONS; PAIN; HYPERALGESIA; NOCICEPTION AB We evaluated the suppression of spinal Fos-like immunoreactivity (FLI) by IV anesthetics in the rat formalin model. Preformalin injection (1.5% subcutaneously) treatment groups included IV saline controls and three IV GABAergic anesthetic groups (pentobarbital 20 mg/kg, propofol 10 mg/kg, or alphaxalone 1.5 mg/kg; n = 12 per group). After perfusion 2 h postformalin, spinal cords were dissected, sliced at 30 mu m, and processed by immunoperoxidase staining with an antibody against the Fos protein. Quantification and determination of the laminar distribution of Fos-labeled nuclei were performed at the L4-5 spinal level ipsilateral to formalin injection. Drug groups demonstrating FLI suppression were comparatively studied in a 5-min postformalin treatment group. Pentobarbital pretreatment failed to suppress FLI. However, significant reductions (percent decrease) of FLI were observed with propofol (63%) and alphaxalone (30%) compared with saline controls. Pre- versus postformalin comparison studies showed that propofol, but not alphaxalone, suppressed FLI more effectively when given preformalin. Given the observed inconsistencies between this study of Fos expression and our previous behavioral study, it is questionable whether anesthetic modulation of noxious stimulus-induced FLI parallels that of behavioral responses. Implications: In this study, we examined whether IV general anesthetics (propofol, alphaxalone, and pentobarbital) prevent injury-induced spinal cord changes. We measured spinal Fos protein after rats received anesthetics before versus after a formalin injection. Fos inhibition patterns were inconsistent with behavioral studies of these anesthetics, suggesting that Fos inhibition does not always correlate with behavioral analgesia. C1 Natl Inst Dent & Craniofacial Res, Pain & Neurosensory Mechanisms Branch, NIH, Bethesda, MD 20892 USA. Douglas Hosp, Res Ctr, Verdun, PQ H4H 1R3, Canada. McGill Univ, Dept Psychol, Montreal, PQ H3A 2T5, Canada. Clin Res Inst Montreal, Pain Mechanisms Res Lab, Montreal, PQ, Canada. Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada. RP Gilron, I (reprint author), Natl Inst Dent & Craniofacial Res, Pain & Neurosensory Mechanisms Branch, NIH, Bldg 10,Room 3C-434,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Coderre, Terence/B-4825-2012 NR 34 TC 17 Z9 21 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD FEB PY 1999 VL 88 IS 2 BP 414 EP 420 DI 10.1097/00000539-199902000-00036 PG 7 WC Anesthesiology SC Anesthesiology GA 163KJ UT WOS:000078404300037 PM 9972767 ER PT J AU Njoku, DB Bourdi, M Martin, JL Greenberg, RS Pohl, LR AF Njoku, DB Bourdi, M Martin, JL Greenberg, RS Pohl, LR TI Autoantibodies associated with inhalational anesthetic hepatitis found in the sera of a large cohort of pediatric anesthesiologists SO ANESTHESIA AND ANALGESIA LA English DT Meeting Abstract C1 Johns Hopkins Med Inst, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. NHLBI, Mol & Cellular Toxicol Sect, LMI, NIH, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD FEB PY 1999 VL 88 IS 2 SU S MA S303 PG 1 WC Anesthesiology SC Anesthesiology GA 165EN UT WOS:000078507400299 ER PT J AU Njoku, DB Pohl, LR Sokoloski, EA Marchick, MR Borkowf, CB Martin, JL AF Njoku, DB Pohl, LR Sokoloski, EA Marchick, MR Borkowf, CB Martin, JL TI Immunochemical evidence against the involvement of cysteine conjugate beta-lyase in compound A nephrotoxicity in rats SO ANESTHESIOLOGY LA English DT Article; Proceedings Paper CT 6th European-International-Society-for-the-Study-of-Xenobiotics Annual Meeting CY JUL 02, 1997 CL GOTHENBURG, SWEDEN SP European Int Soc Study Xenobiot DE bioactivation; kidney; molecular toxicity ID LOW-FLOW SEVOFLURANE; FLUOROMETHYL 2,2-DIFLUORO-1-(TRIFLUOROMETHYL)VINYL ETHER; DEGRADATION PRODUCTS; RENAL-FUNCTION; S-OXIDASE; GLUTATHIONE; ANESTHESIA; TOXICITY; PROTEIN; ISOFLURANE AB Background: Compound A, a degradation product of sevoflurane, causes renal corticomedullary necrosis in rats. Although the toxicity of this compound was originally hypothesized to result from the biotransformation of its cysteine conjugates into toxic thionoacyl halide metabolites by renal cysteine conjugate beta-lyase, recent evidence suggests that alternative mechanisms may be responsible for compound A nephrotoxicity. The aim of this study was to evaluate these issues by determining whether mercapturates and glutathione conjugates of compound A could produce renal corticomedullary necrosis in rats, similar to compound A, and whether renal covalent adducts of the thionacyl halide metabolite of compound A could be detected immunochemically. Methods: Male Wistar rats were administered, intraperitoneally, N-acetylcysteine conjugates (mercapturates) of compound A (90 or 180 mu mol/kg) or glutathione conjugates of compound A (180 mu mol/kg) with or without intraperitoneal pretreatments with aminooxyacetic acid (500 mu mol/kg) or acivicin (250 mu mol/kg). Rats were killed after 24 h, and kidney tissues were analyzed for toxicity by histologic examination or for protein adducts by immunoblotting or immunohistochemical analysis, using antisera raised against the covalently bound thionoacyl halide metabolite of compound A. Results: Mercapturates and glutathione conjugates of compound A both produced renal corticomedullary necrosis similar to that caused by compound A. Aminooxyacetic acid, an inhibitor of renal cysteine conjugate beta-lyase, did not inhibit the toxicity of the mercapturates, whereas acivicin, an inhibitor of gamma-glutamyltranspeptidase, potentiated the toxicity of both classes of conjugates. No immunochemical evidence for renal protein adducts of the thionacyl halide metabolite was found in rats 24 h after the administration of the mercapturates of compound A or in the kidneys of rats, obtained from a previous study, 5 and 24 h after the administration of compound A. Conclusion: The results of this study are consistent with the idea that a mechanism other than the renal cysteine conjugate beta-lyase pathway of metabolic activation is responsible for the nephrotoxicity of compound A and its glutathione and mercapturate conjugates in male Wistar rats. C1 Johns Hopkins Med Inst, Dept Anesthesia & Crit Care, Baltimore, MD 21205 USA. NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP Njoku, DB (reprint author), Johns Hopkins Hosp, Dept Anesthesiol & Crit Care Med, Blalock 15,600 N Wolfe St, Baltimore, MD 21287 USA. NR 35 TC 10 Z9 10 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 FEB PY 1999 VL 90 IS 2 BP 458 EP 469 DI 10.1097/00000542-199902000-00021 PG 12 WC Anesthesiology SC Anesthesiology GA 162BU UT WOS:000078326100020 PM 9952153 ER PT J AU Cohen, PJ AF Cohen, PJ TI Plus ca change SO ANESTHESIOLOGY LA English DT Letter C1 NIDA, Bethesda, MD 20892 USA. RP Cohen, PJ (reprint author), NIDA, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 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 FEB PY 1999 VL 90 IS 2 BP 632 EP 632 DI 10.1097/00000542-199902000-00043 PG 1 WC Anesthesiology SC Anesthesiology GA 162BU UT WOS:000078326100042 PM 9952175 ER PT J AU Ellsworth, DL Manolio, TA AF Ellsworth, DL Manolio, TA TI The emerging importance of genetics in epidemiologic research II. Issues in study design and gene mapping SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE molecular epidemiology; epidemiologic methods; phenotype; human genome; genetic markers; genetic techniques; mapping; hereditary diseases ID GENOME-WIDE SEARCH; LINKAGE DISEQUILIBRIUM; POSITIONAL CLONING; DISEASE; TWIN; DNA; ATHEROSCLEROSIS; HYPERTENSION; LOCALIZATION; FAMILY AB PURPOSE: To provide a synthesis of current approaches to the discovery of genes associated with complex human diseases by examining the joint potential of traditional epidemiologic methods and current molecular techniques for gene discovery. METHODS: A discussion of optimal approaches for defining complex disease phenotypes in genetic epidemiology, ascertainment strategies for estimating genetic influences on disease risk, genomic approaches for localizing complex-disease-susceptibility genes, and the potential synergistic effects of integrating genetic and traditional epidemiologic expertise is provided in the second part of a three-part series on the importance of genetics in epidemiologic research. RESULTS: The ability to quantify genetic influences on disease risk appears highly dependent on the measurement of specific risk factor traits, ascertainment strategies for recruiting study subjects, and a variety of genomic approaches that are rapidly facilitating our ability to identify genes influencing inherited human diseases and to quantify genetic influences on disease risk. CONCLUSIONS: Integrating population-based methods of assessing disease risk with human genetics and genome technology is critical for identifying genetic polymorphisms that influence risk of disease and for defining genetic effects on complex disease etiology. Published by Elsevier Science Inc. C1 NHLBI, Div Epidemiol & Clin Applicat, Epidemiol & Biometry Program, NIH, Bethesda, MD 20892 USA. RP Ellsworth, DL (reprint author), NHLBI, Div Epidemiol & Clin Applicat, Epidemiol & Biometry Program, NIH, 6701 Rockledge Dr MSC 7934, Bethesda, MD 20892 USA. NR 54 TC 36 Z9 38 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD FEB PY 1999 VL 9 IS 2 BP 75 EP 90 DI 10.1016/S1047-2797(98)00064-7 PG 16 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 166AK UT WOS:000078553900001 PM 10037550 ER PT J AU Sorlie, PD Thom, TJ Manolio, T Rosenberg, HM Anderson, RN Burke, GL AF Sorlie, PD Thom, TJ Manolio, T Rosenberg, HM Anderson, RN Burke, GL TI Age-adjusted death rates: Consequences of the year 2000 standard SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE mortality; vital statistics AB PURPOSE: For nearly 60 years, official U.S. mortality statistics have been age-adjusted using the age distribution from the U.S. population for the year 1940. A new population standard, the projected Year 2000 U.S. standard, has been approved for use by the Department of Health and Human Services (DHHS). It will be implemented for official U.S. Government statistics published for deaths occurring in 1999. The new standard reflects the older age distribution of the population; 6.8% of the population was age 65 years or more in 1940, as compared to 12.6% projected for 2000. METHODS: This paper investigates the consequences of the new age distribution standard by comparing death rates by time, place, and population characteristics, adjusted to both the 1940 and projected 2000 population standards. RESULTS: The new standard changes the level of the age-adjusted death rate for total mortality and for many causes of death, as compared to the 1940 standard. For example, the 1995 death rate for diseases of the heart is 138 per 100,000 population when adjusted using the 1940 standard, but is 296 per 100,000 using the Year 2000 standard. The new standard may change the comparison of age-adjusted rates if there are substantial differences in the age-specific rates. For example, the ratio of age-adjusted death rates for ischemic heart disease in black relative to white males is 1.07 using the 1940 standard, but is 0.96 using the Year 2000 standard. CONCLUSIONS: The new Year 2000 age standard has the potential to change both levels and comparisons of age-adjusted rates. Age-adjustment is an averaging process, and consequently, has the potential to view the data effectively as a whole while possibly obscuring important age-specific details. (C) 1999 Elsevier Science Inc. All rights reserved. C1 NHLBI, Epidemiol & Biometry Program, Rockledge Ctr 2, NIH, Bethesda, MD 20892 USA. Natl Ctr Hlth Stat, Div Vital Stat, Hyattsville, MD 20782 USA. Wake Forest Univ, Sch Med, Dept Publ Hlth, Winston Salem, NC 27109 USA. RP Sorlie, PD (reprint author), NHLBI, Epidemiol & Biometry Program, Rockledge Ctr 2, NIH, MSC 7934,6701 Rockledge Dr, Bethesda, MD 20892 USA. NR 12 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD FEB PY 1999 VL 9 IS 2 BP 93 EP 100 DI 10.1016/S1047-2797(98)00061-1 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 166AK UT WOS:000078553900003 PM 10037552 ER PT J AU Carpenter, CL Jarvik, ME Morgenstern, H McCarthy, WJ London, SJ AF Carpenter, CL Jarvik, ME Morgenstern, H McCarthy, WJ London, SJ TI Mentholated cigarette smoking and lung-cancer risk SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE lung neoplasms; menthol; African Americans; Caucasians; smoking ID UNITED-STATES; NEW-JERSEY; VITAMIN-A; WHITE MEN; VEGETABLES; AMERICANS; RECEPTORS; EXPOSURE; CAROTENE; HABITS AB PURPOSE: Menthol smoking may lead to a greater increase in lung-cancer risk than smoking of nonmentholated cigarettes. Mentholation of cigarettes adds additional carcinogenic components to cigarette smoke and increases retention times for cigarette smoke in the lungs. Only two epidemiologic studies have been conducted on menthol smoking and lung cancer, and their results are conflicting, Of note, African American males have much higher rates of lung cancer than Caucasian males despite smoking fewer cigarettes per day. Because the consumption of menthol cigarettes is much more frequent among African Americans, it is of interest to examine the possible association between menthol smoking and lung-cancer risk in this population. METHODS: We examined the association between menthol cigarette smelting and lung-cancer risk among smokers by comparing 337 incident cases of lung cancer with 478 population controls enrolled in a case-control study of lung cancer. Information on smoking history and other known and potential risk factors for lung cancer, including dietary intake, was obtained by in-person interviews. RESULTS: The adjusted odds ratios did not differ appreciably between smelters of mentholated cigarettes versus exclusive nonmentholated cigarette smokers in the overall study group of smokers. The odds ratio (OR) for 32 pack-years or more of mentholated vs. nonmentholated cigarettes was 0.90 (95% confidence interval (CI) = 0.38-2.12) in African Americans and 1.06 (95% CI = 0.47-2.36) in Caucasians, and did not differ for either ethnic group (p = 0.98). CONCLUSIONS: Our results suggest that the lung-cancer risk from smoking mentholated cigarettes resembles the risk from smoking non-mentholated cigarettes. Our data do not support the hypothesis that the increased risk of lung cancer among African Americans is due to the increased prevalence of menthol smoking. (C) 1999 Elsevier Science Inc. All rights reserved. C1 Univ So Calif, Sch Med, Dept Prevent Med, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. Univ Calif Los Angeles, Sch Med, Dept Psychiat, Los Angeles, CA 90024 USA. Vet Adm Hosp W, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Div Canc Prevent & Control Res, Los Angeles, CA 90024 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Carpenter, CL (reprint author), Univ So Calif, Sch Med, Dept Prevent Med, Kenneth Norris Jr Comprehens Canc Ctr, 1441 Eastlake Ave,MS-44, Los Angeles, CA 90033 USA. OI London, Stephanie/0000-0003-4911-5290 FU NCI NIH HHS [N01-CN-25403]; NIDA NIH HHS [DA07272] NR 31 TC 72 Z9 73 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD FEB PY 1999 VL 9 IS 2 BP 114 EP 120 DI 10.1016/S1047-2797(98)00042-8 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 166AK UT WOS:000078553900006 PM 10037555 ER PT J AU Advani, S Pal, S Venzon, D Adde, M Kurkure, PK Nair, CN Sirohi, B Banavali, SD Hawaldar, R Kolhatkar, BB Vats, T Magrath, I AF Advani, S Pal, S Venzon, D Adde, M Kurkure, PK Nair, CN Sirohi, B Banavali, SD Hawaldar, R Kolhatkar, BB Vats, T Magrath, I TI Acute lymphoblastic leukemia in India: An analysis of prognostic factors using a single treatment regimen SO ANNALS OF ONCOLOGY LA English DT Article DE ALL; childhood; India; presentation; prognostic factors; treatment ID CHILDRENS-CANCER-GROUP; CHILDHOOD LEUKEMIAS; PRESENTING FEATURES; EXPERIENCE; THERAPY; RISK; CHEMOTHERAPY; MALNUTRITION; VARIABLES; UPDATE AB Background: In the past, treatment results in Indian children with ALL have been poor, primarily due to inadequate chemotherapy and supportive care, but perhaps reflecting differences from Western countries in the pattern of subtypes. In an attempt to improve survival, we have used a more intensive treatment protocol, MCP841, and examined prognostic factors. Patients and methods: Five hundred thirty previously untreated patients <25 years of age with ALL were entered on study at the Tata Memorial Hospital, Mumbai. Treatment consisted of three successive induction cycles, consolidation and six maintenance cycles. CNS prophylactic therapy consisted of cranial irradiation (2000 cGy) for patients above two years and high-dose cytarabine for patients less than two years. The total treatment duration was two years. Results: Most patients had hepatosplenomegaly (80%) and/or lymphadenopathy (79%) and 21% were of T-cell immunophenotype, but very few (1.3%) had CNS disease. CR was achieved in 484 (91.3%) patients and 145 (29.9%) patients relapsed. There were 36 induction deaths and 49 remission deaths, but the toxic death rate was significantly lower after 1990. In patients treated since 1990, three risk groups could be discerned: 1) WBC <60,000 per mm(3) and no lymphadenopathy (77% event-free survival (EFS) at five years); 2) WBC <60,000 per mm(3) with lymphadenopathy (53% EFS) or, WBC > 60,000 per mm(3) and Hb 6 gm/dl or above (48% EFS); and 3) WBC > 60,000 per mm(3) and Hb below 6 gm/dl (16% EFS). In a multivariate model, only WBC, Hb and lymphadenopathy were significantly associated with EFS (P < 0.01). Conclusions: The CR and EFS rates achieved represent a significant improvement over previous results at this institution. Bulky extramedullary disease was an important risk factor in this series, but age and WBC alone inadequately defined risk groups, suggesting that prognostic factors may vary in different world regions. C1 NCI, Pediat Oncol Branch, DCS, Bethesda, MD 20892 USA. Tata Mem Hosp, Mumbai, India. Texas Tech Univ, Dept Pediat, Amarillo, TX USA. RP NCI, Pediat Oncol Branch, DCS, Bldg 10,Rm 13N240, Bethesda, MD 20892 USA. RI Venzon, David/B-3078-2008 NR 43 TC 49 Z9 50 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD FEB PY 1999 VL 10 IS 2 BP 167 EP 176 DI 10.1023/A:1008366814109 PG 10 WC Oncology SC Oncology GA 178VN UT WOS:000079290000013 PM 10093685 ER PT J AU Hochster, H Strawderman, MH Harris, JE Atkins, MB Oken, M Skeel, RT Jubelirer, SJ Parkinson, D AF Hochster, H Strawderman, MH Harris, JE Atkins, MB Oken, M Skeel, RT Jubelirer, SJ Parkinson, D TI Conventional dose melphalan is inactive in metastatic melanoma: results of an Eastern Cooperative Oncology Group Study (E1687) SO ANTI-CANCER DRUGS LA English DT Article DE Eastern Cooperative Oncology Group; melanoma; melphalan ID ISOLATED LIMB PERFUSION; ADVANCED MALIGNANT-MELANOMA; BONE-MARROW SUPPORT; CHEMOTHERAPY AB Despite reports that i.v. melphalan is active in the settings of conditioning regimens utilizing high-dose chemotherapy for autologous bone marrow transplantation and in isolated limb perfusion for the treatment of malignant melanoma, its activity at conventional doses has never been defined in this disease. We conducted a phase II study of conventional-dose i.v. melphalan (30 mg/m(2)) in 17 patients with metastatic melanoma. All patients were previously untreated with chemotherapy with performance status 0, 1 or 2. Forty seven cycles were given with a median of two cycles. One patient was not evaluable due to early death. There were no responses in the 16 patients, resulting in a 0% response rate (95% confidence interval = 0-17%). We conclude that conventional-dose melphalan by i.v. administration has no appreciable activity in patients with metastatic malignant melanoma. [(C) 1999 Lippincott Williams & Wilkins.]. C1 NYU, Sch Med, Kaplan Canc Ctr, Med Ctr, New York, NY 10016 USA. Rush Presbyterian St Lukes Canc Ctr, Chicago, IL 60612 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. Univ Minnesota, Minneapolis, MN 55407 USA. Med Coll Ohio, Toledo, OH 43699 USA. Charleston Area Med Ctr, Charleston, WV 25314 USA. NCI, Bethesda, MD 20892 USA. RP Hochster, H (reprint author), NYU, Sch Med, Kaplan Canc Ctr, Med Ctr, 160 E 32nd St,2nd Floor, New York, NY 10016 USA. FU NCI NIH HHS [CA25988, CA16395, CA23318] NR 15 TC 9 Z9 9 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4973 J9 ANTI-CANCER DRUG JI Anti-Cancer Drugs PD FEB PY 1999 VL 10 IS 2 BP 245 EP 248 DI 10.1097/00001813-199902000-00014 PG 4 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 188GL UT WOS:000079838400014 PM 10211556 ER PT J AU De Lucca, AJ Jacks, TJ Takemoto, J Vinyard, B Peter, J Navarro, E Walsh, TJ AF De Lucca, AJ Jacks, TJ Takemoto, J Vinyard, B Peter, J Navarro, E Walsh, TJ TI Fungal lethality, binding, and cytotoxicity of syringomycin-E SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID FUSARIUM INFECTIONS; INSECT IMMUNITY; SYRINGAE; CECROPIN; ASPERGILLOSIS; ANTIFUNGAL; PUPAE AB Syringomycin-E (SE) was significantly lethal to Aspergillus and Fusarium species at between 1.9 and 7.8 mu g/ml. SE complexed with the following fungal wall constituents tin order of binding): beta-1,3-glucan > chitin > mannan > ergosterol = cholesterol. Cytotoxicity in HeLa cells was proportional to the SE concentration, while the amount required for cytotoxicity was 3 to 20 times that needed to kill 95% of the fungi tested. C1 USDA ARS, So Reg Res Ctr, New Orleans, LA 70124 USA. Utah State Univ, Dept Biol, Logan, UT 84322 USA. USDA ARS, Biometr Consulting Serv, Beltsville, MD USA. NCI, Immunocompromised Host Sect, Pediat Branch, NIH, Bethesda, MD 20892 USA. RP De Lucca, AJ (reprint author), USDA ARS, So Reg Res Ctr, 1100 Robert E Lee Blvd, New Orleans, LA 70124 USA. RI Takemoto, Jon/A-5309-2011 OI Takemoto, Jon/0000-0001-9919-9168 NR 24 TC 21 Z9 22 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 FEB PY 1999 VL 43 IS 2 BP 371 EP 373 PG 3 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 163UF UT WOS:000078424200030 PM 9925536 ER PT J AU Humphrey, RW Wyvill, KM Nguyen, BY Shay, LE Kohler, DR Steinberg, SM Ueno, T Fukasawa, T Shintani, M Hayashi, H Mitsuya, H Yarchoan, R AF Humphrey, RW Wyvill, KM Nguyen, BY Shay, LE Kohler, DR Steinberg, SM Ueno, T Fukasawa, T Shintani, M Hayashi, H Mitsuya, H Yarchoan, R TI A phase I trial of the pharmacokinetics, toxicity, and activity of KNI-272, an inhibitor of HIV-1 protease, in patients with AIDS or symptomatic HIV infection SO ANTIVIRAL RESEARCH LA English DT Article DE KNI-272; HIV-1 protease; AIDS; HIV; protease inhibitor ID IMMUNODEFICIENCY-VIRUS PROTEASE; RATIONAL DESIGN; DRUG-RESISTANCE; RITONAVIR; PLASMA; ALLOPHENYLNORSTATINE; SAQUINAVIR; INVITRO; I/II; RATS AB The pharmacokinetics, toxicity, and activity of KNI-272, a transition state inhibitor of HIV-1 protease, was assessed in a phase 1 trial. After an initial phase in which the pharmacokinetics were assessed, 37 patients with AIDS or symptomatic HIV infection and 100-400 CD4 cells/mm(3) were entered in an escalating dose study. KNI-272 was administered four times daily for up to 12 weeks. Oral bioavailability ranged from 22 to 55% and was not appreciably different in the fasting and post-prandial state. The dose limiting toxicity was hepatic transaminase elevation; this could be reduced by escalating the dose over 4 weeks. When administered this way, the maximum tolerated oral dose was 40 mg:kg per day. At the highest two tolerated doses (26.4 and 40 mg/kg per day), there was some evidence of an anti-HIV effect with median decreases of 0.2-0.3 log(10) copies:ml plasma HIV RNA; these decreases persisted through 7-8 weeks of treatment. There was an upward trend in the CD4 count at the 40 mg/kg per day dose but not at other doses. Additional studies focused on approaches to improve the therapeutic index of KNI-272 may be warranted. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NCI, HIV & AIDS Malignancy Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Div Clin Sci, Bethesda, MD 20892 USA. NCI, Med Branch, Div Clin Sci, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Pharm, Bethesda, MD 20892 USA. Japan Energy Corp, Tokyo, Japan. RP Yarchoan, R (reprint author), NCI, HIV & AIDS Malignancy Branch, Div Clin Sci, NIH, Bldg 10,Rm 12N226, Bethesda, MD 20892 USA. RI Ueno, Takamasa/F-5788-2013 OI Ueno, Takamasa/0000-0003-4852-4236 NR 36 TC 8 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD FEB PY 1999 VL 41 IS 1 BP 21 EP 33 DI 10.1016/S0166-3542(98)00058-8 PG 13 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 182PZ UT WOS:000079508500002 PM 10321576 ER PT J AU Niebylski, ML Peacock, MG Schwan, TG AF Niebylski, ML Peacock, MG Schwan, TG TI Lethal effect of Rickettsia rickettsii on its tick vector (Dermacentor andersoni) SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID MOUNTAIN-SPOTTED-FEVER; INFECTING WOOD TICKS; WESTERN MONTANA; MOSQUITOS; FECUNDITY; VIRUS; HEMOLYMPH AB Rickettsia rickettsii, the causative agent of Rocky Mountain spotted fever, was lethal for the majority of experimentally and transovarially infected Rocky Mountain wood ticks (Dermacentor andersoni). Overall, 94.1% of nymphs infected as larvae by feeding on rickettsemic guinea pigs died during the molt into adults and 88.3% of adult female ticks infected as nymphs died prior to feeding. In contrast, only 2.8% of uninfected larvae failed to develop into adults over two generations. Infected female ticks incubated at 4 degrees C had a lower mortality (80.9%) than did those held at 21 degrees C (96.8%). Rickettsiae were vertically transmitted to 39.0% of offspring, and significantly fewer larvae developed from infected ticks. The lethal effect of R. rickettsii may explain the low prevalence of infected ticks in nature and affect its enzootic maintenance. C1 NIAID, Microbial Struct & Funct Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Schwan, TG (reprint author), NIAID, Microbial Struct & Funct Lab, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM tom_schwan@nih.gov NR 59 TC 109 Z9 115 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD FEB PY 1999 VL 65 IS 2 BP 773 EP 778 PG 6 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 165AC UT WOS:000078495200062 PM 9925615 ER PT J AU Hanover, JA Lai, ZN Lee, G Lubas, WA Sato, SM AF Hanover, JA Lai, ZN Lee, G Lubas, WA Sato, SM TI Elevated O-linked N-acetylglucosamin metabolism in pancreatic beta-cells SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article ID HEXOSAMINE BIOSYNTHESIS PATHWAY; GLUCOSE-INDUCED DESENSITIZATION; PORE COMPLEX GLYCOPROTEINS; NUCLEAR-PORE; INSULIN-RESISTANCE; GLUTAMINE-FRUCTOSE-6-PHOSPHATE AMIDOTRANSFERASE; TETRATRICOPEPTIDE REPEATS; GLCNAC TRANSFERASE; TRANSPORT SYSTEM; C-MYC AB High intracellular glucose concentrations increase flux though the hexosamine biosynthetic pathway, resulting in elevated UDP-N-acetylglucosamine (GlcNAc) concentrations. The nucleocytoplasmic enzyme O-linked N-acetylglucosaminyltransferase (OGT) uses UDP-GlcNAc as a donor to modify numerous critical substrates, including nuclear pore proteins and transcription factors. Here, we document (a) the overwhelming enrichment of pancreatic OGT transcripts in the beta-cells of the islets of Langerhans, (b) the physiologically significant increase in the level of O-GlcNAc residues present in beta-cells, and (c) the action of streptozotocin, a close analogue of GlcNAc, to selectively inhibit O-GlcNA-case, an enzyme involved in the removal of O-GlcNAc residues, Taken together, these findings suggest that pancreatic beta cells maintain a highly elevated O-GlcNAc metabolism and that the diabetes inducing drug streptozotocin inhibits O-GlcNAcase. (C) 1999 Academic Press. C1 NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Hanover, JA (reprint author), NIDDK, Lab Cell Biochem & Biol, NIH, Bldg 8,Rm 402,8 Ctr Dr MSC 0850, Bethesda, MD 20892 USA. NR 50 TC 82 Z9 82 U1 0 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD FEB 1 PY 1999 VL 362 IS 1 BP 38 EP 45 DI 10.1006/abbi.1998.1016 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 162MN UT WOS:000078350900005 PM 9917327 ER PT J AU Nousari, HC Rencic, A Hsu, R Yancey, KB Anhalt, GJ AF Nousari, HC Rencic, A Hsu, R Yancey, KB Anhalt, GJ TI Anti-epiligrin cicatricial pemphigoid with antibodies against the gamma 2 subunit of laminin 5 SO ARCHIVES OF DERMATOLOGY LA English DT Article ID BASEMENT-MEMBRANE; AUTOANTIBODIES; DISTINCT; PROTEIN; TARGET AB Background: Cicatricial pemphigoid (CP) is a scarring subepithelial mucocutaneous blistering disease characterized by anti-basement membrane zone autoantibodies. Anti-epiligrin CP is an uncommon variant that has been recently characterized. Severe laryngeal involvement is infrequently observed in all forms of CP and has been documented in only 2 patients with anti-epiligrin CP. Observations: We report a case of CP exhibiting extensive laryngeal and ocular involvement. Histological, immunofluorescence, and immunoprecipitation studies confirmed the diagnosis of anti-epiligrin CP. Immunoblotting studies demonstrated the presence of antibodies against the alpha 3 and the gamma 2 subunit of laminin 5. Conclusion: This article expands the diversity of the clinical and immunopathologic features of this newly characterized variant of CP. C1 Johns Hopkins Med Inst, Div Dermatoimmunol, Dept Dermatol, Baltimore, MD 21205 USA. NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Anhalt, GJ (reprint author), Johns Hopkins Med Inst, Div Dermatoimmunol, Dept Dermatol, 720 Rutland Ave,Room 771, Baltimore, MD 21205 USA. NR 23 TC 28 Z9 28 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 FEB PY 1999 VL 135 IS 2 BP 173 EP 176 DI 10.1001/archderm.135.2.173 PG 4 WC Dermatology SC Dermatology GA 169BL UT WOS:000078727600009 PM 10052402 ER PT J AU Avissar, S Schreiber, G Nechamkin, Y Neuhaus, I Lam, GK Schwartz, P Turner, E Matthews, J Naim, S Rosenthal, NE AF Avissar, S Schreiber, G Nechamkin, Y Neuhaus, I Lam, GK Schwartz, P Turner, E Matthews, J Naim, S Rosenthal, NE TI The effects of seasons and light therapy on G protein levels in mononuclear leukocytes of patients with seasonal affective disorder SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID BIPOLAR AFFECTIVE-DISORDER; COUPLED G-PROTEINS; CEREBRAL-CORTEX; BEHAVIORAL-RESPONSES; DEPRESSED-PATIENTS; GTP-BINDING; RAT CORTEX; LITHIUM; BRAIN; INVOLVEMENT AB Background: Information-transducing heterotrimeric G proteins have been implicated previously in the mechanism of action of mood stabilizers and in the pathophysiology of mood disorders. Mononuclear leukocytes of patients with unipolar and bipolar depression have been characterized by reduced measures of the stimulatory and inhibitory G proteins. In this study, patients witt; seasonal affective disorder (SAD) were measured for mononuclear leukocyte G protein levels while depressed during the winter, following light therapy, and in remission during the summer. Methods: Twenty-six patients with SAD and 28 healthy subjects were assessed in the study. The immunoreactivities of G(5)alpha, G(i)alpha, and G beta subunit proteins were de termined by Western blot analysis of mononuclear leukocyte membranes with selective polyclonal antibodies for the various G subunit proteins, followed by densitometric quantitation using an image analysis system. Results: Untreated patients with SAD and winter, atypical-type depression showed significantly reduced mononuclear leukocyte immunoreactive levels of G(s)alpha and G(i)alpha proteins, similar to previous observations in patients with nonseasonal major depression. The reduced G protein levels were normalized with 2 weeks of light therapy. The same patients while in remission during the summer had G protein levels that were similar to those of healthy subjects. Conclusions: G protein-immunoreactive measures in patients with SAD are suggested as a state marker for winter depression, which is normalized by light treatment and during the summer. We speculate that light may ex ert its effects via normalization of transducin (G, protein) levels, which are thought to be reduced in winter depression. C1 Ben Gurion Univ Negev, Dept Clin Pharmacol, Fac Hlth Sci, IL-84105 Beer Sheva, Israel. Ben Gurion Univ Negev, Dept Psychiat, Fac Hlth Sci, IL-84105 Beer Sheva, Israel. NIMH, Clin Psychobiol Branch, NIH, Bethesda, MD 20892 USA. RP Avissar, S (reprint author), Ben Gurion Univ Negev, Dept Clin Pharmacol, Fac Hlth Sci, POB 653, IL-84105 Beer Sheva, Israel. NR 45 TC 31 Z9 31 U1 0 U2 2 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 FEB PY 1999 VL 56 IS 2 BP 178 EP 183 DI 10.1001/archpsyc.56.2.178 PG 6 WC Psychiatry SC Psychiatry GA 166AG UT WOS:000078553600009 PM 10025443 ER PT J AU Chew, EY Sperduto, RD Hiller, R Nowroozi, L Seigel, D Yanuzzi, LA Burton, TC Seddon, JM Gragoudas, ES Haller, JA Blair, NP Farber, M AF Chew, EY Sperduto, RD Hiller, R Nowroozi, L Seigel, D Yanuzzi, LA Burton, TC Seddon, JM Gragoudas, ES Haller, JA Blair, NP Farber, M TI Clinical course of macular holes - The eye disease case-control study SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID TRANSFORMING GROWTH-FACTOR-BETA-2; FELLOW EYES; VITRECTOMY AB Objective: To describe the clinical course of affected and unaffected eyes in patients with idiopathic macular holes. Patients: Prospective study of patients with macular holes enrolled in the Eye Disease Case-Control Study. Main Outcome Measures: The best-corrected visual acuity at follow-up was compared with that at baseline. Changes in the macular holes, including increases in size or spontaneous regression, were assessed. The rates of development of new macular holes in fellow unaffected eyes were estimated. Results: Of the 198 patients examined at baseline, 28 (14.1%) died before reevaluation. Of those who survived, 122 (71.8%) had a follow-up examination. Approximately 34% (34.4%) of all eyes with macular holes had an increase in the size of the macular hole. Forty-five percent of eyes had a decrease in visual acuity of 2 or more lines and 27.8%, of 3 or more lines; 40.9% remained stable, with a gain or loss of fewer than 2 lines. The rate of development of a new macular hole during follow-up in fellow eyes that were unaffected at baseline was 4.3% for 3 or fewer years of follow-up, 6.5% for 4 to 5 years of follow-up, and 7.1% for 6 or more years of follow-up. Spontaneous regression of the macular hole occurred in 3 (8.6%) of 35 patients with a follow-up interval of 6 or more years, whereas no regression occurred in patients with a shorter follow-up. Conclusions: The visual acuity of 45.0% of eyes with macular holes deteriorated by 2 or more lines during follow-up. The rate of development of macular holes in unaffected fellow eyes was low. C1 NEI, Div Biometry & Epidemiol, NIH, Bethesda, MD 20892 USA. Manhattan Eye Ear & Throat Hosp, New York, NY 10021 USA. Med Coll Wisconsin, Dept Ophthalmol, Milwaukee, WI 53226 USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. Johns Hopkins Univ, Wilmer Eye Inst, Baltimore, MD 21218 USA. Univ Illinois, Eye & Ear Infirm, Chicago, IL 60612 USA. RP Chew, EY (reprint author), NEI, Div Biometry & Epidemiol, NIH, Bldg 31,Room 6A52,31 Ctr Dr,MSC 2510, Bethesda, MD 20892 USA. EM echew@nei.nih.gov FU Intramural NIH HHS [Z99 EY999999]; NEI NIH HHS [N01-EY-5-2110, N01-EY-5-2109, N01-EY-5-2111] NR 20 TC 54 Z9 59 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD FEB PY 1999 VL 117 IS 2 BP 242 EP 246 PG 5 WC Ophthalmology SC Ophthalmology GA 166RK UT WOS:000078590800013 PM 10037571 ER PT J AU Datiles, MB Kador, PF AF Datiles, MB Kador, PF TI Type I diabetic cataract SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID ALDOSE REDUCTASE; MELLITUS; LENS C1 NEI, Cataract & Cornea Sect, OGCSB, NIH, Bethesda, MD 20892 USA. RP Datiles, MB (reprint author), NEI, Cataract & Cornea Sect, OGCSB, NIH, Bldg 10,Room 10N226,10 Ctr Dr,MSC 1860, Bethesda, MD 20892 USA. NR 8 TC 6 Z9 7 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 FEB PY 1999 VL 117 IS 2 BP 284 EP 285 PG 2 WC Ophthalmology SC Ophthalmology GA 166RK UT WOS:000078590800029 PM 10037586 ER PT J AU Kim, YS Yi, YS Choi, SG Kim, SJ AF Kim, YS Yi, YS Choi, SG Kim, SJ TI Development of TGF-beta resistance during malignant progression SO ARCHIVES OF PHARMACAL RESEARCH LA English DT Review DE TGF-beta; TGF-beta receptors; TGF-beta resistance; mutation; carcinogenesis ID GROWTH-FACTOR-BETA; II RECEPTOR GENE; SERINE THREONINE KINASE; GASTRIC-CANCER CELLS; MICROSATELLITE INSTABILITY; INHIBITORY RESPONSES; EXPRESSION CLONING; CARCINOMA-CELLS; SMAD PROTEINS; MUTATION AB Transforming growth factor-beta (TGF-beta) is the prototypical multifunctional cytokine, participating in the regulation of vital cellular activities such as proliferation and differentiation as well as a number of basic physiological functions. The effects of TGF-beta are critically dependent on the expression and distribution of a family of TGF-beta receptors, the TGF-beta types I, II, and III. It is now known that a wide variety of human pathology can be caused by aberrant expression and function of these receptors. The coding sequence of the type ii receptor (RII) appears to render it uniquely susceptible to DNA replication errors in the course of normal cell division. By virtue of its key role in the regulation of cell proliferation, TGF-beta RII should be considered as a tumor suppressor gene. High levels of mutation in the TGF-beta RII gene have been observed in a wide range of primarily epithelial malignancies, including colon and gastric cancer. It appears likely that mutation of the TGF-beta RII gene may be a very critical step in the pathway of carcinogenesis. C1 NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Kim, SJ (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. NR 57 TC 17 Z9 18 U1 0 U2 0 PU PHARMACEUTICAL SOCIETY KOREA PI SEOUL PA 1489-3 SUHCHO-DONG, SUHCHO-KU, SEOUL 137-071, SOUTH KOREA SN 0253-6269 J9 ARCH PHARM RES JI Arch. Pharm. Res. PD FEB PY 1999 VL 22 IS 1 BP 1 EP 8 DI 10.1007/BF02976427 PG 8 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 170BM UT WOS:000078785400001 PM 10071951 ER PT J AU Rantanen, T Guralnik, JM Sakari-Rantala, R Leveille, S Simonsick, EM Ling, S Fried, LP AF Rantanen, T Guralnik, JM Sakari-Rantala, R Leveille, S Simonsick, EM Ling, S Fried, LP TI Disability, physical activity, and muscle strength in older women: The women's health and aging study SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article ID MAXIMAL ISOMETRIC STRENGTH; MAINTAINING MOBILITY; 75-YEAR-OLD MEN; LATE-LIFE; AGE; PERFORMANCE; ADULTS; RISK AB Objective: To study associations of motor disability, physical activity, and muscle strength in older women, in particular to investigate whether model of spiraling decrease is expressed in the data. Design: Cross-sectional analysis using data from the baseline measurements of The Women's Health and Aging Study (WHAS). Setting: Participants' homes. Participants: A total of 1,002 disabled women aged 65 years and older living in the community. Outcome Measures: Motor disability was measured by the number of self-reported difficulties in grasping, lifting 101b, walking across a small room, walking 1/4 mile, climbing 10 steps, and doing heavy housework. Level of physical activity was determined from response to a series of questions on the frequency and amount of common activities and physical exercise. Hand grip and knee extension forces were measured using portable hand-held dynamometers. Results: Disability and physical activity were inversely associated, with inactivity being most common among the most disabled women. Those with poorer strength reported more difficulties in motor activities. Greater strength was found among the physically more active. in stratified analyses, the positive association of physical activity on knee extension strength was consistent across disability levels. Multiple regression analysis showed that both physical activity and muscle strength were significant predictors for severity of disability. Structural equation model (LISREL) showed that muscle strength had a mediating role between physical activity and disability; disability was associated with physical inactivity, which correlated with lower muscle strength, which was associated with,greater degree of disability. Conclusion: Even though causality cannot be confirmed in this cross-sectional analysis, our findings suggested a spiraling model of decline in which muscle strength has a significant role, (C) 1999 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation. C1 NIA, Epidemiol Demog & Biometry Program, NIH, Bethesda, MD 20892 USA. Univ Jyvaskyla, Dept Hlth Sci, Jyvaskyla, Finland. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. RP Rantanen, T (reprint author), NIA, Epidemiol Demog & Biometry Program, NIH, 7201 Wisconsin Ave,Gateway Bldg,Suite 3C-309, Bethesda, MD 20892 USA. RI Rantanen, Taina/O-6579-2016; OI Rantanen, Taina/0000-0002-1604-1945; Sakari, Ritva/0000-0001-7869-5541 NR 24 TC 224 Z9 225 U1 1 U2 7 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD FEB PY 1999 VL 80 IS 2 BP 130 EP 135 DI 10.1016/S0003-9993(99)90109-0 PG 6 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 165YG UT WOS:000078549000002 PM 10025485 ER PT J AU Manolio, TA Burke, GL O'Leary, DH Evans, G Beauchamp, N Knepper, L Ward, B AF Manolio, TA Burke, GL O'Leary, DH Evans, G Beauchamp, N Knepper, L Ward, B CA CHS Collaborative Res Grp TI Relationships of cerebral MRI findings to ultrasonographic carotid atherosclerosis in older adults - The cardiovascular health study SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE stroke; cerebrovascular disorders; carotid arteries; atherosclerosis; aged; epidemiology; risk factors ID WHITE-MATTER LESIONS; TRANSIENT ISCHEMIC ATTACK; BRAIN ATROPHY; RISK-FACTORS; BLOOD-FLOW; PLAQUE; DISEASE; ABNORMALITIES; HEMORRHAGE; INFARCTION AB Cerebral magnetic resonance imaging (MRI) has demonstrated a high prevalence of infarct-like lesions, white matter hyperintensities, and evidence of cerebral atrophy in older adults. While these findings are generally believed to be related to ischemia and atherosclerosis, their relationship to atherosclerosis in the carotid arteries remains to be explored. Study subjects were part of the multicenter Cardiovascular Health Study, a cross-sectional study of 3502 women and men greater than or equal to 65 years of age undergoing cranial MRI and carotid ultrasonography. MRI infarcts were detected in 1068 participants (29.3%) and measurable carotid plaque in 2745 (75.3%). MRI infarcts, ventricular and sulcal widening, and white matter score were strongly associated with carotid intimal-medial thickness (IMT) and stenosis degree after adjustment for age and sex (all P < 0.01). Associations with plaque characteristics were less strong and less consistent; MRI infarcts were weakly associated only with surface irregularity, and ventricular size was weakly associated only with lesion density (both P < 0.04). In contrast, sulcal widening was strongly related to plaque characteristics, with scores being higher in those with heterogeneous and irregular plaque (both P < 0.009). Adjustment for other risk factors, and for carotid IMT/stenosis, removed associations of MRI findings with plaque characteristics except for weak relationships remaining between MRI infarcts and surface irregularity and between sulcal score and heterogeneous plaque (both P < 0.03). MRI abnormalities show strong and consistent relationships with increasing carotid IMT and stenosis degree but less strong associations with plaque characteristics, especially after adjusting for IMT and stenosis. C1 NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27109 USA. Tufts Univ, New England Med Ctr, Dept Radiol, Boston, MA 02111 USA. Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP Manolio, TA (reprint author), NHLBI, Div Epidemiol & Clin Applicat, 6701 Rockledge Dr,Room 8160, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [N01-HC-15093, N01-HC-5079, N01-HC-85086] NR 42 TC 123 Z9 124 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD FEB PY 1999 VL 19 IS 2 BP 356 EP 365 PG 10 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 168EV UT WOS:000078679300023 PM 9974419 ER PT J AU Fraenkel, L Zhang, YQ Chaisson, CE Maricq, HR Evans, SR Brand, F Wilson, PWF Felson, DT AF Fraenkel, L Zhang, YQ Chaisson, CE Maricq, HR Evans, SR Brand, F Wilson, PWF Felson, DT TI Different factors influencing the expression of Raynaud's phenomenon in men and women SO ARTHRITIS AND RHEUMATISM LA English DT Article ID CUTANEOUS BLOOD-FLOW; GENERAL-PRACTICE; PREVALENCE; DIAGNOSIS; POPULATION AB Objective. To determine whether the risk profile for Raynaud's phenomenon (RP) is different between men and women. Methods, In this cross-sectional study of 800 women and 725 men participating in the Framingham Offspring Study, the association of age, marital status, smoking, alcohol use, diabetes, hypertension, and hypercholesterolemia with prevalent RP was examined in men and women separately, after adjusting for relevant confounders. Results. The prevalence of RP was 9.6% (n = 77) in women and 5.8% (n = 42) in men, In women, marital status and alcohol use were each associated with prevalent RP (for marital status adjusted odds ratio [OR] 2.3, 95% confidence interval [95% CI] 1.4-3.9; for alcohol use OR 2.2, 95% CI 1.0-5.2), whereas these factors were not associated with RP in men (marital status OR 1.4, 95% CI 0.6-3.5; alcohol use OR 1.0, 95% CI 0.2-4.4). In men, older age (OR 2.3, 95% CI 1.0-5.2) and smoking (OR 2.6, 95% CI 1.1-6.3) were associated with prevalent RP; these factors were not associated with RP in women (older age OR 0.8, 95% CI 0.4-1.6; smoking OR 0.7, 95% CI 0.4-1.1). Diabetes, hypertension, and hypercholesterolemia were not associated with RP in either sex. Conclusion. The results indicate that risk factors for RP differ between men and women. Age and smoking were associated with RP in men only, while the associations of marital status and alcohol use with RP were observed in women only. These findings suggest that different mechanisms influence the expression of RP in men and women. C1 Boston Univ, Arthrit Ctr, Boston, MA 02118 USA. Med Univ S Carolina, Charleston, SC 29425 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. RP Fraenkel, L (reprint author), Boston Univ, Arthrit Ctr, A203,715 Albany St, Boston, MA 02118 USA. FU NHLBI NIH HHS [N01-HC-38038]; NIA NIH HHS [AG-09300]; NIAMS NIH HHS [AR-20613] NR 16 TC 21 Z9 21 U1 0 U2 1 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 FEB PY 1999 VL 42 IS 2 BP 306 EP 310 DI 10.1002/1529-0131(199902)42:2<306::AID-ANR13>3.0.CO;2-G PG 5 WC Rheumatology SC Rheumatology GA 164MW UT WOS:000078469000013 PM 10025925 ER PT J AU Creamer, P Lethbridge-Cejku, M Costa, P Tobin, JD Herbst, JH Hochberg, MC AF Creamer, P Lethbridge-Cejku, M Costa, P Tobin, JD Herbst, JH Hochberg, MC TI The relationship of anxiety and depression with self-reported knee pain in the community: Data from the Baltimore Longitudinal Study of Aging SO ARTHRITIS CARE AND RESEARCH LA English DT Article DE knee pain; osteoarthritis; depression; anxiety ID RHEUMATOID-ARTHRITIS; OSTEO-ARTHRITIS; HEALTH-STATUS; OSTEOARTHRITIS; DISABILITY AB Objective. To investigate the relationship between anxiety and depression and reporting of knee pain in the community. Methods. Subjects (n = 374) were community volunteers aged 40 years and above who are participants in the Baltimore Longitudinal Study of Aging, a prospective multidisciplinary research study of normative aging. Knee pain was defined by the First National Health and Nutrition Examination Survey question "have you ever had pain in or around your knee on most days for at least one month?"; anxiety and depression were measured by the relevant subscales of the Arthritis Impact Measurement Scales questionnaire. All subjects had standing anteroposterior radiographs, read for Kellgren and Lawrence (K+ L) grade. Results. After adjustment for age, women reporting "ever" knee pain had significantly higher anxiety scores than those reporting "never" pain (3.06 +/- 0.26 versus 2.35 +/- 0.27; P = 0.025). Pain reporting was related neither to anxiety scores in men, nor to depression in either sex. Analysis stratified by radiographic severity, adjusted for age and gender, showed that differences in anxiety were confined to those reporting knee pain in the absence of radiographic change (i.e., K + L grade 0). Conclusions. In the community, women reporting knee pain in the absence of radiographic osteoarthritis have higher anxiety scores than those without pain. Depression was not significantly related to knee pain in this population. Psychosocial factors may explain some of the discrepancy between reported knee pain and structural change as seen on x-ray. C1 Univ Maryland, Sch Med, Div Clin Immunol & Rheumatol, Baltimore, MD 21201 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Lethbridge-Cejku, M (reprint author), Univ Maryland, Sch Med, Div Clin Immunol & Rheumatol, Room 8-34 MSTF,10 S Pine St, Baltimore, MD 21201 USA. OI Costa, Paul/0000-0003-4375-1712 NR 20 TC 70 Z9 72 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-7524 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD FEB PY 1999 VL 12 IS 1 BP 3 EP 7 DI 10.1002/1529-0131(199902)12:1<3::AID-ART2>3.0.CO;2-K PG 5 WC Rheumatology SC Rheumatology GA 165AF UT WOS:000078495600002 PM 10513484 ER PT J AU Bourhim, M Poupaert, JH Stables, JP Vallee, L Vamecq, J AF Bourhim, M Poupaert, JH Stables, JP Vallee, L Vamecq, J TI Design, anticonvulsive and neurotoxic properties of retrobenzamides - N-(nitrophenyl)benzamides and N-(aminophenyl)benzamides SO ARZNEIMITTEL-FORSCHUNG-DRUG RESEARCH LA English DT Article DE ameltolide; N-(aminophenyl)benzamide; benzamides, anticonvulsive properties, neurotoxicity; carbamazepine; N-(nitrophenyl)benzamide; phenytoin ID ANTIEPILEPTIC DRUG DEVELOPMENT; MICE; RATS; 4-AMINO-N-(2,6-DIMETHYLPHENYL)BENZAMIDE; LY201116; MODELS AB Design, anticonvulsant properties in maximal electroshock-induced seizures [MES] and seizures induced by subcutaneous administration of pentetrazole (scPtz), and neurotoxicity of retrobenzamides (N-(nitrophenyl)benzamides and N-(aminophenyl) benzamides are reported. These data are further compared with those on carbamazepine, phenytoin, ameltolide and other reference compounds. Studies on retrobenzamides in mice dosed intraperitoneally point out a good anticonvulsant potential in the MES test for the amino derivatives (N-(aminophenyl)benzamides) and moderate activity for corresponding "nitro" derivatives. In rats dosed orally, aminoretrobenzamides were, however, less active in the MES test than in mice dosed intraperitoneally. Differences between experimental animal species and administration routes lead to hypothesize rapid metabolization of compounds, reduced intestinal resorption and increased removal from body. The presence of a methyl substitution on the N-phenyl moiety of aminoretrobenzamides attenuated these discrepancies between mice and rats. Present results indicate that pharmacological values - including the dose offering anticonvulsant protection in 50 % of tested animals (ED50) and protective indices - obtained on some retrobenzamides may compete with phenytoin and carbamazepine values. By contrast with phenytoin, some retrobenzamides further exhibit activity in the scPtz test. C1 Univ Catholique Louvain, Ecole Pharm, Unite Chim Therapeut, Brussels, Belgium. NINDS, Preclin Pharmacol Sect, Epilepsy Branch, DCND,Natl Inst Hlth, Bethesda, MD USA. Ctr Hosp Reg & Univ Lille, Hop Roger Salengro, Serv Malad Infect & Neurol Infantile, Lille, France. RP Vamecq, J (reprint author), CHRU Lille, INSERM, BP 39,369 Rue Jules Guesde,Domaine CERTIA,7340B,T, F-59651 Villeneuve, France. NR 23 TC 1 Z9 1 U1 0 U2 0 PU ECV-EDITIO CANTOR VERLAG MEDIZIN NATURWISSENSCHAFTEN PI AULENDORF PA BANDELSTOCKWEG 20, POSTFACH 1255, D-88322 AULENDORF, GERMANY SN 0004-4172 J9 ARZNEIMITTEL-FORSCH JI Arzneimittelforschung PD FEB PY 1999 VL 49 IS 2 BP 81 EP 87 PG 7 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 171UE UT WOS:000078881800001 PM 10083974 ER PT J AU Gilman, D AF Gilman, D TI Network stability and consciousness? SO BEHAVIORAL AND BRAIN SCIENCES LA English DT Editorial Material ID CORTEX AB A connectionist vehicle theory of consciousness needs to disambiguate its criteria for identifying the relevant vehicles. Moreover, a vehicle theory may appear entirely arbitrary in sorting between what are typically thought of as conscious and unconscious processes. C1 NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. RP Gilman, D (reprint author), NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0140-525X J9 BEHAV BRAIN SCI JI Behav. Brain Sci. PD FEB PY 1999 VL 22 IS 1 BP 155 EP + DI 10.1017/S0140525X99301795 PG 7 WC Psychology, Biological; Behavioral Sciences; Neurosciences SC Psychology; Behavioral Sciences; Neurosciences & Neurology GA 187VK UT WOS:000079808600059 ER PT J AU Losiewicz, MD Kaur, G Sausville, EA AF Losiewicz, MD Kaur, G Sausville, EA TI Different early effects of tyrphostin AG957 and geldanamycins on mitogen-activated protein kinase and p120(cbl) phosphorylation in anti CD-3-stimulated T-lymphoblasts SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE tyrphostin; AG957; geldanamycin; cbl; MAP kinase ID TYROSINE PHOSPHORYLATION; SIGNAL-TRANSDUCTION; MAP KINASE; CELL ACTIVATION; RECEPTOR; INHIBITION; CBL; ANSAMYCINS; PATHWAY; COMPLEX AB AG957, a tyrphostin tyrosine kinase inhibitor, has been shown previously to inhibit p210(bcr-abl) phosphorylation with concurrent inhibition of p210(bcr-abl)-expressing K562 cell growth (Kaur G and Sausville EA, Anticancer Drugs 7: 815-824, 1996). To assess the specificity of the action of AG957, we have examined its effect in another tyrosine kinase-mediated system, anti CD-3-stimulated Jurkat T Acute Lymphoblastic Leukemia cells. We also compared effects of AG957 with those of geldanamycin, which can disrupt tyrosine kinase signaling through binding to heat shock protein (hsp90), and two geldanamycin analogs, 17-amino-17-dimethoxygeldanamycin (17AG) and 17-allylamino-17-demethoxygeldanamycin (17AAG). At concentrations found to produce 90% inhibition of Jurkat T-cell growth, AG957 within 4 hr of addition inhibited mitogen-activated protein (MAP) kinase activation and activity, as shown by a decreased anti CD-3-stimulated erk-2 mobility shift in lysates of treated cells and a decrease in the stimulated myelin basic protein peptide kinase activity in erk-2 immunoprecipitates, respectively. AG957 did not inhibit this activity when added directly to immunoprecipitates. Effects in cells were found to be accompanied by a decrease in the anti CD-3-stimulated phosphorylation of p120(cbl). Under conditions of a similar degree of growth inhibition, geldanamycin initially did not inhibit MAP kinase activation. Geldanamycin analogs did not decrease anti CD-3-induced cbl phosphorylation, but did reduce basal p120(cbl) tyrosine phosporylation. The action of AG957 occurred with an apparent shift of several tyrosine-phosphorylated proteins to apparent higher molecular weights, which also did not occur with the geldanamycins. These results suggest that growth inhibition by AG957 can alter tyrosine kinase signaling systems unrelated to p210(bcr-abl) with a prominent early effect on MAP kinase activation in T-lymphoblasts. AG 957 and geldanamycin affect tyrosine kinase signaling by distinct mechanisms. (C) 1998 Elsevier Science Inc. C1 NCI, Frederick Canc Res & Dev Ctr, Pharmacol & Expt Therapeut Sect,Dev Therapeut Pro, Lab Drug Discovery Res & Dev,Div Canc Treatment &, Frederick, MD 21702 USA. RP Sausville, EA (reprint author), NCI, Dev Therapeut Program, DCTD, Execut Plaza N,Suite 843,6130 Execut Blvd,MSC 745, Rockville, MD 20852 USA. NR 38 TC 13 Z9 13 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 FEB 1 PY 1999 VL 57 IS 3 BP 281 EP 289 DI 10.1016/S0006-2952(98)00293-7 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 152CN UT WOS:000077758200007 PM 9890555 ER PT J AU Tlapak-Simmons, VL Heldermon, C Kempner, ES Weigel, PH AF Tlapak-Simmons, VL Heldermon, C Kempner, ES Weigel, PH TI Properties of the hyaluronan synthase from Group A Streptococcus pyogenes SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT Colloquium on Biology of Hyaluronan CY SEP 21-23, 1998 CL UNIV LEICESTER, LEICESTER, ENGLAND SP Glycobiology Grp, British Connective Tissue Soc HO UNIV LEICESTER ID RADIATION TARGET ANALYSIS; MOLECULAR-CLONING; ACID CAPSULE; MEMBRANE; WEIGHT; GENE; IDENTIFICATION; INACTIVATION; EXPRESSION; VIRULENCE C1 Univ Oklahoma, Hlth Sci Ctr, Dept Biochem & Mol Biol, Oklahoma City, OK 73190 USA. NIAMSD, Phys Biol Lab, Bethesda, MD 20892 USA. RP Weigel, PH (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dept Biochem & Mol Biol, Oklahoma City, OK 73190 USA. FU NIGMS NIH HHS [GM35978] NR 36 TC 2 Z9 2 U1 0 U2 2 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD FEB PY 1999 VL 27 IS 2 BP 105 EP 109 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 168EA UT WOS:000078677300017 PM 10093716 ER PT J AU Di Francesco, V Munson, PJ Garnier, J AF Di Francesco, V Munson, PJ Garnier, J TI FORESST: fold recognition from secondary structure predictions of proteins SO BIOINFORMATICS LA English DT Article ID HIDDEN MARKOV-MODELS; AMINO-ACID-SEQUENCE; CLASSIFICATION; ACCURACY; TOPOLOGY; SEARCH; TOOL AB Motivation: A method for recognizing the three-dimensional fold from the protein amino acid sequence based on a combination of hidden Markov models (HMMs) and secondary structure prediction was recently developed for proteins in the Mainly-Alpha structural class. Here, this methodology is extended to Mainly-Beta and Alpha-Beta class proteins. Compared to other fold recognition methods based on HMMs, this approach is novel in that only secondary structure information is used. Each HMM is trained from known secondary structure sequences of proteins having a similar fold. Secondary structure prediction is performed for the amino acid sequence of a query protein. The predicted fold of a query protein is the fold described by the model fitting the predicted sequence the best. Results: After model cross-validation, the success rare on 44 test proteins covering the three structural classes was found to be 59%. On seven fold predictions performed prior to the publication of experimental structure, the success rate was 71%. In conclusion, this approach manages to capture important information about the fold of a protein embedded in the length avid arrangement of the predicted helices, strands and coils along the polypeptide chain. When a more extensive library of HMMs representing the universe of known structural families is available (work in progress), the program will allow rapid screening of genomic databases and sequence annotation when fold similarity is not detectable from the amino acid sequence. C1 NIH, Analyt Biostat Sect, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. Inst Genom Res, Blolgiza, Rockville, MD 20850 USA. INRA, Biol Cellulaire & Mol Lab, F-78352 Jouy En Josas, France. RP Di Francesco, V (reprint author), NIH, Analyt Biostat Sect, Math & Stat Comp Lab, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. EM valedf@tigr.org; munson@helix.nih.gov; garnier@helix.nih.gov NR 41 TC 35 Z9 35 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD FEB PY 1999 VL 15 IS 2 BP 131 EP 140 DI 10.1093/bioinformatics/15.2.131 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 180GX UT WOS:000079378700006 PM 10089198 ER PT J AU Little, JT Ketter, TA Mathe, AA Frye, MA Luckenbaugh, D Post, RM AF Little, JT Ketter, TA Mathe, AA Frye, MA Luckenbaugh, D Post, RM TI Venlafaxine but not bupropion decreases cerebrospinal fluid 5-hydroxyindoleacetic acid in unipolar depression SO BIOLOGICAL PSYCHIATRY LA English DT Article DE cerebrospinal fluid; venlafaxine; bupropion; depression; 5-hydroxyindoleacetic acid; serotonin ID MONOAMINE METABOLITES; SEROTONIN UPTAKE; NEUROTRANSMITTER METABOLITES; ANTIDEPRESSANTS; IMIPRAMINE; DISORDERS AB Background: While the antidepressants venlafaxine and bupropion are known to have different neurochemical profiles in vitro, their effects on human cerebral metabolism in vivo have not been directly compared. Methods: Cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA), serotonin, 3-methoxy-3,4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were examined in 14 never-hospitalized outpatients with unipolar depression and 10 age-similar healthy controls. Patients received a baseline lumbar puncture (LP), which was repeated after at least 6 weeks of randomized monotherapy with either venlafaxine or bupropion, while controls received only a baseline LP. Results: Patients (n = 9) receiving venlafaxine showed a significant decrease (42%) in their CSF 5-HIAA concentrations after treatment, but no change in other CSF measures. In contrast, patients receiving bupropion (n = 8) showed no change in CSF measures compared to pretreatment values. Conclusions: While the mechanism for this differential effect of venlafaxine remains to be determined, the current study provides confirmation of the different aminergic effects of venlafaxine and bupropion. Biol Psychiatry 1999;45:285-289 (C) 1999 Society of Biological Psychiatry. C1 NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. Karolinska Inst, St Gorans Childrens Hosp, Dept Clin Neurosci, S-11281 Stockholm, Sweden. RP Post, RM (reprint author), NIMH, Biol Psychiat Branch, 10 Ctr Dr MSC-1272, Bethesda, MD 20892 USA. NR 30 TC 27 Z9 27 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 FEB 1 PY 1999 VL 45 IS 3 BP 285 EP 289 DI 10.1016/S0006-3223(98)00078-X PG 5 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 165JZ UT WOS:000078518800007 PM 10023503 ER PT J AU Priola, SA AF Priola, SA TI Prion protein and species barriers in the transmissible spongiform encephalopathies SO BIOMEDICINE & PHARMACOTHERAPY LA English DT Article DE prion protein; scrapie; PrP ID MOUSE NEUROBLASTOMA-CELLS; HAMSTER SCRAPIE AGENT; TRANSGENIC MICE; PRP GENE; RESISTANT FORMS; CULTURED-CELLS; NMR STRUCTURE; CELLULAR PRP; INFECTIVITY; INHIBITION AB In the transmissible spongiform encephalopathies (TSE), the conversion of the normal protease-sensitive host protein PrP-sen to an abnormal protease-resistant form, PrP-res, is a critical step in disease pathogenesis. Amino acid mismatches between PrP-sen and PrP-res can dramatically affect the amount of PrP-res made and modulate the resistance to cross-species transmission of TSE infectivity. Experiments in transgenic mice, tissue culture cells, and cell-free systems have been used to identify the regions in PrP important in PrP-res formation. These studies have all shown that homology in the middle third of the PrP molecule is critical for the species-specific formation of PrP-res. Polymorphisms within this region correlate with the resistance of hamsters and some goats to scrapie and bovine spongiform encephalopathy (BSE) while homology at critical amino acid residues might facilitate cross-species transmission of BSE to humans. Studies such as these have proven invaluable in understanding the molecular basis of species barriers in the TSE as well as the important secondary structures involved in the formation of PrP-res. (C) 1999 Elsevier, Paris. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. RP Priola, SA (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. NR 55 TC 31 Z9 32 U1 0 U2 1 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS CEDEX 15 PA 23 RUE LINOIS, 75724 PARIS CEDEX 15, FRANCE SN 0753-3322 J9 BIOMED PHARMACOTHER JI Biomed. Pharmacother. PD FEB PY 1999 VL 53 IS 1 BP 27 EP 33 DI 10.1016/S0753-3322(99)80057-2 PG 7 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 189GK UT WOS:000079896300006 PM 10221165 ER PT J AU Cheng, H Song, LS Shirokova, N Gonzalez, A Lakatta, EG Rios, E Stern, MD AF Cheng, H Song, LS Shirokova, N Gonzalez, A Lakatta, EG Rios, E Stern, MD TI Amplitude distribution of calcium sparks in confocal images: Theory and studies with an automatic detection method SO BIOPHYSICAL JOURNAL LA English DT Article ID SKELETAL-MUSCLE FIBERS; RAT-HEART CELLS; CA2+ SPARKS; SARCOPLASMIC-RETICULUM; CARDIAC MYOCYTES; VENTRICULAR MYOCYTES; ELEMENTARY EVENTS; RELEASE; MICROSCOPY; (I) AB Determination of the calcium spark amplitude distribution is of critical importance for understanding the nature of elementary calcium release events in striated muscle. In the present study we show, on general theoretical grounds, that calcium sparks, as observed in confocal line scan images, should have a nonmodal, monotonic decreasing amplitude distribution, regardless of whether the underlying events are stereotyped. To test this prediction we developed, implemented, and verified an automated computer algorithm for objective detection and measurement of calcium sparks in raw image data. When the sensitivity and reliability of the algorithm were set appropriately, we observed highly left-skewed or monotonic decreasing amplitude distributions in skeletal muscle cells and cardiomyocytes, confirming the theoretical predictions. The previously reported modal or Gaussian distributions of sparks detected by eye must therefore be the result of subjective detection bias against small amplitude events. In addition, we discuss possible situations when a modal distribution might be observed. C1 NIA, NIH, Ctr Gerontol Res, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. Rush Univ, Dept Mol Biophys & Physiol, Chicago, IL 60612 USA. RP Cheng, H (reprint author), NIA, NIH, Ctr Gerontol Res, Cardiovasc Sci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Song, Long-Sheng/D-5899-2012 NR 33 TC 209 Z9 212 U1 4 U2 12 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD FEB PY 1999 VL 76 IS 2 BP 606 EP 617 DI 10.1016/S0006-3495(99)77229-2 PG 12 WC Biophysics SC Biophysics GA 162VZ UT WOS:000078368800003 PM 9929467 ER PT J AU Bertram, R Smith, GD Sherman, A AF Bertram, R Smith, GD Sherman, A TI Modeling study of the effects of overlapping Ca2+ microdomains on neurotransmitter release SO BIOPHYSICAL JOURNAL LA English DT Article ID SQUID GIANT SYNAPSE; CALCIUM-CHANNEL TYPES; RAPID BUFFERING APPROXIMATION; PRESYNAPTIC ACTIVE ZONES; TRANSMITTER RELEASE; NERVE-TERMINALS; POSTTETANIC POTENTIATION; PROBABILISTIC SECRETION; CHROMAFFIN CELLS; END-PLATES AB Although single-channel Ca2+ microdomains are capable of gating neurotransmitter release in some instances, it is likely that in many cases the microdomains from several open channels overlap to activate Vesicle fusion. We describe a mathematical model in which transmitter release is gated by single or overlapping Ca2+ microdomains produced by the opening of nearby Ca2+ channels. This model accounts for the presence of a mobile Ca2+ buffer, provided either that the buffer is unsaturable or that it is saturated near an open channel with Ca2+ binding kinetics that are rapid relative to Ca2+ diffusion. We show that the release time course is unaffected by the location of the channels (at least for distances up to 50 nm), but paired-pulse facilitation is greater when the channels are farther from the release sites. We then develop formulas relating the fractional release following selective or random channel blockage to the cooperative relationship between release and the presynaptic Ca2+ current. These formulas are used with the transmitter release model to study the dependence of this form of cooperativity, which we call Ca2+ current cooperativity, on mobile buffers and on the local geometry of Ca2+ channels. We find that Ca2+ current cooperativity increases with the number of channels per release site, but is considerably less than the number of channels, the theoretical upper bound. In the presence of a saturating mobile buffer the Ca2+ current cooperativity is greater, and it increases more rapidly with the number of channels. Finally, Ca2+ current cooperativity is an increasing function of channel distance, particularly in the presence of saturating mobile buffer. C1 Penn State Univ, Sch Sci, Erie, PA 16563 USA. Penn State Univ, Ctr Math Biol, Erie, PA 16563 USA. NIH, Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD 20892 USA. RP Bertram, R (reprint author), Penn State Univ, Sch Sci, Erie, PA 16563 USA. NR 71 TC 59 Z9 60 U1 0 U2 1 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD FEB PY 1999 VL 76 IS 2 BP 735 EP 750 DI 10.1016/S0006-3495(99)77240-1 PG 16 WC Biophysics SC Biophysics GA 162VZ UT WOS:000078368800014 PM 9929478 ER PT J AU Thomson, NH Smith, BL Almqvist, N Schmitt, L Kashlev, M Kool, ET Hansma, PK AF Thomson, NH Smith, BL Almqvist, N Schmitt, L Kashlev, M Kool, ET Hansma, PK TI Oriented, active Escherichia coli RNA polymerase: An atomic force microscope study SO BIOPHYSICAL JOURNAL LA English DT Article ID SELF-ASSEMBLED MONOLAYERS; SCANNING TUNNELING MICROSCOPY; SURFACE-TOPOGRAPHY; COVALENT IMMOBILIZATION; PROBE MICROSCOPY; GOLD; PROTEINS; LIQUIDS; MICA; DNA AB Combining a system for binding proteins to surfaces (Sigal, G. B., C. Bamdad, A. Barberis, J. Strominger, and G. NI. Whitesides. 1996, Anal. Chem. 68:490-497) with a method for making ultraflat gold surfaces (Hegner M., P. Wagner, and G. Semenza. 1993. Surface Sci. 291:39-46 1993) has enabled single, oriented, active Escherichia coli RNA polymerase (RNAP) molecules to be imaged under aqueous buffer using tapping-mode atomic force microscopy (AFM). Recombinant RNAP molecules containing histidine tags (hisRNAP) on the C-terminus were specifically immobilized on ultraflat gold via a mixed monolayer of two different omega-functionalized alkanethiols. One alkanethiol was terminated in an ethylene-glycol (EG) group, which resists protein adsorption, and the other was terminated in an N-nitrilotriacetic acid (NTA) group, which binds the histidine tag through two coordination sites with a nickel ion. AFM images showed that these two alkanethiols phase-segregate. Specific binding of the hisRNAP molecules was followed in situ by injecting proteins directly into the AFM fluid cell. The activity of the hisRNAP bound to the NTA groups was confirmed with a 42-base circular single-stranded DNA template (rolling circle), which the RNAP uses to produce huge RNA transcripts. These transcripts were imaged in air after the samples were rinsed and dried, since RNA also has low affinity for the EG-thiol and cannot be imaged under the buffers we used. C1 Univ Calif Santa Barbara, Dept Phys, Santa Barbara, CA 93106 USA. Univ Calif Santa Barbara, Mat Res Lab, Santa Barbara, CA 93106 USA. Stanford Univ, Dept Chem, Palo Alto, CA 94304 USA. NCI, Frederick Canc Res & Dev Ctr, NIH, Frederick, MD 21702 USA. Univ Rochester, Dept Chem, Rochester, NY 14627 USA. RP Smith, BL (reprint author), Univ Calif Santa Barbara, Dept Phys, Santa Barbara, CA 93106 USA. EM bettye@mrl.ucsb.edu RI Thomson, Neil./O-4198-2016; Maddux, Bettye/D-1269-2009 OI Thomson, Neil./0000-0001-7332-790X; Maddux, Bettye/0000-0001-5890-5249 NR 37 TC 55 Z9 57 U1 2 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD FEB PY 1999 VL 76 IS 2 BP 1024 EP 1033 DI 10.1016/S0006-3495(99)77267-X PG 10 WC Biophysics SC Biophysics GA 162VZ UT WOS:000078368800041 PM 9916034 ER PT J AU McSweegan, E AF McSweegan, E TI A tool for assessing impacts on health SO BIOSCIENCE LA English DT Letter C1 NIAID, NIH, Bethesda, MD 20892 USA. RP McSweegan, E (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER INST BIOLOGICAL SCI PI WASHINGTON PA 1444 EYE ST, NW, STE 200, WASHINGTON, DC 20005 USA SN 0006-3568 J9 BIOSCIENCE JI Bioscience PD FEB PY 1999 VL 49 IS 2 BP 92 EP + DI 10.2307/1313531 PG 2 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 159HN UT WOS:000078166700003 ER PT J AU Roman, BL Pham, VN Bennett, PE Weinstein, BM AF Roman, BL Pham, VN Bennett, PE Weinstein, BM TI Non-radioisotopic AFLP method using PCR primers fluorescently labeled with Cy (TM) 5 SO BIOTECHNIQUES LA English DT Article C1 NICHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. RP Weinstein, BM (reprint author), NICHD, Genet Mol Lab, NIH, Bldg 6B,Room 309,6 Ctr Dr, Bethesda, MD 20892 USA. NR 4 TC 11 Z9 13 U1 0 U2 0 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD FEB PY 1999 VL 26 IS 2 BP 236 EP 238 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 167KL UT WOS:000078631700011 PM 10023531 ER PT J AU Wakabayashi, T Messing, A Brenner, M AF Wakabayashi, T Messing, A Brenner, M TI Nonlethal detection of transgene expression in the CNS of founder mice SO BIOTECHNIQUES LA English DT Article ID INTERMEDIATE FILAMENT; RETINA; PROMOTER; THY-1; CELLS AB Determining whether transgenes targeted to the central nervous system (CNS) are expressed has previously required sacrificing fire animal; thus, if a line was to be maintained, it was necessary to generate offspring from the original founder mouse before assay We describe a method for assaying far the expression of a variety of CNS-targeted transgenes that allows for the survival of the founder mice. Many CNS genes are expressed in the retina which can be obtained from a mouse by simple survival surgery. We demonstrate that reverse transcription PCR of RNA isolated from a single eye carr detect the mRNAs for glial fibrillary acidic protein (GFAP), vimentin, neurofilament light chain (NF-68) and Thy-I, all of whose promoters hale been used to direct transgene expression in the CNS. We also show that this method, readily detects expression of an astrocyte-specific GFAP-driven lacZ transgene and a neuron-specific L7-driven lacZ transgene. C1 Univ Alabama, Dept Neurobiol, Birmingham, AL 35294 USA. NINDS, Bethesda, MD 20892 USA. RP Brenner, M (reprint author), Univ Alabama, Dept Neurobiol, 1719 6th Ave S,CIRC 516, Birmingham, AL 35294 USA. FU NINDS NIH HHS [NS-22475] NR 18 TC 5 Z9 5 U1 0 U2 0 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD FEB PY 1999 VL 26 IS 2 BP 302 EP + PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 167KL UT WOS:000078631700023 PM 10023542 ER PT J AU Suarez-Quian, CA Goldstein, SR Pohida, T Smith, PD Peterson, JI Wellner, E Ghany, M Bonner, RF AF Suarez-Quian, CA Goldstein, SR Pohida, T Smith, PD Peterson, JI Wellner, E Ghany, M Bonner, RF TI Laser capture microdissection of single cells from complex tissues SO BIOTECHNIQUES LA English DT Article ID CARCINOMAS; LESIONS AB Laser capture microdissection (LCM) is a nerv method used to select and procure cell clusters from tissue sections. Once captured, the DNA, RNA or protein can be easily extracted from the isolated cells and analyzed by conventional PCR, reverse transcription (RT)-PCR or polyacrylamide gel electrophoresis, including protein zymography far specific macromolecular changes. In LCM, a thermoplastic polymer coating [ethylene vinyl acetate (EVA)] attached to a rigid support is placed in contact with a tissue section. The EVA polymer over microscopically selected cell clusters is precisely activated by a near-infrared laser pulse and then bonds to the targeted area. Removal of the EVA and its support from the tissue section procures the selected cell aggregates for molecular analysis. This initial NIH LCM approach using a flat transfer EVA film has been recently commercialized and has proven to be an effective routine microdissection technique for subsequent macromolecular analysis in many laboratories around the world. However reliable and precise capture of individual cells fron tissue sections has been difficult to perform, with the current LCM instruments. In this report, we describe the capture of individual cells with a new NIH LCM microscope, which epi-irradiates the EVA polymer overlying individual cells with 1-ms laser pulses focused to 6 mu m. A computer-controlled aml precisely positions a 40-mu m-wide strip of a cylindrical EVA surface onto a sample with a light contact force (ca. 0.1 g). The small contact force and contact area on the film on the sample diminishes nonspecific transfer to negligible levels. By slightly rotating the cylinder to provide a renewable transfer surface, concentration of distinct cell type on a single cylinder is possible. Using this novel adaptation, we demonstrate the rapid and practical capture of single cells from different types of tissue sections, including immunostained cells. C1 NICHHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. NIH, Off Res Serv, Bethesda, MD 20892 USA. NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Bonner, RF (reprint author), NICHHD, Lab Integrat & Med Biophys, NIH, Bldg 13,Room 3N17, Bethesda, MD 20892 USA. EM bonner@helix.nih.gov RI Bonner, Robert/C-6783-2015 FU NICHD NIH HHS [R01 HD-23484] NR 12 TC 83 Z9 89 U1 1 U2 10 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD FEB PY 1999 VL 26 IS 2 BP 328 EP 335 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 167KL UT WOS:000078631700026 PM 10023545 ER PT J AU Tanaka, M Hara, T Copeland, NG Gilbert, DJ Jenkins, NA Miyajima, A AF Tanaka, M Hara, T Copeland, NG Gilbert, DJ Jenkins, NA Miyajima, A TI Reconstitution of the functional mouse oncostatin M (OSM) receptor: Molecular cloning of the mouse OSM receptor beta subunit SO BLOOD LA English DT Article ID LEUKEMIA-INHIBITORY FACTOR; COLONY-STIMULATING FACTOR; SIGNAL-TRANSDUCTION; CYTOKINE RECEPTORS; GROWTH-REGULATOR; CELL-LINE; INTERLEUKIN-6; GP130; FAMILY; BINDING AB Oncostatin M (OSM) is a member of the interleukin-6 (IL-6) family of cytokines that share the gp130 receptor subunit. Of these family members, leukemia inhibitory factor (LIF) is most closely related to OSM, and various overlapping biologic activities have been described between human LIF and OSM (hLIF and hOSM). Two types of functional hOSM receptors are known: the type I OSM receptor is identical to the LIF receptor that consists of gp130 and the LIF receptor beta subunit (LIFR beta), and the type II OSM receptor consists of gp130 and the OSM receptor beta subunit (OSMR beta). It is thus conceivable that common biologic activities between hLIF and hOSM are mediated by the shared type I receptor and OSM-specific activities are mediated by the type II receptor. However, in contrast to the human receptors, recent studies have demonstrated that mouse OSM (mOSM) does not activate the type I receptor and exhibits unique biologic activity. To elucidate the molecular structure of the functional mOSM receptor, we cloned a cDNA encoding mOSMR beta, which is 55.5% identical to the hOSMR beta at the amino acid level, mOSM-responsive cell lines express high-affinity mOSM receptors, as well as mOSMR beta, whereas embryonic stem cells, which are responsive to LIF but not to mOSM, do not express mOSMR beta. mOSMR beta alone binds mOSM with low affinity (kd = 13.0 nmol/L) and forms a high-affinity receptor (kd = 606 pmol/L) with gp130. Ba/F3 transfectants expressing both mOSMR beta and gp130 proliferated in response to mOSM, but failed to respond to LIF and human OSM. Thus, the cloned mOSMR beta constitutes an essential and species-specific receptor component of the functional mOSM receptor. Reminiscent of the colocalization of the mOSM and mLIF genes, the mOSMR beta gene was found to be located in the vicinity of the LIFR beta locus in the proximal end of chromosome 15. (C) 1999 by The American Society of Hematology. C1 Univ Tokyo, Inst Mol & Cellular Biosci, Bunkyo Ku, Tokyo 1130032, Japan. NCI, Mammalian Genet Lab, Adv Biosci Labs, Basic Res Program,Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. RP Miyajima, A (reprint author), Univ Tokyo, Inst Mol & Cellular Biosci, Bunkyo Ku, 1-1-1 Yayoi, Tokyo 1130032, Japan. EM miyajima@ims.u-tokyo.ac.jp NR 56 TC 67 Z9 71 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 FEB 1 PY 1999 VL 93 IS 3 BP 804 EP 815 PG 12 WC Hematology SC Hematology GA 161YX UT WOS:000078319100005 PM 9920829 ER PT J AU Goebeler, M Kilian, K Gillitzer, R Kunz, M Yoshimura, T Brocker, EB Rapp, UR Goebeler, M Kilian, K Gillitzer, R Kunz, M Yoshimura, T Brgcker, EB Rapp, UR Ludwig, S AF Goebeler, M Kilian, K Gillitzer, R Kunz, M Yoshimura, T Brocker, EB Rapp, UR Goebeler, M Kilian, K Gillitzer, R Kunz, M Yoshimura, T Brgcker, EB Rapp, UR Ludwig, S TI The MKK6/p38 stress kinase cascade is critical for tumor necrosis factor-alpha-induced expression of monocyte-chemoattractant protein-1 in endothelial cells SO BLOOD LA English DT Article ID FACTOR-KAPPA-B; MAP KINASE; ATHEROSCLEROTIC LESIONS; GENE-EXPRESSION; ACTIVATION; PATHWAYS; LEVEL; INTERLEUKIN-1; TRANSCRIPTION; INHIBITION AB Monocyte chemoattractant protein-1 (MCP-1), a member of the C-C subfamily of chemokines, is important for the local recruitment of leukocytes to sites of inflammatory challenge. Here, we investigated endothelial signaling pathways involving members of the mitogen-activated protein (MAP) kinase superfamily and studied their role for MCP-1 expression in endothelium. We show that tumor necrosis factor-alpha (TNF-alpha), a potent inflammatory activator of endothelium, leads to activation of MAP kinases ERK, p38, and JNK in human umbilical vein endothelial cells (HUVEC). Contribution of MAP kinase pathways to TNF-alpha-induced synthesis of endothelial MCP-1 was then studied by pharmacologic inhibition and transient expression of dominant negative or constitutively active kinase mutants using flow cytometry, Northern blot, and luciferase reporter gene assays. Inhibition of Raf/MEK/ERK or SEK/JNK pathways had no significant effect on MCP-1 levels, whereas blocking the MKK6/p38 pathway by p38 inhibitors SB203580 or SB202190 or by a dominant negative mutant of MKK6, the upstream activator of p38, strongly inhibited TNF-alpha-induced expression of MCP-1. Consistent with that finding, expression of wild-type or constitutively active MKK6 significantly enhanced the effect of limiting TNF-alpha concentrations on MCP-1 synthesis. These data suggest a crucial role for the MKK6/p38 stress kinase cascade in TNF-alpha-mediated endothelial MCP-1 expression. (C) 1999 by The American Society of Hematology. C1 Univ Wurzburg, Inst Med Strahlenkunde & Zellforsch, D-97078 Wurzburg, Germany. Univ Wurzburg, Klin & Poliklin Haut & Geschlechtskrankheiten, D-97078 Wurzburg, Germany. NCI, Immunopathol Sect, Immunobiol Lab, Frederick, MD 21701 USA. RP Ludwig, S (reprint author), Univ Wurzburg, Inst Med Strahlenkunde & Zellforsch, Versbacher Str 5, D-97078 Wurzburg, Germany. RI Goebeler, Matthias/F-7118-2013 NR 37 TC 129 Z9 132 U1 0 U2 2 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 FEB 1 PY 1999 VL 93 IS 3 BP 857 EP 865 PG 9 WC Hematology SC Hematology GA 161YX UT WOS:000078319100010 PM 9920834 ER PT J AU Jaffe, ES Diebold, J Harris, NL Muller-Hermelink, HK Flandrin, G Vardiman, JW AF Jaffe, ES Diebold, J Harris, NL Muller-Hermelink, HK Flandrin, G Vardiman, JW CA WHO TI Burkitt's lymphoma: A single disease with multiple variants SO BLOOD LA English DT Letter ID CLASSIFICATION C1 NCI, Bethesda, MD 20892 USA. Hotel Dieu, Paris, France. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Wurzburg, Wurzburg, Germany. Hop Necker Enfants Malad, Paris, France. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. RP Jaffe, ES (reprint author), NCI, Bethesda, MD 20892 USA. NR 4 TC 12 Z9 15 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 FEB 1 PY 1999 VL 93 IS 3 BP 1124 EP 1124 PG 1 WC Hematology SC Hematology GA 161YX UT WOS:000078319100052 PM 10025990 ER PT J AU Daschner, PJ Ciolino, HP Plouzek, CA Yeh, GC AF Daschner, PJ Ciolino, HP Plouzek, CA Yeh, GC TI Increased AP-1 activity in drug resistant human breast cancer MCF-7 cells SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE AP-1; MDR1; MCF-7 cells; multidrug resistance ID HUMAN MDR1 GENE; P-GLYCOPROTEIN GENE; LEUKEMIA K562 CELLS; MULTIDRUG-RESISTANCE; PROTEIN-KINASE; PROMOTER ACTIVITY; EXPRESSION; ACTIVATION; TRANSCRIPTION; BINDING AB The expression, DNA binding, and transactivating activity of activator protein 1 (AP-1) was examined in a series of multidrug resistant (MDR) MCF-7 human breast cancer cells that have increasing levels of MDR1 gene expression. We observed an increase in the amount of both c-jun and c-fos mRNA in cells with 12-, 65-, or 200-fold higher resistance to adriamycin when compared to drug-sensitive MCF-7 wild type (WT) cells. Electrophoretic mobility shift assays (EMSA) demonstrated an increase in the DNA binding activity of an AP-1 complex in nuclear extracts from MDR MCF-7 cells when compared to extracts from WT cells. We observed a proportional increase in luciferase expression from a reporter vector containing consensus AP-1 binding sites in transiently transfected MDR cells when compared to WT cells, indicating that AP-1 mediated gene expression is increased in drug-resistant MCF-7 cells. Since the MDR1 promoter contains a putative AP-1 binding site, we used EMSA to examine AP-1 binding activity to an oligonucleotide probe that contained the relevant MDR1 promoter sequences (-123 to -108). Nuclear extracts from resistant MCF-7 cells displayed an increased level of DNA binding of Jun/Jun dimers to the probe, indicating that AP-1 was capable of binding to this promoter site. A luciferase reporter construct containing triplicate copies of the MDR1 promoter sequence was expressed at higher levels in transiently transfected MDR cells when compared to expression in WT cells. Co-transfection of WT cells with a c-jun expression vector and either of the AP-1 luciferase constructs demonstrated that c-jun could activate gene expression from both the consensus and the MDR1 AP-1 sites in a dose dependent manner. In addition, RT-PCR and western blot analysis showed that levels of MDR1 mRNA and Pgp were increased in c-jun transfected WT cells. Taken together, these data indicate that increased AP-1 activity may be an important mediator of MDR by regulating the expression of MDR1. C1 NCI, Cellular Def & Carcinogenesis Sect, Basic Res Lab, FCRDC,NIH, Frederick, MD 21702 USA. NCI, Intramural Res Support Program, SAIC, FCRDC, Frederick, MD 21702 USA. RP Yeh, GC (reprint author), NCI, Cellular Def & Carcinogenesis Sect, Basic Res Lab, FCRDC,NIH, Bldg 560,Rm 12-91, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 57 TC 75 Z9 78 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD FEB PY 1999 VL 53 IS 3 BP 229 EP 240 DI 10.1023/A:1006138803392 PG 12 WC Oncology SC Oncology GA 195VP UT WOS:000080273100004 PM 10369069 ER PT J AU Chow, WH Johansen, C Gridley, G Mellemkjaer, L Olsen, JH Fraumeni, JF AF Chow, WH Johansen, C Gridley, G Mellemkjaer, L Olsen, JH Fraumeni, JF TI Gallstones, cholecystectomy and risk of cancers of the liver, biliary tract and pancreas SO BRITISH JOURNAL OF CANCER LA English DT Article DE gallstones; cholecystectomy; neoplasms; liver; biliary tract; pancreas; cohort study ID GALLBLADDER CANCER; DIABETES-MELLITUS; MEDICAL HISTORY; HYPERPLASIA; CARCINOMA AB To examine the association between gallstones and cholecystectomy, we conducted a nationwide population-based cohort study in Denmark. Patients with a discharge diagnosis of gallstones from 1977 to 1989 were identified from the Danish National Registry of Patients and followed up for cancer occurrence until death or the end of 1993 by record linkage to the Danish Cancer Registry, included in the cohort were 60 176 patients, with 471 450 person-years of follow-up. Cancer risks were estimated by standardized incidence ratios (SIRs) and 95% confidence intervals (Cis) stratified by years of follow-up and by cholecystectomy status. Among patients without cholecystectomy, the risks at 5 or more years of follow-up were significantly elevated for cancers of liver (SIR = 2.0, CI = 1.2-3.1) and gallbladder (SIR = 2.7, CI = 1.5-4.4) and near unity for cancers of extrahepatic bile duct (SIR = 1.1), ampulla of Vater (SIR = 1.0) and pancreas (SIR = 1.1). The excess risk of liver cancer was seen only among patients with a history of hepatic disease. Among cholecystectomy patients, the risks at 5 or more years of follow-up declined for cancers of liver (SIR = 1.1) and extrahepatic bile duct (SIR = 0.7), but were elevated for cancers of ampulla of Vater (SIR = 2.0, CI = 1.0-3.7) and pancreas (SIR = 1.3, CI = 1.1-1.6). These findings confirm that gallstone disease increases the risk of gallbladder cancer, whereas cholecystectomy appears to increase the risk of cancers of ampulla of Vater and pancreas. Further research is needed to clarify the carcinogenic risks associated with gallstones and cholecystectomy and to define the mechanisms involved. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. RP Chow, WH (reprint author), NCI, Div Canc Epidemiol & Genet, 6130 Execut Blvd,EPN 418, Bethesda, MD 20892 USA. NR 22 TC 90 Z9 98 U1 3 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 FEB PY 1999 VL 79 IS 3-4 BP 640 EP 644 DI 10.1038/sj.bjc.6690101 PG 5 WC Oncology SC Oncology GA 159GZ UT WOS:000078165200042 PM 10027343 ER PT J AU Olsen, JH Seersholm, N Boice, JD Kjaer, SK Fraumeni, JF AF Olsen, JH Seersholm, N Boice, JD Kjaer, SK Fraumeni, JF TI Cancer risk in close relatives of women with early-onset breast cancer - a population-based incidence study SO BRITISH JOURNAL OF CANCER LA English DT Article DE early-onset breast cancer; familial cancer; hereditary cancer syndromes; cancer susceptibility genes ID LI-FRAUMENI-SYNDROME; BRCA1 MUTATIONS; OVARIAN-CANCER; FAMILY HISTORY; GENETIC EPIDEMIOLOGY; CONTRALATERAL BREAST; ENDOMETRIAL CANCER; YOUNG-WOMEN; PROSTATE; RADIOTHERAPY AB Inherited susceptibility to breast cancer is associated with an early onset and bilateral disease. The extent of familial risks has not, however, been fully assessed in population-based incidence studies. The purpose of the study was to quantify the risks for cancers of the breast, ovary and other sites of close relatives of women in whom breast cancer was diagnosed at an early age. Records collected between 1943 and 1990 at the Danish Cancer Registry were searched, and 2860 women were found in whom breast cancer was diagnosed before age 40. Population registers and parish records were used to identify 14 973 parents, siblings and offspring of these women. Cancer occurrence through to 31 December 1993 was determined within the Cancer Registry's files and compared with national incidence rates. Women with early-onset breast cancer were at a nearly fourfold increased risk of developing a new cancer later in life (268 observed vs 68.9 expected). The excess risk was most evident for second cancer of the breast (181 vs 24.5) and for ovarian cancer (20 vs 3.3). For mothers and sisters, risks for cancers of the breast and ovary were significantly increased by two- to threefold. Bilateral breast cancer and breast-ovarian cancer were very strong predictors of familial risks, with one in four female relatives predicted to develop breast and/or ovarian cancer by age 75. Mothers had a slightly increased risk of colon cancer, but not endometrial cancer. The risk for breast cancer was also increased among fathers (standardized incidence ratio 2.5; 95% CI 0.5-7.4) and especially brothers (29; 7.7-74), although based on small numbers. The risk for prostatic cancer was unremarkable. In this large population-based survey, the first-degree relatives of women who developed breast cancer before age 40 were prone to ovarian cancer as well as male and female breast cancer, but not other tumours that may share susceptibility genes with breast cancer. C1 Danish Canc Soc, Inst Canc Epidemiol, DK-2100 Copenhagen, Denmark. Int Epidemiol Inst, Rockville, MD 20850 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Olsen, JH (reprint author), Danish Canc Soc, Inst Canc Epidemiol, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. NR 43 TC 19 Z9 19 U1 0 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD FEB PY 1999 VL 79 IS 3-4 BP 673 EP 679 DI 10.1038/sj.bjc.6690106 PG 7 WC Oncology SC Oncology GA 159GZ UT WOS:000078165200047 PM 10027348 ER PT J AU Gasch, AT Smith, JA Whitcup, SM AF Gasch, AT Smith, JA Whitcup, SM TI Birdshot retinochoroidopathy SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Article ID RETINAL S-ANTIGEN; HLA-A29 ANTIGEN; UVEITIS; CHORIORETINOPATHY; NEOVASCULARIZATION; ASSOCIATION; THERAPY; DISEASE C1 NEI, NIH, Bethesda, MD 20892 USA. RP Whitcup, SM (reprint author), NEI, NIH, 10 Ctr Dr,Bldg 10 Rm 10N202, Bethesda, MD 20892 USA. NR 54 TC 47 Z9 51 U1 0 U2 1 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD FEB PY 1999 VL 83 IS 2 BP 241 EP 249 DI 10.1136/bjo.83.2.241 PG 9 WC Ophthalmology SC Ophthalmology GA 164CV UT WOS:000078445600029 PM 10396206 ER PT J AU Whitcup, SM Vistica, BP Magone, MT George, RK AF Whitcup, SM Vistica, BP Magone, MT George, RK TI Elevated serum levels of soluble ICAM-1 in uveitis patients predict underlying systemic disease SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Letter ID INTERCELLULAR-ADHESION MOLECULE-1; ENDOTHELIAL-CELLS; E-SELECTIN C1 NEI, NIH, Bethesda, MD 20892 USA. RP Whitcup, SM (reprint author), NEI, NIH, 10 Ctr Dr,Bldg 10,Rm 10N 202, Bethesda, MD 20892 USA. NR 5 TC 5 Z9 5 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD FEB PY 1999 VL 83 IS 2 BP 252 EP 253 PG 2 WC Ophthalmology SC Ophthalmology GA 164CV UT WOS:000078445600032 PM 10396209 ER PT J AU Wright, P Braun, R Babiuk, L Littel-van den Hurk, SD Moyana, T Zheng, CY Chen, Y Xiang, J AF Wright, P Braun, R Babiuk, L Littel-van den Hurk, SD Moyana, T Zheng, CY Chen, Y Xiang, J TI Adenovirus-mediated TNF-alpha gene transfer induces significant tumor regression in mice SO CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS LA English DT Article DE recombinant adenovirus; gene gun; tumor necrosis factor ID NECROSIS FACTOR-ALPHA; CYTOTOXIC T-CELLS; IN-VIVO; PHASE-I; MURINE TUMORS; CANCER; THERAPY; GUN; EXPRESSION; INJECTION AB Recombinant adenovirus vectors are highly efficient at in vitro and in vivo gene delivery. The in vitro infection of a mouse colon adenocarcinoma cell line MCA-26 with the adenovirus AdV-LacZ can reach a maximal 75% of infectivity at an MOI of 1000. intratumoral injection of AdV-LacZ (2X10(9) pfu) resulted in substantial gene transfer in nearly 70% of MCA-26 tumors. After the in vitro infection of AdV-TN-alpha infected MCA-26 cells showed significant secretion of TNF-alpha (45 ng/ml 10(6) cells) in tissue culture. The secretion peaks at day 2 and is diminished at day, 4 following the viral infection. Infected MCA-26 tumor cells secreting TNF-alpha significantly, reduced their tumorigenicity in syngeneic BALB/c mice. In mice bearing small tumors, intratumoral injection of 2X10(-9) pfu of ADV-TNF-alpha virus with a repeated booster treatment resulted in complete regression of three tumors and significant diminution of the other two with a mean tumor-weight of 0.16 g; this is in contrast to 0.85 g and 1.62 g for tumors injected with the control AdV-pLpA and PBS respectively (p<0.01). Mice with complete tumor regression further developed protective immunity against the second challenge of MCA-26 inoculation. In mice bearing large tumors, this treatment also caused significant inhibition of tumor growth with a mean tumor weight of 0.65 g vis-a-vis 3.05 g for tumors injected with the control AdV-pLpA. On the contrary, in mice bearing large tumors, the treatment of tumors with pCI-TNF-alpha delivered by the gene gun did not induce significant tumor inhibition. These results indicate that the adenoviral delivery of TNF-alpha gene is more efficient than the particle-mediated gene gun device, and that adenovirus-mediated cytokine gene therapy may be a useful approach in the clinical management of human solid tumors. C1 Univ Saskatchewan, Saskatoon Canc Ctr, Dept Microbiol, Saskatoon, SK S7N 4H4, Canada. Univ Saskatchewan, Saskatoon Canc Ctr, Dept Pathol, Saskatoon, SK S7N 4H4, Canada. Vet Infect Dis Org, Saskatoon, SK S7N 0W0, Canada. Univ Ottawa, Dept Epidemiol & Community Med, Ottawa, ON, Canada. NIDR, Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. RP Xiang, J (reprint author), Univ Saskatchewan, Saskatoon Canc Ctr, Dept Microbiol, 20 Campus Dr, Saskatoon, SK S7N 4H4, Canada. NR 26 TC 29 Z9 33 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1084-9785 J9 CANCER BIOTHER RADIO JI Cancer Biother. Radiopharm. PD FEB PY 1999 VL 14 IS 1 BP 49 EP 57 DI 10.1089/cbr.1999.14.49 PG 9 WC Oncology; Medicine, Research & Experimental; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Research & Experimental Medicine; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging GA 180PN UT WOS:000079394500008 PM 10850287 ER PT J AU Dorgan, JF Brock, JW Rothman, N Needham, LL Miller, R Stephenson, HE Schussler, N Taylor, PR AF Dorgan, JF Brock, JW Rothman, N Needham, LL Miller, R Stephenson, HE Schussler, N Taylor, PR TI Serum organochlorine pesticides and PCBs and breast cancer risk: results from a prospective analysis (USA) SO CANCER CAUSES & CONTROL LA English DT Article DE breast neoplasms; epidemiology; organochlorine pesticides; polychlorinated biphenyls ID POLYCHLORINATED-BIPHENYLS PCBS; CIGARETTE-SMOKING; BETA-HEXACHLOROCYCLOHEXANE; ADIPOSE-TISSUE; ASIAN WOMEN; EXPOSURE; RESIDUES; WHITE; BLACK; CELLS AB Objective: To prospectively evaluate relationships of organochlorine pesticides and polychlorinated biphenyls (PCBs) with breast cancer, we conducted a case-control study nested in a cohort using the Columbia, Missouri Breast Cancer Serum Bank. Methods: Women donated blood in 1977-87, and during up to 9.5 years follow-up, 105 donors who met the inclusion criteria for the current study were diagnosed with breast cancer. For each case, two controls matched on age and date of blood collection were selected. Five DDT [2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane] analogs, 13 other organochlorine pesticides, and 27 PCBs were measured in serum. Results: Women in the upper three quartiles of hexachlorobenzene were at twice the risk of breast cancer compared to those in the lowest quartile. However, there was no evidence for a dose-response relationship, and the association was limited to women whose blood was collected close to the time of diagnosis. Women with higher serum levels of other organochlorine pesticides and PCBs showed no increased risk of breast cancer overall, although positive associations were suggested for PCB-118 and PCB-138 when brood was collected close to the time of diagnosis. Conclusions: Results of this study do not support a role for organochlorine pesticides and PCBs in breast cancer etiology. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Div Environm Hlth Lab Sci, Natl Ctr Environm Hlth, Atlanta, GA USA. Ellis Fischel Canc Ctr, Columbia, MO USA. Univ Missouri, Hlth Sci Ctr, Columbia, MO USA. Informat Management Serv Inc, Silver Spring, MD USA. NCI, Div Clin Sci, Bethesda, MD 20892 USA. RP Dorgan, JF (reprint author), NCI, Div Canc Epidemiol & Genet, Execut Plaza N,Room 443,6130 Execut Blvd, Bethesda, MD 20892 USA. RI Needham, Larry/E-4930-2011 NR 34 TC 135 Z9 137 U1 2 U2 8 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD FEB PY 1999 VL 10 IS 1 BP 1 EP 11 DI 10.1023/A:1008824131727 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 186JZ UT WOS:000079727100001 PM 10334636 ER PT J AU Hayes, RB Bravo-Otero, E Kleinman, DV Brown, LM Fraumeni, JF Harty, LC Winn, DM AF Hayes, RB Bravo-Otero, E Kleinman, DV Brown, LM Fraumeni, JF Harty, LC Winn, DM TI Tobacco and alcohol use and oral cancer in Puerto Rico SO CANCER CAUSES & CONTROL LA English DT Article DE alcohol drinking; oral cancer; Puerto Rico; salivary gland cancer; tobacco smoking ID SALIVARY-GLAND CANCER; CIGARETTE-SMOKING; WARTHINS TUMOR; RISK-FACTORS; DRINKING; CAVITY AB Objectives: To determine risk for oral cancer in Puerto Rico associated with use of alcohol and tobacco. Methods: In Puerto Rico, alcohol and tobacco use were compared among nonsalivary gland cancers of the mouth and pharynx (n = 342), cancers of major and minor salivary glands (n = 25) and 521 population-based controls. Results: Alcohol (usual use, P-trend < 0.0001 for men and P-trend = 0.02 for women) and tobacco (usual use, Ptrend < 0.0001, for both men and women) were strong independent risk factors for oral cancer in Puerto Rico, with a multiplicative effect from combined exposures. Risks did not vary systematically by use of filter vs. nonfilter cigarettes. Risks with use of other forms of smoked tobacco were about sevenfold among both men and women. Risks decreased only gradually after cessation of tobacco and alcohol use. Tobacco use, but not alcohol, was linked to cancers of the salivary glands. The burden of oral cancer due to alcohol and tobacco use in Puerto Rico (76% for men, 52% for women) agreed closely with earlier estimates for the mainland US population, while about 72% of salivary gland cancer (men and women, combined) was due to tobacco use. Conclusions: Excess risks for oral cancer in Puerto Rico are largely explained by patterns of alcohol and tobacco use. Smoking filter vs. nonfilter cigarettes does not alter risk, while cessation of alcohol and tobacco use appears to reduce risk only gradually. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Puerto Rico, San Juan, PR 00936 USA. NIDR, Bethesda, MD 20892 USA. RP Hayes, RB (reprint author), NCI, Div Canc Epidemiol & Genet, EPN 418, Bethesda, MD 20892 USA. NR 29 TC 97 Z9 97 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD FEB PY 1999 VL 10 IS 1 BP 27 EP 33 DI 10.1023/A:1008876115797 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 186JZ UT WOS:000079727100004 PM 10334639 ER PT J AU Steller, MA Egorin, MJ Trimble, EL Bartlett, DL Zuhowski, EG Alexander, HR Dedrick, RL AF Steller, MA Egorin, MJ Trimble, EL Bartlett, DL Zuhowski, EG Alexander, HR Dedrick, RL TI A pilot phase I trial of continuous hyperthermic peritoneal perfusion with high-dose carboplatin as primary treatment of patients with small-volume residual ovarian cancer SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE continuous hyperthermic peritoneal perfusion high-dose CBDCA; small-volume residual ovarian cancer; systemic exposure; hepatic toxicity ID WHOLE-BODY HYPERTHERMIA; ONCOLOGY-GROUP; INTRAPERITONEAL CARBOPLATIN; RANDOMIZED TRIAL; SOLUTE TRANSPORT; STAGE-III; CELL-LINE; CHEMOTHERAPY; CISPLATIN; CARCINOMA AB Purpose: Because intraperitoneal (i.p.) therapy may provide a therapeutic advantage and because hyperthermia enhances carboplatin (CBDCA) cytotoxicity, we evaluated the feasibility, toxicity, and pharmacokinetics of CBDCA given via continuous hyperthermic peritoneal perfusion (CHPP) in patients with small-volume residual ovarian cancer. Patients and Methods: Six patients underwent optimal cytoreductive procedures (residual disease less than or equal to 5 mm) as initial treatment of stages II and III epithelial ovarian adenocarcinoma. All patients received a 90-min CHPP at a CBDCA dose of 800-1200 mg/m(2), with the perfusate being recirculated rapidly from a reservoir through a heat exchanger, resulting in i.p. temperatures of 41-43 degrees C. Plasma, perfusate, and urine samples were collected and platinum was quantified by flameless atomic absorption spectrophotometry. Results: At no time did any patient's core temperature exceed 40 degrees C. Peak perfusate platinum concentrations were 8- to 15-fold higher than peak ultrafilterable plasma concentrations. The permeability-area product was extremely high and variable (14-90 ml/min), resulting in a regional advantage of 1.9-5.3. The percentage of the dose absorbed ranged widely from 27% to 77%. Dose-limiting hematologic toxicity was observed at a dose of 1200 mg/m(2) and this was associated with a CBDCA AUC in plasma of 11 mg min ml(-1) Conclusions: CHPP with CBDCA was safely given to three patients at a dose of 800 mg/m(2), and dose-limiting hematologic toxicities observed at 1200 mg/m(2) correlated with the plasma CBDCA exposure established when lower doses of CBDCA are given systemically. The pharmacokinetic data are consistent with the expected effect of vigorous mixing on the exposed peritoneal surface area. Variable drug absorption and clearance make the prediction of systemic exposure highly uncertain. These findings may have important implications for novel therapies given i.p. C1 NCI, Gynecol Oncol Sect, Surg Branch, NIH, Bethesda, MD 20892 USA. NIH, Off Res Serv, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. RP Steller, MA (reprint author), Brown Univ, Women & Infants Hosp, 1 Blackstone Pl,3rd Floor, Providence, RI 02905 USA. EM msteller@wihri.org NR 56 TC 47 Z9 48 U1 0 U2 1 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD FEB PY 1999 VL 43 IS 2 BP 106 EP 114 DI 10.1007/s002800050870 PG 9 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 145AJ UT WOS:000077348500002 PM 9923815 ER PT J AU Spencer, DL Masten, SA Lanier, KM Yang, XP Grassman, JA Miller, CR Sutter, TR Lucier, GW Walker, NJ AF Spencer, DL Masten, SA Lanier, KM Yang, XP Grassman, JA Miller, CR Sutter, TR Lucier, GW Walker, NJ TI Quantitative analysis of constitutive and 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced cytochrome P450 1B1 expression in human lymphocytes SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID POLYMERASE CHAIN-REACTION; ADRENAL CYTOCHROME-P450; AH RECEPTOR; RAT CYP1B1; DIOXIN; EXPOSURE; TISSUE; GENE; 4-HYDROXYLATION; MORTALITY AB Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) results in a broad spectrum of biological responses, including altered metabolism, disruption of normal hormone signaling pathways, reproductive and developmental effects, and cancer. Cytochrome P450 1B1 (CYP1B1) is a dioxin-inducible gene that is active in the formation of 4-hydroxyestradiol, a potentially genotoxic catechol estrogen, Therefore, the analysis of CYP1B1 in humans may be useful in establishing relationships between dioxin exposure and adverse health effects. In this study, we examined the expression of CYP1B1 in human peripheral blood lymphocytes of unexposed individuals using a quantitative reverse transcription-PCR method. Absolute CYP1B1 RNA levels varied more than 30-fold in uncultured mononuclear cells obtained from 10 individuals. In vitro treatment of mitogen-stimulated lymphocytes with TCDD for 1-5 days of culture resulted in a peak induction of CYP1B1 after 3 days. The induction of CYP1B1 RNA levels after 3 days of culture was dose-dependent, exhibited a maximum response above 10 nM TCDD, and varied greatly among different individuals. However, the half maximal dose required for this induction was similar between individuals and comparable to that observed in the MCF-7 and HepG2 human cell lines, These observations indicate that CYP1B1 exhibits variable constitutive expression and is inducible in vitro by TCDD in human lymphocytes and that the magnitude of induction varies within the population. These data define the suitability of CYP1B1 for use as a mechanistically based biomarker in ongoing molecular epidemiological studies of human populations exposed to dioxins and related chemicals that bind the aromatic hydrocarbon receptor. C1 NIEHS, NIH, Lab Computat Biol & Risk Anal, Res Triangle Pk, NC 27709 USA. Johns Hopkins Sch Hyg & Publ Hlth, Div Toxicol Sci, Baltimore, MD 21205 USA. RP Walker, NJ (reprint author), NIEHS, NIH, Lab Computat Biol & Risk Anal, POB 12233,MD D4-01, Res Triangle Pk, NC 27709 USA. RI Walker, Nigel/D-6583-2012; masten, scott/R-1403-2016 OI Walker, Nigel/0000-0002-9111-6855; masten, scott/0000-0002-7847-181X FU NIEHS NIH HHS [ES03819, ES08148] NR 35 TC 59 Z9 60 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 1999 VL 8 IS 2 BP 139 EP 146 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 165ZV UT WOS:000078552500004 PM 10067811 ER PT J AU Miller, RW Rabkin, CS AF Miller, RW Rabkin, CS TI Merkel cell carcinoma and melanoma: Etiological similarities and differences SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID NON-HODGKINS-LYMPHOMA; OCULOCUTANEOUS ALBINISM; CUTANEOUS MELANOMA; MALIGNANT-MELANOMA; SKIN-CANCER; 2ND CANCERS; XERODERMA-PIGMENTOSUM; NEVI; TRANSPLANTATION; ASSOCIATION AB Merkel cell carcinoma (MCC) of the skin and cutaneous malignant melanoma can now be compared epidemiologically through the use of population-based data not previously available for MCC, The results may provide new clues to etiology, In this study, United States data covered by the Surveillance, Epidemiology, and End Results (SEER) Program were from nine areas of the United States (similar to 10% of the population). In 1986-1994, 425 cases of MCC were registered. The annual age-adjusted incidence per 100,000 of MCC was 0.23 for whites and 0.01 for blacks; among whites, the ratio of melanoma to MCC was similar to 65 to 1. Only 5% of MCC occurred before age 50, unlike the lifelong risk of nodular and superficial spreading melanoma, Regional incidence rates of both cancers increased similarly with increasing sun exposure as measured by the UVB solar index. The most sun-exposed anatomical site, the face, was the location of 36% of MCC but only 14% of melanoma, Both cancers increased in frequency and aggressiveness after immunosuppression and organ transplantation (36 cases from the Cincinnati Tranplant Tumor registry and 12 from published case reports) and after B-cell neoplasia (5 cases in this study; 13 from case series in the literature). The SEER data contained reports of six patients with both types of cancer; 5 melanomas before the diagnosis of MCC and 1 after diagnosis, MCC and melanoma are similarly related to sun exposure and immunosuppression, but they differ markedly from one another in their distributions by age, race, and anatomical site, especially the face. C1 NCI, Genet Epidemiol Branch, NIH, Bethesda, MD 20892 USA. NCI, Viral Epidemiol Branch, NIH, Bethesda, MD 20892 USA. RP Miller, RW (reprint author), NCI, Genet Epidemiol Branch, NIH, EPS-7018, Bethesda, MD 20892 USA. EM millerr@epndcc.nci.nih.gov NR 54 TC 185 Z9 188 U1 2 U2 6 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 1999 VL 8 IS 2 BP 153 EP 158 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 165ZV UT WOS:000078552500006 PM 10067813 ER PT J AU Meloni-Ehrig, AM Chen, Z Guan, XY Notohamiprodjo, M Shepard, RR Spanier, SS Trent, JM Sandberg, AA AF Meloni-Ehrig, AM Chen, Z Guan, XY Notohamiprodjo, M Shepard, RR Spanier, SS Trent, JM Sandberg, AA TI Identification of a ring chromosome in a myxoid malignant fibrous histiocytoma with chromosome microdissection and fluorescence in situ hybridization SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID PAINTING PROBES; TUMORS AB We investigated the origin of a ring chromosome in a myxoid malignant fibrous histiocytoma (MFH) by microdissection and fluorescence in situ hybridization (FISH) analyses. Cytogenetically, only two ring chromosomes were observed; the smaller ring was seen more frequently. The latter was microdissected, and the material used for FISH. Hybridization of the microdissected labeled DNA to normal metaphase cells revealed that the signal localized only to 20q. Three signals were seen in the tumor cells using either the microdissected 20q probe or chromosome 20 centromeric probe, indicating the involvement of both the long arm and the centromere in the ring chromosome. The short arm of chromosome 20 did not appear to be involved in the formation of the ring chromosome. (C) Elsevier Science Inc., 1999. All rights reserved. C1 Univ Utah, Huntsman Canc Inst, Cytogenet FISH Core Lab, Salt Lake City, UT 84112 USA. Genzyme Genet, Scottsdale, AZ USA. NIH, Human Genome Res Inst, Bethesda, MD 20892 USA. Univ Florida, Coll Med, Dept Orthoped, Gainesville, FL 32610 USA. RP Meloni-Ehrig, AM (reprint author), Univ Utah, Huntsman Canc Inst, Cytogenet FISH Core Lab, 15 N 2030 E,Room 2350, Salt Lake City, UT 84112 USA. RI Guan, Xin-Yuan/A-3639-2009 OI Guan, Xin-Yuan/0000-0002-4485-6017 FU NCI NIH HHS [CA 41183] NR 14 TC 12 Z9 12 U1 0 U2 0 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 FEB PY 1999 VL 109 IS 1 BP 81 EP 85 DI 10.1016/S0165-4608(98)00151-4 PG 5 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 160VD UT WOS:000078251300015 PM 9973967 ER PT J AU McCormick, DL Rao, KVN Steele, VE Lubet, RA Kelloff, GJ Bosland, MC AF McCormick, DL Rao, KVN Steele, VE Lubet, RA Kelloff, GJ Bosland, MC TI Chemoprevention of rat prostate carcinogenesis by 9-cis-retinoic acid SO CANCER RESEARCH LA English DT Article ID 9-CIS RETINOIC ACID; X-RECEPTOR; MAMMARY CARCINOGENESIS; BREAST-CANCER; ALL-TRANS; GROWTH; ALPHA; PREVENTION; INHIBITION; LIGAND AB A chemoprevention study was conducted to evaluate the activity of 9-cis-retinoic acid (9-cis-RA) as an inhibitor of prostate carcinogenesis in male Wistar-Unilever (HsdCpb:Wu) rats. After pretreatment with a sequential regimen of cyproterone acetate (50 mg/kg/day for 21 days) and testosterone propionate (100 mg/kg/day for 3 days), groups of 40 rats received a single i.v. injection of N-methyl-N-nitrosourea (MNU; 30 mg/kg body weight). Beginning 2 weeks after carcinogen administration, rats received chronic exposure to testosterone administered in s.c. implanted silastic capsules, The study was terminated at 13 months after MNU administration, and prostate cancer incidence was determined by histopathological evaluation of step sections of accessory sex glands. Continuous dietary administration of 9-cis-RA at 100 mg/kg diet or 50 mg/kg diet beginning 1 week before MNU administration reduced cancer incidence in the dorsolateral + anterior prostate from 65% in dietary controls to 18 and 20%, respectively (P < 0.001 for both comparisons). Similarly, these dose levels of 9-cis-RA reduced the incidence of cancer in all accessory sex glands from 79% in dietary controls to 48 and 33% (P < 0.01 for both comparisons), respectively. Chronic dietary administration of 9-cis-RA induced no gross or organ-specific toxicity in any animal and did not suppress group mean body weight gain. The potent anticarcinogenic activity of 9-cis-RA in the rat prostate, when considered with its apparent lack of toxicity in rodents, suggests that this and other ligands for the retinoid X receptor merit consideration for evaluation in clinical prostate cancer chemoprevention trials. C1 IIT, Res Inst, Expt Toxicol & Carcinogenesis Div, Chicago, IL 60616 USA. NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. NYU, Sch Med, Dept Environm Med, New York, NY 10016 USA. NYU, Sch Med, Dept Urol, New York, NY 10016 USA. RP McCormick, DL (reprint author), IIT, Res Inst, Expt Toxicol & Carcinogenesis Div, 10 W 35th St, Chicago, IL 60616 USA. FU NCI NIH HHS [N01-CN-35566-02] NR 30 TC 70 Z9 72 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 1999 VL 59 IS 3 BP 521 EP 524 PG 4 WC Oncology SC Oncology GA 163EU UT WOS:000078390900005 PM 9973192 ER PT J AU Kawamori, T Lubet, R Steele, VE Kelloff, GJ Kaskey, RB Rao, CV Reddy, BS AF Kawamori, T Lubet, R Steele, VE Kelloff, GJ Kaskey, RB Rao, CV Reddy, BS TI Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory agent, during the promotion/progression stages of colon cancer SO CANCER RESEARCH LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY AGENT; DIETARY CURCUMIN; TUMOR PROMOTION; DIFERULOYL METHANE; COLORECTAL-CANCER; CELL-LINES; MOUSE SKIN; RAT COLON; APOPTOSIS; CARCINOGENESIS AB Curcumin, derived from the rhizome of Curcuma longa L. and having both antioxidant and anti-inflammatory properties, inhibits chemically induced carcinogenesis in the skin, forestomach, and colon when it is administered during initiation and/or postinitiation stages. This study was designed to investigate the chemopreventive action of curcumin when it is administered (late in the premalignant stage) during the promotion/progression stage of colon carcinogenesis in male F344 rats. We also studied the modulating effect of this agent on apoptosis in the tumors. At 5 weeks of age, groups of male F344 rats were fed a control diet containing no curcumin and an experimental AIN-76A diet with 0.2% synthetically derived curcumin (purity, 99.9%), At 7 and 8 weeks of age, rats intended for carcinogen treatment were given s.c. injections of azoxymethane (AOM) at a dose rate of 15 mg/kg body weight per week. Animals destined for the promotion/progression study received the AIN-76A control diet for 14 weeks after the second AOM treatment and were then switched to diets containing 0.2 and 0.6% curcumin, Premalignant lesions in the colon would have developed by week 14 following AOM treatment. They continued to receive their respective diets until 52 weeks after carcinogen treatment and were then sacrificed, The results confirmed our earlier study in that administration of 0.2% curcumin during both the initiation and postinitiation periods significantly inhibited colon tumorigenesis. In addition, administration of 0.2 % and of 0.6% of the synthetic curcumin in the diet during the promotion/progression stage significantly suppressed the incidence and multiplicity of noninvasive adenocarcinomas and also strongly inhibited the multiplicity of invasive adenocarcinomas of the colon. The inhibition of adenocarcinomas of the colon was, in fact, dose dependent. Administration of curcumin to the rats during the initiation and postinitiation stages and throughout the promotion/progression stage increased apoptosis in the colon tumors as compared to colon tumors in the groups receiving AOM and the control diet, Thus, chemopreventive activity of curcumin is observed when it is administered prior to, during, and after carcinogen treatment as well as when it is given only during the promotion/progression phase (starting late in premalignant stage) of colon carcinogenesis. C1 Amer Hlth Fdn, Div Nutr Carcinogenesis, Valhalla, NY 10595 USA. NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. Gene Print Inc, Bala Cynwyd, PA USA. RP Amer Hlth Fdn, Div Nutr Carcinogenesis, 1 Dana Rd, Valhalla, NY 10595 USA. RI Chinthalapally, Rao/B-3633-2010; Kawamori, Toshihiko/G-7636-2012 FU NCI NIH HHS [CA17613, N01-CN-55150] NR 45 TC 398 Z9 417 U1 2 U2 16 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 1999 VL 59 IS 3 BP 597 EP 601 PG 5 WC Oncology SC Oncology GA 163EU UT WOS:000078390900019 PM 9973206 ER PT J AU Ambrosone, CB Freudenheim, JL Thompson, PA Bowman, E Vena, JE Marshall, JR Graham, S Laughlin, R Nemoto, T Shields, PG AF Ambrosone, CB Freudenheim, JL Thompson, PA Bowman, E Vena, JE Marshall, JR Graham, S Laughlin, R Nemoto, T Shields, PG TI Manganese superoxide dismutase (MnSOD) genetic polymorphisms, dietary antioxidants, and risk of breast cancer SO CANCER RESEARCH LA English DT Article ID LIPID-PEROXIDATION; ALCOHOL-CONSUMPTION; UNITED-STATES; DNA-ADDUCTS; NEW-YORK; CELLS; OVEREXPRESSION; PHENOTYPE; DISEASES; SEQUENCE AB Oxidative stress, resulting from the imbalance between prooxidant and antioxidant states, damages DNA, proteins, cell membranes, and mitochondria and seems to play a role in human breast carcinogenesis. Dietary sources of antioxidants (chemical) and endogenous antioxidants (enzymatic), including the polymorphic manganese superoxide dismutase (MnSOD), can act to reduce the load of oxidative stress. We hypothesized that the valine-to-alanine substitution that seems to alter transport of the enzyme into the mitochondrion. changing its efficacy in fighting oxidative stress, was associated with breast cancer risk and that a diet rich in sources of antioxidants could ameliorate the effects on risk. Data were collected in a case-control study of diet and breast cancer in western New York from 1986 to 1991. Caucasian women with incident, primary, histologically confirmed breast cancer were frequency-matched on age and county of residence to community controls. Blood specimens were collected and processed from a subset of participants in the study (266 cases and 295 controls). Using a RFLP that distinguishes a valine (V) to alanine (A) change in the -9 position in the signal sequence of the protein for MnSOD, we characterized MnSOD genotypes in relation to breast cancer risk, We also evaluated the effect of the polymorphism on risk among low and high consumers of Fruits and vegetables. Premenopausal women who were homozygous for the A allele had a 4-fold increase in breast cancer risk in comparison to those with 1 or 2 V alleles (odds ratio, 4.3; 95% confidence interval, 1.7-10.8). Risk was most pronounced among women below the median consumption of fruits and vegetables and of dietary ascorbic acid and cu-tocopherol, with little increased risk for those with diets rich in these foods, Relationships were weaker among postmenopausal women, although the MnSOD AA genotype was associated with an almost 2-fold increase in risk (odds ratio, 1.8; confidence interval, 0.9-3.6), No appreciable modification of risk by diet was detected for these older women. These data support the hypothesis that MnSOD and oxidative stress play a significant role in breast cancer risk, particularly in premenopausal women, The finding that risk was greatest among women who consumed lo rc er amounts of dietary antioxidants and was minimal among high consumers indicates that a diet rich in sources of antioxidants may minimize the deleterious effects of the MnSOD polymorphism, thereby supporting public health recommendations for the consumption of diets rich in fruits and vegetables as a preventive measure against cancer. C1 Natl Ctr Toxicol Res, Div Mol Epidemiol, Jefferson, AR 72079 USA. SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14214 USA. NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. Univ Arizona, Arizona Canc Ctr, Tucson, AZ 85724 USA. RP Ambrosone, CB (reprint author), Natl Ctr Toxicol Res, Div Mol Epidemiol, 3900 NCTR Rd, Jefferson, AR 72079 USA. RI Shields, Peter/I-1644-2012 FU NCI NIH HHS [CA/ES62995, CA01633, CA11535] NR 45 TC 287 Z9 299 U1 2 U2 8 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 1999 VL 59 IS 3 BP 602 EP 606 PG 5 WC Oncology SC Oncology GA 163EU UT WOS:000078390900020 PM 9973207 ER PT J AU Kass, E Schlom, J Thompson, J Guadagni, F Graziano, P Greiner, JW AF Kass, E Schlom, J Thompson, J Guadagni, F Graziano, P Greiner, JW TI Induction of protective host immunity to carcinoembryonic antigen (CEA), a self-antigen in CEA transgenic mice, by immunizing with a recombinant vaccinia-CEA virus SO CANCER RESEARCH LA English DT Article ID MONOCLONAL-ANTIBODIES; MOLECULAR-BIOLOGY; T-CELLS; RESPONSES; GENE; EXPRESSION; CANCER; IMMUNOTHERAPY; GENERATION; DEFINITION AB Human carcinoembryonic antigen (CEA is a well-characterized oncofetal glycoprotein whose overexpression by human carcinomas has been a target for cancer immunotherapy, Transgenic mice that express CEA as a self-antigen with a tissue distribution similar to that of humans have been developed. This study investigates: (a) the responsiveness of the CEA transgenic (CEA.Tg) mice to endogenous CEA or CEA administered as a whole protein in adjuvant; and (b) whether the presentation of CEA as a recombinant vaccinia virus could generate CEA-specific host immunity. By and large, the CEA.Tg mice were unresponsive to CEA, as shown by the lack of detectable CEA-specific serum antibodies and the inability to prime an in vitro splenic T-cell response to CEA. Furthermore, the administration of whole CEA protein in adjuvant to CEA.Tg mice failed to elicit either anti-CEA Ige titers or CEA-specific T-cell responses. Only weak anti-CEA IgM antibody titers a ere round in those mice. In contrast, CEA.Tg mice immunized with recombinant vaccinia virus expressing CEA generated relatively strong anti-CEA Ige antibody titers and demonstrated evidence of immunoglobulin class switching, These mice also developed T(H)1-type CEA-specific CD4(+) responses and CEA peptide-specific cytotoxicity. The ability to generate CEA-specific host immunity correlated with protection of the CEA,Tg mice against a challenge with CEA-expressing tumor cells, Protection against tumor growth was accomplished with no apparent immune response directed at CEA-positive normal tissues. The results demonstrate the ability to generate an effective antitumor immune response to a tumor self-antigen by immunization with a recombinant vaccinia virus. CEA,Tg mice should be an excellent experimental model to study the effects of more aggressive immunization schemes directed at established tumors with the possible development of accompanying autoimmune responses involving normal tissues. C1 NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. Regina Elena Canc Inst, I-00161 Rome, Italy. Univ Freiburg, D-79104 Freiburg, Germany. RP Greiner, JW (reprint author), NCI, Tumor Immunol & Biol Lab, NIH, Room 8B07,Bldg 10, Bethesda, MD 20892 USA. RI Zhou, Feng/E-9510-2011; Guadagni, Fiorella/J-4432-2013; OI Guadagni, Fiorella/0000-0003-3652-0457; Graziano, Paolo/0000-0001-7066-7896 NR 45 TC 123 Z9 124 U1 1 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 FEB 1 PY 1999 VL 59 IS 3 BP 676 EP 683 PG 8 WC Oncology SC Oncology GA 163EU UT WOS:000078390900030 PM 9973217 ER PT J AU Gutierrez, MI Cherney, B Hussain, A Mostowski, H Tosato, G Magrath, I Bhatia, K AF Gutierrez, MI Cherney, B Hussain, A Mostowski, H Tosato, G Magrath, I Bhatia, K TI Bax is frequently compromised in Burkitt's lymphomas with irreversible resistance to Fas-induced apoptosis SO CANCER RESEARCH LA English DT Article ID PROGRAMMED CELL-DEATH; B-CELLS; CD95 FAS/APO-1; C-MYC; DIFFERENTIAL EXPRESSION; MEDIATED APOPTOSIS; BCL-X; LYMPHOCYTES; LIGAND; LINES AB We have analyzed the Pas-mediated death pathway in a panel of ii Epstein-Barr virus (EBV)-negative and 10 EBV-positive Burkitt's lymphoma (BL) cell lines. We show that the increased expression of Fas in EBV-positive cell lines is mediated via LMP-1. Four of the 21 BL cell lines are readily responsive to Pas-mediated cell death signals. Of the remaining 17 cell lines, 10 can be sensitized by up-regulating Pas either via exogenous expression of LMP-I or via treatment with CD40L. These same cell lines can also be sensitized by treatment with cycloheximide (CHX), which, however, does not result in up-regulation of Pas. Neither up-regulation of Pas, nor treatment with CHX, restore Fas sensitivity in seven BL cell lines. Further analyses indicated that 5 of the 7 cell lines land none of the 14 responsive cell lines) were also compromised in the integrity/expression of the proapoptotic gene Bax. Thus, in most BL cell lines, the Fas pathway seems to be inhibited, although the mechanism of inhibition varies. The correlation between Bax mutation and irreversible (by CD40L or CHX) Pas resistance raises the possibility, for the first time, that Bas may play a critical function in Pas-mediated cell death in BL. C1 NCI, Pediat Oncol Branch, Lymphoma Biol Sect, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Div Hematol Prod, Bethesda, MD 20892 USA. RP Bhatia, K (reprint author), NCI, Pediat Oncol Branch, Lymphoma Biol Sect, NIH, Bldg 10,Room 13N240,10 Ctr Dr,MSC 1928, Bethesda, MD 20892 USA. NR 48 TC 51 Z9 52 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 FEB 1 PY 1999 VL 59 IS 3 BP 696 EP 703 PG 8 WC Oncology SC Oncology GA 163EU UT WOS:000078390900033 PM 9973220 ER PT J AU Keane, MM Ettenberg, SA Nau, MM Russell, EK Lipkowitz, S AF Keane, MM Ettenberg, SA Nau, MM Russell, EK Lipkowitz, S TI Chemotherapy augments TRAIL-induced apoptosis in breast cell lines SO CANCER RESEARCH LA English DT Article ID DRUG-INDUCED APOPTOSIS; ANTI-FAS ANTIBODY; APO-1/FAS RECEPTOR/LIGAND SYSTEM; WILD-TYPE P53; CANCER-CELLS; MEDIATED CYTOTOXICITY; MUTANT P53; POLY(ADP-RIBOSE) POLYMERASE; PROTEASE ACTIVITY; LIGAND TRAIL AB Expression and function of the TRAIL apoptotic pathway was investigated in normal and malignant breast epithelial cells. Glutathione-S-transferase (GST)-TRAIL extracellular domain fusion proteins Here produced to analyze TRAIL-induced apoptosis. Only GST-TRAIL constructs containing regions homologous to the Fas self-association and ligand binding domains could induce apoptosis, GST-TRAIL induced significant (>90%) apoptosis in just one of eight normal and one of eight malignant breast cell lines. All other lines were relatively resistant to TRAIL-induced apoptosis, Activating TRAIL receptors DR I and DR5 were expressed in all normal and malignant breast cell lines. The inhibitory receptor TRID was highly expressed in one of tour normal and two of seven malignant breast cell lines, DR4, DR5, or TRID expression did not correlate with sensitivity to TRAIL-induced apoptosis. Incubation of cell lines with doxorubicin or 5-fluorouracil significantly augmented TRAIL-induced apoptosis in most breast cell lines, By fractional inhibition analysis, the toxicity of the combination of TRAIL and doxorubicin or 5-fluorouracil was synergistic compared with either agent alone. In contrast, melphalan and paclitaxel augmented TRAIL-induced apoptosis in few cell lines, and methotrexate did not augment it in any cell line. Augmentation of TRAIL-induced apoptosis by doxorubicin or 5-fluorouracil was mediated through caspase activation, This was evidenced by the fact that chemotherapy agents that synergized with TRAIL (e.g., doxorubicin) themselves caused cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP), and their toxicity was blocked by the caspase inhibitor Z-Val-Ala-Asp(OMe)-CH2 (ZVAD-fmk), The combination of TRAIL and doxorubicin caused significantly greater caspase-3 and PARP cleavage, and the combined toxicity also was inhibited by ZVAD-fmk. In contrast, chemotherapy agents that did not augment TRAIL-induced apoptosis (e.g., methotrexate) caused minimal caspase-3 and PARP cleavage by themselves, and their toxicity was not inhibited by ZVAD-fmk, These drugs also did not increase caspase-3 or PARP cleavage when combined with TRAIL. Tn summary, few breast cell lines are sensitive to TRAIL-induced apoptosis, and no difference in sensitivity is found between normal and malignant cell lines. Treatment with chemotherapy provides an approach to sensitize breast cancer cells to TRAIL-induced apoptosis. C1 NCI, Div Clin Sci, Med Branch, Natl Naval Med Ctr, Bethesda, MD 20889 USA. RP Lipkowitz, S (reprint author), NCI, Div Clin Sci, Med Branch, Natl Naval Med Ctr, Bldg 8,Room 5101, Bethesda, MD 20889 USA. NR 54 TC 483 Z9 504 U1 4 U2 26 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 FEB 1 PY 1999 VL 59 IS 3 BP 734 EP 741 PG 8 WC Oncology SC Oncology GA 163EU UT WOS:000078390900038 PM 9973225 ER PT J AU Frisch, M Fenger, C van den Brule, AJC Sorensen, P Meijer, CJLM Walboomers, JMM Adami, HO Melbye, M Glimelius, B AF Frisch, M Fenger, C van den Brule, AJC Sorensen, P Meijer, CJLM Walboomers, JMM Adami, HO Melbye, M Glimelius, B TI Variants of squamous cell carcinoma of the anal canal and perianal skin and their relation to human papillomaviruses SO CANCER RESEARCH LA English DT Article ID INSITU HYBRIDIZATION; CANCER; DNA; ASSOCIATION; INFECTION; ETIOLOGY; VULVA; ANUS; RISK AB High-risk types of human papillomaviruses (hrHPVs) may be a necessary cause in cervical cancer and in some subtype of anal, vulvar, and penile cancers. Large studies aimed at characterizing hrHPV-associated and non-hrHPV-associated subtypes of anal carcinomas are, however, lacking. We searched for human papillomavirus type 16 and 13 other hrHPVs in tumor tissue by PCR and performed a systematic histological evaluation of specimens from 386 patients with anal cancer (86% invasive; 302 women and 84 men). Cancers in women and homosexual men were more often hrHPV positive (P < 0.01) and located in the anal canal (P less than or equal to 0.01) than were cancers in heterosexual men. In both women and men, anal canal cancers contained hrHPV clearly more often than did perianal skin cancers, and increasing hrHPV positivity was seen with higher localization in the anal canal. Indeed, 95 and 83% of cancers involving the anal canal in women and men, respectively, were hrHPV positive versus 80 and 28% of perianal skin cancers (P-trend < 0.001). Basaloid feature, adjacent anal intraepithelial neoplasia, poor or absent keratinization, and a predominance of small or medium neoplastic cells were all strongly positively associated with hrHPV status. Like cancer of the uterine cervix, the development of cancer of the anal canal may require infection with hrHPV, whereas a dual etiology of perianal skin cancers bears parallels to vulvar and penile cancers. C1 Statens Serum Inst, Dept Epidemiol Res, Danish Epidemiol Sci Ctr, DK-2300 Copenhagen S, Denmark. Odense Univ Hosp, Dept Pathol, DK-5000 Odense, Denmark. Vrije Univ Amsterdam, Univ Hosp, Dept Pathol, Sect Mol Pathol, NL-1081 HV Amsterdam, Netherlands. Karolinska Inst, Dept Med Epidemiol, S-17177 Stockholm, Sweden. Harvard Univ, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Harvard Ctr Canc Prevent, Boston, MA 02115 USA. Univ Uppsala Hosp, Dept Oncol Radiol & Clin Immunol, S-75185 Uppsala, Sweden. RP Frisch, M (reprint author), NCI, Virol Epidemiol Branch, Div Canc Epidemiol & Genet, 6130 Execut Blvd, Rockville, MD 20852 USA. RI Frisch, Morten/E-9206-2016 OI Frisch, Morten/0000-0002-3864-8860 NR 24 TC 158 Z9 169 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 1999 VL 59 IS 3 BP 753 EP 757 PG 5 WC Oncology SC Oncology GA 163EU UT WOS:000078390900041 PM 9973228 ER PT J AU Fu, YM Yu, ZX Pelayo, BA Ferrans, VJ Meadows, GG AF Fu, YM Yu, ZX Pelayo, BA Ferrans, VJ Meadows, GG TI Focal adhesion kinase-dependent apoptosis of melanoma induced by tyrosine and phenylalanine deficiency SO CANCER RESEARCH LA English DT Article ID CELL-DEATH; EXTRACELLULAR-MATRIX; METASTATIC PHENOTYPE; ENDOTHELIAL-CELLS; MURINE MELANOMA; GROWTH-FACTOR; EXPRESSION; INHIBITION; CALCIUM; RESTRICTION AB We found previously that restriction of tyrosine (Tyr) and phenylalanine (Phe) inhibited growth and metastasis of B16BL6 murine melanoma and arrested these cells in the G(0)-G(1) phase of the cell cycle, Here, we report that deprivation of these two amino acids in vitro induces apoptosis in B16BL6 and in human A375 melanoma cells but not in nontransformed, neonatal murine epidermal cells or human infant foreskin fibroblasts, Four days after deprivation of Tyr and Phe in vitro, 37% of B16BL6 and 51% of A375 melanoma cells were undergoing apoptosis, Apoptosis was not associated with elevation in intracellular calcium or alteration in p53 or c-myc protein expression. Expression and Tyr phosphorylation of focal adhesion kinase (FAK) were inhibited in both melanoma cell lines by deprivation of Tyr and Phe but not by deprivation of glutamine or serum. Tyr phosphorylation of FAK in Tyr- and Phe-deprived melanoma cells was enhanced within 30 min of refeeding with complete DMEM. FAK protein expression recovered within 60 min, and cell viability recovered within 24 h. Genistein, a tyrosine kinase inhibitor that specifically inhibits Tyr phosphorylation of FAK, did not induce apoptosis in A375 melanoma cells at a concentration of 50 mu M. Genistein prevented the recovery of cell viability upon refeeding with Tyr and Phe to previously deprived A375 melanoma cells. These data collectively indicate that apoptosis induced by Tyr and Phe deprivation is FAK-dependent. C1 Washington State Univ, Coll Pharm, Dept Pharmaceut Sci, Pharmacol & Toxicol Grad Program, Pullman, WA 99164 USA. Washington State Univ, Canc Prevent & Res Ctr, Pullman, WA 99164 USA. NHLBI, Pathol Branch, Bethesda, MD 20892 USA. RP Meadows, GG (reprint author), Washington State Univ, Coll Pharm, Dept Pharmaceut Sci, Pharmacol & Toxicol Grad Program, Box 646510, Pullman, WA 99164 USA. FU NCI NIH HHS [F31CA70130, R01CA42465] NR 45 TC 25 Z9 25 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 1999 VL 59 IS 3 BP 758 EP 765 PG 8 WC Oncology SC Oncology GA 163EU UT WOS:000078390900042 PM 9973229 ER PT J AU Shao, JY Sheng, HM Aramandla, R Pereira, MA Lubet, RA Hawk, E Grogan, L Kirsch, IR Washington, MK Beauchamp, RD DuBois, RN AF Shao, JY Sheng, HM Aramandla, R Pereira, MA Lubet, RA Hawk, E Grogan, L Kirsch, IR Washington, MK Beauchamp, RD DuBois, RN TI Coordinate regulation of cyclooxygenase-2 and TGF-beta 1 in replication error-positive colon cancer and azoxymethane-induced rat colonic tumors SO CARCINOGENESIS LA English DT Article ID GROWTH-FACTOR-BETA; FAMILIAL ADENOMATOUS POLYPOSIS; INTESTINAL EPITHELIAL-CELLS; NONSTEROIDAL ANTIINFLAMMATORY DRUG; COLORECTAL-CANCER; TGF-BETA; ASPIRIN USE; RECTAL ADENOMAS; REDUCED RISK; EXPRESSION AB Evidence is accumulating which indicates that cyclo-oxygenase-2 (COX-2) is involved in the pathogenesis of colorectal cancer. We evaluated the expression of COX-2 in replication error-positive (RER) colon cancers, colon cancers metastatic to liver and azoxymethane (AOM)induced rat colonic tumors. Immunohistochemistry showed that COX-2 was low to undetectable in normal human mucosa, but abundant in the RER adenocarcinomas we examined. COX-2 immunoreactivity in metastatic colon cancers was less abundant, but clearly detectable. In the colon of AOM-treated rats, COX-2 protein was not detectable in normal mucosa, but present in most of the epithelial cells comprising the tumors. The TGF-beta 1 staining pattern in these human and rat tumors was similar to that observed for COX-2, The role of TGF-beta in RER adenocarcinomas is complex because of the increased mutation rate of TGF-beta type IT receptors, Northern analysis showed abundant TGF-beta 1 mRNA in AOM-induced tumors, but not in paired mucosa, TGF-beta 1 induced the expression of COX-2 mRNA and protein in intestinal epithelial cells (IEC-6), Chronic TGF-beta 1 treatment caused a TGF-beta-dependent overexpression of COX-2 in rat intestinal epithelial cells (RIE-1), TGF-beta 1 may regulate COX-2 expression during the colonic adenoma to carcinoma sequence. C1 Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA. Vanderbilt Univ, Med Ctr, Dept Surg, Nashville, TN 37232 USA. Vanderbilt Univ, Med Ctr, Dept Pathol, Nashville, TN 37232 USA. Vanderbilt Univ, Med Ctr, Dept Cell Biol, Nashville, TN 37232 USA. Vet Affairs Med Ctr, Nashville, TN 37232 USA. Med Coll Ohio, Toledo, OH 43614 USA. NCI, Bethesda, MD 20892 USA. RP DuBois, RN (reprint author), Vanderbilt Univ, Med Ctr, Dept Med GI, MCN C-2104, Nashville, TN 37232 USA. FU NCEH CDC HHS [NIEHS-00267]; NCI NIH HHS [CA-69457]; NIDDK NIH HHS [DK-47297] NR 54 TC 74 Z9 77 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD FEB PY 1999 VL 20 IS 2 BP 185 EP 191 DI 10.1093/carcin/20.2.185 PG 7 WC Oncology SC Oncology GA 164DW UT WOS:000078448100001 PM 10069452 ER PT J AU Zheng, Y Kramer, PM Lubet, RA Steele, VE Kelloff, GJ Pereira, MA AF Zheng, Y Kramer, PM Lubet, RA Steele, VE Kelloff, GJ Pereira, MA TI Effect of retinoids on AOM-induced colon cancer in rats: modulation of cell proliferation, apoptosis and aberrant crypt foci SO CARCINOGENESIS LA English DT Article ID AZOXYMETHANE-INDUCED FOCI; CHEMOPREVENTIVE AGENTS; F344 RATS; PREVENTION; N-(4-HYDROXYPHENYL)RETINAMIDE; DIFFERENTIATION; MODELS; QUANTIFICATION; IDENTIFICATION; INHIBITION AB We have previously reported that the retinoids, 4-(hydroxyphenyl)retinamide (4-HPR) and 9-cis-retinoic acid (RA) prevented azoxymethane (AOM)-induced colon tumors and along with 2-(carboxyphenyl)retinamide (2-CPR) prevented aberrant crypt foci (ACF), In this study, we evaluated the effect of 2-CPR on AOM-induced colon tumors and the effect of the three retinoids on apoptosis and cell proliferation. Male F344 rats were administrated 15 mg/kg AOM at weeks 7 and 8 of age. 2-CPR (315 mg/kg) was administered in the diet starting either 1 week before or at week 12 after the first dose of AOM. The rats continued to receive the 2-CPR until killed at week 46, Unlike the demonstrated prevention of colon cancer by the other two retinoids, both dosing schedules of 2-CPR resulted in an approximate doubling of the yield of colon tumors. In adenomas, 2-CPR, 4-HPR and 9-cis-RA were equally effective in reducing mitotic activity, while only 4-HPR and 9-cis-RA but not 2-CPR enhanced apoptosis, When administered for only the 6 days prior to killing 4-HPR but not 2-CPR decreased the Mitotic Index and increased the Apoptotic Index in adenomas, In non-involved crypts, chronic exposure to 4-HPR and 9-cis-RA in contrast to 2-CPR reduced the Mitotic Index and enhanced the Apoptotic Index. In concurrence with our previous study, both 2-CPR and 4-HPR were very potent in preventing ACF when administered in the diet starting 1 week before the first dose of AOM and continuing for the 5 weeks of the study. Hence, unlike the other two retinoids, 2-CPR, although very potent in preventing ACF, enhanced rather than prevented AOM-induced colon cancer. Furthermore, our results suggest that the effect of 2-CPR on tumor yield is different from 4-HPR and 9-cis-RA because, unlike them, it does not enhance apoptosis. C1 Med Coll Ohio, Dept Pathol, Toledo, OH 43614 USA. NCI, Chemoprevent Branch, Div Canc Chemoprevent & Control, Bethesda, MD 20892 USA. RP Pereira, MA (reprint author), Med Coll Ohio, Dept Pathol, 3055 Arlington Ave, Toledo, OH 43614 USA. FU NCI NIH HHS [N01-CN-55151, N01-CN-55175] NR 41 TC 88 Z9 90 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 FEB PY 1999 VL 20 IS 2 BP 255 EP 260 DI 10.1093/carcin/20.2.255 PG 6 WC Oncology SC Oncology GA 164DW UT WOS:000078448100011 PM 10069462 ER PT J AU Lantry, LE Zhang, ZQ Crist, KA Wang, Y Kelloff, GJ Lubet, RA You, M AF Lantry, LE Zhang, ZQ Crist, KA Wang, Y Kelloff, GJ Lubet, RA You, M TI 5-aza-2 '-deoxycytidine is chemopreventive in a 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone-induced primary mouse lung tumor model SO CARCINOGENESIS LA English DT Article ID DNA-METHYLTRANSFERASE; SUPPRESSOR GENE; COLON CANCER; METHYLATION; CELLS; HYPERMETHYLATION; EXPRESSION; INACTIVATION; PROGRESSION; NEOPLASIA AB Carcinogenesis is a multistep process in which many alterations in both genetic and epigenetic controls lead to a growth advantage for neoplastic cells. Hypermethylation has been established as the basis of genomic imprinting, but recent studies have also shown that alterations in genomic methylation patterns may contribute to tumorigenesis. The chemical 5-aza-2'-deoxycytidine (5-aza-dC) has been used both in vitro and in vivo to inhibit DNA methylation, In this study, we investigated the chemopreventive efficacy of 5-aza-dC in a well-established primary mouse lung tumor model, Five-week-old male (C3H/HeJ x A/J) F-1 hybrid mice were treated for 24 consecutive weeks with 5-aza-dC, three times per week i.p. Lung tumors were induced with two consecutive weekly doses of 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone starting 1 week after initial treatment with 5-aza-dC, We demonstrated that 5-aza-dC exhibits a chemopreventive effect in this primary mouse lung tumor model which, like human lung adenocarcinomas, harbors an activating K-rns mutation. Treatment with 5-aza-dC resulted in a 23% reduction in tumor incidence, as well as a 42% reduction in tumor multiplicity. This work supports further investigation of methylation inhibitors likes 5-aza-dC for early intervention, prevention and treatment of lung cancer. C1 Med Coll Ohio, Dept Pathol, Toledo, OH 43614 USA. Med Coll Ohio, Dept Surg, Toledo, OH 43614 USA. NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. RP You, M (reprint author), Med Coll Ohio, Dept Pathol, Hlth Educ Bldg,Room 202, Toledo, OH 43614 USA. EM myou@mco.edu FU NCI NIH HHS [CN55184, CA58554] NR 35 TC 49 Z9 54 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD FEB PY 1999 VL 20 IS 2 BP 343 EP 346 DI 10.1093/carcin/20.2.343 PG 4 WC Oncology SC Oncology GA 164DW UT WOS:000078448100024 PM 10069475 ER PT J AU Kubbutat, MHG Ludwig, RL Levine, AJ Vousden, KH AF Kubbutat, MHG Ludwig, RL Levine, AJ Vousden, KH TI Analysis of the degradation function of Mdm2 SO CELL GROWTH & DIFFERENTIATION LA English DT Article ID TRANSCRIPTION FACTORS E2F-1; ONCOPROTEIN MDM2; P53; PROTEIN; DOMAIN; E6; HETERODIMERIZATION; TRANSACTIVATION; EXPRESSION; SUPPRESSOR AB Degradation of the p53 tumor suppressor protein has been shown to be regulated by Mdm2. In this study, we identify regions of Mdm2 that are not required for p53 binding but are essential for degradation. Mdm2 mutants lacking these regions function in a dominant negative fashion, stabilizing endogenous p53 in cells by interfering with the degradative function of the endogenous Mdm2, p53 protein stabilized in this way does not strongly enhance the expression of p21(Waf1/Cip1) th, product of a p53-responsive gene, supporting the model in which binding of Mdma to the NH2-terminal domain of p53 inhibits interaction with other components of the basal transcriptional machinery. Interestingly, COOH-terminal truncations of Mdm2 that retain p53 binding but fail to mediate its degradation are also stabilized themselves. Because Mdm2, like p53, is normally an unstable protein that is degraded through the proteasome, this result suggests a direct link between the regulation of Mdm2 and p53 stability. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA. RP Vousden, KH (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Bldg 560,Room 22-96,W 7th St, Frederick, MD 21702 USA. EM vousden@ncifcrf.gov NR 37 TC 86 Z9 87 U1 0 U2 1 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 FEB PY 1999 VL 10 IS 2 BP 87 EP 92 PG 6 WC Cell Biology SC Cell Biology GA 168HA UT WOS:000078685100002 PM 10074902 ER PT J AU Ronen, D Altstock, RT Firon, M Mittelman, L Sobe, T Resau, JH Woude, GFV Tsarfaty, I AF Ronen, D Altstock, RT Firon, M Mittelman, L Sobe, T Resau, JH Woude, GFV Tsarfaty, I TI Met-HGF/SF mediates growth arrest and differentiation in T47D breast cancer cells SO CELL GROWTH & DIFFERENTIATION LA English DT Article ID FACTOR SCATTER FACTOR; MAMMARY EPITHELIAL-CELLS; FACTOR AUTOCRINE LOOP; C-MET; PROTOONCOGENE PRODUCT; RECEPTOR EXPRESSION; LIPID-ACCUMULATION; HEPATOPOIETIN-A; MELANOMA-CELLS; DNA-SYNTHESIS AB Hepatocyte growth factor/scatter factor (HGF/SF) is a pluripotent growth factor that exerts mitogenic, motogenic, and morphogenic effects. To elucidate the cellular mechanisms underlying the pluripotent function of this growth factor, T47D human breast cancer cells were transfected with human hgf/sf. The hgf/sf-positive clones exhibited different levels of biologically functional HGF/SF expression and up-regulation of endogenous Met (HGF/SF receptor) expression. In addition, a constitutive phosphorylation of the receptor on tyrosine residues was detected, establishing a Met-HGF/SF autocrine loop. The autocrine activation of Met caused marked inhibition in cell growth accompanied by cell accumulation at G(0)/G(1). These cells underwent terminal cell differentiation as determined by morphological changes, synthesis of milk proteins such as beta-casein and alpha-lactalbumin, and production of lipid vesicles. Our results demonstrate that Met-HGF/SF, an oncogenic signal transduction pathway, is capable of inducing growth arrest and differentiation in certain breast cancer cells and, thus, may have potential as therapeutic and/or prognostic tools in breast cancer treatment. C1 Tel Aviv Univ, Sackler Sch Med, Dept Human Microbiol, IL-69978 Ramat Aviv, Israel. Tel Aviv Univ, Sackler Sch Med, Interdepartmental Core Facil, IL-69978 Tel Aviv, Israel. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. RP Tsarfaty, I (reprint author), Tel Aviv Univ, Sackler Sch Med, Dept Human Microbiol, IL-69978 Ramat Aviv, Israel. EM ilants@post.tau.ac.il NR 70 TC 25 Z9 27 U1 0 U2 0 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 FEB PY 1999 VL 10 IS 2 BP 131 EP 140 PG 10 WC Cell Biology SC Cell Biology GA 168HA UT WOS:000078685100006 PM 10074906 ER PT J AU Lee, CK Kim, K Geiman, TM Murphy, WJ Muegge, K Durum, SK AF Lee, CK Kim, K Geiman, TM Murphy, WJ Muegge, K Durum, SK TI Cloning thymic precursor cells: Demonstration that individual pro-T1 cells have dual T-NK potential and individual pro-T2 cells have dual alpha beta-gamma delta T cell potential SO CELLULAR IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; LINEAGE COMMITMENT; PROGENITOR CELLS; COMMON PRECURSOR; DENDRITIC CELLS; THYMOCYTES; RECEPTOR; DIFFERENTIATION; IDENTIFICATION; REARRANGEMENT AB Thymic progenitors have the capacity to generate alpha beta T cells, gamma delta T cells, and NK cells. To determine whether these three lineages derive from a single precursor cell or from different precursors, a procedure was developed for cloning precursor cells from mouse embryonic thymus. The progeny of each pro-T cell clone were then tested for the potential to generate alpha beta, gamma delta, and NK cells. Of these precursor clones, about half displayed dual potential, developing into either T cells or NK cells, demonstrating the existence of a common T/NK precursor cell in the thymus. The other half of the clones were restricted to T cell development. No precursor clones were restricted to NK development. The common T/NK precursors were shown to be of the pro-T1 (CD25(-)) stage whereas the T-restricted precursors were shown to be of the later pro-TS (CD25(+)) stage. Both alpha beta and gamma delta T cells were generated from all clones derived from either pro-T1 or -T2 precursors. This shows that commitment of a cell to the (YP versus gamma delta lineages does not precede rearrangement of the TCR genes (which occurs immediately after the pro-T2 stage). (C) 1999 Academic Press. C1 NCI, Immunoregulat Lab, Div Basic Sci, Frederick, MD 21702 USA. NCI, SAIC, Frederick, MD 21702 USA. RP Lee, CK (reprint author), NCI, Immunoregulat Lab, Div Basic Sci, Frederick, MD 21702 USA. NR 28 TC 5 Z9 5 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0008-8749 J9 CELL IMMUNOL JI Cell. Immunol. PD FEB 1 PY 1999 VL 191 IS 2 BP 139 EP 144 DI 10.1006/cimm.1998.1423 PG 6 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 168GZ UT WOS:000078685000008 PM 9973536 ER PT J AU Shen, SJ Marchick, MR Davis, MR Doss, GA Pohl, LR AF Shen, SJ Marchick, MR Davis, MR Doss, GA Pohl, LR TI Metabolic activation of diclofenac by human cytochrome P450 3A4: Role of 5-hydroxydiclofenac SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; HUMAN-LIVER CYTOCHROME-P-450; CULTURED RAT HEPATOCYTES; PROTEIN ADDUCTS; BENZOQUINONE IMINE; INDUCED HEPATITIS; COVALENT BINDING; CELL INJURY; HEPATOTOXICITY; ACID AB Cytochrome P450 2C11 in rats was recently found to metabolize diclofenac into a highly reactive product that covalently bound to this enzyme before it could diffuse away and react with other proteins. To determine whether cytochromes P450 in human liver could catalyze a similar reaction, we have studied the covalent binding of diclofenac in vitro to liver microsomes of 16 individuals. Only three of 16 samples were found by immunoblot analysis to activate diclofenac appreciably to form protein adducts in a NADPH-dependent pathway. Cytochrome P450 2C9, which catalyzes the major route of oxidative metabolism of diclofenac to produce 4'-hydroxydiclofenac, did not appear to be responsible for the formation of the protein adducts, because sulfaphenazole, an inhibitor of this enzyme, did not affect protein adduct formation. In contrast, troleandomycin, an inhibitor of P450 3A4, inhibited both protein adduct formation and Ei-hydroxylation of diclofenac. These findings were confirmed with the use of baculovirus-expressed human P450 2C9 and P450 3A4. One possible reactive intermediate that would be expected to bind covalently to liver proteins was the p-benzoquinone imine derivative of 5-hydroxydiclofenac. This product was formed by an apparent metal-catalyzed oxidation of 5-hydroxydiclofenac that was inhibited by EDTA, glutathione, and NADPH. The p-benzoquinone imine decomposition product bound covalently to human liver microsomes in vitro in a reaction that was inhibited by GSH. In contrast, GSH did not prevent the covalent binding of diclofenac to human liver microsomes. These results suggest that for appreciable P450-mediated bioactivation of diclofenac to occur in vivo, an individual may have to have both high activities of P450 3A4 and perhaps low activities of other enzymes that catalyze competing pathways of metabolism of diclofenac. Moreover, the p-benzoquinone imine derivative of 5-hydroxydiclofenac probably has a role in covalent binding in the liver only under the conditions where levels of NADPH, GSH, and other reducing agents would be expected to be low. C1 NIH, NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, Bethesda, MD 20892 USA. Merck Res Labs, Dept Drug Metab, W Point, PA 19486 USA. Merck Res Labs, Dept Drug Metab, Rahway, NJ 07065 USA. RP Pohl, LR (reprint author), NIH, NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, Bldg 10,Room 8N110, Bethesda, MD 20892 USA. EM pohll@gwgate.nhlbi.nih.gov NR 49 TC 132 Z9 135 U1 0 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD FEB PY 1999 VL 12 IS 2 BP 214 EP 222 DI 10.1021/tx9802365 PG 9 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 168GW UT WOS:000078684300015 PM 10027801 ER PT J AU Lu, Y Xin, KQ Hamajima, K Tsuji, T Aoki, I Yang, J Sasaki, S Fukushima, J Yoshimura, T Toda, S Okada, E Okuda, K AF Lu, Y Xin, KQ Hamajima, K Tsuji, T Aoki, I Yang, J Sasaki, S Fukushima, J Yoshimura, T Toda, S Okada, E Okuda, K TI Macrophage inflammatory protein-1 alpha (MIP-1 alpha) expression plasmid enhances DNA vaccine-induced immune response against HIV-1 SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE DNA vaccine; HIV-1; MIP-1 alpha; CTL ID IMMUNODEFICIENCY-VIRUS TYPE-1; CELL-MEDIATED-IMMUNITY; DIRECT GENE-TRANSFER; INTRANASAL IMMUNIZATION; CC-CHEMOKINES; CPG MOTIFS; T-CELLS; INFECTION; INOCULATION; MIP-1-BETA AB CD8(+) cell-secreted CC-chemokines, MIP-1 alpha, and MIP-beta have recently been identified as factors which suppress HIV. In this study we co-inoculated MIP-1 alpha expression plasmid with a DNA vaccine constructed from HIV-1 pCMV160IIIB and pcREV, and evaluated the effect of the adjuvant on HIV-specific immune responses following intramuscular and intranasal immunization. The levels of both cytotoxic T lymphocyte (CTL) activity and DTH showed that HIV-specific cell-mediated immunity (CMI) was significantly enhanced by co-inoculation of the MIP-1 alpha expression plasmid with the DNA vaccine compared with inoculation of the DNA vaccine alone. The HIV-specific serum IgG1/IgG2a ratio was significantly lowered when the plasmid was co-inoculated in both intramuscular and intranasal routes, suggesting a strong elicitation of the T helper (Th) 1-type response. When the MIP-1 alpha expression plasmid was inoculated intramuscularly with the DNA vaccine, an infiltration of mononuclear cells was observed at the injection site. After intranasal administration, the level of mucosal secretory IgA antibody was markedly enhanced. These findings demonstrate that MIP-1 alpha expression plasmid inoculated together with DNA vaccine acts as a strong adjuvant for eliciting Th1-derived immunity. C1 Yokohama City Univ, Sch Med, Dept Bacteriol, Kanazawa Ku, Yokohama, Kanagawa 2360004, Japan. Yokohama City Univ, Sch Med, Dept Paediat, Kanazawa Ku, Yokohama, Kanagawa 2360004, Japan. Yokohama City Univ, Sch Med, Dept Internal Med, Kanazawa Ku, Yokohama, Kanagawa 2360004, Japan. Yokohama City Univ, Sch Med, Dept Pathol, Kanazawa Ku, Yokohama, Kanagawa 2360004, Japan. NCI, Immunopathol Sect, Immunobiol Lab, FCRDC, Frederick, MD 21701 USA. RP Okuda, K (reprint author), Yokohama City Univ, Sch Med, Dept Bacteriol, Kanazawa Ku, 3-9 Fukuura, Yokohama, Kanagawa 2360004, Japan. NR 39 TC 50 Z9 62 U1 0 U2 1 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 FEB PY 1999 VL 115 IS 2 BP 335 EP 341 DI 10.1046/j.1365-2249.1999.00793.x PG 7 WC Immunology SC Immunology GA 202DH UT WOS:000080636500017 PM 9933462 ER PT J AU Widemann, BC Balis, FM Adamson, PC AF Widemann, BC Balis, FM Adamson, PC TI Dihydrofolate reductase enzyme inhibition assay for plasma methotrexate determination using a 96-well microplate reader SO CLINICAL CHEMISTRY LA English DT Article ID HIGH-DOSE METHOTREXATE; FLUORESCENCE POLARIZATION IMMUNOASSAY; LIQUID-CHROMATOGRAPHY; CEREBROSPINAL-FLUID; LEUCOVORIN RESCUE; CARBOXYPEPTIDASE-G(2); 7-HYDROXYMETHOTREXATE; PHARMACOKINETICS; SERUM; RADIOIMMUNOASSAY AB Microplate reader assays offer several advantages over conventional spectrophotometric assays. We adapted the dihydrofolate reductase (DHFR) enzyme inhibition assay for use in a 96-well microplate reader to measure plasma methotrexate (MTX) concentrations. The assay is linear from 0.01 to 0.1 mu mol/L. The within-run CVs at 0.03 mu mol/L and 0.08 mu mol/L MTX were 4.0% and 2.7%, respectively, and the interday (total) CVs were 7.6% and 1.8%. Cross-reactivity with the inactive MTX metabolite 2,4-diamino-N-10-methylpteroic acid (DAMPA) was 3.9%, significantly less than that described with commercial immunoassays; with 7-hydroxymethotrexate cross-reactivity was 1.7%. In addition to sensitivity and specificity, the advantages of this assay are small sample volumes, simultaneous analysis of multiple samples, and rapid turnaround. Because of its greater specificity, the DHFR enzyme inhibition assay may be useful when DAMPA is present in plasma samples and HPLC is not available. C1 NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Widemann, BC (reprint author), NCI, Pediat Oncol Branch, NIH, Bldg 10,Rm 13N240,10 Ctr Dr, Bethesda, MD 20892 USA. NR 30 TC 32 Z9 32 U1 0 U2 6 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 FEB PY 1999 VL 45 IS 2 BP 223 EP 228 PG 6 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 165AR UT WOS:000078496700010 PM 9931044 ER PT J AU Shrayer, DP Cole, B Hearing, VJ Wolf, SF Wanebo, HJ AF Shrayer, DP Cole, B Hearing, VJ Wolf, SF Wanebo, HJ TI Immunotherapy of mice with an irradiated melanoma vaccine coupled with interleukin-12 SO CLINICAL & EXPERIMENTAL METASTASIS LA English DT Article DE IL-12; irradiated melanoma vaccine; lymphokines; melanoma; metastasis ID FORMALINIZED EXTRACELLULAR ANTIGENS; NATURAL-KILLER-CELLS; MURINE MELANOMA; ANTITUMOR IMMUNITY; TUMOR-CELLS; METASTATIC MELANOMA; PROTECTIVE IMMUNITY; CYTOKINE PRODUCTION; GAMMA PRODUCTION; IFN-GAMMA AB Interleukin (IL)-12 can activate cytotoxic lymphocytes, stimulate natural killer cell activity, induce the production of INF-gamma and inhibit the development of various experimental tumors. We previously demonstrated that immunotherapy of melanoma bearing mice with an irradiated melanoma vaccine (IMV) coupled with IL-2 or GM-CSF had beneficial effects against primary melanoma growth and against subsequent spontaneous metastasis. We also had found that treatment of melanoma bearing mice with IL-12 (300 ng/day) for 4 weeks inhibited the development of primary melanoma tumors in 40% of mice. The purpose of this study was to investigate the efficacy of combined therapy of experimental melanoma with an IMV prepared from B16F10 melanoma cells coupled with IL-12 treatment. C57BL/6 mice were challenged subcutaneously in the tail with B16F10 melanoma cells and by the 45th day, more than 50% of the mice had developed visible primary melanoma tumors at the injection site. Subsequent immunotherapy of mice with IMV, when coupled with IL-12, provided partial inhibition of primary melanoma tumor growth. Optimal results against primary tumor growth were observed when IMV therapy was coupled with IL-12 at a dose of 50 ng/day. Combination of IMV with IL-12 at a dose of 100 ng/day significantly reduced melanoma metastasis to the lungs compared with control mice, and an improvement in mean survival time was observed in mice treated with a combination of IMV with IL-12 (300 ng/day). C1 Brown Univ, Dept Surg, Providence, RI 02912 USA. Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Genet Inst Inc, Cambridge, MA USA. RP Shrayer, DP (reprint author), Roger Williams Med Ctr, Dept Surg, 825 Chalkstone Ave, Providence, RI 02908 USA. NR 48 TC 6 Z9 6 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0262-0898 J9 CLIN EXP METASTAS JI Clin. Exp. Metastasis PD FEB PY 1999 VL 17 IS 1 BP 63 EP 70 PG 8 WC Oncology SC Oncology GA 203TQ UT WOS:000080723300009 PM 10390149 ER PT J AU Longo, DL Duffey, PL Kopp, WC Heyes, MP Alvord, WG Sharfman, WH Schmidt, PJ Rubinow, DR Rosenstein, DL AF Longo, DL Duffey, PL Kopp, WC Heyes, MP Alvord, WG Sharfman, WH Schmidt, PJ Rubinow, DR Rosenstein, DL TI Conditioned immune response to interferon-gamma in humans SO CLINICAL IMMUNOLOGY LA English DT Article ID CEREBROSPINAL-FLUID; QUINOLINIC ACID; BLOOD; CELLS; IMMUNOSUPPRESSION; IMMUNOMODULATION; METABOLISM; RELEASE; PLASMA; SERUM AB We determined whether a classical conditioning paradigm may be used to condition immunologic responses in normal human subjects receiving an optimal immunostimulating dose of recombinant human interferon-gamma (rhIFN-gamma). We conducted a placebo-controlled, double-blind study of 31 normal volunteers in order to determine whether an initially immune-neutral stimulus, oral propylene glycol (PG), could eventually elicit an immune response as a consequence of its being paired with a known immunostimulatory dose and schedule of rhIFN-gamma. Subjects were randomly assigned to one of three groups: (A) rhIFN-gamma injections paired with PG; (B) normal saline injections paired with PG; (C) rhIFN-gamma injections alone. During the 4-week study, subjects received progressively fewer injections so that, by the final week of the study, no injections were given and groups A and B received only PG. The principal outcome measures were serum concentrations of quinolinic acid (QUIN) and neopterin, two nonspecific but sensitive markers of immune activation, and expression of Fc receptors (CD64) on peripheral blood mononuclear cells. RhIFN-gamma injections produced significant and predictable alterations in each of the measured immune parameters. No group B subject made an immune response. Mean serum QUIN levels were significantly higher at the end of week three for subjects in the experimental condition (group A) than for subjects receiving rhIFN-gamma alone (group %) despite receiving identical doses of rhIFN-gamma. Similarly, the predicted decay in mean serum neopterin levels from the end of week 1 to the end of week 2 was seen in group C but not in group A. The exposure of group A to PG blunted the decline of CD64 expression in week four. The data suggest that the pairing of an unconditioned stimulus (rhIFN-gamma) and a conditioned stimulus (PG) permits the conditioned stimulus alone to prolong a cytokine-induced response in normal humans. C1 NCI, Frederick Canc Res & Dev Ctr, Biol Response Modifiers Program, Frederick, MD USA. SAIC, Clin Serv Program, Frederick, MD USA. NCI, Frederick Canc Res & Dev Ctr, Data Management Serv Inc, Frederick, MD USA. NIMH, Sect Behav Endocrinol, Biol Psychiat Branch, Bethesda, MD 20892 USA. NIMH, Analyt Biochem Sect, Clin Sci Lab, Bethesda, MD 20892 USA. RP Longo, DL (reprint author), NIA, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 41 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD FEB PY 1999 VL 90 IS 2 BP 173 EP 181 DI 10.1006/clim.1998.4637 PG 9 WC Immunology SC Immunology GA 176WW UT WOS:000079175900004 PM 10080828 ER PT J AU Engels, EA Ellis, CA Supran, SE Schmid, CH Barza, M Schenkein, DP Koc, Y Miller, KB Wong, JB AF Engels, EA Ellis, CA Supran, SE Schmid, CH Barza, M Schenkein, DP Koc, Y Miller, KB Wong, JB TI Early infection in bone marrow transplantation: Quantitative study of clinical factors that affect risk SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID STEM-CELL TRANSPLANTATION; COLONY-STIMULATING FACTOR; RESISTANT ESCHERICHIA-COLI; ACUTE MYELOID-LEUKEMIA; BACTERIAL-INFECTIONS; NEUTROPENIC PATIENTS; RANDOMIZED TRIAL; ORAL NORFLOXACIN; HODGKINS-DISEASE; DOUBLE-BLIND AB Infections remain common life-threatening complications of bone marrow transplantation. To examine clinical factors that affect infection risk, we retrospectively studied patients who received bone marrow transplants (53 autologous and 51 allogeneic). Over a median of 27 hospital days, 44 patients developed documented infections. Both autologous transplantation and hematopoietic growth factor use were associated with less prolonged neutropenia and decreased occurrence of infection (P less than or equal to .05). In a survival regression model, variables independently associated with infection risk were the log(10) of the neutrophil count (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.32-0.75), ciprofloxacin prophylaxis (HR, 0.42; 95% CI, 0.19-0.95), empirical intravenous antibiotic use (HR, 0.09; 95% CI, 0.03-0.32), and an interaction between neutrophil count and intravenous antibiotic use (HR, 1.86; 95% CI, 1.06-3.29). In this model, infection risk increases steeply at low neutrophil counts for patients receiving no antibiotic therapy. Ciprofloxacin prophylaxis and particularly intravenous antibiotic therapy provide substantial protection at low neutrophil counts. These results can be used to model management strategies for transplant recipients. C1 Tufts Univ, Sch Med, New England Med Ctr, Div Clin Care Res, Boston, MA 02111 USA. Tufts Univ, Sch Med, New England Med Ctr, Div Clin Decis Making, Boston, MA 02111 USA. Tufts Univ, Sch Med, New England Med Ctr, Div Hematol Oncol, Boston, MA 02111 USA. Tufts Univ, Sch Med, New England Med Ctr, Dept Med,Div Geog Med & Infect Dis, Boston, MA 02111 USA. Tufts Univ, Sch Med, New England Med Ctr, Tupper Inst, Boston, MA 02111 USA. RP Engels, EA (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, 6130 Execut Blvd,EPN 434, Rockville, MD 20822 USA. EM engelse@exchange.nih.gov RI KOC, YENER/L-9529-2015; OI KOC, YENER/0000-0002-3919-9649; Schmid, Christopher/0000-0002-0855-5313 FU AHRQ HHS [T32 HS0006] NR 50 TC 62 Z9 67 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 FEB PY 1999 VL 28 IS 2 BP 256 EP 266 DI 10.1086/515103 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 167DH UT WOS:000078617000021 PM 10064241 ER PT J AU Saag, MS Cloud, GA Graybill, JR Sobel, JD Tuazon, CU Johnson, PC Fessel, WJ Moskovitz, BL Wiesinger, B Cosmatos, D Riser, L Thomas, C Hafner, R Dismukes, WE AF Saag, MS Cloud, GA Graybill, JR Sobel, JD Tuazon, CU Johnson, PC Fessel, WJ Moskovitz, BL Wiesinger, B Cosmatos, D Riser, L Thomas, C Hafner, R Dismukes, WE CA Natl Inst Allergy Infect Dis Mycoses Study Grp TI A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis SO CLINICAL INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT International Conference on Acute Respiratory Infections CY JUL 07-10, 1997 CL CANBERRA, AUSTRALIA SP SmithKline Beecham, Commonwealth Serum Labs, Cochrane Collaborat Review Grp Acute Resp Infect, Natl Ctr Epidemiol & Populat Hlth Australian Natl Univ ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; AMPHOTERICIN-B; CONTROLLED TRIAL AB This study was designed to compare the effectiveness of fluconazole vs. itraconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. HIV-infected patients who had been successfully treated (achieved negative culture of CSF) for a first episode of cryptococcal meningitis were randomized to receive fluconazole or itraconazole, both at 200 mg/d, for 12 months. The study was stopped prematurely on the recommendation of an independent Data Safety and Monitoring Board. At the time, 13 (23%) of 57 itraconazole recipients had experienced culture-positive relapse, compared with 2 relapses (4%) noted among 51 fluconazole recipients (P = .006). The factor best associated with relapse was the patient having not received flucytosine during the initial 2 weeks of primary treatment for cryptococcal disease (relative risk = 5.88; 95% confidence interval, 1.27-27.14; P = .04), Fluconazole remains the treatment of choice for maintenance therapy for AIDS-associated cryptococcal disease. Flucytosine may contribute to the prevention of relapse if used during the first 2 weeks of primary therapy. C1 Univ Alabama, Sch Med, Dept Med, Div Infect Dis,Clin 1917, Birmingham, AL 35294 USA. Univ Alabama, Sch Med, Ctr Comprehens Canc, Biostat Unit, Birmingham, AL USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Wayne State Univ, Div Infect Dis, Detroit, MI USA. George Washington Univ, Dept Med, Washington, DC USA. Univ Texas, Dept Med, San Antonio, TX 78285 USA. Permanente Med Grp, Oakland, CA USA. Janssen Res Fdn, Titusville, NJ USA. NIAID, Bethesda, MD 20892 USA. RP Saag, MS (reprint author), Univ Alabama, Sch Med, Dept Med, Div Infect Dis,Clin 1917, Community Care Bldg,Room 178,908 20th St S, Birmingham, AL 35294 USA. FU NIAID NIH HHS [AI-15082, AI-65296] NR 19 TC 120 Z9 130 U1 0 U2 3 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 FEB PY 1999 VL 28 IS 2 BP 291 EP 296 DI 10.1086/515110 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 167DH UT WOS:000078617000026 PM 10064246 ER PT J AU Gordon, SM Brahim, JS Kent, AA Dionne, RA AF Gordon, SM Brahim, JS Kent, AA Dionne, RA TI Quantifying analgesic onset in the oral surgery model. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 NIDR, NIH, 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 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 1999 VL 65 IS 2 MA PI9 BP 119 EP 119 DI 10.1016/S0009-9236(99)80009-5 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 169KR UT WOS:000078747600010 ER PT J AU Gotschall, RR Marcucci, K Leeder, JS Kearns, GL AF Gotschall, RR Marcucci, K Leeder, JS Kearns, GL TI Cisapride (CIS) biotransformation: Not all CYP3AS are created equal. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 Univ Missouri, Dept Pediat, Kansas City, MO 64110 USA. Univ Missouri, Dept Pharmacol, Kansas City, MO 64110 USA. Childrens Mercy Hosp, Sect Pediat Clin Pharmacol, Kansas City, MO 64108 USA. NICHD PPRU Network, Bethesda, MD USA. NR 0 TC 7 Z9 7 U1 0 U2 0 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 1999 VL 65 IS 2 MA PI39 BP 127 EP 127 DI 10.1016/S0009-9236(99)80039-3 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 169KR UT WOS:000078747600040 ER PT J AU Gaedigk, A Gotschall, RR Forbes, NS Simon, SD Leeder, JS AF Gaedigk, A Gotschall, RR Forbes, NS Simon, SD Leeder, JS TI Accuracy of cytochrome P4502D6 (CYP2D6): Phenotype assignment from genotyping data. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 Childrens Mercy Hosp, Sect Clin Pharmacol & Exp Ther, Kansas City, MO 64108 USA. Childrens Mercy Hosp, NICHD PPRU, Kansas City, MO 64108 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 1999 VL 65 IS 2 MA PI88 BP 139 EP 139 DI 10.1016/S0009-9236(99)80088-5 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 169KR UT WOS:000078747600089 ER PT J AU Gillespie, WR Khoo, KC AF Gillespie, WR Khoo, KC CA PPRU Network TI Population pharmacokinetics in pediatric patients using Bayesian approaches with informative prior distributions based on adults. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 GloboMax LLC, Hanover, MD USA. Roche Labs Inc, Nutley, NJ USA. NICHD, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 1999 VL 65 IS 2 MA PI93 BP 140 EP 140 DI 10.1016/S0009-9236(99)80093-9 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 169KR UT WOS:000078747600094 ER PT J AU Kearns, GL Bradley, JS Abdel-Rahman, S Jacobs, RF AF Kearns, GL Bradley, JS Abdel-Rahman, S Jacobs, RF CA PPRU Network TI Pharmacokinetics (PK) of pleconaril (PLEC) in neonates. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 Childrens Mercy Hosp, Kansas City, MO 64108 USA. Childrens Hosp, San Diego, CA USA. Arkansas Childrens Hosp, Little Rock, AR 72202 USA. NICHD, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 1999 VL 65 IS 2 MA PI91 BP 140 EP 140 DI 10.1016/S0009-9236(99)80091-5 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 169KR UT WOS:000078747600092 ER PT J AU Marcucci, K Gotschall, R Kearns, GL Leeder, JS AF Marcucci, K Gotschall, R Kearns, GL Leeder, JS TI In vitro inhibition of CYP2D6 activity by fenfluramine. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 Childrens Mercy Hosp, Sect Clin Pharmacol & Exp Ther, Kansas City, MO 64108 USA. Childrens Mercy Hosp, NICHD, PPRU, Kansas City, MO 64108 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 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 1999 VL 65 IS 2 MA PI99 BP 142 EP 142 DI 10.1016/S0009-9236(99)80099-X PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 169KR UT WOS:000078747600100 ER PT J AU Preston, KL Huestis, MA Wong, CJ Cone, EJ AF Preston, KL Huestis, MA Wong, CJ Cone, EJ TI Urine and sweat monitoring of illicit opiate use. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 NIDA, Intramural Res Program, Baltimore, MD USA. RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 1999 VL 65 IS 2 MA PII24 BP 153 EP 153 DI 10.1016/S0009-9236(99)80142-8 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 169KR UT WOS:000078747600143 ER PT J AU Davit, B Cherstniakova, S Mojsiak, J Cantilena, L AF Davit, B Cherstniakova, S Mojsiak, J Cantilena, L TI In vitro inhibition of LAAM metabolism by HIV protease inhibitors. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 US FDA, CDER, Rockville, MD 20857 USA. USUHS, Div Clin Pharmacol, Bethesda, MD USA. NIDA, NIH, Rockville, MD 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 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 1999 VL 65 IS 2 MA PII31 BP 154 EP 154 DI 10.1016/S0009-9236(99)80149-0 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 169KR UT WOS:000078747600150 ER PT J AU DePetrillo, PB White, KV Liu, M Hommer, D Goldman, D AF DePetrillo, PB White, KV Liu, M Hommer, D Goldman, D TI Alcohol consumption is associated with decreased cardiac signal complexity. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 NIAAA, DICBR, Clin Studies Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 1999 VL 65 IS 2 MA PII46 BP 158 EP 158 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 169KR UT WOS:000078747600165 ER PT J AU DePetrillo, PB Ruttimann, U AF DePetrillo, PB Ruttimann, U TI Method for determining the Hurst exponent of a fractal time series and its applications to EKG signal analysis. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 NIAAA, DICBR, Clin Studies Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 1999 VL 65 IS 2 MA PII45 BP 158 EP 158 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 169KR UT WOS:000078747600164 ER PT J AU Shoaf, SE Wan, J White, R George, DT AF Shoaf, SE Wan, J White, R George, DT TI Pharmacokinetic modeling of alcohol following IV infusion to men and women. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 NIAAA, DICBR, Clin Studies Lab, 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 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 1999 VL 65 IS 2 MA PII87 BP 168 EP 168 DI 10.1016/S0009-9236(99)80205-7 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 169KR UT WOS:000078747600206 ER PT J AU Forbes, NS Bradford, LD Gotschall, RR Leeder, JS Gaedigk, A AF Forbes, NS Bradford, LD Gotschall, RR Leeder, JS Gaedigk, A TI CYP2D6 allele frequencies in African Americans: Phenotype concordance with dextromethorphan (DM). SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 Childrens Mercy Hosp, Sect Clin Pharmacol & Exp Ther, Kansas City, MO 64108 USA. Childrens Mercy Hosp, NICHD, PPRU, Kansas City, MO 64108 USA. Morehouse Sch Med, Atlanta, GA 30310 USA. NR 0 TC 2 Z9 2 U1 2 U2 2 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 1999 VL 65 IS 2 MA PII94 BP 170 EP 170 DI 10.1016/S0009-9236(99)80212-4 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 169KR UT WOS:000078747600213 ER PT J AU Leeder, JS Gaedigk, A Gotschall, R Van den Anker, J Kearns, GL AF Leeder, JS Gaedigk, A Gotschall, R Van den Anker, J Kearns, GL TI Acquisition of functional CYP2D6 activity in the first year of life. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 Sofia Childrens Hosp, Rotterdam, Netherlands. Childrens Mercy Hosp, NICHD, PPRU, Kansas City, MO 64108 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 1999 VL 65 IS 2 MA OIIB2 BP 176 EP 176 DI 10.1016/S0009-9236(99)80235-5 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 169KR UT WOS:000078747600236 ER PT J AU Lewing, K Gaedigk, A Woods, G Gamis, A Watanabe, M Rothberg, P Kearns, G Leeder, JS AF Lewing, K Gaedigk, A Woods, G Gamis, A Watanabe, M Rothberg, P Kearns, G Leeder, JS TI Tolerance of thiopurine therapy in patients with intermediate thiopurine S-methyl transferase (TPMT) activity. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 Childrens Mercy Hosp, Hematol Oncol Sect, Kansas City, MO 64108 USA. Childrens Mercy Hosp, Clin Pharmacol Sect, Kansas City, MO 64108 USA. Childrens Mercy Hosp, NICHD, PPRU, Kansas City, MO 64108 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 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 1999 VL 65 IS 2 MA OIIB4 BP 176 EP 176 DI 10.1016/S0009-9236(99)80237-9 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 169KR UT WOS:000078747600238 ER PT J AU Leeder, JS Gaedigk, A Gupta, G Simon, S Henne, K Allen, K Rettie, A AF Leeder, JS Gaedigk, A Gupta, G Simon, S Henne, K Allen, K Rettie, A TI Determinants of warfarin S : R ratio in orthopedic surgery (OS) patients. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 Univ Missouri, Dept Pediat, Kansas City, MO 64110 USA. Univ Missouri, Dept Pharmacol, Kansas City, MO 64110 USA. Childrens Mercy Hosp, NICHD, PPRU, Kansas City, MO 64108 USA. NR 0 TC 7 Z9 7 U1 0 U2 0 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 1999 VL 65 IS 2 MA PIII72 BP 194 EP 194 DI 10.1016/S0009-9236(99)80306-3 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 169KR UT WOS:000078747600307 ER PT J AU Rudek, MA Dyer, V Hamilton, JM Pluda, JM Reed, E Figg, WD AF Rudek, MA Dyer, V Hamilton, JM Pluda, JM Reed, E Figg, WD TI Preliminary pharmacokinetics (PK) of COL-3, a matrix metalloproteinase (MMP) inhibitor. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 NCI, Med Branch, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 2 Z9 2 U1 0 U2 0 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 1999 VL 65 IS 2 MA PIII74 BP 195 EP 195 DI 10.1016/S0009-9236(99)80308-7 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 169KR UT WOS:000078747600309 ER PT J AU Ibrahim, S Knapton, A Licht, T Aszalos, A AF Ibrahim, S Knapton, A Licht, T Aszalos, A TI Influence of antipsychotic, antiemetic, and antifungal drugs on the function of P-glycoprotein in Caco-2 cells. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 US FDA, CDER, Rockville, MD 20857 USA. NCI, NIH, Bethesda, MD 20814 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 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 1999 VL 65 IS 2 MA PIII90 BP 199 EP 199 DI 10.1016/S0009-9236(99)80324-5 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 169KR UT WOS:000078747600325 ER PT J AU Mazzotta, P Magee, LA AF Mazzotta, P Magee, LA TI Pharmacologic and non-pharmacologic management of nausea and vomiting of pregnancy; A systematic critical review of the safety and effectiveness of treatment. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract C1 US FDA, CDER, Rockville, MD 20857 USA. NCI, NIH, 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 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 1999 VL 65 IS 2 MA PIII93 BP 199 EP 199 DI 10.1016/S0009-9236(99)80327-0 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 169KR UT WOS:000078747600328 ER PT J AU Guan, J Zhu, XK Brossi, A Tachibana, Y Bastow, KF Verdier-Pinard, P Hamel, E McPhail, AT Lee, KH AF Guan, J Zhu, XK Brossi, A Tachibana, Y Bastow, KF Verdier-Pinard, P Hamel, E McPhail, AT Lee, KH TI Antitumor agents. 192. Antitubulin effect and cytotoxicity of C(7)-oxygenated allocolchicinoids SO COLLECTION OF CZECHOSLOVAK CHEMICAL COMMUNICATIONS LA English DT Article DE colchicinoids; colchicine; allocolchicine; antimitosis; antitumor agents ID BIOLOGICAL EVALUATION; COLCHICINE MODELS; ESTER ANALOGS; THIOCOLCHICINE; CONGENERS; TUBULIN; ETHER; INHIBITORS AB Two allocolchicinoids 6 and 8, prepared from colchicine, together with allo compounds 9-11, made from 6 by reduction and regiodemethylation, were evaluated for antitubulin and antitumor activities. Structures of 6, 8, and 10 were confirmed by X-ray crystallographic analysis. Compounds 6, 8, and 9 have high tubulin binding affinity and display potent inhibitory activities against tubulin polymerization and solid human tumor cell lines. Particularly, drug-resistant KB cell lines, including KB-7d, KB-VCR, and KB-CPT, do not show marked resistance to these compounds. C1 Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Nat Prod Lab, Chapel Hill, NC 27599 USA. NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Duke Univ, Paul M Gross Chem Lab, Durham, NC 27708 USA. RP Lee, KH (reprint author), Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Nat Prod Lab, Chapel Hill, NC 27599 USA. OI Verdier-Pinard, Pascal/0000-0002-6149-6578 NR 23 TC 17 Z9 17 U1 0 U2 3 PU INST ORGANIC CHEM AND BIOCHEM PI PRAGUE 6 PA ACAD SCI CZECH REPUBLIC, FLEMINGOVO NAM 2, PRAGUE 6 166 10, CZECH REPUBLIC SN 0010-0765 J9 COLLECT CZECH CHEM C JI Collect. Czech. Chem. Commun. PD FEB PY 1999 VL 64 IS 2 BP 217 EP 228 DI 10.1135/cccc19990217 PG 12 WC Chemistry, Multidisciplinary SC Chemistry GA 247WY UT WOS:000083245000004 ER PT J AU Watson, MR Horowitz, AM Garcia, I Canto, MT AF Watson, MR Horowitz, AM Garcia, I Canto, MT TI Caries conditions among 2-5-year-old immigrant Latino children related to parents' oral health knowledge, opinions and practices SO COMMUNITY DENTISTRY AND ORAL EPIDEMIOLOGY LA English DT Article DE child; preschool; epidemiology; United States; dental caries; oral health; human; female; male; immigrants; Latinos; Central Americans; Hispanics; prevalence; DMF index; public health dentistry; socioeconomic factors; access to dental care ID BOTTLE TOOTH-DECAY; PRESCHOOL-CHILDREN; PERMANENT DENTITION; DENTAL-CARIES; UNITED-STATES; PATTERNS C1 Univ Maryland, Sch Dent, Baltimore Coll Dent Surg, Dept Pediat Dent, Baltimore, MD 21201 USA. NIDR, Bethesda, MD 20892 USA. Maryland VA Hlth Care Syst, Baltimore, MD USA. RP Watson, MR (reprint author), Univ Maryland, Sch Dent, Baltimore Coll Dent Surg, Dept Pediat Dent, 666 W Baltimore St, Baltimore, MD 21201 USA. EM mwatson@umaryland.edu NR 33 TC 36 Z9 36 U1 3 U2 8 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0301-5661 J9 COMMUNITY DENT ORAL JI Community Dentist. Oral Epidemiol. PD FEB PY 1999 VL 27 IS 1 BP 8 EP 15 DI 10.1111/j.1600-0528.1999.tb01986.x PG 8 WC Dentistry, Oral Surgery & Medicine; Public, Environmental & Occupational Health SC Dentistry, Oral Surgery & Medicine; Public, Environmental & Occupational Health GA 170AA UT WOS:000078781900002 PM 10086921 ER PT J AU Pollycove, M Feinendegen, LE AF Pollycove, M Feinendegen, LE TI Molecular biology, epidemiology, and the demise of the linear no-threshold (LNT) hypothesis SO COMPTES RENDUS DE L ACADEMIE DES SCIENCES SERIE III-SCIENCES DE LA VIE-LIFE SCIENCES LA English DT Editorial Material ID DOSE IONIZING-RADIATION; MECHANISMS; REPAIR; CANCER; SYSTEM AB The prime concern of radiation protection policy since 1959 has been protecting DNA from damage. The 1995 NCRP Report 121 on collective dose states that since no human data provides direct support for the linear no threshold hypothesis (LNT), and some studies provide quantitative data that, with statistical significance, contradict LNT, ultimately, confidence in LNT is based on the biophysical concept that the passage of a single charged particle could cause damage to DNA that would result in cancer. Current understanding of the basic molecular biologic mechanisms involved and recent data are examined before presenting several statistically significant epidemiologic studies that contradict the LNT hypothesis. Over eons of time a complex biosystem evolved to control the DNA alterations (oxidative adducts) produced by about 10(10) free radicals/cell/d derived from 2-3 % of all metabolized oxygen. Antioxidant prevention, enzymatic repair of DNA damage, and removal of persistent DNA alterations by apoptosis, differentiation, necrosis, and the immune system, sequentially reduce DNA damage from about 10(6) DNA alterations/cell/d to about 1 mutation/cell/d. These mutations accumulate in stem cells during a lifetime with progressive DNA damage-control impairment associated with aging and malignant growth. A comparatively negligible number of mutations, an average of about 10(-7) mutations/cell/d, is produced by low LET radiation background of 0.1 cGy/y. The remarkable efficiency of this biosystem is increased by the adaptive responses to low-dose ionizing radiation. Each of the sequential functions that prevent, repair, and remove DNA damage are adaptively stimulated by low-dose ionizing radiation in contrast to their impairment by high-dose radiation. The biologic effect of radiation is not determined by the number of mutations it creates, but by its effect on the biosystem that controls the relentless enormous burden of oxidative DNA damage. At low doses, radiation stimulates this biosystem with consequent significant decrease of metabolic mutations, low-dose stimulation of the immune system may not only prevent cancer by increasing removal of premalignant or malignant cells with persistent DNA damage, but used in human radioimmunotherapy may also completely remove malignant tumors with metastases. The reduction of gene mutations in response to low-dose radiation provides a biological explanation of the statistically significant observations of mortality and cancer mortality risk decrements, and contradicts the biophysical concept of the basic mechanisms upon which, ultimately, the NCRPs confidence in the LNT hypothesis is based. ((C) Academie des sciences / Elsevier, Paris.) C1 Univ Calif San Francisco, US Nucl Regulatory Commiss, San Francisco, CA USA. NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD 20892 USA. RP Pollycove, M (reprint author), Univ Calif San Francisco, US Nucl Regulatory Commiss, San Francisco, CA USA. NR 36 TC 27 Z9 29 U1 0 U2 3 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0764-4469 J9 CR ACAD SCI III-VIE JI Comptes Rendus Acad. Sci. Ser. III-Sci. Vie-Life Sci. PD FEB-MAR PY 1999 VL 322 IS 2-3 BP 197 EP 204 DI 10.1016/S0764-4469(99)80044-4 PG 8 WC Biology; Multidisciplinary Sciences SC Life Sciences & Biomedicine - Other Topics; Science & Technology - Other Topics GA 186LZ UT WOS:000079732400018 PM 10196673 ER PT J AU Feinendegen, LE Bond, VP Sondhaus, CA Altman, KI AF Feinendegen, LE Bond, VP Sondhaus, CA Altman, KI TI Cellular signal adaptation with damage control at low doses versus the predominance of DNA damage at high doses SO COMPTES RENDUS DE L ACADEMIE DES SCIENCES SERIE III-SCIENCES DE LA VIE-LIFE SCIENCES LA English DT Editorial Material ID ADAPTIVE RESPONSE; IONIZING-RADIATION; HUMAN-LYMPHOCYTES; X-RAYS; THYMIDINE KINASE; REPAIR; CELLS; MECHANISMS; IRRADIATION; INDUCTION AB Ionizing radiation is known to potentially interfere with cellular functions at all levels of cell organization and induces DNA lesions apparently with an incidence linearly related to D, also at low doses. On the other hand, low doses have also been observed to initiate a slowly appearing temporary protection against causation and accumulation of DNA lesions, involving the radical detoxification system, DNA repair and removal of DNA damage. This protection apparently does not operate at high doses; it has been described to be nonlinear, increasing initially with D, beginning to decrease when D exceeds approximately 0.1-0.2 Gy, and eventually disappearing at higher D. The various adaptive responses have been shown to last individually from hours to weeks in different cell types and resemble responses to oxidative stress. Damage to DNA is continuously and endogenously produced mainly by reactive oxygen species (ROS) generated in a normal oxidative metabolism. This endogenous DNA damage quantitatively exceeds DNA damage from low-dose irradiation, by several orders of magnitude. Thus, the protective responses following acute low-dose irradiation may be presumed to mainly counteract the endogenous DNA damage. Accordingly, the model described here uses two dose-effect functions, a linear one for causing and a nonlinear one for protecting against DNA damage from whatever cause in the irradiated cells and tissues. The resulting net dose-risk function strongly suggests that the incidence of cancer versus dose in the irradiated tissues is much less likely to be linear than to exhibit a threshold. The observed cancer incidence may even fall below the spontaneous incidence, when D to cells is below approximately 0.2 Gy. However incomplete, these data support a reexamination of the LNT hypothesis. ((C) Academie des sciences / Elsevier, Paris.) C1 NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD 20892 USA. Washington State Univ, Res Fac, Richland, WA USA. Univ Arizona, Dept Radiol, Tucson, AZ USA. Univ Arizona, Radiat Control Off, Tucson, AZ USA. Univ Rochester, Med Ctr, Dept Biochem & Biophys, Rochester, NY USA. RP Feinendegen, LE (reprint author), NIH, Dept Nucl Med, Ctr Clin, Bldg 10,1 C-494, Bethesda, MD 20892 USA. NR 58 TC 30 Z9 30 U1 0 U2 3 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0764-4469 J9 CR ACAD SCI III-VIE JI Comptes Rendus Acad. Sci. Ser. III-Sci. Vie-Life Sci. PD FEB-MAR PY 1999 VL 322 IS 2-3 BP 245 EP 251 DI 10.1016/S0764-4469(99)80051-1 PG 7 WC Biology; Multidisciplinary Sciences SC Life Sciences & Biomedicine - Other Topics; Science & Technology - Other Topics GA 186LZ UT WOS:000079732400025 PM 10196680 ER PT J AU Corn, M AF Corn, M TI Digital libraries: The view from NLM SO COMPUTER LA English DT Article C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Corn, M (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1314 USA SN 0018-9162 J9 COMPUTER JI Computer PD FEB PY 1999 VL 32 IS 2 BP 47 EP 47 PG 1 WC Computer Science, Hardware & Architecture; Computer Science, Software Engineering SC Computer Science GA 162AF UT WOS:000078322200020 ER PT J AU Thompson, B Geller, NL Hunsberger, S Frederick, M Hill, R Jacob, RG Smith, EA Kaufmann, P Freedman, RR Wigley, FM Bielory, L AF Thompson, B Geller, NL Hunsberger, S Frederick, M Hill, R Jacob, RG Smith, EA Kaufmann, P Freedman, RR Wigley, FM Bielory, L TI Behavioral and pharmacologic interventions: The Raynaud's Treatment Study SO CONTROLLED CLINICAL TRIALS LA English DT Article DE intervention design; behavior; pharmacology; attention ID TRIALS AB The Raynaud's Treatment Study (RTS) exemplified clinical trials with treatments that differ qualitatively both in their modes and in their methods of delivery. The RTS compared finger-temperature biofeedback to slow-release nifedipine, a calcium channel blocker, in patients with primary Raynaud's disease. Factors influencing the study design were the nature of the interventions and control measures of the protocol, the possibility of perceived differences by the patients between the treatments once the final protocol was developed, and concern on the part of the investigators over the fact that the primary endpoint was self-reported. This paper presents the final statistical model: a double parallel design with both a placebo group and a nonspecific behavioral control group. (C) Elsevier Science Inc. 1999. C1 Clin Trials & Surveys Corp, Baltimore, MD 21210 USA. NHLBI, Washington, DC USA. Med Univ S Carolina, Charleston, SC 29425 USA. Univ Pittsburgh, Pittsburgh, PA USA. Wayne State Univ, Detroit, MI USA. Johns Hopkins Univ, Med Ctr, Baltimore, MD 21218 USA. New Jersey Med Sch, New Brunswick, NJ USA. RP Thompson, B (reprint author), Clin Trials & Surveys Corp, 350 W Quadrangle, Baltimore, MD 21210 USA. NR 11 TC 14 Z9 14 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD FEB PY 1999 VL 20 IS 1 BP 52 EP 63 DI 10.1016/S0197-2456(98)00046-4 PG 12 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 162VH UT WOS:000078367300005 PM 10027500 ER PT J AU Da Silva, DM Velders, MP Rudolf, MP Schiller, JT Kast, WM AF Da Silva, DM Velders, MP Rudolf, MP Schiller, JT Kast, WM TI Papillomavirus virus-like particles as anticancer vaccines SO CURRENT OPINION IN MOLECULAR THERAPEUTICS LA English DT Article ID CYTOTOXIC-T-LYMPHOCYTES; COTTONTAIL RABBIT PAPILLOMAVIRUS; ANTIBODY-MEDIATED NEUTRALIZATION; L2 CAPSID PROTEINS; PEPTIDE VACCINATION; ANTITUMOR IMMUNITY; DENDRITIC CELLS; MUCOSAL SECRETIONS; CERVICAL-CARCINOMA; SURFACE-ANTIGEN AB Papillomavirus virus-like particles (VLPs) are empty, non-replicative, non-infectious particles that retain conformationally correct epitopes for the generation of antibody responses to the viral capsid proteins. Chimeric human papillomavirus (HPV) virus-like particles incorporating non-structural virus proteins offer an exciting approach for combined prophylactic and therapeutic vaccines against HPV-induced lesions. Both HPV VLPs and chimeric VLPs can induce potent humoral and cellular immune responses when injected into mice, leading to the generation of virus-neutralizing antibodies, priming of CD8+ T-cells and activation of cytotoxic T-cell effector functions. This review summarizes recent advances in the production of chimeric VLPs, the immune response elicited by VLPs and chimeric VLPs, and their ability to generate strong protective and therapeutic antitumor immune responses. C1 Loyola Univ, Cardinal Bernardin Canc Ctr, Maywood, IL 60153 USA. Loyola Univ, Dept Microbiol & Immunol, Maywood, IL 60153 USA. NIH, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Kast, WM (reprint author), Loyola Univ, Cardinal Bernardin Canc Ctr, 2160 S 1st Ave, Maywood, IL 60153 USA. FU NCI NIH HHS [R01 CA74397, R01 CA78399, P01 CA74182]; NIAID NIH HHS [T32 AI07508] NR 60 TC 16 Z9 18 U1 0 U2 1 PU PHARMAPRESS LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1P 6LB, ENGLAND SN 1464-8431 J9 CURR OPIN MOL THER JI Curr. Opin. Mol. Ther. PD FEB PY 1999 VL 1 IS 1 BP 82 EP 88 PG 7 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 342GZ UT WOS:000088638000014 PM 11249689 ER PT J AU Chitnis, AB AF Chitnis, AB TI Control of neurogenesis - lessons from frogs, fish and flies SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Article ID XENOPUS-EMBRYOS; NEURONAL DIFFERENTIATION; NEURAL INDUCTION; ZEBRAFISH EMBRYO; GENES; ECTODERM; EXPRESSION; INHIBITION; PROTEIN; PATTERN AB Two types of genes activated by neural inducers have been identified, those that lead to the activation of proneural genes and those that limit the activity of these genes to specific domains in the neural plate. The analysis of these genes has begun to fill gaps in our understanding of events that lead from neural induction to the generation of neurons within three longitudinal columns in the Xenopus and zebrafish neural plate. C1 NICHHD, Mol Genet Lab, NIH, Unit Vertebrate Neural Dev, Bethesda, MD 20892 USA. RP Chitnis, AB (reprint author), NICHHD, Mol Genet Lab, NIH, Unit Vertebrate Neural Dev, Bldg 6B,Room 3B 315,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 61 TC 80 Z9 80 U1 0 U2 2 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD FEB PY 1999 VL 9 IS 1 BP 18 EP 25 DI 10.1016/S0959-4388(99)80003-8 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 169LB UT WOS:000078748600002 PM 10072374 ER PT J AU O'Donovan, MJ AF O'Donovan, MJ TI The origin of spontaneous activity in developing networks of the vertebrate nervous system SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Article ID WALLABY MACROPUS-EUGENII; DEVELOPING SPINAL-CORD; CHICK-EMBRYO; MOTOR-ACTIVITY; BIOELECTRIC ACTIVITY; HIPPOCAMPAL-NEURONS; GANGLION-CELLS; SYNAPTIC DRIVE; RETINAL WAVES; IN-VITRO AB Spontaneous neuronal activity has been detected in many parts of the developing vertebrate nervous system. Recent studies suggest that this activity depends on properties that are probably shared by ail developing networks. Of particular importance is the high excitability of recurrently connected, developing networks and the presence of activity-induced transient depression of network excitability. In the spinal cord, it has been proposed that the interaction of these properties gives rise to spontaneous, periodic activity. C1 NINDS, Neural Control Lab, NIH, Bethesda, MD 20892 USA. RP O'Donovan, MJ (reprint author), NINDS, Neural Control Lab, NIH, Bethesda, MD 20892 USA. EM odonovan@codon.nih.gov RI o'donovan, michael/A-2357-2015 OI o'donovan, michael/0000-0003-2487-7547 NR 75 TC 286 Z9 290 U1 0 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD FEB PY 1999 VL 9 IS 1 BP 94 EP 104 DI 10.1016/S0959-4388(99)80012-9 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 169LB UT WOS:000078748600011 PM 10072366 ER PT J AU Buonanno, A Fields, RD AF Buonanno, A Fields, RD TI Gene regulation by patterned electrical activity during neural and skeletal muscle development SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Review ID LONG-TERM POTENTIATION; CAMP-RESPONSIVE ELEMENT; IMMEDIATE-EARLY GENES; NMDA-RECEPTOR SUBUNIT; FAST-TWITCH MUSCLE; DIFFERENTIAL REGULATION; CREB PHOSPHORYLATION; DEPENDENT REGULATION; SYNAPTIC PLASTICITY; NEURONAL-ACTIVITY AB Patterned neural activity modifies central synapses during development and the physiological properties of skeletal muscle by selectively repressing or stimulating transcription of distinct genes. The effects of neural activity are mostly mediated by calcium. Of particular interest are the cellular mechanisms that may be used to sense and convert changes in calcium into specific alterations in gene expression. Recent studies have addressed the importance of spatial heterogeneity or of temporal changes in calcium levels for the regulation of gene expression. C1 NIH, Mol Neurobiol Unit, Bethesda, MD 20892 USA. NIH, Unit Neurocytol & Physiol, Dev Neurobiol Lab, Bethesda, MD 20892 USA. RP Buonanno, A (reprint author), NIH, Mol Neurobiol Unit, Bldg 49,Room 5A-38, Bethesda, MD 20892 USA. EM buonanno@helix.nih.gov NR 111 TC 104 Z9 105 U1 0 U2 2 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD FEB PY 1999 VL 9 IS 1 BP 110 EP 120 DI 10.1016/S0959-4388(99)80014-2 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 169LB UT WOS:000078748600013 PM 10072371 ER PT J AU Vazquez, M Moore, L Kennison, JA AF Vazquez, M Moore, L Kennison, JA TI The trithorax group gene osa encodes an ARID-domain protein that genetically interacts with the Brahma chromatin-remodeling factor to regulate transcription SO DEVELOPMENT LA English DT Article DE trithorax group (trx-G); brahma; osa; SWI/SNF complex; chromatin-remodeling; homeotic gene regulation; eyelid (eld) ID YEAST SWI/SNF COMPLEX; DROSOPHILA HOMEOTIC GENES; DNA-BINDING PROTEINS; ANTENNAPEDIA GENE; BITHORAX COMPLEX; MOLECULAR-ORGANIZATION; MULTISUBUNIT COMPLEX; ECTOPIC EXPRESSION; SWI-SNF; FAMILY AB The trithorax group gene brahma (brm) encodes the ATPase subunit of a chromatin-remodeling complex involved in homeotic gene regulation. We report here that brm interacts with another trithorax group gene, osa, to regulate the expression of the Antennapedia P2 promoter. Regulation of Antennapedia by BRM and OSA proteins requires sequences 5' to the P2 promoter. Loss of maternal osa function causes severe segmentation defects, indicating that the function of osa is not limited to homeotic gene regulation. The OSA protein contains an ARID domain, a DNA-binding domain also present in the yeast SWI1 and Drosophila DRI proteins. We propose that the OSA protein may target the BRM complex to Antennapedia and other regulated genes. C1 NIH, Natl Inst Hlth & Human Dev, Genet Mol Lab, Bethesda, MD 20892 USA. Univ Nacl Autonoma Mexico, Inst Biotecnol, Dept Genet & Fis Mol, Cuernavaca 62250, Morelos, Mexico. Univ Calif Santa Cruz, Dept Biol, Santa Cruz, CA 95064 USA. RP Vazquez, M (reprint author), NIH, Natl Inst Hlth & Human Dev, Genet Mol Lab, Bldg 10, Bethesda, MD 20892 USA. EM mvazquez@ibt.unam.mx NR 64 TC 93 Z9 96 U1 0 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE, CAMBS, ENGLAND CB4 4DL SN 0950-1991 J9 DEVELOPMENT JI Development PD FEB PY 1999 VL 126 IS 4 BP 733 EP 742 PG 10 WC Developmental Biology SC Developmental Biology GA 175GU UT WOS:000079085700013 PM 9895321 ER PT J AU Ashcroft, NR Srayko, M Kosinski, ME Mains, PE Golden, A AF Ashcroft, NR Srayko, M Kosinski, ME Mains, PE Golden, A TI RNA-mediated interference of a cdc25 homolog in Caenorhabditis elegans results in defects in the embryonic cortical membrane, meiosis, and mitosis SO DEVELOPMENTAL BIOLOGY LA English DT Article DE cdc25; cortical membrane; embryogenesis; meiosis; nematode; polar body; spindle ID C-ELEGANS; CELL-CYCLE; PROTEIN-KINASE; FISSION YEAST; M-PHASE; TYROSINE PHOSPHORYLATION; PHOSPHATASE-ACTIVITY; ACTIVATES P34CDC2; SEX-DETERMINATION; MITOTIC INDUCER AB The CDC25 dual-specificity phosphatase family has been shown to play a key role in cell cycle regulation. The phosphatase activity of CDC25 drives the cell cycle by removing inhibitory phosphates from cyclin-dependent kinase/cyclin complexes. Although the regulation of CDC25 phosphatase activity has been elucidated both biochemically and genetically in other systems, the role of this enzyme during development is not well understood. To examine the expression pattern and function of CDC25 in Caenorhabditis elegans, we characterized a cdc25 homolog, cdc-25.1, during early embryonic development. The CDC-25.1 protein localizes to oocytes, embryonic nuclei, and embryonic cortical membranes. When the expression of CDC-25.1 was disrupted by RNA-mediated interference, the anterior cortical membrane of fertilized eggs became very fluid during meiosis and subsequent mitotic cell cycles. Mispositioning of the meiotic spindle, defects in polar body extrusion and chromosome segregation, and abnormal cleavage furrows were also observed. We conclude that CDC-25.1 is required for a very early developmental process-the proper completion of meiosis prior to embryogenesis. (C) 1999 Academic Press. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program,Dev Signal Transduct Grp, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. Univ Calgary, Dept Biochem & Mol Biol, Calgary, AB T2N 4N1, Canada. RP Golden, A (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program,Dev Signal Transduct Grp, Gene Regulat & Chromosome Biol Lab, POB B, Frederick, MD 21702 USA. EM golden@ncifcrf.gov RI Srayko, Martin/A-3755-2014; OI Srayko, Martin/0000-0003-0196-0364 NR 99 TC 39 Z9 46 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 FEB 1 PY 1999 VL 206 IS 1 BP 15 EP 32 DI 10.1006/dbio.1998.9135 PG 18 WC Developmental Biology SC Developmental Biology GA 167BX UT WOS:000078613700002 PM 9918692 ER PT J AU Fagot-Campagna, A Knowler, WC Narayan, KMV Hanson, RL Saaddine, J Howard, BV AF Fagot-Campagna, A Knowler, WC Narayan, KMV Hanson, RL Saaddine, J Howard, BV TI HDL cholesterol subfractions and risk of developing type 2 diabetes among Pima Indians SO DIABETES CARE LA English DT Article ID INSULIN-RESISTANCE; HEART-DISEASE; MELLITUS; LIPOPROTEINS; OBESITY; PLASMA; LEVEL; WOMEN; NIDDM AB OBJECTIVE - To examine the relationships between HDL cholesterol subfractions and the incidence of type 2 diabetes and to evaluate potential sex differences in these relationships. RESEARCH DESIGN IND METHODS - Proportional hazards analyses were performed to examine the relationships between HDL subfractions and the development of type 2 diabetes in Pima Indian women and men. Results were controlled for age, BMI, systolic blood pressure, and 2-h glucose. RESULTS - Some 54 of 123 women and 25 of 50 men developed type 2 diabetes during a mean follow-up of 10 (2-19) years. For women, in separate models, high levels of total HDL, HDL2a, and HDL3 were negatively associated with incidence of type 2 diabetes; results were unchanged in models further controlled for fasting insulin level or alcohol consumption For men, the results were inconsistent and associated with wide confidence intervals; high total HDL and HDL3 were positively associated with incidence of type 2 diabetes in models further controlled for fasting insulin level, but the risk estimates were attenuated in models further controlled for alcohol consumption. CONCLUSIONS - High levels of total HDL, HDL2a, and HDL3 were potential protective factors against type 2 diabetes in women after accounting for alcohol consumption and insulin resistance. High levels of total HDL and HDL3 were predictive of type 2 diabetes in men; the relationship in men appeared to be due to an association with alcohol consumption. The sex differences in the effects of HDL cholesterol may be related to the effects of sex hormones or lipoproteins. C1 Ctr Dis Control & Prevent, Div Diabet Translat, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30341 USA. NIDDKD, NIH, Phoenix, AZ USA. Medlant Res Inst, Washington, DC USA. RP Fagot-Campagna, A (reprint author), Ctr Dis Control & Prevent, Div Diabet Translat, Natl Ctr Chron Dis Prevent & Hlth Promot, 4770 Buford Hwy,NE MS-K68, Atlanta, GA 30341 USA. RI Narayan, K.M. Venkat /J-9819-2012; Hanson, Robert/O-3238-2015 OI Narayan, K.M. Venkat /0000-0001-8621-5405; Hanson, Robert/0000-0002-4252-7068 NR 25 TC 15 Z9 15 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD FEB PY 1999 VL 22 IS 2 BP 271 EP 274 DI 10.2337/diacare.22.2.271 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 160DA UT WOS:000078214000014 PM 10333944 ER PT J AU Ghosh, S Langefeld, CD Ally, D Watanabe, RM Hauser, ER Magnuson, VL Nylund, SJ Valle, T Eriksson, J Bergman, RN Tuomilehto, J Collins, FS Boehnke, M AF Ghosh, S Langefeld, CD Ally, D Watanabe, RM Hauser, ER Magnuson, VL Nylund, SJ Valle, T Eriksson, J Bergman, RN Tuomilehto, J Collins, FS Boehnke, M TI The W64R variant of the beta(3)-adrenergic receptor is not associated with Type II diabetes or obesity in a large Finnish sample SO DIABETOLOGIA LA English DT Article DE beta(3)-adrenergic receptor; Type II diabetes; obesity; association ID INSULIN-RESISTANCE SYNDROME; TRP64ARG MUTATION; GENETIC-VARIATION; MORBID-OBESITY; POLYMORPHISM; WEIGHT; NIDDM; FAT; SENSITIVITY; DISRUPTION AB Recent studies have suggested an association between Type II (non-insulin-dependent) diabetes mellitus-related phenotypes and a cytosine-to-thymidine substitution that results in the replacement of tryptophan by arginine at codon 64 (Trp64Arg or W64R) of the beta(3)-adrenergic receptor gene. Here, we present the results of possibly the largest association study to date on the variant in a sample of 526 families with a total of 1725 subjects, 1053 of whom had Type II diabetes. Preliminary calculations suggested that we had excellent power to detect the moderate associations which were reported in previous studies. No associations were found between the W64R variant and the following phenotypes in our sample: Type II diabetes, age at diagnosis for Type II diabetes, measures of obesity, fasting glucose, fasting insulin, minimal model variables, and systolic and diastolic blood pressures. In the analysis of plasma lipids, we detected an association between the variant and HDL ratios (HDL cholesterol/total cholesterol) (p = 0.013), which remained significant even after adjusting for sex, affection status and age. Since W64R homozygotes (n = 11) had the highest HDL ratios, however, heterozygotes had the lowest and the wildtype subjects had intermediate values, we conclude that the W64R variant is unlikely to reduce HDL ratios in a dose-dependent, pathogenic manner. C1 NIH, Genet & Mol Biol Branch, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. Univ Michigan, Dept Biostat, Ann Arbor, MI USA. Duke Univ, Med Ctr, Dept Med, Med Genet Sect, Durham, NC 27710 USA. Natl Inst Publ Hlth, Dept Hlth Promot, Helsinki, Finland. Univ So Calif, Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90033 USA. RP Ghosh, S (reprint author), NIH, Genet & Mol Biol Branch, Natl Human Genome Res Inst, Room 1W108,Bldg 9, Bethesda, MD 20892 USA. FU NHGRI NIH HHS [R01 HG00376, T32 HG00040]; NIDDK NIH HHS [F32 DK09525] NR 38 TC 30 Z9 30 U1 0 U2 2 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD FEB PY 1999 VL 42 IS 2 BP 238 EP 244 DI 10.1007/s001250051144 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 162VJ UT WOS:000078367400016 PM 10064105 ER PT J AU Dimmock, JR Puthucode, RN Tuchek, J Baker, GB Hinko, CN Steinmiller, CL Stables, JP AF Dimmock, JR Puthucode, RN Tuchek, J Baker, GB Hinko, CN Steinmiller, CL Stables, JP TI Anticonvulsant activities of 4-(4 '-fluorophenoxy) benzaldehyde semicarbazone SO DRUG DEVELOPMENT RESEARCH LA English DT Article DE anticonvulsants; semicarbazones; drug screening; preclinical toxicology ID GAMMA-VINYL GABA; MAXIMAL ELECTROSHOCK SCREEN; DRUG DEVELOPMENT PROGRAM; UPTAKE INHIBITORS; SENSITIVE ASSAY; RAT; MICE; ACID; THIOSEMICARBAZONES; CYTOCHROME-P-450 AB A series of aryloxyaryl semicarbazones had been shown previously to possess significant anticonvulsant activity in the maximal electroshock screen in both rats and mice as well as in the subcutaneous pentylenetetrazol test in mice. One member of this series, namely 4-(4 '-fluorophenoxy) benzaldehyde semicarbazone (Compound IV), was selected for detailed studies with a view to determining whether it should proceed to full-scale preclinical evaluation; these results are reported herein. After intraperitoneal injection, Compound IV afforded protection in the Frings audiogenic mouse test. In addition, it had activity in the rat corneal kindling screen after oral administration and in the rat hippocampal kindling screen after intraperitoneal administration, but it was virtually inactive in the amygdala kindling test in rats. When administered by the intravenous route to genetically susceptible epileptic chickens, Compound IV and eight analogs prevented convulsions induced by alternating strobe lights. Compound IV did not display proconvulsant properties when examined in the timed intravenous test in mice nor did this compound cause significant effects on liver weights, microsomal protein yields, and various hepatic enzymes after oral administration to rats. Intraperitoneal injection of Compound IV afforded little or no protection to mice who had received subcutaneously convulsive doses of bicuculline, picrotoxin, or strychnine. This compound did not elevate gamma-aminobutyric acid levels or inhibit gamma-aminobutyric acid uptake. ion-imaging and electrophysiological experiments suggested that the mode of action of this compound could be on calcium and sodium channels. In most of these experiments, Compound IV was superior to the widely used antiepileptic drug phenytoin. (C) 1999 Wiley-Liss, Inc. C1 Univ Saskatchewan, Coll Pharm & Nutr, Saskatoon, SK S7N 5C9, Canada. Univ Saskatchewan, Dept Pharmacol, Saskatoon, SK S7N 0W0, Canada. Univ Alberta, Neurochem Res Unit, Edmonton, AB, Canada. Univ Toledo, Coll Pharm, Toledo, OH 43606 USA. NINDS, NIH, Bethesda, MD 20892 USA. RP Dimmock, JR (reprint author), Univ Saskatchewan, Coll Pharm & Nutr, 110 Sci Pl, Saskatoon, SK S7N 5C9, Canada. NR 51 TC 7 Z9 9 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 0272-4391 J9 DRUG DEVELOP RES JI Drug Dev. Res. PD FEB PY 1999 VL 46 IS 2 BP 112 EP 125 DI 10.1002/(SICI)1098-2299(199902)46:2<112::AID-DDR4>3.0.CO;2-N PG 14 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 190WN UT WOS:000079988400004 ER PT J AU Khan, J Saal, LH Bittner, ML Chen, YD Trent, JM Meltzer, PS AF Khan, J Saal, LH Bittner, ML Chen, YD Trent, JM Meltzer, PS TI Expression profiling in cancer using cDNA microarrays SO ELECTROPHORESIS LA English DT Review DE cDNA microarray; gene expression; cancer research; review ID GENE-EXPRESSION; HUMAN GENOME; DNA MICROARRAY; HYBRIDIZATION; PATTERNS; MAP AB Currently there are over 1 000 000 human expressed sequence tag (EST) sequences available on the public database, representing perhaps 50-90% of all human genes. The cDNA microarray technique is a recently developed tool that exploits this wealth of information for the analysis of gene expression. In this method, DNA probes representing cDNA clones are arrayed onto a glass slide and interrogated with fluorescently labeled cDNA targets. The power: of the technology is the ability to perform a genome-wide expression profile of thousands of genes in one experiment. In our review we describe the principles of the microarray technology as applied to cancer research, summarize the literature on its use so far, and speculate on the future application of this powerful technique. C1 Natl Human Genome Res Inst, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Meltzer, PS (reprint author), Natl Human Genome Res Inst, Canc Genet Branch, NIH, Bldg 49,Room 4A10,49 Convent Dr, Bethesda, MD 20892 USA. RI Saal, Lao/A-2919-2011; Khan, Javed/P-9157-2014 OI Saal, Lao/0000-0002-0815-1896; Khan, Javed/0000-0002-5858-0488 NR 19 TC 105 Z9 110 U1 3 U2 7 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD FEB PY 1999 VL 20 IS 2 BP 223 EP 229 DI 10.1002/(SICI)1522-2683(19990201)20:2<223::AID-ELPS223>3.0.CO;2-A PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 176KD UT WOS:000079149500002 PM 10197427 ER PT J AU Mimnaugh, EG Bonvini, P Neckers, L AF Mimnaugh, EG Bonvini, P Neckers, L TI The measurement of ubiquitin and ubiquitinated proteins SO ELECTROPHORESIS LA English DT Review DE ubiquitin; protein ubiquitination; isopeptidases; immunoblotting; histones; review ID MEDIATED PROTEOLYTIC PATHWAY; KAPPA-B-ALPHA; PROTEASOME PATHWAY; CELL-CYCLE; IN-VIVO; DEPENDENT PROTEOLYSIS; POLYUBIQUITIN CHAINS; ACTIVATING ENZYME; C-JUN; IMMUNOCHEMICAL DETECTION AB Ubiquitination of key cellular proteins involved in signal transduction, gene transcription and cell-cycle regulation usually condemns those proteins to proteasomal or lysosomal degradation. Additionally, cycles of reversible ubiquitination regulate the function of certain proteins in a manner analogous to phosphorylation. In this short review we describe the current methodology for measuring ubiquitin and ubiquitination, provide examples which illustrate how various techniques have been used to study protein ubiquination, alert the readers of pitfalls to avoid, and offer guidelines to investigators newly interested in this novel post-translational protein modification. C1 NCI, Tumor Cell Biol Sect, Med Branch, NIH,Key W Ctr, Rockville, MD 20850 USA. RP Mimnaugh, EG (reprint author), NCI, Tumor Cell Biol Sect, Med Branch, NIH,Key W Ctr, Room 300,9610 Med Ctr Dr, Rockville, MD 20850 USA. EM edmim@box-e.nih.gov NR 99 TC 72 Z9 72 U1 2 U2 5 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD FEB PY 1999 VL 20 IS 2 BP 418 EP 428 DI 10.1002/(SICI)1522-2683(19990201)20:2<418::AID-ELPS418>3.3.CO;2-E PG 11 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 176KD UT WOS:000079149500024 PM 10197449 ER PT J AU Adachi, K Tanaka, T Saito, H Oka, T AF Adachi, K Tanaka, T Saito, H Oka, T TI Hormonal induction of mouse selenocysteine transfer ribonucleic acid (tRNA) gene transcription-activating factor and its functional importance in the selenocysteine tRNA gene transcription in mouse mammary gland SO ENDOCRINOLOGY LA English DT Article ID BETA-CASEIN GENE; TRANSFER RNA(SER)SEC GENE; EPITHELIAL-CELLS; MAP KINASE; EXPRESSION; ELEMENTS; PROTEIN; LINE AB Mouse selenocysteine transfer RNA (tRNA) gene transcription-activating factor (mStaf) is a transcriptional activator that enhances RNA polymerase III-dependent mouse selenocysteine tRNA (tRNA(Sec)) gene transcription. The DNA-binding activity of mStaf in mouse mammary gland undergoes developmental changes, reaching a maximal level during the period of lactation. In this study, we employed an organ culture system to examine the hormonal regulation of mStaf binding and its role in the tRNA(Sec) transcription in the mammary gland. The results showed that mStaf binding in mammary explants was stimulated by treatment with the lactogenic hormones, PRL, insulin, and hydrocortisone and that a specific MEK inhibitor, PD98059, inhibited the hormonal stimulation of mStaf binding. Other kinase inhibitors, such as a Janus kinase inhibitor and a calmodulin kinase inhibitor, had no apparent effect. Northern and Western blot analyses revealed that the level of both mStaf messenger RNA and protein was enhanced by the lactogenic hormones and was reduced by the concomitant treatment with PD98059. The mitogen-activated protein kinase activity in cultured explants was rapidly induced and maintained at high levels by the lactogenic hormones. We also found that the lactogenic hormones increased the amount of tRNA(Sec) in a time-dependent manner, which followed the increase in mStaf binding in cultured mammary explants. These results support the view that mStaf plays a key role in the hormonal stimulation of tRNA(Sec) transcription in the mammary gland. C1 NIDDKD, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. RP Adachi, K (reprint author), NIDDK, LMCB, NIH, Bldg 8,Room 309, Bethesda, MD 20892 USA. NR 26 TC 14 Z9 14 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 1999 VL 140 IS 2 BP 618 EP 623 DI 10.1210/en.140.2.618 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 158ZX UT WOS:000078148300010 PM 9927285 ER PT J AU Maurer, JA Wray, S AF Maurer, JA Wray, S TI Luteinizing hormone-releasing hormone quantified in tissues and slice explant cultures of postnatal rat hypothalami SO ENDOCRINOLOGY LA English DT Article ID LH-RH NEURONS; MEDIAL PREOPTIC AREA; GALANIN GENE-EXPRESSION; MESSENGER-RNA; FEMALE RATS; CATECHOLAMINERGIC INNERVATION; HYBRIDIZATION HISTOCHEMISTRY; TYROSINE-HYDROXYLASE; SEPTOPREOPTIC AREA; CELL-BODIES AB LH-releasing hormone (LHRH) peptide from postnatal rat preoptic area (POA)/hypothalamic tissues in vivo and slice explant cultures maintained in vitro was quantitated using an enzyme-linked immunosorbant assay. Moreover, messenger RNA (mRNA) copy number was calculated in LHRH neurons maintained in culture using in situ hybridization histochemistry with autoradiographic film analysis. POA/hypothalami from postnatal day 5-6 pups averaged 1250 pg of LHRH, with approximately 28% of peptide residing within rostral tissues where most LHRH perikarya reside. Explant cultures maintained 18 days in vitro contained 30.4-92.0 pg/slice with a whole animal total of 244.8 pg. Considering cell numbers in vivo and in vitro, LHRH neurons in whole animal produce 1.0 pg of LHRH/cell, whereas those in culture average 2.0 pg/cell. Furthermore, LHRH mRNA copies/cell in organotypic culture was estimated conservatively at 1410 copies/cell, a relatively high number. This work shows that, compared with whole animal, cultures have substantial LHRH stores, indicating maturation of synthetic activity and/or formation of new terminals in vitro. High LHRH mRNA copy number also suggests a high rate of peptide biosynthesis. Our analysis, demonstrating the dynamic potential of LHRH neurons, suggests that subtle changes in LHRH mRNA expression in all cells or a subpopulation can dramatically alter the LHRH system biosynthetic capacity. C1 NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Wray, S (reprint author), NINDS, Neurochem Lab, NIH, Bldg 36,Room 4D20, Bethesda, MD 20892 USA. EM swray@codon.nih.gov OI wray, susan/0000-0001-7670-3915 NR 72 TC 10 Z9 11 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 1999 VL 140 IS 2 BP 791 EP 799 DI 10.1210/en.140.2.791 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 158ZX UT WOS:000078148300032 PM 9927307 ER PT J AU Spong, CY Lee, SJ McCune, SK Gibney, G Abebe, DT Alvero, R Brenneman, DE Hill, JM AF Spong, CY Lee, SJ McCune, SK Gibney, G Abebe, DT Alvero, R Brenneman, DE Hill, JM TI Maternal regulation of embryonic growth: The role of vasoactive intestinal peptide SO ENDOCRINOLOGY LA English DT Article ID CYCLASE-ACTIVATING POLYPEPTIDE; MESSENGER-RNA EXPRESSION; SYMPATHETIC NEUROBLASTS; BINDING-SITES; T-LYMPHOCYTES; RAT-BRAIN; RECEPTOR; VIP; MOUSE; DIFFERENTIATION AB Vasoactive intestinal peptide (VIP) is an important growth regulator of the embryonic day (E)9-E11 mouse. In comparably aged rat embryos, VIP messenger RNA (mRNA) is not detectable; however, peak concentrations of VIP in maternal rat serum indicate a nonembryonic source. In the current study, mouse maternal and embryonic tissues were examined from E6-E12. Although RT-PCR revealed VIP mRNA in E6-E7 conceptuses, by E8 (when extraembryonic tissues could be separated from the embryo), VIP mRNA was detected only in the decidua/trophoblast. Decidual/trophoblastic VIP mRNA decreased until E10, after which it was not detectable. VIP mRNA was not apparent in the embryo until E11-E12. At E9, VIP immunoreactivity was localized to abundant, diffuse cells in the decidua basalis, which were also immunoreactive for T cell markers. VIP binding sites were dense in the decidua/trophoblast at E6, but gradually decreased until E10, after which they were not apparent. VIP binding sites were detected in embryonic neuroepithelium by E9. The transient presence of VIP binding sites and mRNA in the decidua/trophoblast correlate with the critical period of VIP growth regulation, when VIP mRNA is absent in the embryo. These findings suggest that maternal lymphocytes are the source of VITP's regulating early postimplantation embryonic growth. C1 NICHHD, Sect Dev & Mol Pharmacol, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. George Washington Univ, Childrens Natl Med Ctr, Dept Pediat, Div Neonatol, Washington, DC 20010 USA. RP Hill, JM (reprint author), NICHHD, Sect Dev & Mol Pharmacol, Dev Neurobiol Lab, NIH, Bldg 49,5A-38,MSC 4480,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jh139h@nih.gov NR 32 TC 43 Z9 43 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 1999 VL 140 IS 2 BP 917 EP 924 DI 10.1210/en.140.2.917 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 158ZX UT WOS:000078148300049 PM 9927324 ER PT J AU Abad, V Uyeda, JA Temple, HT de Luca, F Baron, J AF Abad, V Uyeda, JA Temple, HT de Luca, F Baron, J TI Determinants of spatial polarity in the growth plate SO ENDOCRINOLOGY LA English DT Article ID ENDOCHONDRAL BONE-FORMATION; CARTILAGE; CHONDROCYTE; MECHANISM; RABBIT AB Growth of long bones occurs at the growth plate, a layer of cartilage that separates the epiphysis from the metaphysis. Growth plate exhibits spatial polarity. Proliferative chondrocytes undergo terminal differentiation when they approach the metaphyseal, but not the epiphyseal, border of the growth plate. The adjacent bone also exhibits spatial polarity. Metaphyseal, but not epiphyseal, blood vessels and bone cells invade the adjacent growth plate, remodeling it into bone. As a result, the metaphysis, but not the epiphysis, elongates over time. To determine whether cartilage polarity determines bone polarity and/or whether bone polarity determines cartilage polarity, rabbit distal ulnar growth plates were excised, inverted, and reimplanted in their original beds. Thus, cartilage polarity was inverted relative to bone polarity. Histological examination showed that the inverted cartilage polarity was maintained over time. In contrast, the polarity of the adjacent bone reversed after surgery, to match that of the cartilage. Blood vessel and bone cell invasion ceased in the metaphysis and arose in the epiphysis. Longitudinal bone growth (measured with weekly radiographs) occurred at the epiphyseal, not at the metaphyseal, surface of the growth plate. We conclude that the polarity of growth plate cartilage is determined by intrinsic factors. The cartilage polarity then determines the polarity of the adjacent bone and, consequently, the functional polarity of longitudinal bone growth. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. RP Baron, J (reprint author), NICHHD, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N262,10 Ctr Dr,MSC 1862, Bethesda, MD 20892 USA. EM jeffrey_baron@nih.gov NR 16 TC 17 Z9 18 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 1999 VL 140 IS 2 BP 958 EP 962 DI 10.1210/en.140.2.958 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 158ZX UT WOS:000078148300054 PM 9927329 ER PT J AU Fleming, JV Barrett, P Coon, SL Klein, DC Morgan, PJ AF Fleming, JV Barrett, P Coon, SL Klein, DC Morgan, PJ TI Ovine arylalkylamine N-acetyltransferase in the pineal and pituitary glands: Differences in function and regulation SO ENDOCRINOLOGY LA English DT Article ID PARS TUBERALIS; MELATONIN RECEPTORS; MAMMALIAN RETINA; CYCLIC-AMP; EXPRESSION; PHARMACOLOGY; INDUCTION; PROLACTIN; REPRESSOR; PROMOTER AB The enzyme arylalkylamine N-acetyltransferase (AANAT; EC 2.3.1.87) has been conventionally linked with the biosynthesis of melatonin within the pineal gland and retina. This study establishes that AANAT messenger RNA (mRNA) and functional enzyme occurs within the pars tuberalis (PT) and to a lesser degree within the pars distalis (PD) of the sheep pituitary gland; expression in these tissues is approximately 1/15th (PT) and 1/300th (PD) of that in the ovine pineal gland. AANAT mRNA in the PT appears to be expressed in the same cells as the Mel1a receptor. No evidence was obtained to indicate that either PT or PD cells have the ability to synthesize melatonin, suggesting that this enzyme plays a different functional role in the pituitary. We also found that cAMP regulation of the abundance of AANAT mRMA differs between the PT and pineal gland. Forskolin(10 mu M) has no effect on pineal AANAT mRNA levels, yet represses expression in the PT. This suppressive influence could be mediated by ICER (inducible cAMP response early repressor), which is induced by forskolin in both tissues. Although it appears that the specific function and regulation of AANAT in the pituitary gland differ from that in the pineal gland, it seems likely that AANAT may play a role in the broader area of signal transduction through the biotransformation of amines. C1 Rowett Res Inst, Mol Neuroendocrinol Unit, Aberdeen AB21 9SB, Scotland. NICHHD, Sect Neuroendocrinol, Lab Dev Neuroendocrinol, NIH, Bethesda, MD 20892 USA. RP Morgan, PJ (reprint author), Rowett Res Inst, Mol Neuroendocrinol Unit, Greenburn Rd, Aberdeen AB21 9SB, Scotland. EM p.morgan@rri.sari.ac.uk NR 23 TC 22 Z9 23 U1 1 U2 4 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 1999 VL 140 IS 2 BP 972 EP 978 DI 10.1210/en.140.2.972 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 158ZX UT WOS:000078148300056 PM 9927331 ER PT J AU Goehl, TJ AF Goehl, TJ TI Introduction - Reviews in Environmental Health, 1999 SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Goehl, TJ (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 1999 VL 107 SU 1 BP 3 EP 4 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 170TW UT WOS:000078823800001 ER PT J AU Shackelford, RE Kaufmann, WK Paules, RS AF Shackelford, RE Kaufmann, WK Paules, RS TI Cell cycle control, checkpoint mechanisms, and genotoxic stress SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review DE Ataxia telangiectasia; cancer; carcinogens; Cdk; cell cycle; checkpoints; cyclins; DNA repair; genotoxic stress; ionizing radiation; oxidative damage; p53; pRb; UV ID ATAXIA-TELANGIECTASIA CELLS; TUMOR-SUPPRESSOR GENE; LI-FRAUMENI-SYNDROME; MATURATION-PROMOTING FACTOR; CHINESE-HAMSTER OVARY; BENZOPYRENE DIOL EPOXIDE; INDUCED DNA-DAMAGE; WILD-TYPE P53; MISMATCH REPAIR DEFICIENCY; P53-DEPENDENT G(1) ARREST AB The ability of cells to maintain genomic integrity is vital for cell survival and proliferation. Lack of fidelity in DNA replication and maintenance can result in deleterious mutations leading to cell death or, in multicellular organisms, cancer. The purpose of this review is to discuss the known signal transduction pathways that regulate cell cycle progression and the mechanisms cells employ to insure DNA stability in the lace of genotoxic stress. In particular, we focus on mammalian cell cycle checkpoint functions, their role in maintaining DNA stability during the cell cycle following exposure to genotoxic agents, and the gene products that act in checkpoint function signal transduction cascades. Key transitions in the cell cycle are regulated by the activities of various protein kinase complexes composed of cyclin and cyclin-dependent kinase (Cdk) molecules. Surveillance control mechanisms that check to ensure proper completion of early events and cellular integrity before initiation of subsequent events in cell cycle progression are referred to as cell cycle checkpoints and can generate a transient delay that provides the cell more time to repair damage before progressing to the next phase of the cycle. A variety of cellular responses are elicited that function in checkpoint signaling to inhibit cyclin/Cdk activities. These responses include the p53-dependent and p53-independent induction of Cdk inhibitors and the p53-independent inhibitory phosphorylation of Cdk molecules themselves. Eliciting proper G1, S, and G2 checkpoint responses to double-strand DNA breaks requires the function of the Ataxia telangiectasia mutated gene product. Several human heritable cancer-prone syndromes known to alter DNA stability have been found to have defects in checkpoint surveillance pathways. Exposures to several common sources of genotoxic stress, including oxidative stress, ionizing radiation, UV radiation, and the genotoxic compound benzo[a]pyrene, elicit cell cycle checkpoint responses that show both similarities and differences in their molecular signaling. C1 NIEHS, Growth Control & Canc Grp, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. RP Paules, RS (reprint author), NIEHS, Growth Control & Canc Grp, MD F1-05,111 Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM paules@niehs.nih.gov FU NCI NIH HHS [R01 CA081343] NR 490 TC 173 Z9 184 U1 2 U2 18 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 FEB PY 1999 VL 107 SU 1 BP 5 EP 24 DI 10.2307/3434468 PG 20 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 170TW UT WOS:000078823800002 PM 10229703 ER PT J AU Boorman, GA Dellarco, V Dunnick, JK Chapin, RE Hunter, S Hauchman, F Gardner, H Cox, M Sills, RC AF Boorman, GA Dellarco, V Dunnick, JK Chapin, RE Hunter, S Hauchman, F Gardner, H Cox, M Sills, RC TI Drinking water disinfection byproducts: Review and approach to toxicity evaluation SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE trihalomethanes; haloacetic acids; chloroform; drinking water; dibromoacetic acid; trichloroacetic acid; dichloroacetic acid; MX; toxicology; animal studies; carcinogenesis; alternate species ID CHLORINATION BY-PRODUCTS; AQUARIUM FISH MODELS; MALE B6C3F1 MOUSE; DICHLOROACETIC ACID; POTASSIUM BROMATE; ENVIRONMENTAL CARCINOGENESIS; TRICHLOROACETIC-ACID; LIPID-PEROXIDATION; ORYZIAS-LATIPES; TUMOR-INDUCTION AB There is widespread potential for human exposure to disinfection byproducts (DBPs) in drinking water because everyone drinks, bathes, cooks, and cleans with water. The need for clean and safe water led the U.S. Congress to pass the Safe Drinking Water Act more than 20 years ago in 1974. In 1976, chloroform, a trihalomethane (THM) and a principal DBP, was shown to be carcinogenic in rodents. This prompted the U.S. Environmental Protection Agency (U.S. EPA) in 1979 to develop a drinking water rule that would provide guidance on the levels of THMs allowed in drinking water. Further concern was raised by epidemiology studies suggesting a weak association between the consumption of chlorinated drinking water and the occurrence of bladder, colon, and rectal cancer. In 1992 the U.S. EPA initiated a negotiated rulemaking to evaluate the need for additional controls for microbial pathogens and DBPs. The goal was to develop an approach that would reduce the level of exposure from disinfectants and DBPs without undermining the control of microbial pathogens. The product of these deliberations was a proposed stage 1 DBP rule. It was agreed that additional information was necessary on how to optimize the use of disinfectants while maintaining control of pathogens before further controls to reduce exposure beyond stage 1 were warranted. In response to this need, the U.S. EPA developed a 5-year research plan to support the development of the longer term rules to control microbial pathogens and DBPs. A considerable body of toxicologic data has been developed on DBPs that occur in the drinking water, but the main emphasis has been on THMs. Given the complexity of the problem and the need for additional data to support the drinking water DBP rules, the U.S. EPA, the National institute of Environmental Health Sciences, and the U.S. Army are working together to develop a comprehensive biologic and mechanistic DBP database. Selected DBPs will be tested using 2-year toxicity and carcinogenicity studies in standard rodent models, transgenic mouse models and small fish models; in vitro mechanistic and toxicokinetic studies; and reproductive, immunotoxicity, and developmental studies, The goal is to create a toxicity database that reflects a wide range of DBPs resulting from different disinfection practices. This paper describes the approach developed by these agencies to provide the information needed to make scientifically based regulatory decisions. C1 NIEHS, Res Triangle Pk, NC 27709 USA. US EPA, Washington, DC 20460 USA. US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. USA, Ctr Environm Hlth Res, Ft Detrick, MD USA. RP Boorman, GA (reprint author), NIEHS, MD B3-08,POB 12233, Res Triangle Pk, NC 27709 USA. EM boorman@niehs.nih.gov OI Chapin, Robert/0000-0002-5997-1261 NR 95 TC 199 Z9 208 U1 16 U2 149 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 FEB PY 1999 VL 107 SU 1 BP 207 EP 217 DI 10.2307/3434484 PG 11 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 170TW UT WOS:000078823800018 PM 10229719 ER PT J AU Alavanja, MCR Sandler, DP McDonnell, CJ Lynch, CF Pennybacker, M Zahm, SH Mage, DT Steen, WC Wintersteen, W Blair, A AF Alavanja, MCR Sandler, DP McDonnell, CJ Lynch, CF Pennybacker, M Zahm, SH Mage, DT Steen, WC Wintersteen, W Blair, A TI Characteristics of pesticide use in a pesticide applicator cohort: The Agricultural Health Study SO ENVIRONMENTAL RESEARCH LA English DT Article DE pesticides; occupational exposure; cancers; noncancer toxicity; farmers ID BREAST-CANCER; HERBICIDES; RESIDUES; EXPOSURE; FARMERS; WORKERS; RISK AB Data on recent and historic pesticide use, pesticide application methods, and farm characteristics were collected from 35,879 restricted-use pesticide applicators in the first 2 years of the Agricultural Health Study, a prospective study of a large cohort of private and commercial licensed pesticide applicators that is being conducted in Iowa and North Carolina. (In Iowa, applicators are actually "certified," while in North Carolina they are "licensed"; for ease of reference the term license will be used for both states in this paper.) Commercial applicators (studied in Iowa only) apply pesticides more days per year than private applicators in either state. When the types of pesticides being used by different groups are compared using the Spearman coefficient of determination (r(2)), we find that Iowa private and Iowa commercial applicators tend to use the same type of pesticides (r(2) = 0.88). White and non-white private applicators tended to use the same type of pesticides (North Carolina r(2) = 0.89), as did male and female private applicators (Iowa r(2) = 0.85 and North Carolina r(2) = 0.84). There was less similarity (r(2) = 0.50) between the types of pesticides being used by Iowa and North Carolina private applicators. A greater portion of Iowa private applicators use personal protective equipment than do North Carolina private applicators, and pesticide application methods varied by state. This heterogeneity in potential exposures to pesticides between states should be useful for subsequent epidemiologic analyses using internal comparison groups. (C) 1999 Academic Press. C1 NCI, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. SRA Technol Inc, Falls Church, VA USA. Univ Iowa, Iowa City, IA USA. Battelle Survey Res Assoc, Durham, NC USA. US EPA, Res Triangle Pk, NC 27711 USA. US EPA, Athens, GA USA. Iowa State Univ, Ames, IA 50011 USA. RP Alavanja, MCR (reprint author), NCI, Epidemiol & Biostat Program, EPN-543,6130 Executive Blvd, Bethesda, MD 20892 USA. EM alavanjam@epndce.nci.nih.gov RI Zahm, Shelia/B-5025-2015; OI Sandler, Dale/0000-0002-6776-0018 FU NCI NIH HHS [N01-CP-21095, N01-CP-33047, N01-CP-33048] NR 18 TC 34 Z9 36 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 J9 ENVIRON RES JI Environ. Res. PD FEB PY 1999 VL 80 IS 2 BP 172 EP 179 DI 10.1006/enrs.1998.3888 PN 1 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 180YR UT WOS:000079413900014 PM 10092410 ER PT J AU Alavanja, MCR Sandler, DP McDonnell, CJ Mage, DT Kross, BC Rowland, AS Blair, A AF Alavanja, MCR Sandler, DP McDonnell, CJ Mage, DT Kross, BC Rowland, AS Blair, A TI Characteristics of persons who self-reported a high pesticide exposure event in the Agricultural Health Study SO ENVIRONMENTAL RESEARCH LA English DT Article DE pesticides; pesticide poisoning; accidental exposures; farmers; exposure assessment AB Characteristics of persons who report high pesticide exposure events (HPEE) were studied in a large cohort of licensed pesticide applicators from Iowa and North Carolina who enrolled in the Agricultural Health Study between December 1993 and December 1995. Fourteen percent reported having "an incident or experience while using any pesticide which caused an unusually high personal exposure." After taking into account total number of applications made and education, females (OR= 0.76), applicators from NC (OR = 0.65), and privately licensed applicators (OR = 0.65) were less likely to have reported an HPEE. Work practices more common among both private and commercial applicators with an HPEE included delay in changing clothing or washing after pesticide application, mixing pesticide application clothing with the family wash, washing up inside the house after application, applying pesticides within 50 yards of their well,and storing pesticides in the home. Job characteristics more common among those with an HPEE included self-repair of application equipment and first pesticide use more than 10 years in the past. These job characteristics explained much of the difference in reported HPEE between males and females, but not between IA and NC subjects or between commercial or private applicators. (C) 1999 Academic Press. C1 NCI, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. NIEHS, Res Triangle Pk, NC 27709 USA. SRA Technol Inc, Falls Church, VA USA. US EPA, Res Triangle Pk, NC 27711 USA. Univ Iowa, Iowa City, IA 52242 USA. RP Alavanja, MCR (reprint author), NCI, Epidemiol & Biostat Program, 6130 Execut Blvd, Bethesda, MD 20892 USA. OI Sandler, Dale/0000-0002-6776-0018 FU NCI NIH HHS [N01-CP-21095, N01-CP-33047, N01-CP-33048] NR 10 TC 15 Z9 17 U1 1 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 J9 ENVIRON RES JI Environ. Res. PD FEB PY 1999 VL 80 IS 2 BP 180 EP 186 DI 10.1006/enrs.1998.3887 PN 1 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 180YR UT WOS:000079413900015 PM 10092411 ER PT J AU Ho, HTB Jenkins, NA Copeland, NG Gilbert, DJ Winkles, JA Louie, HWY Lee, FK Chung, SSM Chung, SK AF Ho, HTB Jenkins, NA Copeland, NG Gilbert, DJ Winkles, JA Louie, HWY Lee, FK Chung, SSM Chung, SK TI Comparisons of genomic structures and chromosomal locations of the mouse aldose reductase and aldose reductase-like genes SO EUROPEAN JOURNAL OF BIOCHEMISTRY LA English DT Article DE aldose reductase; androgen regulated vas deferens protein; chromosomal organization; chromosome mapping; fibroblast growth factor regulated protein ID VAS-DEFERENS; DIABETIC COMPLICATIONS; ANDROGEN REGULATION; PROTEIN; EXPRESSION; CELLS; IDENTIFICATION; ORGANIZATION; SEQUENCES; INDUCTION AB Aldose reductase (AR), best known as the first enzyme in the polyol pathway of sugar metabolism, has been implicated in a wide variety of physiological functions and in the etiology of diabetic complications. We have determined the structures and chromosomal locations of the mouse AR gene (Aldor1) and of two genes highly homologous to Aldor1: the fibroblast growth factor regulated protein gene (Fgfrp) and the androgen regulated vas deferens protein gene (Avdp). The number of introns and their locations in the mouse Aldor1 gene are identical to those of rat and human AR genes and also to those of Fgfrp and Avdp. Mouse Aldor1 gene was found to be located near the Cald1 (Caldesmon) and Pm (Pleiotropin) loci at the proximal end of chromosome 6. The closely related genes Fgfrp and Avdp were also mapped in this region of the chromosome, suggesting that these three genes may have arisen by a gene duplication event. C1 Univ Hong Kong, Inst Mol Biol, Hong Kong, Peoples R China. NCI, Mammalian Genet Lab, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD USA. Amer Red Cross, Holland Lab, Dept Vasc Biol, Rockville, MD USA. RP Chung, SK (reprint author), Univ Hong Kong, Inst Mol Biol, 8 Sassoon Rd, Hong Kong, Peoples R China. FU NHLBI NIH HHS [HL-54710, HL-39727] NR 26 TC 8 Z9 9 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0014-2956 J9 EUR J BIOCHEM JI Eur. J. Biochem. PD FEB PY 1999 VL 259 IS 3 BP 726 EP 730 DI 10.1046/j.1432-1327.1999.00110.x PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 169FN UT WOS:000078737000021 PM 10092857 ER PT J AU Hopf, M Gohring, W Kohfeldt, E Yamada, Y Timpl, R AF Hopf, M Gohring, W Kohfeldt, E Yamada, Y Timpl, R TI Recombinant domain IV of perlecan binds to nidogens, laminin-nidogen complex, fibronectin, fibulin-2 and heparin SO EUROPEAN JOURNAL OF BIOCHEMISTRY LA English DT Article DE basement membranes; binding assays; proteoglycan structure; recombinant production ID EPIDERMAL-GROWTH-FACTOR; DENSITY-LIPOPROTEIN-RECEPTOR; SULFATE PROTEOGLYCAN BINDS; CELL-ADHESION MOLECULES; COLLAGEN TYPE-IV; BASEMENT-MEMBRANE; EXTRACELLULAR-MATRIX; STRUCTURAL CHARACTERIZATION; CORE PROTEIN; EPITHELIAL MORPHOGENESIS AB Domain IV of mouse perlecan, which consists of 14 immunoglobulin superfamily (IG) modules, was prepared from recombinant human cell culture medium in the form of two fragments, IV-1 (IG2-9, 100 kDa) and IV-2 (IG10-15, 66 kDa). Both fragments bound to a heparin column, being eluted at ionic strengths either below (IV-2) or above (IV-1) physiological level, and could thus be readily purified. Electron microscopy demonstrated an elongated shape (20-25 nm), and folding into a native structure was indicated by immunological assay and CD spectroscopy. Solid-phase and surface plasmon resonance assays demonstrated strong binding of fragment IV-1 to fibronectin, nidogen-1, nidogen-2 and the laminin-1-nidogen-1 complex, with K-d values in the range 4-17 nM. The latter binding apparently occurs through nidogen-1, as shown by the formation of ternary complexes. Only moderate binding was observed for fibulin-2 and collagen IV and none for fibulin-1 and BM-40. Fragment IV-2 showed a more restricted pattern of binding, with only weaker binding to fibronectin and fibulin-2. None of these activities could be demonstrated for recombinant fragments corresponding to the N-terminal perlecan domains I to III. This indicates a special role for domain IV in the integration of perlecan into basement membranes and other extracellular structures via protein-protein interactions. C1 Max Planck Inst Biochem, D-82152 Martinsried, Germany. NIDR, NIH, Bethesda, MD 20892 USA. RP Timpl, R (reprint author), Max Planck Inst Biochem, Am Klopferspitz 18A, D-82152 Martinsried, Germany. NR 60 TC 108 Z9 109 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0014-2956 J9 EUR J BIOCHEM JI Eur. J. Biochem. PD FEB PY 1999 VL 259 IS 3 BP 917 EP 925 DI 10.1046/j.1432-1327.1999.00127.x PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 169FN UT WOS:000078737000046 PM 10092882 ER PT J AU Kruth, HS Chang, J Ifrim, I Zhang, WY AF Kruth, HS Chang, J Ifrim, I Zhang, WY TI Characterization of patocytosis: endocytosis into macrophage surface-connected compartments SO EUROPEAN JOURNAL OF CELL BIOLOGY LA English DT Article DE endocytosis; phagocytosis; macrophages; lipoproteins; patocytosis ID LOW-DENSITY-LIPOPROTEIN; MOUSE PERITONEAL-MACROPHAGES; MONOCYTE-DERIVED MACROPHAGES; ASIALOGLYCOPROTEIN RECEPTOR; LYSOSOMOTROPIC AMINES; HEPATOMA-CELLS; PLATELETS; ACTIN; CYTOCHALASIN; PHAGOCYTOSIS AB Previously, we described a unique macrophage endocytosis pathway in which aggregated low density lipoproteins and microcrystalline cholesterol induce and enter a labyrinth of membrane-bound compartments that remain connected to the cell surface. We now show that certain types of non-lipid particles such as polystyrene microspheres and colloidal gold also induce and enter macrophage surface-connected compartments (SCC), a process we call patocytosis, A common property among particles that stimulate patocytosis is their hydrophobic nature. Both aggregated LDL and microcrystalline cholesterol that we showed previously to stimulate patocytosis are hydrophobic, We now show that hydrophobic polystyrene microspheres and gold particles but not their hydrophilic counterparts triggered patocytosis. Uptake by patocytosis was limited to hydrophobic polystyrene microsphere particles less than 0.5 mu m in diameter. Hydrophobic polystyrene microspheres greater than this size entered macrophages by phagocytosis, Actin-independent capping of hydrophobic polystyrene microspheres on the plasma membrane preceded actin-dependent uptake of the microspheres into SCC. Sequential rounds of microsphere uptake into SCC over two successive days could occur. There was some mixing of initial and subsequently accumulated microspheres in SCC, SCC formed from plasma membrane invaginations that connected with spaces created by unfolding of stacks of internal microvilli. Microsphere transport from plasma membrane invaginations into these spaces was inhibited by primaquine, patocytosis is a unique endocytic process in macrophages triggered by small hydrophobic particles that provides a mechanism to sequester large amounts of these materials within a labyrinth of SCC. C1 NHLBI, Sect Expt Atherosclerosis, NIH, Bethesda, MD 20892 USA. RP Kruth, HS (reprint author), NHLBI, Sect Expt Atherosclerosis, NIH, Bldg 10,Room 5N-113,10 Ctr Dr MSC 1422, Bethesda, MD 20892 USA. NR 29 TC 29 Z9 31 U1 0 U2 1 PU URBAN & FISCHER VERLAG PI JENA PA BRANCH OFFICE JENA, P O BOX NO.100 537, D-07705 JENA, GERMANY SN 0171-9335 J9 EUR J CELL BIOL JI Eur. J. Cell Biol. PD FEB PY 1999 VL 78 IS 2 BP 91 EP 99 PG 9 WC Cell Biology SC Cell Biology GA 177PT UT WOS:000079220100002 PM 10099931 ER PT J AU Bouloc, A Walker, P Grivel, JC Vogel, JC Katz, SI AF Bouloc, A Walker, P Grivel, JC Vogel, JC Katz, SI TI Immunization through dermal delivery of protein-encoding DNA: a role for migratory dendritic cells SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; INTRADERMAL GENE IMMUNIZATION; ANTIGEN-PRESENTING CELLS; MARROW-DERIVED CELLS; PLASMID DNA; IN-VIVO; LANGERHANS CELLS; PROTECTION; INDUCTION; VACCINES AB The early mechanisms by which DNA-dependent immunization occurs remain poorly understood. We determined whether intradermal injection of a cytomegalovirus (CMV) promoter-driven plasmid encoding hen egg lysozyme (pCMV:HEL) induced sensitization against the encoded protein, and whether cutaneous dendritic cells (DC) were involved in this sensitization. Both humoral and cellular responses to HEL were observed. DC that migrated from skin explant culture 3 days after injection of pCMV:HEL DNA contained mRNA encoding HEL. They induced a 3.5-7-fold increase in [H-3]thymidine incorporation by HEL protein-primed CD4(+) T cells compared to that induced by DC from mice injected with control plasmid. DC emigrating from skin explants recovered from pCMV:HEL injected mice also sensitized naive mice after adoptive transfer and induced the generation of CTL. Thus following DNA delivery within the dermis, DC can induce primary and secondary immune responses. C1 NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. NCI, Genet Lab, NIH, Bethesda, MD 20892 USA. RP Bouloc, A (reprint author), NCI, Dermatol Branch, NIH, Bldg 10,Rm 12N238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. NR 49 TC 51 Z9 53 U1 0 U2 2 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD FEB PY 1999 VL 29 IS 2 BP 446 EP 454 DI 10.1002/(SICI)1521-4141(199902)29:02<446::AID-IMMU446>3.3.CO;2-1 PG 9 WC Immunology SC Immunology GA 167XD UT WOS:000078658700009 PM 10064060 ER PT J AU Yu, P Morawetz, RA Chattopadhyay, S Makino, M Kishimoto, T Kikutani, H AF Yu, P Morawetz, RA Chattopadhyay, S Makino, M Kishimoto, T Kikutani, H TI CD40-deficient mice infected with the defective murine leukemia virus LP-BM5def do not develop murine AIDS but produce IgE and IgG1 in vivo SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE immunodeficiency disease; co-stimulatory molecule; knockout; isotype switching ID RETROVIRUS-INDUCED IMMUNODEFICIENCY; SYNDROME MAIDS; LEISHMANIA-MAJOR; IMMUNE-RESPONSES; CD40 LIGAND; B-CELLS; T-CELLS; DISEASE; RESISTANCE; DEFICIENT AB CD40-deficient mice, when inoculated with the LP-BM5def murine retorvirus, become infected and show virus expression similar to wild-type mice. However, unlike the wild-type mice, CD40-deficient mice do not develop symptoms of immunodeficiency, lymphoproliferative disease and the typical histological changes in the lymphoid tissue. These results show that the CD40-CD40 ligand (CD40L) interaction in vivo is essential for anergy induction and the subsequent development of immunodeficiency and pathologic expansion of lymphocytes. Infected CD40-deficient mice and their littermates express a similar pattern of cytokine mRNA, which is not biased towards a Th2 phenotype. Nevertheless, hypergammaglobulinemia is induced in infected wild-type and CD40-deficient mice. Surprisingly, murine AIDS infection even induces IgE production in CD40-deficient mice in vivo. Our data demonstrate that antibody class switch to IgE and IgG1 can be induced by a retroviral infection in vivo even in the absence of CD40-CD40L interaction and an apparent switch to a Th2 cytokine production. C1 Osaka Univ, Microbial Dis Res Inst, Dept Mol Immunol, Suita, Osaka 565, Japan. NIAID, Immunopathol Lab, NIH, Bethesda, MD USA. Kagoshima Univ, Fac Med, Ctr Chron Viral Dis, Div Human Retroviruses, Kagoshima 890, Japan. Osaka Univ, Sch Med, Dept Med 3, Suita, Osaka 565, Japan. RP Kikutani, H (reprint author), Osaka Univ, Microbial Dis Res Inst, Dept Mol Immunol, 3-1 Yamada Oka, Suita, Osaka 565, Japan. EM kikutani@ragtime.biken.osaka-u.ac.jp RI Kikutani, Hitoshi/C-9525-2009; Kishimoto, Tadamitsu/C-8470-2009 NR 39 TC 14 Z9 14 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD FEB PY 1999 VL 29 IS 2 BP 615 EP 625 DI 10.1002/(SICI)1521-4141(199902)29:02<615::AID-IMMU615>3.0.CO;2-I PG 11 WC Immunology SC Immunology GA 167XD UT WOS:000078658700027 PM 10064078 ER PT J AU Suri-Payer, E Amar, AZ McHugh, R Natarajan, K Margulies, DH Shevach, EM AF Suri-Payer, E Amar, AZ McHugh, R Natarajan, K Margulies, DH Shevach, EM TI Post-thymectomy autoimmune gastritis: fine specificity and pathogenicity of anti-H/K ATPase-reactive T cells SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE autoimmune gastritis; H/K ATPase; Th1/Th2 cell; regulatory T cell; neonatal thymectomy ID MOLECULAR TARGETS; ALPHA-SUBUNIT; DISEASE; EXPRESSION; IDENTIFICATION; TRIPHOSPHATASE; PATHOGENESIS; THYMUS; MICE AB Thymectomy at day 3 of life (d3Tx) results in the development of organ-specific autoimmunity. We have recently shown that d3Tx BALB/c mice which develop autoimmune gastritis contain CD4(+) T cells specific for the gastric parietal cell proton pump, H/K ATPase. Here, we demonstrate that freshly explanted gastric lymph node (LN) cells from d3Tx mice react significantly to the H/K ATPase alpha chain, but only marginally to the beta chain. Two H/K ATPase-reactive T cell lines were derived from the gastric LN of d3Tx mice. Both are CD4(+), TCR alpha/beta(+), and I-A(d) restricted, and recognize distinct peptides from the H/K ATPase alpha chain. One cell line secretes Th1 and the other Th2 cytokines, but both are equally potent in inducing gastritis with distinct profiles of cellular infiltration in nu/nu recipient animals. Neither of the cell lines induced disease in normal BALB/c recipients and transfer of disease to nu/nu recipients was blocked by co-transfer of normal BALB/c spleen cells containing CD4(+) CD25(+) cells. Although CD4(+) CD25(+) T cells are thought to emigrate from the thymus after day 3 of life, they could be identified in LN of 2-day-old animals. The capacity of CD4(+) CD25(+) T cells to abrogate the pathogenic activity in vivo of both activated Th1/Th2 lines strongly suggests that this suppressor T cell population may have a therapeutic role in other models of established autoimmunity. The availability of well-characterized lines of autoantigen-specific T cells should greatly facilitate the analysis of the mechanism of action and target of the CD4(+) CD25(+) immunoregulatory cells. C1 NIAID, Immunol Lab, NIH, Cellular Immunol Sect, Bethesda, MD 20892 USA. NIAID, Mol Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Shevach, EM (reprint author), NIAID, Immunol Lab, NIH, Cellular Immunol Sect, Bldg 10,Room 11N311,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. EM ems1@box-e.nih.gov RI Margulies, David/H-7089-2013; OI Margulies, David/0000-0001-8530-7375 NR 29 TC 106 Z9 106 U1 0 U2 1 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD FEB PY 1999 VL 29 IS 2 BP 669 EP 677 DI 10.1002/(SICI)1521-4141(199902)29:02<669::AID-IMMU669>3.0.CO;2-J PG 9 WC Immunology SC Immunology GA 167XD UT WOS:000078658700033 PM 10064084 ER PT J AU Xin, YC Zhang, YM Mallet, JM Glaudemans, CPJ Sinay, P AF Xin, YC Zhang, YM Mallet, JM Glaudemans, CPJ Sinay, P TI Synthesis of C-oligosaccharides that mimic their natural O-analogous immunodeterminants in binding to monoclonal immunoglobulins SO EUROPEAN JOURNAL OF ORGANIC CHEMISTRY LA English DT Article DE C-disaccharide; C-glycosides; carbohydrates; glycosylation; sugar lactone ID PROTEIN-BOUND STATE; H-TYPE-II; CONFORMATIONAL DIFFERENCES; EXPEDITIOUS SYNTHESIS; DERIVATIVES; GLYCOSIDES; LACTOSE; DISACCHARIDES; SUGARS; ALPHA AB We have stereoselectively synthesized the analogues of the methyl beta-glycosides of (1-->6)-beta-D-galacto-oligosaccharides (up to tetrasaccharide), in which the interglycosidic oxygen atoms are replaced by a methylene group. C1 Ecole Normale Super, CNRS, Dept Chim, F-75231 Paris 05, France. NIH, Med Chem Lab, Bethesda, MD 20892 USA. RP Sinay, P (reprint author), Ecole Normale Super, CNRS, Dept Chim, 24 Rue Lhomond, F-75231 Paris 05, France. EM glau@helix.nih.gov; Pierre.Sinay@ens.fr RI Mallet, Jean-Maurice/H-2113-2011 OI Mallet, Jean-Maurice/0000-0001-8570-9542 NR 36 TC 32 Z9 32 U1 0 U2 4 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 1434-193X J9 EUR J ORG CHEM JI Eur. J. Org. Chem. PD FEB PY 1999 IS 2 BP 471 EP 476 PG 6 WC Chemistry, Organic SC Chemistry GA 166FV UT WOS:000078566300014 ER PT J AU Sommer, MA Tehovnik, EJ AF Sommer, MA Tehovnik, EJ TI Reversible inactivation of macaque dorsomedial frontal cortex: effects on saccades and fixations SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE saccadic eye movements; fixations; dorsomedial frontal cortex; supplementary eye field; frontal eye field; reversible inactivation ID SUPPLEMENTARY EYE FIELD; CONDITIONAL OCULOMOTOR ASSOCIATIONS; SUPERIOR COLLICULUS NEURONS; MEMORY-GUIDED SACCADES; RHESUS-MONKEYS; MOTOR AREA; ELECTRICAL-STIMULATION; COMPENSATORY SACCADES; CORTICAL CONTROL; VISUAL TARGETS AB Neural recording and electrical stimulation results suggest that the dorsomedial frontal cortex (DMFC) of macaque is involved in oculomotor behavior. We reversibly inactivated the DMFC using lidocaine and examined how saccadic eye movements and fixations were affected. The inactivation methods and monkeys were the same as these used in a previous study of the frontal eye field (FEF), another frontal oculomotor region. In the first stage of the present study, monkeys performed tasks that required the generation of single saccades and fixations. During 15 DMFC inactivations, we found only mild, infrequent deficits. This contrasts with our prior finding that FEF inactivation causes severe, reliable deficits in performance of these tasks. In the second stage of the study, we investigated whether DMFC inactivation affected behavior when a monkey was required to make more than one saccade and fixation. We used a double-step task: two targets were flashed in rapid succession and the monkey had to make two saccades to foveate the target locations. In each of five experiments, DMFC inactivation caused a moderate, significant deficit. Both ipsi- and contraversive saccades were disrupted. In two experiments, the first saccades were made to the wrong place and had increased latencies. In one experiment, first saccades were unaffected, but second saccades were made to the wrong place and had increased latencies. In the remaining two experiments, specific reasons for the deficit were not detected. Saline infusions into DMFC had no effect. Inactivation of FEF caused a larger double-step deficit than did inactivation of DMFC. The FEF inactivation impaired contraversive first or second saccades of the sequence. In conclusion, our results suggest that the DMFC makes an important contribution to generating sequential saccades and fixations but not single saccades and fixations. Compared with the FEF, the DMFC has a weaker, less directional, more task-dependent oculomotor influence. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. RP Sommer, MA (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Room 2A50,9000 Rockville Pike, Bethesda, MD 20892 USA. FU NEI NIH HHS [EY-08502] NR 59 TC 35 Z9 36 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0014-4819 J9 EXP BRAIN RES JI Exp. Brain Res. PD FEB PY 1999 VL 124 IS 4 BP 429 EP 446 DI 10.1007/s002210050639 PG 18 WC Neurosciences SC Neurosciences & Neurology GA 168BT UT WOS:000078671400003 PM 10090655 ER PT J AU Tergau, F Wanschura, V Canelo, M Wischer, S Wassermann, EM Ziemann, U Paulus, W AF Tergau, F Wanschura, V Canelo, M Wischer, S Wassermann, EM Ziemann, U Paulus, W TI Complete suppression of voluntary motor drive during the silent period after transcranial magnetic stimulation SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE transcranial magnetic stimulation; silent period; voluntary motor drive; motor threshold; human ID CORTICAL STIMULATION; BRAIN-STIMULATION; CORTICOSPINAL NEURONS; CORTEX STIMULATION; COIL ORIENTATION; CEREBRAL-CORTEX; INTACT MAN; EXCITABILITY; INHIBITION; RESPONSES AB To evaluate changes in the motor system during the silent period (SP) induced by transcranial magnetic stimulation (TMS) of the motor cortex, we investigated motor thresholds as parameters of the excitability of the cortico-muscular pathway after a suprathreshold conditioning stimulus in the abductor digiti minimi muscle (ADM) of normal humans. Since the unconditioned motor threshold was lower during voluntary tonic contraction than at rest (31.9+/-5.4% vs. 45.6+/-7.5%), it is suggested that the difference between active and resting motor threshold indicates the magnitude of the voluntary drive on the cortico-muscular pathway. Therefore, we compared conditioned resting and active motor threshold (cRMT and cAMT) during the SP. cRMT showed an intensity-dependent period of elevation of more than 200 ms in duration and approximately 17% of the maximum stimulator output above the unconditioned threshold, due to decreased excitability of the cortico-muscular pathway after the conditioning stimulus. Some 30-40 ms after the conditioning stimulus, cAMT approximated cRMT, indicating complete suppression of the voluntary motor drive. This suppression did not start directly after the conditioning stimulus since cAMT was still significantly lower than the cRMT within the first 30-40 ms. Threshold elevation was significantly longer than the SP (220+/-41 vs. 151+/-28 ms). Recovery of the voluntary motor drive started late in the SP and was nearly complete at the end of the SP, although thresholds were still significantly elevated. We conclude that the SP is largely due to a suppression of voluntary motor drive, while the threshold elevation is a different inhibitory phenomenon that is of less importance for the generation of the SP, at least in its late part. It is argued that the pathway of fast cortico-spinal fibers activated by TMS is partially different from the pathway involved in the maintenance of tonic voluntary muscle activation. C1 Univ Gottingen, Dept Clin Neurophysiol, D-37075 Gottingen, Germany. NINDS, NIH, Bethesda, MD 20892 USA. RP Tergau, F (reprint author), Univ Gottingen, Dept Clin Neurophysiol, Robert Koch Str 40, D-37075 Gottingen, Germany. RI Paulus, Walter/A-3544-2009 OI Paulus, Walter/0000-0001-5549-8377 NR 34 TC 85 Z9 85 U1 1 U2 2 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0014-4819 J9 EXP BRAIN RES JI Exp. Brain Res. PD FEB PY 1999 VL 124 IS 4 BP 447 EP 454 DI 10.1007/s002210050640 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 168BT UT WOS:000078671400004 PM 10090656 ER PT J AU Mallia, CM Aguirre, V McGary, E Tang, Y Scandurro, AB Liu, C Noguchi, CT Beckman, BS AF Mallia, CM Aguirre, V McGary, E Tang, Y Scandurro, AB Liu, C Noguchi, CT Beckman, BS TI Protein kinase C alpha is an effector of hexamethylene bisacetamide-induced differentiation of friend erythroleukemia cells SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE protein kinase C alpha; beta-globin; erythroleukemia ID PHORBOL ESTER; NIH-3T3 CELLS; RETINOIC ACID; BETA; ERYTHROPOIETIN; PROLIFERATION; LOCALIZATION; EXPRESSION; ISOFORMS; TRANSLOCATION AB The program of biochemical and molecular events necessary for commitment to erythroid cell differentiation is particularly well characterized in murine Friend erythroleukemia cell lines. Commitment to hemoglobin synthesis in response to a variety of chemical inducers, including hexamethylene bisacetamide and dimethyl sulfoxide is completed by 24 h and proceeds to terminal differentiation by 96 h. Phorbol 12-myristate 13-acetate, a classical tumor promoter phorbol ester that binds to protein kinase C, blocks differentiation in a reversible manner, suggesting an important role for protein kinase C signaling pathways. The classical protein kinase C isoforms alpha, beta I, and beta II, play distinct roles in the transduction of proliferative and differentiative signals in human, as well as in murine, erythroleukemia cells. Protein kinase C alpha has been implicated in differentiation of human erythroleukemia cells although its translocation to the nucleus has not been observed. Taking advantage of the ability of phorbol 12-myristate 18-acetate to block differentiation in Friend erythroleukemia cells, we determined the localization of the predominant protein kinase C isoforms alpha and beta I during differentiation and in response to their blockade. The ability of phorbol myristate acetate to preferentially diminish protein kinase C alpha-protein localization to the nucleus by 24 h and thereby block differentiation induced by hexamethylene bisacetamide was paralleled by the ability of protein kinase C alpha antisense transfection to block differentiation. In addition, beta-globin transcription, assessed by polymerase chain reaction, was significantly decreased in protein kinase C alpha antisense-transfected cells compared to that seen in vector transfected ones. Taken together, these data suggest an important temporal role for nuclear protein kinase C alpha localization in Friend erythroleukemia cell differentiation. (C) 1999 Academic Press. C1 Tulane Univ, Sch Med, Tulane Canc Ctr, Dept Pharmacol, New Orleans, LA 70112 USA. NIDDK, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. RP Beckman, BS (reprint author), Tulane Univ, Sch Med, Dept Pharmacol SL83, 1430 Tulane Ave, New Orleans, LA 70112 USA. NR 32 TC 12 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 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD FEB 1 PY 1999 VL 246 IS 2 BP 348 EP 354 DI 10.1006/excr.1998.4312 PG 7 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 162WZ UT WOS:000078371200011 PM 9925750 ER PT J AU Guillouf, C Wang, TS Liu, J Walsh, CE Poirier, GG Moustacchi, E Rosselli, F AF Guillouf, C Wang, TS Liu, J Walsh, CE Poirier, GG Moustacchi, E Rosselli, F TI Fanconi anemia C protein acts at a switch between apoptosis and necrosis in mitomycin C-induced cell death SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE Fanconi anemia; apoptosis; caspase; mitomycin C ID FAS-MEDIATED APOPTOSIS; DNA FRAGMENTATION; POLY(ADP-RIBOSE) POLYMERASE; HEMATOPOIETIC-CELLS; ICE/CED-3 PROTEASE; CYTOCHROME-C; FACTOR-ALPHA; BCL-2; MITOCHONDRIAL; GENE AB Deregulation of apoptosis seems to be a hallmark of the Fanconi anemia (FA) syndrome. In order to further define the role of the FA protein from complementation group C (FAC) in apoptosis, we characterized parameters modified during the mitomycin-C (MMC)-induced apoptotic program. It is shown that despite a higher level of cell death for FA compared to normal lymphoblasts after MMC treatment, FA cells do not display a marked DNA fragmentation. Furthermore, while playing a central role in MMC apoptosis of normal lymphoblasts, the activity of caspase-3-like proteases is altered in FA cells. Interestingly, the disruption of the mitochondrial transmembrane potential (Delta psi), an early event that can lead to apoptotic or to necrotic death, is accomplished similarly in FA and in normal cells. Finally, it is shown that the overexpressed FAC protein inhibited the apoptotic steps, with the exception of the decrease of the Delta psi Altogether, our results indicate that the FAC protein acts at a step preceding the activation of the caspases and after the modification of the Delta psi, a decision point at which cells can be pushed toward either apoptosis or necrosis and which, consequently, regulates the balance between the two modes of cell death. (C) 1999 Academic Press. C1 Inst Curie, CEA, LRC 1, CNRS,UMR 218, F-75248 Paris 05, France. NHLBI, Hematol Branch, DIR, Bethesda, MD 20892 USA. Univ N Carolina, Gene Therapy Ctr, Chapel Hill, NC 27599 USA. CHU Laval, Mol Endocrinol Lab, PolyADP Ribose Metab Grp, St Foy, PQ, Canada. Univ Laval, St Foy, PQ G1K 7P4, Canada. RP Rosselli, F (reprint author), Inst Curie, CEA, LRC 1, CNRS,UMR 218, Rech 26 Rue Ulm, F-75248 Paris 05, France. EM rosselli@curie.fr NR 73 TC 29 Z9 29 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD FEB 1 PY 1999 VL 246 IS 2 BP 384 EP 394 DI 10.1006/excr.1998.4316 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 162WZ UT WOS:000078371200015 PM 9925754 ER PT J AU Ralston, E Ploug, T AF Ralston, E Ploug, T TI Caveolin-3 is associated with the T-tubules of mature skeletal muscle fibers SO EXPERIMENTAL CELL RESEARCH LA English DT Article ID NITRIC-OXIDE SYNTHASE; MUSCULAR-DYSTROPHY; SMOOTH-MUSCLE; SARCOLEMMA; EXPRESSION; CELLS; GLUT4; COMPONENT; MEMBRANE; NETWORK AB Caveolae are abundant in skeletal muscle and their coat contains a specific isoform of caveolin, caveolin-3, It has been suggested that during muscle development, caveolin-3 is associated with the T-tubules, but that in adult muscle it is found on the plasma membrane only. We have studied the distribution of caveolin-3 in single skeletal muscle; fibers from adult rat soleus by confocal immunofluorescence and by immunogold electron microscopy. We found that caveolin-3 occurs at the highest density on the plasma membrane but is also present in the core of the fibers, at the I-band/A-band interface where it is associated with the T-tubules, In neither domain of the muscle surface does caveolin-3 colocalize with the glucose transporter GLUT4 and there is no evidence for internalization of the caveolae in muscle. (C) 1999 Academic Press. C1 NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. Rigshosp, Copenhagen Muscle Res Ctr, DK-2200 Copenhagen, Denmark. Univ Copenhagen, Panum Inst, Dept Med Physiol, DK-2200 Copenhagen, Denmark. RP Ralston, E (reprint author), NINDS, Neurobiol Lab, NIH, Bldg 36,Rm 2A21, Bethesda, MD 20892 USA. NR 21 TC 45 Z9 45 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD FEB 1 PY 1999 VL 246 IS 2 BP 510 EP 515 DI 10.1006/excr.1998.4305 PG 6 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 162WZ UT WOS:000078371200028 PM 9925767 ER PT J AU Caspers-Velu, LE Wadhwani, KC Rapoport, SI Kador, PF AF Caspers-Velu, LE Wadhwani, KC Rapoport, SI Kador, PF TI Iris vasculopathy in galactose-fed rats SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE blood-aqueous barrier; galactose; diabetes; permeability; blood vessels ID BLOOD-AQUEOUS BARRIER; ALDOSE REDUCTASE; RETINAL BARRIER; PERMEABILITY; TRACER; MICROPEROXIDASE; RETINOPATHY; PREVENTION; TRANSPORT AB Increased iris vessel permeability observed in diabetics has also been reported to occur in diabetic animals and galactose-fed rats. The potential role of aldose reductase in the induction of iris vessel changes has been investigated in rats fed a 50%, galactose diet with/without the aldose reductase inhibitors AL 1576, sorbinil or ponalrestat for 7 to 18 months. Compared to normal control rats, long-term galactose-fed rats display a breakdown of the blood-aqueous barrier due to iris vessel changes that include focal straightening, dilation, constriction, increased permeability, ischemia and new vessel proliferation. The onset and progression of these iridal vessel changes were prevented by the aldose reductase inhibitors AL 1576 and sorbinil, and reduced by Ponalrestat, Computerized analyses of lumen areas of iris vessels indicated an 18-fold decrease in the vascular area near the pupillary boarder in untreated galactose-fed rats compared with age-matched controls and galactose-fed rats treated with aldose reductase inhibitors, These observations linking iris vessel changes with galactose-feeding, coupled with the fact that aldose reductase inhibitors also prevent these changes, strongly suggest a link between the sorbitol pathway and the appearance and progression of iris vessel changes. (C) 1999 Academic Press. C1 NEI, Lab Ocular Therapeut, NIH, Bethesda, MD 20892 USA. NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. RP Caspers-Velu, LE (reprint author), Hop Univ St Pierre, Serv Ophthalmol, 322 Rue Haute, B-1180 Brussels, Belgium. NR 34 TC 3 Z9 3 U1 0 U2 0 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 J9 EXP EYE RES JI Exp. Eye Res. PD FEB PY 1999 VL 68 IS 2 BP 211 EP 221 DI 10.1006/exer.1998.0594 PG 11 WC Ophthalmology SC Ophthalmology GA 179UN UT WOS:000079348000007 PM 10068486 ER PT J AU Zhang, SR Skalsky, Y Garfinkel, DJ AF Zhang, SR Skalsky, Y Garfinkel, DJ TI MGA2 or SPT23 is required for transcription of the Delta 9 fatty acid desaturase gene, OLE1, and nuclear membrane integrity in Saccharomyces cerevisiae SO GENETICS LA English DT Article ID MESSENGER-RNA; DELTA(9)-DESATURASE GENE; ACETYL-COENZYME; YEAST-CELLS; MUTANTS; TRANSFORMATION; TEMPERATURE; INHERITANCE; CYTOCHROME-B5; CARBOXYLASE AB MGA2 and SPT23 are functionally and genetically redundant homologs in Saccharomyces cerevisiae. Both genes are implicated in the transcription of a subset of genes, including Ty retrotransposons and Ty-induced mutations. Neither gene is essential for growth, but mga2 spt23 double mutants are inviable. We have isolated a gene-specific activator, SW15, and the Delta 9 fatty acid desaturase of yeast, OLE1, as multicopy suppressors of an mga2 Delta spt23 temperature-sensitive mutation (spt23-ts). The le iel of unsaturated fatty acids decreases 35-40% when the mga2 Delta spt23-ts mutant is incubated at 37 degrees. Electron microscopy of these cells reveals a separation of inner and outer nuclear membranes that is sometimes accompanied by vesiclelike projections in the intermembrane space. The products of Ole1p catalysis, oleic acid and palmitoleic acid, suppress mga2 Delta spt23-ts and mga2 Delta spt23 Delta lethality and restore normal nuclear membrane morphology. Furthermore, the level of the OLE1 transcript decreases more than 15-fold in the absence of wild-type Mga2p and Spt23p. Our results suggest that Mga2p/Spt23p control cell viability by stimulating OLE1 transcription. C1 NCI, Movable Genet Elements Sect, Gene Regulat & Chromosome Biol Lab,Adv BioSci Lab, Basic Res Program,Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA. RP NCI, Movable Genet Elements Sect, Gene Regulat & Chromosome Biol Lab,Adv BioSci Lab, Basic Res Program,Frederick Canc Res & Dev Ctr, POB B, Ft Detrick, MD 21702 USA. EM garfinke@mail.ncifcrf.gov NR 49 TC 103 Z9 106 U1 0 U2 6 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 EI 1943-2631 J9 GENETICS JI Genetics PD FEB PY 1999 VL 151 IS 2 BP 473 EP 483 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 164KF UT WOS:000078462500006 PM 9927444 ER PT J AU Gu, J Guan, XY Ashlock, MA AF Gu, J Guan, XY Ashlock, MA TI Isolation of human transcripts expressed in hamster cells from YACs by cDNA representational difference analysis SO GENOME RESEARCH LA English DT Article ID DIRECT SELECTION; GENES; SEQUENCES; IDENTIFICATION; DNA AB Gene isolation methods used during positional cloning rely on physical contigs consisting of bacterial artificial chromosomes, P1, or cosmid clones. However, in most instances, the initial framework For physical mapping consists of contigs of yeast artificial chromosome (YACs), large vectors that are suboptimal substrates For gene isolation. Here we report a strategy to identify gene sequences contained within a YAC by using cDNA representational difference analysis (RDA) to directly isolate transcripts expressed from the YAC in mammalian cells. The RDA tester cDNAs were generated from a previously reported hamster cell line derived by stable transfer of a 590-kb YAC (911D5) that expressed NPC1, the human gene responsible for Niemann-Pick type C (NP-C). The driver cDNAs were generated from a control hamster cell line that did not contain the YAC that expressed NPC1. Among the gene fragments obtained by RDA, NPC1 was the most abundant product. In addition, two non-NPC1 fragments were isolated that were mapped to and expressed from 911D5. One of these RDA gene fragments (7-R) spans more than one exon and has 98% sequence identity with a human cDNA clone reported previously as an expressed sequence tag (EST), but not mapped to a chromosomal region. The other fragment (2-R) that had no significant sequence similarities with known mammalian genes or ESTs, was Further localized to the region of overlap between YACs 911D5 and 844E3. The latter YAC is part of a contig across the NP-C candidate region, but does not contain NPC1. This two-part approach in which stable YAC transfer is followed by cDNA RDA should be a useful adjunct strategy to expedite the cloning of human genes when a YAC contig is available across a candidate interval. C1 NIH, Natl Human Genome Res Inst, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. NIH, Natl Human Genome Res Inst, Canc Genet Branch, Bethesda, MD 20892 USA. RP Ashlock, MA (reprint author), NIH, Natl Human Genome Res Inst, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. RI Guan, Xin-Yuan/A-3639-2009 OI Guan, Xin-Yuan/0000-0002-4485-6017 NR 17 TC 4 Z9 4 U1 0 U2 3 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 FEB PY 1999 VL 9 IS 2 BP 182 EP 188 PG 7 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 169VU UT WOS:000078770400010 PM 10022983 ER PT J AU Kuehl, PM Weisemann, JM Touchman, JW Green, ED Boguski, MS AF Kuehl, PM Weisemann, JM Touchman, JW Green, ED Boguski, MS TI An effective approach for analyzing "prefinished" genomic sequence data SO GENOME RESEARCH LA English DT Article ID DATABASES; SHOTGUN; REGIONS; DNA AB Ongoing efforts to sequence the human genome are already generating large amounts of data, with substantial increases anticipated over the next few years. In most cases, a shotgun sequencing strategy is being used, which rapidly yields most of the primary sequence in incompletely assembled sequence contigs ("prefinished" sequence) and more slowly produces the final, completely assembled sequence ("finished" sequence). Thus, in general, prefinished sequence is produced in excess of finished sequence, and this trend is certain to continue and even accelerate over the next few years. Even at a prefinished stage, genomic sequence represents a rich source of important biological information that is of great interest to many investigators. However, analyzing such data is a challenging and daunting task, both because of its sheer volume and because it can change on a day-by-day basis. To facilitate the discovery and characterization of genes and other important elements within prefinished sequence, we have developed an analytical strategy and system that uses readily available software tools in new combinations. Implementation of this strategy for the analysis of prefinished sequence data from human chromosome 7 has demonstrated that this is a convenient, inexpensive, and extensible solution to the problem of analyzing the large amounts of preliminary data being produced by large-scale sequencing efforts. Our approach is accessible to any investigator who wishes to assimilate additional information about particular sequence data en route to developing richer annotations of a finished sequence. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. NIH, Natl Human Genome Res Inst, Genome Technol Branch, Bethesda, MD 20892 USA. Univ Maryland, Dept Mol & Cell Biol, Baltimore, MD 21201 USA. RP Boguski, MS (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM boguski@ncbi.nim.nih.gov NR 25 TC 4 Z9 5 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD FEB PY 1999 VL 9 IS 2 BP 189 EP 194 PG 6 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 169VU UT WOS:000078770400011 PM 10022984 ER PT J AU Crackower, MA Sinasac, DS Xia, J Motoyama, J Prochazka, M Rommens, JM Scherer, SW Tsui, LC AF Crackower, MA Sinasac, DS Xia, J Motoyama, J Prochazka, M Rommens, JM Scherer, SW Tsui, LC TI Cloning and characterization of two cytoplasmic dynein intermediate chain genes in mouse and human SO GENOMICS LA English DT Article ID HAND SPLIT FOOT; LEFT-RIGHT ASYMMETRY; DROSOPHILA-MELANOGASTER; SPINDLE ORIENTATION; CULTURED-CELLS; LIGHT-CHAIN; EXPRESSION; COMPLEX; CHROMOSOME; INVERSUS AB Cytoplasmic dynein is a large multisubunit microtubule-based motor protein, which mediates movement of numerous intracellular organelles. We report here the identification of the human homologue of cytoplasmic dynein intermediate chain 1 gene (DNCI1) located on human chromosome 7q21.3-q22.1. The mouse orthologue (Dnci1) was identified along with another highly related gene, Dnci2, and their RNA in situ expression patterns were examined during mouse embryogenesis. Dnci1 was found to have a highly restricted expression domain in the developing forebrain as well as the peripheral nervous system (PNS), while Dnci2 displayed a broad expression profile throughout the entire central nervous system and most of the PNS. A dynamic expression profile was also found for Dnci2 in the developing mouse limb bud. The data presented here provide a framework for the further analysis of the functional role of Dnci1 and Dnci2 in mouse and DNCI1 in human. (C) 1999 Academic Press. C1 Hosp Sick Children, Dept Genet, Toronto, ON M5G 1X8, Canada. Univ Toronto, Dept Mol & Med Genet, Toronto, ON, Canada. Hosp Sick Children, Dept Endocrinol, Toronto, ON M5G 1X8, Canada. NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. RP Tsui, LC (reprint author), Hosp Sick Children, Dept Genet, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM lctsui@genet.sickkids.on.ca RI Tsui, Lap-chee/A-1081-2010; Howe, Jennifer/I-9013-2012; Scherer, Stephen /B-3785-2013 OI Scherer, Stephen /0000-0002-8326-1999 NR 48 TC 29 Z9 32 U1 0 U2 3 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 FEB 1 PY 1999 VL 55 IS 3 BP 257 EP 267 DI 10.1006/geno.1998.5665 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 169WD UT WOS:000078771400001 PM 10049579 ER PT J AU Stephan, DA Hoffman, EP AF Stephan, DA Hoffman, EP TI Physical mapping of the rippling muscle disease locus SO GENOMICS LA English DT Article ID HUMAN SKELETAL-MUSCLE; ALPHA-ACTIN GENE; HUMAN GENOME; REPEAT POLYMORPHISM; EXPRESSION; SEQUENCE; MAP; CLONING; DNA; CHROMOSOME-1 AB Rippling muscle disease (RMD) is an autosomal dominant disorder characterized by electrically silent, percussion induced muscular contractions. We previously reported the localization of a gene for RMD to 1q41-q42 by genome-wide linkage analysis in a large family from Oregon. This RMD gene was initially found to be contained within a 12-cM interval with a maximum multipoint lod score of 3.56. A YAC/BAC contig was assembled by STS content mapping and database searches spanning the nonrecombinant interval containing the RMD gene (RMD1). The physical map, in conjunction with recent mapping information from various other sources, clarified the order of genetic markers in this region and necessitated redefinition of the RMD genetic interval by linkage analysis with the newly ordered markers. Polymorphisms that mapped to the YACs in this contig were genotyped in this family and used to provide statistical support for narrowing of the critical genetic interval to 3 cM, corresponding to a maximum possible physical distance of 4.0 Rib. In addition, recombination breakpoint mapping supported the evidence that RMD1 must reside within this interval between markers D1S446 and D1S2680. ESTs (82) were mapped to the YACs spanning the region known to contain the RMD1 gene, and of these, 9 become strong positional candidates. The physical and refined genetic maps of this RMD locus set the stage for isolation of the responsible gene and elucidation of a novel patho-mechanism of calcium homeostasis in skeletal muscle. (C) 1999 Academic Press. C1 Univ Pittsburgh, Sch Med, Dept Mol Genet & Biochem, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Sch Med, Dept Human Genet, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Sch Med, Dept Pediat, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA. RP Stephan, DA (reprint author), Natl Human Genome Res Inst, NIH, 36 Convent Dr 3D05, Bethesda, MD 20892 USA. EM dstephan@nhgri.nih.gov FU NINDS NIH HHS [NS34913] NR 33 TC 12 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 0888-7543 J9 GENOMICS JI Genomics PD FEB 1 PY 1999 VL 55 IS 3 BP 268 EP 274 DI 10.1006/geno.1998.5689 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 169WD UT WOS:000078771400002 PM 10049580 ER PT J AU Liu, M Parker, RMC Darby, K Eyre, HJ Copeland, NG Crawford, J Gilbert, DJ Sutherland, GR Jenkins, NA Herzog, H AF Liu, M Parker, RMC Darby, K Eyre, HJ Copeland, NG Crawford, J Gilbert, DJ Sutherland, GR Jenkins, NA Herzog, H TI GPR56, a novel secretin-like human G-protein-coupled receptor gene SO GENOMICS LA English DT Article ID 7-SPAN TRANSMEMBRANE MOLECULE; ORGANIZATION; SUPERFAMILY; EXPRESSION; MEMBER; CD97; CLONING AB A novel gene product, GPR56, with homology to the seven transmembrane-domain receptor superfamily, has been cloned by PCR amplification using degenerate oligonucleotide primers and subsequent screening of a human heart cDNA library. The isolated 2.8-kb cDNA clone encodes a protein of 693 amino acids that shows highest identity (32%) to HE6, a member of a subclass of the class B secretin-like G-protein-coupled receptors. Northern analysis of various human tissues revealed a wide distribution of the transcript with highest levels found in thyroid gland, brain, and heart. In situ hybridization analysis of human thyroid gland as well as rat heart and brain tissue confirms these results and identifies the hippocampus and hypothalamic nuclei as brain areas with particularly high expression of GPR56 mRNA. The high level of mRNA expression, its wide distribution, and the mucin-like extracellular domain of the receptor protein suggest a possible role for this receptor in cell-cell interaction processes. The human gene for GPR56 has been isolated and its exon-intron structure determined. The total length of the human GPR56 gene is approximately 15 kb, and it consists of 13 exons. Fluorescence in situ hybridization, PCR analysis of somatic cell hybrids, and interspecific mouse backcross mapping have localized the genes to human chromosome 16q13 and mouse chromosome 8. (C) 1999 Academic Press. C1 St Vincents Hosp, Garvan Inst Med Res, Neurobiol Program, Sydney, NSW 2010, Australia. Womens & Childrens Hosp, Dept Cytogenet & Mol Genet, Ctr Med Genet, Adelaide, SA 5006, Australia. NCI, Mammalian Genet Lab, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Herzog, H (reprint author), St Vincents Hosp, Garvan Inst Med Res, Neurobiol Program, 384 Victoria St, Sydney, NSW 2010, Australia. RI Sutherland, Grant/D-2606-2012; Crawford, Joanna /F-9135-2013 OI Crawford, Joanna /0000-0003-0786-6889 NR 18 TC 49 Z9 50 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 FEB 1 PY 1999 VL 55 IS 3 BP 296 EP 305 DI 10.1006/geno.1998.5644 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 169WD UT WOS:000078771400006 PM 10049584 ER PT J AU Probst, FJ Chen, KS Zhao, Q Wang, AH Friedman, TB Lupski, JR Camper, SA AF Probst, FJ Chen, KS Zhao, Q Wang, AH Friedman, TB Lupski, JR Camper, SA TI A physical map of the mouse shaker-2 region contains many of the genes commonly deleted in Smith-Magenis syndrome (del17p11.2p11.2) SO GENOMICS LA English DT Article ID CDNA SEQUENCE; EXPRESSION; HOMOLOG; 17P11.2; FAMILY; DIOXIN; FLII AB We report the construction of a physical map of the region of mouse chromosome 11 that encompasses shaker-2 (sh2), a model for the human nonsyndromic deafness DFNB3. DFNB3 maps within the common deletion region of Smith-Magenis syndrome (SMS), del(17) (p11.2p11.2). Eleven of the genes mapping within the SMS common deletion region have murine homologs on the sh2 physical map. The gene order in this region is not perfectly conserved between mouse and human, a finding to be considered as we engineer a mouse model of Smith-Magenis syndrome. (C) 1999 Academic Press. C1 Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. Texas Childrens Hosp, Dept Pediat, Houston, TX 77030 USA. Michigan State Univ, Grad Program Genet, E Lansing, MI 48824 USA. Natl Inst Deafness & Other Commun Disorders, Mol Genet Lab, NIH, Rockville, MD 20850 USA. RP Camper, SA (reprint author), Univ Michigan, Dept Human Genet, 4301 MSRB 3,1500 W Med Ctr Dr, Ann Arbor, MI 48109 USA. RI Chen, Ken-Shiung/A-2204-2011 FU NICHD NIH HHS [R01 HD30428]; NIDCD NIH HHS [Z01 DC 00038, Z01 DC 00035] NR 25 TC 19 Z9 20 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD FEB 1 PY 1999 VL 55 IS 3 BP 348 EP 352 DI 10.1006/geno.1998.5669 PG 5 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 169WD UT WOS:000078771400014 PM 10049592 ER PT J AU Jin, DY Kozak, CA Pangilinan, F Spencer, F Green, ED Jeang, KT AF Jin, DY Kozak, CA Pangilinan, F Spencer, F Green, ED Jeang, KT TI Mitotic checkpoint locus MAD1L1 maps to human chromosome 7p22 and mouse chromosome 5 SO GENOMICS LA English DT Article C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Ctr Med Genet, Baltimore, MD 21205 USA. RP Jeang, KT (reprint author), NIAID, Mol Microbiol Lab, NIH, Bldg 4,Room 306,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Jeang, Kuan-Teh/A-2424-2008 NR 5 TC 16 Z9 18 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD FEB 1 PY 1999 VL 55 IS 3 BP 363 EP 364 DI 10.1006/geno.1998.5654 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 169WD UT WOS:000078771400017 PM 10049595 ER PT J AU Boni, R Zhuang, ZP Burg, G Vortmeyer, A AF Boni, R Zhuang, ZP Burg, G Vortmeyer, A TI Microdissection: use in molecular oncological dermatology SO HAUTARZT LA German DT Review DE microdissection; gene; cutaneous tumors; tumor suppressor gene ID ENDOCRINE NEOPLASIA TYPE-1; MERKEL CELL-CARCINOMA; POLYMERASE CHAIN-REACTION; CUTANEOUS MELANOMA; ALLELIC DELETION; MUTATIONS; GENE; CHROMOSOME-11; TUMORS AB Microdissection allows the procurement of selective cell populations or single cells of archival sections or frossen tissue. Most cutaneous tumors can not be cultivated or consist of heterogeneous cell populations. Thus, microdissection is an important prerequisite for molecular genetic analyses of cutaneous neoplasms. This review describes the microdissection and its application in dermatologic oncology is demonstrated. C1 Univ Zurich Hosp, Dermatol Klin, CH-8091 Zurich, Switzerland. NCI, Dept Pathol, NIH, Bethesda, MD USA. RP Boni, R (reprint author), Univ Zurich Hosp, Dermatol Klin, Gloriastr 31, CH-8091 Zurich, Switzerland. NR 20 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0017-8470 J9 HAUTARZT JI Hautarzt PD FEB PY 1999 VL 50 IS 2 BP 98 EP 102 DI 10.1007/s001050050871 PG 7 WC Dermatology SC Dermatology GA 171ZT UT WOS:000078895400002 PM 10097951 ER PT J AU Simons-Morton, BG Crump, AD Haynie, DL Saylor, KE AF Simons-Morton, BG Crump, AD Haynie, DL Saylor, KE TI Student-school bonding and adolescent problem behavior SO HEALTH EDUCATION RESEARCH LA English DT Article ID RISK AB Adolescent problem behavior, including substance use, school misconduct and delinquency, is a national concern, Implicit in the concept of middle school is the recognition that students who develop positive social bonds with their school are more likely to perform well academically, and refrain from misconduct and other antisocial behavior. However, little scientific attention has been given to the complex interactions between middle school students and the school environment. Prior to implementing a middle school problem behavior prevention program we conducted a survey in the seven middle schools in one US school district. Out of 4668 grade 6-8 students enrolled, 4263 (91.3%) completed the survey, Student-school bonding was positively correlated with school adjustment (r = 0.49) and perceived school climate (r = 0.77), but inversely correlated with problem behavior (r = -0.39 to -0.43). Problem behavior was significantly higher (P < 0.001) among males than females and among students in higher grades. Conversely, school bonding, climate and adjustment were significantly higher (P < 0.001) among females than males, but declined significantly from one grade to the next. The data support the conclusion that school bonding is associated with problem behavior, We describe the development of a multiple-component intervention in middle schools designed to increase student-school bonding and prevent problem behavior. C1 NICHD, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. Behav & Hlth Res Inc, Rockville, MD 20852 USA. RP Simons-Morton, BG (reprint author), NICHD, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd,7B05, Rockville, MD 20852 USA. OI Simons-Morton, Bruce/0000-0003-1099-6617; Haynie, Denise/0000-0002-8270-6079 NR 46 TC 93 Z9 94 U1 2 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1153 J9 HEALTH EDUC RES JI Health Educ. Res. PD FEB PY 1999 VL 14 IS 1 BP 99 EP 107 DI 10.1093/her/14.1.99 PG 9 WC Education & Educational Research; Public, Environmental & Occupational Health SC Education & Educational Research; Public, Environmental & Occupational Health GA 168KX UT WOS:000078692900010 PM 10537951 ER PT J AU Gavrilin, YI Khrouch, VT Shinkarev, SM Krysenko, NA Skryabin, AM Bouville, A Anspaugh, LR AF Gavrilin, YI Khrouch, VT Shinkarev, SM Krysenko, NA Skryabin, AM Bouville, A Anspaugh, LR TI Chernobyl accident: Reconstruction of thyroid dose for inhabitants of the Republic of Belarus SO HEALTH PHYSICS LA English DT Article DE Chernobyl; I-131; I-129; thyroid AB The Chernobyl accident in April 1986 resulted in widespread contamination of the environment with radioactive materials, including I-131 and other radioiodines, This environmental contamination led to substantial radiation doses in the thyroids of many inhabitants of the Republic of Belarus, The reconstruction of thyroid doses received by Belarussians is based primarily on exposure rates measured against the neck of more than 200,000 people in the more contaminated territories; these measurements were carried out within a few weeks after the accident and before the decay of I-131 to negligible levels. Preliminary estimates of thyroid dose have been divided into 3 classes: Class 1 ("measured" doses), Class 2 (doses "derived by affinity"), and Class 3 ("empirically-derived" doses), Class 1 doses are estimated directly from the measured thyroidal I-131 content of the person considered, plus information on lifestyle and dietary habits. Such estimates are available for about 130,000 individuals from the contaminated areas of the Gomel and Mogilev Oblasts and from the city of Minsk, Maximum individual doses are estimated to range up to about 60 Gy, For every village with a sufficient number of residents with Class 1 doses, individual thyroid dose distributions are determined for several age groups and levels of milk consumption. These data are used to derive Class 2 thyroid dose estimates for unmeasured inhabitants of these villages. For any village where the number of residents with Class 1 thyroid doses is small or equal to zero, individual thyroid doses of Class 3 are derived from the relationship obtained between the mean adult thyroid dose and the deposition density of I-131 Cs-137 in villages with Class 2 thyroid doses presenting characteristics similar to those of the village considered. In order to improve the reliability of the Class 3 thyroid doses, an extensive program of measurement of I-129 in soils is envisaged. C1 Minist Publ Hlth Russia, Inst Biophys, State Res Ctr Russia, Moscow, Russia. Minist Publ Hlth, Gomel, Byelarus. Sci Res Inst Radiat Med, Gomel Branch, Gomel, Byelarus. NCI, Radiat Effects Branch, Bethesda, MD 20892 USA. Lawrence Livermore Natl Lab, Dose Reconstruct Program, Livermore, CA 94550 USA. NR 34 TC 53 Z9 55 U1 0 U2 3 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 FEB PY 1999 VL 76 IS 2 BP 105 EP 119 DI 10.1097/00004032-199902000-00002 PG 15 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 161AR UT WOS:000078266000001 PM 9929121 ER PT J AU Cabral, F Trimble, E Reed, E Sarosy, G AF Cabral, F Trimble, E Reed, E Sarosy, G TI Future directions with taxane therapy SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article ID HAMSTER OVARY CELLS; GYNECOLOGIC-ONCOLOGY-GROUP; PHASE-II TRIAL; COLONY-STIMULATING FACTOR; DOSE-INTENSE TAXOL; RECURRENT ADENOCARCINOMA; MICROTUBULE ORGANIZATION; TUBULIN ISOTYPES; GENETIC-ANALYSIS; ALPHA-TUBULIN AB The potential biochemical and genetic mechanisms by which a cell might experience a decreased sensitivity to taxanes and other drugs of this class are discussed in the first part of this article. The use of taxanes in the current gynecologic-oncologic clinical setting is reviewed with special consideration given to the pharmacokinetics of taxane in relation to dose intensity and length of administration. C1 NCI, Med Ovarian Canc Sect, Med Branch, Div Clin Sci, Bethesda, MD 20892 USA. NCI, Surg Sect, Clin Invest Branch,Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. Univ Texas, Sch Med, Dept Integrat Biol Pharmacol & Physiol, Houston, TX USA. RP Sarosy, G (reprint author), NCI, Med Ovarian Canc Sect, Med Branch, Div Clin Sci, Bldg 82,Room 113,9030 Old Georgetown Rd, Bethesda, MD 20892 USA. NR 87 TC 6 Z9 6 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD FEB PY 1999 VL 13 IS 1 BP 21 EP + DI 10.1016/S0889-8588(05)70152-0 PG 22 WC Oncology; Hematology SC Oncology; Hematology GA 176HC UT WOS:000079144800003 PM 10080068 ER PT J AU Mason, AL Lau, JYN Hoang, N Qian, KP Alexander, GJM Xu, LZ Guo, LS Jacob, S Regenstein, FG Zimmerman, R Everhart, JE Wasserfall, C Maclaren, NK Perrillo, RP AF Mason, AL Lau, JYN Hoang, N Qian, KP Alexander, GJM Xu, LZ Guo, LS Jacob, S Regenstein, FG Zimmerman, R Everhart, JE Wasserfall, C Maclaren, NK Perrillo, RP TI Association of diabetes mellitus and chronic hepatitis C virus infection SO HEPATOLOGY LA English DT Article ID HIGH PREVALENCE; UNITED-STATES; GENOTYPES; ASSAY; RISK AB While patients with liver disease are known to have a higher prevalence of glucose intolerance, preliminary studies suggest that hepatitis C virus (HCV) infection may be an additional risk factor for the development of diabetes mellitus, To further study the correlation of HCV infection and diabetes, we performed a retrospective analysis of 1,117 patients with chronic viral hepatitis and analyzed whether age, sex, race, hepatitis B virus (HBV) infection, HCV infection, and cirrhosis were independently associated with diabetes. In addition, a case-control study was conducted to determine the seroprevalence of HCV infection in a cohort of 594 diabetics and 377 clinic patients assessed for thyroid disease. In the former study after the exclusion of patients with conditions predisposing to hyperglycemia, diabetes was observed in 21% of HCV-infected patients compared with 12% of HBV-infected subjects (P = .0004), Multivariate analysis revealed that HCV infection (P =.02) and age (P =.01) were independent predictors of diabetes, In the diabetes cohort, 4.2% of patients were found to be infected with HCV compared with 1.6% of control patients (P =.02), HCV genotype 2a was observed in 29% of HCV-RNA-positive diabetic patients versus 3% of local HCV-infected controls (P <.005). In conclusion, the data suggest a relatively strong association between HCV infection and diabetes, because diabetics have an increased frequency of HCV infection, particularly with genotype 2a, Furthermore, it is possible that HCV infection may serve as an additional risk factor for the development of diabetes, beyond that attributable to chronic liver disease alone. C1 Alton Ochsner Med Fdn & Ochsner Clin, Sect Gastroenterol & Hepatol, New Orleans, LA 70121 USA. Univ Florida, Div Gastroenterol Hepatol & Nutr, Gainesville, FL USA. Univ Cambridge, Sch Clin Med, Dept Med, Cambridge, England. Alton Ochsner Med Fdn & Ochsner Clin, Endocrinol Sect, New Orleans, LA 70121 USA. NIDDKD, Div Digest Dis & Nutr, Bethesda, MD 20892 USA. Univ Florida, Dept Pathol & Lab Med, Gainesville, FL USA. RP Mason, AL (reprint author), Alton Ochsner Med Fdn & Ochsner Clin, Sect Gastroenterol & Hepatol, 1520 Jefferson Highway, New Orleans, LA 70121 USA. EM amason@ochsner.org RI Mason, Andrew/D-2938-2013 OI Mason, Andrew/0000-0002-0470-9522 FU NICHD NIH HHS [HD19469-11] NR 24 TC 419 Z9 434 U1 2 U2 4 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD FEB PY 1999 VL 29 IS 2 BP 328 EP 333 DI 10.1002/hep.510290235 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 162FB UT WOS:000078333900003 PM 9918906 ER PT J AU Sakashita, N Takeya, M Kishida, T Stackhouse, TM Zbar, B Takahashi, K AF Sakashita, N Takeya, M Kishida, T Stackhouse, TM Zbar, B Takahashi, K TI Expression of von Hippel-Lindau protein in normal and pathological human tissues SO HISTOCHEMICAL JOURNAL LA English DT Article ID TUMOR-SUPPRESSOR GENE; ENDOTHELIAL GROWTH-FACTOR; RENAL-CARCINOMA CELLS; UP-REGULATION; DISEASE; MUTATIONS; IDENTIFICATION; LOCALIZATION; PRODUCT; ANGIOGENESIS AB To examine the localization of von Hippel-Lindau (VHL) protein in human tissues, we produced four novel monoclonal antibodies against human VHL protein. Western blot analysis revealed that two of these antibodies recognized the epitope in amino acid sequence 60-89 of the VHL protein and the others recognized sequences 54-60 and 189-213. In a wild-type VHL gene-transfected cell line, immunocytochemistry and immunoelectron microscopy demonstrated the intracytoplasmic localization of VHL protein, particularly in mitotic cells. In normal human tissues, VHL protein was detected immunohistochemically in epithelial cells covering the body surface and the alimentary, respiratory, and genitourinary tracts; in secretory epithelial cells of exocrine and endocrine organs; in parenchymal cells of visceral organs; in cardiomyocytes; in neurons in nervous tissue; in lymphocytes in lymphoid tissue; and in macrophages. In pathological specimens, VHL protein was expressed in VHL-related tumor, as well as in endothelial cells, fibroblasts, and pericytes, all of which are involved in active angiogenesis. These findings suggest that these monoclonal antibodies can be useful for various immunological assays and that the VHL protein plays fundamental roles in physiological and pathological situations, especially in neovascularization. C1 Kumamoto Univ, Sch Med, Dept Pathol 2, Kumamoto 8600811, Japan. Yokohama City Univ, Sch Med, Dept Urol, Kanazawa Ku, Yokohama, Kanagawa 2360004, Japan. NCI, Immunobiol Lab, Frederick Canc Res Facil & Dev Ctr, Frederick, MD 21702 USA. RP Takahashi, K (reprint author), Kumamoto Univ, Sch Med, Dept Pathol 2, 2-2-1 Honjo, Kumamoto 8600811, Japan. NR 30 TC 33 Z9 34 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0018-2214 J9 HISTOCHEM J JI Histochem.J. PD FEB PY 1999 VL 31 IS 2 BP 133 EP 144 DI 10.1023/A:1003554712386 PG 12 WC Cell Biology SC Cell Biology GA 202QW UT WOS:000080664500007 PM 10416685 ER PT J AU Le Roith, D AF Le Roith, D TI Insulin-like growth factor SO HORMONE AND METABOLIC RESEARCH LA English DT Editorial Material C1 NIDDK, Diabet Branch, HIH, Bethesda, MD 20892 USA. RP Le Roith, D (reprint author), NIDDK, Diabet Branch, HIH, 10 Ctr DR MSC 1770, Bethesda, MD 20892 USA. NR 0 TC 6 Z9 6 U1 0 U2 1 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 FEB-MAR PY 1999 VL 31 IS 2-3 BP 41 EP 42 DI 10.1055/s-2007-978696 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 186HE UT WOS:000079722200001 PM 10226779 ER PT J AU Lopaczynski, W Harris, S Nissley, P AF Lopaczynski, W Harris, S Nissley, P TI Activation of extracellular signal-regulated kinases 1 and 2 by insulin-like growth factor I in human osteosarcoma MG-63 cells SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE insulin-like growth factor I receptor; mono Q ion exchange chromatography; nuclear extracellular signal-regulated kinase 2 ID MAP KINASE; MITOGEN; RECEPTOR; ERKS; PHOSPHORYLATION; IDENTIFICATION AB The activation of extracellular signal-regulated kinases 1 and 2 by insulin-like growth factor I in human osteosarcoma MG-63 cells was examined by Mono Q ion exchange chromatography of cell extracts and measurement of myelin basic protein kinase activity, and by immunoblotting of cell extracts with a phospho-specific extracellular signal-regulated kinase antibody. Extracellular signal-regulated kinase 1 appeared to be activated in resting cells and addition of insulin-like growth factor I resulted in the activation primarily of extracellular signal-regulated kinase 2. Extracellular signal-regulated kinase 2 was found in the nucleus after addition of insulin-like growth factor I. C1 NCI, NIH, Bethesda, MD 20892 USA. RP Nissley, P (reprint author), NCI, NIH, Bldg 10,Rm 4N115, Bethesda, MD 20892 USA. NR 17 TC 2 Z9 2 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 FEB-MAR PY 1999 VL 31 IS 2-3 BP 65 EP 69 DI 10.1055/s-2007-978700 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 186HE UT WOS:000079722200005 PM 10226783 ER PT J AU Lee, CY Cohen, FJ Wu, HB Ooi, GT Rechler, MM AF Lee, CY Cohen, FJ Wu, HB Ooi, GT Rechler, MM TI The absence of 150-kDa insulin-like growth factor complexes in fetal rat serum is not due to a lack of functional acid-labile subunit SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE ALS mRNA; liver; development; ALS protease activity; IGFBP-3 ID BINDING-PROTEIN COMPLEX; FACTOR (IGF)-BINDING PROTEIN-3; MESSENGER-RNAS; FACTOR-II; IGF-I; EXPRESSION; ONTOGENY; IGFBP-3; LIVER AB Most of the insulin-like growth factors (IGFs) in adult rat or human plasma circulate in 150-kDa heterotrimeric complexes with IGF-binding protein-3 (IGFBP-3) and an acid-labile subunit (ALS). These 150-kDa complexes are not present, however, in rat serum at birth. As ALS is the critical determinant in the formation of the 150-kDa complexes in adult rat serum, the present study asks whether the absence of 150-kDa complexes in fetal rat serum results from a low abundance of ALS. We report that ALS mRNA is expressed in term fetal rat liver at 30% of the levels in adult liver, that radioiodinated rat ALS is not proteolyzed by incubation with fetal rat serum, and that sufficient functional ALS is present in fetal rat serum to form 150-kDa complexes with recombinant human IGFBP-3, These results indicate that the low levels of 150-kDa complexes in perinatal rat serum are not due to low circulating levels of ALS. C1 NIDDKD, Growth & Dev Sect, Mol & Cellular Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Rechler, MM (reprint author), NIDDKD, Growth & Dev Sect, Mol & Cellular Endocrinol Branch, NIH, Bldg 10 Room 8D12, Bethesda, MD 20892 USA. NR 25 TC 4 Z9 4 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 FEB-MAR PY 1999 VL 31 IS 2-3 BP 182 EP 185 DI 10.1055/s-2007-978717 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 186HE UT WOS:000079722200022 PM 10226800 ER PT J AU Wu, HB Lee, CY Rechler, MM AF Wu, HB Lee, CY Rechler, MM TI Proteolysis of insulin-like growth factor binding protein-3 in serum from pregnant, non-pregnant and fetal rats by matrix metalloproteinases and serine proteases SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE TIMP; recombinant MMP-3; IGFBP-3; ALS ID I IGF-I; EXPRESSION; IGFBP-3; COMPLEX AB The insulin-like growth factors (IGFs) in adult mammalian plasma circulate predominantly in 150-kDa complexes that also contain IGF-binding protein-3 (IGFBP-3) and an acid-labile subunit. Proteolysis of IGFBP-3 within the 150-kDa complex decreases its affinity for IGFs, facilitating their release to the tissues. By contrast,150-kDa complexes are not detected in serum from fetal or pregnant adult rats. Decreased complex formation results from insufficient availability of IGFBP-3 due to increased IGFBP-3 proteolysis. The present study characterizes IGFBP-3 protease activity in serum from fetal, pregnant and non-pregnant adult rats by comparing the effect of different protease inhibitors. Proteolysis of exogenous recombinant human IGFBP-3 (for fetal and pregnancy serum) or endogenous ICFBP-3 (for non-pregnant adult rat serum) following incubation at 37 degrees C was measured by ligand blotting. In all three sera, ICFBP-3 proteolysis was inhibited completely by: (i) EDTA, a chelator of divalent cations. Inhibition was reversed by zinc, but not by calcium ions; (ii) 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF), an inhibitor of serine proteases; and (iii) a specific tissue inhibitor of matrix metalloproteinases (TIMP-1). Recombinant human matrix metalloproteinase-3 (MMP-3) proteolyzed recombinant human IGFBP-3 or endogenous rat IGFBP-3 in nonpregnancy serum pretreated with AEBSF to inactivate endogenous serine proteases. These results suggest that serine proteases initiate the activation of latent MMP precursor, and that the activated MMP directly degrades IGFBP-3. C1 NIDDKD, Growth & Dev Sect, Mol & Cellular Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Wu, HB (reprint author), NIDDKD, Growth & Dev Sect, Mol & Cellular Endocrinol Branch, NIH, Bldg 10 Room 8D12, Bethesda, MD 20892 USA. NR 26 TC 20 Z9 21 U1 0 U2 1 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 FEB-MAR PY 1999 VL 31 IS 2-3 BP 186 EP 191 DI 10.1055/s-2007-978718 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 186HE UT WOS:000079722200023 PM 10226801 ER PT J AU Peterson, RJ Goldman, D Long, JC AF Peterson, RJ Goldman, D Long, JC TI Nucleotide sequence diversity in non-coding regions of ALDH2 as revealed by restriction enzyme and SSCP analysis SO HUMAN GENETICS LA English DT Article ID STRAND CONFORMATION POLYMORPHISM; CYSTIC-FIBROSIS GENE; NUCLEAR-DNA POLYMORPHISMS; LINKAGE-DISEQUILIBRIUM; ALDEHYDE DEHYDROGENASE; DIASTROPHIC DYSPLASIA; ALCOHOL SENSITIVITY; MAXIMUM-LIKELIHOOD; MITOCHONDRIAL-DNA; HUMAN-EVOLUTION AB The simultaneous analysis of closely linked nucleotide substitutions has recently become possible. However, it is not known whether the construction of molecular haplotypes will be a generally useful strategy for nuclear genes. Furthermore, whereas mobility-shift methods are widely used for the discovery of nucleotide substitutions, the yield of these methods has rarefy been evaluated. This paper investigates these issues in non-coding regions of ALDH2, the gene that encodes aldehyde dehydrogenase 2 (ALDH2). Screening 20 Europeans, 20 native Americans, and 20 Asians by using restriction enzyme and single-strand conformation polymorphism (SSCP) analysis has revealed 16 variable sites. SSCP yields slightly fewer than the number of nucleotide substitutions predicted by the restriction enzyme digests. Estimates of nucleotide diversity are similar to those of other genes, suggesting that the pattern of polymorphism in ALDH2 offers a preview of what can be expected in many human nuclear genes. Eight of the variable sites discovered here and four sites discovered by others have been genotyped in 756 people from 17 populations across five continents. An expectation-maximization method has used to estimate haplotype states and frequencies. Only three haplotypes are common worldwide, and a fourth haplotype is common in, but private to, Asia. Although allele frequencies differ among sites, linkage disequilibrium is almost maximal across ALDH2. This suggests that haplotype construction at ALDH2 is particularly successful. The ALDH2 result, in conjunction with linkage disequilibrium results from other genes, indicates that haplotype construction will be a generally useful genomic strategy. C1 NIAAA, Sect Populat Genet & Linkage, Neurogenet Lab, Bethesda, MD 20892 USA. Penn State Univ, Dept Anthropol, University Pk, PA 16802 USA. RP Long, JC (reprint author), NIAAA, Sect Populat Genet & Linkage, Neurogenet Lab, Pk 5 Bldg,Rm 451 MSC 8110,12420 Parklawn Dr, Bethesda, MD 20892 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 63 TC 33 Z9 33 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD FEB PY 1999 VL 104 IS 2 BP 177 EP 187 DI 10.1007/s004390050932 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 178QF UT WOS:000079276900010 PM 10190330 ER PT J AU Quezado, MM Moskaluk, CA Bryant, B Mills, SE Merino, MJ AF Quezado, MM Moskaluk, CA Bryant, B Mills, SE Merino, MJ TI Incidence of loss of heterozygosity at p53 and BRCA1 loci in serous surface carcinoma SO HUMAN PATHOLOGY LA English DT Article DE LOH; 17q; serous surface carcinoma ID EPITHELIAL OVARIAN-TUMORS; MOLECULAR-GENETIC CHANGES; ALLELIC DELETION; CHROMOSOME 17Q; FREQUENT LOSS; CANCER; MUTATIONS; BREAST; REGION; MALIGNANCIES AB Serous surface carcinoma (SSC) is a neoplasm histologically indistinguishable from typical serous carcinomas that arise from the ovary bur has a distinct clinical presentation. It is characterized by widespread peritoneal dissemination at presentation, but the ovaries are grossly normal in size and shape. If the carcinoma involves the ovaries microscopically, the tumor is confined to the surface or is minimally invasive, The recognition of this entity is important, because in some studies it appears to have a poorer prognosis than stage-matched serous cancers of the ovary. Loss of heterozygosity (LOH) of the p53 (17p) and BRCA1 (17q) tumor suppressor genes has been frequently identified in sporadic ovarian carcinomas. Although 17p LOH is correlated with common p53 gene mutations, inactivating mutations of the BRCA1 gene are uncommon in sporadic ovarian cases. In contrast, germline BRCA1 mutations are responsible for some hereditary forms of ovarian cancer, where it has been suggested that germline BRCA1 mutations confer a more favorable prognosis, In this study, 12 sporadic SSC were assessed for the presence of allelic deletions on the p53 and BRCA1 gene loci. DNA from both tumor and normal cells was obtained for LOH studies using tissue microdissection. Polymerase chain reaction (PCR) amplification was performed with the polymorphic DNA markers TP53 (17p13.1/p53 gene) and D17S579 (17q/BRCA1 gene). LOH in the p53 and BRCA1 loci was detected in 62.5% and 66.6% of the cases, respectively. In 50% of tumors informative for both markers, it is possible that an entire chromosome may be lost. In conclusion, we have shown that LOH of the p53 and BRCA1 loci is a frequent event in sporadic SSC, similar to what has been described in the usual form of serous ovarian carcinoma. Mutational analysis will be necessary to determine the exact role of these genes in this group of tumors. HUM PATHOL 30:203-207. This is a US government work. There are no restrictions on its use. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Univ Virginia, Dept Pathol, Surg Pathol Sect, Charlottesville, VA USA. RP Merino, MJ (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Room 2N212,10 Ctr Dr, Bethesda, MD 20892 USA. NR 39 TC 15 Z9 16 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD FEB PY 1999 VL 30 IS 2 BP 203 EP 207 DI 10.1016/S0046-8177(99)90277-0 PG 5 WC Pathology SC Pathology GA 167DF UT WOS:000078616800015 PM 10029450 ER PT J AU Cardillo, C Kilcoyne, CM Waclawiw, M Cannon, RO Panza, JA AF Cardillo, C Kilcoyne, CM Waclawiw, M Cannon, RO Panza, JA TI Role of endothelin in the increased vascular tone of patients with essential hypertension SO HYPERTENSION LA English DT Article DE endothelin; hypertension, essential; vascular tone; receptors, endothelin; blood flow ID PLASMA ENDOTHELIN; RECEPTOR ANTAGONIST; ET(B) RECEPTORS; BLOOD-PRESSURE; HEART-FAILURE; RESISTANCE; BLOCKADE; POTENT; ET(A); EXPRESSION AB We investigated the possible role of endothelin in the increased vasoconstrictor tone of hypertensive patients using antagonists of endothelin receptors. Forearm blood flow (FBF) responses (strain-gauge plethysmography) to intraarterial infusion of blockers of endothelin-A (ETA) (BQ-123) and endothelin-B (ETB) (BQ-788) receptors, separately and in combination, were measured in hypertensive patients and normotensive control subjects. In healthy subjects, BQ-123 alone or in combination with BQ-788 did not significantly modify FBF (P=0.78 and P=0.63, respectively). In hypertensive patients, in contrast, BQ-123 increased FBF by 33+/-7% (P<0.001 Versus baseline), and the combination of BQ-123 and BQ-788 resulted in a greater vasodilator response (63+/-12%; P=0.006 versus BQ-123 alone in the same subjects). BQ-788 produced a divergent vasoactive effect in the two groups, with a decrease of FBF (17+/-5%; P=0.004 versus baseline) in control subjects and transient vasodilation (15+/-7% after 20 minutes) in hypertensive patients (P<0.001, hypertensives versus controls). The vasoconstrictor response to endothelin-1 was slightly higher (P=0.04) in hypertensive patients (46+/-4%) than in control subjects (32+/-4%). Our data indicate that patients with essential hypertension have increased vascular endothelin activity, which may be of pathophysiological relevance to their increased vascular tone. In these patients, nonselective ETA and ETB blockade seems to produce a greater vasodilator effect than selective ETA blockade. C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. RP Panza, JA (reprint author), NHLBI, Cardiol Branch, NIH, Bldg 10,Room 7B-15, Bethesda, MD 20892 USA. NR 33 TC 191 Z9 195 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 FEB PY 1999 VL 33 IS 2 BP 753 EP 758 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 168CM UT WOS:000078673300028 PM 10024340 ER PT J AU Vaquero, JJ Seidel, J Siegel, S Gandler, WR Green, MV AF Vaquero, JJ Seidel, J Siegel, S Gandler, WR Green, MV TI Performance characteristics of a compact position-sensitive LSO detector module (vol 17, pg 967, 1998) SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Correction C1 NIH, Dept Nucl Med, Bethesda, MD 20892 USA. RP Green, MV (reprint author), NIH, Dept Nucl Med, Bldg 10,Room 1C401,MSC 1180, Bethesda, MD 20892 USA. RI Vaquero, Juan Jose/D-3033-2009 OI Vaquero, Juan Jose/0000-0001-9200-361X NR 1 TC 0 Z9 0 U1 0 U2 0 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017-2394 USA SN 0278-0062 J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD FEB PY 1999 VL 18 IS 2 BP 184 EP 184 DI 10.1109/TMI.1999.759130 PG 1 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 190CG UT WOS:000079943500010 ER PT J AU Ortiz, M Wine, JW Lohrey, N Ruscetti, FW Spence, SE Keller, JR AF Ortiz, M Wine, JW Lohrey, N Ruscetti, FW Spence, SE Keller, JR TI Functional characterization of a novel hematopoietic stem cell and its place in the c-kit maturation pathway in bone marrow cell development SO IMMUNITY LA English DT Article ID COLONY-FORMING CELLS; CFU-S; PROGENITOR CELLS; MOUSE; SPLEEN; RECONSTITUTION; SEPARATION; EXPRESSION; TRANSPLANTATION; ENRICHMENT AB While the majority of purified pluripotential hematopoietic stem cells (PHSC) express c-Kit, the receptor for steel factor, we have phenotypically and functionally separated a distinct class of PHSC that does not express c-Kit. In contrast to c-Kit-postive (c-Kit(pos)) PHSC, the c-Kit-negative (C-Kit(neg)) PHSC do not proliferate in response to multiple hematopoietic growth factors in vitro and do not radioprotect or form macroscopic spleen colonies (CFU-s) when transplanted into lethally irradiated recipients. However, the C-Kit(neg) PHSC show delayed or slow reconstitution kinetics when cotransplanted with radioprotective bone marrow cells. c-Kit(neg) PHSCs cells can give rise to c-Kit(pos) cells with CFU-s activity, radioprotective activity, and PHSC activity. Thus, constituitive hematopoiesis is maintained by c-Kit(pos) PHSCS cells that are recruited from a more primitive quiescent c-Kit(neg) PHSC population, which represents a critical developmental stage in definitive hematopoiesis. C1 SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Lab Leukocyte Biol, Frederick, MD 21702 USA. RP Keller, JR (reprint author), SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. EM kellerj@mail.ncifcrf.gov FU NCI NIH HHS [N01-CO-56000] NR 33 TC 56 Z9 56 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD FEB PY 1999 VL 10 IS 2 BP 173 EP 182 DI 10.1016/S1074-7613(00)80018-7 PG 10 WC Immunology SC Immunology GA 173GF UT WOS:000078972200005 PM 10072070 ER PT J AU O'Brien, SJ Yuhki, N AF O'Brien, SJ Yuhki, N TI Comparative genome organization of the major histocompatibility complex: lessons from the Felidae SO IMMUNOLOGICAL REVIEWS LA English DT Review ID CLASS-I GENES; CAPTIVE BREEDING PROGRAMS; ANTIGEN-BINDING SITE; IMMUNOLOGICAL SURVEILLANCE; NUCLEOTIDE SUBSTITUTION; OVERDOMINANT SELECTION; BALANCING SELECTION; NATURAL-SELECTION; MHC POLYMORPHISM; MAREKS-DISEASE AB The mammalian major histocompatibility complex (MHC) has taught both immunologists and evolutionary biologists a great deal about the patterns and processes that have led to immune defenses. Driven principally by human and mouse studies, comparative MHC projects among other mammalian species offer certain advantages in connecting MHC genome characters to natural situations. We have studied the MHC in the domestic cat and in several wild species of Felidae. Our observations affirm class I and class II homology with other mammalian orders, derivative gene duplications during the Felidae radiation, abundant persistent trans-species allele polymorphism, recombination-derived amino acid motifs, and inverted ratios of non-synonymous to silent substitutions in the MHC peptide-binding regions, consistent with overdominant selection in class I and II genes. MHC diversity as quantified in population studies is a powerful barometer of historic demographic reduction for several endangered species including cheetahs, Asiatic lions, Florida panthers and tigers. In two cases (Florida panther and cheetah), reduced MHC variation may be contributing to uniform population sensitivity to emerging infectious pathogens. The Felidae species, nearly all endangered and monitored for conservation concerns, have allowed a glimpse of species adaptation, mediated by MHC divergence, using comparative inferences drawn from human and mouse models. C1 NCI, Lab Genom Divers, Frederick, MD 21702 USA. RP O'Brien, SJ (reprint author), NCI, Lab Genom Divers, Frederick, MD 21702 USA. EM obrien@mail.ncifcrf.gov NR 99 TC 37 Z9 47 U1 1 U2 29 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD FEB PY 1999 VL 167 BP 133 EP 144 DI 10.1111/j.1600-065X.1999.tb01387.x PG 12 WC Immunology SC Immunology GA 188MP UT WOS:000079851100010 PM 10319256 ER PT J AU Carrington, M AF Carrington, M TI Recombination within the human MHC SO IMMUNOLOGICAL REVIEWS LA English DT Review ID MAJOR HISTOCOMPATIBILITY COMPLEX; CLASS-II REGION; FIELD GEL-ELECTROPHORESIS; HLA-B ALLELES; LINKAGE DISEQUILIBRIUM; MEIOTIC RECOMBINATION; HOT-SPOT; SINGLE-SPERM; SACCHAROMYCES-CEREVISIAE; NUCLEOTIDE SUBSTITUTION AB Recombination (crossing over) in the human MHC is thought to have played a role in generation of novel alleles at various HLA loci. It is also responsible for the diversity observed at the haplotype level, although the functional consequences of this activity are nor clear. Historic and family studies of recombination have provided estimations of recombination fractions across the MHC and identified potential hotspots for recombination in the class II region. Other characteristics of recombination in the human MHC such as haplotype specificity in recombination frequency and localized sequence motifs involved in recombination have been considered, but have been difficult to address given the constraints of human population studies. Single-sperm typing holds promise in overcoming some of the limitations inherent in the study of recombination in human populations. Both family-based and sperm typing analyses of recombination, along with our knowledge of Linkage disequilibrium patterns in the MHC, may provide novel information regarding the evolution of HLA haplotypes that will be difficult to obtain by other means. C1 NCI, SAIC Frederick, IRSP, Frederick, MD 21702 USA. RP Carrington, M (reprint author), NCI, SAIC Frederick, IRSP, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 107 TC 76 Z9 82 U1 0 U2 3 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD FEB PY 1999 VL 167 BP 245 EP 256 DI 10.1111/j.1600-065X.1999.tb01397.x PG 12 WC Immunology SC Immunology GA 188MP UT WOS:000079851100020 PM 10319266 ER PT J AU Kumar, A Ta, D Henderson, D Mushinski, JF Reed, JC Kuus-Reichel, K Saedi, MS AF Kumar, A Ta, D Henderson, D Mushinski, JF Reed, JC Kuus-Reichel, K Saedi, MS TI bcl2 and v-abl oncogenes cooperate to immortalize murine B cells that secrete antigen specific antibodies SO IMMUNOLOGY LETTERS LA English DT Article DE bcl2; upsilon-abl; oncogenes; immortalization; B cells ID C-MYC; HEMATOPOIETIC-CELLS; TRANSGENIC MICE; PRE-B; RAPID INDUCTION; LEUKEMIA-VIRUS; ABELSON VIRUS; T-CELLS; GENE; RAS AB In this manuscript, a general strategy was designed and used to rapidly test whether any combination(s) of p53, v-abl, bc12 and ras oncogenes could act cooperatively to immortalize B cells. Here we report that only the combination of v-abl and bc12 was successful. Splenic B cells from beta galactosidase-immunized mice were stimulated in vitro with lipopolysaccharide and dextran sulphate for 48 h and co-infected with ecotropic A-MuLV (v-abl) and amphotropic pZip-bcl2 (human bc12) viruses. When inoculated i.p. into naive pristane-primed mice, these B cells generated mesenteric lymphadenopathy, intraperitoneal lymph nodules and ascites in 100% (8/8) of the mice within 36-53 days. The ascites fluid contained 69.5-122 mu g/ml IgG and 2.5-13 mu g/ml IgM against the immunogen. The ascites cells were passed intraperitoneally up to three times. In all passages, ascites tumors were generated, and the ascites fluid contained beta galactosidase-specific Ige and IgM, indicating that some immunoglobulin secreting B cells had been immortalized. Neither ascites nor tumors were produced when B cells infected with only one of the viruses was injected into the mice. The presence of each oncogene in ascites cells was verified by immunohistochemistry or RT-PCR. This study provides evidence for the cooperativity of an unexpected pair of oncogenes in B cell immortalization. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Hybritech Inc, San Diego, CA 92196 USA. NCI, Mol Genet Sect, Genet Lab, Bethesda, MD 20892 USA. Burnham Inst, Ctr Canc Res, La Jolla, CA 92037 USA. RP Saedi, MS (reprint author), Hybritech Inc, POB 269006, San Diego, CA 92196 USA. NR 31 TC 4 Z9 4 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2478 J9 IMMUNOL LETT JI Immunol. Lett. PD FEB PY 1999 VL 65 IS 3 BP 153 EP 159 DI 10.1016/S0165-2478(98)00085-6 PG 7 WC Immunology SC Immunology GA 168FN UT WOS:000078681200002 PM 10065737 ER PT J AU Shearer, GM Pinto, LA Clerici, M AF Shearer, GM Pinto, LA Clerici, M TI Alloimmunization for immune-based therapy and vaccine design against HIV/AIDS SO IMMUNOLOGY TODAY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-HELPER; HIV TYPE-1; HLA-DR; HISTOCOMPATIBILITY; ANTIGEN; LYMPHOCYTES; INFECTION; MACAQUES; CELLS AB Recent studies have demonstrated protective effects of alloimmunization in the SIV model. Here, Gene Shearer, Ligia Pinto and Mario Clerici raise the possibility that alloimmunization against a spectrum of HLA-disparate leukocytes be considered for immune-based therapy and as an AIDS vaccine. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Univ Milan, Cattedra Immunol, Milan, Italy. RP Shearer, GM (reprint author), NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. EM Gene_Shearer@nih.gov; pintol@exchange.nih.gov; mago@imiucca.csi.unimi.it NR 49 TC 31 Z9 32 U1 0 U2 1 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 FEB PY 1999 VL 20 IS 2 BP 66 EP 71 DI 10.1016/S0167-5699(98)01392-9 PG 6 WC Immunology SC Immunology GA 181BL UT WOS:000079420700004 PM 10098324 ER PT J AU Calcutt, MJ Kim, MF Karpas, AB Muhlradt, PF Wise, KS AF Calcutt, MJ Kim, MF Karpas, AB Muhlradt, PF Wise, KS TI Differential posttranslational processing confers intraspecies variation of a major surface lipoprotein and a macrophage-activating lipopeptide of Mycoplasma fermentans SO INFECTION AND IMMUNITY LA English DT Article ID FREQUENCY PHASE VARIATION; ANTIGENIC VARIATION; HUMAN MONOCYTES; FRAMESHIFT MUTATION; MURINE MACROPHAGES; MEMBRANE-PROTEINS; SEQUENCE-ANALYSIS; BEHCETS-DISEASE; PEPTIDE MOTIFS; GENE AB The malp gene of Mycoplasma fermentans is shown to occur in single copy but to encode two discrete translated forms of lipid-modified surface protein that can be differentially expressed on isolates within this species: MALP-2, a 14-amino-acid (2-kDa) lipopeptide with potent macrophage-stimulatory activity (P. F. Muhlradt, M. Kiess, H. Meyer, R. Sussmuth, and G. Jung, J. Exp. Med. 185:1951-1958, 1997), and MALP-404, an abundant, full-length (404-amino-acid) surface lipoprotein of 41 kDa, previously designated P41 (K. S. Wise, M. F. Kim, P. M, Theiss, and S.-C. Lo, Infect. Immun. 61:3327-3333, 1993), The sequences, transcripts, and translation products of malp were compared between clonal isolates of strains PG18 (known to express P41) and II-29/1 (known to express high levels of MALP-2), Despite conserved malp DNA sequences containing full-length open reading frames and expression of full-length monocistronic transcripts in both isolates, Western blotting using a monoclonal antibody (MAb) to the N-terminal MALP-2 peptide revealed marked differences in the protein products expressed. Whereas PG18 expressed abundant MALP-404 with detectable MALP-2, II-29/1 revealed no MALP-404 even in samples containing a large comparative excess of MALP-2. Colony immunoblots with the MAb showed uniform surface expression of MALP-2 in II-29/1 populations. A second MAb to an epitope of MALP-404 outside the MALP-2 sequence predictably failed to stain II-29/1 colonies but uniformly stained PG18 populations, Collectively, these results provide evidence for novel posttranscriptional (probably posttranslational) processing pathways leading to differential intraspecies expression of a major lipoprotein, and a potent macrophage-activating lipopeptide, on the surface of M. fermentans. In the course of this study, a striking conserved motif (consensus, TD-G--DDKSFNQSAWE--), designated SLA, was identified in MALP-404; this motif is also distributed among selected lipoproteins and species from diverse bacterial genera, including Bacillus, Borrelia, Listeria, Mycoplasma, and Treponema. In addition, malp was shown to flank a chromosomal polymorphism. In eight isolates of M. fermentans examined, malp occurred upstream of an operon encoding the phase-variable P78 ABC transporter; but, in three of these isolates, a newly discovered insertion sequence, IS1630 (of the IS30 class), was located between these genes. C1 Univ Missouri, Sch Med, Dept Mol Microbiol & Immunol, Columbia, MO 65212 USA. NICHHD, Dev & Mol Immun Lab, Bethesda, MD 20892 USA. Gesell Biotechnol Forsch GmbH, Immunobiol Res Grp, D-38124 Braunschweig, Germany. RP Wise, KS (reprint author), Univ Missouri, Sch Med, Dept Mol Microbiol & Immunol, M616 Med Sci Bldg, Columbia, MO 65212 USA. EM wisek@health.missouri.edu FU NIAID NIH HHS [AI32219] NR 66 TC 54 Z9 55 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD FEB PY 1999 VL 67 IS 2 BP 760 EP 771 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 160VE UT WOS:000078251400042 PM 9916088 ER PT J AU Jakob, T Walker, PS Krieg, AM von Stebut, E Udey, MC Vogel, JC AF Jakob, T Walker, PS Krieg, AM von Stebut, E Udey, MC Vogel, JC TI Bacterial DNA and CpG-containing oligodeoxynucleotides activate cutaneous dendritic cells and induce IL-12 production: Implications for the augmentation of Th1 responses SO INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY LA English DT Article; Proceedings Paper CT 22nd Symposium of the Collegium-Internationale-Allergologicum - From Molecular Science to the Treatment of Allergy CY SEP 12-16, 1998 CL CORFU, GREECE SP Collegium Int Allergologicum DE dendritic cells; DNA; Langerhans cells; IL-12; oligodeoxynucleotides ID CADHERIN-MEDIATED ADHESION; NECROSIS-FACTOR-ALPHA; IMMUNOSTIMULATORY DNA; GAMMA PRODUCTION; MURINE; ADJUVANTS; MOTIFS; IMMUNIZATION; SEQUENCES; IMMUNITY AB Background: Unmethylated CpG sequences in bacterial DNA act as adjuvants selectively inducing Th1 predominant immune responses during genetic vaccination or when used in conjunction with protein Ag. The precise mechanism of this adjuvant effect is unknown. Because dendritic cells (DC) are thought to be crucially involved in T cell priming and Th1/Th2 education during vaccination via skin, we characterized the effects of bacterial DNA and CpG-containing oligodeoxynucleotides (CpG ODN) on cutaneous DC. Methods and Results: Stimulation with CpG ODN 1826 (6 mu g/ml) induced activation of immature Langerhans cell (LC)-like DC as determined by an increased expression of MHC class II and costimulatory molecules, loss of E-cadherin-mediated adhesion and increased ability to stimulate allogeneic T cells. Composition-matched control ODN 1911 lacking CpG sequences at equal concentrations was without effect. In comparison to LPS and ODN 1911, CpG ODN 1826 selectively stimulated DC to release large amounts of IL-12 (p40) and little IL-6 or TNF-alpha within 18 h and detectable levels of IL-12 p70 within 72 h. Stimulation with Escherichia coli DNA, but not calf thymus DNA, similarly induced DC maturation and IL-12 p40 production. Injection of CpG ODN into murine dermis induced enhanced expression of MHC class II and CD86 by LC in the overlying epidermis and intracytoplasmic IL-12 p40 accumulation in a subpopulation of activated LC. Conclusion: Bacterial DNA and CpG ODN stimulate DC in vitro and in vivo and may preferentially elicit Th1-predominant immune responses because they can activate and mobilize DC, inducing them to produce IL-12. C1 NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. Vet Affairs Med Ctr, Iowa City, IA 52242 USA. Univ Iowa, Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. RP Jakob, T (reprint author), Tech Univ Munich, Klin & Poliklin Dermatol & Allergol, Biedersteiner Str 29, D-80802 Munich, Germany. RI Jakob, Thilo/J-1621-2012 NR 21 TC 64 Z9 66 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1018-2438 J9 INT ARCH ALLERGY IMM JI Int. Arch. Allergy Immunol. PD FEB-APR PY 1999 VL 118 IS 2-4 BP 457 EP 461 DI 10.1159/000024163 PG 5 WC Allergy; Immunology SC Allergy; Immunology GA 193LE UT WOS:000080137100128 PM 10224474 ER PT J AU Apasov, SG Sitkovsky, MV AF Apasov, SG Sitkovsky, MV TI The extracellular versus intracellular mechanisms of inhibition of TCR-triggered activation in thymocytes by adenosine under conditions of inhibited adenosine deaminase SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE adenosine deaminase; adenosine; apoptosis; G proteins; purinergic receptors; severe combined immunodeficiency disease; TCR; thymocytes ID DEPENDENT PROTEIN-KINASE; T-CELL DEVELOPMENT; HUMAN LYMPHOCYTES; PURINERGIC RECEPTOR; POSITIVE SELECTION; EFFECTOR FUNCTIONS; DNA FRAGMENTATION; C-ALPHA; APOPTOSIS; DEATH AB The absence or low levels of adenosine deaminase (:ADA) in humans result in severe combined immunodeficiency (SCID), which is characterized by hypoplastic thymus, T lymphocyte depletion and autoimmunity. Deficiency of ADA causes increased levels of both intracellular and extracellular adenosine, although only the intracellular lymphotoxicity of accumulated adenosine is considered in the pathogenesis of ADA SCID, It is shown that extracellular but not intracellular adenosine selectively inhibits Ton-triggered up-regulation of activation markers and apoptotic events in thymocytes under conditions of ADA deficiency. The effects of intracellular adenosine are dissociated from effects of extracellular adenosine in experiments using an adenosine transporter blocker. We found that prevention of toxicity of intracellular adenosine led to survival of TCR-cross-linked thymocytes in long-term (4 days) assays, but it was not sufficient for normal T cell differentiation under conditions of inhibited ADA. Surviving TCR-cross-linked thymocytes had a non-activated phenotype due to extracellular adenosine-mediated, TCR-antagonizing signaling. Taken together the data suggest that both intracellular toxicity and signaling by extracellular adenosine may contribute to pathogenesis of ADA SCID. Accordingly, extracellular adenosine may act on thymocytes, which survived intracellular toxicity of adenosine during ADA deficiency by counteracting TCR signaling. This, in turn, could lead to failure of positive and negative selection of thymocytes, and to additional elimination of thymocytes or autoimmunity of surviving T cells. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Sitkovsky, MV (reprint author), NIAID, Immunol Lab, NIH, 10 Ctr Dr MSC 1892, Bethesda, MD 20892 USA. NR 54 TC 41 Z9 41 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD FEB PY 1999 VL 11 IS 2 BP 179 EP 189 DI 10.1093/intimm/11.2.179 PG 11 WC Immunology SC Immunology GA 169FD UT WOS:000078736100007 PM 10069416 ER PT J AU Ravussin, E Gautier, JF AF Ravussin, E Gautier, JF TI Metabolic predictors of weight gain SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE body weight; energy expenditure; physical activity; respiratory quantity; insulin sensitivity; sympathetic nervous system ID ENERGY-EXPENDITURE; BODY-WEIGHT; PIMA-INDIANS; INSULIN RESISTANCE; HUMAN OBESITY; SAN-ANTONIO; LOWER RATES; DETERMINANTS; CHILDREN; WOMEN AB Human obesity is the result of both environmental and genetic factors. In this manuscript, we briefly review the metabolic factors predicting body weight gain in Pima Indians, a population prone to obesity. The metabolic predictors of weight gain are: 1) a low metabolic rate, 2) low levels of physical activity, 3) low rates of fat oxidation, 4) insulin sensitivity, 5) low sympathetic nervous system activity, and 6) low plasma leptin concentrations. In contrast, obesity is associated with high metabolic rate, high fat oxidation, low insulin sensitivity and high plasma leptin concentration. This observation emphasizes the need to conduct prospective studies to obtain a better understanding of the etiology of obesity. In addition, genetic studies will help to identify new pathways involved in the pathophysiology of obesity. C1 NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. RP Ravussin, E (reprint author), Lilly Corp Ctr, Drop Code 0545, Indianapolis, IN 46285 USA. NR 44 TC 86 Z9 86 U1 0 U2 3 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD FEB PY 1999 VL 23 SU 1 BP 37 EP 41 DI 10.1038/sj.ijo.0800793 PG 5 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 169XK UT WOS:000078774700006 PM 10193860 ER PT J AU Norman, RA Permana, P Tanizawa, Y Ravussin, E AF Norman, RA Permana, P Tanizawa, Y Ravussin, E TI Absence of genetic variation in some obesity candidate genes (GLP1R, ASIP, MC4R MC5R) among Pima Indians SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE polymorphisms; percent body fat; obesity ID GLUCAGON-LIKE PEPTIDE-1; RECEPTOR GENE; AGOUTI GENE; MICE; ASSOCIATION; EXPRESSION; GLUCOSE AB OBJECTIVE: To examine the obesity candidate genes glucagon-like-peptide receptor (GLP1R), agouti signaling protein (ASlP) and the melanocortin receptors 4 and 5 (MC4R and MC5R) for DNA polymorphisms in their coding regions. SUBJECTS: Unrelated, non-diabetic Pima Indians (8 to 12 from each extreme of body fat). MEASUREMENTS: DNA sequencing within the coding regions of each gene. RESULT: Only one variant was detected, a silent substitution in exon 6 of GLP1R. CONCLUSION: The exclusion of any common amino-acid polymorphisms (allele frequency greater than or equal to 0.20). implies that structural variants of these genes do not contribute to variation in the high level of obesity observed among the Pima Indians. C1 NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. Yamaguchi Univ, Sch Med, Dept Internal Med 3, Yamaguchi, Japan. RP Norman, RA (reprint author), Genset Corp, 875 Prospect St, La Jolla, CA 92037 USA. NR 17 TC 13 Z9 13 U1 1 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 FEB PY 1999 VL 23 IS 2 BP 163 EP 165 DI 10.1038/sj.ijo.0800786 PG 3 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 159UA UT WOS:000078191900009 PM 10078851 ER PT J AU Hahn, SM Russo, A Cook, JA Mitchell, JB AF Hahn, SM Russo, A Cook, JA Mitchell, JB TI A multidrug-resistant breast cancer cell line induced by weekly exposure to doxorubicin SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE multidrug-resistance; breast cancer; doxorubicin ID CYTO-TOXICITY; GLUTATHIONE DEPLETION; TUMOR-CELLS; CHEMOTHERAPY; ADRIAMYCIN; CARCINOMA; EXPRESSION; MODULATION; MELPHALAN; TRANSPORT AB Attempts to study drug resistance in vitro have focused on continuous exposure of cell lines to cytotoxic agents that results in marked resistance. In an effort to examine drug resistance in an environment that is more typical of a clinical setting, monolayered human breast cancer cells (MCF-7) were exposed weekly for one hour to doxorubicin at a concentration that is achieved in vivo (0.1 mu g/ml). After 20 weeks, the treated cell line (C20) was found to be resistant to doxorubicin by a factor of 2.0-2.5 at the 10 and 1% cell survival level compared to parent MCF-7 cells. Additionally, cross resistance to other chemotherapeutic agents including etoposide, vincristine, cisplatin, and mitomycin C was observed. Similar to other models of in vitro drug resistance, no modification of radiosensitivity was observed in C20 cells. The p170 glycoprotein was not overexpressed on C20 cells as assessed by the anti-p170 glycoprotein monoclonal antibody C219 staining nor was mRNA for the mdr-1 or MRP gene overexpressed. In addition, the mdr-blocking agent verapamil had no effect on the level of resistance encountered in tissue culture. C20 cells did not differ from the parent cell line with respect to cell cycle distribution, doubling time, GSH, GSH peroxidase, GSH reductase or GSH transferase levels. After a one-hour exposure to doxorubicin, lower intracellular doxorubicin levels were found in C20 cells compared to the parent line which provides at least a partial explanation for resistance, although the mechanism for this is unclear. Although the magnitude of resistance observed in the C20 cell line is low compared to other in vitro models of drug resistance, the modest level of drug resistance is probably sufficient to explain drug resistance seen clinically. The model of non-mdr mediated drug resistance presented may be a more relevant model for the evaluation of drug resistance in vitro. C1 NCI, Radiat Biol Branch, Div Clin Sci, Bethesda, MD 20892 USA. Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. RP Mitchell, JB (reprint author), NCI, Radiat Biol Branch, Div Clin Sci, Bldg 10,Room B3-B69, Bethesda, MD 20892 USA. NR 32 TC 16 Z9 16 U1 0 U2 1 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD FEB PY 1999 VL 14 IS 2 BP 273 EP 279 PG 7 WC Oncology SC Oncology GA 160BU UT WOS:000078211100010 PM 9917502 ER PT J AU Westergaard, GC Haynie, MK Lundquist, AL Suomi, SJ AF Westergaard, GC Haynie, MK Lundquist, AL Suomi, SJ TI Carrying, sharing, and hand preference in tufted capuchins (Cebus apella) SO INTERNATIONAL JOURNAL OF PRIMATOLOGY LA English DT Article DE bipedalism; capuchin; carrying; food sharing; hand preference ID FOOD; MONKEYS AB We examined the relationship among carrying, food-sharing, and hand preference in tufted capuchins (Cebus apella). The rationale was to evaluate further the use of Cebus as an alternative primate model to Pan for behavior relevant to early hominid evolution. We first examined bipedalism and food-sharing within an established social group, and then examined the direction and strength of hand preference for food carrying in an expanded sample. Several aspects of capuchin behavior warrant discussion. First, bipedal carrying and food-sharing occurred more frequently when we provided bulky foods than when we provided smaller foods. Second, food-sharing was characterized by passive tolerance, rather than active giving between subjects. Third, subjects shared food primarily with immatures and followed a pattern of reciprocal exchange. Finally, we found no evidence for population-level hand preference for carrying. We posit that an away of behavioral similarities among Cebus, Pan, and Homo evolved through convergent processes, and in this regard capuchins can be seen as an alternative primate model to chimpanzees for the evolution of early hominid behavior C1 NICHHD, Comparat Ethol Lab, Bethesda, MD USA. RP Westergaard, GC (reprint author), NIH, Anim Ctr, POB 529, Poolesville, MD 20837 USA. NR 20 TC 9 Z9 10 U1 1 U2 6 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0164-0291 J9 INT J PRIMATOL JI Int. J. Primatol. PD FEB PY 1999 VL 20 IS 1 BP 153 EP 162 DI 10.1023/A:1020592402625 PG 10 WC Zoology SC Zoology GA 178ZQ UT WOS:000079299400008 ER PT J AU Carper, DA Sun, JK Iwata, T Zigler, JS Ibaraki, N Lin, LR Reddy, V AF Carper, DA Sun, JK Iwata, T Zigler, JS Ibaraki, N Lin, LR Reddy, V TI Oxidative stress induces differential gene expression in a human lens epithelial cell line SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID NF-KAPPA-B; GLUTATHIONE-PEROXIDASE; HYDROGEN-PEROXIDE; ALTERNATIVE EXON; SPLICING FACTOR; ORGAN-CULTURE; DAMAGE; INHIBITION; CATARACT; PROTEIN AB PURPOSE. To identify differentially expressed genes in a human lens epithelial cell line exposed to oxidative stress. METHODS. Reverse transcriptase-polymerase chain reaction (RT-PCR) differential display was used to evaluate differential gene expression in a human lens epithelial cell line (SRA 01-04) when cells were exposed for 3 hours to a single bolus of 200 mu M hydrogen peroxide. differentially expressed genes were identified through DNA sequencing and a nucleotide database search. Differential expression was confirmed by northern blot and RT-PCR analyses. RESULTS. Using 18 primer sets, 28 RT-PCR products were differentially expressed between control and hydrogen peroxide-treated cells. In stressed cells, mitochondrial transcripts nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit 4 and cytochrome b were downregulated 4-fold. Of the cytoplasmic mRNAs, glutamine cyclotransferase decreased 10-fold, whereas cytokine-inducible nuclear protein, alternative splicing factor 2, and beta-hydroxyisobutryl-coenzyme A hydrolase increased 2-, 4-, and 10-fold, respectively. Analysis of mitochondrial transcripts in a 24-hour time course showed that NADH dehydrogenase subunit 4 mRNA decreased by 2-fold as early as 1 hour after oxidative stress, whereas the rate of decrease was slower for cytochrome b, cytochrome oxidase III, and 16S rRNA. CONCLUSIONS. Oxidative stress induced specific expressed gene changes in hydrogen peroxide-treated lens cells, including genes involved in cellular respiration and mRNA and peptide processing. These early changes may reflect pathways involved in the defense, pathology or both of the Lens epithelium, which is exposed to oxidative stress throughout life. C1 NEI, Lab Mechanisms Ocular Dis, NIH, Bethesda, MD 20892 USA. Nippon Med Sch, Dept Ophthalmol, Bunkyo Ku, Tokyo 113, Japan. Oakland Univ, Eye Res Inst, Rochester, MI USA. RP Carper, DA (reprint author), NEI, Lab Mechanisms Ocular Dis, NIH, Bldg 6,Room 232,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 37 TC 39 Z9 43 U1 0 U2 1 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 FEB PY 1999 VL 40 IS 2 BP 400 EP 406 PG 7 WC Ophthalmology SC Ophthalmology GA 162XW UT WOS:000078373500017 PM 9950599 ER PT J AU Lichtstein, D Levy, T Deutsch, J Steinitz, M Zigler, JS Russell, P AF Lichtstein, D Levy, T Deutsch, J Steinitz, M Zigler, JS Russell, P TI The effects of digitalis-like compounds on rat lenses SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID ENDOGENOUS OUABAIN; CATARACTOUS LENSES; ATPASE ACTIVITY; K-ATPASE; NA+; IDENTIFICATION; PROTEIN; CELLS; MICE AB PURPOSE. Fundamental to the maintenance of ionic concentration gradients and transparency of the lens is the activity of Na+,K+-adenosine triphosphatase (ATPase) in the epithelial layer. Recent studies have identified endogenous digitalis-like compounds (DLCs) and 19-norbufalin and its peptide derivatives in human cataractous lenses. These compounds inhibit the activity of Na+,K+- ATPase and have been suggested to be involved in cataract formation. The present experiments were designed to test this hypothesis by determining the ability of digitalis and DLCs to induce changes in protein composition and leakage from rat lenses in organ culture. METHODS. DLCs were determined in rat lenses using three independent assays: interaction with ouabain antibodies, interaction with bufalin antibodies, and inhibition of [H-3]-ouabain binding to red blood cells. Rat lenses were incubated in modified TC-199 medium in 5% CO2 atmosphere at 37 degrees C for the time of the experiment. The onset of cataractogenesis was assessed by measuring protein leakage from Lenses and by crystallin composition in the lens and media. RESULTS. DLCs were present in rat lens with concentrations:to 30 times higher in the capsular-epithelial layer than in the lens fibers regions. Ouabain, bufalin. digoxin, and DLC induced dose- and time-dependent leakage of protein from rat lenses. Lenses incubated with these compounds showed alterations in crystallin content consistent with changes that initiate opacity. hll the compounds caused a multilayrering of epithelial cells in the region surrounding the mitotic area and, at the same time, cell death in the central anterior region. CONCLUSIONS. Digitalis and endogenous DLCs are cataractogenic factors. These results, together with the demonstration of DLCs in the normal lens and their increased levels in human cataractous lenses, strongly suggest their involvement in the molecular mechanisms responsible for cataract formation. C1 Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Physiol, IL-91120 Jerusalem, Israel. Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Pharmaceut Chem, IL-91120 Jerusalem, Israel. Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Pathol, IL-91120 Jerusalem, Israel. NEI, Lab Mechanisms Ocular Dis, Bethesda, MD 20892 USA. RP Lichtstein, D (reprint author), Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Physiol, POB 12272, IL-91120 Jerusalem, Israel. NR 39 TC 15 Z9 15 U1 1 U2 2 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 FEB PY 1999 VL 40 IS 2 BP 407 EP 413 PG 7 WC Ophthalmology SC Ophthalmology GA 162XW UT WOS:000078373500018 PM 9950600 ER PT J AU Hou, L Yang, YH Mattay, VS Frank, JA Duyn, JH AF Hou, L Yang, YH Mattay, VS Frank, JA Duyn, JH TI Optimization of fast acquisition methods for whole-brain relative cerebral blood volume (rCBV) mapping with susceptibility contrast agents SO JMRI-JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE CBV; perfusion; bolus tracking (BT); spiral imaging; EPI ID MR CONTRAST AB Fast gradient-echo magnetic resonance scan techniques with spiral and rectilinear (echoplanar) k-space trajectories were optimized to perform! bolus-tracking studies of human brain. Cerebral hemodynamics were studied with full brain coverage, a spatial resolution of 4 mm, and a temporal resolution of 2 seconds. The sensitivity of the techniques to detect image signal-intensity changes during the first pass of the contrast agent was studied at a range of TEs using dedicated experiments. For single-shot versions of spiral scanning and echoplanar imaging techniques with a 0.1-mmol/kg injection of gadolinium diethylenetriamine pentaacetic acid using a mechanical injector at 10 mL/sec under 1.5 T, the maximum sensitivity was obtained at TEs between 35 and 45 msec, At TEs less than 35 msec, signal-intensity artifacts were observed in the images. Analysis of the point-spread function revealed that susceptibility changes induced by the contrast agent can result in signal shifts to neighboring voxels, These artifacts are attributed to susceptibility-related signal changes during the acquisition window. J, Magn, Reson, Imaging 1999;9:233-239. (C) 1999 Wiley-Liss, Inc. C1 NIH, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. RP Duyn, JH (reprint author), NIH, Lab Diagnost Radiol Res, Bldg 10,Room B1N-256, Bethesda, MD 20892 USA. RI Duyn, Jozef/F-2483-2010 NR 16 TC 15 Z9 15 U1 0 U2 1 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1053-1807 J9 JMRI-J MAGN RESON IM JI JMRI-J. Magn. Reson. Imaging PD FEB PY 1999 VL 9 IS 2 BP 233 EP 239 DI 10.1002/(SICI)1522-2586(199902)9:2<233::AID-JMRI13>3.0.CO;2-V PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 193PC UT WOS:000080144400013 PM 10077019 ER PT J AU Bulte, JWM de Cuyper, M Despres, D Frank, JA AF Bulte, JWM de Cuyper, M Despres, D Frank, JA TI Short- vs. long-circulating magnetoliposomes as bone marrow-seeking MR contrast agents SO JMRI-JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE superparamagnetic iron oxide; liposome; bone marrow; MR imaging ID SUPERPARAMAGNETIC IRON-OXIDE; LIPOSOMAL DRUG-DELIVERY; POLY(ETHYLENE GLYCOL); FREQUENCY-DEPENDENCE; RELAXATION-TIMES; GENE-THERAPY; HUMAN MDR1; IN-VIVO; CHEMOTHERAPY; PARTICLES AB We evaluated the relaxation enhancement and biodistribution of short- vs. long-circulating magnetoliposomes as a new contrast agent for magnetic resonance (MR) imaging of bone marrow. Magnetoliposomes with (ML-PEG) and without (ML) incorporation of polyethylene glycol (PEG, Mw 2000) were prepared, measuring 40 nm in diameter with 1-6 iron oxide crystals/vesicle. PEGylation selectively enhanced the T2 relaxivity of magnetoliposomes by 10% to 15%, with R1 and R2 values of 3 and 240 s(-1)/mM at 1.5 T and 37 degrees C, ML (n = 6) and ML-PEG (n = 6) preparations were administered IV into young (6-8 weeks old) and adult (>1 year old) Sprague-Dawley rats at 100 mu mol Fe/kg, PEGylation increased blood half-life (P < 0.05 for t > 30 minutes), following a biexponential clearance with a long half-life of 53.2 +/- 13.2 minutes. The clearance of ML was monoexponential, with a half-life 7.4 +/- 0.4 minutes. MR imaging revealed a pronounced uptake in bone marrow, including the iliac bone, femur, tibia, and upper and lower vertebrae. The bone marrow uptake of ML-PEG was comparable to that of MI,, with both reaching a plateau within 30 minutes following injection. Fast spin-echo Ta-weighted imaging was found to provide optimal contrast enhancement and allowed a clear depiction of red to yellow marrow conversion due to normal aging. While the use of magnetoliposomes can provide the added benefit of therapeutic drug or gene delivery, further investigation is warranted to assess their usefulness in differentiating normal vs. abnormal marrow conditions, J. Magn. Reson. Imaging 1999;9:329-335, (C) 1999 Wiley-Liss, Inc. C1 NIH, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. RP Bulte, JWM (reprint author), NIH, Lab Diagnost Radiol Res, Bldg 10,Room B1N256,10 Ctr Dr,MSC 1074, Bethesda, MD 20892 USA. RI Bulte, Jeff/A-3240-2008 OI Bulte, Jeff/0000-0003-1202-1610 NR 46 TC 75 Z9 77 U1 1 U2 8 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1053-1807 J9 JMRI-J MAGN RESON IM JI JMRI-J. Magn. Reson. Imaging PD FEB PY 1999 VL 9 IS 2 BP 329 EP 335 DI 10.1002/(SICI)1522-2586(199902)9:2<329::AID-JMRI27>3.0.CO;2-Z PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 193PC UT WOS:000080144400027 PM 10077033 ER PT J AU Bryant, LH Brechbiel, MW Wu, CC Bulte, JWM Herynek, V Frank, JA AF Bryant, LH Brechbiel, MW Wu, CC Bulte, JWM Herynek, V Frank, JA TI Synthesis and relaxometry of high-generation (G = 5, 7, 9, and 10) PAMAM dendrimer-DOTA-gadolinium chelates SO JMRI-JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE dendrimer; Gd(DOTA); relaxometry; macromolecular contrast agent ID IMAGING CONTRAST AGENTS; MACROCYCLES; EXCHANGE; TUMORS; WATER AB A series of high-generation (G) ethylenediamine-core poly-amidoamine (PANAM dendrimers corresponding to G = 5, 7, 9, and 10 were conjugated with the bifunctional chelate 2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-N,N',N ",N"'-tetraacetate (p-SCN-Bz-DOTA), Gadolinium (III) ion was added to the macromolecules, and the 1/T1 and 1/T2 NMRD profiles were measured at 3 degrees, 23 degrees, and 37 degrees C, The synthesis resulted in preparations that ranged from an average of 127 chelates and 96 Gd3+ ions per G = 5 dendrimer to an average of 3727 chelates and1860 Gd3+ ions per G = 10 dendrimer. At 20 MHz and 23 degrees C, the 1/T1 ion relaxivity increased from 30 mM(-1) s(-1) for the G = 5 to 35 mM(-1) s(-1) for the G = 7 PAMAM dendrimer-DOTA-Gd, reaching a plateau at 36 mM(-1) s(-1) for the G = 9 and G = 10 dendrimers, A similar plateau was observed for 1/T2 with values of 36 mM(-1) s(-1) for G = 5, 42 mM(-1) s(-1) for G = 7, and 45 mM(-1) s(-1) for the G = 9 and G = 10 dendrimers, This "saturation'' of ion relaxivity for high-generation dendrimers occurred over the entire frequency range studied. The 1/T1 and 1/T2 relaxivities decreased as the temperature decreased for each generation of dendrimer studied, implying that slow water exchange of bound water molecules with the bulb solvent limits the relaxivity, In such circumstances, increases in the rotational correlation time of the macromolecules associated with higher generations of dendrimer does not result in significant increases in the ion relaxivity, Although the ion relaxivity does not increase, the total molecular relaxivities increased from 2880 mM(-1) s(-1) to 66960 mM(-1) s(-1) for the G = 5 to the G = 10 dendrimer, The current findings are relevant for the design of high-generation dendrimer-based receptor agents. J, Magn. Reson,Imaging 1999; 9:348-352, (C) 1999 Wiley-Liss, Inc. C1 NIH, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. RP Bryant, LH (reprint author), NIH, Lab Diagnost Radiol Res, Bldg 10,Room B1N256,10 Ctr Dr,MSC 1074, Bethesda, MD 20892 USA. RI Bulte, Jeff/A-3240-2008 OI Bulte, Jeff/0000-0003-1202-1610 NR 18 TC 179 Z9 182 U1 5 U2 42 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1053-1807 J9 JMRI-J MAGN RESON IM JI JMRI-J. Magn. Reson. Imaging PD FEB PY 1999 VL 9 IS 2 BP 348 EP 352 DI 10.1002/(SICI)1522-2586(199902)9:2<348::AID-JMRI30>3.0.CO;2-J PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 193PC UT WOS:000080144400030 PM 10077036 ER PT J AU Ioannidis, JPA Goedert, JJ McQueen, PG Enger, C Kaslow, RA AF Ioannidis, JPA Goedert, JJ McQueen, PG Enger, C Kaslow, RA TI Comparison of viral load and human leukocyte antigen statistical and neural network predictive models for the rate of HIV-1 disease progression across two cohorts of homosexual men SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY LA English DT Article; Proceedings Paper CT 5th Conference on Retroviruses and Opportunistic Infections CY FEB 01-05, 1998 CL CHICAGO, ILLINOIS DE viral load; HLA antigens; disease progression; artificial intelligence; neural networks, computer; predictive models ID MAJOR HISTOCOMPATIBILITY COMPLEX; IMMUNODEFICIENCY-VIRUS INFECTION; PLASMA; AIDS; LYMPHOCYTES; ASSOCIATION; VIREMIA; RNA AB We compared the performance of HIV-I RNA and models based on human leukocyte antigen (HLA) in predicting the rate of HIV-1 disease progression using both linear regression and neural network models across two different cohorts of homosexual men. In all, 139 seroconverters from the Multicenter AIDS Cohort Study were used as the training set and 97 seroconverters from the District of Columbia Gay (DCG) cohort were used for validation to assess the generalizability of trained predictive models. Both viral load and HLA markers were strongly predictive of disease progression (p < .0001 and p = .001, respectively), with viral load superior to HLA (change in -2 log likelihood [-2LL] 26.7 and 10.2, respectively, in proportional hazards models). Consideration of both HLA markers and viral load offered no significant predictive advantage over viral load alone in most cases; however, HLA-based predictions obtained from neural networks modeling improved the discrimination among patients with high viral load (p = .02). Viral load, HLA scores, and rapid disease progression were moderately correlated (p < .01 for all three pairs of these variables). The median viral load was 10(3.70) copies/ml among DCG patients who had more favorable than unfavorable HLA markers and 10(4.66) copies/ml among patients with more unfavorable than favorable HLA markers, Viral load is a simpler, stronger predictor of disease progression than early developed HLA models, but neural network methods and further refined HLA models may offer additional prognostic information, especially for rapid progressors. The correlation between viral load and HLA markers suggests a possible HLA effect on setting viral load levels. C1 NIAID, Div Aids, HIV Res Branch, Bethesda, MD 20892 USA. NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NIH, Div Comp Res & Technol, Bethesda, MD 20892 USA. Johns Hopkins Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Univ Alabama, Sch Publ Hlth, Dept Epidemiol, Program Epidemiol Infect & Immun, Birmingham, AL 35294 USA. RP Ioannidis, JPA (reprint author), 23A Kalavryton St, Ano Voula 16673, Greece. EM jioannid@otenet.gr RI Ioannidis, John/G-9836-2011 FU NCRR NIH HHS [5-M01-RR-00722]; NIAID NIH HHS [U01-AI-35042, U01-AI-35043] NR 37 TC 11 Z9 11 U1 0 U2 1 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. Hum. Retrovirol. PD FEB 1 PY 1999 VL 20 IS 2 BP 129 EP 136 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 163ET UT WOS:000078390800004 PM 10048899 ER PT J AU Biro, FM Striegel-Moore, R McMahon, RP Crawford, P Obarzanek, E Morrison, JA Falkner, F AF Biro, FM Striegel-Moore, R McMahon, RP Crawford, P Obarzanek, E Morrison, JA Falkner, F TI Timing of menarche influences adiposity and ponderosity, but not regional distribution of fat. SO JOURNAL OF ADOLESCENT HEALTH LA English DT Meeting Abstract C1 Univ Cincinnati, NHLBI, Growth & Hlth Study, Cincinnati, OH USA. RI McMahon, Robert/C-5462-2009 NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD FEB PY 1999 VL 24 IS 2 BP 91 EP 91 PG 1 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 164ZK UT WOS:000078493300026 ER PT J AU Rogers, AS Culnane, M Zimmer, B Abdalian, S AF Rogers, AS Culnane, M Zimmer, B Abdalian, S CA ACTG 220 Protocol Team TI Can adolescents be enrolled in AIDS clinical trials? The results of ACTG Protocol 220. SO JOURNAL OF ADOLESCENT HEALTH LA English DT Meeting Abstract C1 Childrens Natl Med Ctr, Washington, DC 20010 USA. Montefiore Med Ctr, Bronx, NY 10467 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. NICHD, NIH, Bethesda, MD USA. Frontier Sci, Buffalo, NY USA. Tulane Med Ctr, New Orleans, LA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD FEB PY 1999 VL 24 IS 2 BP 119 EP 119 PG 1 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 164ZK UT WOS:000078493300082 ER PT J AU Burstein, GR Waterfield, G Hauptman, P Quinn, TC Gaydos, CA Joffe, A AF Burstein, GR Waterfield, G Hauptman, P Quinn, TC Gaydos, CA Joffe, A TI Chlamydia screening by urine based DNA amplification in adolescent males attending school based health centers SO JOURNAL OF ADOLESCENT HEALTH LA English DT Meeting Abstract C1 Johns Hopkins Univ, Baltimore, MD USA. Baltimore City Hlth Dept, Baltimore, MD USA. NIH, Bethesda, MD 20892 USA. RI Gaydos, Charlotte/E-9937-2010 NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD FEB PY 1999 VL 24 IS 2 BP 120 EP 120 PG 1 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 164ZK UT WOS:000078493300084 ER PT J AU Eggleston, PA Creticos, PS Lockey, R Platts-Mills, TAE Sheffer, A Taggart, VS Shapas, TJ Clobes, A Scheuttenberg, W Shapas, TJ AF Eggleston, PA Creticos, PS Lockey, R Platts-Mills, TAE Sheffer, A Taggart, VS Shapas, TJ Clobes, A Scheuttenberg, W Shapas, TJ CA Ad Hoc Working Grp Environm Allergens TI Environmental allergen avoidance in allergic asthma SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Editorial Material ID DUST MITE ALLERGEN; INNER-CITY CHILDREN; HOUSE-DUST; CONTROLLED TRIAL; BRONCHIAL HYPERRESPONSIVENESS; COCKROACH ALLERGEN; CHANGING PATTERNS; FELIS-DOMESTICUS; PARTICLE-SIZE; RISK-FACTORS C1 Amer Acad Allergy Asthma & Immunol, Execut Off, Milwaukee, WI 53202 USA. NHLBI, Bethesda, MD USA. Allergy Control Prod Inc, Bethesda, MD USA. Honeywell Inc, Minneapolis, MN 55408 USA. Clorox Co, Oakland, CA USA. RP Eggleston, PA (reprint author), Amer Acad Allergy Asthma & Immunol, Execut Off, 611 E Wells St, Milwaukee, WI 53202 USA. NR 45 TC 2 Z9 2 U1 0 U2 1 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 FEB PY 1999 VL 103 IS 2 BP 203 EP 205 PN 1 PG 3 WC Allergy; Immunology SC Allergy; Immunology GA 167JW UT WOS:000078630100004 ER PT J AU Garraud, O Mollis, SN Holland, SM Sneller, MC Malech, HL Gallin, JI Nutman, TB AF Garraud, O Mollis, SN Holland, SM Sneller, MC Malech, HL Gallin, JI Nutman, TB TI Regulation of immunoglobulin production in hyper-IgE (Job's) syndrome SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE cytokines; hyper-IgE; IFN-gamma; IgE; IgG4; IL-4; IL-12; IL-13; Job's syndrome ID HUMAN B-CELLS; NECROSIS-FACTOR-ALPHA; HUMAN HELMINTH INFECTIONS; INTERFERON-GAMMA; HYPERIMMUNOGLOBULIN-E; T-CELLS; MONONUCLEAR-CELLS; INTERLEUKIN-12 SUPPRESSES; HUMAN-LYMPHOCYTES; IGG4 PRODUCTION AB Background: The hyper-IgE (HIE), or Job's, syndrome is a rare, complex disorder characterized by high levels of serum IgE in childhood and chronic dermatitis with recurrent, often severe sinopulmonary and skin infections. Although the etiology of HIE syndrome is unknown, there is evidence that patients with HIE have abnormalities in cellular immune responses, as well as in the production of polyclonal and antigen-specific antibodies, Furthermore, there appears to be a common (but still undefined) mechanism underlying the regulation of IgE and IgG4 in this condition. Objective: We sought to assess the role of cytokines or cytokine receptor blockade in regulating IgE and IgG4 production in HIE. Methods: PBMCs were isolated from patients with HIE (n = 9) and normal individuals (n = 8), and IgE and IgG4 production was assessed spontaneously, in the presence of recombinant IL-4, IL-13, IL-6, IL-8, IL-12, and IFN-gamma, under conditions in which the n-4R was blocked or when these cytokines were neutralized by specific monoclonal or polyclonal antibodies. Results: In PBMCs from patients with HIE, a significant (P <.01) reduction in the spontaneously produced IgE (and IgG4) was induced by either IFN-gamma or IL-12, although neither cytokine could totally abrogate the immunoglobulin production, Whereas spontaneous IgE land IgG4) production was not affected by exogenous IL-4 and IL-13, neutralizing antibodies to IL-4 and IL-13 also significantly (P < .01) reduced the production of IgE and IgG4, a finding supported by the observation of increased expression of IgE germline transcripts in these patients. In contrast to the neutralization of IL-4 and IL-13 protein, anti-IL-4R antibodies or soluble n-4R completely suppressed IgE and IgG4 production in HIE. Similarly, IL-8 or antibodies to IL-6 and TNF-alpha, cytokines known to affect IL-4-dependent IgE production, completely inhibited both IgE and IgG4 production. Conclusion: These data show that overproduction of IgE and IgG4 can be regulated by a number of cytokines affecting the IL-4-dependent pathway of IgE/IgG4 production in HIE and suggest new targets for therapeutic intervention. C1 NIAID, Helminth Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. NIAID, Immunol Dis Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Nutman, TB (reprint author), NIAID, Helminth Immunol Sect, Parasit Dis Lab, NIH, Bldg 4,Room 126, Bethesda, MD 20892 USA. NR 54 TC 31 Z9 31 U1 0 U2 2 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 1999 VL 103 IS 2 BP 333 EP 340 DI 10.1016/S0091-6749(99)70510-5 PN 1 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 167JW UT WOS:000078630100023 PM 9949327 ER PT J AU Dombrowski, M Thom, E McNellis, D AF Dombrowski, M Thom, E McNellis, D TI Maternal-Fetal Medicine Units (MFMU) studies of inhaled corticosteroids during pregnancy SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article AB Few prospective clinical trials exist to address the use of asthma medications during pregnancy in relation to neonatal outcomes. There is a need to identify favorable pregnancy outcomes in relation to the successful treatment of pregnant women with asthma. To this end, 3 studies have been initiated: (1) a retrospective analysis of inhaled steroid use in a maternal-fetal medicine research center, (2) a large observational cohort study assessing the effects of different types of asthma treatments on perinatal outcomes, and (3) a randomized clinical trial comparing theophylline and inhaled beclomethasone in the treatment of pregnant women with moderately severe asthma. Preliminary information on all 3 studies is described. C1 Wayne State Univ, Hutzel Hosp, Dept Obstet & Gynecol, Detroit, MI 48201 USA. George Washington Univ, Rockville, MD USA. NICHHD, NIH, Rockville, MD USA. RP Dombrowski, M (reprint author), Wayne State Univ, Hutzel Hosp, Dept Obstet & Gynecol, 4707 St Antoine, Detroit, MI 48201 USA. NR 2 TC 11 Z9 11 U1 0 U2 0 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 FEB PY 1999 VL 103 IS 2 SU S BP S356 EP S359 DI 10.1016/S0091-6749(99)70263-0 PN 2 PG 4 WC Allergy; Immunology SC Allergy; Immunology GA 171KA UT WOS:000078861500007 PM 9949338 ER PT J AU Risby, TH Jiang, L Stoll, S Ingram, D Spangler, E Heim, J Cutler, R Roth, GS Rifkind, JM AF Risby, TH Jiang, L Stoll, S Ingram, D Spangler, E Heim, J Cutler, R Roth, GS Rifkind, JM TI Breath ethane as a marker of reactive oxygen species during manipulation of diet and oxygen tension in rats SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE dietary restriction; aging; hypoxia; breath analysis ID MEDIATED LIPID-PEROXIDATION; ANTIOXIDANT ENZYME-ACTIVITIES; FOOD RESTRICTION; METABOLIC-RATE; LIVER; REPERFUSION; GENERATION; CHILDREN AB Breath ethane, O-2 consumption, and CO2 production were analyzed in 24-mo-old female Fischer 344 rats that had been fed continuously ad libitum (AL) or restricted 30% of AL level (DR) diets since 6 wk of age. Rats were placed in a glass chamber that was first flushed with air, then with a gas mixture containing 12% O-2. After equilibration, a sample of the outflow was collected in gas sampling bags for subsequent analyses of ethane and CO2. The Oa and CO2 levels were also directly monitored in the outflow of the chamber. O-2 consumption and CO2 production increased for DR rats. Hypoxia decreased O-2 consumption and CO2 production for the AL-fed and DR rats. These changes reflect changes in metabolic rate due to diet and Pot. A significant decrease in ethane generation was found in DR rats compared with AL-fed rats. Under normoxic conditions, breath ethane decreased from 2.20 to 1.61 pmol ethane/ml CO2. During hypoxia the levels of ethane generation increased, resulting in a DR-associated decrease in ethane from 2.60 to 1.90 pmol ethane/ml CO2. These results support the hypothesis that DR reduces the level of oxidative stress. C1 NIA, Gerontol Res Ctr, Cellular & Mol Biol Lab, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. RP Rifkind, JM (reprint author), NIA, Gerontol Res Ctr, Cellular & Mol Biol Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. FU NIEHS NIH HHS [ES-03156] NR 31 TC 23 Z9 24 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD FEB PY 1999 VL 86 IS 2 BP 617 EP 622 PG 6 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 191EQ UT WOS:000080009800027 PM 9931199 ER PT J AU Konerding, DE Cheatham, TE Kollman, PA James, TL AF Konerding, DE Cheatham, TE Kollman, PA James, TL TI Restrained molecular dynamics of solvated duplex DNA using the particle mesh Ewald method SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE DNA structure; molecular dynamics; particle mesh Ewald; solvated refinement ID B-DNA; IMMUNOGLOBULIN GENES; NUCLEIC-ACIDS; OCTAMER MOTIF; PROTEINS; CONFORMATIONS; SIMULATIONS; DISTANCE; SYSTEMS; NOE AB Restrained and unrestrained aqueous solution molecular dynamics simulations applying the particle mesh Ewald (PME) method to DNA duplex structures previously determined via in vacuo restrained molecular dynamics with NMR-derived restraints are reported. Without experimental restraints, the DNA decamer, d(CATTTGCATC).d(GATGCAAATG) and trisdecamer, d(AGCTTGCCTTGAG).d(CTCAAGGCAAGCT), structures are stable on the nanosecond time scale and adopt conformations in the B-DNA family. These free DNA simulations exhibit behavior characteristic of PME simulations previously performed on DNA sequences, including a low helical twist, frequent sugar pucker transitions, B-I-B-II(epsilon - zeta) transitions and coupled crankshaft (alpha - gamma) motion. Refinement protocols similar to the original in vacuo restrained molecular dynamics (RMD) refinements but in aqueous solution using the Cornell et al, force field [Cornell et al. (1995) J. Am. Chem. Sec., 117, 5179-5197] and a particle mesh Ewald treatment produce structures which fit the restraints very well and are very similar to the original in vacuo NMR structure, except for a significant difference in the average helical twist. Figures of merit fur the average structure found in the RMD PME decamer simulations in solution are equivalent to the original in vacuo NMR structure while the figures of merit for the free MD simulations are significantly higher. The free MD simulations with the PME method, however, lead to some sequence-dependent structural features in common with the NMR structures, unlike free MD calculations with earlier force fields and protocols. There is some suggestion that the improved handling of electrostatics by PME improves long-range structural aspects which are not well defined by the short-range nature of NMR restraints. C1 Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA. NHLBI, Lab Biophys Chem 12A 2041, NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, Grad Grp Biophys, San Francisco, CA 94143 USA. RP James, TL (reprint author), Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA. FU NCI NIH HHS [CA-25644]; NIGMS NIH HHS [GM-39247] NR 26 TC 30 Z9 31 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 FEB PY 1999 VL 13 IS 2 BP 119 EP 131 DI 10.1023/A:1008353423074 PG 13 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 170JM UT WOS:000078802600003 PM 10070753 ER PT J AU Ottiger, M Bax, A AF Ottiger, M Bax, A TI Bicelle-based liquid crystals for NMR-measurement of dipolar couplings at acidic and basic pH values SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE alignment; bicelle; dipolar coupling; liquid crystal; pH; stability; ubiquitin ID HUMAN UBIQUITIN; RESOLUTION; RELAXATION; PROTEINS AB It is demonstrated that mixtures of ditetradecyl-phosphatidylcholine or didodecyl-phoshatidylcholine and dihexyl-phosphatidylcholine in water form lyotropic liquid crystalline phases under similar conditions as previously reported for bicelles consisting of dimyristoyl-phosphatidylcholine (DMPC) and dihexanoyl-phosphatidylcholine (DHPC). The carboxy-ester bonds present in DMPC and DHPC are replaced by ether linkages in their alkyl analogs, which prevents acid- or base-catalyzed hydrolysis of these compounds. N-15-H-1 dipolar couplings measured for ubiquitin over the 2.3-10.4 pH range indicate that this protein retains a backbone conformation which is very similar to its structure at pH 6.5 over this entire range. C1 NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Ottiger, M (reprint author), NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. NR 21 TC 140 Z9 143 U1 1 U2 14 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 FEB PY 1999 VL 13 IS 2 BP 187 EP 191 DI 10.1023/A:1008395916985 PG 5 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 170JM UT WOS:000078802600010 PM 10070759 ER PT J AU Cheatham, TE Cieplak, P Kollman, PA AF Cheatham, TE Cieplak, P Kollman, PA TI A modified version of the Cornell et al. force field with improved sugar pucker phases and helical repeat SO JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; TRNA(ASP) ANTICODON HAIRPIN; B-DNA TRANSITION; A-DNA; TRIPLE-HELIX; AQUEOUS-SOLUTION; NUCLEIC-ACIDS; CONFORMATIONAL-ANALYSIS; HAMMERHEAD RIBOZYME; ORGANIC-MOLECULES AB We have examined some subtle parameter modifications to the Cornell et al. force field, which has proven quite successful in reproducing nucleic acid properties, but whose C2'-endo sugar pucker phase and helical repeat for B DNA appear to be somewhat underestimated. Encouragingly, the addition of a single V(2) term involving the atoms C(sp(3))-O-(sp(3))-C(sp(3))-N(sp(2)), which can be nicely rationalized because of the anomeric effect (lone pairs on oxygen are preferentially oriented relative to the electron withdrawing N), brings the sugar pucker phase of C2'-endo sugars to near perfect agreement with ab initio calculations (W near 162 degrees). Secondly, the use of high level ab initio calculations on entire nucleosides (in contrast to smaller model systems necessitated in 1994-95 by computer limitations) lets one improve the chi torsional potential for nucleic acids. Finally, the O(sp(3))-C(sp(3))-C(sp(3))-O(sp(3)) V(2) torsional potential has been empirically adjusted to reproduce the ab initio calculated relative energy of C2'-endo and C3'-endo nucleosides. These modifications are tested in molecular dynamics simulations of mononucleosides (to assess sugar pucker percentages) and double helices of DNA and RNA (to assess helical and sequence specific structural properties). In both areas, the modified force field leads to improved agreement with experimental data. C1 Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA. Univ Warsaw, Dept Chem, PL-02093 Warsaw, Poland. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Kollman, PA (reprint author), Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA. EM pak@cgl.ucsf.edu FU NCI NIH HHS [CA-25644] NR 79 TC 672 Z9 678 U1 1 U2 32 PU ADENINE PRESS PI SCHENECTADY PA 2066 CENTRAL AVE, SCHENECTADY, NY 12304 USA SN 0739-1102 J9 J BIOMOL STRUCT DYN JI J. Biomol. Struct. Dyn. PD FEB PY 1999 VL 16 IS 4 BP 845 EP 862 PG 18 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 183GV UT WOS:000079546600007 PM 10217454 ER PT J AU Nath, D Slocombe, PM Stephens, PE Warn, A Hutchinson, GR Yamada, KM Docherty, AJP Murphy, G AF Nath, D Slocombe, PM Stephens, PE Warn, A Hutchinson, GR Yamada, KM Docherty, AJP Murphy, G TI Interaction of metargidin (ADAM-15) with alpha(v)beta(3) and alpha(5)beta(1) integrins on different haemopoietic cells SO JOURNAL OF CELL SCIENCE LA English DT Article DE metargidin; ADAM-15; integrin; disintegrin; metallaprotease; alpha(v)beta(3); alpha(5)beta(1); adhesion; ligand ID METALLOPROTEASE-DISINTEGRIN PROTEIN; NECROSIS-FACTOR-ALPHA; LIGAND-BINDING; GENE FAMILY; SIGNAL-TRANSDUCTION; EMERGING PARADIGMS; ADHESION MOLECULE; GROWTH-FACTOR; RECEPTOR; RGD AB Metargidin (ADAM-15) is a type I transmembrane glycoprotein belonging to the ADAM (A Disintegrin and Metalloprotease Domain) family of proteins and is widely expressed in different tissues and cell types. Members of this family contain an amino-terminal metalloprotease domain followed by a disintegrin domain, a cysteine-rich region and a membrane proximal EGF-like domain. The disintegrin domain of metargidin contains an RGD tripeptide sequence, suggesting that it may potentially interact with the integrin family of proteins, Here we identify integrin ligands for metargidin on haemopoietic cells, by using a chimeric protein containing the extracellular domain of metargidin fused to the Fc portion of human IgG, Binding activity to a panel of human cell lines was analysed by solid-phase cell-adhesion assays. Metargidin bound to a monocytic cell line, U937, and a T cell line, MOLT-4 in a specific manner. Adhesion was divalent cation- and temperature- dependent and strongly enhanced by Mn2+, all features of integrin-mediated binding. Using a panel of anti-integrin antibodies we show that alpha(v)beta(3) is a ligand for metargidin on U937 cells. In contrast, for MOLT-4 cells, the integrin alpha(5)beta(1) contributes to cell binding. Adhesion was mediated by the disintegrin domain of metargidin as RGD-based peptides inhibited cell binding to both cell lines. The specificity of the interaction between both alpha(v)beta(3) and alpha(5)beta(1) and metargidin was further confirmed by solid-phase adhesion assays using purified recombinant integrins. These results together indicate that metargidin can function as a cell adhesion molecule via interactions with alpha(v)beta(3) and alpha(5)beta(1) integrins. C1 Univ E Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, England. Celltech Ltd, Slough SL1 4EN, Berks, England. NIH, Lab Cranofacial Dev Biol, Bethesda, MD 20892 USA. NIH, Regenerat Branch, Bethesda, MD 20892 USA. RP Nath, D (reprint author), Univ E Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, England. EM D.Nath@uea.ac.uk FU Wellcome Trust NR 50 TC 161 Z9 168 U1 0 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE, CAMBS, ENGLAND CB4 4DL SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD FEB PY 1999 VL 112 IS 4 BP 579 EP 587 PG 9 WC Cell Biology SC Cell Biology GA 174EU UT WOS:000079021800015 PM 9914169 ER PT J AU Tao, L Wang, RH Enkemann, SA Trumbore, MW Berger, SL AF Tao, L Wang, RH Enkemann, SA Trumbore, MW Berger, SL TI Metabolic regulation of protein-bound glutamyl phosphates: Insights into the function of prothymosin alpha SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID CELL-CYCLE; IN-VITRO; GENE; EXPRESSION; PHOSPHORYLATION; PROLIFERATION; THYMOSIN-ALPHA-1; SEQUENCE; PRODUCTS; THYMUS AB Prothymosin alpha gene expression accompanies growth of all mammalian cells. The protein, which is abundant, exceedingly acidic, and localized to the nucleus, is further distinguished by the presence of clustered phosphorylated glutamic acid residues (Trumbore et al., 1997, J Biol Chem 272:26394-26404). These glutamyl phosphates are energy rich and unstable in vivo and in vitro (Wang et al., 1997, J Biol Chem 272:26405-26412). To understand the function of prothymosin alpha in greater detail, the turnover of its phosphates was examined in metabolically manipulated cells. Phosphate half-lives in growing, mock transfected, and vector-transfected COS cells were compared with the half-life in cells transfected with the prothymosin alpha gene to determine the fate of the predominantly ectopic phosphorylated protein. The values obtained-72-75 min in cells with normal levels of the protein, but 118 min in cells with surplus prothymosin alpha-led us to conclude that underutilized phosphates persist whereas functioning phosphates disperse. Cell-cycle-specific differences in the half-lives were observed in NIH3T3 cells: 72 min while cycling, 83 or 89 min during arrest in or progression through S phase, but 174 min during M-phase arrest. In the presence of actinomycin D, the value was about 145 min regardless of whether cells were quiescent or growing. In these experiments, reduced utilization of prothymosin alpha's glutamyl phosphates, signaled by an increase in their half-lives, accompanied the attenuation or abolition of transcription. Our data suggest that prothymosin a fuels an energy-requiring step in the production, processing, or export of RNA. I Cell Physiol 178:154-163, 1999. Published 1999 Wiley-Liss, Inc.dagger. C1 NCI, Sect Genes & Gene Prod, NIH, Bethesda, MD 20892 USA. RP Berger, SL (reprint author), NCI, Sect Genes & Gene Prod, NIH, Bldg 37,Room 6A-17, Bethesda, MD 20892 USA. NR 40 TC 12 Z9 13 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD FEB PY 1999 VL 178 IS 2 BP 154 EP 163 DI 10.1002/(SICI)1097-4652(199902)178:2<154::AID-JCP4>3.0.CO;2-V PG 10 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 153LU UT WOS:000077835200004 PM 10048579 ER PT J AU de Nichilo, MO Katz, BZ O'Connell, B Yamada, KM AF de Nichilo, MO Katz, BZ O'Connell, B Yamada, KM TI De novo expression of pp125(FAK) in human macrophages regulates CSK distribution and MAP kinase activation but does not affect focal contact structure SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID PROTEIN-TYROSINE KINASE; CULTURED HUMAN MACROPHAGES; MEDIATED CELL-ADHESION; C-SRC; SIGNAL-TRANSDUCTION; SUBSTRATE P130(CAS); EXTRACELLULAR-MATRIX; V-SRC; INTEGRIN; PHOSPHORYLATION AB The protein tyrosine kinase pp125(FAK) (focal adhesion kinase, or FAK) is expressed by a variety of cell types and has been implicated in integrin-mediated signaling events. We explored the potential functions of FAK by expressing it de novo in a cell type lacking FAK. We showed previously that cultured human macrophages lack FAK yet still have well-formed focal contacts. Adenovirus-mediated expression of FAK results in the appearance of FAK protein, which localizes to focal contacts and becomes tyrosine-phosphorylated without perturbing overall cell morphology or focal contacts. FAK associates With CSK 48 h after infection and recruits it to focal contacts. Tyrosine phosphorylation of p130(cas) but not of paxillin is stimulated after FAK expression. The phosphorylation of p130(cas) is lost at 48 h in parallel with CSK accumulation in focal contacts. The ERK2 form of MAP kinase is similarly activated at 12-24 h, but it also returns to low levels at 48 h. These findings demonstrate that FAK can be reconstituted to focal contacts in cells that lack it without affecting cell morphology or focal contact structure. FAK can regulate the distribution and activities of elements of the MAP kinase signaling pathway. J Cell Physiol 178:164-172, 1999. Published 1:999 Wiley-Liss, Inc.dagger. C1 NIDCR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. NIDCR, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD USA. RP Yamada, KM (reprint author), NIDCR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bldg 30,Room 421,30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. EM ky4w@nih.gov OI O'Connell, Brian/0000-0003-4529-7664; Yamada, Kenneth/0000-0003-1512-6805 NR 45 TC 3 Z9 3 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD FEB PY 1999 VL 178 IS 2 BP 164 EP 172 DI 10.1002/(SICI)1097-4652(199902)178:2<164::AID-JCP5>3.0.CO;2-R PG 9 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 153LU UT WOS:000077835200005 PM 10048580 ER PT J AU Chen, Y McCarron, RM Bembry, J Ruetzler, C Azzam, N Lenz, FA Spatz, M AF Chen, Y McCarron, RM Bembry, J Ruetzler, C Azzam, N Lenz, FA Spatz, M TI Nitric oxide modulates endothelin 1-induced Ca2+ mobilization and cytoskeletal F-actin filaments in human cerebromicrovascular endothelial cells SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE actin; brain endothelial cells; Ca2+ mobilization; cGMP; endothelin; nitric oxide ID DEPENDENT PROTEIN-KINASE; SMOOTH-MUSCLE CELLS; SIGNAL-TRANSDUCTION; HUMAN NEUTROPHILS; TONE; RAT; INHIBITION; RECEPTORS; MECHANISM; ARTERIES AB A functional interrelation between nitric oxide (NO), the endothelial-derived vasodilating factor, and endothelin 1 (ET-1), the potent vasoconstrictive peptide, was investigated in microvascular endothelium of human brain. Nor-1 dose-dependently decreased the ET-l-stimulated mobilization of Ca2+. This response was mimicked with cGMP and abrogated by inhibitors of guanylyl cyclase or cGMP-dependent protein kinase G. These findings indicate that NO and ET-I interactions involved in modulation of intracellular Ca2+ are mediated by cGMP/protein kinase G. In addition, Nor-1-mediated effects were associated with rearrangements of cytoskeleton F-actin filaments. The results suggest mechanisms by which NO-ET-1 interactions may contribute to regulation of microvascular function. C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. USN, Med Res Inst, Bethesda, MD USA. Johns Hopkins Univ, Sch Med, Dept Neurosurg, Baltimore, MD 21205 USA. RP Spatz, M (reprint author), NINDS, Stroke Branch, NIH, 36 Convent Dr,MSC 4128, Bethesda, MD 20892 USA. NR 28 TC 26 Z9 27 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD FEB PY 1999 VL 19 IS 2 BP 133 EP 138 PG 6 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 185KZ UT WOS:000079669300003 PM 10027767 ER PT J AU Morris, ED Chefer, SI Lane, MA Muzic, RF Wong, DF Dannals, RF Matochik, JA Bonab, AA Villemagne, VL Grant, SJ Ingram, DK Roth, GS London, ED AF Morris, ED Chefer, SI Lane, MA Muzic, RF Wong, DF Dannals, RF Matochik, JA Bonab, AA Villemagne, VL Grant, SJ Ingram, DK Roth, GS London, ED TI Loss of D-2 receptor binding with age in rhesus monkeys: Importance of correction for differences in striatal size SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE positron emission tomography; partial volume; dopamine; raclopride; aging ID POSITRON EMISSION TOMOGRAPHY; C-11 RACLOPRIDE BINDING; LIVING HUMAN-BRAIN; F-18 N-METHYLSPIROPERIDOL; DOPAMINE-RECEPTORS; COMPUTED-TOMOGRAPHY; DIETARY RESTRICTION; ENDOGENOUS DOPAMINE; GRAPHICAL ANALYSIS; BASAL GANGLIA AB The relation between striatal dopamine D-2 receptor binding and aging was investigated in rhesus monkeys with PET. Monkeys (n = 18, 39 to 360 months of age) were scanned with C-11-raclopride; binding potential in the striatum was estimated graphically. Because our magnetic resonance imaging analysis revealed a concomitant relation between size of striatum and age, the dynamic positron emission tomography (PET) data were corrected for possible partial volume (PV) artifacts before parameter estimation. The age-related decline in binding potential was 1% per year and was smaller than the apparent effect if the age-related change in size was ignored. This is the first in vivo demonstration of a decline in dopamine receptor binding in nonhuman primates. The rate of decline in binding potential is consistent with in vitro findings in monkeys but smaller than what has been measured previously in humans using PET. Previous PET studies in humans, however, have not corrected for PV error, although a decline in striatal size with age has been demonstrated. The results of this study suggest that PV correction must be applied to PET data to accurately detect small changes in receptor binding that may occur in parallel with structural changes in the brain. C1 NIDA, Brain Imaging Sect, Baltimore, MD 21224 USA. NIA, Baltimore, MD 21224 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Johns Hopkins Univ, Baltimore, MD USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Morris, ED (reprint author), NIDA, Brain Imaging Sect, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. FU NIDA NIH HHS [DA11080]; NIMH NIH HHS [MH42821]; PHS HHS [HP24-061] NR 44 TC 47 Z9 49 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD FEB PY 1999 VL 19 IS 2 BP 218 EP 229 PG 12 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 185KZ UT WOS:000079669300013 PM 10027777 ER PT J AU Prufer, K Veenstra, TD Jirikowski, GF Kumar, R AF Prufer, K Veenstra, TD Jirikowski, GF Kumar, R TI Distribution of 1,25-dihydroxyvitamin D3 receptor immunoreactivity in the rat brain and spinal cord SO JOURNAL OF CHEMICAL NEUROANATOMY LA English DT Article DE steroids; brain; immunohistochemistry; calcitriol; VDR ID NERVE GROWTH-FACTOR; MEMBRANE CALCIUM-PUMP; VITAMIN-D-SOLTRIOL; CALCITRIOL RECEPTOR; CHOROID-PLEXUS; TARGET-CELLS; D-3 RECEPTOR; NEURONS; SITES; LOCALIZATION AB A complete mapping study on the 1,25-dihydroxyvitamin D3 receptor immunoreactivity within the rat central nervous system was performed with a monoclonal and a polyclonal antibody. Specific immunostaining was observed within both nuclear and cytoplasmic compartments of a variety of cells in the cerebellum, mesopontine area, diencephalon, cortex, spinal cord, and limbic system. Both monoclonal and polyclonal antibodies provided similar staining patterns. The monoclonal antibody stained distinct domains within the nuclei of all and the cytoplasm of specific neuronal cell types, like motor neurons, Purkinje cells, and pyramidal cells of the cortex more clearly than the polyclonal antibody. The expression of vitamin D3 receptor in the rat central nervous system was confirmed by in situ hybridisation. The widespread distribution of vitamin D3 receptor in distinct portions of the sensory, motor, and limbic brain systems suggests multiple functional properties of 1,25-dihydroxyvitamin D3 in the central nervous system. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Univ Jena Klinikum, Inst Anat 2, D-07740 Jena, Germany. NIDDK, NIH, LCBB, Bethesda, MD 20892 USA. Mayo Clin & Mayo Fdn, Dept Med & Biochem & Mol Biol, Nephrol Res Unit, Rochester, MN 55905 USA. RP Jirikowski, GF (reprint author), Univ Jena Klinikum, Inst Anat 2, Teichgraben 7, D-07740 Jena, Germany. FU NIDDK NIH HHS [R01 DK025409, DK 25409] NR 44 TC 129 Z9 133 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0891-0618 J9 J CHEM NEUROANAT JI J. Chem. Neuroanat. PD FEB PY 1999 VL 16 IS 2 BP 135 EP 145 DI 10.1016/S0891-0618(99)00002-2 PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 187PC UT WOS:000079794400003 PM 10223312 ER PT J AU Lombardi, WJ Andreason, PJ Sirocco, KY Rio, DE Gross, RE Umhau, JC Hommer, DW AF Lombardi, WJ Andreason, PJ Sirocco, KY Rio, DE Gross, RE Umhau, JC Hommer, DW TI Wisconsin card sorting test performance following head injury: Dorsolateral fronto-striatal circuit activity predicts perseveration SO JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY LA English DT Article ID PROGRESSIVE SUPRANUCLEAR PALSY; CEREBRAL BLOOD-FLOW; POSITRON EMISSION TOMOGRAPHY; PARKINSONS-DISEASE; PREFRONTAL CORTEX; LOBE LESIONS; MULTIPLE-SCLEROSIS; COGNITIVE DEFICITS; ALZHEIMERS-DISEASE; SCHIZOPHRENIA AB The Wisconsin Card Sorting Test (WCST) has been argued to be a sensitive indicator of frontal lobe function. However, several recent studies have failed to find a consistent relationship between structural damage to this cortical area and perseveration on the test. In the present study, positron emission tomography (PET) imaging with F-18-fluorodeoxyglucose was used to examine the relationship of regional brain metabolism to perseverative responding on the WCST in patients with a history of closed-head injury. An inverse relationship was found between perseverative responses and metabolism in the right, but not the left, dorsolateral prefrontal cortex and caudate nucleus. Perseverative responding was not related to metabolism in several other regions of the frontal lobes and basal ganglia, including the putamen and the frontal poles bilaterally. These data suggest that the functional integrity of the right dorsolateral frontal-subcortical circuit is critical for WCST performance. C1 NIAAA, Clin Studies Lab, Bethesda, MD 20892 USA. Toronto Hosp, Dept Surg, Div Neurosurg, Toronto, ON, Canada. Univ Toronto, Toronto, ON, Canada. RP Lombardi, WJ (reprint author), Univ Utah, Dept Neurosci, 50 N Med Dr, Salt Lake City, UT 84132 USA. NR 57 TC 103 Z9 106 U1 1 U2 7 PU SWETS ZEITLINGER PUBLISHERS PI LISSE PA P O BOX 825, 2160 SZ LISSE, NETHERLANDS SN 1380-3395 J9 J CLIN EXP NEUROPSYC JI J. Clin. Exp. Neuropsychol. PD FEB PY 1999 VL 21 IS 1 BP 2 EP 16 DI 10.1076/jcen.21.1.2.940 PG 15 WC Psychology, Clinical; Clinical Neurology; Psychology SC Psychology; Neurosciences & Neurology GA 214VN UT WOS:000081348400002 PM 10420997 ER PT J AU Brucker-Davis, F Oldfield, EH Skarulis, MC Doppman, JL Weintraub, BD AF Brucker-Davis, F Oldfield, EH Skarulis, MC Doppman, JL Weintraub, BD TI Thyrotropin-secreting pituitary tumors: Diagnostic criteria, thyroid hormone sensitivity, and treatment outcome in 25 patients followed at the national institutes of health SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID INAPPROPRIATE SECRETION; STIMULATING HORMONE; SOMATOSTATIN ANALOG; ADENOMAS; HYPERTHYROIDISM; RESISTANCE; OCTREOTIDE; EXPRESSION; RECEPTORS; SUBUNIT AB We report a large series of 25 patients with TSH-secreting tumors (23 macroadenomas) followed at the NIH. Hyperthyroid symptoms were severe in 14 patients, mild in 8, and absent in 3. Patients were divided into 2 groups according to whether their thyroid had been treated (n = 11) or not (n = 14). In untreated patients, the classical diagnostic criteria (unresponsive TRH test, high cr-subunit, and high alpha-subunit/TSH ratio) were present, respectively, in 10, 8, and 12 cases (sensitivity, 71%, 75%, and 83%; specificity, 96%, 90%, and 65%). In treated patients, the respective sensitivities of the TRH test, cr-subunit, and alpha-subunit/TSH ratio were 64%, 90%, and 90%, and their specificities were 100%, 82%, and 73%. Studies of thyroid hormone action revealed no evidence of acquired resistance to thyroid hormone in TSH-secreting tumors. Apparent cure was achieved in 35% of cases by surgery alone and in 22% more by combined therapies. Three deaths occurred, including 1 from metastatic thyrotroph carcinoma. Six patients had residual tumor, with symptoms of hyperthyroidism controlled with octreotide in 5. The size and invasiveness of the tumor, duration of symptoms, and intensity of hyperthyroidism were the main prognostic factors. Thus, early diagnosis and treatment are the keys to a good outcome. C1 NIH, Dept Radiol, Bethesda, MD 20892 USA. NINDS, Bethesda, MD 20892 USA. NIDDKD, Mol & Cellular Endocrinol Branch, Bethesda, MD 20892 USA. RP Skarulis, MC (reprint author), NIH, Dept Radiol, Bldg 10,Room 8S235-B,10 Ctr Dr,MSC 1770, Bethesda, MD 20892 USA. NR 42 TC 127 Z9 142 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 1999 VL 84 IS 2 BP 476 EP 486 DI 10.1210/jc.84.2.476 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 164KW UT WOS:000078464000016 PM 10022404 ER PT J AU Doppman, JL Chang, R Oldfield, EH Chrousos, G Stratakis, CA Nieman, LK AF Doppman, JL Chang, R Oldfield, EH Chrousos, G Stratakis, CA Nieman, LK TI The hypoplastic inferior petrosal sinus: A potential source of false-negative results in petrosal sampling for Cushing's disease SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CORTICOTROPIN-RELEASING HORMONE; INTERNAL JUGULAR-VEIN; ECTOPIC ACTH SYNDROME; DIFFERENTIAL-DIAGNOSIS; CAVERNOUS SINUS; CARCINOID-TUMOR; DEXAMETHASONE; STIMULATION; DISTINGUISH; METYRAPONE AB Our purpose was to describe the hypoplastic or plexiform inferior petrosal sinus as a potential cause of false-negative sampling results in patients with Cushing's disease. Five hundred and one patients with surgically proven Cushing's disease and negative or equivocal magnetic resonance imaging scans of the pituitary gland underwent petrosal sinus sampling. Four patients (0.8%) with surgically proven Cushing's disease had false-negative results of petrosal sinus sampling. Retrograde inferior petrosal sinograms in these patients were reviewed to evaluate the anatomy of the inferior petrosal sinuses for abnormalities that could have contributed to this misdiagnosis. In addition, the retrograde inferior petrosal sinograms of 100 consecutive patients were reviewed to establish the frequency of asymmetric and/or hypoplastic inferior petrosal sinuses. All four patients with false-negative results of petrosal sampling demonstrated a hypoplastic or plexiform inferior petrosal sinus ipsilateral to an ACTH-secreting microadenoma. When the sampling catheter was in the hypoplastic petrosal sinus, retrograde sinograms from the contralateral side demonstrated anomalous drainage patterns on the side of the hypoplastic sinus. Because the negative results of petrosal sinus sampling false-suggested the presence of the ectopic ACTH syndrome, curative transsphenoidal surgery in these four patients was delayed up to 31 months. We conclude that the presence of a unilateral hypoplastic or plexiform inferior petrosal sinus can result in anomalous drainage from the pituitary gland that may lead to false-negative sampling results in patients with Cushing's disease. C1 NICHHD, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. NINDS, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Doppman, JL (reprint author), NICHHD, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, Bldg 10,Room 1C660,10 Ctr Dr MSC 1182, Bethesda, MD 20892 USA. EM jdoppman@nih.gov NR 23 TC 60 Z9 66 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 1999 VL 84 IS 2 BP 533 EP 540 DI 10.1210/jc.84.2.533 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 164KW UT WOS:000078464000024 PM 10022412 ER PT J AU Olsen, JH Johansen, C Sorensen, HT McLaughlin, JK Mellemkjaer, L Steffensen, FH Fraumeni, JF AF Olsen, JH Johansen, C Sorensen, HT McLaughlin, JK Mellemkjaer, L Steffensen, FH Fraumeni, JF TI Lipid-lowering medication and risk of cancer SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE lipid lowering drugs; neoplasms; pharmacoepidemiology; cohort studies ID TOTAL SERUM-CHOLESTEROL; LOW BLOOD CHOLESTEROL; HEART-DISEASE; MORTALITY; PRAVASTATIN; POPULATION; PREVENTION; TRIALS; DRUGS; DEATH AB Low or declining levels of serum cholesterol have been associated with increased mortality from cancer. We conducted a population-based cohort study of 1882 patients from one Danish county who received lipid-lowering drugs between January 1, 1991 and December 31, 1994. During the follow-up period of up to 4 years, 41 cancers were observed among users of lipid-lowering drugs, with 42.9 expected, to yield an age- and sex-standardized incidence ratio of 1.0 (95% confidence interval, 0.7-1.3). Although limited by small numbers and short follow up period, examination by site of cancer and type of drug provided no evidence of an association. Further research is needed, however, with longer follow-up to assess more fully any potential cancer risk with these medications. I CLIN EPIDEMIOL 52;2:167-169, 1999. (C) 1999 Elsevier Science Inc. C1 Danish Canc Soc, Inst Canc Epidemiol, DK-2100 Copenhagen O, Denmark. Univ Aarhus, Danish Epidemiol Sci Ctr, Aarhus, Denmark. Aarhus Univ Hosp, Dept Med 5, DK-8000 Aarhus, Denmark. Int Epidemiol Inst, Rockville, MD USA. Aalborg Hosp, Dept Internal Med M, Aalborg, Denmark. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Olsen, JH (reprint author), Danish Canc Soc, Inst Canc Epidemiol, Strandblvd 49, DK-2100 Copenhagen O, Denmark. OI Steffensen, Flemming Hald/0000-0003-0252-6631 NR 24 TC 24 Z9 24 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD FEB PY 1999 VL 52 IS 2 BP 167 EP 169 DI 10.1016/S0895-4356(98)00147-4 PG 3 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 168NY UT WOS:000078700200011 PM 10201659 ER PT J AU Goodman, JL Nelson, CM Klein, MB Hayes, SF Weston, BW AF Goodman, JL Nelson, CM Klein, MB Hayes, SF Weston, BW TI Leukocyte infection by the granulocytic ehrlichiosis agent is linked to expression of a selectin ligand SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID SIALYL-LEWIS-X; HUMAN ALPHA(1,3)FUCOSYLTRANSFERASE GENE; CARBOHYDRATE LIGAND; MOLECULAR-CLONING; T-CELLS; ANTIGEN; ADHESION; ELAM-1; DETERMINANT; RECOGNITION AB Human granulocytic ehrlichiosis (HGE) is an emerging tickborne illness caused by an intracellular bacterium that infects neutrophils. Cells susceptible to HGE express sialylated Lewis x (CD15s), a ligand for cell selectins. We demonstrate that adhesion of HGE to both HL60 cells and normal bone marrow cells directly correlates with their CD15s expression. HGE infection of HL60 cells, bone marrow progenitors, granulocytes, and monocytes was blocked by monoclonal antibodies against CD15s. However, these antibodies did not inhibit HGE binding, and anti-CD15s was capable of inhibiting the growth of HGE after its entry into the target cell. In contrast, neuraminidase treatment of HL60 cells prevented both HGE binding and infection. A cloned cell line (HL60-A2), derived from HL60 cells and resistant to HGE, was deficient in the expression of alpha-(1,3)fucosyltransferase (Fuc-TVII), an enzyme known to be required for CD15s biosynthesis. Less than 1% of HL60-A2 cells expressed CD15s, and only these rare CD15s-expressing cells bound HGE and became infected. After transfection with Fuc-TVII, cells regained CD15s expression, as well as their ability to bind HGE and become infected. Thus, CD15s expression is highly correlated with susceptibility to HGE, and it, and/or a closely related sialylated and alpha-(1,3) fucosylated molecule, plays a key role in HGE infection, an observation that may help explain the organism's tropism for leukocytes. C1 Univ Minnesota, Sch Med, Dept Med, Div Infect Dis, Minneapolis, MN 55455 USA. NIAID, Rocky Mt Lab, NIH, Hamilton, MT 59840 USA. Univ N Carolina, Sch Med, Dept Pediat, Chapel Hill, NC 27599 USA. RP Goodman, JL (reprint author), Univ Minnesota, Sch Med, Dept Med, Div Infect Dis, 516 Delaware St, Minneapolis, MN 55455 USA. FU NIAID NIH HHS [1RO1AI40952-01, 5RO1-AI37772-07] NR 30 TC 63 Z9 64 U1 0 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD FEB PY 1999 VL 103 IS 3 BP 407 EP 412 DI 10.1172/JCI4230 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 166MX UT WOS:000078581400014 PM 9927502 ER PT J AU Chou, CL Knepper, MA van Hoek, AN Brown, D Yang, BX Ma, TH Verkman, AS AF Chou, CL Knepper, MA van Hoek, AN Brown, D Yang, BX Ma, TH Verkman, AS TI Reduced water permeability and altered ultrastructure in thin descending limb of Henle in aquaporin-1 null mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID FREEZE-FRACTURE; CHANNEL; CHIP28; KIDNEY; LOOP; LOCALIZATION; SEGMENTS; CLONING; TUBULES AB It has been controversial whether high water permeability in the thin descending limb of Henle (TDLH) is required for formation of a concentrated urine by the kidney. Freeze-fracture electron microscopy (FFEM) of rat TDLH has shown an exceptionally high density of intramembrane particles (IMPs), which were proposed to consist of tetramers of aquaporin-1 (AQP1) water channels. In this study, transepithelial osmotic water permeability(P-f) was measured in isolated perfused segments (0.5-1 mm) of TDLH in wild-type (+/+), AQP1 heterozygous (+/-), and AQP1 null (-/-) mice. P-f was measured at 37 degrees C using a 100 mM bath-to-lumen osmotic gradient of raffinose, and fluorescein isothiocyanate (FITC)-dextran as the luminal volume marker. P-f was (in cm/s): 0.26 +/- 0.02 ([+/+]; SE, n = 9 tubules), 0.21 +/- 0.01 ([+/-]; n = 12), and 0.031 +/- 0.007 ([-/-]; n = 6) (P < 0.02, [+/+] vs. [+/-]; P < 0.0001, [+/+] vs. [-/-]). FFEM of kidney medulla showed remarkably fewer IMPs in TDLH from (-/-) vs. (+/+) and (+/-) mice. IMP densities were (in mu m(-2), SD, 5-12 micrographs): 5,880 +/- 238 (+/+); 5,780 +/- 450 (+/-); and 877 +/- 420 (-/-). IMP size distribution analysis revealed mean LMP diameters of 8.4 nm ([+/+] and [+/-]) and 5.2 nm([-/-]). These results demonstrate that AQP1 is the principal water channel in TDLH and support the view that osmotic equilibration along TDLH by water transport plays a key role in the renal countercurrent concentrating mechanism. The similar P-f and AQP1 expression in TDLH of(+/+) and (+/-) mice was an unexpected finding that probably accounts for the unimpaired urinary concentrating ability in (+/-) mice. C1 Univ Calif San Francisco, Cardiovasc Res Inst, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Cardiovasc Res Inst, Dept Physiol, San Francisco, CA 94143 USA. NIH, Kidney & Electrolyte Metab Lab, Bethesda, MD 20892 USA. Massachusetts Gen Hosp E, Renal Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp E, Program Membrane Biol, Boston, MA 02114 USA. RP Verkman, AS (reprint author), Univ Calif San Francisco, Cardiovasc Res Inst, Dept Med, 1246 Hlth Sci E Tower, San Francisco, CA 94143 USA. FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999]; NHLBI NIH HHS [HL-59198, HL-60288, R01 HL059198]; NIDDK NIH HHS [DK-35124, P01 DK038452, R01 DK035124, R01 DK055864, R37 DK035124] NR 31 TC 139 Z9 144 U1 0 U2 2 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD FEB PY 1999 VL 103 IS 4 BP 491 EP 496 DI 10.1172/JCI5704 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 170VF UT WOS:000078827200009 PM 10021457 ER PT J AU Liu, YJ Wada, R Kawai, H Sango, K Deng, CX Tai, T McDonald, MP Araujo, K Crawley, JN Bierfreund, U Sandhoff, K Suzuki, K Proia, RL AF Liu, YJ Wada, R Kawai, H Sango, K Deng, CX Tai, T McDonald, MP Araujo, K Crawley, JN Bierfreund, U Sandhoff, K Suzuki, K Proia, RL TI A genetic model of substrate deprivation therapy for a glycosphingolipid storage disorder SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID TAY-SACHS-DISEASE; LYSOSOMAL STORAGE; SANDHOFF-DISEASES; MOUSE MODELS; N-BUTYLDEOXYNOJIRIMYCIN; TARGETED DISRUPTION; HEXA GENE; MICE; MUCOPOLYSACCHARIDOSIS; GANGLIOSIDOSIS AB Inherited defects in the degradation of glycosphingolipids (GSLs) cause a group of severe diseases known as GSL storage disorders. There are currently no effective treatments for the majority of these disorders. We have explored a new treatment paradigm, substrate deprivation therapy, by constructing a genetic model in mice. Sandhoff's disease mice, which abnormally accumulate GSLs, were bred with mice that were blocked in their synthesis of GSLs. The mice with simultaneous defects in GSL synthesis and degradation no longer accumulated GSLs, had improved neurologic function, and had a much longer life span. However, these mice eventually developed a late-onset neurologic disease because of accumulation of another class of substrate, oligosaccharides. The results support the validity of the substrate deprivation therapy and also highlight some limitations. C1 NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. Tokyo Metropolitan Inst Med Sci, Dept Tumor Immunol, Tokyo 1138613, Japan. NIMH, Sec Behav Neuropharmacol, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. Univ Bonn, Kekule Inst Organ Chem & Biochem, D-53121 Bonn, Germany. Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. RP Proia, RL (reprint author), NIDDKD, Genet Dev & Dis Branch, NIH, Bldg 10,Room 9D-20,10 Ctr Dr MSC 1810, Bethesda, MD 20892 USA. RI Proia, Richard/A-7908-2012; deng, chuxia/N-6713-2016 FU NICHD NIH HHS [P30 HD003110, P30-HD 03110]; NINDS NIH HHS [R01 NS024453, R01-NS 24453] NR 30 TC 126 Z9 126 U1 0 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD FEB PY 1999 VL 103 IS 4 BP 497 EP 505 DI 10.1172/JCI5542 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 170VF UT WOS:000078827200010 PM 10021458 ER PT J AU Singh-Naz, N Sleemi, A Pikis, A Patel, KM Campos, JM AF Singh-Naz, N Sleemi, A Pikis, A Patel, KM Campos, JM TI Vancomycin-resistant Enterococcus faecium colonization in children SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID NOSOCOMIAL OUTBREAK; RISK-FACTORS; EPIDEMIOLOGY; INFECTION AB Nosocomial vancomycin-resistant Enterococcus (VRE) infections have been described in only small numbers of pediatric patients. In none of these studies were multivariate analyses performed to assess which factors were independent risk factors in these patients. In the present cohort study of patients admitted to our hematology/oncology unit, surveillance cultures revealed a colonization rate of 24% and all isolates were identified as Enterococcus faecium, Risk factors associated with colonization with VRE identified by multiple logistic regression analysis included young age and chemotherapy with antineoplastic agents, cefotaxime, vancomycin, and ceftazidime, A molecular epidemiological teal, pulsed-field gel electrophoresis, was used to determine the relatedness of the VRE isolates detected. DNA analysis by this method identified two major clusters of VRE isolates. Young children with gastrointestinal colonization with VRE, without evidence of clinical infection, can serve as a reservoir for the spread of VRE. C1 Childrens Natl Med Ctr, Dept Infect Dis, Washington, DC 20010 USA. Childrens Natl Med Ctr, Dept Lab Med, Washington, DC 20010 USA. Childrens Natl Med Ctr, Ctr Hlth Serv & Clin Res, Childrens Res Inst, Washington, DC 20010 USA. George Washington Univ, Sch Med, Dept Pediat, Washington, DC 20052 USA. George Washington Univ, Sch Med, Dept Pathol, Washington, DC USA. George Washington Univ, Sch Med, Dept Immunol Microbiol, Washington, DC USA. George Washington Univ, Sch Med, Sch Publ Hlth, Washington, DC USA. Louisiana State Univ, Med Ctr, Dept Obstet & Gynecol, New Orleans, LA 70112 USA. Natl Inst Dent & Craniofacial Res, Ora Infect & Immun Branch, NIH, Bethesda, MD USA. RP Singh-Naz, N (reprint author), Childrens Natl Med Ctr, Dept Infect Dis, 111 Michigan Ave NW, Washington, DC 20010 USA. NR 25 TC 44 Z9 45 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD FEB PY 1999 VL 37 IS 2 BP 413 EP 416 PG 4 WC Microbiology SC Microbiology GA 158UV UT WOS:000078136500026 PM 9889230 ER PT J AU De Pascalis, R Del Pezzo, M Nardone, G Budillon, G Lavitola, A AF De Pascalis, R Del Pezzo, M Nardone, G Budillon, G Lavitola, A TI Performance characteristics of an enzyme-linked immunosorbent assay for determining salivary immunoglobulin G response to Helicobacter pylori SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID GASTRIC-CARCINOMA; DIAGNOSTIC-TESTS; IMMUNE-RESPONSE; INFECTION; CAGA; IGG; IMMUNOASSAY; ANTIBODY; SEROLOGY; STRAINS AB We evaluated the salivary immunoglobulin G (IgG) immune response to Helicobacter pylori in 70 subjects by enzyme-linked immunosorbent assay (ELISA). Subjects with a positive H. pylori culture showed significantly higher titers of antibodies than subjects with no detectable H. pylori: the overall sensitivity and specificity of the test were 84 and 90%, respectively. The detection of salivary anti-H. pylori IgG antibodies may be considered as an alternative to serum IgG detection for ease of sample collection or when blood samples are not available in screening of patients with dyspepsia. C1 Univ Naples Federico II, Dipartimento Biol & Patol Cellulare & Mol, Cattedra Microbiol Clin, I-80131 Naples, Italy. Univ Naples Federico II, Dipartimento Patol Sistemat, Cattedra Gastroenterol, I-80131 Naples, Italy. RP De Pascalis, R (reprint author), NCI, Tumor Immunol & Biol Lab, NIH, Bldg 10,Rm 5B38,9000 Rockville Pike, Bethesda, MD 20892 USA. OI Nardone, Gerardo/0000-0001-8344-6523 NR 34 TC 14 Z9 14 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD FEB PY 1999 VL 37 IS 2 BP 430 EP 432 PG 3 WC Microbiology SC Microbiology GA 158UV UT WOS:000078136500030 PM 9889234 ER PT J AU Maslow, JN Dawson, D Carlin, EA Holland, SM AF Maslow, JN Dawson, D Carlin, EA Holland, SM TI Hemolysin as a virulence factor for systemic infection with isolates of Mycobacterium avium complex SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID DNA PROBES; INTRACELLULARE; AIDS; BACTEREMIA AB Isolates of the Mycobacterium avium complex were examined for hemolysin expression. Only invasive isolates of M. avium were observed to be hemolytic (P < 0.001), with activity the greatest for isolates of serovars 4 and 8. Thus, M. avium hemolysin appears to represent a virulence factor necessary for invasive disease. C1 VA Med Ctr, Med Serv, Infect Dis Sect, Boston, MA USA. Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. Queensland Hlth, Lab Microbiol & Pathol, Brisbane, Qld, Australia. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Maslow, JN (reprint author), Vet Adm Med Ctr Jamaica Plain, Res Serv 151, 150 S Huntington Ave, Boston, MA 02130 USA. EM maslow.joel_n.md@boston.va.gov NR 17 TC 15 Z9 15 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD FEB PY 1999 VL 37 IS 2 BP 445 EP 446 PG 2 WC Microbiology SC Microbiology GA 158UV UT WOS:000078136500035 PM 9889239 ER PT J AU Peyton, CL Schiffman, M Lorincz, AT Hunt, WC Mielzynska, I Bratti, C Eaton, S Hildesheim, A Morera, LA Rodriguez, AC Herrero, R Sherman, ME Wheeler, CM AF Peyton, CL Schiffman, M Lorincz, AT Hunt, WC Mielzynska, I Bratti, C Eaton, S Hildesheim, A Morera, LA Rodriguez, AC Herrero, R Sherman, ME Wheeler, CM TI Comparison of PCR- and hybrid capture-based human papillomavirus detection systems using multiple cervical specimen collection strategies (vol 36, pg 3248, 1998) SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Correction C1 Univ New Mexico, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. Digene Corp, Silver Spring, MD USA. NCI, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. Caja Costarricense Seguro Social, San Jose, Costa Rica. RP Peyton, CL (reprint author), Univ New Mexico, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. NR 1 TC 3 Z9 4 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD FEB PY 1999 VL 37 IS 2 BP 478 EP 478 PG 1 WC Microbiology SC Microbiology GA 158UV UT WOS:000078136500045 ER PT J AU Smith, MA Rubinstein, L Anderson, JR Arthur, D Catalano, PJ Freidlin, B Heyn, R Khayat, A Krailo, M Land, VJ Miser, J Shuster, J Vena, D AF Smith, MA Rubinstein, L Anderson, JR Arthur, D Catalano, PJ Freidlin, B Heyn, R Khayat, A Krailo, M Land, VJ Miser, J Shuster, J Vena, D TI Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ACUTE MYELOID-LEUKEMIA; ACUTE NONLYMPHOCYTIC LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; 2ND MALIGNANT NEOPLASMS; GERM-CELL TUMORS; COMPLICATING HODGKINS-DISEASE; SEMUSTINE METHYL-CCNU; DNA TOPOISOMERASE-II; BREAST-CANCER; ADJUVANT CHEMOTHERAPY AB Purpose: The incidence of secondary leukemia after epipodophyllotoxin treatment and the relationship between epipodophyllotoxin cumulative dose and risk are not well characterised. The Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) has developed a monitoring plan to obtain reliable estimates of the risk of secondary leukemia after epipodophyllotoxin treatment. Methods: Twelve NCl-supported cooperative group clinical trials were identified that use epipodophyllotoxins at low (< 1.5 g/m(2) etoposide), moderate (1.5 to 2.99 g/m(2) etoposide), or higher (greater than or equal to 3.0 g/m2 etoposide) cumulative doses. Cases of secondary leukemia (including treatment-related myelodysplastic syndrome) occurring on these trials have been reported to CTEP, as has duration of follow-up for all patients, thereby allowing calculation of cumulative 6-year incidence rates of secondary leukemia for each etoposide dose group. Results: The calculated cumulative 6-year risks for development of secondary leukemia for the low, moderate, and higher cumulative dose groups were 3.3%, (95% upper confidence bound of 5.9%), 0.7% (95% upper confidence bound of 1.6%), and 2.2%, (95% upper confidence bound of 4.6%), respectively. Conclusion: Within the context of the epipodophyllotoxin cumulative dose range and schedules of administration encompassed by the monitoring plan regimens, and within the context of multiagent chemotherapy regimens that include alkylating agents, doxorubicin, and other agents, factors other than epipodophyllotoxin cumulative dose seem to be of primary importance in determining the risk of secondary leukemia. Data obtained by the CTEP secondary leukemia monitoring plan support the relative safety of using epipodophyllotoxins according to the therapeutic plans outlined in the monitored protocols. (C) 1999 by American Society of Clinical Oncology. C1 NCI, EPN, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. EMMES Corp, Potomac, MD USA. RP Smith, MA (reprint author), NCI, EPN, Canc Therapy Evaluat Program, Room 741, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA-30969, CA-30138, CA-24507] NR 58 TC 174 Z9 178 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB PY 1999 VL 17 IS 2 BP 569 EP 577 PG 9 WC Oncology SC Oncology GA 163CH UT WOS:000078384500021 PM 10080601 ER PT J AU Yu, F Venzon, DJ Serrano, J Goebel, SU Doppman, JL Gibril, F Jensen, RT AF Yu, F Venzon, DJ Serrano, J Goebel, SU Doppman, JL Gibril, F Jensen, RT TI Prospective study of the clinical course, prognostic factors, causes of death, and survival in patients with long-standing Zollinger-Ellison syndrome SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SOMATOSTATIN RECEPTOR SCINTIGRAPHY; MULTIPLE ENDOCRINE NEOPLASIA; METASTATIC NEUROENDOCRINE TUMORS; ISLET-CELL-CARCINOMA; MALIGNANT GASTRINOMA; AGGRESSIVE RESECTION; BONE METASTASES; LIVER-TRANSPLANTATION; DUODENAL GASTRINOMAS; SURGICAL-MANAGEMENT AB Purpose: The long-term clinical course of unselected patients with gastrinomas as well as other functional pancreatic endocrine tumors (PETs) in whom the excess-hormone stare is controlled is largely unknown. To address this issue, patients with gastrinomas were assessed. Patients and Methods: Two hundred twelve patients with Zollinger-Ellison syndrome (ZES) were prospectively studied. All had controlled acid hypersecretion and were assessed yearly, with a mean follow-up period of 13.8 +/- 0.6 years (range, 0.1 to 31 years). Annual assessments of possible factors that might affect prognosis or treatment approaches were performed, such as those for tumor size and location; the presence, location, and extent of metastases; and the occurrence of ectopic Cushing's syndrome or another PET syndrome. Deaths were categorized as ZES-related or non-ZES-related and classified into different causes. Results: Thirty-one percent of patients died, all of non-acid-related causes. One half died of a ZES-related cause; they differed from those who died of non-ZES deaths by having a large primary tumor, more frequently a pancreatic tumor; lymph node, liver, or bone metastases; ectopic Cushing's syndrome; or higher gastrin levels. The extent of liver metastases correlated with survival rate. The presence of liver metastases alone only moderately decreased survival time; however, the additional development of bone metastases or ectopic Cushing's syndrome markedly decreased survival rate. Conclusions: In ZES, gastrinoma growth is now the main single determinant of long-term survival, with one half of patients dying a gastrinoma-related death and none an acid-related death. Large primary tumors that are pancreatic in location, the development of liver metastases, (especially if associated with bone metastases or Cushing's syndrome), and the extent of liver metastases are all important prognostic factors. The identification of these factors allows the recognition of subgroups that can be used to tailor antitumor treatment approaches. (C) 1999 by American Society of Clinical Oncology. C1 NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Jensen, RT (reprint author), NIDDKD, Digest Dis Branch, NIH, Bldg 10,Rm 9C-103,10 Ctr Dr MSC 1804, Bethesda, MD 20892 USA. RI Venzon, David/B-3078-2008 NR 91 TC 192 Z9 197 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB PY 1999 VL 17 IS 2 BP 615 EP 630 PG 16 WC Oncology SC Oncology GA 163CH UT WOS:000078384500027 PM 10080607 ER PT J AU Gail, MH Rimer, BK AF Gail, MH Rimer, BK TI Risk of risk-based mammography screening, ages 40 to 49 - In reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. RP Gail, MH (reprint author), NCI, Bethesda, MD 20892 USA. NR 6 TC 1 Z9 1 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 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB PY 1999 VL 17 IS 2 BP 737 EP 738 PG 2 WC Oncology SC Oncology GA 163CH UT WOS:000078384500048 ER PT J AU Bovo, D Rugge, M Shiao, YH AF Bovo, D Rugge, M Shiao, YH TI Origin of spurious multiple bands in the amplification of microsatellite sequences SO JOURNAL OF CLINICAL PATHOLOGY-MOLECULAR PATHOLOGY LA English DT Article DE microsatellite; polymerase chain reaction artifact; multiple bands ID REPEATS AB Multiple band artifacts are seen commonly in the analyses of short repetitive sequences, also known as microsatellites, using the polymerase chain reaction (PCR). In this study, the conditions of PCR were examined for five microsatellite loci (D2S119, D2S123, D5S409, D11S904, and interferon alpha) in an attempt to eliminate this artifact. In addition, and a possible mechanism for the formation of the multiple band artifact in non-denaturing polyacrylamide gel electrophoresis was also explored. The intensity of multiple bands increased when the numbers of PCR cycles were increased. The multiple bands were abolished simply by reducing PCR cycle numbers and were reproduced from single specific PCR products undergoing alternate denaturation and reassociation without primer extension. This finding suggests that formation of multiple bands in non-denaturing gel electrophoresis is a result of improper annealing of PCR fragments, rather than being the result of polymerase slippage and 3' non-template extension, as has been reported previously. C1 NCI, Comparat Carcinogenesis Lab, Frederick Canc Res & Dev Ctr, NIH, Frederick, MD 21702 USA. Univ Padua, Dept Pathol, I-35121 Padua, Italy. Univ Padua, Dept Pathol, I-35121 Padua, Italy. RP Shiao, YH (reprint author), NCI, Comparat Carcinogenesis Lab, Frederick Canc Res & Dev Ctr, NIH, Bldg 538,Room 205, Frederick, MD 21702 USA. RI Rugge, Massimo/K-7525-2016 NR 8 TC 31 Z9 31 U1 0 U2 10 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1366-8714 J9 J CLIN PATHOL-MOL PA JI J. Clin. Pathol.-Mol. Pathol. PD FEB PY 1999 VL 52 IS 1 BP 50 EP 51 PG 2 WC Pathology SC Pathology GA 164CK UT WOS:000078444700010 ER PT J AU Dionne, RA Gordon, SM Tahara, M Rowan, J Troullos, E AF Dionne, RA Gordon, SM Tahara, M Rowan, J Troullos, E TI Analgesic efficacy and pharmacokinetics of ketoprofen administered into a surgical site SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; DOUBLE-BLIND; PLACEBO; ACETAMINOPHEN; FLURBIPROFEN; ASPIRIN; KIDNEY; RISK; PAIN; TISSUE AB A series of three clinical trials in the oral surgery model evaluated the analgesic efficacy and pharmacokinetics of ketoprofen administered locally as a strategy for decreasing systemic exposure to nonsteroidal anti-inflammatory drugs (NSAIDs). A gel formulation was administered directly into extraction sites 1 hour following oral surgery, and pain intensity was evaluated for 6 hours. Significantly less pain was seen following peripheral administration of both 10 and 30 mg ketoprofen in comparison to the placebo. In a second study, peripheral administration of the 10 mg dose resulted in greater analgesia than oral administration of the same dose formulation or the placebo. The third study demonstrated lower plasma drug levels following the peripheral route of the same dose or ingestion of a 25 mg oral capsule. These data indicate that administration of an NSAID to a peripheral site of tissue injury results in greater analgesia than oral administration and suggests the potential for less drug toxicity through lower circulating drug levels. C1 NIDR, Pain & Neurosensory Mechanisms Branch, NIH, Bethesda, MD 20892 USA. RP Dionne, RA (reprint author), NIDR, Pain & Neurosensory Mechanisms Branch, NIH, 10 Ctr Dr,Room 1N-103, Bethesda, MD 20892 USA. NR 25 TC 17 Z9 18 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0091-2700 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD FEB PY 1999 VL 39 IS 2 BP 131 EP 138 DI 10.1177/00912709922007679 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 160UC UT WOS:000078248600004 PM 11563404 ER PT J AU Gordon, SM Dubner, R Dionne, RA AF Gordon, SM Dubner, R Dionne, RA TI Antihyperalgesic effect of the N-methyl-D-aspartate receptor antagonist dextromethorphan in the oral surgery model SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article ID DORSAL HORN NEURONS; AMINO-ACID RECEPTORS; RAT SPINAL NEURONS; NMDA RECEPTOR; POSTOPERATIVE PAIN; DOUBLE-BLIND; POSTHERPETIC NEURALGIA; NEUROPATHIC PAIN; KNEE-JOINT; CORD AB Peripheral neuronal barrage from tissue injury produces central nervous system hyper excitability through the activation of N-methyl-D-aspartate (NMDA) receptor sites by excitatory amino acids and neuropeptides. This study evaluated if attenuation of NMDA receptor activation with dextromethorphan (DM) suppresses the postoperative development of hyperalgesia. Seventy-five-patients undergoing oral surgery in a parallel-group, double-blind study randomly received either a placebo or the maximally tolerated dose of DM administered orally prior to and continuing for 48 hours following surgery. Pain as measured by category, visual analog, and verbal descriptor scales was not significantly different between groups during the first 6 hours following surgery. However, pain at 48 hours was decreased in the DM group as measured by scales for pain intensity and unpleasantness. Subjects in the DM group also self-administered fewer acetaminophen tablets for unrelieved pain over 24 to 48 hours postoperatively. The results suggest that DM at maximally tolerated doses does not produce an analgesic effect in the immediate postoperative period but reduces pain at 48 hours. This may be related to antagonism of NMDA receptors necessary for the expression of hyperalgesia associated with noxious afferent input postoperatively. (C) 1999 the American College of Clinical Pharmacology. C1 NIDR, Pain & Neurosensory Mechanisms Branch, NIH, Bethesda, MD 20892 USA. RP Dionne, RA (reprint author), NIDR, Pain & Neurosensory Mechanisms Branch, NIH, 10 Ctr Dr,Room 1N-103, Bethesda, MD 20892 USA. NR 47 TC 10 Z9 10 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0091-2700 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD FEB PY 1999 VL 39 IS 2 BP 139 EP 146 DI 10.1177/00912709922007688 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 160UC UT WOS:000078248600005 PM 11563405 ER PT J AU Frye, MA Luckenbaugh, D Kimbrell, TA Constantino, C Grothe, D Cora-Locatelli, G Ketter, TA AF Frye, MA Luckenbaugh, D Kimbrell, TA Constantino, C Grothe, D Cora-Locatelli, G Ketter, TA TI Possible gabapentin-induced thyroiditis SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Letter ID BIPOLAR; THYROTOXICOSIS; DISORDERS; LITHIUM C1 NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. NIDDKD, Bethesda, MD 20892 USA. Natl Inst, Dept Clin Pharm, Ctr Clin, Bethesda, MD USA. Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. RP Frye, MA (reprint author), Univ Calif Los Angeles, Inst Psychiat, Los Angeles, CA 90095 USA. NR 10 TC 5 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD FEB PY 1999 VL 19 IS 1 BP 94 EP 95 DI 10.1097/00004714-199902000-00015 PG 2 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 157VK UT WOS:000078082200014 PM 9934948 ER PT J AU Weed, DL AF Weed, DL TI Towards a philosophy of public health SO JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH LA English DT Article ID PROSTATE-SPECIFIC ANTIGEN; CANCER SCREENING TRIAL; CURRENT GOLD STANDARD; INFORMED CONSENT; MEDICAL-ETHICS; EPIDEMIOLOGY; INTERVENTION; PREVENTION; SOCIETY; MEN C1 NCI, Prevent Oncol Branch, Div Canc Prevent, Bethesda, MD 20892 USA. RP Weed, DL (reprint author), NCI, Prevent Oncol Branch, Div Canc Prevent, Execut Plaza S,Suite T-41,6130 Execut Blvd Msc 71, Bethesda, MD 20892 USA. NR 48 TC 20 Z9 20 U1 0 U2 4 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0143-005X J9 J EPIDEMIOL COMMUN H JI J. Epidemiol. Community Health PD FEB PY 1999 VL 53 IS 2 BP 99 EP 104 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 159PT UT WOS:000078183200006 PM 10396470 ER PT J AU Cohen, RI McKay, R Almazan, G AF Cohen, RI McKay, R Almazan, G TI Cyclic AMP regulates PDGF-stimulated signal transduction and differentiation of an immortalized optic-nerve-derived cell line SO JOURNAL OF EXPERIMENTAL BIOLOGY LA English DT Article DE oligodendrocyte precursor; cell line; SV40 large T-antigen; immortalization; proliferation; differentiation; PDGF receptor; growth factor ID ALPHA-RECEPTOR EXPRESSION; GLIAL PROGENITOR-CELL; GROWTH-FACTOR; OLIGODENDROCYTE DIFFERENTIATION; PROTEIN-KINASE; MONOCLONAL-ANTIBODY; ADENYLATE-CYCLASE; GENE-EXPRESSION; PLASMA-MEMBRANE; SCHWANN-CELLS AB To facilitate the study of the molecular events underlying the development of optic-nerve-derived oligodendrocytes and their growth-factor-related signal transduction events, we immortalized perinatal rat optic nerve cells with a temperature-sensitive simian virus 40 large T-antigen, carrying the tsA58 and U19 mutations, via a retrovirus vector. The line, tsU19-9, was selected on the basis of the expression of the neural precursor marker nestin, At the permissive temperature, 33 degrees C, tsU19-9 cells had a flat epithelial morphology, In contrast, following exposure to platelet-derived growth factor (PDGF), a factor important in the lineage progression of oligodendrocytes, or in the presence of dibutyryl cyclic AMP at 39 degrees C (the non-permissive temperature), the cells underwent morphological and antigenic differentiation to cells characteristic of the oligodendrocyte lineage. We used this cell line to investigate the binding characteristics of PDGF and related signalling cascades. Competition binding, phosphoinositide hydrolysis and intracellular Ca2+ mobilization assays all demonstrated that the three different isoforms of PDGF (AA, AB and BB) bound to and acted on the cell line. Overnight exposure to forskolin, a treatment that initiated morphological and phenotypic progression into an oligodendrocyte lineage, decreased PDGF-BB-induced intracellular Ca2+ mobilization and inhibited basal and PDGF-stimulated [H-3]thymidine incorporation. Our results demonstrate that tsU19-9 may serve as a resource to study early optic-nerve oligodendrocyte development. C1 McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ H3G 1Y6, Canada. NINds, NIH, Bethesda, MD 20892 USA. RP Almazan, G (reprint author), McGill Univ, Dept Pharmacol & Therapeut, 3655 Drummond St, Montreal, PQ H3G 1Y6, Canada. EM galmazan@pharma.mcgill.ca NR 71 TC 18 Z9 19 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE, CAMBS, ENGLAND CB4 4DL SN 0022-0949 J9 J EXP BIOL JI J. Exp. Biol. PD FEB PY 1999 VL 202 IS 4 BP 461 EP 473 PG 13 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 173FZ UT WOS:000078971600012 PM 9914153 ER PT J AU Nakamura, MC Linnemeyer, PA Niemi, EC Mason, LH Ortaldo, JR Ryan, JC Seaman, WE AF Nakamura, MC Linnemeyer, PA Niemi, EC Mason, LH Ortaldo, JR Ryan, JC Seaman, WE TI Mouse Ly-49D recognizes H-2D(d) and activates natural killer cell cytotoxicity SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE natural killer cells; major histocompatibility complex; receptors; cytotoxicity; rodent ID IL-2-ACTIVATED NK CELLS; CLASS-I RECOGNITION; MEMBRANE-PROTEINS; MULTIGENE FAMILY; GENE-COMPLEX; MHC; MOLECULES; RECEPTORS; RAT; SPECIFICITY AB Although activation of natural killer (NK) cytotoxicity is generally inhibited by target major histocompatibility complex (MHC) class I expression, subtle features of NK allorecognition suggest that NK cells possess receptors that are activated by target MHC I. The mouse Ly-49D receptor has been shown to activate NK cytotoxicity, although recognition of MHC class I has not been demonstrated previously. To define Ly-49D-ligand interactions, we transfected the mouse Ly-49D receptor into the rat NI( line, RNK-16 (RNK.mLy-49D). As expected, anti-Ly-49D monoclonal antibody 12A8 specifically stimulated redirected lysis of the Fc receptor-bearing rat target YB2/0 by RNK.mLy-49D transfectants. RNK.mLy-49D effectors were tested against YB2/0 targets transfected with the mouse MHC I alleles H-2D(d), D-b, K-k, or K-b. RNK.mLy-49D cells lysed YB2/0.D-d targets more efficiently than untransfected YB2/0 or YB2/0 transfected with D-b, K-k, or K-b. This augmented lysis of H-2D(d) targets was specifically inhibited by F(ab')(2) anti-Ly-49D (12A8) and F(ab')(2) anti-H-2D(d) (34-5-8S). RNK.mLy-49D effecters were also able to specifically lyse Concanavalin A blasts isolated from H-2(b) mice (BALB/c, B10.D2, and DBA/2) but not from H-2(b) or H-2(k) mice. These experiments show that the activating receptor Ly-49D specifically interacts with the MHC I antigen, H-2D(d), demonstrating the existence of alloactivating receptors on murine NK cells. C1 Vet Adm Med Ctr, Immunol Arthrit Sect, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. NCI, Expt Immunol Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. RP Nakamura, MC (reprint author), Vet Adm Med Ctr, Immunol Arthrit Sect, 4150 Clement St, San Francisco, CA 94121 USA. FU NCI NIH HHS [R29 CA60944, R01 CA69299]; NIAMS NIH HHS [K11 AR01927] NR 39 TC 113 Z9 113 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 FEB 1 PY 1999 VL 189 IS 3 BP 493 EP 500 DI 10.1084/jem.189.3.493 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 164NK UT WOS:000078470300006 PM 9927511 ER PT J AU Braun, MC He, JP Wu, CY Kelsall, BL AF Braun, MC He, JP Wu, CY Kelsall, BL TI Cholera toxin suppresses interleukin (IL)-12 production and IL-12 receptor beta 1 and beta 2 chain expression SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE interleukin 12; monocytes; dendritic cells; Th1 and Th2 cells; cholera toxin ID IMMUNOGLOBULIN-A RESPONSES; MUCOSAL IMMUNE-RESPONSES; T-CELL ACTIVATION; ORAL TOLERANCE; B-SUBUNIT; TH2 CELLS; IMMUNOLOGICAL CONSEQUENCES; LABILE ENTEROTOXIN; T-HELPER-2 CELLS; GAMMA PRODUCTION AB Cholera toxin (CT) is a potent mucosal vaccine adjuvant, which has been shown to induce T helper cell type 2 (Th2) responses in systemic and mucosal tissues. We report that CT inhibits the production of interleukin (IL)-12, a major Th2 counterregulatory cytokine. IL-12 p70 production by stimulated human monocytes was inhibited by CT in a dose-dependent manner. This suppression occurred at the level of gene transcription, was maximal at low concentrations of CT, and was dependent on the A subunit of the toxin, since purified CT B subunit had minimal effect. CT also inhibited the production of IL-12 p70 by monocyte-derived dendritic cells, as well as the production of tumor necrosis factor alpha, but trot IL-10, IL-6, or transforming growth factor (TGF)-beta(1), by stimulated monocytes. The effects of CT were not due to autocrine production of IL-10, TGF-beta(1), or prostaglandin E-2. CT inhibited the production of IFN-gamma by anti-CD3-stimulated human peripheral blood mononuclear cell, due in part to suppression of IL-12 production, but also to the inhibition of expression of the beta 1 and beta 2 chains of the IL-12 receptor on T cells. In vivo, mice given CT before systemic challenge with lipopolysaccharide had markedly reduced serum levels of IL-12 p40 and interferon gamma. These data demonstrate two novel mechanisms by which CT can inhibit Th1 immune responses, and help explain the ability of mucosally administered CT to enhance Th2-dependent immune responses. C1 NIAID, Immune Cell Inteact Unit, Mucosal Immun Sect, NIH, Bethesda, MD 20892 USA. NIAID, Clin Immunol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Kelsall, BL (reprint author), 10-11N238,10 Ctr Dr, Bethesda, MD 20892 USA. EM kelsall@nih.gov NR 89 TC 178 Z9 182 U1 1 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD FEB 1 PY 1999 VL 189 IS 3 BP 541 EP 552 DI 10.1084/jem.189.3.541 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 164NK UT WOS:000078470300011 PM 9927516 ER PT J AU Mcnamara, L Macphail, AP Mandishona, E Bloom, P Paterson, AC Rouault, TA Gordeuk, VR AF Mcnamara, L Macphail, AP Mandishona, E Bloom, P Paterson, AC Rouault, TA Gordeuk, VR TI Non-transferrin-bound iron and hepatic dysfunction in African dietary iron overload SO JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE high-performance liquid chromatography; liver disease; serum ferritin; transferrin saturation ID IDIOPATHIC HEMOCHROMATOSIS; SERUM FERRITIN; PLASMA IRON; THALASSEMIA AB Background: Circulating iron is normally bound to transferrin. Non-transferrin-bound iron (NTBI) has been described in most forms of iron overload, but has not been studied in African dietary iron overload. This abnormal iron fraction is probably toxic, but this has not been demonstrated. Methods: High-pressure liquid chromatography was used to assay serum NTBI in 25 black African subjects with iron overload documented by liver biopsy and in 170 relatives and neighbours. Levels of NTBI were correlated with indirect measures of iron status and conventional liver function tests. Results: Non-transferrin-bound iron (> 2 mu mol/L) was present in 43 people, 22 of patients of whom underwent liver biopsy and 21 relatives and neighbours. All but four of these had evidence of iron overload on the basis of either liver biopsy or elevated transferrin and serum ferritin concentrations. Among all 195 subjects, the presence of NTBI in serum was independently related to elevations in alanine and aspartate aminotransferase activity and bilirubin concentration. This relationship between serum NTBI and hepatic dysfunction was confirmed in the subgroup of 25 subjects with iron overload documented by liver biopsy. Non-transferrin-bound iron correlated significantly with elevations in alanine and aspartate aminotransferase activities after adjustment for hepatic iron grades, inflammation and diet. Conclusions: Non-transferrin-bound iron was found to bit commonly present in African patients with dietary iron overload and to correlate with transferrin saturation and serum ferritin concentration. The independent relationship between NTBI and elevated liver function tests suggests that it may be part of a pathway leading to hepatic injury. C1 Univ Witwatersrand, Sch Pathol, Dept Anat Pathol, Johannesburg, South Africa. NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. George Washington Med Ctr, Dept Med, Washington, DC USA. RP Macphail, AP (reprint author), Univ Witwatersrand, Dept Med, 7 York Rd, ZA-2193 Parktown, South Africa. FU NICHD NIH HHS [1-HD-3-3196] NR 25 TC 26 Z9 26 U1 0 U2 1 PU BLACKWELL SCIENCE ASIA PI CARLTON PA 54 UNIVERSITY ST, P O BOX 378, CARLTON, VICTORIA 3053, AUSTRALIA SN 0815-9319 J9 J GASTROEN HEPATOL JI J. Gastroenterol. Hepatol. PD FEB PY 1999 VL 14 IS 2 BP 126 EP 132 DI 10.1046/j.1440-1746.1999.01830.x PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 170CH UT WOS:000078787900005 PM 10029292 ER PT J AU Mejia-Alvarez, R Kettlun, C Rios, E Stern, M Fill, M AF Mejia-Alvarez, R Kettlun, C Rios, E Stern, M Fill, M TI Unitary Ca2+ current through cardiac ryanodine receptor channels under quasi-physiological ionic conditions SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Article DE Ca2+ release; sarcoplasmic reticulum; Ca2+ spark; excitation-contraction coupling; planar bilayers ID CALCIUM-RELEASE CHANNEL; FROG SKELETAL-MUSCLE; SARCOPLASMIC-RETICULUM; RAT-HEART; SPARKS; CONDUCTION; MEMBRANES; EVENTS; MODEL AB Single canine cardiac ryanodine receptor channels were incorporated into planar lipid bilayers. Single-channel currents were sampled at 1-5 kHz and filtered at 0.2-1.0 kHz. Channel incorporations were obtained in symmetrical solutions (20 mM HEPES-Tris, pH 7.4, and pCa 5). Unitary Ca2+ currents were monitored when 2-30 mM Ca2+ was added to the lumenal side of the channel. The relationship between the amplitude of unitary Ca2+ current (at 0 mV holding potential) and lumenal [Ca2+] was hyperbolic and saturated at similar to 4 pA. This relationship was then defined in the presence of different symmetrical CsCH3SO3 concentrations (5, 50, and 150 mM). Under these conditions, unitary current amplitude was 1.2 +/- 0.1, 0.65 +/- 0.1, and 0.35 +/- 0.1 pA in 2 mM lumenal Ca2+; and 3.3 +/- 0.4, 2.4 +/- 0.2, and 1.63 +/- 0.2 pA in 10 mM lumenal Ca2+ (n > 6). Unitary Ca2+ current was also defined in the presence of symmetrical [Mg2+] (1 mM) and low [Cs+] (5 mM). Under these conditions, unitary Ca2+ current in 2 and 10 mM lumenal Ca2+ was 0.66 +/- 0.1 and 1.52 +/- 0.06 pA, respectively. In the presence of higher symmetrical [Cs+] (50 mM), Mg2+ (1 mM), and lumenal [Ca2+] (10 mM), unitary Ca2+ current exhibited an amplitude of 0.9 +/- 0.2 pA (n = 3). This result indicates that the actions of Cs+ and Mg2+ on unitary Ca2+ current were additive. These data demonstrate that physiological levels of monovalent cation and Mg2+ effectively compete with Ca2+ as charge carrier in cardiac ryanodine receptor channels. If lumenal free Ca2+ is 2 mM, then our results indicate that unitary Ca2+ current under physiological conditions should be <0.6 pA. C1 Loyola Univ, Stritch Sch Med, Dept Physiol, Maywood, IL 60153 USA. Rush Univ, Sch Med, Dept Physiol & Mol Biophys, Chicago, IL 60612 USA. NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21214 USA. RP Fill, M (reprint author), Loyola Univ, Stritch Sch Med, Dept Physiol, 2160 S 1st Ave, Maywood, IL 60153 USA. NR 28 TC 110 Z9 111 U1 1 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1295 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD FEB PY 1999 VL 113 IS 2 BP 177 EP 186 DI 10.1085/jgp.113.2.177 PG 10 WC Physiology SC Physiology GA 165ZZ UT WOS:000078552900004 PM 9925817 ER PT J AU Kjellberg, L Wang, ZH Wiklund, F Edlund, K Angstrom, T Lenner, P Sjoberg, I Hallmans, G Wallin, KL Sapp, M Schiller, J Wadell, G Mahlck, CG Dillner, J AF Kjellberg, L Wang, ZH Wiklund, F Edlund, K Angstrom, T Lenner, P Sjoberg, I Hallmans, G Wallin, KL Sapp, M Schiller, J Wadell, G Mahlck, CG Dillner, J TI Sexual behaviour and papillomavirus exposure in cervical intraepithelial neoplasia: a population-based case-control study SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID VIRUS-LIKE PARTICLES; POLYMERASE CHAIN-REACTION; SERUM ANTIBODIES; RISK-FACTORS; HPV DNA; TRANSMITTED DISEASES; GENERAL PRIMERS; WOMEN; INFECTION; TYPE-16 AB Sexual history is an established risk determinant for cervical neoplasia. It is not clear if human papillomavirus (HPV) exposure entirely explains the sexual behaviour-related risk or if other sexually transmitted agents may act as cofactors for HPV in carcinogenesis. The aim of this study was to elucidate whether HPV exposure or HPV persistence explains the sexual history-related risk of high-grade cervical intraepithelial neoplasia (CIN) using a population-based case-control study of most of the 254 women referred to colposcopy in the Vasterbotten county in Sweden because of an abnormal cervical smear during October 1993 to December 1995 and 320 age-matched women from the general population. The women were interviewed for sexual history and tested for presence of serum antibodies to HPV-16, -18 and -33 as well as for presence of HPV DNA in cervical brush samples. HPV-16, -18 and -33 seropositivity was specific for the corresponding type of HPV DNA, dependent on the lifetime sexual history and associated with a two- to threefold increased risk of CIN 3. There was no sexual history-related risk of CIN among HPV-seropositive women and adjustment for HPV DNA presence explained the sexual history-related risk of GIN. In conclusion, HPV exposure appeared to explain the sexual history-related risk of high-grade CIN. C1 Karolinska Inst, Ctr Microbiol & Tumor Biol, S-17177 Stockholm, Sweden. Univ Hosp No Sweden, Dept Obstet & Gynecol, Umea, Sweden. Univ Hosp No Sweden, Ctr Oncol, Umea, Sweden. Univ Hosp No Sweden, Dept Clin Virol, Umea, Sweden. Univ Hosp No Sweden, Dept Clin Cytol, Umea, Sweden. Univ Hosp No Sweden, Dept Nutr Res, Umea, Sweden. Univ Mainz, Dept Med Microbiol, D-6500 Mainz, Germany. NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. Univ Tampere, Sch Publ Hlth, FIN-33101 Tampere, Finland. RP Dillner, J (reprint author), Karolinska Inst, Ctr Microbiol & Tumor Biol, Box 280, S-17177 Stockholm, Sweden. EM joakim.dillner@mtc.ki.se NR 41 TC 64 Z9 67 U1 0 U2 0 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING, BERKS, ENGLAND RG7 1AE SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD FEB PY 1999 VL 80 BP 391 EP 398 PN 2 PG 8 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 168MM UT WOS:000078696800015 PM 10073699 ER PT J AU Bontkes, HJ de Gruijl, TD Walboomers, JMM Schiller, JT Dillner, J Helmerhorst, TJM Verheijen, RHM Scheper, RJ Meijer, CJLM AF Bontkes, HJ de Gruijl, TD Walboomers, JMM Schiller, JT Dillner, J Helmerhorst, TJM Verheijen, RHM Scheper, RJ Meijer, CJLM TI Immune responses against human papillomavirus (HPV) type 16 virus-like particles in a cohort study of women with cervical intraepithelial neoplasia II. Systemic but not local IgA responses correlate with clearance of HPV-16 SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID MUCUS ANTIBODIES; TGF-BETA; PREVALENCE; ANTIGENS; CAPSIDS; LESIONS; CELLS; SERUM; DNA AB To investigate whether there is an association between local or systemic IgG and IgA responses against human papillomavirus (HPV) type 16 virus-like particles (VLP) containing L1 and L2 and the possible influence of these responses on clearance of HPV-16 and its associated lesions, cervical mucus samples from 125 patients and plasma samples from 100 patients, all participating in a non-intervention cohort study of women with abnormal cytology, were analysed. The results show that local IgG and IgA HPV-16 VLP-specific antibodies do not correlate with virus clearance, However, systemic IgG responses were more frequently detected in patients with a persistent infection (11/24) compared with patients with cleared HPV-16 infections (3/28, P= 0.006). Furthermore, the ultimate development of high-grade lesions was associated with systemic VLP-specific IgG reactivity (P = 0.026). By contrast, systemic IgA responses were correlated with virus clearance (7/28 clearance compared with 1/24 persistence patients, P = 0.06). This correlation was statistically significant when only those clearance patients who tested HPV-16 DNA-positive at more than one visit were included in the analysis (5/11 compared with 1/24, P = 0.007), As these systemic IgA responses were not accompanied by local IgA responses, the systemic IgA responses in HPV-16 clearance patients are suggested to be a by-product of a successful cellular immune response induced at the local lymph nodes, mediated by cytokines. C1 Free Univ Amsterdam Hosp, Dept Pathol, NL-1007 MB Amsterdam, Netherlands. Free Univ Amsterdam Hosp, Dept Obstet & Gynaecol, NL-1007 MB Amsterdam, Netherlands. NCI, Cellular Oncol Lab, Div Basic Sci, Bethesda, MD 20892 USA. Karolinska Inst, Ctr Microbiol & Tumor Biol, Stockholm, Sweden. RP Walboomers, JMM (reprint author), Free Univ Amsterdam Hosp, Dept Pathol, POB 7057, NL-1007 MB Amsterdam, Netherlands. NR 24 TC 79 Z9 83 U1 0 U2 0 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING, BERKS, ENGLAND RG7 1AE SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD FEB PY 1999 VL 80 BP 409 EP 417 PN 2 PG 9 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 168MM UT WOS:000078696800017 PM 10073701 ER PT J AU Guidry, G AF Guidry, G TI A method for counterstaining tissues in conjunction with the glyoxylic acid condensation reaction for detection of biogenic amines SO JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY LA English DT Article DE biogenic amines; catecholamine; histofluorescence; glyoxylic acid; counterstain; malachite green AB A method is described for counterstaining tissue for use with the glyoxylic acid reaction for visual detection of biogenic amines. Counterstaining is achieved by addition of the fluorescent dye malachite green to the sucrose-phosphate-glyoxylic acid (SPG) solution used for processing of cryostat sections of unfixed tissues. When bound to tissues, the dye provides red-orange fluorescence of background tissue, which contrasts well with the green to yellow fluorescence induced by the glyoxylic acid reaction product formed with biogenic amines. The counterstaining technique is demonstrated in a number of catecholamine-containing peripheral tissues and is compared to sections that were processed without counterstaining. C1 NINDS, Neural Dev Sect, NIH, Bethesda, MD 20892 USA. RP Guidry, G (reprint author), NINDS, Neural Dev Sect, NIH, Bldg 36,Room 2B08,36 Convent Dr, Bethesda, MD 20892 USA. NR 7 TC 9 Z9 9 U1 0 U2 1 PU HISTOCHEMICAL SOC INC PI SEATTLE PA UNIV WASHINGTON, DEPT BIOSTRUCTURE, BOX 357420, SEATTLE, WA 98195 USA SN 0022-1554 J9 J HISTOCHEM CYTOCHEM JI J. Histochem. Cytochem. PD FEB PY 1999 VL 47 IS 2 BP 261 EP 264 PG 4 WC Cell Biology SC Cell Biology GA 161BT UT WOS:000078268700015 PM 9889262 ER PT J AU Suh, WK Derby, MA Cohen-Doyle, MF Schoenhals, GJ Fruh, K Berzofsky, JA Williams, DB AF Suh, WK Derby, MA Cohen-Doyle, MF Schoenhals, GJ Fruh, K Berzofsky, JA Williams, DB TI Interaction of murine MHC class I molecules with tapasin and TAP enhances peptide loading and involves the heavy chain alpha(3) domain SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; DEPENDENT REDUCTASE ERP57; CELL-SURFACE; MONOCLONAL-ANTIBODIES; CALNEXIN; BINDING; ANTIGEN; EXPRESSION; TRANSPORT; DISSOCIATION AB In human cells the association of MHC class I molecules with TAP is thought to be mediated by a third protein termed tapasin, We now show that tapasin is present in murine TAP-class I complexes as well, Furthermore, we demonstrate that a mutant H-2D(d) molecule that does not interact with TAP due to a Glu to Lys mutation at residue 222 of the H chain (D-d(E222K)) also fails to bind to tapasin. This finding supports the view that tapasin bridges the association between class I and TAP and implicates residue 222 as a site of contact with tapasin, The inability of D-d(E222K) to interact with tapasin and TAP results in impaired peptide loading within the endoplasmic reticulum. However, significant acquisition of peptides can still be detected as assessed by the decay kinetics of cell surface D-d(E222K) molecules and by the finding that prolonged viral infection accumulates sufficient target structures to stimulate T cells at 50% the level observed with wild-type D-d. Thus, although interaction with tapasin and TAP enhances peptide loading, it is not essential. Finally, a cohort of D-d(E222K) molecules decays more rapidly on the eel surface compared with wild-type D-d molecules but much more slowly than peptide-deficient molecules, This suggests that some of the peptides obtained in the absence of an interaction with tapasin and TAP are suboptimal, suggesting a peptide-editing function for tapasin/TAP in addition to their role in enhancing peptide loading. C1 Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RW Johnson Pharmaceut Res Inst, San Diego, CA 92121 USA. RP Williams, DB (reprint author), Univ Toronto, Dept Biochem, Med Sci Bldg, Toronto, ON M5S 1A8, Canada. NR 64 TC 77 Z9 77 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 FEB 1 PY 1999 VL 162 IS 3 BP 1530 EP 1540 PG 11 WC Immunology SC Immunology GA 160YM UT WOS:000078261000039 PM 9973410 ER PT J AU Clay, TM Custer, MC McKee, MD Parkhurst, M Robbins, PF Kerstann, K Wunderlich, J Rosenberg, SA Nishimura, MI AF Clay, TM Custer, MC McKee, MD Parkhurst, M Robbins, PF Kerstann, K Wunderlich, J Rosenberg, SA Nishimura, MI TI Changes in the fine specificity of gp100((209-217))-reactive T cells in patients following vaccination with a peptide modified at an HLA-A2.1 anchor residue SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-INFILTRATING LYMPHOCYTES; MELANOMA ANTIGEN GP100; PERIPHERAL-BLOOD LYMPHOCYTES; METASTATIC MELANOMA; SYNTHETIC PEPTIDE; MULTIPLE EPITOPES; REACTIVE CTL; IN-VITRO; RECOGNITION; RECEPTOR AB In a recent clinical trial, HLA-A2(+) melanoma patients were vaccinated with a peptide derived from the melanoma Ag gp100, which had been modified at the second position (g9-209 2M) to enhance MHC binding affinity. Vaccination led to a significant increase in lymphocyte precursors in 10 of 11 patients but did not result in objective cancer responses. We observed that some postvaccination PBMC cultures were less reactive,vith tumor cells than they were with g9-209 peptide-pulsed T2 cells. In contrast, g9-209-reactive tumor-infiltrating lymphocyte cultures generally reacted equally with tumor cells and g9-209 peptide-pulsed T2 cells, To investigate this difference in T cell reactivity, T cell, cloids derived from the PBMC of three patients vaccinated with g9-209 2M were compared with T cell cloids isolated from g9-209-reactive TIL cultures. All of the T cell cloids obtained from TIL reacted with HLA-A2(+), gp100(+) melanoma cell lines as well as with g9-209 and g9-209 2M peptide-pulsed targets. In contrast, only 3 of 20 PBMC-derived T cell cloids reacted with melanoma cell lines in addition to g9-209 and to g9-209 2M peptide-pulsed targets. Twelve of twenty PBMC-derived cloids reacted with g9-209 and g9-209 2M peptide-pulsed targets but not with melanoma cell lines, And 5 of 20 PBMC-derived cloids recognized only the g9-209 2M-modified peptide-pulsed targets. These results suggest that immunizing patients with the modified peptide affected the T cell repertoire by expanding an array of T cells with different fine specificities, only some of which recognized melanoma cells. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Nishimura, MI (reprint author), NCI, Surg Branch, NIH, Bldg 10 2B06,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 37 TC 84 Z9 84 U1 1 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 FEB 1 PY 1999 VL 162 IS 3 BP 1749 EP 1755 PG 7 WC Immunology SC Immunology GA 160YM UT WOS:000078261000067 PM 9973438 ER PT J AU Bieganowska, K Hollsberg, P Buckle, GJ Lim, DG Greten, TF Schneck, J Altman, JD Jacobson, S Ledis, SL Hanchard, B Chin, J Morgan, O Roth, PA Hafler, DA AF Bieganowska, K Hollsberg, P Buckle, GJ Lim, DG Greten, TF Schneck, J Altman, JD Jacobson, S Ledis, SL Hanchard, B Chin, J Morgan, O Roth, PA Hafler, DA TI Direct analysis of viral-specific CD8(+) T cells with soluble HLA-A2/Tax11-19 tetramer complexes in patients with human T cell lymphotropic virus-associated myelopathy SO JOURNAL OF IMMUNOLOGY LA English DT Article ID I-ASSOCIATED MYELOPATHY; TROPICAL SPASTIC PARAPARESIS; SPINAL-CORD; LYMPHOCYTES; DISEASE; EXPRESSION; CHEMOKINES; ANTIBODIES; ACTIVATION; CLONES AB Human T cell lymphotropic virus-I (HTLV-I)-associated myelopathy is a slowly progressive neurologic disease characterized by inflammatory infiltrates in the central nervous system accompanied by clonal expansion of HTLV-I-reactive CD8(+) T-cells, In patients carrying the HLA-A2 allele, the immune response is primarily directed to the Tax11-19 peptide. The frequency, activation state, and TCR usage of HLA-A2/Tax11-19 binding T cells in patients with HTLV-I-associated myelopathy was determined using MHC class I tetramers loaded with the Tax11-19 peptide. Circulating Tax11-19-reactive T cells were found at very high frequencies, approaching 1:10 circulating CD8(+) T cells. T cells binding HLA-A2/Tax11-19 consisted of heterogeneous populations expressing different chemokine receptors and the IL-2R beta-chain but not the IL-2R alpha-chain, Additionally, Tax11-19-reactive CD8+ T cells used one predominant TCR V beta-chain for the recognition of the HLA-A2/Tax11-19 complex. These data provide direct evidence for high frequencies of circulating Tax11-19-reactive CD8(+) T cells in patients with HTLV-1-associated myelopathy. C1 Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Johns Hopkins Sch Med, Baltimore, MD 21205 USA. Emory Univ, Dept Microbiol, Atlanta, GA 30322 USA. NIH, Viral Immunol Sect, Bethesda, MD 20892 USA. Beckman Coulter, Miami, FL 33116 USA. Univ W Indies, Dept Med, Kingston 7, Jamaica. RP Hafler, DA (reprint author), Brigham & Womens Hosp, Ctr Neurol Dis, 77 Ave Louis Pasteur, Boston, MA 02115 USA. RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 FU NIAID NIH HHS [P01 AI39671, AI42518]; NINDS NIH HHS [R01-NS 24247] NR 35 TC 115 Z9 115 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 FEB 1 PY 1999 VL 162 IS 3 BP 1765 EP 1771 PG 7 WC Immunology SC Immunology GA 160YM UT WOS:000078261000069 PM 9973440 ER PT J AU Abu-Elyazeed, R Wierzba, TF Mourad, AS Peruski, LE Kay, BA Rao, M Churilla, AM Bourgeois, AL Mortagy, AK Kamal, SM Savarino, SJ Campbell, JR Murphy, JR Naficy, A Clemens, JD AF Abu-Elyazeed, R Wierzba, TF Mourad, AS Peruski, LE Kay, BA Rao, M Churilla, AM Bourgeois, AL Mortagy, AK Kamal, SM Savarino, SJ Campbell, JR Murphy, JR Naficy, A Clemens, JD TI Epidemiology of enterotoxigenic Escherichia coli diarrhea in a pediatric cohort in a periurban area of lower Egypt SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 45th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene CY DEC 01-05, 1996 CL BALTIMORE, MD SP Amer Soc Trop Med & Hyg ID COLONIZATION FACTOR ANTIGEN; LONGITUDINAL DATA-ANALYSIS; INFANTILE DIARRHEA; ORAL IMMUNIZATION; RURAL BANGLADESH; RISK-FACTORS; CHILDREN; ANTIBODIES; VACCINE; MILK AB Enterotoxigenic Escherichia coli (ETEC) are diverse pathogens that express heat-labile (LT) and/or heat-stable (ST) enterotoxins, yet little is known about whether epidemiologic patterns of pediatric ETEC diarrhea vary by the expressed ETEC toxin phenotype, In total, 242 Egyptian children aged <3 years were prospectively followed in 1993-1995. ETEC episodes were detected during twice-weekly home visits, and asymptomatic ETEC excretion was identified from monthly cross-sectional surveys. ETEC episodes were 0.6 per child-year. ST-only ETEC was 2.6 times (P < .001) more common in warmer than cooler months, while LT-only ETEC showed no seasonal variation. Ownership of a household sanitary latrine, but not breast-feeding, was associated with a lower risk of both enterotoxin phenotypes, Coexpression of a colonization factor by LT- or ST-only ETEC strengthened the association with diarrhea, These findings indicate that the epidemiologic patterns of LT-only and ST-only ETEC are not identical and that disease interventions should include improved household sanitation. C1 USN, Med Res Unit 3, Cairo, Egypt. NICHHD, NIH, Bethesda, MD 20892 USA. Natl Naval Med Ctr, Bethesda, MD 20814 USA. RP Abu-Elyazeed, R (reprint author), USN, Med Res Unit 3, Attn Code 101F,PSC 452,Box 5000, FPO, AE 09835 USA. FU NICHD NIH HHS [Y1-HD-0026-01] NR 36 TC 51 Z9 54 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD FEB PY 1999 VL 179 IS 2 BP 382 EP 389 DI 10.1086/314593 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 162QB UT WOS:000078357300012 PM 9878022 ER PT J AU Breman, JG Johnson, KM van der Groen, G Robbins, CB Szczeniowski, MV Ruti, K Webb, PA Meier, F Heymann, DL AF Breman, JG Johnson, KM van der Groen, G Robbins, CB Szczeniowski, MV Ruti, K Webb, PA Meier, F Heymann, DL CA Ebola Virus Study Teams TI A search for Ebola virus in animals in the Democratic Republic of the Congo and Cameroon: Ecologic, virologic, and serologic surveys, 1979-1980 SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID MONKEYPOX VIRUS; IDENTIFICATION; RNA AB More than 30 years after the first outbreak of Marburg virus disease in Germany and Yugoslavia and 20 years after Ebola hemorrhagic fever first occurred in central Africa, the natural history of filoviruses remains unknown. In 1979 and 1980, animals in the Democratic Republic of the Congo and Cameroon were collected during the dry season near the site of the 1976 Ebola hemorrhagic fever epidemic, The study objectives were to identify local animals and search for evidence of Ebola virus in their tissues. A total of 1664 animals representing 117 species was collected, including >400 bats and 500 rodents, Vero and CV-1 cells and IFA and RIA were used for virus and antibody detection, respectively, No evidence of Ebola virus infection was found. This study was limited in time and animal collections and excluded insects and plants. Long-term, prospective, multidisciplinary comparative studies will yield more information than will repeat short forays on the ecology of filoviruses. C1 WHO, Smallpox Eradicat Unit, CH-1211 Geneva, Switzerland. Museum Nat Hist, Geneva, Switzerland. Ctr Dis Control & Prevent, Special Viral Pathogens Branch, Natl Ctr Infect Dis, Atlanta, GA USA. Inst Trop Med, Dept Microbiol, B-2000 Antwerp, Belgium. Natl Museum Nat Hist, Smithsonian Inst, Div Mammals, Washington, DC 20560 USA. WHO, Kinshasa, Zaire. Minist Publ Hlth, Programme Elargi Vaccinat, Kinshasa, Zaire. Org Lutte Endemies Afrique Cent, Yaounde, Cameroon. Carnegie Museum Nat Hist, Pittsburgh, PA USA. SW Missouri State Univ, Springfield, MO 65802 USA. Catholic Mission Diocese Doume, Mouloundou, Cameroon. RP Breman, JG (reprint author), NIH, Fogarty Inst Ctr, Bldg 31,Room B2C39,31 Ctr Dr,MSC 2220, Bethesda, MD 20892 USA. EM jbreman@nih.gov NR 30 TC 48 Z9 52 U1 5 U2 29 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD FEB PY 1999 VL 179 SU 1 BP S139 EP S147 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 163HQ UT WOS:000078400300024 PM 9988177 ER PT J AU Ida, H Rennert, OM Kato, S Ueda, T Oishi, K Maekawa, K Eto, Y AF Ida, H Rennert, OM Kato, S Ueda, T Oishi, K Maekawa, K Eto, Y TI Severe skeletal complications in Japanese patients with type 1 Gaucher disease SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Article ID ENZYME REPLACEMENT THERAPY; BONE-MARROW TRANSPLANTATION; MUTATIONS; IDENTIFICATION; GLUCOCEREBROSIDASE; ALGLUCERASE; CHILDREN; FEATURES AB To better characterize skeletal complications in Japanese patients with type I Gaucher disease (GD), we performed genotyping and clinical and radiological analysis of 35 patients, the vast majority of this population, Skeletal complications tend to be very common, severe and rapidly progressive in Japanese patients with type 1 GD. Twenty (57%) of these patients manifested end points of severe bone disease including avascular necrosis, pathological fracture and/or bone crisis. Mean time from presentation/diagnosis of GD until presentation of this involvement was 3 years 6 months +/- 4 years I month. Prevalence of severe bone disease is significantly higher in splenectomized than in non-splenectomized patients-81% (17/21) versus 21% (3/14) (p = 0.0007, Fisher's exact test). Four (29%) of 14 patients receiving enzyme replacement therapy (ERT) or bone marrow transplantation (BMT) manifested severe bone involvement for the first time during or after treatment. All cases occurred in children in whom ERT doses had been lowered after only brief administration of higher starting doses (n = 3) or partial donor marrow engraftment resulted in low glucocerebrosidase (GCR) activity (n = 1). These observations suggest that splenectomy may correlate with accelerated skeletal deterioration with severe skeletal disease, at least in patients with severe phenotypic expression. They also suggest that it is important that sufficient GCR is available in paediatric patients with severe phenotypic expression. Hence ERT dosages should be based on disease severity and on age, with sustained administration of full doses in patients at greater risk of important skeletal complications. C1 Jikei Univ, Sch Med, Dept Pediat, Minato Ku, Tokyo 105, Japan. Jikei Univ, Sch Med, Dept Gene Therapy, Inst DNA Med, Tokyo 105, Japan. NIH, Natl Inst Child Hlth, Ctr Res Mother & Children, Bethesda, MD 20892 USA. Nippon Med Sch, Dept Pediat, Tokyo 113, Japan. RP Ida, H (reprint author), Jikei Univ, Sch Med, Dept Pediat, Minato Ku, 3-25-8, Tokyo 105, Japan. NR 28 TC 18 Z9 19 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0141-8955 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD FEB PY 1999 VL 22 IS 1 BP 63 EP 73 DI 10.1023/A:1005451300167 PG 11 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 170JG UT WOS:000078802100008 PM 10070619 ER PT J AU Braunstein, SL AF Braunstein, SL TI Mutational analysis of 7-dehydrocholesterol reductase in holoprosencephaly patients SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract C1 NICHD, Heritable Disorders Branch, NIH, Bethesda, MD USA. Brown Univ, Providence, RI 02912 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD FEB PY 1999 VL 47 IS 2 SU S BP 23A EP 23A PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 158VG UT WOS:000078137600122 ER PT J AU Fahimian, NA Porter, FD AF Fahimian, NA Porter, FD TI Genomic characterization of murine sterol delta 8-isomerase for future gene targeting. SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract C1 NICHD, HDB, NIH, Bethesda, MD USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90095 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD FEB PY 1999 VL 47 IS 2 SU S BP 23A EP 23A PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 158VG UT WOS:000078137600123 ER PT J AU Bretsky, PM Harris, T Seeman, TE AF Bretsky, PM Harris, T Seeman, TE TI Associations between circulating interleukin-6 (IL-6) levels and successful aging. SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract C1 Univ So Calif, Sch Med, Los Angeles, CA 90089 USA. NIA, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Los Angeles, CA 90024 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD FEB PY 1999 VL 47 IS 2 SU S BP 95A EP 95A PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 158VG UT WOS:000078137600509 ER PT J AU Brooks, PJ Wise, DS Berry, DA Somers, RL Mackie, H Robbins, JH AF Brooks, PJ Wise, DS Berry, DA Somers, RL Mackie, H Robbins, JH TI Mammalian cells repair 8,5 '-cyclo-2 '-deoxyadenosine in DNA by nucleoside excision repair. SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract C1 NIAA, Bethesda, MD USA. NCI, NIH, Bethesda, MD 20892 USA. Glen Res Corp, Sterling, VA USA. Berry & Associates Inc, Dexter, MI USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD FEB PY 1999 VL 47 IS 2 SU S BP 130A EP 130A PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 158VG UT WOS:000078137600702 ER PT J AU Vidwans, AS Kim, S Coffin, DO Wink, DA Hewett, SJ AF Vidwans, AS Kim, S Coffin, DO Wink, DA Hewett, SJ TI Nitric oxide attenutates NMDA receptor-induced neuronal cell death independent of their intrinsic nitrosative abilities SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract C1 Univ Connecticut, Sch Med, Dept Pediat, Div Neonatol, Farmington, CT 06030 USA. Univ Connecticut, Sch Med, Dept Pharmacol, Farmington, CT 06030 USA. NCI, Tumor Biol Sect, Radiat Biol Branch, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD FEB PY 1999 VL 47 IS 2 SU S BP 165A EP 165A PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 158VG UT WOS:000078137600883 ER PT J AU Gulson, BL Gray, B Mahaffey, KR Jameson, CW Mizon, KJ Patison, N Korsch, MJ AF Gulson, BL Gray, B Mahaffey, KR Jameson, CW Mizon, KJ Patison, N Korsch, MJ TI Comparison of the rates of exchange of lead in the blood of newly born infants and their mothers with lead from their current environment SO JOURNAL OF LABORATORY AND CLINICAL MEDICINE LA English DT Article ID IN-VIVO MEASUREMENTS; BONE; MICE; MOBILIZATION; INTOXICATION; METABOLISM; ABSORPTION; PREGNANCY; EXPOSURE; WORKERS AB Newly born infants (n = 15) were monitored for 6 months after birth or for longer periods to evaluate the changes in isotopic composition and lead concentration in infants as compared with that in women from the same population groups and to determine the clearance rates of lead from blood in the infants. These data represent the first published results for serial blood sampling in a relatively large cohort of newly born infants. Blood lead concentrations decrease from the cord to samples taken at 60 to 90 days and then increase by amounts varying from negligible to 166%. In spite of concern about individual susceptibility to lead pharmacokinetics, changes in isotopic ratio followed a smooth decrease over time for 9 of the 11 infants born to migrant parents, and the patterns of variation were quite reproducible. Data for 2 of 4 infants born to multigenerational Australian parents exhibited little change in isotopic ratio over time, and in the other two cases, the changes were attributed to diet. The rate of exchange (t(1/2)) for the migrant infants of lead in blood derived from the mother during pregnancy and the lead from the current environment was calculated by using a linear function and ranged from 65 to 131 (91 +/- 19, mean +/- SD) days. The half-lives for the exchange of skeletal and environmental lead for 7 of the 8 women before significant mobilization of lead from the maternal skeleton ranged from 50 to 66 (59 +/- 6) days. One explanation for the longer half lives for infants as compared with the mothers may be the proportionally higher contribution of current environmental (Australian) lead in the infants at parturition. Exchanges of lead in infants are more complex than for the adults, reflecting inputs from sources such as maternal skeletal lead during breast feeding. C1 Macquarie Univ, Grad Sch Environm, Sydney, NSW 2109, Australia. Macquarie Univ, Sch Chem, Sydney, NSW 2109, Australia. CSIRO, Sydney, NSW, Australia. US EPA, Natl Ctr Environm Assessment, Cincinnati, OH 45268 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Gulson, BL (reprint author), Macquarie Univ, Grad Sch Environm, Sydney, NSW 2109, Australia. FU NIEHS NIH HHS [N01-ES-05292] NR 31 TC 11 Z9 12 U1 0 U2 0 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0022-2143 J9 J LAB CLIN MED JI J. Lab. Clin. Med. PD FEB PY 1999 VL 133 IS 2 BP 171 EP 178 DI 10.1016/S0022-2143(99)90010-0 PG 8 WC Medical Laboratory Technology; Medicine, General & Internal; Medicine, Research & Experimental SC Medical Laboratory Technology; General & Internal Medicine; Research & Experimental Medicine GA 164ZJ UT WOS:000078493200010 PM 9989769 ER PT J AU van Dijk, KW van Vlijmen, BJM van't Hof, HB van der Zee, A Santamarina-Fojo, S van Berkel, TJC Havekes, LM Hofker, MH AF van Dijk, KW van Vlijmen, BJM van't Hof, HB van der Zee, A Santamarina-Fojo, S van Berkel, TJC Havekes, LM Hofker, MH TI In LDL receptor-deficient mice, catabolism of remnant lipoproteins requires a high level of apoE but is inhibited by excess apoE SO JOURNAL OF LIPID RESEARCH LA English DT Article DE adenovirus-mediated gene transfer; LDL receptor-related protein; hypertriglyceridemia; VLDL-triglyceride lipolysis; hepatic VLDL triglyceride production ID HEPARAN-SULFATE PROTEOGLYCANS; LOW-DENSITY LIPOPROTEINS; HUMAN APOLIPOPROTEIN E2; TRANSGENIC MICE; CHYLOMICRON REMNANTS; HEPATIC-UPTAKE; KNOCKOUT MICE; IN-VIVO; PROTEIN; BINDING AB To investigate the quantitative requirement for apolipoprotein (apo) E in the clearance of lipoproteins via the non-low density lipoprotein (LDL) receptor mediated pathway, human APOE was overexpressed at various levels in the livers of mice deficient for both the endogenous Apoe and Ldlr genes (Apoe-/-.Ldlr-/-) using adenovirus-mediated gene transfer. We found that a low level of APOE expression, that was capable of reducing the hyperlipidemia in Apoe-/- mice, did not result in a reduction of the hyperlipidemia in Apoe-/-.Ldlr-/- mice. Surprisingly, a very high level of APOE expression also did not result in a reduction of hypercholesterolemia in Apoe-/-.Ldlr-/- mice, despite very high levels of circulating apoE (>160 mg/dl). Only a moderately high level of APOE expression resulted in a reduction of serum cholesterol level (from 35.2 +/- 6.7 to 14.6 +/- 2.3 mmol/l) and the disappearance of VLDL from the serum. Moreover, the very high level of APOE expression resulted in a severe hypertriglyceridemia in Apoe-/-.Ldlr-/- mice and not Apoe-/- mice (25.7 +/- 8.9 and 2.2 +/- 1.8 mmol/l, respectively). This hypertriglyceridemia was associated with an APOE-induced increase in the VLDL triglyceride production rate and an inhibition of VLDL-triglyceride lipolysis. We conclude from these data that, for efficient clearance, the non-LDL receptor-mediated pathway requires a higher level of APOE expression as compared to the LDL receptor, but is more sensitive to an APOE-induced increase in VLDL production and inhibition of VLDL-triglyceride lipolysis. C1 Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. Leiden Amsterdam Ctr Drug Res, Dept Biopharmaceut, Leiden, Netherlands. TNO, Gaubius Lab, NL-2300 AK Leiden, Netherlands. NIH, Mol Dis Branch, Bethesda, MD 20892 USA. Acad Hosp Leiden, Dept Cardiol, Leiden, Netherlands. Acad Hosp Leiden, Dept Internal Med, Leiden, Netherlands. RP van Dijk, KW (reprint author), Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. RI Willems van Dijk, Ko/A-1798-2008 OI Willems van Dijk, Ko/0000-0002-2172-7394 NR 47 TC 26 Z9 26 U1 1 U2 1 PU LIPID RESEARCH INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD FEB PY 1999 VL 40 IS 2 BP 336 EP 344 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 163NY UT WOS:000078412700018 PM 9925664 ER PT J AU Driscoll, AK Hearn, GK Evans, VJ Moore, KA Sugland, BW Call, V AF Driscoll, AK Hearn, GK Evans, VJ Moore, KA Sugland, BW Call, V TI Nonmarital childbearing among adult women SO JOURNAL OF MARRIAGE AND THE FAMILY LA English DT Article DE fertility history; marital fertility; nonmarital fertility; out-of-wedlock births; premarital fertility ID UNITED-STATES; PREMARITAL BIRTH; EDUCATIONAL-ATTAINMENT; CHANGING ATTITUDES; UNMARRIED MOTHERS; MARITAL-STATUS; WHITE WOMEN; LIFE-COURSE; MARRIAGE; FERTILITY AB We look at fertility and economic outcomes of women with three types of nonmarital births and women who have marital births, The sample is front the National Survey of Families and Households. Net of controls, married and unmarried women with a recent birth are equally likely, to have another birth, Never-married and previously married mothers are more likely to have another nonmarital birth than are other women. Additional nonmarital births to never-married women are associated with being on welfare, not being employed; and having low household income. C1 NICHD, Demog & Behav Sci Branch, Populat Res Ctr, Bethesda, MD 20892 USA. Brigham Young Univ, Ctr Studies Family, Provo, UT 84602 USA. RP Driscoll, AK (reprint author), 4301 Connecticut Ave NW,Suite 100, Washington, DC 20008 USA. NR 35 TC 18 Z9 18 U1 0 U2 0 PU NATL COUNCIL FAMILY RELATIONS PI MINNEAPOLIS PA 3989 CENTRAL AVE NE #550, MINNEAPOLIS, MN 55421 USA SN 0022-2445 J9 J MARRIAGE FAM JI J. Marriage Fam. PD FEB PY 1999 VL 61 IS 1 BP 178 EP 187 DI 10.2307/353892 PG 10 WC Family Studies; Sociology SC Family Studies; Sociology GA 173DB UT WOS:000078965000014 ER PT J AU Holland, SM AF Holland, SM TI Stimulating the phagocytes: progress and problems SO JOURNAL OF MEDICAL MICROBIOLOGY LA English DT Editorial Material ID INTERFERON-GAMMA-RECEPTOR; MYCOBACTERIAL INFECTION; VISCERAL LEISHMANIASIS; INTERLEUKIN-12; DEFICIENCY; SUSCEPTIBILITY; MUTATION C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Holland, SM (reprint author), NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. NR 17 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-2615 J9 J MED MICROBIOL JI J. Med. Microbiol. PD FEB PY 1999 VL 48 IS 2 BP 111 EP 112 PG 2 WC Microbiology SC Microbiology GA 206AK UT WOS:000080853700001 PM 9989636 ER PT J AU Shibata, R Feng, YR Gee, D Norwood, D Xiao, XD Zeichner, SL Martin, MA Dimitrov, DS AF Shibata, R Feng, YR Gee, D Norwood, D Xiao, XD Zeichner, SL Martin, MA Dimitrov, DS TI Telomere dynamics in monkeys: Increased cell turnover in macaques infected with chimeric simian-human immunodeficiency viruses SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Article DE HIV; SHIV; telomeres; telomerase; monkeys; macaques; cynomolgus; pig-tailed; rhesus; pathogenesis; cell turnover ID HIV-1 INFECTION; HUMAN FIBROBLASTS; RAPID TURNOVER; CD4(+); LYMPHOCYTES; LENGTH; CD8(+); PATHOGENESIS; DISEASE; SUBSET AB To address the question of how cell turnover is affected by retroviral infections, we used the telomeric terminal restriction fragments (TRFs) as markers of cell replicative history and measured their length in macaques infected with chimeric simian-human immunodeficiency viruses (SHIVs). The TRF lengths of mononuclear cells in 104 samples, including longitudinal samples from nine cynomolgus and ten pig-tailed macaques infected with SHIV, and in samples from 26 uninfected macaques, were quantitated by an improved method, based on two-dimensional calibration of DNA sizes, pulsed field electrophoresis, and high-resolution Southern blot images. The average TRF lengths of peripheral blood mononuclear cells (PBMCs) from uninfected pig-tailed (14.9 +/- 1.6 kbp) and cynomolgus (14.1 +/- 1.8 kbp) macaques were about 3 and 5 kbp longer than those of human infants and 30-year-old adults, respectively. The rate of TRF length shortening in infected pigtailed macaques was significantly (P = 0.035) higher (2.2-fold) than in uninfected monkeys. The TRFs in SHIV-infected cynomolgus monkeys, which, in general, had lower viral loads than pig-tailed macaques, shortened on average more rapidly (1.6-fold) than in uninfected animals, but the difference was not statistically significant. The TRFs of mononuclear cells from the lymph nodes of two rapidly progressing SHIV-infected macaques that developed AIDS and died also shortened in parallel but somewhat more rapidly than in the PBMCs. These results suggest that the rate of PBMC turnover in macaques could be increased several-fold during infections by immunodeficiency viruses, likely due to immune activation by SHIV antigens. C1 NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, DBS,NIH, Frederick, MD 21702 USA. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. NCI, HIV & AIDS Malignancies Branch, NIH, Bethesda, MD 20892 USA. RP Dimitrov, DS (reprint author), NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, DBS,NIH, Bldg 469,Room 216,POB B,Miller Dr, Frederick, MD 21702 USA. NR 26 TC 8 Z9 8 U1 0 U2 2 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD FEB PY 1999 VL 28 IS 1 BP 1 EP 10 PG 10 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 197KZ UT WOS:000080365100001 PM 10372535 ER PT J AU Wolfe, SE Howard, DE Schetz, JA Cheng, CJ Webber, R Beatty, DM Chronwall, BM Morris, SJ AF Wolfe, SE Howard, DE Schetz, JA Cheng, CJ Webber, R Beatty, DM Chronwall, BM Morris, SJ TI Dopamine D-2-receptor isoforms expressed in AtT20 cells inhibit Q-type high-voltage-activated Ca2+ channels via a membrane-delimited pathway SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE video microscopy; fluorescence measurements; melanotropes; KCL and KCS cell lines ID RECEPTOR-MEDIATED INHIBITION; RAT PARS-INTERMEDIA; PROOPIOMELANOCORTIN GENE-EXPRESSION; CORTICOTROPIN-RELEASING FACTOR; DEPENDENT CALCIUM CHANNELS; BETA-GAMMA-SUBUNITS; G-PROTEINS; ION CHANNELS; P-TYPE; INTRACELLULAR CALCIUM AB Dopamine D-2, receptors both acutely and chronically inhibit high-voltage-activated Ca2+ channels (HVA-CCs). Two alternatively spliced isoforms, D-2L (long) and D-2S (short), are expressed at high levels in rat pituitary intermediate lobe melanotropes but are lacking in anterior lobe corticotropes. We stably transfected D-2L and D-2S into corticotrope-derived AtT20 cells. Both isoforms coupled to inhibition of Q-type calcium channels through pertussis toxin-sensitive G proteins. Thus, we have created a model system in which to study the kinetics of D-2-receptor regulation of Ca2+ channels. Rapid inhibition of HVA-CCs was characterized using a novel fluorescence Video imaging technique for the measurement of millisecond kinetic events. We measured the time elapsed (lag time) between the arrival of depolarizing isotonic 66 mM K+, sensed by fluorescence from included carboxy-X-rhodamine (CXR), and the beginning of increased intracellular Ca2+ levels (sensed by changes in indo 1 fluorescence ratio). The lag time averaged 350-550 ms, with no significant differences among cell types. Addition of the D-2-agonist quinpirole (250 mu M) to the K+/CXR solution significantly increased the lag times for D-2-expressing cells but did not alter the lag time for AtT20 controls. The increased lag times for D-2L- and D-2S-transfected cells suggest that at least a fraction of the Ca2+ channels was inhibited within the initial 350550 ms. As this inhibition time is too fast for a multistep second messenger pathway, we conclude that inhibition occurs via a membrane-limited diffusion mechanism. C1 Univ Missouri, Sch Biol Sci, Div Biochem & Mol Biol, Kansas City, MO 64110 USA. Univ Missouri, Sch Biol Sci, Div Cell Biol & Biophys, Kansas City, MO 64110 USA. NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. Res & Diagnost Antibodies, Berkeley, CA USA. RP Morris, SJ (reprint author), Univ Missouri, Sch Biol Sci, Div Biochem & Mol Biol, 103-BSB 5007 Rockhill Rd, Kansas City, MO 64110 USA. NR 75 TC 9 Z9 9 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD FEB PY 1999 VL 72 IS 2 BP 479 EP 490 DI 10.1046/j.1471-4159.1999.0720479.x PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 159FR UT WOS:000078161800004 PM 9930719 ER PT J AU Sihag, RK Jaffe, H Nixon, RA Rong, XH AF Sihag, RK Jaffe, H Nixon, RA Rong, XH TI Serine-23 is a major protein kinase A phosphorylation site on the amino-terminal head domain of the middle molecular mass subunit of neurofilament proteins SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE neurofilament protein; phosphorylation; protein kinase A; mass spectrometry; phosphopeptides ID MAMMALIAN NEUROFILAMENTS; SEQUENCE-ANALYSIS; NF-M; IDENTIFICATION; PEPTIDES; NEURONS AB We have shown previously that phosphate groups on the amino-terminal head domain region of the middle molecular mass subunit of neurofilament proteins (NF-M) are added by second messenger-dependent protein kinases, Here, we have identified Ser(23) as a specific protein kinase A phosphorylation site on the native NF-M subunit and on two synthetic peptides, S-1, ((RRVPTETRSSF24)-R-14) and S-2, ((21)RSSFSRVSGSPSSGFRSQSWS(41)), localized within the amino-terminal head domain region. Ser(23) was identified as a phosphorylation site on the P-32-labeled alpha-chymotryptic peptide that carried >80% of the P-32-phosphates incorporated into the NF-M subunit by protein kinase A. The synthetic peptides S-1, and S-2, were phosphorylated 18 and two times more efficiently by protein kinase A than protein kinase C, respectively. Neither of the peptides was phosphorylated by casein kinase II. The sequence analyses of the chemically modified phosphorylated serine residues showed that Ser(23) was the major site of phosphorylation for protein kinase A on both S-1, and S-2, peptides. Low levels of incorporation of P-32-phosphates into Ser(22), Ser(28), and Ser(32) by protein kinase A were also observed. Protein kinase C incorporated P-32-phosphates into Ser(22), Ser(23), Ser(25), Ser(28) Ser(32), and a threonine residue, but none of these sites could be assigned as a major site of phosphorylation. Analyses of the phosphorylated synthetic peptides by liquid chromatography-tandem mass spectrometry also showed that protein kinase A phosphorylated only one site on peptide S-1, and that ions with up to four phosphates were detected on peptide S-2,. Analysis of the data from the tandem ion trap mass spectrometry by using the computer program PEPSEARCH did not unequivocally identify the specific sites of phosphorylation on these serine-rich peptides. Our data suggest that Ser(23) is a major protein kinase A-specific phosphorylation site on the amino-terminal head region of the NF-M subunit, Phosphorylation of Ser(23) on the NF-M subunit by protein kinase A may play a regulatory role in neurofilament assembly and/or the organization of neurofilaments in the axon. C1 NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. NINDS, Prot Peptide Sequencing Facil, NIH, Bethesda, MD 20892 USA. Harvard Univ, McLean Hosp, Sch Med, Labs Mol Neurosci, Belmont, MA 02178 USA. RP NINDS, Neurobiol Lab, NIH, Bldg 36,Room 2A-21,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 32 TC 23 Z9 23 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD FEB PY 1999 VL 72 IS 2 BP 491 EP 499 DI 10.1046/j.1471-4159.1999.0720491.x PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 159FR UT WOS:000078161800005 PM 9930720 ER PT J AU Kapatos, G Hirayama, K Shimoji, M Milstien, S AF Kapatos, G Hirayama, K Shimoji, M Milstien, S TI GTP cyclohydrolase I feedback regulatory protein is expressed in serotonin neurons and regulates tetrahydrobiopterin biosynthesis SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE 5,6,7,8-tetrahydrobiopterin; GTP cyclohydrolase I; GTP cyclohydrolase I feedback regulatory protein; dopamine; serotonin ID MESSENGER-RNA EXPRESSION; RAT-BRAIN; COFACTOR; PURIFICATION; BIOPTERIN; TYROSINE; TISSUES; CLONING AB Tetrahydrobiopterin, the coenzyme required for hydroxylation of phenylalanine, tyrosine, and tryptophan, regulates its own synthesis through feedback inhibition of GTP cyclohydrolase I (GTPCH) mediated by a regulatory subunit, the GTP cyclohydrolase feedback regulatory protein (GFRP). In the liver, L-phenylalanine specifically stimulates tetrahydrobiopterin synthesis by displacing tetrahydrobiopterin from the GTPCH-GFRP complex. To explore the role of this regulatory system in rat brain, we examined the localization of GFRP mRNA using double-label in situ hybridization. GFRP mRNA expression was abundant in serotonin neurons of the dorsal raphe nucleus but was undetectable in dopamine neurons of the midbrain or norepinephrine neurons of the locus coeruleus. Simultaneous nuclease protection assays for GFRP and GTPCH mRNAs showed that GFRP mRNA is most abundant within the brainstem and that the ratio of GFRP to GTPCH mRNA is much higher than in the ventral midbrain. Two species of GFRP mRNA differing by similar to 20 nucleotides in length were detected in brainstem but not in other tissues, with the longer, more abundant form being common to other brain regions. It is interesting that the pineal and adrenal glands did not contain detectable levels of GFRP mRNA, although GTPCH mRNA was abundant in both. Primary neuronal cultures were used to examine the role of GFRP-mediated regulation of GTPCH on tetrahydrobiopterin synthesis within brainstem serotonin neurons and midbrain dopamine neurons. L-phenylalanine increased tetrahydrobiopterin levels in serotonin neurons to a maximum of twofold in a concentration-dependent manner, whereas D-phenylalanine and L-tryptophan were without effect. In contrast, tetrahydrobiopterin levels within cultured dopamine neurons were not altered by L-phenylalanine. The time course of this effect was very rapid, with a maximal response observed within 60 min. Inhibitors of tetrahydrobiopterin biosynthesis prevented the L-phenylalanine-induced increase in tetrahydrobiopterin levels. 7,8-Dihydroneopterin, a reduced pteridine capable of inhibiting GTPCH in a GFRP-dependent manner, decreased tetrahydrobiopterin levels in cultures of both serotonin and dopamine neurons. This inhibition was reversed by L-phenylalanine in serotonin but not in dopamine neurons. Our data suggest that GTPCH activity within serotonin neurons is under a tonic inhibitory tone mediated by GFRP and that tetrahydrobiopterin levels are maintained by the balance of intracellular concentrations of tetrahydrobiopterin and L-phenylalanine. In contrast, although tetrahydrobiopterin biosynthesis within dopamine neurons is also feedback-regulated, L-phenylalanine plays no role, and therefore tetrahydrobiopterin may have a direct effect on GTPCH activity. C1 Wayne State Univ, Sch Med, Dept Psychiat & Behav Neurosci, Cellular & Clin Neurobiol Program, Detroit, MI 48201 USA. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Kapatos, G (reprint author), Wayne State Univ, Sch Med, Dept Psychiat & Behav Neurosci, Cellular & Clin Neurobiol Program, 2309 Scott Hall,540 E Canfield, Detroit, MI 48201 USA. FU NINDS NIH HHS [NS26081] NR 23 TC 30 Z9 31 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD FEB PY 1999 VL 72 IS 2 BP 669 EP 675 DI 10.1046/j.1471-4159.1999.0720669.x PG 7 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 159FR UT WOS:000078161800024 PM 9930739 ER PT J AU Bearer, EL Reese, TS AF Bearer, EL Reese, TS TI Association of actin filaments with axonal microtubule tracts SO JOURNAL OF NEUROCYTOLOGY LA English DT Article ID SQUID GIANT-AXON; GREEN-ALGA BRYOPSIS; INTERMEDIATE FILAMENTS; AXOPLASMIC ORGANELLES; ELECTRON-MICROSCOPY; MOLECULAR MOTORS; CYTOSKELETON; MYOSIN; ORGANIZATION; MOTILITY AB Axoplasmic organelles move on actin as well as microtubules in vitro and axons contain a large amount of actin, but little is known about the organization and distribution of actin filaments within the axon. Here we undertake to define the relationship of the microtubule bundles typically found in axons to actin filaments by applying three microscopic techniques: laser-scanning confocal microscopy of immuno-labeled squid axoplasm; electronmicroscopy of conventionally prepared thin sections; and electronmicroscopy of touch preparations-a thin layer of axoplasm transferred to a specimen grid and negatively stained. Light microscopy shows that longitudinal actin filaments are abundant and usually coincide with longitudinal microtubule bundles. Electron microscopy shows that microfilaments are interwoven with the longitudinal bundles of microtubules. These bundles maintain their integrity when neurofilaments are extracted. Some, though not all microfilaments decorate with the S1 fragment of myosin, and some also act as nucleation sites for polymerization of exogenous actin, and hence are definitively identified as actin filaments. These actin filaments range in minimum length from 0.5 to 1.5 mu m with some at least as long as 3.5 mu m. We conclude that the microtubule-based tracks for fast organelle transport also include actin filaments. These actin filaments are sufficiently long and abundant to be ancillary or supportive of fast transport along microtubules within bundles, or to extend transport outside of the bundle. These actin filaments could also be essential for maintaining the structural integrity of the microtubule bundles. C1 Marine Biol Lab, Woods Hole, MA 02543 USA. NINCDS, NIH, Bethesda, MD 20854 USA. Brown Univ, Dept Pathol, Providence, RI 02912 USA. RP Bearer, EL (reprint author), Marine Biol Lab, Woods Hole, MA 02543 USA. FU CIT NIH HHS [CTR 3192]; NIGMS NIH HHS [R01 GM047368, GM47368] NR 34 TC 28 Z9 28 U1 0 U2 3 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0300-4864 J9 J NEUROCYTOL JI J. Neurocytol. PD FEB PY 1999 VL 28 IS 2 BP 85 EP 98 DI 10.1023/A:1007025421849 PG 14 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 265PW UT WOS:000084253400001 PM 10590510 ER PT J AU Whiteside, MB Quan, N Herkenharn, M AF Whiteside, MB Quan, N Herkenharn, M TI Induction of pituitary cytokine transcripts by peripheral lipopolysaccharide SO JOURNAL OF NEUROENDOCRINOLOGY LA English DT Article DE endotoxin; interleukin-1 beta converting enzyme; interleukin-1 P; interleukin-1 receptor antagonist; peripheral lipopolysaccharide; pituitary cytokine transcripts; tumour necrosis factor ID CORTICOTROPIN-RELEASING-FACTOR; CENTRAL-NERVOUS-SYSTEM; KAPPA-B-ALPHA; MESSENGER-RNA; POSTERIOR PITUITARY; ACTH RELEASE; RAT-BRAIN; INTERLEUKIN-1; ENDOTOXIN; HORMONE AB Systemically administered lipopolysaccharide (LPS) elicits profound changes in pituitary hormone secretion. Pro-inflammatory cytokines have been proposed as mediators of these responses. In this study, we used in-situ hybridization histochemistry to investigate LPS-induced cytokine gene expression in the rat pituitary. After i.p. or i.v. injection of various doses of LPS, mRNA for the immediate-early gene I kappa Bu tan inhibitor of NF-kappa B, a transcription factor that regulates the expression of many pro-inflammatory cytokines) was induced in the anterior lobe as early as 0.5 h. The induced I kappa B alpha mRNA expression peaked at 1 h. In the posterior lobe, I kappa B alpha mRNA was first induced at 0.5 h and peaked at 2 h. A similar spatiotemporal pattern of interleukin-1b (IL-1) mRNA induction was observed. In addition, at 2 h after injection, TNF alpha, IL-1 beta converting enzyme (ICE), and IL-1 receptor antagonist (IL-1RA) mRNAs were induced in both anterior and posterior robes. Type 1 IL-1 receptor(lL-1R1) mRNA was constitutively expressed in the pituitary, and its expression level did not change after the LPS injection. Interestingly, the mRNA coding for glial fibrillary acidic protein (GFAP), an astrocyte marker, was selectively induced in the posterior lobe at 2 h after LPS injection, suggesting that LPS affects pituicyte function. Together, these results suggest that LPS acts directly on the pituitary to rapidly induce cytokine expression. Locally synthesized cytokines may activate cytokine receptor bearing cells to modulate the endocrine activities of the pituitary. C1 NIMH, Funct Neuroanat Sect, Bethesda, MD 20892 USA. RP Quan, N (reprint author), NIMH, Funct Neuroanat Sect, Bldg 36,Room 2D15, Bethesda, MD 20892 USA. NR 28 TC 28 Z9 28 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0953-8194 J9 J NEUROENDOCRINOL JI J. Neuroendocrinol. PD FEB PY 1999 VL 11 IS 2 BP 115 EP 120 PG 6 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 169RB UT WOS:000078761400005 PM 10048466 ER PT J AU Kusano, K House, SB Gainer, H AF Kusano, K House, SB Gainer, H TI Effects of osmotic pressure and brain-derived neurotrophic factor on the survival of postnatal hypothalamic oxytocinergic and vasopressinergic neurons in dissociated cell culture SO JOURNAL OF NEUROENDOCRINOLOGY LA English DT Article DE oxytocin; vasopressin; coexistence; osmotic pressure; dissociated cell culture; BDNF; hypothalamus ID CENTRAL-NERVOUS-SYSTEM; SUPRAOPTIC NEURONS; MAGNOCELLULAR NEURONS; HYPEROSMOTIC STIMULI; RAT HYPOTHALAMUS; NUCLEUS; COEXPRESSION; NEUROPHYSIN; EXPRESSION; RECEPTORS AB Neurons from hypothalamic paraventricular nuclei (PVN) and supraoptic nuclei (SON) from postnatal day 6-8 rats were enzymatically dissociated and separately maintained in monolayer cultures for 14 days. The osmotic pressure of the culture medium, based an Neurobasal medium (Life Technologies), was varied (255, 300 and 330 mOsm/l) by adjustment using mannitol. The survival of oxytocin (OT), vasopressin (VP) and oxytocin-vasopressin (OT/VP) coexpressing neurons were studied under these varied conditions, and the identification of the cell phenotypes in the cultures was carried out by using double-label immunofluorescence, Under control osmolar conditions (300 mOsm/l) equivalent numbers of OT and VP neurons were found in the SON (P=0.8398) and PVN (P=0.4721) cultures. The OT neurons' survival did not change in 255 or 330 mOsm media in the SON cultures, but the VP neurons in the SON cultures were significantly increased in 255 mOsm/l medium as compared to control (300 mOsm/l) medium (P=0.0088). No significant changes were found in VP neuron survival in SON cultures between the 300-330 mOsm/l media (P=0.2372). Similar data were obtained for the VP neurons in PVN-derived cultures, but the OT neurons in these cultures survived significantly better at 300 mOs/l than at 255 mOsm/l (P<0.0001), but were not significantly different at 330 mOsm/l (P = 0.1208). In general, the VP neurons were more vulnerable than OT neurons to increases of culture medium osmolarity with respect to their survival. The number of OT/VP coexpressing neurons was greater in SON-derived cell cultures as compared to PVN-derived cell cultures, and their numbers were higher in the lower osmolarity media. The effects of adding brain-derived neurotrophic factor (BDNF) to the culture medium: on survival were determined. BDNF significantly increased the numbers of all three types of neurons in both PVN and SON cell cultures (P = 0.0001-0.0060). The phenotypically identified cells, cultured in the 300 mOsm/l medium, responded by depolarization or hyperpolarization when transferred to hypertonic or hypotonic perfusion salines, respectively. C1 NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Gainer, H (reprint author), NINDS, Neurochem Lab, NIH, Bldg 36,4D-20, Bethesda, MD 20892 USA. EM hgat-nih@codon.nih.gov NR 41 TC 16 Z9 16 U1 0 U2 2 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0953-8194 J9 J NEUROENDOCRINOL JI J. Neuroendocrinol. PD FEB PY 1999 VL 11 IS 2 BP 145 EP 152 PG 8 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 169RB UT WOS:000078761400009 PM 10048470 ER PT J AU Yang, DS Fitzgibbon, EJ Miles, FA AF Yang, DS Fitzgibbon, EJ Miles, FA TI Short-latency vergence eye movements induced by radial optic flow in humans: Dependence on ambient vergence level SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID OCULAR RESPONSES; VIEWING DISTANCE; TRANSLATION; MOTION; SCENE AB Radial patterns of optic flow, such as those experienced by moving observers who look in the direction of heading, evoke vergence eye movements at short latency. We have investigated the dependence of these responses on the ambient vergence level. Human subjects faced a large tangent screen onto which two identical random-dot patterns were back-projected. A system of crossed polarizers ensured that each eye saw only one of the patterns, with mirror galvanometers to control the horizontal positions of the images and hence the vergence angle between the two eyes. After converging the subject's eyes at one of several distances ranging from 16.7 cm to infinity, both patterns were replaced with new ones (using a system of shutters and two additional projectors) so as to simulate the radial flow associated with a sudden 4% change in viewing distance with the focus of expansion/contraction imaged in or very near both foveas. Radial-flow steps induced transient vergence at latencies of 80-100 ms, expansions causing increases in convergence and contractions the converse. Based on the change in vergence 90-140 ms after the onset of the steps, responses were proportional to the preexisting vergence angle (and hence would be expected to be inversely proportional to viewing distance under normal conditions). We suggest that this property assists the observer who wants to fixate ahead while passing through a visually cluttered area (e.g., a forest) and so wants to avoid making vergence responses to the optic flow created by the nearby objects in the periphery. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Miles, FA (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Rm 2A50,49 Convent Dr, Bethesda, MD 20892 USA. NR 8 TC 19 Z9 19 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD FEB PY 1999 VL 81 IS 2 BP 945 EP 949 PG 5 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 170XR UT WOS:000078832800052 PM 10036301 ER PT J AU Kim, M Lee, HS LaForet, G McIntyre, C Martin, EJ Chang, P Kim, TW Williams, M Reddy, PH Tagle, D Boyce, FM Won, L Heller, A Aronin, N DiFiglia, M AF Kim, M Lee, HS LaForet, G McIntyre, C Martin, EJ Chang, P Kim, TW Williams, M Reddy, PH Tagle, D Boyce, FM Won, L Heller, A Aronin, N DiFiglia, M TI Mutant huntingtin expression in clonal striatal cells: Dissociation of inclusion formation and neuronal survival by caspase inhibition SO JOURNAL OF NEUROSCIENCE LA English DT Article DE NH2-terminal huntingtin fragments; nuclear inclusions; cytoplasmic inclusions; full-length huntingtin; apoptosis; apoptotic bodies; membrane blebbing; Z-VAD-FMK; Z-DEVD-FMK; striatal hybrid cells ID INTRANUCLEAR INCLUSIONS; PROTEASES; APOPTOSIS; PROTEIN; BRAIN; DISEASE; TRACT; DEATH AB Neuronal intranuclear inclusions are found in the brains of patients with Huntington's disease and form from the polyglutamine-expanded N-terminal region of mutant huntingtin. To explore the properties of inclusions and their involvement in cell death, mouse clonal striatal cells were transiently transfected with truncated and full-length human wild-type and mutant huntingtin cDNAs. Both normal and mutant proteins localized in the cytoplasm, and infrequently, in dispersed and perinuclear vacuoles. Only mutant huntingtin formed nuclear and cytoplasmic inclusions, which increased with polyglutamine expansion and with time after transfection. Nuclear inclusions contained primarily cleaved N-terminaI products, whereas cytoplasmic inclusions contained cleaved and larger intact proteins. Cells with wild-type or mutant protein had distinct apoptotic features (membrane blebbing, shrinkage, cellular fragmentation), but those with mutant huntingtin generated the most cell fragments (apoptotic bodies). The caspase inhibitor Z-VAD-FMK significantly increased cell survival but did not diminish nuclear and cytoplasmic inclusions. In contrast, Z-DEVD-FMK significantly reduced nuclear and cytoplasmic inclusions but did not increase survival. A series of N-terminal products was formed from truncated normal and mutant proteins and from full-length mutant huntingtin but not from full-length wild-type huntingtin. One prominent N-terminal product was blocked by Z-VAD-FMK. In summary, the formation of inclusions in clonal striatal cells corresponds to that seen in the HD brain and is separable from events that regulate cell death. N-terminal cleavage may be linked to mutant huntingtin's role in cell death. C1 Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Univ Massachusetts, Med Ctr, Dept Med, Worcester, MA 01655 USA. Univ Massachusetts, Med Ctr, Dept Cell Biol, Worcester, MA 01655 USA. NIH, Bethesda, MD 20892 USA. Univ Chicago, Dept Pharmacol & Physiol Sci, Chicago, IL 60637 USA. RP DiFiglia, M (reprint author), Massachusetts Gen Hosp, MGH E, Lab Cellular Neurobiol, 149 13th St, Charlestown, MA 02129 USA. RI Kim, Manho/J-2738-2012 FU NIMH NIH HHS [MH28942]; NINDS NIH HHS [NS16367, NS31579] NR 31 TC 217 Z9 219 U1 0 U2 3 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 FEB 1 PY 1999 VL 19 IS 3 BP 964 EP 973 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 161JQ UT WOS:000078285800011 PM 9920660 ER PT J AU Chen, MY Lonser, RR Morrison, PF Governale, LS Oldfield, EH AF Chen, MY Lonser, RR Morrison, PF Governale, LS Oldfield, EH TI Variables affecting convection-enhanced delivery to the striatum: a systematic examination of rate of infusion, cannula size, infusate concentration, and tissue-cannula sealing time SO JOURNAL OF NEUROSURGERY LA English DT Article DE bulk flow; brain; convection; drug delivery; parameter; variable; rat ID IRON-OXIDE PARTICLES; BRAIN; FLOW; PERFUSION; MATTER AB Object. Although recent studies have shown that convection can be used to distribute macromolecules within the central nervous system (CNS) in a homogeneous, targeted fashion over clinically significant volumes and that the volume of infusion and target location (gray as opposed to white matter) influence distribution, little is known about other factors that may influence optimum use of convection-enhanced distribution. To understand the variables that affect convective delivery more fully, we examined the rate of infusion, delivery cannula size, concentration of infusate, and preinfusion sealing time. Methods. The authors used convection to deliver 4 mu l of C-14-albumin to the striatum of 40 rats. The effect of the rate of infusion (0.1, 0.5, 1, and 5 mu l/minute), cannula size (32, 28, and 22 gauge), concentration of infusate (100%, 50%, and 25%), and preinfusion sealing time (0 and 70 minutes) on convective delivery was examined using quantitative autoradiography, National Institutes of Health image analysis software, scintillation analysis, and histological analysis. Higher rates of infusion (1 and 5 mu l/minute) caused significantly (p < 0.05) more leakback of infusate (22.7 +/- 11.7% and 30.3 +/- 7.8% [mean +/- standard deviation], respectively) compared with lower rates (0.1 mu l/minute [4 +/- 3.6%] and 0.5 mu l/minute [5.2 +/- 3.6%]). Recovery of infusate was significantly (p < 0.05) higher at the infusion rate of 0.1 mu l/minute (95.1 +/- 2.8%) compared with higher rates (85.2 +/- 4%). The use of large cannulae (28 and 22 gauge) produced significantly (p < 0.05) more leakback(35.7 +/- 8.1% and 21.1 +/-: 7.5%, respectively) than the smaller cannula (32 gauge [5.2 +/- 3.6%]). Varying the concentration of the infusate and the preinfusion sealing time did not alter the volume of distribution, regional distribution, or infusate recovery. Conclusions. Rate of infusion and cannula size can significantly affect convective distribution of molecules, whereas preinfusion sealing time and variations in infusate concentration have no effect in this small animal model. Understanding the parameters that influence convective delivery within the CNS can be used to enhance delivery of potentially therapeutic agents in an experimental setting and to indicate the variables that will need to be considered for optimum use of this approach for drug delivery in the clinical setting. C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NIH, Biomed Engn & Instrumentat Program, Div Intramural Res Resources, Natl Ctr Res Resources, Bethesda, MD 20892 USA. RP Oldfield, EH (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,Room 5D37-1414, Bethesda, MD 20892 USA. NR 18 TC 198 Z9 200 U1 0 U2 4 PU AMER ASSOC NEUROLOGICAL SURGEONS PI CHARLOTTESVILLE PA UNIV VIRGINIA, 1224 WEST MAIN ST, STE 450, CHARLOTTESVILLE, VA 22903 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD FEB PY 1999 VL 90 IS 2 BP 315 EP 320 DI 10.3171/jns.1999.90.2.0315 PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 168RU UT WOS:000078707100017 PM 9950503 ER PT J AU Pluta, R AF Pluta, R TI Reversal of vasospasm SO JOURNAL OF NEUROSURGERY LA English DT Letter C1 Natl Inst Hlth, Bethesda, MD 20892 USA. RP Pluta, R (reprint author), Natl Inst Hlth, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI CHARLOTTESVILLE PA UNIV VIRGINIA, 1224 WEST MAIN ST, STE 450, CHARLOTTESVILLE, VA 22903 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD FEB PY 1999 VL 90 IS 2 BP 373 EP 373 PG 1 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 168RU UT WOS:000078707100028 PM 9950513 ER PT J AU Calabresi, PA Martin, R Jacobson, S AF Calabresi, PA Martin, R Jacobson, S TI Chemokines in chronic progressive neurological diseases: HTLV-1 associated myelopathy and multiple sclerosis SO JOURNAL OF NEUROVIROLOGY LA English DT Article DE multiple sclerosis; HTLV-1; chemokine receptors; migration ID CENTRAL-NERVOUS-SYSTEM; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; NECROSIS-FACTOR-ALPHA; I-ASSOCIATED MYELOPATHY; HUMAN HERPESVIRUS-6; MATRIX METALLOPROTEINASE-9; INTERFERON BETA-1B; VIRUS TYPE-1; SPINAL-CORD; T-CELLS AB It is hypothesized that in MS and HTLV-1, chemokine and chemokine receptor expression are important mechanisms by which T cells migrate to sites of inflammation. Preliminary evidence supports the roles of several chemokines, including MIP 1 beta, in mediating the enhanced migration capacity of MS derived PBLs. In addition, the ligand CCR-5 seems to be up regulated on PBLs from some MS patients. Analysis of T cell clones does not reveal a definite correlation between cytokine phenotype and chemokine receptor profile, The chemokines and chemokine receptor family are likely to be important molecules in chronic progressive neurological diseases, in which immune cells invade the central nervous system. C1 Brown Univ, Rhode Isl Hosp, Dept Clin Neurosci, Providence, RI 02903 USA. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Calabresi, PA (reprint author), Brown Univ, Rhode Isl Hosp, Dept Neurol, 110 Lockwood St,Suite 3-42, Providence, RI 02903 USA. NR 50 TC 18 Z9 18 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD FEB PY 1999 VL 5 IS 1 BP 102 EP 108 DI 10.3109/13550289909029751 PG 7 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 161ZH UT WOS:000078320100013 PM 10190696 ER PT J AU Carrasquillo, JA White, JD Paik, CH Raubitschek, A Le, N Rotman, M Brechbiel, MW Gansow, OA Top, LE Perentesis, P Reynolds, JC Nelson, DL Waldmann, TA AF Carrasquillo, JA White, JD Paik, CH Raubitschek, A Le, N Rotman, M Brechbiel, MW Gansow, OA Top, LE Perentesis, P Reynolds, JC Nelson, DL Waldmann, TA TI Similarities and differences in In-111- and Y-90-labeled 1B4M-DTPA antiTac monoclonal antibody distribution SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE In-111; Y-90; radioimmunotherapy; monoclonal antibody; pharmacokinetics ID B-CELL LYMPHOMA; HUMAN T-CELLS; COMPARATIVE BIODISTRIBUTION; HODGKINS-DISEASE; BREAST-CANCER; Y-90; RADIOIMMUNOTHERAPY; ANTIGEN; DTPA; TAC AB Monoclonal antibodies (MoAb) labeled with Y-90 are being used for radioimmunotherapy. Because Y-90 is a beta emitter, quantitative information from imaging is suboptimal. With the concept of a "matched pair" of isotopes, (111)ln is used as a surrogate marker for Y-90. We evaluated the differences in biodistribution between (111)ln- and Y-90-labeled murine antiTac MoAb directed against the IL-2R alpha receptor. Methods: The antiTac was conjugated to the 2-(4-isothiocyanatobenzyl)-6-methyl-diethylenetriamine pentaacetic acid (1B4M-DTPA, also known as MX-DTPA). Nine patients with adult T-cell leukemia were treated. Patients received approximately 185 MBq (5 mCi) (111)ln-labeled antiTac for imaging and 185-555 MBq (5-15 mCi) Y-90-labeled antiTac for therapy. The immunoreactivity of (111)ln-labeled antiTac was 90% +/- 6%, whereas for Y-90-labeled antiTac, it was 74% +/- 12%. Results: The differences in blood and plasma kinetics of the two isotopes were small. The area underneath the blood radioactivity curve was 1.91 percentage +/- 0.58 percentage injected dose (%ID) x h/mL for (111)ln and 1.86% +/- 0.64 %ID x h/mL for Y-90. Urinary excretion of Y-90 was significantly greater than that of (111)ln in the first 24 h (P = 0.001), but later, the excretion of (111)ln was significantly greater (P = 0.001 to P = 0.04). Core biopsies of bone marrow showed a mean of 0.0029 +/- 0.0012 %ID/g for (111)ln, whereas the 90Y concentration was 0.0049 +/- 0.0021 %ID/g. Analyses of activity bound to circulating cells showed concentrations of 500- 30,000 molecules of antiTac per cell. When cell-bound activity was corrected for immunoreactive fraction, the ratio of (111)ln to Y-90 in circulating cells was 1.11 +/- 0.17. Three biopsies of tumor-involved skin showed ratios of (111)ln to Y-90 of 0.7, 0.9 and 1.1. Conclusion: This study shows that differences typically ranging from 10% to 15% exist in the biodistribution between (111)ln- and Y-90-labeled antiTac. Thus, it appears that (111)ln can be used as a surrogate marker for( 90)Y when labeling antiTac with the 1B4M chelate, although underestimates of the bone marrow radiation dose should be anticipated. C1 NCI, Dept Nucl Med, Warren G Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NCI, Metab Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. NCI, Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Carrasquillo, JA (reprint author), NCI, Dept Nucl Med, Warren G Magnuson Clin Ctr, NIH, Bldg 10,Room 1C496,10 Ctr Dr, Bethesda, MD 20892 USA. RI Carrasquillo, Jorge/E-7120-2010; OI Carrasquillo, Jorge/0000-0002-8513-5734 NR 38 TC 74 Z9 75 U1 0 U2 6 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD FEB PY 1999 VL 40 IS 2 BP 268 EP 276 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 163PD UT WOS:000078413200020 PM 10025834 ER PT J AU Freudenheim, JL Sinha, R AF Freudenheim, JL Sinha, R TI Symposium: Interaction of diet and nutrition with genetic susceptibility in cancer - Overview SO JOURNAL OF NUTRITION LA English DT Editorial Material C1 SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14214 USA. NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20892 USA. RP Freudenheim, JL (reprint author), SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14214 USA. RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 NR 7 TC 2 Z9 2 U1 0 U2 0 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD FEB PY 1999 VL 129 IS 2 SU S BP 550S EP 551S PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 167YP UT WOS:000078662900024 PM 10064329 ER PT J AU Lai, C Shields, PG AF Lai, C Shields, PG TI The role of interindividual variation in human carcinogenesis SO JOURNAL OF NUTRITION LA English DT Article; Proceedings Paper CT Symposium on Assembly and Physiology of Apolipoprotein B-Containing Lipoproteins - Its Not Just for Heart Disease Anymore, as part of Experimental Biology 98 CY APR 18-22, 1998 CL SAN FRNACISCO, CALIFORNIA SP Amer Soc Nutr Sci, Energy & Macronutrient Res Interest Sect, Egg Nutr Ctr, Amer Heart Assoc, W States Affiliate, Merck Res Labs, Bristol Meyers Squibb Pharmaceut Res Inst, Parke Davis Pharmaceut Res DE carcinogenesis; epidemiology; carcinogen metabolism; genetic polymorphism; nutrition ID GLUTATHIONE-S-TRANSFERASE; SQUAMOUS-CELL CARCINOMA; HYDROCARBON-DNA ADDUCTS; INCREASED MUTAGEN SENSITIVITY; LUNG-CANCER; GENETIC SUSCEPTIBILITY; HETEROCYCLIC AMINES; RISK FACTOR; POLYMORPHISM; HEAD AB The process of chemical carcinogenesis is a complex multistage process initiated by DNA damage in growth control genes. Carcinogens enter the body from a variety of sources, but most require metabolic activation before they can damage DNA. There are multiple protective processes that include detoxification and conjugation, DNA repair and programmed cell death, Most of these functions exhibit wide interindividual variation in the population and thus are thought to affect cancer risk. The role of gene-environment interactions is being explored, and current data indicate that genetic susceptibilities can modify carcinogen exposures from the diet and tobacco smoking, although much more data exist for the latter. This review addresses the relationships of human carcinogenesis to these interindividual differences of phase I, phase II and DNA repair enzymes. C1 NCI, Mol Epidemiol Sect, Human Carcinogenesis Lab, Div Basic Sci,NIH, Bethesda, MD 20892 USA. RP Shields, PG (reprint author), NCI, Mol Epidemiol Sect, Human Carcinogenesis Lab, Div Basic Sci,NIH, Bethesda, MD 20892 USA. NR 34 TC 10 Z9 12 U1 0 U2 0 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD FEB PY 1999 VL 129 IS 2 SU S BP 552S EP 555S PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 167YP UT WOS:000078662900025 PM 10064330 ER EF